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Colchicine for the secondary prevention of cardiovascular events

Author/s: 
Fahim Ebrahimi, Ramin Ebrahimi, Maximilian Beer, Christof Manuel Schönenberger, Hannah Ewald, Matthias Briel, Perrine Janiaud, Julian Hirt

Rationale
People with cardiovascular disease are at risk of recurrent major adverse cardiovascular events, and chronic low‐grade inflammation may be a major underlying factor. Treatment with low‐dose colchicine has been proposed for the secondary prevention of cardiovascular events in individuals at high cardiovascular risk. A previous Cochrane review showed considerable uncertainty regarding the benefits and harms of this approach.

Objectives
To evaluate the benefits and harms of low‐dose colchicine in the prevention of cardiovascular events in adults with a history of stable CVD or following myocardial infarction or stroke.

Search methods
We conducted a comprehensive search of the literature until February 2025 using Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the drugs@FDA database, references of key papers, and references of included studies.

Eligibility criteria
Randomised controlled trials (RCTs) comparing the use of low‐dose colchicine for a minimum of six months versus any control intervention in patients of any age with cardiovascular disease (i.e. history of stable cardiovascular disease, previous myocardial infarction or stroke).

Outcomes
Our critical outcomes were all‐cause mortality, myocardial infarction, and serious adverse events.

Our important outcomes were cardiovascular mortality, stroke, all‐cause hospitalisations, coronary revascularisation (percutaneous coronary intervention (PCI)/angioplasty or coronary artery bypass graft (CABG)), quality of life, and gastrointestinal adverse events (i.e. diarrhoea, nausea, abdominal pain, or vomiting).

Risk of bias
Two authors independently assessed the risk of bias using the Cochrane RoB2 tool.

Synthesis methods
We conducted meta‐analyses using the random‐effects model. We generated forest plots to facilitate visualisation of the data. We did not perform any subgroup analysis.

We used GRADE to assess the certainty of evidence for all critical outcomes and for cardiovascular mortality, stroke, and coronary revascularisation. This was carried out by two review authors working independently.

Included studies
We included 12 studies involving 22,983 randomised participants. The follow‐up in the studies ranged from 6 to 80 months. Overall, 11,524 participants were assigned to low‐dose colchicine treatment and 11,459 were assigned to a control intervention, which constituted either usual care plus placebo or usual care only. The doses of colchicine used were 0.5 mg once or twice daily. At baseline, the mean age of participants ranged from 57 to 74 years. Most participants (79.4%) were male.

Synthesis of results
There is high‐certainty evidence that low‐dose colchicine treatment reduces the risk of myocardial infarction, with a risk ratio (RR) of 0.74 (95% confidence interval (CI) 0.57 to 0.96; 22,153 participants, 8 studies; I2 = 51%), yielding an absolute risk reduction of 9 fewer events (95% CI 16 fewer to 2 fewer) per 1000 patients, when the myocardial infarction rate is about 4% (36 events per 1000 patients) in the control group.

There is also high‐certainty evidence that low‐dose colchicine reduces the risk of stroke with a RR of 0.67 (95% CI 0.47 to 0.95; 22,483 participants, 10 studies; I2 = 40%), yielding an absolute risk reduction of 8 fewer events (95% CI 12 fewer to 1 fewer) per 1000 patients, when the stroke rate is about 2% (22 events per 1000 patients) in the control group.

There is high‐certainty evidence that the use of low‐dose colchicine does not increase the rate of serious adverse events (RR 0.98, 95% CI 0.94 to 1.02; 15,677 participants, 4 studies; I2 = 0%). However, gastrointestinal adverse events were more common under treatment with colchicine (RR 1.68, 95% CI 1.11 to 2.57; 22,185 participants, 10 studies; I2 = 91%).

For all other outcomes assessed, the evidence is of moderate certainty. Colchicine probably results in little to no difference in all‐cause mortality (RR 1.01, 95% CI 0.84 to 1.21; 22,747 participants, 10 studies; I2 = 1%; moderate‐certainty evidence), in cardiovascular mortality (RR 0.94, 95% CI 0.73 to 1.22; 22,271 participants; 8 studies; I2 = 13%; moderate‐certainty evidence), and coronary revascularisation (RR 0.83, 95% CI 0.64 to 1.08; 13,705 participants, 5 studies; I2 = 40%; moderate‐certainty evidence).

There is no evidence about the benefits or harms of colchicine on quality‐of‐life or on the risk of all‐cause hospitalisation.

Authors' conclusions
People with cardiovascular disease using low‐dose colchicine as secondary prevention for at least six months benefit from reduced rates of myocardial infarction and stroke, without an increase in serious adverse events. Moderate‐certainty evidence did not show a benefit from low‐dose colchicine for the risk of mortality (i.e. all‐cause and cardiovascular mortality) or coronary revascularisation rates. Colchicine use was associated with an increased risk of gastrointestinal adverse events, which were typically described as mild and transient in nature. Additional studies are warranted to investigate the benefits and harms of low‐dose colchicine in relevant subgroups and in specific indications, such as long‐term use in individuals with stable coronary artery disease versus limited‐time use following acute coronary syndrome.

Funding
Review author FE was supported by the Margot und Erich Goldschmidt & Peter René Jacobson Foundation. Review author CMS was supported by the Janggen Pöhn Foundation and the Swiss National Science Foundation (MD‐PhD grant Number: 323530_221860).

Registration
This review is based on its protocol, which is available via DOI 10.1002/14651858.CD014808, and a previous review, which is available via DOI 10.1002/14651858.CD011047.pub2.

Keywords 
Coronary Intervention coronary artery disease secondary prevention

Anticoagulation and Antiplatelet Therapy for Atrial Fibrillation and Stable Coronary Disease: Meta-Analysis of Randomized Trials

Author/s: 
Sina Rashedi, Mohammad Keykhaei, Alyssa Sato, Philippe Gabriel Steg

Background: The optimal long-term antithrombotic strategy in patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) remains uncertain. Individual randomized controlled trials (RCTs) had variations in their reported results and were not powered for effectiveness outcomes.

Objectives: This study aimed to pool the results of RCTs comparing the effectiveness and safety of oral anticoagulation (OAC) monotherapy vs OAC plus single antiplatelet therapy (SAPT) in patients with AF and stable CAD.

Methods: We systematically searched PubMed, Embase, and ClinicalTrials.gov until September 09, 2024. The primary effectiveness outcome was a composite of myocardial infarction, ischemic stroke, systemic embolism, or death. The primary safety outcome was major bleeding. We obtained unpublished results from principal investigators of the included RCTs, as needed, to calculate pooled HRs and 95% CIs and to perform prespecified subgroup analyses.

Results: Among 690 screened records, 4 RCTs with 4,092 randomized patients were included (2 using edoxaban, 1 using rivaroxaban, and 1 using any oral anticoagulant; mean age 73.9 years, 20.1% women). The median follow-up durations ranged from 12 to 30 months (overall estimated weighted mean follow-up of 21.9 months). There were no statistically significant differences between OAC monotherapy vs OAC plus SAPT in the primary effectiveness outcome (7.3% vs 8.2%; HR: 0.90; 95% CI: 0.72-1.12), myocardial infarction (1.0% vs 0.7%; HR: 1.51; 95% CI: 0.75-3.04), ischemic stroke (1.9% vs 2.1%; HR: 0.89; 95% CI: 0.57-1.37), all-cause death (4.2% vs 5.3%; HR: 0.94; 95% CI: 0.49-1.80), or cardiovascular death (2.4% vs 3.0%; HR: 0.79; 95% CI: 0.54-1.15). OAC monotherapy was associated with a lower risk of major bleeding than OAC plus SAPT (3.3% vs 5.7%; HR: 0.59; 95% CI: 0.44-0.79). Subgroup analyses did not show significant interactions for effectiveness but suggested that the magnitude of bleeding reduction may be greater among men (Pinteraction = 0.03) and among patients with diabetes mellitus (Pinteraction = 0.04).

Conclusions: In patients with AF and stable CAD, OAC monotherapy, compared with OAC plus SAPT, was not associated with a statistically significant increased risk of ischemic events but resulted in a significantly reduced risk of bleeding.

Keywords 
anticoagulants atrial fibrillation coronary artery disease ischemia platelet aggregation inhibitors

Management of Atrial Fibrillation

Author/s: 
Francis J Alenghat, Jason T Alexander, Gaurav A Upadhyay

Atrial fibrillation has a lifetime prevalence of 15% to 40% and predisposes patients to stroke and cardiac dysfunction. This JAMA Clinical Guidelines Synopsis focuses on recommendations for long-term management of AF, including new paradigms for rhythm control and stroke risk reduction.

Keywords 
atrial fibrillation coronary artery disease heart disease Cardiology Rhythm Disorders heart failure

Initial Invasive or Conservative Strategy for Stable Coronary Disease

Author/s: 
Maron, DJ, Hochman, JS, Reynolds, HR, Bangalore, S, O'Brien, SM, Boden, WE, Chaitman, BR, Senior, R, Lopez-Sendon, J, Alexander, KP, Lopes, RD, Shaw, LJ, Berger, JS, Newman, JD, Sidhu, MS, Goodman, SG, Ruzyllo, W, Gosselin, G, Maggioni, AP, White, HD, Bhargava, B, Min, JK, Mancini, GBJ, Berman, DS, Picard, MH, Kwong, RY, Ali, ZA, Mark, DB, Spertus, JA, Krishnan, MN, Elghamaz, A, Moorthy, N, Hueb, WA, Demkow, M, Mavromatis, K, Bockeria, O, Peteiro, J, Miller, TD, Szwed, H, Doerr, R, Keltai, M, Selvanayagam, JB, Steg, PG, Held, C, Kohsaka, S, Mavromichalis, S, Kirby, R, Jeffries, NO, Harrell, FE Jr, Rockhold, FW, Broderick, S, Ferguson, TB Jr, Williams, DO, Harrington, RA, Stone, GW, Rosenberg, Y, ISCHEMIA Research Group

Background: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain.

Methods: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction.

Results: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32).

Conclusions: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Keywords 
coronary artery disease cardiac ischemia cardiac interventions

The Underappreciated Problem of Cardiac Disease in Women

Barbra Streisand and Noel Bairey Merz, MD, director of the Streisand Women’s Heart Center at Cedars-Sinai in Los Angeles, California, discuss the problem of cardiovascular disease in women and especially coronary microvascular disease, which causes an unusual presentation of cardiac ischemic disease in women.

Keywords 
coronary artery disease coronary microvascular dysfunction audio podcast

Primary Prevention of Cardiovascular Disease

Author/s: 
Jain, A, Davis, AM

Atherosclerotic CVD remains the leading cause of death for people of most racial/ethnic groups. In 2010, the AHA suggested metrics of ideal cardiovascular health in 7 domains (blood pressure, physical activity, cholesterol, diet, weight, smoking, and blood glucose). There have since been multiple related guideline updates and scientific statements. In 2017, the ACC/AHA Task Force on Clinical Practice Guidelines commissioned an updated guideline integrating existing and new recommendations into a unified and “user-friendly” document on primary prevention of ASCVD.

Keywords 
CAD coronary artery disease guidelines American Heart Association American College of Cardiology CVD cardiovascular disease primary prevention

Meta-Analysis of Oral Anticoagulant Monotherapy as an Antithrombotic Strategy in Patients With Stable Coronary Artery Disease and Nonvalvular Atrial Fibrillation

Author/s: 
Lee, SR, Rhee, TM, Kang, DY, Choi, EK, Oh, S, Lip, GYH

Guidelines recommend oral anticoagulant (OAC) monotherapy without antiplatelet therapy (APT) in patients with nonvalvular atrial fibrillation (AF) with stable coronary artery disease (CAD) of >1 year after myocardial infarction or percutaneous coronary intervention. More evidences are required for the safety and efficacy of OAC monotherapy compared with OAC plus APT. PubMed, EMBASE, and Cochrane Database of Systematic Reviews were systematically searched up to February 2019. Nonrandomized studies and randomized clinical trials comparing OAC monotherapy with OAC plus single APT (SAPT) for patients with stable CAD and nonvalvular AF. The primary end point was major adverse cardiovascular events (composite of ischemic or thrombotic events) and secondary outcomes included major bleeding, stroke, all-cause death, and net adverse events (composite of ischemic, thrombotic, or bleeding events). From 6 trials, 8,855 patients were included. There was no significant difference in major adverse cardiovascular event in patients with AF treated using OAC plus SAPT compared with those treated with OAC monotherapy (hazard ratio [HR] 1.09; 95% confidence interval [CI] 0.92 to 1.29). OAC plus SAPT was associated with a significantly higher risk of major bleeding compared with OAC monotherapy (HR 1.61; 95% CI 1.38 to 1.87), as well as in terms of net adverse event (HR 1.21; 95% CI 1.02 to 1.43). There were no significant differences in rates of stroke and all-cause death. In conclusion, in this meta-analysis, OAC monotherapy and OAC plus SAPT treatment showed similar effectiveness, but OAC monotherapy was significantly associated with a lower risk of bleeding compared with OAC plus SAPT in patients with nonvalvular AF and stable CAD.

Keywords 
atrial fibrillation coronary artery disease CAD myocardial infarction stroke
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