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Contemporary Use of Dual Antiplatelet Therapy for Preventing Cardiovascular Events
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Contemporary Use of Dual Antiplatelet Therapy for Preventing Cardiovascular Events

Andrew M. Goldsweig, MD; Kimberly J. Reid, MS; Kensey Gosch, MS; Fengming Tang, MS; Margaret C. Fang, MD, MPH; Thomas M. Maddox, MD, MSc; Paul S. Chan, MD, MSc; David J. Cohen, MD, MSc; and Jersey Chen, MD, MPH
Use of dual antiplatelet therapy was modest for patients with existing cardiovascular disease for whom subgroup analysis from a landmark clinical trial suggested benefit in preventing cardiovascular events, and low for patients with multiple risk factors without established cardiovascular disease, for whom increased cardiovascular events were suggested.
Use of DAPT in patients with multiple risk factors who may be harmed by treatment was low and decreased. Given the increased risk of all-cause and cardiovascular mortality in this subgroup, the CHARISMA investigators concluded that there is no role for DAPT for primary prevention of CVD.18 It is reassuring to note that DAPT prescription for primary prevention was low in our study, but for unclear reasons, 3.5% of these patients were still prescribed DAPT. While it is possible that there was misclassification of patients into the 2 study groups (eg, either patients met CHARISMA criteria for established CVD which were not recorded in the registry or patients met undocumented exclusion criteria such as AF or PCI), we cannot exclude the possibility that a small number of patients with multiple cardiovascular risk factors were prescribed both aspirin and clopidogrel, either unaware that or choosing not to believe that this regimen might cause harm. Overall, it appears that clinicians have largely avoided the use of clopidogrel for primary prevention in patients with multiple risk factors. Outpatient registries such as PINNACLE may prove useful for monitoring the extent to which patients continue to receive DAPT despite evidence suggesting potential harm.

Physicians apply the CHARISMA subgroup analyses’ findings somewhat inconsistently, avoiding DAPT for the multiple risk factor subgroup but prescribing DAPT to a modest fraction of patients with established CVD. However, it is reasonable for clinicians to hold the findings of the 2 subgroup analyses to somewhat different standards. On one hand, because harm was suggested to be likely for patients with multiple risk factors, clinicians would demand a high burden of proof that DAPT is truly safe and efficacious, thus limiting its use. On the other hand, some patients with known CVD may be at such high risk for recurrent events that DAPT was prescribed, even though the evidence of benefit from subgroup analyses was weak, because harm was unlikely.

Given the divergent CHARISMA subgroup results, physicians must employ a clinical judgment approach to DAPT therapy, with the goal of minimizing harm while selectively offering treatment to high-risk individuals even though evidence of benefit is not conclusive. Ultimately, a prospective randomized trial of DAPT would be required to conclude that DAPT benefits patients with established CVD; however, such a trial is unlikely because US patent protection for clopidogrel expired in 2012.17 In the absence of direct evidence from randomized clinical trials, comparative effectiveness studies may have to suffice for providing future evidence to guide optimal use of DAPT for patients with established CVD.

Limitations. Our study should be interpreted in the context of the following limitations. First, PINNACLE did not record all the CVD and risk factor information collected by the CHARISMA trial, and our modified definitions did not fully replicate CHARISMA entry criteria. Our study had fewer patients in the multiple risk factor subgroup relative to the established CVD subgroup compared with CHARISMA. Second, we do not know how many patients prescribed DAPT underwent PCI greater than 1 year prior to registry entry, and some physicians may elect to prescribe DAPT for a prolonged period for patients at elevated risk of stent thrombosis. The optimal duration of DAPT following PCI remains a subject of debate,12,18, 20 and several large, controlled trials to investigate this issue are ongoing.19 Lastly, our findings reflect the prescribing patterns of clinicians who report data to the PINNACLE registry. Data collection began in 2008, 2 years after the publication of CHARISMA; prescription patterns may differ at nonparticipating clinical practices, and our findings may not be generalizable.

CONCLUSION

In a large, community-based registry of outpatients with cardiovascular disease, we found that prescription rates of dual antiplatelet therapy for secondary prevention of MACEs in patients with established CVD were modest and stable over time. DAPT for primary prevention in asymptomatic patients with multiple cardiovascular risk factors was low and decreased, but it was still prescribed to 1 out of 30 patients despite evidence suggesting increased MACEs in this subgroup.

Acknowledgment

PINNACLE Registry is an initiative of the American College of Cardiology Foundation and MedAxiom. The Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership is a Founding Sponsor of the PINNACLE Registry. Bristol-Myers Squibb and Sanofi are manufacturers of clopidogrel, but have neither reviewed nor approved this manuscript.

Author Affiliations: Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, and Yale-New Haven Hospital, New Haven, CT (AMG); Saint Luke’s Mid America Heart and Vascular Institute, University of Missouri-Kansas City, Kansas City (KR, KG, FT, DJC, PSC); Department of Internal Medicine, University of California-San Francisco, San Francisco (MCF); Veterans Administration Eastern Colorado Health Care System and Department of Internal Medicine (Cardiology), University of Colorado, Denver (TMM); Kaiser Permanente, Mid-Atlantic Permanente Research Institute, Rockville, MD (JC).

Funding Source: This research was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR). The views expressed in this manuscript represent those of the authors, and do not necessarily represent the official views of the NCDR or its associated professional societies identified at www.ncdr.com. Dr Chen is supported by an Agency for Healthcare Research and Quality (AHRQ) Career Development Award (1K08HS018781-01). Dr Chan is supported by a Career Development Grant Award (K23HL102224) from the National Heart, Lung, and Blood Institute. Dr Maddox is supported by a Veterans Administration Health Services Research and Development Career Development Award.
 
Author Disclosures: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. 

Authorship Information: Concept and design (JC, DJC, MCF, AMG); acquisition of data (KJR, TMM); analysis and interpretation of data (PSC, JC, DJC, MCF, AMG, KG, KJR, TF, TMM); drafting of the manuscript (AMG, KJR, TMM); critical revision of the manuscript for important intellectual content (PSC, JC,DJC, MCF, AMG, TF, TMM); statistical analysis (AMG, KG, TF); and supervision (JC).
       
Address correspondence to: Jersey Chen, MD, MPH, Kaiser Permanente, Mid-Atlantic Permanente Research Institute, 2101 East Jefferson St, 3 West, Rockville, MD 20852. E-mail: jersey.chen@kp.org.
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