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Risk–Benefit Profile of Long-Term Dual- Versus Single-Antiplatelet Therapy Among Patients With Ischemic Stroke: A Systematic Review and Meta-analysis

Meng Lee, MD; Jeffrey L. Saver, MD; Keun-Sik Hong, MD, PhD; Neal M. Rao, MD; Yi-Ling Wu, MS; and Bruce Ovbiagele, MD, MS
[+] Article and Author Information

From Chang Gung Memorial Hospital, Chiayi, Taiwan; University of California, Los Angeles, Los Angeles, California; Ilsan Paik Hospital, Goyang, South Korea; and Medical University of South Carolina, Charleston, South Carolina.

Financial Support: Dr. Lee was supported by grant CMRPG6B0111 from Chang Gung Memorial Hospital. Dr. Saver was supported by SPOTRIAS (Specialized Programs of Translational Research in Acute Stroke) award P50 NS044378 from the National Institutes of Health. Dr. Ovbiagele was supported by grant U01 NS079179 from the National Institutes of Health.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-2954.

Corresponding Author: Bruce Ovbiagele, MD, MSc, Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, CSB 301, MSC 606, Charleston, SC 29425-6160.

Current Author Addresses: Dr. Lee and Ms. Wu: Department of Neurology, Chang Gung University College of Medicine, Chang Gung Memorial Hospital, 6 West Sec., Chiapu Road, Puzi City, Chiayi County, Taiwan.

Drs. Saver and Rao: UCLA Stroke Center, 710 Westwood Boulevard, Los Angeles, CA 90095.

Dr. Hong: Department of Neurology, Ilsan Paik Hospital, 2240 Daewha-dong, Ilsanseo-gu, Goyang, South Korea.

Dr. Ovbiagele: Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, CSB 301, MSC 606, Charleston, SC 29425-6160.

Author Contributions: Conception and design: M. Lee, B. Ovbiagele.

Analysis and interpretation of the data: M. Lee, J.L. Saver, K. Hong, N.M. Rao, Y. Wu, B. Ovbiagele.

Drafting of the article: M. Lee, J.L. Saver, K. Hong, N.M. Rao, B. Ovbiagele.

Critical revision of the article for important intellectual content: M. Lee, J.L. Saver, K. Hong, N.M. Rao, B. Ovbiagele.

Final approval of the article: M. Lee, J.L. Saver, K. Hong, B. Ovbiagele.

Provision of study materials or patients: M. Lee.

Statistical expertise: M. Lee, Y. Wu.

Obtaining of funding: M. Lee.

Administrative, technical, or logistic support: M. Lee, B. Ovbiagele.

Collection and assembly of data: M. Lee, K. Hong.


Ann Intern Med. 2013;159(7):463-470. doi:10.7326/0003-4819-159-7-201310010-00006
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Background: Dual-antiplatelet regimens for prevention of recurrent stroke promote antithrombotic effects but may increase the risk for hemorrhage.

Purpose: To qualitatively and quantitatively examine the risk for recurrent stroke and intracranial hemorrhage (ICH) linked to long-term dual- and single-antiplatelet therapy among patients with ischemic stroke and transient ischemic attack.

Data Sources: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials through March 2013 without language restrictions.

Study Selection: The search identified 7 randomized, controlled trials that involved a total of 39 574 participants and reported recurrent stroke and ICH as outcome measures.

Data Extraction: All data from eligible studies were independently abstracted by 2 investigators according to a standard protocol.

Data Synthesis: Recurrent stroke risk did not differ between patients receiving dual-antiplatelet therapy and those receiving aspirin monotherapy (relative risk [RR], 0.89 [95% CI, 0.78 to 1.01]) or clopidogrel monotherapy (RR, 1.01 [CI, 0.93 to 1.08]). Risk for ICH did not differ between patients receiving dual-antiplatelet therapy and those receiving aspirin monotherapy (RR, 0.99 [CI, 0.70 to 1.42]) but was greater among patients receiving dual-antiplatelet therapy than among those receiving clopidogrel monotherapy (RR, 1.46 [CI, 1.17 to 1.82]).

Limitation: Agents used in dual- and single-antiplatelet therapies varied across trials, and the relatively modest number of trials limited subgroup analysis.

Conclusion: Compared with monotherapy, dual-antiplatelet therapy lasting more than 1 year after an index ischemic stroke or transient ischemic attack is not associated with a greater reduction in overall recurrent stroke risk. However, long-term dual-antiplatelet therapy is linked to higher risk for ICH than clopidogrel monotherapy in this patient population.

Primary Funding Source: Chang Gung Memorial Hospital.

Figures

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Appendix Figure.

Summary of evidence search and selection.

CENTRAL = Cochrane Central Register of Controlled Trials.

* Articles were excluded if the studies were reviews or duplicates, had treatment duration <1 y, compared 2 types of monotherapy or 2 types of dual therapy, or did not involve patients with stroke or transient ischemic attack.

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Figure 1.

Separate and pooled RR and 95% CI estimates for recurrent stroke (dual therapy vs. monotherapy), stratified by comparator.

A = aspirin; C = clopidogrel; CHARISMA = Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; D = dipyridamole; ESPRIT = European/Australasian Stroke Prevention in Reversible Ischaemia Trial; JASAP = Japanese Aggrenox Stroke Prevention vs. Aspirin Programme; MATCH = Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischaemic Attack or Ischaemic Stroke; PRoFESS = Prevention Regimen for Effectively Avoiding Second Strokes; RR = relative risk; SPS3 = Secondary Prevention of Small Subcortical Strokes.

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Figure 2.

Separate and pooled RR and 95% CI estimates for intracranial hemorrhage (dual therapy vs. monotherapy), stratified by comparator.

A = aspirin; C = clopidogrel; CHARISMA = Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; D = dipyridamole; ESPRIT = European/Australasian Stroke Prevention in Reversible Ischaemia Trial; JASAP = Japanese Aggrenox Stroke Prevention vs. Aspirin Programme; MATCH = Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischaemic Attack or Ischaemic Stroke; PRoFESS = Prevention Regimen for Effectively Avoiding Second Strokes; RR = relative risk; SPS3 = Secondary Prevention of Small Subcortical Strokes.

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