Lancet 1997;350(9076):461-468

Background: In the ACME trial, percutaneous transluminal coronary angioplasty (PTCA) improved symptoms in patients with single-vessel stable coronary artery disease, but it did not lead to reduction in myocardial infarction or mortality, which were not primary endpoints and the study was under powered for these endpoints. The available data on the efficacy of PTCA for reducing hard endpoints were limited. Moreover, the findings from surgery trials had been inconsistent, as discussed in prior reviews.

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The second Randomized Intervention Treatment of Angina (RITA-2) trial sought to test the hypothesis that coronary angioplasty compared to medical therapy improves outcomes in patients with coronary artery disease.

Patients: Eligible patients were recruited from the United Kingdom and Ireland. Patients had to have significant stenosis amenable to dilation, in at least one major coronary artery. A significant coronary lesion was defined as a 50% or greater diameter stenosis in at least two radiographic projections or at least 70% diameter stenosis in one projection.

Patients were not required to have current symptoms. Patients with multivessel coronary disease, occluded coronaries or who had abnormal left ventricular function were allowed to be enrolled, as well as patients with unstable angina if the most recent episode was at least 7 days before randomization. Patients were excluded if they had left main disease, prior revascularization procedure or recent myocardial infarction.

Baseline characteristics: There were about 70,000 patients who underwent coronary angiogram during the recruitment phase. Around, 2,750 patients were eligible and among them 1,018 were randomized – 504 randomized to the PTCA arm and 514 to the medical therapy arm. The main reasons for not randomizing eligible patients were clinician’s decision or patient’s refusal.

The average age of enrolled patients was 58 years and 82% were men. Approximately 47% had prior myocardial infarction and 9% took medications for diabetes.

Approximately 20% reported no angina at the time of randomization. Single-vessel coronary artery disease was present in 60% of the patients, 2-vessel in 33% and 3-vessel in 7%.

Approximately 87% were taking aspirin, 13% were taking lipid lower drugs, 67% were taking beta-blockers, 50% were taking calcium channel blockers, and 44% were taking long acting nitrates.

Procedures: Patients were randomized to coronary angioplasty or medical therapy. Randomization was stratified by center, extent of coronary disease and the presence of recent unstable angina. PTCA was to be performed within 3 months of randomization. In patients with multivessel disease, not all lesions had to be dilated. Multivessel dilatation could be staged over more than one procedure. Conventional balloon dilatation was the intended strategy, but stents were permissible if the initial angioplasty result was unsatisfactory.

Aspirin was recommended in all patients. Lipid lowering drugs were prescribed at the discretion of the treating physician.

Patients were followed at 3 months, 6 months, then yearly.

Endpoints: The primary endpoint was a composite of all-cause death or non-fatal myocardial infarction at 5-years. Secondary endpoints included unstable angina, heart failure, arrhythmias, angina based on the Canadian Cardiovascular Society classification, anti-anginal drug use, and exercise duration on a symptom-limited treadmill test.

Analysis was performed based on the intention-to-treat principle. The sample size to achieve 80% power at an alpha level of 0.05 was 1,400. This was based on the assumption that the event rate of the primary outcome is 15% at 5-years in the medical arm, and that PTCA would reduce the primary outcome by 33%. The study enrolled less patients than planned due to slow recruitment.

Results: The median follow up time was 2.7 years. Among the 504 patients randomized to PTCA, the procedure was performed in 417 (93%) patients. Among the 514 patients randomized to medical therapy, 118 (23%) underwent PTCA or coronary bypass surgery.

PTCA increased the risk of the primary composite outcome (6.3% vs 3.3%, RR: 1.92, 95% CI: 1.08 – 3.41; p= 0.02). This difference was primarily driven by more non-fatal myocardial infarction with PTCA (4.2% vs 1.9%; p value not provided). All-cause death was not significantly different between both groups (2.2% with PTCA vs 1.4% with medical therapy; p= 0.32).

No significant differences noted in unstable angina (9.9% with PTCA vs 9.1% with medical therapy; p value not provided), heart failure (1.6% with PTCA vs 2.9% with medical therapy; p= 0.15) or arrhythmias (3.0% with PTCA vs 1.4% with medical therapy; p= 0.08).

Symptoms improved significantly in both treatment groups. The improvement in symptoms was greater with PTCA at 3 months (16.5% more patients with grade 2+ angina in the medical arm; p< 0.0001) but the difference was smaller at 2 years (7.6% more patients with grade 2+ angina in the medical arm; p= 0.02). These differences disappeared at 3 years. More patients in the PTCA arm were not taking anti-anginal medications at 3 years (36.2% vs 13.8%). PTCA led to greater improvement in exercise time compared to medical therapy but the differences were small (mean difference favoring PTCA was 35s at 3 months and 25s at 1 year).

No subgroup analysis was provided for the primary outcome.

Conclusion: In patients with coronary artery disease without recent myocardial infarction, PTCA compared to medical therapy worsened the primary outcome of all-cause death or non-fatal myocardial infraction with a number needed to harm of approximately 33 patients over 2.7 years follow up. This difference was largely due to more non-fatal myocardial infarction in the PTCA arm. PTCA led to greater improvement in symptoms at 3 months but there were no significant differences at 3 years.

Read the results above and compare our conclusion with the authors’ conclusion: [In patients with coronary artery disease considered suitable for either PTCA or medical care, early intervention with PTCA was associated with greater symptomatic improvement, especially in patients with more severe angina. When managing individuals with angina, clinicians must balance these benefits against the small excess hazard associated with PTCA due to procedure-related complications].

Medical and percutaneous interventions for coronary artery disease have advanced since the publication of this trial. However, reviewing older trials remains crucial to understand the evolution of the cardiology field and why certain interventions are no longer used. Studying the history of these treatments is important because it sheds light on how current practices have been shaped.

This trial serves as a reminder that a bias toward interventions exists in medicine; the authors’ conclusion downplayed the harms associated with PTCA while emphasizing its potential benefits for symptom relief, even though this was not the primary outcome and is highly subject to bias based on the study design. The trial also has reporting bias; subgroup analysis was not provided for the primary outcome but rather for the secondary endpoints of symptom relief and exercise tolerance. Additionally, the effects of PTCA on symptom relief and exercise tolerance were reported at various time points that seem to have been chosen to emphasize the protentional benefits of PTCA.

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N Engl J Med 2024;390:1372-1381

Background: Beta-blockers are prescribed to the majority of patients with acute myocardial infarction. The bulk of evidence supporting this practice comes from trials published in the 1980s - BHAT and ISIS-I. Since the publication of these seminal trials, the care of patients with acute myocardial infarction has significantly changed with improvement in antiplatelet therapy, the addition of high-intensity statins and renin–angiotensin–aldosterone system antagonists in addition to early revascularization for STEMI patients. Furthermore, myocardial injury is now detected based on high-sensitivity troponin assays which can detect smaller myocardial infarctions. Therefore, there is a lack of evidence whether beta-blockers provide benefit for patients with acute myocardial infarction in the current era.

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The Randomized Evaluation of Decreased Usage of Beta-Blockers after Acute Myocardial Infarction (REDUCE-AMI) trial sought to assess whether long-term oral beta-blocker treatment improves outcomes in patients with acute myocardial infarction and preserved left ventricular ejection fraction.

Patients: Eligible patients were adults, 1 to 7 days after myocardial infarction who underwent coronary angiography and echocardiography. Patients were required to have obstructive coronary artery disease on coronary angiography defined as stenosis of ≥50%, a fractional flow reserve of ≤0.80, or an instantaneous wave-free ratio of ≤0.89 at any time point before randomization. Left ventricular Ejection fraction on echocardiogram had to be ≥50%. Patients were excluded if they had contraindications to beta-blockers or if the treating physician determined that treatment with beta-blockers is indicated for other conditions.

Baseline characteristics: The trial randomized 2,508 patients to the beta-blockers group and 2,512 patients to the control group. The average age of patients was 65 years with 78% being men. About 20% were current smokers, 46% had hypertension, 14% had diabetes, 7% had prior myocardial infarction and < 1% had prior heart failure.

The index event was STEMI in 35% of the patients. About 96% underwent percutaneous coronary intervention. The median heart rate was 74 bpm and the median systolic blood pressure was 151 mm Hg.

Medications at discharge included aspirin in 97% of the patients, P2Y12 inhibitors in 96%, ACEi or ARBs in 80% and statins in 99%.

Procedures: Patients were randomized 1:1 to receive metoprolol succinate (first choice), bisoprolol (second choice) or no beta-blockers. The target doses were at least 100 mg daily for metoprolol succinate and at least 5 mg daily for bisoprolol. Patients in the control group were discouraged from using beta-blockers; they did not receive placebo. If a patient was on beta-blocker therapy at the time of enrollment and was randomly assigned to the no–beta-blocker group, the beta-blocker had to tapered off over a period of 2 to 4 weeks.

Endpoints: The primary end point was a composite of death from any cause or new myocardial infarction. Secondary end points were death from any cause, death from cardiovascular causes, myocardial infarction, hospitalization for atrial fibrillation as primary diagnosis, and heart failure hospitalization. There were three safety endpoints: 1- Hospitalization for bradycardia, second- or third-degree atrioventricular block, hypotension, syncope, or implantation of a pacemaker, 2- hospitalization for asthma or chronic obstructive pulmonary disease as a primary diagnosis and 3- hospitalization for stroke.

Data on clinical end points were not centrally adjudicated but rather obtained from the SWEDEHEART registry and the Swedish Population Registry.

Statistical analysis was performed based on the intention-to-treat principle. Before trial initiation, the estimated event rate in the control group was 7.2%/ year and at least 16.7% lower event rate in the beta-blocker group was considered clinically meaningful. During the trial, the actual event rate in control group was 3%/ year. Given this event rate, a 25% lower event rate in the beta-blocker group was considered clinically meaningful. A total of 379 primary end point events were needed in order to have 80% power at a two-sided alpha of 0.05, to detect the 25% lower event rate with beta-blockers. The estimated number of patients needed was about 5,000.

Results: Among the patients who attended the SWEDEHEART registry, 1500/1831 (81.9%) of the beta-blocker group were still taking beta-blockers after 11 to 13 months; compared to 269/ 1886 (14.3%) in the no beta-blocker group.

After a median follow up time of 3.5 years, beta-blockers did not the reduce the composite primary endpoint compared to no beta-blockers (7.9% vs 8.3%, HR: 0.96; 95% CI, 0.79 - 1.16; p= 0.64). There were no significant differences in death from any cause (3.9% vs 4.1%), death from cardiovascular causes (1.5% vs 1.3%), myocardial infarction (4.5% vs 4.7%), hospitalization for atrial fibrillation (1.1% vs 1.4%) or hospitalization for heart failure (0.8% vs 0.9%).

Safety endpoints were also not significantly different between both groups; 3.4% vs 3.2% for the bradyarrhythmia, syncope or hypotension endpoint, 0.6% in both groups for the hospitalization for asthma or COPD endpoint and 1.4% vs 1.8% for hospitalization for stroke.

There were no significant subgroup interactions.

Conclusion: In patients with acute myocardial infarction who underwent coronary angiography and had preserved left ventricular systolic function, treatment with beta-blockers did not improve outcomes over a 3.5-year follow-up. Events were infrequent in the trial; 1.4% for cardiovascular death, 4.6% for recurrent myocardial infarction and 0.8% for hospitalization for heart failure. The low event rate in this population in the current era makes it difficult to demonstrate additional benefit with more therapies.

The open-label design of the study may have introduced performance bias; however, this bias is expected to favor beta-blockers given the superiority design of the study. Another limitation, as noted by the authors, is that outcomes were obtained from the SWEDEHEART registry and the Swedish Population Registry and were not centrally adjudicated. However, this is expected to affect both groups equally.

We believe the divergent results between this trial and older beta-blocker trials in myocardial infarction patients such as BHAT and ISIS-1 which were published in the 1980s, is due to the significant improvement in the management of acute myocardial infarction over time including improved medical therapy in addition to early revascularization for STEMI patients. This improved patient care has led to significantly lower mortality rates over time. For instance, all-cause death in the control arm of REDUCE-AMI is significantly lower than that of BHAT and ISIS-1, at 4.1% vs 9.8% and 11.9%, respectively. This is despite REDUCE-AMI having a longer follow-up period of 3.5 years compared to 2.1 years and 1 year in the earlier trials.

In conclusion, this study does not provide evidence that beta-blockers improve outcomes for patients with acute myocardial infarction and preserved ejection fraction in the contemporary era.

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N Engl J Med 2024;390:1455-1466

Background

Despite advances in the care of patients after myocardial infarction, there remains residual risk of heart failure and death. The amount of risk parallels the degree of left ventricular systolic dysfunction. Previous studies have shown that the drug class of sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular risk (especially recurrent heart failure) in multiple clinical situations.

The goal of the placebo-controlled Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction (EMPACT-MI) trial was to determine whether empagliflozin reduced the risk of heart failure or death in patients with acute MI and either a new reduction in LV function or signs of congestion, or both.

Patients

Adult patients who had been hospitalized with MI within 14 days before randomization. There had to be a new LVEF <45% or signs/symptoms of congestion that resulted in treatment during the index hospital admission.

There also had to be another risk factor, which the authors wrote that enriched the risk for heart failure or death. This could include many things: age of 65 years or older; a newly developed LVEF < 35%; a history of MI, atrial fibrillation, or type 2 diabetes; an estimated glomerular filtration rate (GFR) of less than 60 ml per minute per 1.73 m2 of body-surface area; an elevated natriuretic peptide or uric acid level; an elevated pulmonary artery or right ventricular systolic pressure; three-vessel coronary artery disease; peripheral artery disease; or no revascularization for the index myocardial infarction.The key exclusion criteria was the a previous diagnosis of heart failure or any reason that the patient was planning to take SGLT2i.

Baseline Characteristics

The average age of patients was 63 years. Only a quarter were women. More than 80% were white. Approximately 75% of patients had STEMI, the rest, NSTEMI. A total of 78% of the patients had a LVEF < 45%, and 57% had signs or symptoms of congestion that resulted in treatment during the index hospitalization. For the patients with signs or symptoms of congestion, only 20% had a LVEF of at least 45%. 

The most common enrichment factors were age > 65 (50%), Type 2 DM (32%) and 3-vessel CAD (31%). Slightly more than 70% of patients had more than one enrichment factor.

Approximately 20% of patients had an LVEF > 45%. Slightly more than half of patients had an LVEF between 35% and 45%.

Trial Procedures

Randomization was 1:1 to empagliflozin 10mg daily or matching placebo. The trial was conducted between 2020-2023 at 451 sites in 22 countries. The median time from admission to randomization was 5 days. The trial had a streamlined design, with the collection of essential data only, including information about specific safety events, and mainly remote follow-up of patients (by means of a Web-based application or a telephone call) with only a few face-to-face visits; the trial assessed investigator-reported end-point events rather than centrally adjudicated end-point events. Specifically, follow up included a remote visit at 2 weeks, a face-to-face visit at 6 months, and remote visits every 6 months thereafter until the end of the trial, when a final telephone call was performed.

Endpoints

The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis.

The key secondary end points in the prespecified hierarchical testing strategy were the total number of hospitalizations for heart failure or death from any cause, the total number of nonelective cardiovascular hospitalizations or death from any cause, the total number of nonelective hospitalizations for any cause or death from any cause, and the total number of hospitalizations for myocardial infarction or death from any cause.

Trial authors estimated that 532 patients with a primary end-point event would provide the trial with 85% power to detect a 23% lower risk of an event in the empagliflozin group than in the placebo group, with a two-sided type I error of 0.05. However, the trial originally planned to enroll about 3300 patients, with the option to enroll 5000 patients. But then the trial was further increased to 6500 patients.

Key secondary endpoints were assessed using a prespecified hierarchical testing procedure. This began with the primary endpoint.

Results

An interesting aspect of this trial, and more recent post-MI trials is that the ratio of screened to enrolled patients is almost 1:1. Whereas older trials screened many more patients than were enrolled, in EMPACT, only 88 of 6600 screened patients were excluded. In total, approximately 3200 patients were randomized in both arm.

After a median follow-up of 18 months, a primary end-point event — a first hospitalization for heart failure or death from any cause — occurred in 8.2% in the empagliflozin group and in 9.1% in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P=0.21). 

A look at the two components showed that there were fewer heart failure hospitalizations in the empagliflozin group (3.6% vs 4.7%; HR 0.77 (0.60–0.98)) Overall death were similar in both groups. As for secondary endpoints, total heart failure hospitalizations was 2.4 vs 3.6 events, respectively, per 100 patient-years (rate ratio, 0.67; 95% CI, 0.51 to 0.89). The composite of total heart failure hospitalizations or death were not significantly different (HR 0.87 0.68-1.10). CV death was 4% in both groups.

There were no obvious subgroup effects nor differences in safety.

Conclusions

The addition of empagliflozin did not significantly reduce a composite endpoint of heart failure admissions and death.

Even the reduction in heart failure admissions was modest. Given the medication burden of the typical patient after myocardial infarction, coupled with the high cost of this drug class, we see no strong evidence for routine use of SGLT2i in EMPACT-MI-type patients.

The null results of this trial and PARADISE-MI speak to the beneficial effects of modern post-MI care—including mostly rapid revascularization with PCI. It is difficult to improve on baseline care of the MI patient in 2024.

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NEJM 2021:385:1845-55.

Background Over two decades had passed since the publications of the seminal trials comparing ACE inhibitors with placebo in post-MI patients with LV dysfunction and congestive heart failure (SAVE, AIRE and TRACE). The VALIANT trial, published in 2003, found that the ARB drug Valsartan was as effective as Captopril in improving survival and reducing cardiovascular morbidity in this patient population. Thus, for many years, a cornerstone of managing post-MI patients with LV dysfunction and heart failure involved afterload reduction with ACE inhibitors or ARBs.

Then in 2014, the landscape of heart failure management changed with the publication of the PARADIGM-HF trial which found that Entresto, a drug combining the ARB Valsartan and the neprilysin inhibitor Sacubitril, significantly reduced death and heart failure hospitalizations. We will review PARDIGM-HF later since it enrolled patients with chronic, stable heart failure and not post-MI patients. The rationale for the combination drug is that it simultaneously blocks the renin-angiotensin system and inhibits of the breakdown of several vasoactive peptides including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), serving to enhance vasodilation and reduce blood volume.

The PARADISE-MI trial sought to test the hypothesis that early initiation of Sacubitril-Valsartan in post-MI patients with LV dysfunction and congestive heart failure would reduce cardiovascular death or incident heart failure compared to the ACE inhibitor Ramipril.

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Patients Adults without a history of heart failure who had a spontaneous MI within 0.5 to 7 days before presentation who had either a LVEF of /= 70 years, diabetes, previous MI, eGFR <60, atrial fibrillation, LVEF <30%, Killip class III or IV, or a STEMI without reperfusion within 24 hours of presentation. Key exclusion criteria included clinical instability defined as receiving intravenous diuretics, vasodilators, inotropes or vasopressors within 24 hours of randomization; an eGFR <30; serum potassium >5.2 mmol/L; a history of angioedema or inability to take an ACEi or an ARB.

Baseline characteristics The average age of patients was 64 years and nearly 70% were men. Sixteen percent of patients had a prior MI, more than 40% had diabetes and two-thirds had hypertension. The average ejection fraction was 36% and two-thirds of patients had an anterior MI. Almost 60% had a Killip class of II or above. Patients were hemodynamically stable with an average blood pressure slightly above 120/70 mmHg and heart rate of 77 beats per minute. The average eGFR was 72. Almost 90% of patients underwent percutaneous coronary intervention and 80% received a drug eluting stent for the primary MI. At the time of randomization, nearly 80% of patients were on an ACE inhibitor or ARB, over 40% were on a MRA, 85% were on a beta blocker and 44% were on a diuretic.

Procedures Patients were randomized 1:1 to receive either Sacubitril-Valsartan or Ramipril. Treatment with ACE inhibitors or ARBs was discontinued at randomization. Clinical evaluations were scheduled for weeks 1, 2, and 4 and then at 2 and 4 months and every 4 months thereafter. Three doses of each drug were available to the investigators to use at their own discretion (1.25 mg, 2.5 mg, or 5 mg of ramipril administered twice daily; or 24 mg of sacubitril plus 26 mg of valsartan, 49 mg of sacubitril plus 51 mg of valsartan, or 97 mg of sacubitril plus 103 mg of valsartan administered twice daily), with the highest dose of each drug as the target.

Endpoints The primary study endpoint was a composite of cardiovascular death or incident heart failure, whichever occurred first. Incident heart failure was defined as hospitalization for heart failure or outpatient episodes of symptomatic heart failure treated with intravenous or sustained oral diuretic therapy.

Secondary endpoints were a composite of death from cardiovascular causes or hospitalization for heart failure; a composite of hospitalization for heart failure or an outpatient episode of symptomatic heart failure; a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; and the total number of (first or recurrent) nonfatal cardiovascular events (hospitalizations for heart failure, myocardial infarction, or stroke). Additional secondary outcomes included the number of deaths from cardiovascular causes and the total number of deaths. All prespecified outcomes were adjudicated by a clinical outcome committee blinded to treatment-group assignment.

Data on all reported adverse events and serious adverse events were compiled for safety assessments. Hypotension, hyperkalemia, renal dysfunction, cough, and angioedema were prespecified adverse events of interest, with reports of angioedema adjudicated by a separate committee.

PARADISE-MI was an event driven trial. The investigators estimated that 708 primary-outcome events would provide the trial with 80% power to detect a hazard ratio of 0.81 for the primary composite outcome in a time-to-event analysis, with the use of a two-sided alpha level of 0.05. They estimated that following 5650 patients for a mean of 19 months would provide the target number of primary events. That number represented an upward revision from the original plan that called for enrollment of 4650 patients. This was done on the basis of a prespecified blinded assessment of cumulative incidence that was performed when approximately half the patients had undergone randomization and had reached the 3-month time point.

Results 5661 patients were included in the final analysis; 2831 in the ramipril group and 2830 in the sacubitril-valsartan group. The mean follow-up time was 1.8 years or 22 months. Compared to ramipril, sacubitril-valsartan did not significantly reduce the composite primary endpoint of cardiovascular death or incident heart failure (12% vs 13%; HR 0.90; 95% CI 0.78-1.04) or any of the secondary endpoints including all-cause death (8% vs 9%; HR 0.88; 95% CI 0.73-1.05).

Serious adverse events (SAE) occurred in 40.3% of patients in the sacubitril-valsartan group compared to 39.8% in the ramipril group (p=0.58) and those leading to treatment discontinuation occurred in 12.6% vs 13.4%, respectively (p=0.39). Hypotension was significantly increased in the sacubitril-valsartan group (28.3% vs 21.9%; p<0.001) whereas cough was increased in the ramipril group (9.0% vs 13.1%; p<0.001). There were no other notable significant differences in other serious adverse events.

The average time to randomization in the trial was 4.3 days. At the final assessment, 67.5% of the sacubitril-valsartan group were receiving the target dose of 97-103 mg twice daily and 76.5% of the ramipril group were receiving the target dose of 5 mg twice daily.

Conclusions In patients with AMI complicated by a LVEF

Hypotension was significantly increased with sacubitril-valsartan, with a number needed to harm of approximately 16 patients, and is likely what limited achievement of target dosing of the drug in the trial compared to ramipril (67.5% vs 76.5%).

The PARADISE-MI trial does not provide justification for use of sacubitril-valsartan over ACE inhibitors or valsartan alone in post-MI patients who would meet the inclusion criteria of the trial.

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N Engl J Med 2019;381:2497-2505

Background: Inflammation increases the risk of atherosclerosis, and reducing inflammation with canakinumab, a monoclonal antibody that neutralizes interleukin-1β, reduced plasma markers of inflammation and the risk of future myocardial infarctions but was associated with small yet statistically significant increased risk of fatal infections. Methotrexate, in the CIRT trial, did not reduce plasma markers of inflammation or cardiovascular events.

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Colchicine, extracted from the plant autumn crocus, is a potent inexpressive anti-inflammatory medication that has been used for centuries, and is used for conditions like gout, familial Mediterranean fever and pericarditis.

The Colchicine Cardiovascular Outcomes Trial (COLCOT) sought to test the hypothesis that colchicine is superior to placebo in reducing cardiovascular events in patients with recent myocardial infarction.

Patients: Eligible patients were adults who had myocardial infarction within 30 days of enrollment, had any planned revascularization completed, and were on guidelines recommended treatment. Exclusion criteria included severe heart failure, left ventricular ejection fraction <35%, stroke within 3 months, CABG within the previous 3 years or planned, inflammatory bowel disease or chronic diarrhea, clinically significant non-transient hematologic abnormalities, severe renal disease, long-term systemic glucocorticoid therapy, plus a few others.

Baseline characteristics: The trial randomized 2,366 patients to colchicine and 2,379 patients to placebo. The average age of patients was 61 years with 81% being men. The average body mass index was 28 kg/m2. About 30% were current smokers, 51% had hypertension, 20% had diabetes, 16% had prior myocardial infarction, 2% had history of heart failure, and 3% had history of stroke or TIA. Percutaneous coronary intervention for the index myocardial infarction was performed in 93% of the patients. The average time from index event to randomization was 13 days. Aspirin was prescribed in 99% of the patients, other antiplatelets in 98%, and statins in 99%.

Procedures: Patients were randomized 1:1 to receive colchicine 0.5mg oral daily or placebo, in a double-blind fashion. Follow up visits or phone assessments were performed at 1, 3, and 6 months and every 3 months thereafter.

Endpoints: The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. Secondary endpoints included components of the primary endpoint as well as death from any cause.

Statistical analysis was performed based on the intention-to-treat principle. The trial was event driven. It was estimated that a total of 4,500 patients and 301 primary endpoint events would give the trial 80% power to detect 27% relative reduction of the primary endpoint with colchicine compared to placebo. The assumed event rate in the placebo arm was 7% at 2 years.

Results: After a median follow up time of 22.6 months, colchicine reduced the primary composite endpoint compared to placebo (5.5% vs 7.1%, HR: 0.77, 95% CI: 0.61 - 0.96; p=0.02). The reduction in the composite primary endpoint was primarily driven by significant reduction in urgent hospitalization for angina leading to coronary revascularization (1.1% vs 2.1%, HR: 0.50, 95% CI: 0.31 - 0.81) and stroke (0.2% vs 0.8%, HR: 0.26, 95% CI: 0.10 - 0.70). There was no significant reduction in death from cardiovascular causes (0.8% vs 1.0%), resuscitated cardiac arrest (0.2% vs 0.3%), myocardial infarction (3.8% vs 4.1%) or death from any cause (1.8% in both arms).

Data on Hs-CRP at baseline and 6 months were available from 207 patients. At baseline, geometric mean of hs-CRP was 4.27 mg/L in the colchicine group and 5.09 mg/L in the control group. The adjusted geometric mean percentage changed at 6 months was not significantly different between both treatment groups; - 70.0% in the colchicine group and -66.6% in the control group.

Data on subgroup analysis was provided in the supplement but no interaction testing was provided. The groups with the largest reduction in the composite primary endpoint with colchicine were previous smokers (5.3% vs 8.8%, HR: 0.59, 95% CI: 0.41 - 0.85) and patients with diabetes (8.7% vs 13.1%, HR: 0.65, 95% CI: 0.44 - 0.96).

Serious adverse events were overall similar between both treatment groups (16.4% vs 17.2%; p= 0.47). Pneumonia was slightly more common with colchicine (0.9% vs 0.4%; p= 0.03). Nausea was also more common with colchicine (1.8% vs 1.0%; p= 0.02), however, diarrhea was not significantly different between both treatment groups (9.7% vs 8.9%; p= 0.35).

Conclusion: In patients with recent myocardial infarction, colchicine reduced the risk of cardiovascular events compared to placebo with a number needed to treat of approximately 63 patients over 23 months. The difference in events was primarily driven by reduction in urgent hospitalization for angina leading to coronary revascularization, and stroke. No significant difference was observed in myocardial infarction, cardiovascular death or death from any cause.

Data on hs-CRP were available from a small number of patients and should be interpreted with caution. Nonetheless, it is noteworthy that baseline hs-CRP was higher in the placebo group, and both groups showed significant reductions in hs-CRP at 6 months (-70.0% with colchicine and -66.6% with placebo). This highlights the concept of regression to the mean and underscores the importance of assessing treatment effects relative to a well-matched control group.

In our opinion, colchicine should not be routinely used in patients post myocardial infarction as the benefit was modest and primarily driven by a “soft” endpoint without significant reduction in myocardial infarction or cardiovascular death. 

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N Engl J Med 2019;380:752-762

Background: Growing body of evidence suggests the role of inflammation in atherosclerosis. The CANTOS trial, discussed earlier, provided further evidence for that hypothesis. In the CANTOS trial, canakinumab a monoclonal antibody that neutralizes interleukin-1β led to fewer myocardial infarctions compared to placebo.

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The Cardiovascular Inflammation Reduction Trial (CIRT) sought to test the hypothesis that an alternative approach to reduce inflammation using low-dose methotrexate, also lowers cardiovascular events compared to placebo. Low-dose methotrexate was chosen since it’s widely used, inexpensive and was shown, in observational studies, to lower cardiovascular events in patients with rheumatoid arthritis and psoriatic arthritis compared to other drugs or placebo.

Patients: Patients were enrolled if they had history of myocardial infarction or multivessel coronary artery disease and had either type II diabetes mellitus or metabolic syndrome. Patients had to be medically stable and had completed any planned revascularization. Exclusion criteria were many and included patients with chronic liver disease, chronic inflammatory conditions, chronic infectious diseases, HIV positive, chronic use of immunosuppressive therapy or women of childbearing potential.

Baseline characteristics: The trial randomized 2,391 patients to the low-dose methotrexate arm and 2,395 patients to the placebo arm. The average age of patients was 66 years with 81% being men. The median body mass index was 31 kg/m2. About 61% had prior myocardial infarction, 34% had diabetes, 32% had metabolic syndrome and 13% had congestive heart failure. The median total cholesterol was 141 mg/dL, median LDL was 68 mg/dL and the median hs-CRP was 1.5 mg/L.

Procedures: The study had a run-in phase in which patients were administered 1 mg of oral folic acid daily in addition to oral methotrexate once weekly, initially at 5 mg, then increased to 10 mg, and finally to 15 mg. This phase was conducted in an open-label manner, and patients were excluded from further participation if they experienced adverse events, including laboratory abnormalities related to the treatment.

Patients who were able to tolerate the 15 mg dose of methotrexate for 2 consecutive weeks without adverse events, were randomized in 1:1 fashion to receive methotrexate at a dose of 15 mg or placebo in a double-blinded fashion. All patients took folate daily. At 4 months, the dose of methotrexate was increased to 20 mg. Symptoms and laboratory variables were assessed every 2 months and the dose of methotrexate, or placebo, was adjusted as needed. Randomization was stratified based on the type of index event, time since the index event and metabolic syndrome alone or diabetes.

Endpoints: Initially, the primary endpoint of the trial was a composite endpoint of the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Approximately 5 years into the trial, the composite end point was expanded to include hospitalization for unstable angina that led to urgent coronary revascularization. This increased the statistical power and allowed for smaller sample size. Death from any cause was included as a secondary endpoint.

Statistical analysis was performed based on the intention-to-treat principle. Based on the new composite primary endpoint, it was estimated that a total of 5,500 patients and 634 primary endpoint events would give the trial 90% power to detect 23% relative reduction of the new composite primary endpoint, with methotrexate compared to placebo. The data safety and monitoring board recommended early termination of the trial for futility.

Results: Out of 6,158 patients who entered the open label run-in phase, 997 (16.2%) patients were excluded due to symptoms or adverse events, 129 (2.1%) patients were excluded due to laboratory values out of range, and 4,786 (77.7%) patients were randomized.

At 8 months, methotrexate compared to placebo, did not result in greater reduction in hs-CRP, interleukin-1β, or interleukin-6.

After a median follow-up time of 2.3 years, the rate of the final composite primary endpoint was similar in both treatment groups [8.4% (4.13%/ year) with methotrexate vs 8.6% (4.31%/ year) with placebo, HR: 0.96, 95% CI: 0.79 – 1.16; p= 0.67]. There was no significant difference in death from any cause [4.0% (1.80%/ year) vs 3.5% (1.55%/ year)], cardiovascular death [2.0% (0.92%/ year) vs 1.8% (0.80%/ year)], nonfatal myocardial infarction [4.7% (2.29%/ year) vs 4.8% (2.32%/ year)], nonfatal stroke [1.2% (0.55%/ year) vs 1.3% (0.60%/ year)], or hospitalizations for unstable angina that led to urgent revascularization [1.7% (0.81%/ year) vs 2.1% (1.01%/ year)].

Mouth sores and oral pain were more common with methotrexate [4.0% (1.95%/ year) vs 2.3% (1.13%/ year); p= 0.001]. Non-basal-cell skin cancer was also more common with methotrexate [1.3% (0.61%/ year) vs 0.4% (0.20%/ year); p= 0.002]. Serious infections [4.6% (2.24%/ year) vs 5.1% (2.47%/ year); p= 0.50] and serious bleeding [1.3% (0.63%/ year) vs 1.0% (0.50%/ year); p= 0.44] were not significantly different between both treatment groups.

Data on subgroup analysis was not provided in the main paper or supplement.

Conclusion: In patients with history of myocardial infarction or multivessel coronary artery disease, low-dose methotrexate did not reduce cardiovascular events compared to placebo.

The authors proposed several reasons why the results of CIRT contrast the results of CANTOS in which canakinumab, a monoclonal antibody targeting interleukin-1β was used. First, CANTOS limited enrollment to patients with elevated hs-CRP while CIRT did not require that. Consequently, the median hs-CRP was significantly higher in CANTOS at 4.2 mg/L compared to 1.5 mg/L in CIRT. Furthermore, canakinumab in CANTOS lowered interleukin-6 and hs-CRP levels by 35-40% compared to placebo, while methotrexate in CIRT did not lower interleukin-6, hs-CRP or interleukin-1β. This suggests that the effectiveness of reducing atherosclerosis risk may vary depending on the specific pathway targeted. Other notable findings are higher LDL levels in CANTOS compared to CIRT (82 mg/ dL vs 68 mg/ dL). In addition, all patients had history of myocardial infarction in CANTOS compared to 61% in CIRT.

Another important teaching point from this trial is the use of a run-in period with the active drug, methotrexate. Although employing a run-in period is beneficial for assessing adherence and eliminating early dropouts, it can introduce selection bias. This can occur by excluding patients who experience adverse events from the study drug, methotrexate in this case, and thereby favor the balance of benefits and harms in favor of the study drug.

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N Engl J Med 2017;377:1119-1131

Background The hypothesis tested in the CANTOS Trial reflected an emerging view of atherosclerosis development and progression - that it was not simply a matter of plasma cholesterol but also systemic inflammation. In the manuscript’s introduction the authors cite data on the independent association of certain inflammatory markers with an increased risk of cardiovascular events independent of lipid levels.

For an anecdote that I suspect many cardiologists and general practitioners will relate to, I am involved with managing many younger women (<65 years of age) who lack “traditional” cardiovascular risk factors but have atherosclerotic CVD which typically presents as an ACS event. The thread that ties these women together is their history of a systemic inflammatory disorder like rheumatoid arthritis or inflammatory bowel disease. Since the publication of CANTOS and other trials, the relationship between systemic inflammatory disease and CVD has gained broader recognition but remains underrecognized. For a very general overview of this topic I would direct readers to the following link, which is free to read: Cardio-Rheumatology: Prevention of Cardiovascular Disease in Inflammatory Disorders - PubMed (nih.gov)

The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) tested the hypothesis that Canakinumab, which is a fully human monoclonal antibody targeting interleukin-1 beta would reduce recurrent cardiovascular events in patients with a history of MI and persistent proinflammatory response.

Patients Eligible patients had a history of MI and a hs-CRP level >/= 2 mg/L despite use of aggressive secondary prevention strategies. The trial sought to enroll stable patients and thus, broad exclusion criteria were applied which included any patient with a history of recurrent infection or with any condition that could render a patient immunocompromised, such as ongoing use of other systemic inflammatory treatments. Thus, it should be appreciated that patients with severe systemic inflammation were excluded.

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Baseline characteristics There were 17,482 patients with a previous MI who underwent screening in the central laboratory and 10,061 (57.6%) were randomized. Among these patients, the most common exclusions were due to hs-CRP <2 mg/L (46%), active tuberculosis or tuberculosis risk factors (25%) and exclusionary concomitant disorders (10%). The mean age of participants was 61 years, 26% were women and 41% had diabetes. Nearly all patients were taking antithrombotic agents and lipid lowering agents. The median hs-CRP was 4.2 mg/L and the median LDL was 82 mg/dL.

Procedures Patients were randomized 1.5:1:1:1 to receive placebo, canakinumab 50mg, canakinumab 150 mg or canakinumab 300 mg. All doses of canakinumab and placebo were administered subcutaneously once every 3 months; however, for the 300 mg canakinumab dose, the regimen was 300 mg every 2 weeks for the first 2 doses and then once every 3 months thereafter. Randomization was stratified by time from index MI.

Endpoints The primary efficacy endpoint was a composite endpoint that included time to first occurrence of cardiovascular death, nonfatal MI or nonfatal stroke in a time-to-event analysis. Secondary endpoints included individual components of the primary endpoint as well as others. Endpoint adjudication was done by a committee blinded to treatment assignment.

The trial was designed to have 90% power to detect a 20% lower event rate in the primary endpoint for at least 1 of the 3 doses of canakinumab compared to placebo. It was estimated that 17,200 patients would need to be enrolled in order to accrue 1,400 events over a 5 year period. While the trial was ongoing, at the request of the sponsor, the sample size was reduced to 10,000 and follow up was extended by 1 year in an effort to still achieve 1,400 events.

The formal evaluation of significance for individual doses was adjusted for multiple comparisons. The prespecified 2-sided P value thresholds for statistical significance for the primary endpoint were 0.01058 for the 300 mg canakinumab dose versus placebo and 0.02115 for tests of the other 2 canakinumab doses individually versus placebo.

Results Canakinumab was effective in lowering hs-CRP with 48 months reductions from baseline of 26%, 37% and 41% for 50 mg, 150 mg and 300 mg dose groups compared to placebo. Canakinumab did not change LDL or HDL cholesterol but did increase triglycerides by 4-5% compared to placebo.

Compared to placebo and according to the prespecified P value thresholds for the trial, the 150 mg canakinumab dose significantly reduced the primary endpoint of cardiovascular death, nonfatal MI and stroke (14% vs 16%; p=0.021); however, the 50 mg (14.4% vs 16%; p=0.30) and 300 mg (14.2% vs 16%; p=0.031) doses did not. The statistically significant difference for the 150 mg dose was driven by reduction in nonfatal MI (7.0% vs 8.7%; p=0.005) that was accentuated in the 150 mg dose group compared to the 50 and 300 mg doses.

No significant differences in nonfatal stroke (placebo rate [2.8%], 50 mg rate [2.7%], 150 mg rate [2.8%], and 300 mg rate [2.3%]), CV death (placebo rate [5.4%], 50 mg rate [4.3%], 150 mg rate [4.8%], and 300 mg rate [5.1%]) or all cause death (placebo rate [11.2%], 50 mg rate [10.5%], 150 mg rate [10.4%], and 300 mg rate [10.6%]) were seen in the trial.

When all canakinumab groups were combined, canakinumab significantly reduced the primary endpoint (14.2% vs 16%; p=0.02) and nonfatal MI (7.5% vs 8.7%; p=0.03) but not CV death or all cause death. These results should be de-emphasized as this was not the primary analysis framework for the trial.

The results of standard subgroup testing is not presented in the manuscript or supplement. Regarding adverse events, neutropenia was significantly more common in the canakinumab group as well as death from infection. Patients who died from infection were older and more likely to have diabetes. Thrombocytopenia was also more common in the canakinumab group but not major bleeding events. Canakinumab reduced arthritis and gout as well as cancer death.

Conclusions In patients with a previous MI and persistently elevated hs-CRP, the 150 mg dose of canakinumab reduced the primary composite endpoint. The estimated number of patients needed to treat with 150 mg of canakinumab to prevent 1 primary outcome event over 3.7 years is approximately 50. The difference in events was driven mainly by nonfatal MI. Significant differences in nonfatal stroke, CV death and all-cause death were not observed for the 150 mg group compared to placebo nor for any of the other canakinumab groups. When other canakinumab dose groups are compared to placebo or when all canakinumab groups are combined, the results generally mirror those of the 150 mg dose group.

Canakinumab significantly increased neutropenia, thrombocytopenia and death from infection compared to placebo. Information on subgroups is not provided.

Via its action on reducing systemic inflammation, canakinumab reduces cardiac events in well-selected patients with a history of MI and persistently elevated hs-CRP; however, the clinical effect is small (NNT = 50) and driven by nonfatal events. Serious adverse events, such as death from infection, are increased with canakinumab and it is possible that in unselected patient populations, particularly those with severe systemic inflammation and systemic inflammatory disorders that these adverse events could overwhelm any potential benefits.

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N Engl J Med 2015;372:2387-2397

Background: Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, effectively lower low-density lipoprotein (LDL) and improve cardiovascular outcomes across different populations. High-intensity statins exhibit greater efficacy in lowering LDL and decreasing non-fatal cardiac events compared to moderate-intensity statins. Nonetheless, due to the residual risk of cardiac events, and concerns about the safety and tolerability of high intensity statins, there is a growing demand for newer therapeutic options.

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Ezetimibe acts on the Niemann–Pick C1–like 1 (NPC1L1) protein, inhibiting cholesterol absorption from the intestine. When combined with statins, ezetimibe further decreases LDL levels by an average of 23 to 24%.

The IMPROVE-IT trial sought to test the hypothesis that adding ezetimibe to simvastatin is superior to simvastatin alone in reducing cardiovascular events in patients with recent acute coronary syndrome.

Patients: Patients were enrolled if they had acute coronary syndrome (STEMI, NSTEMI or high-risk unstable angina) in the preceding 10 days, and were at least 50 years old. LDL levels within 24 hours of the acute coronary syndrome (ACS) had to be at least 50 mg/dL but less than or equal to 125 mg/dL in lipid-therapy naïve patients or less than or equal to 100 mg/dL in patients receiving lipid lowering therapy. Patients were excluded if they had hemodynamic or electrical instability following the ACS event, planned CABG, active liver disease, creatinine clearance< 30 ml/min, or they had chronic lipid lowering therapy of simvastatin> 40mg, atorvastatin 40mg or more, any dose of rosuvastatin, or any ezetimibe/simvastatin combination.

Baseline characteristics: The average age of patients was 64 years with 76% being men. The average weight was 83 kg. About 27% had diabetes, 61% had hypertension, 21% had prior myocardial infarction, 4% had congestive heart failure and 33% were current smokers. The median creatinine clearance was 85 ml/ min. The index event was STEMI in 29% of the patients, NSTEMI in 47% and unstable angina in the rest. Coronary angiogram was performed in 88% of the patients and percutaneous coronary intervention was performed in 70%. The mean LDL was 94 mg/dL and was similar in both groups.

Procedures: Patients were randomized 1:1 in a double blinded fashion to receive simvastatin 40mg daily plus ezetimibe 10mg daily or simvastatin 40mg daily plus placebo. Patients had follow-up visits at 30 days, 4 months, and every 4 months thereafter.

In both study groups, if LDL level was higher than 79 mg/dL on two consecutive measurements, the simvastatin dose was increased to 80 mg per day. This practice continued until June 2011, approximately one year after the study's randomization concluded, when the Food and Drug Administration advised limiting new prescriptions of simvastatin 80 mg daily. If LDL levels were higher than 100 mg/dL on the new regimen, the study drug could be discontinued, and more potent therapy could be initiated. Patients were followed for at least 2.5 years and for up to 7 years.

Endpoints: The primary efficacy end point was a composite endpoint of death from cardiovascular disease, a major coronary event (defined as nonfatal myocardial infarction, unstable angina requiring hospital admission, or coronary revascularization occurring at least 30 days after randomization), or nonfatal stroke. The trial also reported death from any cause as part of one of the secondary composite endpoints. Safety variables included liver enzymes and creatine kinase levels, myopathy or rhabdomyolysis, gallbladder-related adverse events or cancer.

Statistical analysis was performed based on the intention-to-treat principle. To achieve 90% power for detecting 9.375% lower relative risk for the primary end point with simvastatin–ezetimibe combination compared to simvastatin alone, an estimated sample size of 18,000 patients and 5,250 primary events was required.

Results: The trial randomized 18,144 patients in 39 countries; 9067 randomized to the simvastatin–ezetimibe combination and 9077 to the simvastatin monotherapy group.

The simvastatin–ezetimibe combination led to greater reduction in LDL. At 1 year, the mean LDL was 53 mg/dL in the simvastatin–ezetimibe combination group and 70 mg/dL in the simvastatin monotherapy group. The simvastatin dose was increased to 80mg per day in 6% of the patients in the simvastatin–ezetimibe group and 27% in the simvastatin monotherapy group.

The use of simvastatin–ezetimibe led to greater reduction in the primary endpoint compared simvastatin monotherapy (32.7% vs 34.7%, HR: 0.94; 95% CI: 0.89 - 0.99; p= 0.016). This reduction in the composite primary endpoint was primarily driven by reduction in non-fatal myocardial infarction (12.8% vs 14.4%) as well as ischemic stroke (3.4% vs 4.1%). There was no significant difference in death from any cause (15.4% vs 15.3%) or death from cardiovascular causes (6.9% vs 6.8%).

The benefits of simvastatin–ezetimibe were more pronounced in patients who were 75 years or older (39.0% vs 47.6%, HR 0.80, 95% CI: 0.70 - 0.90; p for interaction= 0.005) and in patients with diabetes (40.0% vs 45.5%, HR: 0.86, 95% CI: 0.78 - 0.94; p for interaction= 0.023).

No significant differences in safety endpoints were observed between both groups. Elevation of liver enzymes 3 times or more the upper limited of normal occurred in 2.5% of the patients in the simvastatin–ezetimibe combination group and 2.3% in the simvastatin monotherapy group.

Conclusion: In patients with recent acute coronary syndrome, the combination of simvastatin–ezetimibe as compared to simvastatin monotherapy improved the primary composite outcome of death from cardiovascular disease, major coronary events, or nonfatal stroke. This reduction was modest, about 6% relative reduction, and was primarily driven by reduction in non-fatal myocardial infarctions and ischemic strokes. The trial results supports the hypothesis that lower LDL levels improves outcomes regardless of how it’s achieved.

The trial has good interval validity but the external validity is limited in the current era because simvastatin is infrequently used nowadays with atorvastatin and rosuvastatin being the preferred agents. Patients taking atorvastatin 40mg or more and patients taken any dose of rosuvastatin at baseline were excluded from the trial. Furthermore, it’s unclear why the trial did not permit the inclusion of patients whose LDL exceeded certain limits as only patients with mild elevation in LDL at baseline were permitted to be enrolled.

This trial does not answer the question most physicians may encounter in their practice: What’s the benefit of adding ezetimibe to high-intensity statins or prescribing it to patients with moderate or high elevation in LDL levels?

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N Engl J Med 1992;326:10-16

Background: Revascularization with coronary artery bypass surgery improves symptoms in patients with chronic stable angina as seen in the European Coronary Surgery Study. Percutaneous transluminal coronary angioplasty (PTCA) is less invasive compared to surgery and is associated with less mortality and morbidity. Consequently, its use increased significantly in the late 1980s and early 1990s, driven by its perceived benefits over medical therapy alone due to the ability of PTCA to reduce coronary artery luminal stenosis.

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The Angioplasty Compared to Medicine (ACME) study sought to test the hypothesis that PTCA improves symptoms in patients with single vessel sable coronary artery disease.

Patients: Eligible patients were recruited from Veterans Affairs centers. Patients had to have 70 – 99% stenosis in the proximal two thirds of one major epicardial coronary artery plus one of the following: stable angina pectoris, very positive exercise-tolerance test (ST-segment depression ≥3 mm) or a myocardial infarction within the past 3 months.

Baseline characteristics: The study screened 9,573 patients and among them only 212 (2.2%) were enrolled – 107 randomized to medical therapy and 105 to PTCA. The reasons for patients’ exclusion were provided in table 1 of the manuscript. Some key exclusion criteria were previous CABG, unstable angina, prior PTCA, 3-vessel disease or lesions not suitable for PTCA.

The average age of enrolled patients was 63 years. Approximately 30% had prior myocardial infarction, 53% had hypertension, 18% had diabetes, 1% had congestive heart failure, and 31% were current smokers. There were more employed participants in the PTCA arm 42% vs 29%. The average systolic blood pressure was 136 mm Hg. The average total cholesterol was 230 mg/dl.

The average duration participants did on the treadmill was 8.8 minutes. Approximately 38% had LAD disease, 25% had LCx disease, and 37% had RCA disease.

Procedures: All patients were admitted to the hospital. Anti-anginal medications were stopped for at least 24 hours and exercise stress test that included thallium Scintigraphy was performed. The test was considered positive if there was horizontal or down-sloping ST-segment depression ≥ 1.0 mm in one or more leads measured 80 msec after the J point that occurred during or after treadmill exercise testing. Patients who had angina during the test but did not meet the above criteria could be included if there was evidence on thallium scanning of a reversible defect in the area corresponding to the index lesion. If the test showed ischemia, patients were then assigned to PTCA or medical therapy.

All patients received aspirin 325 mg/day. Patients in the medical arm received one or combination of the following: nitrates, beta-blockers or calcium channel blockers. Patients in the PTCA arm received calcium channel blockers before and for one month after the procedure, and nitroglycerin during and for 12 hours after the procedure.

Patients were followed monthly. Patients were admitted to the hospital 6 months after randomization, for repeat exercise testing and coronary angiogram. For patients in the medical arm, this exercise testing was performed while they continued their anti-anginal medications. In contrast, patients in the PTCA arm stopped their anti-anginal medications for at least 24 hours before the test.

Endpoints: The primary end points were changes in exercise tolerance, angina attacks and the use of nitroglycerin. Change in the degree of stenosis in the index lesion was measured as a secondary endpoint.

Analysis was performed based on the intention-to-treat principle. The sample size to achieve 95% power at an alpha level of 0.05 was 192. This was based on the assumption that PTCA would increase exercise duration by 1-minute compared to medical therapy. To account for potential loss to follow-up, the recruitment goal was set at 200 patients.

Results: Among the 105 patients assigned to PTCA, 95% underwent the procedure, and among them, the procedure was considered successful in 82%. Successful PTCA was defined >20% decrease in percent stenosis of all lesions in which dilation was attempted. Among the 107 patients assigned to medical therapy, 10% underwent PTCA.

The mean duration from randomization to follow-up exercise testing was approximately 7 months. PTCA led to greater increase in exercise time compared to medical therapy alone (2.1 minutes vs 0.5 minutes; p< 0.0001) as well as time to onset of angina (2.6 minutes vs 0.8 minutes; p <0.01). Patients in the PTCA arm had numerically greater reduction in angina episodes (-15/ month vs -7/ month; p= 0.06). Reduction in nitroglycerin use was not significantly different between both groups (-9/ month with PTCA vs -5/ month with medical therapy; p= 0.25).

There was no significant difference in myocardial infarction (4.8% with PTCA vs 2.8% with medical therapy; p= 0.50) or death (0.0% with PTCA vs 0.9% with medical therapy; p= 1.0). The one patient who died in the medical arm died as a result of a PTCA procedure.

The change in degree of stenosis was not significant in the medical arm (77% at baseline vs 75% at 6 months). In the PTCA arm, stenosis was reduced immediately after angioplasty (76% vs 36%) but then increased again at follow up to 54%.

Conclusion: In patients with single-vessel stable coronary artery disease, PTCA improved exercise duration and symptoms compared to medical therapy alone.

The study is limited by small sample size, but more importantly, it was highly selective, with only 2.2% of screened patients being enrolled. It is, however, valuable that the authors provided reasons for patients’ exclusions which helps physicians determine which of their patients would have qualified for the trial.

Another significant limitation is the lack of blinding, which could introduce bias in the assessment of symptoms and exercise capacity. Additionally, the results of PTCA were not durable, and lesions worsened during 6 months follow-up, compared to the initial results achieved.

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For full review of the trials, please see https://cardiologytrials.substack.com/

N Engl J Med 2019;381:1524-1534

Background Dual antiplatelet therapy after percutaneous coronary intervention had become a standard of care. Both prasugrel and ticagrelor had been shown to provide more rapid and consistent platelet inhibition than clopidogrel. Randomized controlled trials had shown both drugs were superior to clopidogrel in patients with acute coronary syndromes.

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The two drugs have different loading strategies in patients who have acute coronary syndromes without ST-segment elevation. In these patients, ticagrelor is usually administered as pretreatment before diagnostic angiography, but prasugrel is administered only after the coronary anatomy has been assessed by means of diagnostic angiography since no advantage has been observed when prasugrel is used as pretreatment.

Before ISAR-REACT 5, there had been no direct comparisons of the two antiplatelet drugs. ISAR-REACT 5 was an investigator-initiated multicenter, non-industry funded RCT to compare the efficacy and safety of the two treatments in patients with acute coronary syndrome.

Patients The trial enrolled 4013 patients from 23 centers. Patients were eligible with either STEMI, NSTEMI or unstable angina for which intervention was planned. Exclusion criteria included intolerance of either drugs, history of stroke or intracranial bleeding or any condition that increased the risk of bleeding. Patients could not be on concomitant oral or i.v. therapy with drugs affecting CYP3A4 system.

Baseline Characteristics There were 2012 patients assigned to ticagrelor and 2006 patients assigned to prasugrel. The suspected diagnosis at admission was STEMI in 41%, NSTEMI in 46%, and unstable angina in 13% of the patients. The average age was 64 years. Female sex was 24%. Average systolic blood pressure and heart rate was 144 mmHg and 77 bpm. All factors were well balanced.

Trial Procedures Therapy with ticagrelor was started at a loading dose of 180 mg and continued at a maintenance dose of 90 mg twice daily. Patients who were assigned to ticagrelor received the loading dose as soon as possible after randomization. Therapy with prasugrel was started at a loading dose of 60 mg and continued at a maintenance dose of 10 mg once per day. A reduced maintenance dose of 5 mg daily was recommended in patients who were 75 years of age or older and in those who had a body weight of less than 60 kg.

Prasugrel therapy turned on presentation. STEMI patients were given prasugrel as soon as possible after randomization. In those without STEMI, the loading dose was delayed until knowledge of the coronary anatomy. Prasugrel loading was given before crossing the lesion. In patients with a coronary angiography–confirmed acute coronary syndrome who were not considered to be candidates for PCI but who were considered to be candidates for conservative therapy, dual antiplatelet therapy (aspirin and the randomly assigned trial medication) was recommended.

About 83% of patients received PCI, 2% CABG and 13-14% were managed conservatively. Clinical follow-up was scheduled at 30 days, 6 and 12 months.

Endpoints The primary end point was a composite of death, MI, or stroke at 1 year after randomization. Secondary end points included the safety end point, which was the incidence of bleeding at 1 year (type 3, 4, or 5 on the Bleeding Academic Research Consortium [BARC] scale, which ranges from 0 to 5, with higher values indicating more severe bleeding), the incidence of the individual components of the primary end point at 1 year, and the incidence of definite or probable stent thrombosis at 1 year.

The sample-size calculation assumed a primary endpoint would occur in 10% in the ticagrelor group vs 12.9% in the prasugrel group. This led to an estimate of 1900 patients in each group and 80% power to detect a relative risk reduction of 22% in the ticagrelor group. All analyses, including the analysis of the primary end point, were performed according to the intention-to-treat principle Only the safety end point was analyzed in a modified intention-to-treat population, which included all patients who received at least one dose of the randomly assigned trial drug and were assessed for bleeding events up to 7 days after discontinuation of the trial drug.

Results At discharge, 81% of patients in both groups received the randomly assigned trial drug. Slightly more patients in the ticagrelor group stopped taking the study drug by one year (15.2 vs 12.5%). One-year follow-up was complete in all but 90 patients (41 patients in the ticagrelor group and 49 patients in the prasugrel group).

A primary end-point event (death, MI, stroke) occurred in 184 of 2012 patients (9.1%) in the ticagrelor group and 137 of 2006 patients (6.8%) in the prasugrel group (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P=0.006).

The composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 161 of 2012 patients (8.1%) in the ticagrelor group and 124 of 2006 patients (6.3%) in the prasugrel group (hazard ratio, 1.32; 95% CI, 1.04 to 1.66).

The rates of death, stroke and stent thrombosis did not statistically differ in the two groups. But the risk of MI was 63% higher in the ticagrelor group (4.8% vs 3.0%; HR 1.63; 95% CI, 1.18 to 2.25).

Major bleeding was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P=0.46).

No heterogenous treatment effects were obvious from the subgroup analyses.

Discussion For patients with acute coronary syndrome who were considered for intervention, prasugrel was superior to ticagrelor for the reduction of the primary endpoint. The effect size was large (ticagrelor 36% worse compared to prasugrel), and this was statistically robust. The reduction was obtained without an increase in bleeding.

The trialists noted that this was not simply a comparison of drugs, but a comparison of treatment strategies. Authors had assumed that pre-treatment of ticagrelor would be superior. But this trial showed that a prasugrel-based strategy with deferred loading (after knowing the coronary anatomy) was superior.

The primary endpoint finding was bolstered by the composite of cardiovascular death, MI and stroke also being 32% higher in the ticagrelor arm.

This was an investigator-initiated non-industry funded study with an event rate in the ticagrelor arm similar to expected findings. We find this compelling evidence for the superiority of prasugrel in this patient population.

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N Engl J Med 2013;369:999-1010

Background: Adding P2Y12 inhibitors to aspirin improves outcomes in patients with acute coronary syndrome. Yet, debate persisted regarding the optimal timing for administering these drugs in patients undergoing percutaneous coronary intervention (PCI). The ATLANTIC trial showed that pre-hospital administration of ticagrelor did not improve outcomes compared to in-hospital administration, in patients with ST elevation myocardial infarction.

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The ACCOAST trial sought to test the hypothesis that administering the P2Y12 inhibitor, prasugrel, 2-48 hours before angiography in non-ST elevation myocardial infarction patients is superior to administering it during PCI.

Patients: Patients were enrolled if they had non-ST elevation myocardial infarction. Patients were scheduled to undergo angiography with possible PCI within 2-48 hours after randomization. Patients were excluded if they had cardiogenic shock, refractory ventricular arrhythmias, prior hemorrhagic or ischemic stroke or TIA, history of intracranial neoplasms, history of intracranial AV malformations or aneurysm, surgery within 4 weeks, active bleeding or history of bleeding diathesis or had high risk of bleeding based on the judgement of the investigator.

Baseline characteristics: The average age of patients was 64 years with 72% being men. The average weight was 82 kg. About 20% had diabetes, 45% had hyperlipidemia, 62% had hypertension and 33% were current smokers. Creatinine clearance was ≤ 30 ml/min in 3% of the patients and GRACE score was < 140 in 77% of them. Beta-blockers were given in 84% of the patients, statins in 90%, angiotensin-receptor blockers in 13% and ACE inhibitors in 70%.

After randomization, 68.7% of the patients underwent PCI while 25.1% were treated medically. CABG within 7 days was performed in 6.2% of the patients.

Procedures: Patients were randomized 1:1 to receive pretreatment with prasugrel or matching placebo (control group). Those in the pretreatment group received a 30 mg loading dose of prasugrel before coronary angiography with an additional 30 mg if angiography confirmed the need for PCI. Patients in the control group received placebo before coronary angiography and a 60 mg loading dose of prasugrel in patients undergoing PCI. Only the initial 30 mg loading dose of prasugrel or placebo were administered, if a decision, after coronary angiography, was made to pursue CABG or medical therapy.

Endpoints: The primary efficacy end point was a composite endpoint of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or the need for rescue therapy with glycoprotein IIb/IIIa inhibitors. Follow up for the primary endpoint was 7 days post randomization. Secondary endpoints included death from any cause, stent thrombosis and a composite endpoint of death from cardiovascular causes, myocardial infarction, or stroke.

Safety end points were major or minor bleeding according to Thrombolysis in Myocardial Infarction (TIMI) criteria.

Statistical analysis was performed on the intention-to-treat principle. To achieve 80% power with two-sided alpha of 0.05 for detecting 24% relative risk reduction in the pretreatment compared to the control group, 400 patients with the primary outcome and approximately 4,100 enrolled patients would be needed.

Results: The trial randomized 2,037 patients to the pre-treatment group and 1,996 to the control group. The median time from the initial loading dose to PCI was 4.3 hours.

The incidence of the composite primary end point was similar between both treatment groups (10.0% in the pre-treatment group vs 9.8% in the control group, HR: 1.02, 95% CI: 0.84 – 1.25; p= 0.81). There was no significant difference between both treatment groups in any of the components of the primary end point, death from any cause, or stent thrombosis. Results were similar for patients who underwent PCI (about two thirds of study participants).

There were more major bleeding events at 7 days in the pretreatment group (2.6% vs 1.4%, HR: 1.90, 95%: 1.19 – 3.02; p= 0.006). Major bleeding events not related to CABG were also higher in the pre-treatment group (1.3% vs 0.5%; p= 0.003). In the PCI cohort, 12 patients in the pre-treatment group had life-threatening bleeding compared to 2 in the control group. Most bleedings in this cohort were access site bleeding, pericardial bleeding and retroperitoneal bleeding.

Subgroup analysis for the primary efficacy endpoint did not identify any subgroup who would benefit from pre-treatment with prasugrel.

Conclusion: In patients with non-ST elevation myocardial infarction undergoing coronary angiography within 48 hours of admission, pre-treatment with prasugrel did not improve ischemic events and resulted in more major bleeding.

The results of this trial led to the recommendation that prasugrel should be used after coronary anatomy is defined and PCI is chosen as the treatment strategy. This approach will reduce the risk of bleeding complications without increasing the risk of ischemic events.

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N Engl J Med 2014;371:1016-1027

Background: Prior trials have demonstrated that combining P2Y12 inhibitors with aspirin in patients with acute coronary syndrome reduces cardiovascular events. Prasugrel, in the TRITON-TIMI 38 trial, and ticagrelor, in the PLATO trial, were administered in the hospital.

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Older trials had suggested that early administration of glycoprotein IIb/IIIa inhibitors improves outcomes in patients with ST elevation myocardial infarction (STEMI).

The ATLANTIC trial sought to test the hypothesis that pre-hospital compared to in-hospital administration of the P2Y12 inhibitor, ticagrelor, improves outcomes in patients with STEMI.

Patients: Patients were enrolled if they had STEMI and had experienced symptoms for at least 30 minutes but no longer than 6 hours, and were expected to have EKG to balloon inflation of less than 120 minutes. Patients were excluded if they had prior intracranial bleeding, moderate to severe liver disease, gastrointestinal bleeding within 6 months, planned fibrinolytic therapy or required dialysis.

Baseline characteristics: The average age of patients was 61 years with 80% being men. The average weight was 80 kg. About 14% had diabetes, 9% had prior myocardial infarction, 4% had chronic obstructive pulmonary disease and 2% had chronic renal failure. TIMI risk score was 0-2 in 61% of the patients. About 90% had Killip class I. Coronary angiography was performed in 98% of the patients and percutaneous coronary intervention (PCI) with stent placement was performed in 82%. The use of glycoprotein IIb/IIIa inhibitors was high in the study and was administered before percutaneous coronary intervention in 29% of the patients.

Procedures: Patients were randomized 1:1 to receive ticagrelor en route to the hospital/ catheterization lab (group 1) or at the catheterization lab (group 2). In group 1, patients received ticagrelor 180mg en route to the hospital and placebo in the catheterization lab. In group 2, patients received placebo en route to the hospital and ticagrelor 180mg in the catheterization lab. Following that, all patients received ticagrelor 90mg twice daily for at least 30 days and the treatment was recommended to continue for 12 months. Clinical endpoints were adjudicated up to 30-days post randomization.

Endpoints: There were two coprimary endpoints – proportion of patients who did not have 70% or greater resolution in their ST-segment elevation before PCI and proportion of patients without TIMI grade III flow in the infarcted artery before PCI. Review of EKG and angiographic data was blinded.

A secondary prespecified endpoint included the composite of all-cause death, myocardial infarction, stent thrombosis, stroke or urgent revascularization at 30 days.

Analysis was performed based on the modified intention-to-treat principle, defined as patients who received at least one loading dose of the study drug. Patients with missing EKG or angiographic data were excluded from the primary endpoint analysis.

The sample size estimate was based on an anticipated event rate of 15% in the control group for the EKG endpoint. They estimated that 779 patients would be needed in each group to show a 6% absolute difference with 80% power and an alpha of 2.5%.

Results: The trial randomized 1,862 patients, 909 patients to the prehospital group and 953 to the in-hospital group. The median time from randomization to angiography was 48 minutes and the median time between the two loading doses was 31 minutes.

There was no significant difference in the proportion of patients who did not have 70% or more ST segment resolution before PCI (86.8% for the pre-hospital group vs 87.6% for the in-hospital group, OR: 0.93, 95% CI: 0.69 – 1.25; p= 0.63) or the proportion of patients who did not have TIMI III flow in the infarcted artery before PCI (82.6% for the pre-hospital group vs 83.1% for the in-hospital group, OR: 0.97, 95% CI: 0.75 – 1.25; p= 0.82).

There was also no significant difference for the secondary composite endpoint (4.5% vs 4.4%, OR: 1.03, 95% CI: 0.66 – 1.60; p= 0.91). Stent thrombosis at 30-days was lower in the pre-hospital group (0.2% vs 1.2%, OR: 0.19, 95% CI: 0.04 – 0.86; p= 0.02). Myocardial infarction was not significantly different between both groups (0.8% vs 1.1%; p= 0.53). All-cause death was numerically higher in the pre-hospital group (3.3% vs 2.0%, OR: 1.68, 95% CI: 0.94 – 3.01; p= 0.08).

Major bleeding not related to CABG was not significantly different between both treatment groups (1.3% in both groups using the TIMI criteria and 2.9% in the pre-hospital group vs 2.5% in the in-hospital group, using the STEEPLE criteria).

Conclusion: In patients with STEMI, pre-hospital administration of ticagrelor did not improve outcomes compared to in-hospital administration. Although pre-hospital administration of ticagrelor reduced stent thrombosis at 30-days, this did not reduce all-cause mortality. In fact, all-cause mortality was numerically higher in the pre-hospital group.

A notable finding is that within the in-hospital group, definite stent thrombosis occurred in 1.2% of patients while 1.1% were adjudicated to have myocardial infarction. Stent thrombosis is a serious condition that leads to myocardial infarction. The trial protocol used many definitions for myocardial infarction. This underscores the complexity of counting and adjudicating events in clinical trials and highlights the importance of relying on outcomes less susceptible to bias, such as mortality.

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JAMA. 2013;309(12):1241-1250

Background Case reports as early as the 1950s suggested chelation of lead might reduce angina. The popularity of chelation accelerated around the turn of the century. Small underpowered trials of chelation were inconclusive. Mainstream medicine considered chelation unproven and potentially hazardous.

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Chelation with disodium EDTA binds divalent and some trivalent cations, including calcium, magnesium, lead, cadmium, zinc, iron, aluminum, and copper, which facilitates their urinary excretion. High dose vitamins are often co-administered with chelation.

The NIH-funded Trial to Assess Chelation Therapy (TACT) trial was conducted to respond to the public health problem posed by EDTA chelation therapy: namely, that large numbers of patients could be exposed to undefined risks for unproven benefits. TACT was a double-blind placebo-controlled 2x2 factorial randomized trial enrolling 1708 patients to test chelation therapy.

Patients Eligibility for TACT required patients be older than 50 years, have a creatinine of < 2 mg/dl, and have survived a previous myocardial infarction. Exclusion criteria included platelet count less than 100 000/μL, abnormal liver function, BP > 160/100 mm Hg, past intolerance to the chelation or vitamin components, chelation therapy within 5 years, coronary or carotid revascularization planned or having taken place within 6 months, cigarette smoking within 3 months, active heart failure or heart failure hospitalization within 6 months, or inability to tolerate 500-mL infusions weekly. Enrollment began in 2003 and follow-up continued until 2011. There were 134 sites; 60% of which were established chelation centers.

Baseline Characteristics The median age of patients was 65 years, 18% were women and the median body mass index was 30. More than 90% of patients had had either percutaneous coronary intervention or coronary bypass surgery. Approximately 31% of patients had diabetes. Use of guideline directed medications was typical of a well-treated population of post-MI patients. Procedures The active 10-component chelation solution consisted of up to 3 g of disodium EDTA; 7 g of ascorbic acid; 2 g of magnesium chloride; 100 mg of procaine; 2500 U of unfractionated heparin; 2 mEq of potassium chloride; 840 mg of sodium bicarbonate; 250 mg of pantothenic acid; 100 mg of thiamine; 100 mg of pyridoxine; and sterile water to make up 500 mL of solution. The identical-appearing placebo solution consisted of 500 mL of normal saline and 1.2% dextrose (2.5 g total).

The chelation or placebo infusions were administered through a peripheral intravenous line, weekly for the first 30 infusions, followed by an additional 10 infusions 2 to 8 weeks apart.

Patient also received an oral vitamin-mineral regimen vs an oral placebo.

In this review, we focus on the intention-to-treat comparison of EDTA chelation vs placebo.Endpoints The primary endpoint was a composite of death, reinfarction, stroke, coronary revascularization, or hospitalization for angina.

TACT trialists had planned to enroll 2300 patients over three years with a follow-up of one year. Enrollment was slow, and with permission from the data safety monitoring board (DSMB) enrollment was decreased to 1700 patients and follow-up was extended. The resultant power was 85% to detect a 25% reduction in the primary endpoint assuming a 2.5% per year event rate in the placebo arm.

Over the course of the trial, the DSMB requested 11 interim analyses of the data. Because of the increased monitoring, the level of statistical significance required for the primary endpoint was enhanced to a P value of less than 0.036.

Results After a median follow-up of 55 months, a primary end point occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (hazard ratio [HR]: 0.82 [95% CI: 0.69-0.99]; p= .035). There was no effect on total mortality (10% vs 11%, HR: 0.93, 95% CI: 0.70-1.25; p= 0.64). Myocardial infarction and coronary revascularization favored chelation (6% vs 8% and 15% vs 18%, respectively), however this did not reach statistical significance for either endpoints.

Subgroup analysis revealed a potentially important heterogenous treatment effect. In patients with diabetes (about a third of patients) there was an approximate 40% reduction in the primary endpoint (HR: 0.61, 95% CI: 0.45-0.83; p= 0.002).

There were no significant differences in adverse effects between the two groups.

The trialists did sensitivity analyses centering on patients who withdrew from the trial or were lost to follow-up. The comparison of the 2 groups remained significant even if the percentage of events among withdrawn/lost patients in the active group was 25% higher than in the placebo group.

Conclusions The results of the TACT trial surprised the cardiology community. Prior beliefs were pessimistic because heavy metals was not a proven causal factor in atherosclerosis. What’s more, the majority of patients were enrolled from non-traditional medical centers.

Yet the effect size was both clinically important and statistically significant. The effect size in the diabetes subgroup, which was pre-specified, was even larger and more robust statistically than the general results. In fact, there was essentially no signal of benefit from chelation in non-diabetic patients. If this was confirmed, it would be a major finding both therapeutically and scientifically, as it would have discovered heavy metal exposure as an important cause of atherosclerosis.

The Journal of the American Medical Association published the manuscript along with an explanatory letter from the editors, and an accompanying editorial from Dr. Steve Nissen, which challenged the internal validity of the trial.

The results of TACT did not lead to widespread adoption of chelation, but it did lead primary investigator Gervasio Lamas to seek (and obtain) funding for a TACT 2 trial to study chelation in patients with diabetes. Experts often refer to subgroup findings as “hypothesis-generating” and so it was with the TACT 1 and TACT 2 trials.

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N Engl J Med 2012;366:9-19

Background Following an acute coronary syndrome, individuals have a substantially elevated risk of recurrent events, compared to a similar individual who did not experience ACS, despite the use of appropriate risk reducing therapies. This is termed “residual risk” and the concept has been mentioned in prior reviews. The quest to lower residual risk continues to be a major driver of new products and therapeutic concepts in cardiovascular medicine.

Rivaroxaban is an oral anticoagulant that directly and selectively inhibits factor Xa. Factor Xa initiates the final common pathway of the coagulation cascade resulting in the formation of thrombin. Thrombin promotes platelet aggregation.

At the time the trial was undertaken, both aspirin and thienopyridines were established agents that worked via different mechanisms, downstream of thrombin formation, to stop platelets from sticking together. Could the addition of an agent that inhibits thrombin formation, upstream of platelet activation and aggregation, reduce risk further without causing a prohibitive increase in bleeding risk?

A meta-analysis of small trials involving the use of warfarin, in addition to aspirin, suggested that warfarin, an indirect inhibitor of thrombin, could improve cardiovascular outcomes. And a phase 2 dose finding trial with rivaroxaban provided further support. Thus, the ATLAS ACS-TIMI 51 trial sought to test the hypothesis that adding rivaroxaban to standard therapies, at 2.5 or 5 mg twice daily, would reduce cardiovascular events compared to placebo.

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Patients Adults who had presented with an acute coronary syndrome (STEMI, NSTEMI or unstable angina). Patients under 55 years of age had to have either diabetes or a history of a previous MI. Patients were excluded if they had a platelet count <90k, hemoglobin <10g/dl, creatinine clearance <30 ml/min, clinically significant GI bleed within 12 months, previous intracranial hemorrhage or previous stroke or TIA.

Baseline characteristics Patients averaged 62 years of age with 36% greater than or equal to 65 and only 9% greater than or equal to 75. The majority of patients were either white (73%) or Asian (21%). Existing medical conditions were typical for an ACS population. The index diagnosis was a STEMI in 50% with the other half split fairly evenly between NSTEMI and UA. The majority of patients enrolled were from Eastern Europe (39%) and Asia (21%). Nearly all patients were on aspirin (99%) and a thienopyridine (93%) and 83% were on a statin drug.

Procedures Patients were enrolled within 7 days after hospital admission for an ACS. They had to be stable at the time of enrollment with the initial revascularization strategies completed. They were randomly assigned in a 1:1:1 fashion to twice daily rivaroxaban 2.5 mg, rivaroxaban 5 mg or placebo with a maximum follow-up of 31 months. All patients were to receive standard medical therapy. Patient follow-up occurred at 4 weeks, 12 weeks and every 12 weeks thereafter.

Endpoints The primary endpoint was a composite of death from cardiovascular causes, myocardial infarction, or stroke (ischemic, hemorrhagic, or stroke of uncertain cause). The primary safety endpoint was TIMI major bleeding not related to CABG surgery.

As prespecified by the investigators, the efficacy analyses were performed with the use of a modified intention-to-treat principle; however, they performed sensitivity efficacy analyses using a standard intention-to-treat approach. *Since the statistical significance of the main findings did not meaningfully change with either approach, we report the p-values based on the standard approach since using a modified approach is unconventional.

The investigators determined they would need 983 primary endpoint events to provide a power of 96% to detect a 22.5% relative reduction between the combined-dose group receiving rivaroxaban and the placebo group with a 2-sided alpha of 0.05. This would also yield a power of 90% to determine a relative risk reduction of 22.5% for each rivaroxaban dose group compared to placebo separately.

Results There were 15,526 patients who underwent randomization (5,174 at 2.5 mg rivaroxaban, 5,176 at 5 mg rivaroxaban, and 5,176 with placebo). The median time from index event to randomization was 4.7 days.

Compared to placebo, patients receiving either dose of rivaroxaban experienced a significant reduction in the primary composite endpoint (8.9% vs 10.7%; HR 0.84; 95% CI 0.74-0.96; p=0.002). This was driven by reductions in cardiovascular death (3.3% vs 4.1%; p=0.05) and nonfatal MI (5.5% vs 6.6%; p=0.01). The difference in stroke numerically favored the placebo group but was not statistically significant (1.6% vs 1.2%; p=0.19). The difference in all-cause death numerically favored the combined rivaroxaban group but was not statistically significant (3.7% vs 4.5%; p=0.08).

TIMI major bleeding not associated with CABG was significantly increased in the combined rivaroxaban group (2.1% vs 0.7%; HR 3.96; 95% CI 2.46-6.38; p<0.001). All components of bleeding were significantly increased in the combined rivaroxaban group with the exception of fatal bleeding (0.3% vs 0.2%; p=0.66).

When specifically looking at the 2.5 mg or 5 mg rivaroxaban dose compared to placebo, no significant differences were noted in the primary composite endpoint or primary safety endpoint. However, the endpoints of death from CV causes (2.7% vs 4.1%; p=0.005) and all-cause death (2.9% vs 4.5%; p=0.02) favored the 2.5 mg dose of rivaroxaban vs placebo compared to the 5 mg dose of rivaroxaban vs placebo ([4.0% vs 4.1%; p=0.57 for CV death] & [4.4% vs 4.5%; p=0.89 for all-cause dearth]). Non-fatal MI, on the other hand, favored the 5 mg dose of rivaroxaban vs placebo (4.9% vs 6.6%; p=0.008) compared to the 2.5 mg dose (6.1% vs 6.6%; p=0.09).

In the manuscript abstract, the authors highlighted the outsized reductions in CV death and all-cause death observed in the 2.5 mg rivaroxaban dose compared to placebo; however, this was likely due to the play of chance from low statistical power as there was not a commensurate difference in fatal bleeding between the 2.5 mg and 5 mg rivaroxaban dose to account for these differences and non-fatal MI favored the 5 mg rivaroxaban dose.

Inspection of individual subgroups does not show any statistically significant interactions; however, possible treatment effect heterogeneity is evident for patients with a previous history of stroke or TIA (this represents a very small group) and for patients with diabetes.

Conclusions Compared to placebo, 2.5 or 5 mg of rivaroxaban twice daily significantly reduced the primary composite endpoint of cardiovascular death, non-fatal MI and stroke with a NNT of approximately 50 patients. It also significantly increased TIMI major bleeding not associated with CABG with a NNH of approximately 70 patients. No statistically significant difference was observed for all cause death.

In our opinion, the authors introduced spin in the manuscript abstract by highlighting outsized differences in CV death and all cause death in the 2.5 mg rivaroxaban dose vs placebo group that were more likely false positive findings from low power than real treatment response variation based on the difference in rivaroxaban dose.

Finally, it is unlikely that results from this trial can be generalized to the average patient with recurrent ACS events. Such patients are generally older with significant comorbidities like reduced hemoglobin levels, chronic kidney disease or cerebrovascular disease. These patients were either explicitly excluded or severely underrepresented in the trial.

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N Engl J Med 2010;363:930-942

Background By 2010, dual antiplatelet therapy had been established as beneficial during and after percutaneous coronary intervention for acute coronary syndromes. Optimal dosing however remained unknown. This included the best loading dose of clopidogrel and optimal dose of aspirin.

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The Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events−Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT–OASIS 7) trial was designed to determine whether a doubling of the loading and initial maintenance doses of clopidogrel is superior to the standard-dose regimen and whether higher-dose aspirin (300 to 325 mg daily) is superior to lower-dose aspirin (75 to 100 mg daily) in patients with acute coronary syndromes referred for an early invasive strategy.

Patients Adult patients who presented with a non-ST-segment elevation acute coronary syndrome (ACS) or an ST-segment elevation myocardial infarction. Patients had to have had coronary angiography with a plan to perform PCI within 72 hours. Major exclusion criteria were an increased risk of bleeding or active bleeding and a known allergy to clopidogrel or aspirin. 

Baseline Characteristics Nearly all patients had angiography. About 68% had PCI and 32% did not have PCI due to lack of significant (≤70%) stenosis. About a quarter of patients had coronary-artery bypass surgery. The average age of patients was 61 years; 27% female sex, and 70% had a diagnosis of unstable angina or NSTEMI. The median time to randomization in patients with unstable angina/NSTEMI was 3.4 days vs 0.6 days in patients with

STEMI. About 60% of patients were white, and 22% were Asian. The co-existing cardiac risk factors, such as smoking, hypertension, diabetes and previous MI were similar in all the trial arms, and typical of most trials at the time.

Procedures The CURRENT-OASIS 7 trial had 2x2 factorial design. First, comparing in a double-blind fashion, a double dose vs standard dose clopidogrel regimen. In the second component, patients were randomly assigned in an open-labeled fashion to higher- or lower-dose aspirin.

Immediately after randomization and before coronary angiography, patients randomly assigned to double-dose clopidogrel received a loading dose of 600 mg on day 1, followed by 150 mg once daily on days 2 through 7. Patients assigned to standard-dose clopidogrel received a 300-mg loading dose on day 1 before angiography, followed by 75 mg once daily on days 2 through 7. On days 8 through 30, both the double-dose and standard-dose groups received 75 mg of clopidogrel once daily.

Patients randomly assigned to lower-dose aspirin received 75 to 100 mg daily on days 2 through 30, and those randomly assigned to higher-dose aspirin received 300 to 325 mg daily on days 2 through 30. An initial loading dose of aspirin 300 mg was used in both arms on day 1. Other therapies, such as anti-thrombotics were left to the discretion of the treating doctors. Endpoints The primary endpoint was cardiovascular death, myocardial infarction, or stroke at 30 days. The sample-size calculation estimated an event rate of 11% at 30 days with standard-dose clopidogrel or lower-dose aspirin. That would have led to 14,000 patients to have 90% power to detect a 16% reduction in the primary endpoint. Lower-than expected event rates required an increase in sample size to 25,000 patients. This allowed for an 80% power to detect a 16% reduction in the primary endpoint.

Results  A primary outcome event occurred in 4.2% of patients in the double-dose clopidogrel group at 30 days, as compared with 4.4% in the standard-dose group (hazard ratio, 0.94, 95% confidence interval [CI], 0.83 to 1.06; P=0.30). The rate of death from any cause did not differ significantly between the double-dose and standard-dose groups (2.3% and 2.4%, respectively; hazard ratio with the double dose, 0.96; 95% CI, 0.82 to 1.13; P=0.61). Major bleeding occurred more often in the double-dose arm (2.5 vs 2.0% HR 1.24; 95% CI 1.05-1.46).

For the aspirin comparison, the rate of primary outcome events did not differ: 4.2% in the higher-dose arm vs 4.4% in the lower-dose arm. Death from any cause was not statistically different in either arm. Major bleeding rates were also similar in the two aspirin arms (2.3% in both arms).

The authors described a “nominally significant” interaction between clopidogrel dose and aspirin dose for the primary outcome. Among patients assigned to higher-dose aspirin, the primary outcome occurred in 3.8% of patients in the double-dose clopidogrel group, as compared with 4.6% of patients in the standard-dose clopidogrel group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98; P=0.03). But in the lower dose aspirin group, there were no significant differences in the primary outcome between double-dose and standard-dose clopidogrel (4.5% vs 4.2% HR 1.07 95% CI 0.90-1.26, respectively). The p-value for the interaction here was 0.04. Subgroup analyses showed generally consistent results. One possible heterogenous treatment effect in the double- vs standard-dose clopidogrel comparison turned on whether the patient had PCI or did not have PCI. In the 68% (≈17,000) of patients who had PCI, double dose clopidogrel reduced the primary outcome by 15% (3.9% vs 4.5%) vs increasing it by 14% in the no PCI group (4.9% vs 4.3%). The p-value for interaction was 0.03. There were no indications of heterogenous treatment effects depending on aspirin.

Conclusions In patients with ACS, double dose clopidogrel or aspirin compared to standard dose did not significantly reduce the composite endpoint of cardiovascular death, MI or stroke. Double dose clopidogrel did increase major bleeding with a NNH of approximately 200 patients. Treatment effect heterogeneity, favoring the double dose clopidogrel strategy, was suggested for patients undergoing PCI.

This trial serves as a good example of the limitations of surrogate endpoints in predicting hard outcomes. Previous studies had demonstrated that higher doses of clopidogrel led to faster and more substantial platelets inhibition. The observed increase in bleeding events with double-dose clopidogrel supported these findings. Nonetheless, it did not correspond to better ischemic outcomes.

As for the dose of aspirin, there was no added benefit (or increase in bleeding) with higher dose aspirin beyond 75-100 mg.

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N Engl J Med 2012;367:1297-1309

Background: In patients with acute coronary syndrome, clinical guidelines recommend early angiography particularly in those deemed moderate to high risk. However, a proportion of patients do not undergo revascularization, and these patients have poorer outcomes compared to those who do undergo revascularization.

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The TRITON-TIMI 38 trial demonstrated that prasugrel, when compared to clopidogrel, reduces ischemic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). Notably, in the TRITON-TIMI 38 trial, 99% of the patients underwent PCI at the time of randomization.

Expanding upon the findings of TRITON-TIMI 38, the TRILOGY ACS trial sought to test the hypothesis that aspirin plus prasugrel is superior to aspirin plus clopidogrel in patients with acute coronary syndrome, without ST segment elevation, who are managed medically without revascularization.

Patients: Patients were enrolled if they had unstable angina or non-ST elevation myocardial infarction and were treated medically without revascularization, within 10 days of the index event. Patients with non-ST elevation myocardial infarction had elevated cardiac biomarkers. Patients with unstable angina had ST-segment depression of more than 1 mm in two or more electrocardiographic leads and negative cardiac biomarkers. Patients had to have one of the following: age of 60 years or older, diabetes mellitus, prior myocardial infarction or prior revascularization with either PCI or coronary-artery bypass grafting (CABG). Main exclusion criteria were history of stroke or TIA (this group had net harm with prasugrel in TRITON-TIMI 38), renal failure requiring dialysis and patients taking oral anticoagulants.

Baseline characteristics: The trial enrolled 9,326 patients at 966 sites in 52 countries. The average age of patients was 66 years, with 78% were below 75 years old, and 61% were men. About 70% of the patients had non-ST elevation myocardial infraction as their index event. The average GRACE score was 122. About 82% had hypertension, 59% had hyperlipidemia, 38% had diabetes, 43% had prior myocardial infarction and 20% were current or recent smokers. The majority of patients were stable, with 88% classified as Killip class I.

Angiography before randomization was performed in 41% of the patients. Medications at randomization included beta-blockers in 78% of the patients, ACEi or ARB in 75%, statins in 83% and proton pump inhibitors in 25%.

Procedures: The trial was conducted as double-blind double-dummy study. Patients who underwent randomization within 72 hours after the first medical contact received a loading dose of 30mg of prasugrel followed by 10mg daily. The maintenance dose of prasugrel was 5mg daily for patients aged 75 years or older or patients who weighed less than 60 kg. Patients who underwent randomization after 72 hours of the first medical contact received open label clopidogrel before randomization and the maintenance study drug after randomization. Clopidogrel was given as a loading dose of 300mg followed by a maintenance dose of 75mg daily. Aspirin was given in all patients and the recommended dose was 100mg per day or less. Study drugs were given for a minimum of 6 months and a maximum of 30 months.

Endpoints: The primary efficacy endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke among patients < 75 years old. Safety endpoints were bleeding not related to CABG based on Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria for severe or life-threatening bleeding and Thrombolysis in Myocardial Infarction (TIMI) criteria for major bleeding, and neoplasms.

Analysis was performed based on the intention-to-treat principle. The trial was event-driven. To ensure 90% power to detect 22% relative risk reduction of prasugrel over clopidogrel with a two-sided alpha of 5%, a total of 688 patients, <75 years old, with primary efficacy events would be needed. Sample size was not calculated for patients 75 years or older as this analysis was exploratory.

Results: The trial randomized 4,663 patients to the prasugrel group and 4,663 patients to the clopidogrel group. The median duration of follow up was 17.1 months.

At 30 months, the primary efficacy end point was not significantly different between both treatment arms for patients <75 years old (13.9%/ year with prasugrel vs 16.0%/ year with clopidogrel, HR: 0.91, 95% CI: 0.79 – 1.05; p= 0.21) or for the whole population (18.7%/ year with prasugrel vs 20.3%/ year with clopidogrel, HR: 0.96, 95% CI: 0.86 – 1.07; p= 0.45). There were no significant differences for the outcomes of all-cause death, cardiovascular death, non-fatal myocardial infarction or non-fatal stroke for patients <75 years old or the whole population.

Severe or life-threatening non-CABG bleeding was also not significantly different between both treatment arms for patients <75 years based on the GUSTO criteria (0.9%/ year with prasugrel vs 0.6%/ year with clopidogrel, HR: 0.94, 95% CI: 0.44 – 1.99; p= 0.87) and TIMI criteria (2.1%/ year with prasugrel vs 1.5%/ year with clopidogrel, HR: 1.31, 95% CI: 0.81 – 2.11; p= 0.27). Similar findings were noted for the whole population. New non-benign neoplasms in the whole population were similar between both treatment arms (1.9% vs 1.8%; p= 0.79).

On subgroup analysis for the primary efficacy endpoint, for patients <75 years, current or recent smokers, and patients taking proton pump inhibitors did better with prasugrel with an interaction P value of <0.001 and 0.02, respectively. Subgroup analysis for the bleeding endpoint for patients <75 years showed that patients who took an aspirin dose of <100mg/ day did better with clopidogrel, p for interaction= 0.018. These subgroup analyses should be viewed as hypothesis generating.

Conclusion: In patients presenting with unstable angina or non-ST elevation myocardial infarction who are managed medically without revascularization, prasugrel did not improve outcomes compared to clopidogrel.

The disparate findings observed in TRITON-TIMI 38 and TRILOGY ACS underscore the critical need to refrain from extrapolating trial outcomes from one population to another.

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N Engl J Med 2011;364:1607-1616

Background: The three pivotal trials of coronary artery bypass graft surgery (CABG) we previously reviewed, largely included patients with normal left ventricular function. Observational studies suggested that CABG improved survival over medical therapy in patients with coronary artery disease and systolic heart failure.

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The Surgical Treatment for Ischemic Heart Failure (STICH) trial sought to test the hypothesis that CABG reduces mortality in patients with coronary artery disease and left ventricular systolic dysfunction.

Of note, the STICH had two hypotheses: medical therapy vs CABG (hypothesis 1) or CABG vs CABG plus surgical ventricular reconstruction (hypothesis 2) “patients in all arms received medical therapy according to the guidelines at that time”. In this review we focus on hypothesis 1. We are also reporting the 5-year results of STICH since that was the primary intended follow up time.

Patients: Eligible patients had coronary artery disease that was amenable to surgery and left ventricular ejection fraction of 35% or less. Patients were excluded if they had recent myocardial infarction, cardiogenic shock within 72 hours of randomization, life expectancy <3 years due to non-cardiac illness, poor treatment adherence, or 50% or more left main disease.

Baseline characteristics: The study enrolled 1212 patients – 602 assigned to medical therapy alone and 610 assigned to medical therapy plus CABG. The average age of patients was 60 years with 88% being men. The median body mass index was 27 kg/m2. Approximately 77% had prior myocardial infarction, 60% had hyperlipidemia, 60% had hypertension, 39% had diabetes, 8% had chronic kidney disease, 8% had prior stroke and 21% were active smokers. Approximately 3% had previous CABG.

NYHA class was II in 52% of the patients and III in 34%. Approximately 30% of the patients had two vessel disease and 60% had three vessel disease. Left main stenosis (50% or more) was present in 3% of the patients and left anterior descending artery stenosis (75% or more) was present in 68%.

Medications at baseline were as follows: beta-blockers in 85%, ACEi or ARB in 90%, potassium-sparing diuretic in 46%, aspirin in 83% and statins in 81%.

Procedures: Patients were randomly assigned to receive medical therapy alone or medical therapy plus CABG. Guideline-based medical treatment and devices were recommended by a lead cardiologist at each center. The surgeries were performed by surgeons who provided data on at least 25 patients with an ejection fraction of 40% or less, in whom they performed CABG, and had an operative mortality of 5% or less.

CABG was to be performed within 14 days after randomization. Patients were followed up at the time of discharge or at 30 days, every 4 months for the first year then every 6 months thereafter.

Endpoints: The primary end point was all-cause death. Secondary endpoints included death from cardiovascular causes and death from any cause or hospitalization for cardiovascular causes.

Statistical analysis was performed based on the intention-to-treat principle. The original sample size was 2,000 patients to be followed for 3 years. Assuming a 3-year mortality of 25% in the medical arm, this would give the study 90% power to detect 25% mortality reduction with CABG. Due to slow enrollment, the sample size was reduced to 1,200 patients and the follow up time was increased to 5 years.

Results: The median follow up time was 56 months. Among the patients assigned to surgery, 555 (91%) underwent CABG, of whom 91% received at least one arterial conduit. Among the patients assigned to the medical arm, 100 (17%) underwent CABG.

CABG did not reduce mortality compared to medical therapy alone (36% with CABG vs 41% with medical therapy, HR, 0.86, 95% CI: 0.72 - 1.04; p=0.12). CABG reduced cardiovascular death (28% vs 33%, HR: 0.81, 95% CI 0.66 - 1.00; p=0.05) and the composite secondary endpoint of death from any cause or hospitalization for cardiovascular causes (58% vs 68%, HR: 0.74, 95% CI: 0.64 - 0.85; p<0.001).

There were no significant subgroup interactions based on baseline characteristics. The hazard ratio with CABG for selected high risk subgroups is as follows: 0.93 for age 65 or above, 0.80 for younger than 65, 0.92 for patients with diabetes, 0.83 for patients without diabetes, 0.79 for 3-vessel disease and 0.82 for left main or left anterior descending artery disease. The hazard ratio for patients without left main or left anterior descending artery disease was 0.97. Hazard ratio was 0.75 for women and 0.87 for men. P for interaction was > 0.20 for the above groups.

Conclusion: In patients with coronary artery disease and left ventricular ejection fraction of 35% or less, CABG did not improve survival compared to medical therapy alone, over 5 years follow up.

This was an important trial since medical therapy and surgical techniques improved significantly since the publication of the three pivotal trials that were published in the 1970s and 1980s. It’s important to appreciate that this trial included a high-risk group; over one third were dead at 5 years. In comparison, the mortality rate in the Coronary Artery Bypass Graft Surgery Trialists Collaboration was 30.5% in the medical arm at 10-years follow up.

An important limitation of the trial is the lack of details regarding the number of patients screened to enrolled, along with the reasons for slow enrollment or characteristics of excluded patients. This makes it difficult for physicians to determine the proportion of their patients who would have been eligible for the trial.

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N Engl J Med 2009;361:1045-57.

Background Similar to Prasugrel, Ticagrelor is a direct-acting oral antagonist of the adenosine diphosphate receptor P2Y12. Unlike clopidogrel that requires transformation of the prodrug to the active metabolite, Ticagrelor provides faster and more consistent P2Y12 inhibition.

In the TRITON-TIMI 38 trial, Prasugrel compared to clopidogrel reduced myocardial infarction in patients with ACS but was associated with more major bleeding and subgroup interactions were evident for patients who were older, had a history of stroke or risk factors for bleeding and who were generally at higher risk for recurrent events.

The Study of Platelet Inhibition and Patient Outcomes (PLATO) sought to test the hypothesis that Ticagrelor is superior to clopidogrel for the prevention of vascular events and death in patients presenting with ACS.

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Patients Eligible patients were hospitalized for ACS, with or without ST-segment elevation (STE), whose onset of symptoms occurred within the previous 24 hours. For patients without STE, at least 2 of the following criteria were required: 1) ST-segment changes on ECG indicating ischemia, 2) a positive biomarker indicating myocardial necrosis, or 3) one or more risk factors including age ≥60 years, previous MI or CABG, CAD with stenosis of ≥50% in at least 2 vessels, history of ischemic stroke, TIA, carotid stenosis, cerebral revascularization, diabetes, peripheral arterial disease or CKD based on creatinine clearance <60 ml/min. STEMI was traditionally defined. Key exclusion criteria included any contraindication against the use of clopidogrel, fibrinolytic therapy within 24 hours, a need for oral anticoagulation, an increased risk of bradycardia, and concomitant therapy with a strong cytochrome P-450 3A inhibitor or inducer.

Baseline characteristics The median age of patients was 62 years with 15% being ≥75 years and 72% were men; over 90% were white. The index event was UA or NSTEMI in approximately 60% and STEMI in 38%. Only 81% of patients underwent coronary angiography. PCI was performed in 64% of patients (was 99% in TRITON-TIMI 38) and CABG was performed in 10%. Interestingly, the majority of patients stented received only a bare metal stent (65%). 20% of patients had a prior MI, 25% had diabetes, 65% had hypertension and 36% were habitual smokers. Only 4% of patients had CKD defined as a creatinine clearance ≤60 ml/min or a history of ischemic stroke.

Procedures All drugs were administered in a double-blind, double-dummy fashion. Ticagrelor was given as a loading dose of 180 mg followed by 90 mg twice daily for all patients. For patients who had not been on clopidogrel for at least 5 days prior to randomization, a 300 mg loading dose of clopidogrel was given followed by a dose of 75 mg daily. Others in the clopidogrel group continued to receive a maintenance dose of 75 mg daily.

For patients undergoing PCI more than 24 hours after randomization, an additional dose of their study drug was given at the time of PCI, which was 300 mg of clopidogrel, at the investigator’s discretion, or 90 mg of ticagrelor. In patients undergoing CABG, it was recommended that the study drug be withheld for 5 days in the clopidogrel group and for 24 to 72 hours in the Ticagrelor group.

Outpatient visits occurred at 1, 3, 6, 9, and 12 months, with a safety follow-up visit 1 month after the end of treatment, which was scheduled to continue for 12 months. Notably, patients left the study at their 6- or 9- month visit if the targeted number of primary endpoint events had occurred by that time.

Endpoints The primary efficacy endpoint was the time to the first occurrence of a composite endpoint of death from vascular causes, myocardial infarction, or stroke. Investigators estimated that 1780 primary endpoint events would be required to achieve 90% power to detect a 13.5% relative risk reduction of the primary endpoint in the ticagrelor group, based on an event rate of 11% in the clopidogrel group at 12 months (≤9.5% vs 11%). The consistency of treatment effects over time was assessed from randomization to 30 days and from 31 to 360 days. The primary safety endpoint was the first occurrence of any major bleeding event. Treatment effect heterogeneity was explored in 25 prespecified subgroups and 8 post hoc subgroups without adjustment for multiplicity, which is standard.

Results A total of 18,624 patients from 862 sites in 43 countries were enrolled. There were 9,333 patients assigned to the Ticagrelor group and 9,291 assigned to clopidogrel. The median duration of therapy was 277 days (approximately 9 months). Ticagrelor significantly reduced the primary composite endpoint compared to clopidogrel (9.8% vs 11.7%; HR 0.84; 95% CI 0.77-0.92; P<0.001). This reduction was driven by significant differences in both the rates of nonfatal MI between groups (5.8% vs 6.9%; HR 0.84; 95% CI 0.75-0.95; P=0.005) and death from vascular causes (4.0% vs 5.1%; p=0.001). There was no significant difference in stroke (1.5% vs 1.3%; p=0.22). There was a statistically significant difference in all-cause death (4.5% vs 5.9%; p<0.001) but this should be interpreted cautiously as the trial was underpowered for detection of a smaller, more feasible difference in this endpoint (i.e. based on the event rate in control group, approximately 48,000 patients would be needed to detect a 10% difference in all-cause death with 80% power).

In the prespecified landmark analysis, benefit from ticagrelor was observed from randomization through day 30 (4.8% vs 5.4%; P=0.045) and from 31 days onward (5.3% vs 6.6%; p<0.001).

Also of note, there was a statistically significant reduction in stent thrombosis. For the primary safety endpoint, Ticagrelor did not significantly increase major bleeding (11.6% vs 11.2%; HR 1.04, 95% CI 0.95-1.13; p=0.43); however, it did significantly increase Non-CABG related major bleeding (4.5% vs 3.8%; p=0.03).

Of particular importance for contemporary clinical practice, Ticagrelor significantly increased shortness of breath (13.8% vs 7.8%; p<0.001). This side effect is commonly encountered in the clinical setting and requires careful consideration.

Less striking treatment response variation was observed for ticagrelor in this trial than for prasugrel in TRITON-TIMI 38. Most importantly, there was no observed difference in the treatment effect for patients based on “planned treatment approach” and thus, for patients reflective of those enrolled in the trial, ticagrelor is more effective than clopidogrel whether patients undergo PCI or not.

For the subgroups presented in the Figure 2 of the supplement, a significant interaction was noted based on region of enrollment with patients in North America seemingly doing worse with ticagrelor. It should be noted that such patients accounted for only 10% of total enrollment; however, the interaction p value was strong 0.05. It is hard to explain this interaction beyond the play of chance.

The strongest interaction signal involved patients categorized according to whether they were above or below the sex-specific median weight (82 kg for men and 71 kg for women). Lower weight patients were at higher risk of events but the treatment effect was significantly reduced compared to their higher weight counterparts with an interaction p value for this subgroup of 0.04. This interaction signal is consistent with what was observed in TRITON-TIMI 38.

Finally, patients 75 or above accounted for 15% of the overall cohort and predictably experienced a significantly higher rate of the primary endpoint but the difference in the effect was much less than half of what it was compared to lower risk patients under 75 years. In this case the interaction p value was only 0.22 due to low power. This signal was also consistent with TRITON-TIMI 38.

Conclusions In patients with ACS regardless of management strategy (early invasive vs conservative) and whether revascularization is performed or not, ticagrelor reduced the rate of cardiovascular events; including nonfatal MI and death due to vascular causes. For patients similar to those enrolled in PLATO, approximately 50 patients would need to be treated with ticagrelor instead of clopidogrel to prevent 1 person from having a nonfatal MI or dying from a vascular cause; approximately 140 patients would need to be treated to cause 1 person to have a non-CABG-related major bleeding event.

The benefit from Ticagrelor is realized early in treatment (0-30 days) and beyond (>31 days onward) as demonstrated by the landmark analysis in this study. Patients above 75 benefit less with Ticagrelor as do patients who are low weight based on sex-specific norms. Dyspnea is a frequently occurring side effect of Ticagrelor.

Addendum (December 23, 2024): Our initial review of the PLATO trial, published in April 2024, was based on the data available to us at that time.

We have since became aware of new information that reduces our confidence in the PLATO results. This new information has major implications for clinical practice.

Despite representing only 6.9% of the total P2Y12 inhibitor prescriptions among Medicare beneficiaries in 2020, Ticagrelor accounted for nearly two-thirds of total Medicare spending on these drugs in the same year.

We summarize important points below but you can refer to this investigation at BMJ for more details.

1. Unexplained Regional Variation: In our original review, we highlighted the treatment effect interaction based on region of enrollment, where ticagrelor was less effective compared to clopidogrel for patients enrolled in North America.

It appeared to be a strong signal and was associated with a p-value for the interaction of 0.05. However, we were cautious in our interpretation since overall, patients enrolled in North America represented a relatively small fraction of total patients and we could not think of a reasonable explanation.

Information in the BMJ investigation now sheds new light on these findings. In our review, we only presented data contained in the supplement accompanying the PLATO trial manuscript, which categorized patients based on region of enrollment but did not provide country specific information.

The BMJ report notes that in a separate subgroup analysis, based on country of randomization, the primary outcome was numerically higher with ticagrelor in the United States (12.6% vs 10.1%, HR: 1.27, 95% CI: 0.92 – 1.75). This subgroup represented 7.6% of the total trial participants. Overall, 9.7% of trial participants were enrolled from North America. This means the US data drove the findings from the North American subgroup.

The explanation provided by AstraZeneca (the manufacturer of ticagrelor) to explain the observed treatment effect heterogeneity was that aspirin dosing in the United States was higher than in other countries. It even led the FDA to issue a black box warning to avoid an aspirin maintenance dose of >100 mg in patients taking ticagrelor.

An extensive statistical analysis of the regional variation in PLATO yielded four interesting points. First what was the prior likelihood of observing a ticagrelor vs clopidogrel HR of > 1.25 in the US, when the overall HR was actually equal to 0.84? That probability is ≤ 0.01. This alone suggests more than chance. Second point: a strong US/nonUS interaction was noted for each of the 3 components of the primary endpoint—CV death, MI, stroke. Third: they found a very strong interaction between treatment and median aspirin dose, and, importantly, the aspirin interaction effect was similar in US and nonUS settings. Fourth, an analysis of contract research organization (CRO) vs sponsor monitoring of the site accounted for 61% of the treatment-by- region interaction. The authors downplayed this finding because of the four countries monitored by a CRO (Israel, US, Georgia and Russia), the US made up the majority and thus is confounded by the aspirin interaction. Noteworthy was a lack of direct analysis of CRO vs sponsor test for interaction.

One problem though: the BMJ investigation found that the lead author, Kevin Carroll was the head statistician at AstraZeneca and had worked at the company for 20 years. Carroll presented the PLATO results at the FDA advisory meeting. The paper lists Carroll as having no conflicts. Carroll told the BMJ that he had disposed of all conflicts of interest before submitting that analysis.

But, in our opinion, the aspirin explanation does not pass muster because of biologic implausibility. See next section:

How would a higher dose of aspirin reduce the efficacy of ticagrelor?

The primary composite endpoint was vascular death, MI or stroke. If the higher aspirin dose impacted this, we would hypothesize that it caused more major bleeding in the ticagrelor group with some events resulting in vascular death, type 2 MI and hemorrhagic stroke, driving the treatment effect in favor of clopidogrel. But there is no evidence of this.

The figure below is from the original subgroup plots provided in the PLATO supplement. The difference in the treatment effect for the primary endpoint for North American patients is striking but there is no difference for major bleeding.

In our opinion and the opinion of others, the role of supervision of the centers could be important. Most centers were monitored by the sponsor. Four countries (Israel, US, Georgia and Russia) were monitored by a contract research organization. All four of these countries had numerically higher rates of the primary outcome in the ticagrelor group.

This has major implications and we do not take them lightly. Essentially, it suggests malfeasance on the part of the sponsor. So is there anything else to support such a claim? Well, yes.

2. Concerns about event adjudication. Based on a report from Victor Serebruany, an adjunct faculty member at Johns Hopkins University, and the BMJ investigation, FDA records indicated that site reports documented 504 myocardial infarctions in patients who received ticagrelor compared to 548 in patients who received clopidogrel. However, after adjudication, the count increased only for the clopidogrel group, reaching 593. There was also some imbalance among groups in adjudicating death. These imbalances raise concerns about potential unblinding and result tampering. We read many of the authors’ replies and we did not find a clear explanation of why all readjudicated extra MIs were in the clopidogrel group (45 clopidogrel; ticagrelor 0).

3. There were also concerns about the accuracy of death records as sites death records did not always match the FDA records.

We cite from the BMJ:

The BMJ’s analysis also found omissions in PLATO’s landmark publication. The paper, published in NEJM and reported as an intent-to-treat analysis, reports 905 total deaths from any cause among all randomized patients. An internal company report states, however, that 983 patients had died at this point. While 33 deaths occurred after the follow-up period, the NEJM tally still leaves out 45 deaths “discovered after withdrawal of consent.” The BMJ obtained some records for patients whose deaths were not reported in NEJM (see table 1) and asked the journal for a response.

NEJM editor in chief Eric Rubin told The BMJ that “for older manuscripts, correction is not necessarily appropriate unless there would be an effect on clinical practice,” concluding that “it does not appear that correcting this 15-year-old article is going to have any impact.”

It is noteworthy that the United States Department of Justice launched a formal investigation into the PLATO trial in 2013; however, the probe was closed in 2014. The BMJ column cited a spokesperson for the US attorney’s office who said…”we determined that the allegations lacked sufficient merit such that it was not in the best interests of the US to intervene in the suit.”

4. Mortality reduction in PLATO defies explanation: Shortly after PLATO was published, Drs. Victor Serebruany and Dan Atar wrote an editorial in the European Heart Journal titled: The PLATO trial: do you believe in magic?

They noted that the overall HR for all-cause death ticagrelor vs clopidogrel was 0.78 (95% CI: 0.69 - 0.89; p< 0.001). There were 107 more lives saved with ticagrelor vs clopidogrel. To explain the surprise of this massive effect size, they compared it to the COMMIT trial of clopidogrel vs placebo in patients with acute MI. In COMMIT, 119 lives were saved with clopidogrel (vs placebo), but COMMIT had three-fold more patients than PLATO—and the gain was vs placebo. They tempt the reader to ask: how could ticagrelor fare that well against a drug that crushed placebo?

We note two other reasons to be concerned about the outsized mortality reduction in PLATO. One is plausibility. The all-cause mortality benefit exceeded the reduction in MI, CV death or stroke. Given the numerically higher rate of bleeding, how else does ticagrelor reduce death vs clopidogrel? The second reason is the lack of such a signal in Phase 2 studies, such as this one.

5. PLATO results are on outlier: Multiple observational studies have failed to replicate the benefits of ticagrelor observed in the PLATO trial. While observational studies are inherently limited by confounding factors and are inferior to randomized trials, their findings warrant a re-evaluation of ticagrelor’s benefits. Furthermore, two randomized trials—one conducted predominantly in Japanese patients and another in South Korea—did not demonstrate the superiority of ticagrelor, instead showing higher bleeding rates and a numerical increase in ischemic events.

Ticagrelor also significantly underperformed against another new antiplatelet drug, prasugrel. In the non-industry-funded ISAR-REACT 5 trial, which enrolled patients with acute coronary syndrome, the primary event of death, MI, or stroke was 36% higher in the ticagrelor arm (9.3% vs 6.9%, HR 1.36, 95% CI: 1.09 - 1.70). Major bleeding was also numerically higher in the ticagrelor arm.

6. PLATO authors have responded to these arguments.

We provide links to four of the authors responses.

* Thrombosis and Hemostasis https://www.wellesu.com/10.1160/TH11-03-0162

* Stroke https://www.ahajournals.org/doi/10.1161/strokeaha.111.000514

* Inter J of Cardiol https://doi.org/10.1016/j.ijcard.2014.06.029

* Circulation https://doi.org/10.1161/CIRCULATIONAHA.111.047498

Conclusion

These are vitally important revelations regarding PLATO and ticagrelor. The FDA advisory committee recommended that FDA require a confirmatory trial. This was not done. As such, ticagrelor gained serious market share in the non-clopidogrel antiplatelet market for more than a decade. Yet no other compelling evidence for its benefit over clopidogrel has come to light. It clearly underperformed vs prasugrel.

These old and new revelations have changed our positive view of ticagrelor. We no longer have confidence in this drug.

We strongly agree with the recommendation for another properly controlled trial. We also believe this highlights the benefits of having either two regulatory trials or a single regulatory trial combined with a mandated post-approval trial. These revelations also emphasize the benefits of robust critical appraisal and skeptical but not cynical approaches to surprising evidence.

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Note to readers: Since going live with Cardiology Trials Substack in January of 2024 we have been exclusively covering trials that we have categorized as belonging to the major subject heading “Acute Coronary Syndrome” belonging to the subsection “Medicines”.

Our indexing scheme was described in one of our original posts and we encourage our audience to read it if you have not already. This is pertinent because the next several trials being presented may seem to come out of the blue but we assure you there is a method.

N Engl J Med 2007;357:2001-15.

Background Up to now we have presented trials involving major foundational medical therapies for acute coronary syndrome which include aspirin, thrombolytic agents and anticoagulation, but not those involving percutaneous coronary intervention (PCI) as they are reserved for another section.

But, by the turn of the 21st century, PCI had become the dominant up-front strategy for revascularization in many countries around the world. Clinical trials demonstrated it improved outcomes, the main one being re-infarction, compared to thrombolysis in patients with STEMIs, and there was an evolving evidence for it in non-ST-segment elevation acute coronary syndrome (STEACS) as well, where thrombolysis had not demonstrated any significant benefits.

As PCI became dominant, antithrombotic strategies for optimizing outcomes following PCI evolved along with it. These early trials generally involved a mixture of patient phenotypes (acute vs elective PCI) and were relatively small and of limited quality by comparison to many of the seminal trials presented thus far. Instead of presenting each of these smaller studies, we direct readers to a narrative review that nicely describes the evolution of dual-antiplatelet therapy for PCI and other indications.

Briefly: dual-antiplatelet therapy with aspirin and ticlopidine, an antiplatelet agent belonging to the drug class of thienopyridines, which inhibits platelet aggregation induced by ADP, was found superior to aspirin alone or aspirin plus anticoagulation when PCI was performed; however, there were concerns about its safety.

Clopidogrel was developed after ticlopidine; it had a similar mechanism of action but less safety concerns and could be given as a loading dose to produce more rapid effects. Despite limited evidence from clinical trials comparing it head-to-head with ticlopidine it became the dominant thienopyridine agent on the market and still has a prominent role in the management of cardiovascular diseases today.

Following PCI and dual-antiplatelet therapy with aspirin and clopidogrel, patients continue to have an elevated risk of coronary events, in general, and in-stent related coronary events, in particular. Some of this risk has been attributed to limitations of clopidogrel itself. Clopidogrel has modest antiplatelet effects (compared to other thienopyridines) with substantial interpatient variability due to genetic polymorphisms that impact clopidogrel metabolism and antiplatelet efficacy. Clopidogrel also has a delayed onset of action, which is especially relevant regarding its ability to protect against the dreaded adverse event of early in-stent thrombosis.

Prasugrel is a thienopyridine—developed after clopidogrel—that inhibits platelet aggregation more rapidly, consistently and to a greater extent. The Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38 trial sought to test the hypothesis that prasugrel would reduce major cardiovascular events compared to clopidogrel in patients with acute coronary syndrome undergoing PCI.

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Patients Eligible patients had either moderate-to-high risk unstable angina (UA) or NSTEMI or STEMI. UA and NSTEMI were defined by ischemic symptoms lasting 10 minutes or more and occurring within 72 hours before randomization, a TIMI risk score of 3 or more, and either ST-segment deviation of 1 mm or more or elevated levels of a cardiac biomarker of necrosis. STEMI was traditionally defined. Key exclusion criteria included an increased risk of bleeding, anemia, thrombocytopenia, a history of pathologic intracranial findings, or the use of any thienopyridine within 5 days before enrollment.

Baseline characteristics The median age of patients was 61 years with 13% being ≥75 years and 74% were men; over 90% were white. The index event was UA or NSTEMI in 74% and STEMI in 26%.  PCI was performed in 99% of patients and split evenly between those receiving bare metal or drug eluting stent(s).  18% of patients had a prior MI, 23% had diabetes, 64% had hypertension and 38% were tobacco users. Only 11% of patients had CKD defined as a creatinine clearance ≤60 ml/min.

Procedures A loading dose of prasugrel 60 mg or clopidogrel 300 mg was given in a double blind manner anytime between randomization up to 1 hour after leaving the catheterization laboratory. In order to be randomized, the plan for PCI had to be known. This could occur before going to the cath lab for planned PCI, if the anatomy was already known or occur in the cath lab during the case where anatomy was determined and PCI was performed. If PCI was planned, patients were eligible to undergo pretreatment with the study drug for up to 24 hours prior to PCI.

Treating physicians determined the vessels treated, devices used, and adjunctive medication administered to support PCI. After PCI, patients received maintenance doses of either prasugrel 10 mg daily or clopidogrel 75 mg daily. Use of aspirin at a dose of 75 to 162 mg daily was recommended. Study visits were conducted at hospital discharge, 30 days, 90 days, and 3-month intervals thereafter, for a total of 6 to 15 months.

Endpoints The primary efficacy endpoint was a composite of cardiovascular death, nonfatal MI or stroke during the follow up period. A prespecified “landmark” analysis was undertaken to compare the primary endpoint event rate up to 3 days following randomization and from day 3 to the end of the study. The sample size calculation was event-driven and it was determined that 875 primary endpoint events would provide 90% power to detect a relative risk reduction of 20%. A prespecified analysis performed after 650 events revealed a lower than anticipated event rate and the investigators increased the sample size accordingly.

Results A total of 13,608 patients (10,074 with UA or NSTEMI and 3534 with STEMI), from 707 sites in 30 countries were enrolled. There were 6,813 patients assigned to the prasugrel group and 6,795 assigned to clopidogrel. The median duration of therapy was 14.5 months. Prasugrel significantly reduced the primary composite endpoint compared to clopidogrel (9.9% vs 12.1%; HR 0.81; 95% CI 0.73-0.90; P<0.001). This reduction was driven by significant differences in the rates of nonfatal MI between groups (7.3 vs 9.5%; HR 0.76; 95% CI 0.67–0.85; P<0.001) but not cardiovascular death (2.1% vs 2.4%; P=NS) or stroke (1.0% vs 1.0%; P=NS). There was also no difference in all-cause death (3.0% vs 3.2%; P=NS).

In the prespecified landmark analysis, benefit from prasugrel was observed before day 3 (4.7% vs 5.6%; P=0.01) and from 3 days onward (5.6% vs 6.9%; P=0.003).

Treatment response variation in the trial was observed based on age, susceptibility to bleeding and history of stroke or TIA. Some of this data is summarized in the primary Forest plot of major subgroups and also in a table that details patient risk based on combinations of traits.

Subgroups Patients with a history of stroke or TIA accounted for a small minority of patients; however, prasugrel numerically increased the PEP in these patients compared to clopidogrel (19.1% vs 14.4%; P=NS) but was underpowered to achieve statistical significance. There was a statistically significant interaction in this subgroup compared to prasugrel use in all other patients without a stroke or TIA (9.5% vs 12.3%; P for interaction = 0.02).

Patients <65 composed the majority of patients (n=8,322) and the difference in the PEP between prasugrel and clopidogrel was 8.1% vs 10.6% - a relative difference of 24%. Patients 65-74 years of age accounted for 3,477 patients and the relative difference in the PEP was 14% (10.7% vs 12.3%). There were 1,809 patients ≥75 years of age whose risk of a PEP event was nearly twice as high as those <65 but the relative risk reduction was only 6% (17.2% vs 18.3%) with the 95% CI crossing 1.0. Treatment response variation is also suggested for women compared to men. Importantly, there was no signal of treatment response heterogeneity based on ACS index event (UA or NSTEMI vs STEMI).

Patients with any of the following traits (age ≥75, body weight <60 kg or history of stroke or TIA) accounted for 20% of patients in the trial and had an elevated risk of the PEP compared to patients without this combination; however, they did not benefit from prasugrel (patients with combination of traits; 16.1% vs 16.0%; patients without any traits; 8.3% vs 11.0%) and there was a strong interaction between these subgroups (P for interaction = 0.008).

Safety: In regard to safety, prasugrel significantly increased the composite endpoint of non-CABG-related TIMI major bleeding (2.4% vs 1.8%; HR 1.32; 95% CI 1.03–1.68; P=0.03). Individual components of this key safety endpoint that were significantly different between groups included spontaneous bleeding, life-threatening bleeding and fatal bleeding. There were also highly statistically significant differences in the individual endpoints of bleeding requiring transfusion and CABG-related TIMI major bleeding.

Conclusions In patients with ACS undergoing PCI, prasugrel (vs clopidogrel) reduces the rate of cardiovascular events; mainly driven by nonfatal MI. For patients similar to those enrolled in TRITON-TIMI 38, approximately 50 patients would need to be treated with prasugrel instead of clopidogrel to prevent 1 person from having a nonfatal MI; approximately 170 patients would need to be treated to cause 1 person to have a non-CABG-related major bleeding event.

There is a significant benefit of prasugrel that is realized very early in treatment as demonstrated by the landmark analysis in this study. This is likely due to the faster onset of action of prasugrel compared to clopidogrel conferring a reduction in very early in-stent events. It should be noted that continued differences in treatment are observed over the entire course of the study.

Caution is advised in treating patients with a history of stroke or TIA, who are over 75 years of age and below a body weight 60 kg as such patients derived less benefit and would be expected to garner more treatment related harm. Caution is also advised in treating any patients with increased bleeding risks. These patients were generally excluded from the trial but the specifics regarding how this exclusion criteria was applied in the main manuscript of the trial are lacking.

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N Engl J Med 2008; 358:2218-2230

Background The use of percutaneous coronary intervention (PCI) is associated with improved outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Nonetheless, there was a need to further improve survival rates. As seen in OASIS-6, the 30-day mortality in the control arm was still high at 8.9%. Glycoprotein IIb/IIIa inhibitors emerged as a potential solution. US clinicians widely adopted these agents; their use soared to over 90% of STEMI cases undergoing primary PCI. But IIb/IIIa inhibitors increase the risk of bleeding and thrombocytopenia.

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Bivalirudin, a direct thrombin inhibitor, has been shown to reduce bleeding when used instead of heparin plus glycoprotein IIb/IIIa inhibitors in patients with ACS without ST segment elevation. The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial sought to test the hypothesis that bivalirudin is superior to the combination of heparin plus glycoprotein IIb/IIIa inhibitors in patients with STEMI who were undergoing primary PCI.

Patients Patients were enrolled if they were within 12 hours from the onset of symptoms and had ST-segment elevation of 1 mm or more in two or more contiguous leads, new left bundle-branch block or had posterior myocardial infarction. There were numerous exclusion criteria including bleeding diathesis, coagulopathy, intracerebral mass, prior hemorrhagic stroke, platelet count< 100,000 cells/ ml, hemoglobin< 10 g/dl plus many more.

Baseline characteristics The trial enrolled 3,602 patients. The average age of patients was 60 years and 77% were men. About 53% had hypertension, 43% had hyperlipidemia, 16% had diabetes, 11% had prior myocardial infarction and 46% were current smokers. The majority of patients were stable, with 91.5% classified as Killip class I. Primary PCI was performed in about 93% of the patients and coronary artery bypass graft surgery in 1.7%.

Heparin before coronary angiography was administrated in 76.3% in the heparin plus glycoprotein IIb/IIIa inhibitor arm and 65.8% in the bivalirudin arm. During coronary angiography heparin was administered in 98.9% patients in the heparin plus a glycoprotein IIb/IIIa inhibitor arm and 2.6% in the bivalirudin arm. Glycoprotein IIb/IIIa inhibitors were given to 94.5% patient in the heparin plus glycoprotein IIb/IIIa inhibitors arm and 7.2% in the bivalirudin arm.

Procedures The trial was open-label and patients were randomly assigned 1:1 to receive unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor or bivalirudin alone. Heparin was administered to keep activated clotting time of 200 to 250 seconds. An initial intravenous bolus of 60 IU/ kg was given followed by boluses as needed. Bivalirudin was administered intravenously with an initial bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hour. A glycoprotein IIb/IIIa inhibitor was administered before PCI in all the patients in the heparin group. It was also administered in selected patients in the bivalirudin group if there was no reflow or there was a large thrombus after PCI. The main glycoprotein IIb/IIIa inhibitors used were abciximab or eptifibatide.

Endpoints The study had two primary endpoints at 30-days. The first endpoint was major bleeding not related to coronary artery bypass graft surgery. The second endpoint was a composite endpoint of major bleeding, all-cause death, reinfarction, target-vessel revascularization for ischemia or stroke.

Analysis was performed based on the intention-to-treat principle. Assuming a 30-day event rate of 9% for the first endpoint and 12% for the second endpoint in the heparin plus glycoprotein IIb/IIIa inhibitor group and 6% for the first endpoint and 9% for the second endpoint in the bivalirudin group, a sample size of 1,700 patients in each group would have 99% power to show superiority of bivalirudin for the first endpoint and 80% power for the second endpoint.

Results The study randomized 1,802 patients to the heparin plus glycoprotein IIb/IIIa inhibitor group and 1,800 patients to the bivalirudin group.

The first primary endpoint was significantly lower with bivalirudin (4.9% vs 8.3%, RR: 0.60, 95% CI: 0.46 - 0.77; p<0.001). The secondary endpoint was also lower with bivalirudin (9.2% vs 12.1%; RR: 0.76; 95% CI: 0.63 - 0.92; p= 0.005) which was driven by lower rate of major bleeding. The endpoint of all-cause death, reinfarction, target-vessel revascularization for ischemia or stroke was similar between both treatment groups (5.5% with heparin plus glycoprotein IIb/IIIa inhibitors vs 5.4% with bivalirudin; p= 0.95). All-cause death was lower with bivalirudin (2.1% vs 3.1%; p= 0.047). Stent thrombosis within 24 hours was higher with bivalirudin (1.3% vs 0.3%; p< 0.001) but similar between both treatment arms at 30-days (2.5% with bivalirudin vs 1.9% with heparin plus glycoprotein IIb/IIIa inhibitors; p= 0.30).

Conclusion In patients presenting with STEMI undergoing PCI, bivalirudin reduces major bleeding compared to combination heparin plus glycoprotein IIb/IIIa inhibitor.

Blinding of outcomes assessment mitigates some of the bias inherent in an open-label trial. About two thirds of patients in the study, including in the bivalirudin arm, received heparin before coronary angiography which may have affected ischemic events.

The current study does not support the use of bivalirudin over heparin in patients with STEMI as patients in the heparin arm also received glycoprotein IIb/IIIa inhibitor, a practice that is not common anymore. Nonetheless, bivalirudin is safer compared to the combination of heparin plus glycoprotein IIb/IIIa inhibitor in STEMI patients undergoing PCI, without increasing ischemic events.

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JAMA. 2006;295(13):1519-1530

Background Previous trials demonstrated that aspirin and thrombolytic therapy improve prognosis in patients with ST elevation myocardial infarction (STEMI). The addition of heparin to aspirin and thrombolysis did not improve outcomes in patients with STEMI (see GISSI-2 trial). Fondaparinux, a synthetic pentasaccharide that inhibits factor Xa, was tested in OAISIS-5, and was found to be noninferior to enoxaparin in patients with acute coronary syndrome (without STEMI) and was associated with less bleeding.

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The Sixth Organization for the Assessment of Strategies for Ischemic Syndromes (OASIS-6) trial sought to test the hypothesis that fondaparinux is superior to the standard of care in patients with STEMI.

Patients Patients were enrolled if they had STEMI and were within 24 hours from onset of symptoms. The time window was later shortened to 12 hours. Patients at high risk for bleeding (this was not clearly defined), receiving oral anticoagulants or who had serum creatinine levels greater than 3.0 mg/dL were excluded.

Baseline characteristics The trial enrolled 12,092 patients. The average age of patients was 62 years and 72% were men. The mean heart rate and systolic blood pressure on admission were 76 bpm and 134 mm Hg, respectively. About half had hypertension, 18% had diabetes, 14% had heart failure, 13% had prior myocardial infarction, 7% had prior stroke, and 4% had prior coronary artery bypass graft or percutaneous coronary intervention (PCI). About 58% were active or former smokers.

In-hospital medications, after randomization, included aspirin in 97% of the patients, beta-blockers in 84%, ACEi or ARB in 80%, clopidogrel or ticlopidine in 58% and glycoprotein IIb/IIIa receptor antagonist in 16%.

During the index hospitalization, coronary angiography was performed in about 44% of the patients but primary percutaneous coronary intervention was performed in 31%. Thrombolytic therapy was given in 45% of the patients.

Procedures OASIS-6 was a randomized double-blind trial. Patients were divided into two groups based on the investigator’s judgment - Group 1: No indication for heparin and group 2: Indication for heparin, thrombolysis or PCI. Patients in group 1 received fondaparinux 2.5 mg subcutaneously once daily or matching placebo. Patients in group 2 received fondaparinux 2.5 mg subcutaneously once daily + heparin placebo or heparin + fondaparinux placebo. For patients who received heparin, an initial bolus of 60 IU/kg was given followed by an infusion of 12 IU/kg per hour for 24-48 hours. A placebo bolus and continuous infusion were used in the fondaparinux group, in group 2. Fondaparinux was given for 8 days or until hospital discharge, or whichever came first. To maintain blinding, all patients in group 2 had aPTT checked and a central system produced either a real or sham value.

Endpoints The primary efficacy endpoint was all-cause death or reinfarction at 30 days. Secondary endpoint was the primary endpoint at 9 days, and at 3 and 6 months (only half the patients were followed for 6 months). Safety endpoints included major and minor bleeding.

Based on an event rate of 8% at 9 days, the estimated sample size to have 90% power to detect 20% relative risk reduction with fondaparinux was 10,000. However, after 8,000 patients were enrolled, the event rate was lower than expected so the sample size was increased to 12,000 and the primary endpoint was changed to 30 days.

Results The study assigned 6,036 patients to the fondaparinux group and 6,056 to control group. The fondaparinux group included 2,823 patients from group 1 and 3,213 patients in group 2. The control group included 2,835 patients in group 1 and 3,221 patients in group 2.

Death or reinfarction was lower with fondaparinux at 9 days (7.4% vs. 8.9%, HR: 0.83, 95% CI: 0.73 – 0.94; p= 0.003), at 30-days (9.7% vs. 11.2%, HR: 0.86, 95% CI: 0.77 – 0.96; p= 0.008) and at 3-6 months (13.4% vs. 14.8%, HR: 0.88, 95% CI: 0.79 – 0.97; p= 0.008). Death was significantly lower with fondaparinux at 9 days (6.1% vs 7.0%; p= 0.04), 30-days (7.8% vs 8.9%; p= 0.03) and 3-6 months (10.5% vs 11.6%; p= 0.03).

Severe hemorrhage was not significantly different between both treatment arms (1.0% in the fondaparinux group and 1.3% in the control group, HR: 0.77, 95%: 0.55 –1.08; p= 0.13).

The beneficial effect of fondaparinux on the primary outcome was larger for group 1 at 9 days and 30 days. The absolute risk reduction in the primary endpoint with fondaparinux in group 1 vs group 2 was 2.6% vs 0.5% at 9 days and 2.8% vs. 0.4% at 30-days. Another important subgroup is patients who underwent PCI where fondaparinux had no benefit.

During the initial hospitalization, 1898 patients allocated to receive UFH or placebo and 1890 patients allocated to receive fondaparinux underwent any primary PCI in the hospital. Death and MI did not differ significantly at 30 days. In patients who had coronary angiography, fondaparinux was associated with guiding catheter-related thrombosis, (0 vs 22; P < .001) as well as more coronary complications (225 vs 270; P = .04).

Conclusion In patients presenting with STEMI, fondaparinux reduces death or re-infarction at 9 and 30 days. The benefit was primarily derived from group 1 who did not receive heparin. Furthermore, patients who underwent PCI had no benefit with fondaparinux. The blinding in the trial with the use of sham aPTT values enhanced the internal validity of the trial.

In our opinion, this trial does not support the routine use of fondaparinux over heparin in patients presenting with STEMI for two main reasons:

* First, the trial does not delineate why in group 1 heparin was not indicated (as noted, this was based on the investigator’s judgement). Since most of the benefit seen with fondaparinux stemmed from this group, it is plausible the results would have been null if this group received heparin instead of placebo. The limited information available regarding group 1 also hinders our ability to apply these findings to our patient population.

* Second, less than half of the patients in the trial underwent coronary angiography, whereas the procedure is now performed in the majority of STEMI patients. Among the patients who underwent coronary angiography in the trial, fondaparinux had no benefit and was associated with more catheter-related thrombosis and coronary complications.

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N Engl J Med 2006; 354:1464-1476

Background: Prior studies showed that combined antiplatelets and anticoagulants reduce ischemic events in patients with acute coronary syndrome but increases the risk of bleeding. We saw this in the FRISC trial where low-molecular-weight heparin plus aspirin reduced the primary endpoint of death or nonfatal myocardial infarction compared to placebo at 6 days but also increased minor bleeding events (8.2% vs 0.3%).

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Fondaparinux is a synthetic pentasaccharide that inhibits factor Xa and has a long half-life (17 – 21 hours). In contrast, low-molecular-weight heparin is biologic and has a half-life of 3 - 6 hours.

Pilot studies showed that fondaparinux may be as effective as enoxaparin in patients with acute coronary syndrome. The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-5) trial sought to test the hypothesis that in patients with unstable angina or NSTEMI, fondaparinux would be noninferior to enoxaparin in reducing ischemic events but would be associated with less bleeding.

Patients: Patients were enrolled if they had at least two of the following criteria: at least 60 years of age, elevated cardiac biomarkers (troponin or creatine kinase MB) or ischemic EKG changes but not ST elevation. Patients were excluded if they had contraindication to low-molecular-weight heparin, recent hemorrhagic stroke or serum creatine of 3 mg/dl or more.

Baseline characteristics: The trial enrolled 20,078 patients. The average age of patients was 67 years with 62% being men. About 45% had unstable angina and the rest had NSTEMI. Prior myocardial infarction was present in 26% of the patients, stroke in 6%, heart failure in 14%, hypertension in 67% and diabetes in 25%. About half the patients were active or former smokers.

After randomization, about 98% of the patients were on aspirin, 67% were on clopidogrel or ticlopidine, 75% were on ACEi or ARB and 87% were on beta-blockers.

During first hospital stay, coronary angiography was performed in 63% of the patients but percutaneous coronary intervention was performed in only 34% and this was similar between both treatment groups. Coronary artery bypass graft (CABG) was performed in 9% in the enoxaparin group and 9.6% in the fondaparinux group.

Procedures: The trial was a double-blind, double-dummy trial. Patients were randomly assigned within 24 hours of onset of symptoms to receive fondaparinux at a dose of 2.5 mg once daily plus placebo twice daily or enoxaparin at a dose of 1 mg/ kg twice daily plus placebo once daily. All medications and placebo were administered using subcutaneous injection. Fondaparinux was given until hospital discharge or up to 8 days (whichever occurred first).  Enoxaparin was given for 2 – 8 days. Coronary angiogram was permitted at any time.

Endpoints: The primary efficacy endpoint was a composite endpoint that included death, myocardial infarction or refractory ischemia at 9 days. The primary safety endpoint was major bleeding. Secondary endpoint included the primary endpoint and its individual components at 30 days and end of the study (up to 180 days).

Based on an expected incidence of 8% at 9 days for the primary endpoint and a noninferiority margin of 1.185 for a one-sided alpha level of 2.5%, the estimated sample size was 16,000. However, a blinded review after the first 4,000 patients were enrolled showed a lower than expected event rate. Therefore, the sample size was increased to 20,000 patients.

Results: The study randomized 10,057 patients to receive fondaparinux and 10,021 to receive enoxaparin. At 9 days, the primary composite end point occurred in 5.8% patients assigned to fondaparinux and 5.7% patients assigned to enoxaparin (HR: 1.01, 95% CI: 0.90 - 1.13; p= 0.007 for non-inferiority). All components of the primary endpoint were also similar between both treatment arms at 9 days.

At 30 and 180 days, there was no significant difference in the composite primary endpoint between both treatment arms. However, death (secondary endpoint) was significantly lower with fondaparinux at 30 days (2.9% vs 3.5%; p= 0.02) and the difference persistent at 180 days (5.8% vs 6.5%; p= 0.05).

Major bleeding at 9 days was significantly lower with fondaparinux (2.2% vs. 4.1%; HR: 0.52,  95% CI: 0.44 - 0.61; p<0.001).

There were no significant differences in subgroups for the primary efficacy endpoint at 9 days. Similarly, bleeding was lower with fondaparinux across different subgroups.

For patients who underwent coronary angiography, catheter-related thrombus was significantly more common with fondaparinux (0.9% vs 0.3%, p= 0.001).

Conclusion: In patients admitted with unstable angina or NSTEMI, the use of fondaparinux as compared to enoxaparin resulted in similar risk of death, myocardial infarction or refractory ischemia at 9 days, but a significantly lower risk of bleeding. The NNT to prevent major bleeding with fondaparinux was 52. Fondaparinux increased the risk of catheter-related thrombus. The double-blind, double-dummy design enhanced the internal validity of the trial and reduced performance bias.

Whether the results of this study apply to the contemporary practice is unclear due to the high rate of coronary angiography and the frequent use of radial access in the current era. However, based on our interpretation of OASIS-5 we feel that Fondaparinux should be considered at least an equal alternative to low-molecular-weight heparin in patients admitted with ACS without ST segment elevation.

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Two trials in acute coronary syndrome - CURE (clopidogrel in acute coronary syndrome) and DIGAMI 2 (glucose control in acute coronary syndrome)

European Heart Journal, Volume 26, Issue 7, 2005, 650–661

Background  Patients with diabetes have a higher risk of death after myocardial infarction than those without diabetes. There are many possible reasons for this difference. One may be that diabetic patients have detrimental responses during the acute phase of MI. In the DIGAMI 1 trial, patients with diabetes and AMI were randomized to intensive glucose control via IV insulin or standard care. Although the primary endpoint of all-cause mortality at 3 months was not statistically significant, the 1-year mortality was reduced by 30% in the IV-insulin group.  The DIGAMI 1 trial had lower than expected mortality which led to wide confidence intervals.

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The hypothesis of the DIGAMI 2 trial was early and continued insulin-based metabolic control is a key to mortality reduction in patients with diabetes and AMI.

Patients Eligible patients with type 2 diabetes or an admission blood glucose > 198 mg/dl who were admitted to participating CCU were eligible if they had suspected AMI due to symptoms (chest pain >15 min during the preceding 24 h) and/or recent ECG signs (new Q-waves and/or ST-segment deviations in two or more leads). Exclusion criteria were inability to cope with insulin treatment or to receive information on the study; residence outside the hospital catchment area; participation in other studies.

Baseline Characteristics The trial recruited 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and suspected acute myocardial infarction. At hospital discharge, approximately 85% of patients fulfilled the diagnosis of MI. Nearly half of these were STEMI. The remaining patients had unstable angina. The mean duration of diabetes was 8 years but about 20% of patients had diabetes of less than one year duration. Almost a third of patients had had a previous MI. Thirty percent of patients were on some form of insulin treatment before randomization. At randomization, HbA1c was 7.2, 7.3, and 7.3% in groups 1, 2, and 3, respectively.  The three groups were well matched in most respects, however, there were significantly fewer previous Mis and trend towards fewer patients with HTN, DM and HF in group 3.

Evidence-based treatments for MI was extensive in all groups. Nearly all eligible patients had acute revascularization.

Trial procedures DIGAMI 2 was carried out in 44 centers in Sweden, Finland, Norway, and Denmark. It had three treatment arms: a 24 h insulin–glucose infusion followed by a subcutaneous insulin-based long-term glucose control (group 1); a 24 h insulin–glucose infusion followed by standard glucose control (group 2), and, routine metabolic management according to local practice (group 3).

The authors attempted to balance randomization and simulate the DIGAMI 1 trial by communicating baseline variables before randomization—which was based on an algorithm that included prognostic markers from the first DIGAMI trial. The goal was to improve the ability to compare the two DIGAMI trials. During the first 24 h, blood glucose was followed according to the infusion protocol in groups 1 and 2 and at the discretion of the attending physician in charge in group 3 (standard care).

In groups 1 and 2, glucose-lowering treatment was initiated with a glucose–insulin infusion with the objective to decrease blood glucose as fast as possible and keep it between 126 and 180 mg/dl.  The infusion lasted until stable normoglycemia and at least for 24 h. In group 1, subcutaneous insulin was initiated at the cessation of the infusion. The treatment goal for patients in group 1 was a fasting blood glucose level of 90–126 mg/dl and a non-fasting level of <180 mg/dl. Apart from the initial insulin–glucose infusion given to patients in group 2, the glucose-lowering treatment in groups 2 and 3 was at the discretion of the responsible physician and according to local routines.

Endpoints: The primary objective of DIGAMI 2 was to compare total mortality between treatment groups 1 and 2 during the time of follow-up. A secondary objective was to compare the total mortality between groups 2 and 3, and a tertiary objective to compare morbidity, such as non-fatal reinfarction, congestive heart failure, and stroke, among the three groups.

The estimated 2-year mortality was close to 35% in group 3; however, adjusted to 30% to correct for time-trends in mortality. It was assumed that the mortality would be lowered to 17% in group 1 and 23% in group 2 corresponding to a mortality reduction of 25% between each of three treatment strategies. These assumptions would require a sample size of 1150 patients in groups 1 and 2 and 700 patients in group 3 for a two-tailed test with an alpha-value of 0.05 and a power of at least 85%

DIGAMI 2 planned to enroll 3000 patients but the trial was terminated prematurely due to slow enrollment. The authors write that it was a truly investigator-initiated trial with a low budget.

Results: The median study duration was 2.1 years. Blood glucose was significantly reduced after 24 hours in all groups, but more in groups 1 and 2 (164 and 164 mg/dl) than in group 3 (180 mg/dl). HbA1c did not differ significantly among groups 1–3 (∼6.8%) at the end of follow-up.

Hypoglycemia (glucose < 54 mg/dl) was more frequent during the initial 24 hours in Group 1 (12.7%) and Group 2 (9.6%) than Group 3 (1%).

After 2 years of follow-up, the Kaplan–Meier estimated mortality was 23.4% among patients in group 1 compared with 21.2% in group 2 (HR=1.03; 95% CI=0.79–1.34; P=0.832). The corresponding proportion in group 3 was 17.9% (group 1 vs. 3: HR=1.26, CI=0.92–1.72; P=0.157). The adjusted HR for the slight imbalance in previous diseases between groups 1 and 3 was 1.19 (CI=0.86–1.64; P=0.29). The comparison of mortality between groups 2 and 3 yielded a hazard ratio of 1.23 (CI=0.89–1.69; P=0.203).

There were no significant differences in morbidity expressed as non-fatal reinfarctions and strokes among the three groups.

Conclusion: Insulin infusion and tight glycemic control in the acute phase post myocardial infarction did not improve mortality or cardiovascular outcomes.

The authors used many words to explain why DIGAMI 2 did not confirm DIGAMI 1. They mentioned factors such as a) the lower-than-expected power (due to early termination), b) the fact that group 1 did not achieve its strict goal of glucose lowering, c) that there were crossovers wherein 14% of patients in Group 3 received insulin-glucose infusions against protocol, and d) that overall mortality in all groups was lower than expected. It seemed to us that the nonsignificant effect on mortality came as a surprise.

Our conclusion, however, is that DIGAMI 2 enrolled more patients with broader entry criteria and in the setting of excellent baseline care, more aggressive glucose-lowering therapy did not reduce death rate. The lessons of these 2 trials will be repeated in coming trials. That is, caution is warranted in smaller trials with large effect sizes, and, as baseline care improves, it becomes harder to show incremental benefit of new therapies—especially aggressive ones.

Editor note:

Link to an article on the importance of stress induced hyperglycemia: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672537/

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N Engl J Med 2001;345:494-502.

Background The established medical treatments for acute coronary syndrome reviewed so far include aspirin and thrombolytics along with a smaller role for short-term anticoagulation.

Angiotensin converting enzymes inhibitors and, to a lesser extent, beta blockers were also found to reduce recurrent ischemic events and death as well as heart failure and ventricular remodeling. The EPHESUS trial, which studied Eplerenone in this patient population was not published until several years later.

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Despite the benefits of the above therapies, patients who experienced an ACS event were still at a substantially higher risk for experiencing recurrent events compared to patients who never experienced an ACS event. Significant interest remained in finding additional agents to reduce “residual risk” (i.e., the risk of recurrent events that is left over after initiating effective therapies).

Imagine a heart attack survivor has a 20% risk of experiencing death, non-fatal MI or heart failure over the next 5 years. Now imagine that all known effective therapies cumulatively reduce that risk by 30% (a 6% absolute reduction in risk); the residual risk for events over 5 years would still be 14%, which is still high, and significantly higher than patients who never experienced an ACS event (e.g., primary prevention patients).

Thienopyridine derivatives, including clopidogrel, are antiplatelet agents with a different mechanism of action than aspirin. Up to this point in time they demonstrated efficacy in patients who had received a coronary stent for reducing myocardial infarction compared to either aspirin alone or warfarin. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial sought to test the hypothesis that 3 to 12 months of clopidogrel plus aspirin versus aspirin alone would reduce the rate of cardiovascular events (a composite endpoint) compared to aspirin alone in patients with ACS and no ST-segment elevation.

Patients Patients were eligible if they had been hospitalized within 24 hours after the onset of symptoms, who had either ECG changes or an elevation in cardiac enzymes at entry, and did not have ST-segment elevation. Exclusion criteria included a contraindication to antithrombotic or antiplatelet therapy, high bleeding risk or severe heart failure, those who were taking oral anticoagulants, and those who had undergone coronary revascularization in the previous 3 months or had received intravenous glycoprotein IIb/IIIa receptor inhibitors in the previous 3 days.

Baseline characteristics No information in the main manuscript is provided on the ratio of patients eligible to those enrolled, which limits our ability to make inferences about external validity. The average age of participants was 64 years of age and nearly 40% were woman, which is historically higher than the trials reviewed up to this point. The average time from pain onset to randomization was 14 hours. The diagnoses at study entry were unstable angina in 75% and MI in 25%. Many patients in the trial has a history of MI (32%) or revascularization (18%) in the past and the majority were either current or former smokers (61%). Most patients (94%) had some ECG abnormality; the most common being ST depression (42%) and T-wave inversion (36%).

Procedures Immediately following randomization patients were administered a 300 mg loading dose of clopidogrel or matching placebo followed by 75 mg per day of clopidogrel or matching placebo for 3 to 12 months (the mean duration of treatment was 9 months). Aspirin was started or continued simultaneously with the study drug or placebo. Follow-up assessments occurred at discharge, at 1 and 3 months, and then every 3 months until the end of the study (12 months).

Endpoints The first primary endpoint was the composite of death from cardiovascular causes (death for which there was no clearly documented nonvascular cause), nonfatal MI (which required at least 2 of 3 findings: ischemic chest pain, elevation of cardiac markers or ECG changes consistent with MI) or stroke (new focal neurological deficit of vascular origin lasting >24 hr and was subdivided into intracranial hemorrhage, ischemia, or uncertain cause) at 12 months. The second primary endpoint was the composite of the first primary endpoint or refractory ischemia. Secondary outcomes included severe ischemia, heart failure, and the need for revascularization. Safety related outcomes included life-threatening, major bleeding (requiring transfusion of ≥2 units of blood) or all other bleeding.

The study was initially designed to include 9000 patients, with an anticipated primary event rate of 12-14% in the placebo group; however, because the event rate was lower than anticipated, the size of the study was increased as the trial was ongoing, with an adjusted rate of 10% in the placebo group. A final sample size of 12,500 patients was based on an anticipated 17% risk reduction for the primary composite endpoint with 90% power and a two-sided alpha level of 0.045.

Results 12,562 patients were included in the final analysis; 6,303 in the placebo group and 6,259 in the clopidogrel group. During the initial hospital stay, 21% of patients in the clopidogrel group and 23% of patients in the placebo group underwent revascularization.

At 1-year clopidogrel significantly reduced the occurrence of the first primary composite endpoint (RR 0.80; 9.3% vs 11.4%; 95% CI 0.72-0.90) and second primary composite endpoint (RR 0.86; 16.5% vs 18.8%; 95% CI 0.79-0.94). These differences were driven primarily by reducing nonfatal MI (RR 0.77; 5.2% vs 6.7%; 95% CI 0.0.67-0.89). There were no significant differences in death from cardiovascular or non-cardiovascular causes, stroke or refractory ischemia.

Compared to placebo, clopidogrel significantly increased major bleeding (RR 1.38; 3.7% vs 2.7%; 95% CI 1.13-1.67). However, there was no significant excess of major bleeding in patients undergoing CABG surgery (RR 1.48; 1.3% vs 1.1%; 95% CI 0.93-1.71). The median time for clopidogrel discontinuation before CABG surgery was 5 days.

Results from various subgroups are presented for the first primary composite endpoint and suggest the possibility of important treatment effect heterogeneity. Patients with a history of revascularization represented a minority of patients in the study (18%) and experienced higher rates of events but derived a significantly greater benefit from clopidogrel compared to those not previously revascularized (RR 0.58 vs 0.89).

Patients >65 years of age made up about half of study participants, and experienced event rates >2x higher than those ≤65 years of age, but derived less benefit from clopidogrel (RR 0.87 vs 0.71). The same was true based on risk tertiles. Patients at low and intermediate risk of experiencing events based on risk scores, experienced similar risk reductions from clopidogrel of 76% and 69% respectively; however, those at the highest risk received less benefit (RR 91%). Finally, women appeared to benefit less than men (RR 89% vs 76%).

Notably, there was no evidence of treatment effect heterogeneity based on whether patients underwent revascularization or not following randomization.

During the trial, clopidogrel was discontinued temporarily (≥5 days) in 46% of patients mainly due to the need for a surgical procedure. A total of 21% of patients discontinued clopidogrel permanently compared to 18% in the placebo group.

Conclusions In patients admitted to the hospital for unstable angina or NSTEMI, clopidogrel for 3-12 months plus aspirin, reduced the rate of a composite primary endpoint compared to aspirin alone and was associated with a number needed to treat of approximately 50 patients. This benefit was driven almost entirely by reducing nonfatal MI. Clopidogrel increased major bleeding with an NNH of approximately 100 patients.

In our opinion, the benefit conferred by clopidogrel in this patient population is modest and the external validity is uncertain as no information is provided on patients enrolled compared to those who were eligible/screened. Patients with prior histories of revascularization derived the greatest benefit; however, several higher risk subgroups including older patients (>65 years of age) and the third of patients who were at the highest risk of experiencing events derived significantly less benefit. Women, also derived less benefit. In the groups less likely to benefit, we would expect them to experience higher rates of adverse events as well and thus, it is possible they derive no net benefit from clopidogrel or could even experience net harm.

While thienopyridines have come to be considered a foundational treatment for ACS, evidence of their benefit from the CURE trial is modest at best; based mainly on reduction of a nonfatal endpoint.

The CURE trial results should be translated cautiously, especially for patients who are older, frail and more susceptible to adverse events.

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Two trials of statin therapy in acute coronary syndrome. See https://cardiologytrials.substack.com/ for more details.

NEJM 2004;350:1495-504.

Background The benefit of cholesterol lowering with statins compared to placebo had been demonstrated in multiple trials across a range of cholesterol starting levels in patients with and without a history of coronary artery disease.

The average reduction in cholesterol from baseline levels in these trials was in the range of 25% to 35%. Guidelines at the time this trial was undertaken recommended an LDL treatment target of <100 mg/dl.

The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial sought to test the hypothesis that more intensive LDL lowering with atorvastatin 80 mg daily would reduce a composite endpoint of cardiovascular events compared to less intensive LDL lowering with pravastatin 40 mg daily in patients hospitalized with ACS.

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Patients Patients had to be ≥18 years of age and hospitalized for either AMI or high-risk unstable angina in the preceding 10 days. They had to be in stable condition and were to be enrolled after a PCI, if one was planned. Finally, they had to have a total cholesterol level ≤240 mg/dl. For patients already on long term lipid lowering therapy they had to have a total cholesterol level of ≤200 mg/dl. Exclusion criteria including coexisting conditions that shortened expected survival to less than 2 years, were receiving any statin at a dose of 80 mg daily at the time of index event, had undergone PCI within the previous 6 months or CABG within the previous months or were scheduled to undergo CABG in response to the index event, had serious hepatic illness or had a creatinine level >2 mg/dl.

Baseline characteristics The average age of patients was 58 years and 78% were men; 90% were white. The index event was unstable angina in 30%, NSTEMI in 36% and STEMI in 34%. Seventy percent of patients underwent PCI for the treatment of their index event. Less than 20% of patients had a prior MI, 18% had diabetes and 50% had hypertension. The median total cholesterol was 180 mg/dl, LDL was 106 mg/dl, HDL was 39 mg/dl and triglycerides were 150 mg/dl.

Procedures Eligible patients were randomly assigned to receive either atorvastatin 80 mg or pravastatin 40 mg daily in a double-blind fashion. Patients were seen for follow-up visits and received dietary counseling at 30 days, at 4 months and every 4 months thereafter until their final study visit in August or September 2003. Blood samples were obtained at randomization, at 30 days, at 4, 8, 12, and 16 months and at the final study visit for measurement of lipids and other components that were part of the safety assessment. Measurements were made at core laboratories. The dose of either study drug could be cut in half if liver enzymes or creatinine kinase was elevated (levels not specified) or in the presence of myalgias (criteria not defined).

Endpoints The primary endpoint was the time from randomization to the first occurrence of a component of the primary composite endpoint, which included: all-cause death, nonfatal MI, documented unstable angina requiring hospitalization, revascularization with PCI or CABG if either were performed 30 days after index event, and stroke. Secondary endpoints were occurrence of each component of the primary composite endpoint as well as a composite of death from coronary heart disease, nonfatal MI or revascularization occurring at least 30 days after index event and another composite consisting of death from coronary heart disease and nonfatal MI.

The study was designed to test whether pravastatin 40 was non-inferior to atorvastatin 80 with respect to the event rate for the primary composite endpoint at 2 years. To claim non-inferiority for pravastatin, the one-sided 95% confidence interval for the relative risk of the 2-year event rate in the pravastatin group could not exceed 1.17, corresponding to a hazard ratio of 1.198. Assuming a two-year event rate of 22% in the atorvastatin group and that the two treatments had equivalent efficacy, it was determined that 2000 patients per group would give the study a statistical power of 87 percent and that this power would be preserved if follow-up continued until 925 end-point events had occurred.

Basically, if the upper bound of the 95% CI showed that pravastatin 40 was not worse than atorvastatin 80 by more than 17%, the investigators could claim it was noninferior.

Results 4,162 patients were included in the final analysis; 2,063 in the pravastatin group and 2,099 in the atorvastatin group. Average follow-up time was 2 years. Compared to atorvastatin, pravastatin did not meet the prespecified criteria for noninferiority set by the investigators. The rates of the primary composite endpoint in the pravastatin and atorvastatin groups were 26.3% and 22.4%, respectively and the upper bound of the 95% CI was 25% (it had to be 17% or less to claim noninferiority). The investigators performed further analyses which demonstrated the superiority of atorvastatin compared to pravastatin; however, the presentation of these results in the main manuscript are not in a traditional format due to the prespecified hypothesis that was tested.

The only individual component of the primary composite endpoint that was significantly reduced at 2 years by atorvastatin was revascularization. The rates of death in the atorvastatin and pravastatin groups were 2.2% and 3.2%, respectively and the difference was not statistically significant. Post-hoc power for this endpoint was only 51% at an alpha of 0.05.

The authors report that subgroup data showed consistent effects; however, inspection of the forest plot reveals the possibility of treatment effect heterogeneity with no benefit for atorvastatin 80 compared to pravastatin 40 for patients ≥65 years of age, those taking a statin at baseline, those with baseline LDL <125 mg/dl, and those whose index event was a STEMI.   

The rates of treatment discontinuation in the pravastatin and atorvastatin groups were 33% and 30%, respectively at 2 years. Medication was discontinued due to elevated LFT’s in 1.1% of patients on pravastatin compared to 3.3% of patients on atorvastatin (p<0.001). It was discontinued for myalgias or elevated creatine kinase in 2.7% of pravastatin group compared to 3.3% of atorvastatin group (p=NS). There were no documented cases of rhabdomyolysis in either group.

At the time of randomization, a median of seven days after the onset of the index event, the median LDL cholesterol levels were 106 mg/dl before treatment in each group. The LDL cholesterol levels achieved during follow-up were 95 mg/dl in the pravastatin group and 62 mg/dl in the atorvastatin group (P<0.001).

Conclusions In patients with ACS, pravastatin 40 mg did not meet non-inferiority compared to atorvastatin 80 mg. The difference in a composite endpoint that included 5 individual components was statistically lower in the atorvastatin group with a number needed to treat of 25 patients.

The achieved difference in LDL lowering was significantly greater in the atorvastatin group. Notably, the only individual component of the primary endpoint that was significantly reduced was revascularization.

Inspection of various subgroups suggests the possibility of treatment effect heterogeneity for several important subgroups including patients ≥65 years of age.

The trial helped establish lower LDL targets for secondary prevention but also highlights the diminishing gains of such therapy.

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For full review of the trials, please visit https://cardiologytrials.substack.com/

JAMA 2001;285:1711-18.

Background Statin therapy had been shown to improve blood cholesterol and improve long-term outcomes in patients with stable coronary artery disease with significant effects evident after 2 years of treatment.

These early trials excluded patients with recent acute coronary syndromes and thus, the possibility of early benefit from statin therapy in this patient population was untested. But, patients with ACS are the most vulnerable to experiencing recurrent events in the early period following an initial event and certain physiologic effects of statins were theorized to be beneficial during this period. These effects included improvement in endothelial function, decreased platelet aggregation and thrombus deposition, and reduced vascular inflammation.

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study sought to test the hypothesis that early treatment with high dose atorvastatin in patients with unstable angina or non-Q-wave AMI would reduce early ischemic events and death.

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Patients Eligible patients were ≥18 years of age of experienced unstable angina or non-Q-wave AMI within the 24-hour period before hospitalization. The definition of unstable angina was strictly applied and in contemporary practice, all would meet criteria for NSTEMI. Patients were excluded for the following reasons: serum cholesterol >270 mg/dl but there was no lower limit; if coronary revascularization was planned or anticipated at the time of screening; evidence of Q-wave AMI within preceding 4 weeks; CABG surgery within the preceding 3 months; PCI within the preceding 6 months; left bundle branch block or paced rhythm; severe CHF; concurrent treatment with other lipid-lowering agents, vitamin E, drugs associated with rhabdomyolysis in combination with statins; severe anemia; renal failure requiring dialysis; hepatic dysfunction (ALT >2 ULN); insulin-dependent diabetes; pregnancy or lactation.

Baseline characteristics The average age of patients was 65 years and two-thirds were men; 86% were white. Approximately one quarter of patients had a prior MI, 23% had non-insulin-dependent diabetes and 55% had hypertension. The average time to randomization from hospital admission was about 2.5 days. The inclusion event was unstable angina in 46% and non-Q-wave AMI in the remainder. Non-cholesterol lowering cardiac medicines were similar prior to, during and following the hospitalization index event.

Procedures Between 24 and 96 hours after hospital admission, patients received either atorvastatin 80 mg per day or matching placebo for 16 weeks. Treating physicians were instructed not measure serum lipid levels in the local hospital laboratory during the study period. All patients received instruction and counseling on a low cholesterol diet. Patients were seen in follow-up 2, 6, and 16 weeks after initiation of therapy. Laboratory testing was performed centrally at baseline and at 6 and 16 weeks.

Endpoints The primary endpoint was a composite of all-cause death, nonfatal MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence requiring emergency hospitalization. The recurrent ischemia endpoint required both exacerbation of the patient’s usual symptoms and new objective evidence of ischemia with definite change from a comparison study performed after the index ischemic event. Secondary endpoints were occurrence of each component of the primary composite endpoint as well as nonfatal stroke; new or worsening heart failure requiring hospitalization, worsening angina requiring hospitalization but without objective evidence of ischemia, coronary revascularization, time to first occurrence of any primary or secondary endpoint, and percentage changes in blood lipid levels from baseline to 16 weeks.

An initial sample size requirement of 2,100 was based on an assumption of a 20% primary composite event rate in the control group and 14% rate in the atorvastatin-treated group (17% overall rate), with an alpha of 0.05 and 95% power. The sample size was then increased to 3,000 upon the recommendation of the steering committee. This, after a blinded analysis of pooled data from the first 1,260 patients indicated the event rate was lower than anticipated (13% overall). A sample size of 3,000 would confer 95% power to detect a 30% relative treatment effect and 80% power to detect a 25% relative effect at an alpha of 0.05.

Results 3,086 patients were included in the final analysis; 1,548 in the placebo group and 1,538 in the atorvastatin group. All patients were followed for 16 weeks. Compared to placebo, atorvastatin significantly reduced the risk of the primary composite endpoint (RR 0.84; 14.8% vs 17.4%%; 95% CI 0.70-1.00; p=0.048). For the individual components, there were no significant differences in death (4.2% vs 4.4%), nonfatal MI (6.6% vs 7.3%), or resuscitated cardiac arrest (0.5% vs 0.6%), but there was a statistically significant reduction in the endpoint of emergency rehospitalization for recurrent symptomatic ischemia (RR 0.74; 6.2% vs 8.4%; 95% CI 0.57-0.95).

For the secondary endpoints, there were significant reductions in stroke in the atorvastatin group but this was based on a small number of events.

Perhaps unexpectedly, there was a numerical increase in coronary revascularization procedures in the atorvastatin group despite there being a statistically significant reduction in emergency hospitalizations for recurrent ischemia as mentioned above.

Data on subgroups was not presented.

Compliance with prescribed study treatment was 86% in the atorvastatin group and 88% in the placebo group. Treatment was discontinued prematurely in 11.2% of the atorvastatin group compared to 10.3% in the placebo group. No serious adverse events occurred with a frequency of more than 1% in either group. An increase in LFTs (>3x ULN) occurred in 2.5% in the atorvastatin group and 0.6% of patients in the placebo group; 3 of these patients in the atorvastatin group were hospitalized with hepatitis and each case resolved following discontinuation of the drug. There were no documented cases of myositis.

After 16 weeks, LDL cholesterol had increased by an adjusted mean of 12% to 135 mg/dl in the placebo group and decreased by an adjusted mean of 40% to 72 mg/dl in the atorvastatin group. Total cholesterol and triglycerides also decreased significantly in the atorvastatin group compared to placebo and there were no significant changes in HDL cholesterol.

Conclusions In patients admitted to the hospital with non-Q-wave acute coronary syndromes, high dose atorvastatin significantly reduced a composite primary endpoint of cardiovascular events over the first 16 weeks of treatment with an NNT of 38; however, this was driven by a reduction in emergency hospitalizations for recurrent ischemia.

There is no evidence from this trial that high dose statin therapy reduces the individual endpoints of death or nonfatal MI over this period; nor did it reduce coronary revascularization, which is counterintuitive given the significant increase in emergency hospitalizations for recurrent ischemia. Coronary revascularization events were twice as likely to occur as emergency hospitalizations.

The external validity of the trial is limited by the restricted nature of the study population. Patients were excluded if revascularization was planned during initial admission, which in many places is the standard of care for ACS up to the present day. Furthermore, higher risk ACS subgroups were excluded, including patients with insulin-dependent diabetes, advanced heart failure and ESRD. The relatively unimpressive clinical benefit observed in MIRACL should not be assumed to extend to such patients. It would not be unreasonable to conclude that the results from MIRACL do not apply to the average patient with ACS in contemporary practice.

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Two trials of blood glucose lowering and low-molecular-weight heparin in patients with acute coronary syndrome.See https://cardiologytrials.substack.com/ for more details

Lancet 1996;347:561-68.

Background In most of the prior AMI trials presented here, patients with non_ST-segment myocardial infarction (NSTEMI) and/or unstable angina were included with patients with ST-segment myocardial infarction (STEMI). Patients with NSTEMI usually represented about 1/3 of trial participants.

It had become clear based on subgroup analyses from the previous trials that NSTEMI patients did not benefit from thrombolysis. So, while intravenous anticoagulation with heparin was not found to be beneficial in GISSI-2 or ISIS-3, where thrombolysis was also used, there remained the possibility that it may benefit patients with unstable coronary syndromes who were not candidates for thrombolytic therapy.

This smaller trial represents a departure from the general eligibility criteria for the AMI trials that we have already reviewed. The Fragmin During Instability in Coronary Artery Disease (FRISC) study group sought to test the hypothesis that subcutaneous low-molecular-weight heparin, in combination with aspirin, reduces death and new cardiac events in patients with unstable CAD. For the purposes of this study, unstable CAD represents unstable angina and NSTEMI.

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Patients Patients had to be men older than 40 years and women at least 1 year after menopause admitted to the hospital for chest pain within the previous 72 hours. All patients had to have either newly developed or increased angina symptoms during the previous 2 months or persisting chest pain with suspicion for AMI and at least one of the following ECG criteria: transient or persistent ST depression of ≥ 0.1 mV or T-wave inversion of ≥ 0.1 mV in at least 2 adjacent leads without pathological Q waves in the ischemic leads. Essentially, the authors were selecting patients with unstable angina or NSTEMIs and not STEMIs or completed infarcts. There were many exclusion criteria for the trial including the presence of conditions with an increased risk of bleeding, known renal or liver insufficiency, indications for thrombolysis, suspected myocarditis and many others; however, it is worth noting there was no upper age limit.

Baseline characteristics There were 5,137 patients who met eligibility criteria and 1,506 (29%) were randomized. The 3 most common reasons for exclusion were risk of bleeding (20%), compliance problems (15%), and Q waves or bundle branch block (14%). Patients with other severe disease accounted for 4% of exclusions and those with renal or liver insufficiency accounted for 2%.

The median age of participants was 69 years and approximately 65% were men. 20% of participants were active smokers, 13% had diabetes and nearly 30% had a previous heart attack. Patients with NSTEMI accounted for close to 40% of participants and the remainder had unstable angina.

Procedures Treatment was started as soon as possible after admission. During the first 6 days (acute phase), 120 IU per kg bodyweight (maximum dose of 10,000 IU) of dalteparin or placebo was injected every 12 hr. There was then a home treatment phase. For the next 35-45 days—at home— 7,500 IU of dalteparin or placebo was injected once daily. Patients stayed in the hospital during the acute phase for at least 5 days and on day 5-8 were discharged with the lower home dose. On day 40-50, the treatment was stopped and the final follow-up visit was scheduled 5-7 months after trial enrollment.

Endpoints The primary endpoint was the rate of death and new myocardial infarction during the first 6 days. Secondary endpoints were the rates of death and new MI after 40 and 150 days, the frequency of revascularization procedures and need for heparin infusion, and a composite endpoint.

Cause of death and myocardial infarction were verified by the independent endpoint committee who had to differentiate a new event from an inclusion event. Safety endpoints included major and minor bleeding. Major bleeding was defined by a drop of ≥2 g/dL in hemoglobin with associated signs or symptoms of bleeding, and minor bleeding was any other bleeding not meeting the former criteria.

A sample size of 1,500 was based on a power of 0.80 to detect a reduction in the primary composite endpoint from 6% to 3% at a 2-sided alpha of 5%. Subgroup analyses were prespecified and a “high-risk group” was defined by the presence of at least 2 of the following variables: age >70, previous MI, medically treated heart failure, or diabetes.

Results 1,506 patients were included in the final analysis; 757 in the placebo group and 741 in the dalteparin group. At 6 days, dalteparin significantly reduced the occurrence of the primary endpoint (RR 0.37; 1.8% vs 4.8%; 95% CI 0.20-0.68), which was driven by myocardial infarction (RR 0.33; 1.4% vs 4.4%; 95% CI 0.16-0.60). There was no difference in death between groups (RR 0.88; 0.9% vs 1.1%; 95% CI 0.32-2.48) and minor bleeding events were much more common in the dalteparin group (8.2% vs 0.3%).

At 40 (8.0% vs 10.7%) and 150 (14.0% vs 15.5%) days, differences between groups were less pronounced for the primary endpoint and the results, in favor of dalteparin, were not statistically significant. Bleeding events, driven by minor bleeding, continued to be much higher for the dalteparin group.

Subgroup analyses are presented at 6 and 40 days and are generally concordant across subgroups, meaning the treatment effect goes in the same direction, but these analyses should be viewed skeptically as they represent small sample sizes, particularly compared to subgroups in the earlier mega trials. Subgroup data suggests concordant results for patients less than or greater than 70 years of age and for patients meeting high risk criterion compared to those not meeting it.

Conclusions In patients with unstable angina and NSTEMI, dalteparin reduced the primary endpoint of death or nonfatal MI compared to placebo at 6 days and was associated with a NNT of 33 patients. This was driven by a reduction in nonfatal MI. The results were no longer significant at 40 or 150 days. This trial is limited by small sample size and highly selected patient population.

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J Am Coll Cardiol 1995;26:57-65.

Background Patients with diabetes have higher short- and long-term rates of mortality following acute myocardial infarction (AMI). Possible explanations for this include increased fatty acid metabolism, compromising glycolysis in ischemic and nonischemic areas as well as impairment of platelet and fibrinolytic function. This led to the theory that both processes could be improved with insulin infusion. Small studies at the time provided conflicting results.

The Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial sought to test the hypothesis that rapid improvement of metabolic control in diabetic patients with AMI by means of insulin-glucose infusion would decrease early mortality and that continued good metabolic control would improve subsequent prognosis.

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Patients Patients admitted to the CCUs of 19 Swedish hospitals with suspected AMI within the preceding 24 hours with a blood glucose level >11 mmol/l (198 mg/dl) with or without a previous history of diabetes mellitus. Exclusion criteria included inability to participate for reasons of health, refusal to give consent, residence outside the catchment area or enrollment in other studies.

Baseline characteristics There were 1,240 patients who met inclusion criteria and 50% were excluded, mainly due to inability or unwillingness to participate. Compared to those enrolled, excluded patients were older (72 years of age) and more were women. The majority of those enrolled were men (62%) at an average age of 68 years. Nearly 40% had a history of previous MI and 22% had congestive heart failure. The mean time from the onset of symptoms to randomization was 13 hours. More than 80% of patients were non-insulin dependent. The average HbA1c at randomization was 8% and the blood glucose was 279 mg/dl.

Procedures Patients randomized to insulin therapy were started on an insulin-glucose infusion at 30 ml/h and blood glucose was checked after 1 hour. The infusion rate was adjusted according to protocol. The infusion was continued until stable normoglycemia was attained for ≥24 hours. Subcutaneous administration of insulin was given immediately after cessation of the infusion, according to a multidose regimen, with the aim of maintaining normoglycemia. Serum potassium was measured immediately before the infusion and then after 6, 12, and 24 hr and was checked immediately in patients who developed any kind of clinically significant arrhythmia. Control patients were treated according to standard coronary care unit practice and did not receive insulin unless it was deemed clinically indicated.

Endpoints The primary endpoint was all-cause mortality at 3 months. The investigators hypothesized that the insulin-glucose infusion followed by multidose subcutaneous insulin for 3 months would reduce the mortality rate by 30%, from a 35% mortality rate in the control group (35/100 to 24.5/100). Based on that assumption, a sample size of 600 was needed to demonstrate the expected mortality reduction with a 5% significance level and power of 80%.

Results 620 patients were randomized, 306 to the intervention group and 314 to the control group. The blood glucose level was significantly lower in the insulin group 24 hours after randomization (173 mg/dl vs 211 mg/dl; p<0.0001) and at hospital discharge (148 mg/dl vs 162 mg/dl; p<0.01) but not at 3 months (153 mg/dl vs 162 mg/dl; p=NS) or 1 year (averages not provided). HbA1c was significantly lower at 3 months (7.0% vs 7.5%; p<0.01). Hypoglycemia during insulin infusion occurred in 15% of patients in the intervention group and none in the control group and hospital length of stay was significantly longer in the intervention group (11.3 vs 9.5 day; p=0.04).

At 3 months, insulin treatment did not significantly reduce the primary endpoint of mortality compared to controls (12.4% vs 15.6%; p=NS); however, the 1 year mortality (not the primary endpoint) was significantly lower (18.6% vs 26.1%; p=0.03).

Results are provided for subgroups of patients based on risk groups classified according to whether they were insulin dependent or not at baseline, and whether they were at high cardiovascular risk or not at baseline. Interestingly, a very large and statistically significant difference was observed for patients in the lowest risk stratum (no insulin, low cardiovascular risk). The average mortality in this group was the lowest (6.5% vs 13.5% at 3 months) and the risk reduction was more than 3x greater (55%) than in all other groups who experienced progressively higher mortality rates (risk reduction ranged from -11% to 15% at 3 months). In contrast the average mortality in the highest risk group was unchanged at 3 months (24.4% vs 26.0%; p=NS) and 1 year (41.0% vs 46.0%; p=NS).

Conclusions In the DIGAMI trial, insulin-infusion followed by multidose subcutaneous insulin did not significantly reduce the primary endpoint of all-cause mortality at 3 months compared to control. Insulin infusion was associated with increased length of hospital stay and hypoglycemia.

Overall, the mortality rate in DIGAMI was lower than anticipated and the trial was underpowered. Furthermore, the anticipated risk reduction, which formed the basis of sample size estimates was unrealistically optimistic at 30%. Had it been 20% the sample size would have had to been 4 times larger at 2,572 patient. If the authors had chosen a 10% mortality reduction as their minimal clinically important difference (an historically realistic estimate for mortality reduction), the sample size would have needed to be 10,722. Thus, the 1-year results should be viewed with extreme skepticism and at best are hypothesis generating only.

For multiple interventions reviewed thus far (nitrates and magnesium), we have reviewed false positive signals generated from small, underpowered studies that were reversed when appropriately powered trials were undertaken.

Finally, the results of the risk-based subgroups in DIGAMI suggest important treatment effect heterogeneity but should also be viewed with extreme caution due to low power in the overall trial.

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Two of important trials of ACE inhibition and aldosterone blockade post myocardial infarction. See https://cardiologytrials.substack.com/ for more details.

NEJM 2003;348:1309-21.

Background In patients with chronic systolic heart failure, aldosterone blockade reduced death and cardiovascular hospitalizations when added to an ACE inhibitor (RALES trial), which will be reviewed in the section involving trials in patients with chronic heart failure. Efficacy of aldosterone blockade in patients with acute myocardial infarction, complicated by LV dysfunction, had not yet been tested.

Aldosterone blockade was believed to prevent ventricular remodeling and collagen formation after AMI as well as a number of other important pathophysiological mechanisms.

The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) was designed to test the hypothesis that the selective aldosterone blocker, eplerenone, would reduce mortality and cardiovascular hospitalizations in patients with AMI complicated by LV dysfunction and heart failure.

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Patients Patients were eligible for randomization 3 to 14 days after AMI with LV dysfunction based on an EF of ≤40% and clinical heart failure based on the presence of pulmonary rales, chest X-ray showing pulmonary venous congestion or the presence of a third heart sound. In patients with diabetes, the presence of clinical heart failure was not a requirement. Exclusion criteria included the use of potassium-sparing diuretics, serum creatinine >2.5 mg/dl, or serum potassium >5 mmol/l.

Baseline characteristics The average age of patients was 65 years and over 70% were men; 90% were white. Approximately one quarter of patients had a prior MI, more than 30% had diabetes and 60% had hypertension. The average ejection fraction was 34%. Patients were hemodynamically stable with an average blood pressure of 119/72 mmHg. The average time to randomization from AMI was 7 days. Nearly 50% of patients underwent thrombolysis or angioplasty for the primary MI and at the time of randomization 86% of patients were on an ACE inhibitor, 88% on aspirin, 47% on statins, 75% on beta-blockers, and 60% on diuretics.

Procedures Patients received either eplerenone 25 mg daily or a matching placebo for 4 weeks and then the dose was increased to 50 mg daily. If at any time during the study the serum potassium was >5.5 mmol/l, the dose of the study drug was reduced or temporarily discontinued until the serum potassium was <5.5 mmol/l. Follow-up visits took place at 1 and 4 weeks, 3 months, and every 3 months thereafter until the termination of the study. Serum potassium was measured 48 hr after the initiation of treatment, at 1, 4 and 5 weeks, at all scheduled study visits, and within 1 week after any dose change.

Endpoints There were 2 primary endpoints. The first was all-cause death, which was tested at the 0.04 level of significance. The second was a composite of death from cardiovascular causes or hospitalizations for cardiovascular events, which was tested at the 0.01 level of significance. The trial was designed to enroll 6200 patients and to continue until 1012 deaths occurred. With testing all-cause death at the 0.04 level of significance, the study had 88.3% power to detect an 18.5% relative difference between groups.

Results About 3300 patients were enrolled in the eplerenone and placebo groups. The mean follow-up was 1.3 years (16 months). Compared to placebo, eplerenone significantly reduced all-cause death (RR 0.85; 14.4% vs 16.7%; 95% CI 0.75-0.96; p=0.008) and the composite of cardiovascular death or cardiovascular hospitalization (RR 0.87; 26.7% vs 30.0%; 95% CI 0.79-0.95; p=0.002).

For the secondary endpoints, there were significant reductions in the composite of death from any cause or any hospitalization, cardiovascular death, patients with a hospitalization for heart failure and total number of heart failure hospitalizations. There were no significant differences in the number of patients experiencing any hospitalization or the total number of any hospitalizations.

Four subgroups groups demonstrated treatment effect heterogeneity in that eplerenone did not reduce all-cause death: patients with a pulse pressure <45 mmHg, baseline serum creatinine ≥1 mg/dl, no history of hypertension at baseline and inability to take an ACE or beta blocker. The p values for the interaction terms were <0.05 in each case.

During the study, 16% of the eplerenone group permanently discontinued the study drug compared to 15% in the placebo group. Withdrawals due to adverse events were the same in both groups. Serious hyperkalemia (potassium ≥6 mm/l) was significantly higher in the eplerenone group (5.5% vs 3.9%; p=0.002) but serious hypokalemia (potassium <3.5 mm/l) was significantly lower (8.4% vs 13.1%; p<0.001). The mean dose of eplerenone during the study was 43 mg in the intervention group.

Conclusions In patients with AMI complicated by heart failure and significant LV dysfunction, eplerenone significantly reduced the primary endpoints of all-cause death and the composite of cardiovascular death and cardiovascular hospitalizations, with NNTs of 43 and 30, respectively.

There did appear to be subgroups of patients who did not benefit from eplerenone; particularly patients with low pulse pressure, serum creatinine ≥1 mg/dl, no history of hypertension or inability to take an ACE inhibitor or beta blocker - in essence, patients who are less robust and/or with more severe heart failure following AMI benefited less or not at all.

Hyperkalemia occurred more often in patients on eplerenone but was countered by lower rates of hypokalemia. The external validity of the trial is limited by the frequency of outpatient visits and laboratory monitoring, which is likely challenging to replicate in real-world settings. Furthermore, treatment response variation discussed above makes it unlikely that many patients in clinical practice would benefit from the drug.

In EPHESUS, we begin to see the diminishing effects of adding more and more medical therapies to the repertoire for the same medical condition. Despite it being a clearly positive trial for the most important outcome of all-cause death and the composite of cardiovascular death or hospitalization, there was no difference in patients hospitalized for any cause or the total number of hospitalizations.

Eplerenone use in post-MI patients with reduced EF needs to be individualized to patients who are robust enough to benefit from it. The phenotypical patient, most likely to benefit, is someone <65 years of age who is hypertensive or normotensive (hypertensive better), despite being on an ACE, ARB or ARNI, with normal kidney function.

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NEJM 1995;333:1670-6.

Background Up to this point in history, a series of trials had been conducted using ACEi’s in post-MI patients. A small to moderate short-term benefit had been shown when the drugs were started immediately (GISSI-3 and ISIS-4) and much greater long-term benefits were demonstrated when the drugs were started 5-11 days, on average, following AMI in patients with LV dysfunction and congestive heart failure (SAVE and AIRE).

The SAVE and AIRE trials, however, were more selective and it was not clear how representative they were among all potentially eligible patients. Thus, TRACE authors sought to re-test the hypotheses tested in SAVE and AIRE with a focus on generalizability of trial procedures and results. Specifically, the Trandolapril Cardiac Evaluation Study (TRACE) sought to test the hypothesis that trandolapril would reduce all-cause mortality in post-MI patients with LV dysfunction when used in the majority of consecutively screened, potentially eligible patients.

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Patients Consecutive patients ≥18 years of age who were hospitalized with a confirmed AMI were screened between day 2 and 6 after the onset of symptoms. All screen eligible patients underwent echocardiography and those with a wall motion index of ≤1.2, which corresponds to an EF ≤35%, were considered for enrollment. The key exclusion criteria included an absolute or relative contraindication to an ACEi or a definite need for an ACEi, severe uncontrolled diabetes, a serum sodium <125 mmol per liter or a serum creatinine >2.3 mg/dl.

Baseline characteristics The average age of patients was 68 years and 72% were men. Approximately one third of patients had a prior MI, 13% had diabetes, 23% had hypertension and smoking status was not listed. The average wall motion index was 1.0. Two thirds of patients had a Q wave MI (anterior 47% and inferior 19%).

The mean time to randomization was 4.5 days. Forty-five percent of patients received thrombolysis. The average blood pressure and heart rate were 120/70 mmHg and 76 beats per minute, respectively. At the time of randomization 16% of patients were receiving a beta blocker and 28% digoxin. Before randomization, 60% of patients had been classified as Killip class ≥2 and at the time of randomization it was 21%.

A total of 6,676 consecutive patients experienced an AMI of whom 2,606 had a wall motion index of ≤1.2. There was an inverse relationship between wall motion index and mortality. In patients with scores ≥1.3, 40% had signs of CHF and the 1-year mortality rate was 12%. Among patients with scores ≤1.2, 74% had signs of CHF and the 1-year mortality was 34%.

Of the 2,606 eligible patients, 859 (33%) were excluded. The most common reasons for exclusion included need for mandatory ACE inhibition [6%], cardiogenic shock [4%], death during screening [3%], renal failure or a single kidney [2%], intolerance of the test dose of trandolapril [1%], lack of consent [8%], or other reasons [8%].

Altogether, 1,749 (67%) of patients with a wall motion index score ≤1.2 were enrolled.

Procedures Eligible patients were given a test dose of 0.5 mg of trandolapril, which led to the exclusion of 1% of patients. These patients were not included in the ITT analysis. Double-blind medication was started between day 3 and day 7 after AMI. Patients were randomly assigned to receive 1 mg of trandolapril once daily or matching placebo. After two days, the dose was increased to 2 mg once daily. After four weeks, the dose was again increased, to 4 mg once daily. If the highest dose was not tolerated, patients could continue with a dose of 2 mg or 1 mg once daily, but the drug was withdrawn if a dose of 1 mg once daily was not tolerated.

Outpatient visits were scheduled one and three months after the infarction, with subsequent visits every three months. Echocardiography was repeated after 3, 6, and 12 months.

The original protocol specified that treatment would continue for at least 12 months. When the results of the SAVE study were published in 1992, showing no survival benefit until after almost one year of treatment with ACE inhibitors, the steering committee decided (without any knowledge of the results of the study) to extend the closing date to 24 months after the last random assignment.

Endpoints The primary study endpoint was all-cause mortality. Secondary endpoints were death from a cardiovascular cause, sudden death, progression to severe heart failure, recurrent MI, and change in wall motion index.

The investigators estimated they would need a sample size of 1,500 patients to detect a 25% relative reduction in the risk of death with 80% power and 1-sided alpha of 2.5%. This was based on an estimated death rate of 30% at 12 months in the placebo group; however, the steering committee increased the sample size to 1,860 patients to allow for the possibility of a lower-than-expected placebo mortality rate.

In the spring of 1992 the overall mortality of randomized patients followed for 1 year was 24%. Inclusion of patients was therefore terminated at the end of June 1992 at the point where 1,749 patients had been randomized.

Results The final analysis included 1,749 patients; 876 in the trandolapril group and 873 in the placebo group.

Information on the percentage of patients discharged on various doses of the study drug are not provided.

Compared to placebo, trandolapril significantly reduced all cause death by 22% [(35% vs 42%; 95 percent confidence interval, 0.67 to 0.91 p = 0.001)}. The mortality curves diverged early (Kaplan–Meier estimate of mortality at one month 9% vs 11%) and continued to diverge throughout the follow-up period. Trandolapril also significantly reduced secondary endpoints, including death from CV causes, sudden death, and progression to severe heart failure but it did not significantly reduce reinfarction.

Examination of subgroups showed no evidence of treatment effect heterogeneity for all cause mortality, but again, similar to the SAVE and AIRE trials, the size of TRACE limits subgroup testing.

Premature withdrawals from study drug, not including death, occurred in 37% of patients in the trandolapril group compared to 36% in the placebo group. The most common reason for withdrawal was need for treatment with an open-label ACEi and this occurred more in the placebo group. Withdrawal due to cough, hypotension and reduction in kidney function were rare in both groups but slightly more common in patients on trandolapril compared to placebo.

Conclusions In the majority (67%) of consecutively screened patients with AMI complicated by left ventricular dysfunction, trandolapril significantly reduced death over at least 2 years of follow-up with a number needed to treat of approximately 14 patients.

Results from TRACE strengthen support for ACEi in post-MI patients, and the trial has high external validity. It not only tested the intervention in two-thirds of potentially eligible patients but was highly transparent about why patients were excluded.

A clinician looking to apply the procedures used in TRACE to the management of patients in clinical practice would not have to guess whether or not their patient would have been included. This is rare in clinical research and the investigators should be applauded for their efforts.

Investigators studying ACEi in post-MI patients have triangulated the population of patients who benefit from this therapy. In our opinion, TRACE provides the final piece to the puzzle. There is no doubt about the clinical efficacy of these drugs in the overwhelming majority of post-MI patients and higher risk patients stand to benefit the most.

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Two important trials of beta-blockers in patients with acute myocardial infarction. See https://cardiologytrials.substack.com/ for full details.

Lancet 2005;366:1622-32

Background Beta blockers were routinely used for the early management of patients with AMI; however, their efficacy and safety remained uncertain in this clinical scenario.

Recall that in the BHAT trial, propranolol reduced death 2 years following an AMI with an NNT of approximately 33 but the cohort was highly selected, the drug was started, on average, 14 days following admission and those over the age of 70 were excluded. ISIS-1 found that atenolol reduced death with an NNT of approximately 100 when started immediately in lower risk AMI patients but treatment effect heterogeneity was observed in patient subgroups with higher risk features.

The ClOpidogrel and Metoprolol Infarction Trial (COMMIT) sought to test the hypothesis that early beta-blockade with metoprolol would reduce cardiac events and death in a broad population of patients with AMI.

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Patients Patients with suspected myocardial infarction, who presented with ST elevation, left-bundle branch block, or ST depression within 24 hours of symptom onset were eligible. Patient eligibility was ultimately determined by the responsible physician but protocol guidance suggested the following relative contraindications: persistently low blood pressure (SBP <100 mmHg) or low heart rate (<50 bpm), heart block, or cardiogenic shock. Unlike previous trials, evidence of moderate heart failure (Killip II or III) was not an exclusion criteria. 

Baseline characteristics The average age of participants was 61 and the majority were male (72%). The mean SBP and heart rate at entry were 128 mmHg and 82 beats per minute, respectively. Less than 10% had a previous MI. ST elevation was present in 87% of patients, ST depression in 7%, and bundle branch block in 6%. Thirty percent of patients had heart rate ≥90 bpm upon admission and 7% of those had a heart rate ≥110 bpm. Thirty three percent of patients had SBP <120 mmHg at study entry. Approximately 25% of patients were classified as Killip class II (20%) corresponding to the presence of rales, crackles, an S3,  elevated JVP or pulmonary venous congestion on chest x-ray or Killip class III (5%) corresponding to frank pulmonary edema.

Procedures This trial had a 2x2 factorial design but we will focus only on the metoprolol comparison. Following randomization, patients were immediately given metoprolol or placebo via the following sequence of interventions:

* An immediate intravenous injection of 5 mg of metoprolol or matching placebo, given over 2- 3 minutes.

* About 2-3 minutes later, if the heart rate was >50 bpm and the SBP was >90 mmHg, another 5 mg of metoprolol or matching placebo was injected.

* About 2-3 minutes later, another 5 mg of metoprolol or matching placebo was injected if the heart rate and SBP met the above parameters.

* 15 minutes after these intravenous doses, a 50 mg metoprolol or placebo tablet was to be given and repeated every 6 hours during days 0-1.

* From day 2 onward, 200 mg of sustained-release metoprolol or placebo was to be given for up to 4 weeks or until hospital discharge (whichever came first) unless some definite contraindication was thought to have arisen.

At hospital discharge or at day 28 (whichever came first), a single-sided follow-up form was to be completed. No further follow-up was sought. Post-discharge use of aspirin, beta-blocker, and other established therapies was encouraged but not monitored.

Endpoints There were 2 prespecified co-primary outcomes. One was a composite of death, reinfarction or cardiac arrest and the other was all-cause death during the scheduled treatment period (i.e., until hospital discharge or day 28).

The investigators estimated the event rate in the placebo group for the primary composite endpoint would be 14% prior to the start of the study; however, that estimate was reduced to 10% as the study proceeded. Thus, they estimated a sample size of 45,000 patients would be needed to detect a 10% reduction in the primary composite endpoint with 95% statistical power and a p value of 0.05.

Results 45,852 participants were randomized from 1250 hospitals. 90% of beta blocker-allocated participants received all 3 doses of IV medicine and 86% completed treatment with an oral medication. The average treatment duration was 15 days.

There were 22,929 patients in the metoprolol group and 22,923 in the placebo group. Compared to placebo, metoprolol did not significantly reduce the primary composite endpoint (OR 0.96; 9.4% vs 9.9%; 95% CI 0.90-1.01; p=0.10) or all-cause death (OR 0.99; 7.7% vs 7.8%; 95% CI 0.92-1.05; p=0.69). Metoprolol use reduced reinfarction (2.0% vs 2.5%) and ventricular fibrillation (2.5% vs 3.0%) but increased cardiogenic shock (5.0% vs 3.9%). Metoprolol use also increased heart failure without shock (14.1% vs 12.7%), persistent hypotension without shock (6.0% vs 2.9%), and bradycardia (5.4% vs 2.2%).

Treatment effect heterogeneity was evident based on exploratory subgroups. Patients whose MI’s were complicated by hemodynamic instability or heart failure and who were higher risk for experiencing adverse events did worse with metoprolol. For example, for patients with SBP <120 mmHg, death rates were 9.6% in the metoprolol group compared to 8.8% in the placebo group but were 6.8% and 7.6% in those whose SBP was 120-139 mmHg.

A similar but more striking trend was evident based on heart rate and Killip class. For patients with heart rate ≥110 bpm, death rates were 20.3% in the metoprolol group and 18.3% in the placebo group but were 6.0% and 6.6% in those whose heart rate was 70-89 bpm. For patients classified as Killip class III, death rates were 19.7% in the metoprolol group and 16.5% in the placebo group but were 5.8% and 6.1% in those classified as Killip class I.

Conclusions IV metoprolol followed by oral administration over approximately 15 days did not reduce cardiovascular events or death in patients presenting with AMI. Unlike the ISIS-1 trial, patients presenting with heart failure and hemodynamic instability were NOT excluded from COMMIT and this explains the divergent results and this fact is critically important for clinical translation. In the discussion section of the manuscript the authors present data from a meta-analysis of effects of IV followed by oral beta-blocker therapy. It shows fairly consistent results across trials for death, reinfarction and VF when the low-risk patients from COMMIT are combined with prior studies including ISIS-1 and many other smaller trials.

The COMMIT trial is an important trial in the management of acute coronary syndrome as it addressed a critical gap in the evidence. In low-risk, hemodynamically stable AMI patients, beta blocker use confers a clinically small but statistically significant reduction in death, reinfarction and VF; however, in higher-risk, unstable patients with heart failure, beta blocker use increases death and cardiogenic shock and should be used with extreme caution or avoided altogether.

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Lancet 2001;357:1385-90.

Background While beta blockers were frequently used in patients with acute myocardial infarction complicated by heart failure, at the time the CAPRICORN trial was undertaken, supportive evidence from contemporary, large scale randomized trials was lacking.

The BHAT and ISIS-1 trials, reviewed in this section, were published in 1982 and 1986, respectively; before contemporary therapies like thrombolysis/revascularization and ACE-inhibition had been established. These early trials also excluded patients with overt heart failure or those who had concerning signals, such as soft hemodynamics.

The CAPRICORN trial sought to test the hypothesis that early initiation of carvedilol in patients with AMI complicated by heart failure and LV dysfunction would reduce morbidity and mortality compared to placebo.

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Patients Eligible patients were 18 years or older with a stable, definite myocardial infarction occurring 3-21 days prior to randomization with either a left ventricular ejection fraction of ≤40% or a wall motion index score of ≤1.3 and who were receiving an ACE inhibitor for at least 48 hr and were on a stable dose for at least 24 hr.

Patients could have received IV diuretics during the acute phase but were excluded if they continued to require IV diuretics or inotropes or had uncontrolled heart failure. Other reasons for exclusion included unstable angina, SBP <90 mmHg, heart rate <60 bpm or unstable insulin dependent diabetes. Patients with any other indication to receive beta blockers were also excluded as were individuals on inhaled beta 2 agonists or steroids.

Baseline characteristics The average age of patients was 63 years and over 70% were men. Approximately one third of patients had a prior MI, more than 20% had diabetes and 50% had hypertension. The average ejection fraction was 32% and over half of patients had an anterior MI. Patients were hemodynamically stable with an average blood pressure slightly above 120/70 mmHg and heart rate of 77 beats per minute. Nearly 50% of patients underwent thrombolysis or angioplasty for the primary MI and, at the time of randomization, 98% of patients were on an ACE inhibitor and 86% were on aspirin.

Procedures Patients received either carvedilol or an identical placebo. Study medication was titrated up to the highest tolerated dose for each patient, to a maximum of 25 mg twice daily. The initial dose was 6.25 mg twice daily. If not tolerated, it was re-administered or reduced by half. If that dose was not tolerated the patient received no study medication but was followed up anyway. After successful initial dosing the patient returned as an outpatient every 3-10 days for assessment of tolerability and further up-titration. In the absence of adverse events or clinical heart failure and if the heart rate was >50 bpm and the systolic BP was >80 mmHg, the dose was increased to the next level. The patient remained in the outpatient department for 2hr to ensure that no side effects ensued.

During the maintenance period patients were reviewed every 3 months during the first year and every 4 months thereafter. Investigators were encouraged to review the dose of study medication at every visit and to ensure that doses of other drugs, especially ACE inhibitors, were adjusted accordingly to achieve optimum dose levels.

Endpoints The original primary endpoint was all-cause mortality and the trial was intended to run until a total of 633 primary endpoint events occurred. However, during a masked analysis the data and safety monitoring committee noted that overall mortality was lower than predicted and that the study could not be completed with the original sample size and power as planned. The steering committee, therefore, designated co-primary endpoints. The first was a new composite primary endpoint of all-cause mortality or cardiovascular hospital admission and the second was all-cause mortality.

The trial was still intended to run until 633 primary endpoint events occurred with the original sample size. The alpha (false-positive) was divided between the 2 primary endpoints so that the composite endpoint of all-cause mortality and cardiovascular hospitalization was tested at 0.045 and all-cause mortality was tested at 0.005. Secondary endpoints included sudden death, hospitalization for heart failure, recurrent nonfatal MI, and all-cause mortality or nonfatal MI.

Results 1,959 patients were included in the final analysis; 984 in the placebo group and 975 in the carvedilol group. The mean follow-up was 1.3 years. Compared to placebo, carvedilol did not significantly reduce the composite primary endpoint of all-cause death or cardiovascular hospitalization (HR 0.92; 35% vs 37%; 95% CI 0.80-1.07) or all-cause death alone (HR 0.77; 12% vs 15%; 95% CI 0.6-0.98).

The authors present the all-cause mortality result as positive; however, it is NOT. In table 1, the p for all-cause mortality is 0.031, which is >0.005. Thus, there is a good chance that the mortality result represents a false positive finding.

For the secondary endpoints, there were reductions in nonfatal MI and the combined endpoint of all-cause death or nonfatal MI for patients in the carvedilol group but these results are based on a relatively small number of events.

Of the 940 patients who entered the maintenance phase in the carvedilol group, 74% reached the maximum dose of 25 mg bid while 11% and 7% reached 12.5 mg bid and 6.25 mg bid.

There is no subgroup data or safety data presented in the main paper.   

Conclusions In patients with AMI complicated by heart failure and significant LV dysfunction, carvedilol did not significantly reduce all-cause death or cardiovascular hospitalizations compared to placebo.

This trial is often presented and discussed as a positive trial but it is not. The appropriately powered endpoint in this case was the composite primary endpoint, which was clearly negative.

The difference in all-cause mortality is based on a small number of events with a post-hoc power of 19.3% at the prespecified alpha of 0.005. The reported p-value for all-cause mortality was 0.031, which was much higher than the prespecified p value of ≤ 0.005 to declare a positive result. Due to the underpowered nature of all-cause death, the investigators chose to make the alpha as low as it was to avoid making false positive claims but then they did so anyway!

While power is generally taught to infer a trial’s strength to avoid false negative results, low power also increases a trial’s susceptibility to false positive results. We have discussed this with small trials involving magnesium and nitrates, which were highlighted by the meta-analyses presented in the ISIS 4 publication.

In conclusion, CAPRICORN was a negative trial. Its primary results were negative and differences in secondary endpoints, including the reduction in death, should be viewed as “hypothesis generating” only. It does not clearly establish a beneficial role for beta blockers in post-MI patients with significant LV dysfunction and heart failure.

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Lancet 1994;344(8922):563-570

Background: Several randomized trials have assessed the benefits of coronary artery bypass graft surgery (CABG) in patients with chronic stable angina. We reviewed three major trials in this area: The Veterans Administration Cooperative Study, the European Coronary Surgery Study, and the CASS study. These trials yielded divergent results, likely due to differences in patients included and surgical conduits used.

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The aim of this study was to conduct a patient-level meta-analysis of these three major trials, plus four additional smaller trials, to compare the long-term effects, at 10 years, of coronary artery bypass surgery versus medical therapy.

Note to readers: We are including this meta-analysis among our reviews since it’s frequently referenced when discussing the benefits of coronary artery bypass surgery.

Patients: Patients were included from 7 trials of coronary artery bypass surgery in chronic stable angina. Patients entered the trials between 1972 and 1984. Left ventricular systolic function was considered abnormal if the ejection fraction was < 50%. Coronary artery was considered to be diseased if it had a stenosis > 50%. Angiographic data were available from all trials except one of the four smaller trials.

Baseline characteristics: The study included a total of 2,649 patients; 1,324 patients were assigned to receive surgery and 1,325 were assigned to receive medical therapy. The three major trials contributed 2,233 (84.3%) patients while the four smaller trials combined contributed 416 (15.7%) patients. The average age of patients was 51 years with 97% being men. The mean ejection fraction was 59%. About 60% had prior myocardial infarction, 26% had hypertension, 4% had heart failure, 10% had diabetes, and 84% had smoking history.

Approximately 10% had single vessel disease, 32% had two-vessel disease, and 51% had three-vessel disease. Left main disease was present in about 7% of the patients, and about 59% had proximal left anterior descending artery disease.

Procedures: Individual patients’ data were collected on a standardized form. Patients in the trials were randomly assigned to coronary artery bypass surgery or medical therapy.

Endpoints: The primary end point was all-cause death. The statistical analysis was performed based on the intention-to-treat principle, irrespective of crossover. Authors also sought to assess the interaction of treatments based on the extent of coronary artery disease, left ventricular dysfunction and some comorbid conditions.

Results: The authors reported mortality at 5, 7 and 10 years. In this review, we will focus on the 10 years results as this was the intention of the study and most patients had 10-year follow-up data available. Of those assigned to surgery, 93.7% underwent the procedure, while 37.4% of patients initially assigned to medical therapy ended up having surgery. Among the patients assigned to surgery, the 30-day operative mortality was 3.2%. The mean number of grafts used was 2.4 and 9.9% of the patients received an internal mammary artery graft.

Antiplatelets were used by 18.8% of the patients in the medical arm and 25.5% in the surgical arm.

CABG significantly reduced mortality compared to medical therapy alone (26.4% vs 30.5%, OR: 0.83, 95% CI: 0.70 – 0.98; p= 0.03). CABG reduced mortality in patients with left main disease (OR: 0.67; p= 0.24 “this is insignificant due to small sample size”) and in patients with three vessel disease (OR: 0.76; p=0.02). CABG also reduced mortality in patients with one or two vessel disease if they had left anterior descending artery disease (OR and p value for 10-years were not provided). Absolute values were not provided for any of these subgroups at 10-years.

Authors reported no significant interactions based on history of hypertension, smoking or prior myocardial infarction (no event rate or results of interaction testing were provided for these groups). At 5-years, patients with left ventricular dysfunction derived similar benefit with surgery compared to patients with normal left ventricular function (p for interaction= 0.90).

Conclusion: In patients with stable angina pectoris and > 50% stenosis in at least one of the major coronary arteries, coronary artery bypass surgery compared to medical therapy alone reduced death at 10-years with a number need to treat of approximately 24 patients. The benefit was seen in patients with left main disease, three vessel disease and patients with left anterior descending artery disease. No benefit was seen in patients with one or two vessel disease if they did not have left anterior descending artery disease.

Of note, unlike most current meta-analyses that rely on trial-level data, this type of meta-analysis provides significantly higher level of evidence as it uses patient-level data. This method allows for the categorization of patients based on uniform definitions, the ability to reperform the analysis and helps address some limitations in previous trials. For example, the current study used an intention-to-treat analysis, while the Veterans Administration Cooperative study used a "modified intention-to-treat analysis."

Despite these strengths, some limitations from the original trials carry over to this study such as the small number of patients with left main disease (about 7% of study population) and the infrequent use of internal mammary artery (about 10%). Furthermore, the advancement in both medical therapies as well as surgical techniques since the publication of this study, limit its external validity in the current era.

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Two seminal trials of ACEi in patients with acute myocardial infarction complicated by heart failure or left ventricular systolic dysfunction. See https://cardiologytrials.substack.com for full details

Lancet 1993;342:821-28.

Background The Survival After Ventricular Enlargement (SAVE) trial demonstrated that administration of the angiotensin converting enzyme inhibitor (ACEi) captopril, following MI complicated by LV dysfunction (EF ≤40%) but without clinical heart failure significantly improved morbidity and mortality over 3.5 years of follow-up.

Yet many post-MI patients at the time had clinical heart failure and this represented a vulnerable population of patients with significantly increased morbidity and mortality compared to those without clinical heart failure.

The Acute Infarction Ramipril Efficacy (AIRE) trial sought to test the hypothesis that administration of Ramipril to patients with AMI complicated by acute congestive heart failure would reduce morbidity and mortality vs a placebo.

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Patients Eligible patients were 18 years of age or older with a definite AMI occurring 2 to 9 days prior to randomization with clinical evidence of congestive heart failure at any time after the index MI. While clinical evidence of heart failure was mandatory for study entry, it could be transient and not necessarily present at the time of randomization. Patients were excluded with NYHA IV heart failure (these patients would receive ACEi therapy regardless), heart failure of primary valvular or congenital etiology, or patients with any recognized contraindications to ACEi therapy were excluded.

Baseline characteristics The average age of patients was 65 years and 74% were men. Approximately one quarter of patients had had a prior MI, 12% had diabetes, 30% had hypertension and smoking status was not listed. The ejection fraction of study participants was not systematically assessed as part of the study protocol. 62% had a Q wave MI and the predominant location was anterior. The mean time to randomization was 5 days. Approximately 60% of patients received thrombolysis. The average blood pressure and heart rate were not provided. At the time of randomization 22% of patients were receiving a beta blocker and 12% digoxin.

Many more patients (52,019) were reviewed than ultimately enrolled (1,986). The main reasons for exclusion were no definitive MI (21,302) and no definite heart failure (16,989). The authors estimate that among eligible patients with a definitive MI and heart failure that approximately half were enrolled. Information on those enrolled versus not enrolled was not provided.

Procedures Patients were initiated on Ramipril 2.5 mg twice daily or matching placebo for 2 days after which the dose was increased to 5 mg twice daily. If patients could not tolerate the 5 mg twice daily dose they were discharged on 2.5 mg twice daily. For patients who could not tolerate the 2.5 mg dose they were given 1.25 mg twice daily for 2 days with attempts to up-titrate to 2.5 mg and 5 mg at discharge. For patients that could not tolerate at least 2.5 mg twice daily at discharge they were NOT discharged on the 1.25 mg dose. These patients were withdrawn from study treatment but followed up at the prespecified visit intervals and were included in the intention-to-treat analysis.

Outpatient visits were scheduled at 1 month and 3 months following discharge from the index hospitalization and every 3 months thereafter until study close. Monitoring of renal function and electrolytes was done at the discretion of study investigators based on their normal practice. During follow up patients could be started on any medication with exception of an ACEi.

Endpoints The primary study endpoint was all-cause mortality. The secondary endpoint was time to first event including (death, progression to NYHA class 4 heart failure, reinfarction or stroke).

The investigators estimated they would need a sample size of 2,000 patients to detect a 25% relative reduction in the risk of death with 80% power and 2-sided alpha of 5%. This was based on an estimated death rate of 20% at 15 months in the placebo group and 15% in the Ramipril group.

Results 2,006 patients were recruited from 144 centers in 14 countries. However, 20 patients from 1 center were excluded from the final analysis due to inconsistencies in the data. According to investigators the exclusion of these patients did not meaningfully change the final results. The final analysis included 1,986 patients; 1004 in the Ramipril group and 982 in the placebo group.

90% of study participants were discharged from the hospital on study drug. In the Ramipril group, 77% were on the 5 mg dose, 14% were on the 2.5 mg dose and 9% were on no therapy. In the placebo group, 86% were on the 5 mg dose, 7% on the 2.5 mg dose and 7% on no therapy.Patients were followed for an average of 15 months and only 1 was lost to follow-up.

Compared to placebo, Ramipril significantly reduced all cause death by 27% (17% vs 23%; p = 0.002). Ramipril also significantly reduced the secondary composite endpoint of time to first validated event (including death, progression to severe heart failure, reinfarction or stroke) by 19% (28% vs 34%; p = 0.008). Differences in this composite endpoint were mainly driven by death and progression to severe heart failure.

Examination of subgroups showed no evidence of treatment effect heterogeneity but again, similar to the SAVE trial, the size of the trial limits subgroup testing.

Premature withdrawals from study drug, not including death, occurred in 352 patients in the Ramipril group compared to 318 in the placebo group. Intolerance to the drug was cited as a factor in 126 of the Ramipril withdrawals and 68 of the placebo withdrawals whereas progression to severe heart failure was cited in 58 Ramipril withdrawals and 92 placebo. Syncope was more common in Ramipril treated patients compared to placebo (2.4% vs 1.7%) and so was hypotension (4.2% vs 2.3%) but not renal failure (1.5% vs 1.2%).

Conclusions In patients with AMI complicated by clinical congestive heart failure, Ramipril significantly reduced death over 1.3 years of follow-up with a number needed to treat of approximately 17 patients.

Ramipril also significantly reduced a composite of events, which were mainly driven by death and progression to severe heart failure.

Unlike the SAVE trial, which did not estimate a particular sample size for hypothesis testing, AIRE was specifically designed to test whether Ramipril would reduce death by 25% over 15 months and indeed, it did! Thus, results from AIRE not only support but add legitimacy to findings from SAVE.

One perceived limitation of AIRE, particularly when viewed through a contemporary lens, is its lack of ejection fraction estimation. There should be no doubt that these were sick patients in whom, significant LV dysfunction would have been present in most. We base this claim on the observation that the death rate in AIRE at 1.3 years in the placebo group was nearly equal to SAVE at 3.5 years (23% vs 25%). This highlights that development of clinical heart failure (regardless of LV function) confers a worse prognosis than LV dysfunction without heart failure.

In our opinion, the external validity of AIRE is high for a trial performed 30 years ago. The average start date for treatment was 5 days post MI complicated by clinical heart failure. This is longer than we would anticipate in contemporary practice by 2 or 3 days but not unreasonable, especially for post-MI patients with tenuous hemodynamics requiring intravenous diuretic therapy.

Furthermore, the dose titration parameters and follow up schedule in AIRE can be approximated in clinical practice. Also, no obvious treatment effect heterogeneity was noted across important subgroups (e.g., age > vs < 65 years) but these analyses are limited due to the overall sample size. Finally, no strict limits were placed on blood pressure and heart rate at study entry.

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NEJM 1992;327:669-77

Background After a large heart attack, cardiac hemodynamics are altered, which leads to a series of changes in the heart muscle itself. The immediate consequence of a large heart attack is decreased myocardial contractility. This leads to a reduction in stroke volume and cardiac output. Compensatory mechanisms governed by the renin-angiotensin-aldosterone system and sympathetic nervous system become activated and may lead to ventricular dilation or “remodeling”, which has negative short and long-term consequence for the heart muscle.

By the mid-1980’s, angiotensin converting enzyme inhibitors (ACEi) were commonly used for patients with chronic systolic heart failure and laboratory work had shown they could improve ventricular remodeling, reduce heart failure and prolong survival in animal models of AMI.

Several studies had also shown promise in humans but they were too small to test hypotheses involving hard clinical endpoints. The Survival and Ventricular Enlargement (SAVE) trial sought to test the hypothesis that administration of captopril to patients with AMI complicated by left ventricular dysfunction but who did not have overt heart failure requiring vasodilatory therapy would reduce morbidity and mortality over long-term follow-up.

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Patients Eligible patients were between 21 to 80 years of age with a definite myocardial infarction occurring 3 to 16 days prior to randomization with a left ventricular ejection fraction (EF) ≤40%, measured by radionuclide ventriculography. Patients were excluded with relative contraindications to ACEi or if an ACEi was indicated for treatment of symptomatic congestive heart failure or systemic hypertension. Other exclusion criteria included serum creatinine >2.5 mg/dl, other conditions limiting survival (unspecified) or who had an unstable course following AMI (also unspecified).

Baseline characteristics The average age of patients was 59 years and 82% were men. Approximately one third of patients had a prior MI, more than 20% had diabetes, 40% had hypertension and over 50% were current smokers. The average ejection fraction was 31% and over half of patients had an anterolateral Q wave MI. The mean time to randomization was 11 days. Prior to randomization approximately a third received thrombolysis, over 50% underwent coronary angiography, and approximately 25% underwent either percutaneous coronary angioplasty or coronary artery bypass surgery. At the time of randomization, the average blood pressure was 113/70 mmHg and heart rate was 78 beats per minute. Within 24 hours of randomization approximately one third of patients received a beta blocker and a quarter received digoxin.

Procedures There was a mini run-in period where all 2,250 eligible patients were given a test dose of 6.25 mg of captopril. This led to exclusion of 19 patients (3 for ischemic discomfort and 16 for symptomatic hypotension).

Patients received either captopril or placebo. The initial dose of the blinded study drug was 12.5 mg but could be administered at 6.25 mg to patients who had marked, yet asymptomatic, reduction in BP with the run-in dose. The target dose was 25 mg three times a day by the end of the in-hospital phase and was gradually increased to 50 mg three times a day unless side effects occurred. There was no prespecified level of blood pressure in the titration regimen.

Outpatient visits were scheduled 2 weeks following randomization and then every 3 months during year 1 and every 4 months thereafter. Compliance with the study drug was assessed by pill count.

Endpoints There were no prespecified hypothesis tests used to determine sample size. Prospectively defined measures of outcomes included all cause death, cardiovascular death, incidence of clinical congestive heart failure and first hospitalization for heart failure. Once the clinical endpoint committee was notified of a diagnosis of clinical heart failure the study medication was discontinued so open-label therapy with an ACEi could be started.

Results 2,231 patients were included in the final analysis; 1116 in the placebo group and 1115 in the captopril group. The mean follow-up was 3.5 years. Blood pressure increased from baseline in both groups but to differing extents. At 3 months, BP was 125/77 in the placebo group compared to 119/74 in the captopril group. The average heart rate was 74 in both groups.

Compared to placebo, captopril significantly reduced all cause death by 19% (20% vs 25%; p = 0.019) and cardiovascular death by 21% (17% vs 21%; p = 0.014). It also reduced clinical heart failure by 37% (11% vs 16%; p <0.001), heart failure hospitalization (14% vs 17%; p = 0.019), and nonfatal MI (12% vs 15%; p = 0.015).

Examination of subgroups for the endpoints of all-cause mortality and cardiovascular mortality reveals the effect of captopril was generally preserved across groups; however, given the size of the trial we feel that all subgroup analyses are limited.

At 1 year, 82% of patients in the placebo group and 79% of patients in the captopril group were still taking their assigned therapy and at the end of the study it was 73% and 70%. In the captopril group, 79% who were still taking the assigned drug were on the target dose by the end of the study. Side effects that occurred more often in the captopril group included dizziness (5%), altered taste (2%), cough (6%) and diarrhea (2%).             

Conclusions In patients with AMI complicated by significant LV dysfunction but not overt clinical heart failure, captopril significantly reduced death over 3.5 years of follow-up with a number needed to treat of approximately 20 patients. Statistically significant reductions were noted across all prespecified outcomes including cardiovascular mortality, incident congestive heart failure, hospitalization for heart failure and nonfatal MI. No obvious treatment effect heterogeneity was noted across subgroups of patients but these analyses were limited due to the overall sample size.

We urge caution in accepting these results, which may seem robust on the surface. A 20% relative reduction and 5% absolute reduction in death may be unrealistic without much precedent from previous trials to base this on. Had the authors sought to test a more conservative estimate of mortality reduction, like 10%, the sample size would have needed to be over 4x higher. We estimate that 9,094 patients would be required to show a relative reduction of 10% or 2.5% absolute reduction at an alpha of 0.05 and power of 80%.

From a clinical translation standpoint, it should be noted that patients were not eligible for enrollment until at least 3 days following AMI and the average start date was day 11.

Patients over 80 years of age were excluded and a mini run-in period with a test dose of captopril was given which led to the exclusion of 16/2,250 eligible participants. Despite these limits, in many other ways, external validity was high, especially compared to earlier beta blocker trials. No limits were placed on blood pressure and heart rate at study entry and dose titration protocols were not strictly governed.

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Discussion of two landmark trials of ACEi and nitrates in acute coronary syndrome. ISIS-4 had also an arm for magnesium. The story of magnesium is very interesting!!!

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