Therapeutics
Review: Dual-antiplatelet therapy does not reduce recurrent stroke but can increase ICH
Lee M, Saver JL, Hong KS, et al. Risk–benefit profile of long-term dual- versus single-antiplatelet therapy among patients with ischemic stroke: a systematic review and meta-analysis. Ann Intern Med. 2013; 159:463-470.
Clinical impact ratings: F ★★★★★★✩ H ★★★★★✩✩ N ★★★★★✩✩ Question
Source of funding: No external funding.
In patients with ischemic stroke or transient ischemic attack (TIA), how do long-term dual- and single-antiplatelet therapies compare for recurrent stroke and intracranial hemorrhage (ICH)?
For correspondence: Dr. B. Ovbiagele, Medical University of South Carolina, Charleston, SC, USA. E-mail: [email protected]. ■
Commentary
Review scope Included studies compared dual- and single-antiplatelet therapy for ≥ 1 year in patients with a history of ischemic stroke or TIA. Exclusion criteria were aspirin dose < 50 mg/d or > 325 mg/d, > 50% of patients with atrial fibrillation, or dual-antiplatelet therapy in > 10% of comparator group. Primary outcomes were recurrent stroke and ICH (including traumatic brain hemorrhage). Secondary outcomes included major gastrointestinal (GI) bleeding.
Review methods PubMed, EMBASE/Excerpta Medica (both to Mar 2013), Cochrane Central Register of Controlled Trials, reviews, and reference lists were searched for randomized controlled trials (RCTs). 7 RCTs (n = 39 574, mean age range 63 to 67 y, 63% to 72% men, treatment duration 1.3 to 3.5 y) met selection criteria. Studies compared clopidogrel (2 RCTs) or dipyridamole (2 RCTs) plus aspirin with aspirin alone; clopidogrel (1 RCT) or dipyridamole (1 RCT) plus aspirin with clopidogrel alone; and ticlopidine plus aspirin with ticlopidine alone (1 RCT). 3 RCTs had adequate randomization, 6 had clear allocation concealment, 5 had blinding, and 4 reported < 2% attrition.
Main results Dual-antiplatelet therapy did not differ from aspirin monotherapy for recurrent stroke or ICH and increased ICH compared with clopidogrel monotherapy (Table). dual-antiplatelet therapy increased major GI bleeding (Table).
Conclusion In patients with ischemic stroke or transient ischemic attack, long-term dual-antiplatelet therapy does not reduce recurrent stroke compared with monotherapy; it does increase risk for intracranial hemorrhage compared with clopidogrel monotherapy.
Lee and colleagues present evidence that, in patients with stroke, long-term dual-antiplatelet therapy with aspirin plus clopidogrel or dipyridamole does not reduce recurrent stroke compared with either aspirin or clopidogrel alone, but it is associated with increased risk for bleeding. This finding in patients with stroke is contrary to the benefit seen in patients with acute coronary syndrome (ACS), treated for 1 year after the event (1), who might therefore be exempt from the recommendation against dualantiplatelet therapy. Many cardiologists continue dual-antiplatelet therapy for longer than 1 year, both in patients with ACS and in those with coronary stents. A recent study showed that initiation of aspirin and clopidogrel within 24 hours of onset of TIA or stroke had benefits over aspirin alone (2). A similar ongoing trial in the USA is assessing the efficacy of treatment within 12 hours of onset (3). Hence, very early combination antiplatelet therapy, continued for 3 to 6 months, may yet show benefit in patients with stroke or TIA. There may be subsets of stroke patients who could benefit from combination antiplatelet therapy. A trial in patients with symptomatic intracranial artery stenosis suggested that intensive medical therapy, which included aspirin and clopidogrel, resulted in better outcomes than angioplasty and stenting, and a lower risk for stroke than predicted from earlier studies (4). Combination antiplatelet therapy is used routinely in patients with arterial stents. Combination antiplatelet therapy was superior to aspirin for stroke prevention in patients with atrial fibrillation, although there was an increased bleeding risk (5). Delineation of which subgroups of patients with stroke should be treated with combination antiplatelet therapy must await further studies, and combination therapy should not be used routinely in patients with stroke.
Dual- vs single-antiplatelet (aspirin or clopidogrel) therapy in patients with ischemic stroke* Outcomes
Comparators Number of trials (n)
Weighted event rates Dual† Single
RRR (95% CI)
NNT (CI)
11% (−1 to 22)
NS
Recurrent stroke
Aspirin
4 (11 373)
7.0%
7.8%
ICH
Aspirin
4 (11 373)
1.0%
1.1%
At 1.3 to 3.5 y
1% (−42 to 30)
RRI (CI)
NS
NNH (CI)
Recurrent stroke
Clopidogrel
2 (27 931)
9.0%
8.9%
1% (−7 to 8)
NS
ICH
Clopidogrel
2 (27 931)
1.3%
0.9%
46% (17 to 82)
237 (133 to 642)
1 (3020)
3.8%
1.9%
105% (31 to 220)
52 (25 to 174)
2 (27 931)
0.34%
0.13%
162% (10 to 522)
479 (149 to 7752)
Major GI bleeding
Aspirin Clopidogrel
*GI = gastrointestinal; ICH = intracranial hemorrhage; NS = not significant; other abbreviations defined in Glossary. Weighted event rates, RRR, RRI, NNH, and CI calculated from control event rates and relative risks in article using a random-effects model. †Clopidogrel or dipyridamole plus aspirin.
21 January 2014 | ACP Journal Club | Volume 160 • Number 2
Howard S. Kirshner, MD Vanderbilt University Medical Center Nashville, Tennessee, USA References 1. Yusuf S, Zhao F, Mehta SR, et al; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345:494-502. 2. Wang Y, Wang Y, Zhao X, et al; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11-9. 3. Platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT) trial. clinicaltrials.gov/show/ NCT00991029. (accessed 7 Nov 13). 4. Chimowitz MI, Lynn MJ, Derdeyn CP, et al; SAMMPRIS Trial Investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365:993-1003. 5. Connolly SJ, Pogue J, Hart RG, et al; ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009; 360:2066-78. © 2014 American College of Physicians
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JC5
Review: Dual-antiplatelet therapy does not reduce recurrent stroke but can increase ICH
Lee M, Saver JL, Hong KS, et al. Risk–benefit profile of long-term dual- versus single-antiplatelet therapy among patients with ischemic stroke: a systematic review and meta-analysis. Ann Intern Med. 2013; 159:463-470.
Clinical impact ratings: F ★★★★★★✩ H ★★★★★✩✩ N ★★★★★✩✩ Question
Source of funding: No external funding.
In patients with ischemic stroke or transient ischemic attack (TIA), how do long-term dual- and single-antiplatelet therapies compare for recurrent stroke and intracranial hemorrhage (ICH)?
For correspondence: Dr. B. Ovbiagele, Medical University of South Carolina, Charleston, SC, USA. E-mail: [email protected]. ■
Commentary
Review scope Included studies compared dual- and single-antiplatelet therapy for ≥ 1 year in patients with a history of ischemic stroke or TIA. Exclusion criteria were aspirin dose < 50 mg/d or > 325 mg/d, > 50% of patients with atrial fibrillation, or dual-antiplatelet therapy in > 10% of comparator group. Primary outcomes were recurrent stroke and ICH (including traumatic brain hemorrhage). Secondary outcomes included major gastrointestinal (GI) bleeding.
Review methods PubMed, EMBASE/Excerpta Medica (both to Mar 2013), Cochrane Central Register of Controlled Trials, reviews, and reference lists were searched for randomized controlled trials (RCTs). 7 RCTs (n = 39 574, mean age range 63 to 67 y, 63% to 72% men, treatment duration 1.3 to 3.5 y) met selection criteria. Studies compared clopidogrel (2 RCTs) or dipyridamole (2 RCTs) plus aspirin with aspirin alone; clopidogrel (1 RCT) or dipyridamole (1 RCT) plus aspirin with clopidogrel alone; and ticlopidine plus aspirin with ticlopidine alone (1 RCT). 3 RCTs had adequate randomization, 6 had clear allocation concealment, 5 had blinding, and 4 reported < 2% attrition.
Main results Dual-antiplatelet therapy did not differ from aspirin monotherapy for recurrent stroke or ICH and increased ICH compared with clopidogrel monotherapy (Table). dual-antiplatelet therapy increased major GI bleeding (Table).
Conclusion In patients with ischemic stroke or transient ischemic attack, long-term dual-antiplatelet therapy does not reduce recurrent stroke compared with monotherapy; it does increase risk for intracranial hemorrhage compared with clopidogrel monotherapy.
Lee and colleagues present evidence that, in patients with stroke, long-term dual-antiplatelet therapy with aspirin plus clopidogrel or dipyridamole does not reduce recurrent stroke compared with either aspirin or clopidogrel alone, but it is associated with increased risk for bleeding. This finding in patients with stroke is contrary to the benefit seen in patients with acute coronary syndrome (ACS), treated for 1 year after the event (1), who might therefore be exempt from the recommendation against dualantiplatelet therapy. Many cardiologists continue dual-antiplatelet therapy for longer than 1 year, both in patients with ACS and in those with coronary stents. A recent study showed that initiation of aspirin and clopidogrel within 24 hours of onset of TIA or stroke had benefits over aspirin alone (2). A similar ongoing trial in the USA is assessing the efficacy of treatment within 12 hours of onset (3). Hence, very early combination antiplatelet therapy, continued for 3 to 6 months, may yet show benefit in patients with stroke or TIA. There may be subsets of stroke patients who could benefit from combination antiplatelet therapy. A trial in patients with symptomatic intracranial artery stenosis suggested that intensive medical therapy, which included aspirin and clopidogrel, resulted in better outcomes than angioplasty and stenting, and a lower risk for stroke than predicted from earlier studies (4). Combination antiplatelet therapy is used routinely in patients with arterial stents. Combination antiplatelet therapy was superior to aspirin for stroke prevention in patients with atrial fibrillation, although there was an increased bleeding risk (5). Delineation of which subgroups of patients with stroke should be treated with combination antiplatelet therapy must await further studies, and combination therapy should not be used routinely in patients with stroke.
Dual- vs single-antiplatelet (aspirin or clopidogrel) therapy in patients with ischemic stroke* Outcomes
Comparators Number of trials (n)
Weighted event rates Dual† Single
RRR (95% CI)
NNT (CI)
11% (−1 to 22)
NS
Recurrent stroke
Aspirin
4 (11 373)
7.0%
7.8%
ICH
Aspirin
4 (11 373)
1.0%
1.1%
At 1.3 to 3.5 y
1% (−42 to 30)
RRI (CI)
NS
NNH (CI)
Recurrent stroke
Clopidogrel
2 (27 931)
9.0%
8.9%
1% (−7 to 8)
NS
ICH
Clopidogrel
2 (27 931)
1.3%
0.9%
46% (17 to 82)
237 (133 to 642)
1 (3020)
3.8%
1.9%
105% (31 to 220)
52 (25 to 174)
2 (27 931)
0.34%
0.13%
162% (10 to 522)
479 (149 to 7752)
Major GI bleeding
Aspirin Clopidogrel
*GI = gastrointestinal; ICH = intracranial hemorrhage; NS = not significant; other abbreviations defined in Glossary. Weighted event rates, RRR, RRI, NNH, and CI calculated from control event rates and relative risks in article using a random-effects model. †Clopidogrel or dipyridamole plus aspirin.
21 January 2014 | ACP Journal Club | Volume 160 • Number 2
Howard S. Kirshner, MD Vanderbilt University Medical Center Nashville, Tennessee, USA References 1. Yusuf S, Zhao F, Mehta SR, et al; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001; 345:494-502. 2. Wang Y, Wang Y, Zhao X, et al; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11-9. 3. Platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT) trial. clinicaltrials.gov/show/ NCT00991029. (accessed 7 Nov 13). 4. Chimowitz MI, Lynn MJ, Derdeyn CP, et al; SAMMPRIS Trial Investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365:993-1003. 5. Connolly SJ, Pogue J, Hart RG, et al; ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009; 360:2066-78. © 2014 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/929674/ by a University of California San Diego User on 05/21/2017
JC5
