Cardiology Trials – Détails, épisodes et analyse

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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