Colchicine and Acute Coronary Syndromes: A New Trick for an Old Drug? : Journal of Cardiovascular Pharmacology

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Commentary

Colchicine and Acute Coronary Syndromes: A New Trick for an Old Drug?

Amin, Ghadir*,†; Massoud, Gaelle MD*,†; Fares, Souha PhD*; Booz, George W. PhD§; Zouein, Fouad A. PhD*,†,¶

Author Information
Journal of Cardiovascular Pharmacology: November 2022 - Volume 80 - Issue 5 - p 631-632
doi: 10.1097/FJC.0000000000001358

Acute coronary syndromes (ACS) including ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, and unstable angina, constitute a major cause of morbidity and mortality worldwide despite advances in treatment.1 According to the American Heart Association, 31.6% of men and 15.1% of women over the age of 40 will suffer from myocardial infarction (MI).2 A combination of interventional and medical management is established for optimal treatment of ACS. Percutaneous coronary intervention or fibrinolytics is crucial for early reperfusion and can improve short- and long-term outcomes when coupled with appropriate medical therapy, including dual-antiplatelets, anticoagulants, statins, and ꞵ-blockers.1 Despite advances in treatment, the therapeutic management of ACS remains suboptimal because of the high risk of adverse cardiac events. Inflammation plays a well-documented role in atherosclerotic plaque formation, development, rupture, and subsequent MI complications.3 The subsequent events are believed to emanate from unresolved inflammation, referred to as residual inflammation.4

Colchicine was primarily introduced and approved for decades as an anti-inflammatory drug for gout and familial Mediterranean fever. More recently, colchicine has been explored as a potential drug in the field of cardiovascular diseases. The rationale for this involves the central mechanism of colchicine in inhibiting the function of microtubules and consequently blocking neutrophil chemotaxis and degranulation, and preventing the assembly of inflammasomes and the expression of cytokines.5 As these actions are pivotal in underpinning different cardiovascular diseases, the clinical efficacy and safety of the drug have been investigated in a range of conditions. Assessments have resulted in a well-defined recommendation for colchicine as a first-line treatment for acute and recurrent pericarditis.6 Contemporary studies are concerned with the clinical value of colchicine in coronary syndromes.

In their systematic review and meta-analysis, Bao et al7 assessed the use of colchicine in ACS by addressing endpoint parameters and adverse effects. Three databases were searched, PubMed, Embase, and CENTRAL. At the end of the selection, 9 randomized controlled trials of low risk of bias were included. Publication dates spanned the years 2012–2022. A total of 7207 patients were integrated into the analysis. Efficacy endpoint parameters included were recurrence of MI, coronary revascularization, and stroke. Colchicine was not able to significantly reduce the incidence of recurrent MI in ACS patients [RR 0.75, 95% confidence interval (CI), 0.49–1.14; P = 0.18; I2 = 33%]; however, the authors reported a significant reduction in revascularization (an index of tissue hypoxia) by 54% (RR 0.46, 95% CI, 0.29–0.73; P < 0.01; I2 = 1%) and stroke by 61% (RR 0.39, 95% CI, 0.18–0.81; P = 0.01; I2 = 0). There was no significant difference in all-cause mortality (RR 1.25, 95% CI, 0.70–2.24; P = 0.46; I2 = 10%). Nor was there an improvement in cardiovascular mortality. On safety endpoint parameters, the risk of infection was not affected; however, colchicine intervention was demonstrated to increase gastrointestinal adverse reactions (RR 1.89, 95% CI, 1.25–2.84; P < 0.01).

Although the efficacy and safety of colchicine has been become well-studied in the chronic form of coronary syndrome,8 this meta-analysis is the first to examine patients in the acute phase of the disease. One of the important considerations in this review is the conduction of analysis on separate well-defined indicators, rather than the general surrogate of total major adverse cardiovascular events “MACE.” It highlights the promising clinical value of colchicine for limiting ischemic events in ACS patients and alerts future studies on the gaps in proof or knowledge that need to be considered for further investigation. On the downside, the studies included in the analysis used different definitions for MI and did not report troponin levels, which perhaps weakens the interpretation of the results.

The most common adverse event associated with colchicine is gastrointestinal intolerance. Discrepancies were encountered in the studies involved pertaining to the presence or absence of loading doses and the duration of follow-up. Therefore, subgroup analysis was performed. A loading dose was not superior to the use of an ordinary dose suggesting that it holds no added benefit for ACS patients. Another notable finding is that GI effects may not persist with long-term treatment because tolerance seems to develop over time. The biological implications behind GI adverse events are well-studied,9 but clarifications on the increase in all-cause mortality are not yet available. The overall paucity of such fatal events, however, limits the power of this finding.

It is agreed that a new therapeutic target is needed to improve outcomes in ACS. Anti-inflammatory approaches are nowadays forecasted as the centerpiece for achieving better outcomes in cardiovascular diseases. Although the meta-analysis supports the anti-inflammatory effect of colchicine in ACS, it is a challenge to evaluate its effectiveness through prospective randomized clinical trials. The characteristics revealed for colchicine through emerging studies are encouraging. The low cost, ease of administration, pluripotent effects, and somewhat tolerable safety profile of colchicine arguably provide superiority over newer biologicals, particularly in developing countries, or favor its use as an adjunct medication with the newly approved monoclonal antibody canakinumab.10 Its narrow therapeutic index and approaching patent expiration date may be seen as unattractive features. Nevertheless, larger high-end point trials are warranted for definitive conclusion on the use of colchicine in ACS.

ACKNOWLEDGMENTS

GWB acknowledges the support of the Pharmacology Clinical Research Core of the University of Mississippi Medical Center.

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