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Correspondence |

CilostazolEvidence of Cilostazol Risks and Benefits: Same Evidence, Different Conclusions FREE TO VIEW

Sergio Bellmunt, MD; Pablo Alonso-Coello, MD, PhD
Author and Funding Information

From the Hospital de la Santa Creu i Sant Pau - Angiology, Vascular and Endovascular Surgery (Dr Bellmunt); Institute of Biomedical Research (IIB Sant Pau) (Drs Bellmunt and Alonso-Coello); and Iberoamerican Cochrane Center (Dr Alonso-Coello).

Correspondence to: Sergi Bellmunt, MD, Angiology, Vascular and Endovascular Surgery, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 171, Barcelona, Barcelona 08041, Spain; e-mail: sbellmunt@santpau.cat


Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Bellmunt participated as a consultant to Otsuka Pharmaceutical Co during the reevaluation of cilostazol by the European Medicines Agency. Drs Bellmunt and Alonso-Coello are coauthors of “Antithrombotic Therapy in Peripheral Artery Disease” in the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(2):435-436. doi:10.1378/chest.13-1791
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Published online
To the Editor:

The risk-benefit ratio of cilostazol in claudication was recently reevaluated by the European Medicines Agency (EMA).1 Around the same time, the topic was discussed during the development of the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (AT9).2 The differences between the two entities in interpreting the evidence are of concern. Having participated in both processes, we highlight here the most important discrepancies.

The EMA stated that the modest benefits of cilostazol are only greater than its risks in a limited subgroup of patients. It has restricted its use in patients with claudicant disease who have had recent coronary events or undergone coronary stent treatments and also stated cilostazol should not be given to patients also receiving two or more additional antiplatelet or anticoagulant medicines.

In contrast, the AT9 panel concluded cilostazol is more likely to confer benefits than harm in patients with claudication and that the rate of adverse effects is similar to that of placebo. Confidence in the evidence, however, is low.

The safety of cilostazol can be further evaluated by taking indirect evidence in coronary patients into account. In studies comparing patients receiving aspirin and thienopyridine to other patients receiving aspirin, thienopyridine, and cilostazol, the addition of cilostazol showed a protective effect in major adverse cardiovascular events (myocardial infarction, stroke, and death) and no differences in major bleeding (OR, 0.72; 95% CI, 0.60-0.86; 547 events; and OR, 1.07; 95% CI, 0.66-1.73; 68 events, respectively).3,4

On what basis did the EMA restrict the drug? The EMA reevaluation was initially triggered by a safety report on cilostazol. No one disputes that drug safety reports are crucial to monitor and evaluate adverse events, but these data were not considered during the evaluation process. In our opinion, however, such action in this case was appropriate because it was unclear whether the adverse events detected in the safety report were due to the drug, to the patients’ cardiovascular condition, or to other concomitant drugs. Reading the EMA recommendations, it seems that the EMA values an unlikely potential increase in the risk of adverse events—not observed to date in large randomized controlled trials—more highly than a likely improvement in the quality of life for these patients.

Although we do not share the EMA’s restrictions, these are not incompatible with the AT9 guidelines. We can affirm that our recommendations are still totally valid worldwide.

References

Cilostazol-containing medicines. European Medicines Agency website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/03/news_detail_001746.jsp&mid = WC0b01ac058004d5c1. Accessed July 30, 2013.
 
Alonso-Coello P, Bellmunt S, McGorrian C, et al; American College of Chest Physicians. Antithrombotic therapy in peripheral artery disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2_suppl):e669S-e690S.
 
Tamhane U, Meier P, Chetcuti S, et al. Efficacy of cilostazol in reducing restenosis in patients undergoing contemporary stent based PCI: a meta-analysis of randomised controlled trials. EuroIntervention. 2009;5(3):384-393. [CrossRef] [PubMed]
 
Jang JS, Jin HY, Seo JS, et al. A meta-analysis of randomized controlled trials appraising the efficacy and safety of cilostazol after coronary artery stent implantation. Cardiology. 2012;122(3):133-143. [CrossRef] [PubMed]
 

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References

Cilostazol-containing medicines. European Medicines Agency website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/03/news_detail_001746.jsp&mid = WC0b01ac058004d5c1. Accessed July 30, 2013.
 
Alonso-Coello P, Bellmunt S, McGorrian C, et al; American College of Chest Physicians. Antithrombotic therapy in peripheral artery disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2_suppl):e669S-e690S.
 
Tamhane U, Meier P, Chetcuti S, et al. Efficacy of cilostazol in reducing restenosis in patients undergoing contemporary stent based PCI: a meta-analysis of randomised controlled trials. EuroIntervention. 2009;5(3):384-393. [CrossRef] [PubMed]
 
Jang JS, Jin HY, Seo JS, et al. A meta-analysis of randomized controlled trials appraising the efficacy and safety of cilostazol after coronary artery stent implantation. Cardiology. 2012;122(3):133-143. [CrossRef] [PubMed]
 
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