Critical appraisal of colchicine for the secondary prevention of cardiovascular diseases: a cumulative-dose meta-analysis

Sep 29, 2026

Uploaded by McQueen

Letter to the Editor critically examines Li et al’s cumulative-dose colchicine meta-analysis in secondary prevention of cardiovascular diseases. The appraisal highlights concerns that the ≥90 mg-day cutoff reflects an ecological, study-level construct rather than patient-level biology, and that aggregate odds ratios may distort time-to-event findings versus hazard ratios or restricted mean survival time. It also notes limitations in biomarker evidence, pooled trial heterogeneity, insufficient toxicity assessment beyond death, and lack of stratified evaluation for drug interactions and ancestry-related pharmacogenomic factors.

LanguageEnglish

CategoryHealthcare

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Pages2

Reading Time5 min

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Letter to the Editor

Methodological concerns with cumulative dose thresholds and aggregate analyses

Interpretation of biomarkers and immune plausibility

Heterogeneity of pooled trials and sensitivity considerations

Safety assessment limitations and interaction risks

Pharmacogenomic and ancestry stratification needs

Future synthesis recommendations and reporting guidance

Letter to the Editor Critical appraisal of “Colchicine for the secondary prevention of cardiovascular diseases: a cumulative-dose meta-analysis of randomized controlled trials including 31,397 subjects worldwide” Asra Amjad, MBBSa , Muhammad Junaid, MBBSb , Umair Ali, Pharm-Dc , Muddassir Khalid, MBBSd ,* To the Editor, Li et al’s new meta-analysis on cumulative colchicine dose and cardiovascular outcomes caught our attention [1] . Although this study provides helpful and instructive data, some methodological issues should be examined more closely since they might have increased the explored advantages of colchicine in secondary prevention. The suggested ≥90 mg-day barrier is an ecological fallacy and is a study-level construct rather thana patient-level biology. Genetic background, renal clearance, and adherence all influence pharmacokinetic variance. An individual participant data (IPD) study with exposure-response modeling is considerably more appropriate to account for drug exposure, renal state, and adherence because of these person-level intricacies, which make an aggregate cutoff risk oversimplification[2] . For occurrences that were reported as time-to-event outcomes, the study combined odds ratios. When dangers change over time, odds ratios based on total counts may skew the results. More trustworthy metrics, like hazard ratios or restricted mean survival time, are necessary in these situations to produce accurate estimates and guarantee clinical interpretability[3] . Although a decrease in C-reactive protein was mentioned as proof, even slight adjustments to one biomarker are insufficient to demonstrate a therapeutic effect. In order to connect biological effect with results, previous anti-inflammatory trials have demonstrated the necessity of a multi-marker inflammatory profile, including aDepartment of Medicine, Islamic International Medical College Rawalpindi Pakistan (Riphah International University), Islamabad, Pakistan, bDepartment of Medicine, Lady Reading Hospital, Peshawar, Pakistan, cDepartment of Pharmacy, University of Swabi, Swabi, Pakistan and dDepartment of Medicine, Nishtar Medical University, Multan, Pakistan Sponsorships or competing interests that may be relevant to the content are disclosed at the end of this article. *Corresponding author. Address: Department of Medicine, Nishtar Medical University, Nishtar Road, Multan, Pakistan. Tel.: +92 3330333544. [E-mail: dr.muddassirkhalid@gmail.com](E-mail: dr.muddassirkhalid@gmail.com) (M. Khalid). Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Annals of Medicine & Surgery (2026) 88:1060–1061 Received 5 October 2025; Accepted 13 November 2025 Published online 3 December 2025 [http://dx.doi.org/10.1097/MS9.0000000000004430](http://dx.doi.org/10.1097/MS9.0000000000004430) NLRP3 activation, neutrophil–lymphocyte ratio, and interleukin (IL)-1β activity [4] . This emphasizes that complete immune signals, not isolated surrogates, are the foundation of biological plausibility. A misleading sense of uniform efficacy is created when diverse trial contexts, such as post-myocardial infarction, percutaneous coronary intervention, chronic coronary artery disease, and stroke populations, are pooled. Crucially, CLEAR-SYNERGY (Colchicine and Spironolactone in Patients with Acute Myocardial Infarction/SYNERGY Stent Registry), the biggest acute MI study, showed no benefit and ought to be given the proper weight in sensitivity analysis[5] . Conclusions run the risk of overstating generalizability across extremely diverse populations if subtle weighting is not used. Clinically significant toxicities such as myopathy, marrow suppression, and gastrointestinal intolerance were not sufficiently addr

FAQs

Why is the ≥90 mg-day barrier considered problematic in this appraisal?

It is described as an ecological fallacy and a study-level construct rather than patient-level biology, because genetics, renal clearance, and adherence influence pharmacokinetic variability.

What concerns are raised about using odds ratios for time-to-event outcomes?

When risks change over time, odds ratios based on total counts may bias results; the letter calls for hazard ratios or restricted mean survival time for more accurate and clinically interpretable estimates.

What does the letter suggest to improve safety and applicability of findings?

It argues that toxicities beyond death (e.g., myopathy, marrow suppression, GI intolerance) were insufficiently addressed, and recommends stratified safety studies accounting for medication interactions and ancestry-related pharmacogenomic differences.

Sep 29, 2026

Uploaded by McQueen