Therapeutics
Review: Antiplatelet therapies are more effective in smokers than nonsmokers
Gagne JJ, Bykov K, Choudhry NK, et al. Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison. BMJ. 2013;347:f5307.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★✩✩ Question What are the relative efficacies of clopidogrel and newer antiplatelet agents in smokers and nonsmokers?
Overall, antiplatelet therapies, compared with control, reduce the composite outcome by 25% to 47% in smokers and by 8% to 18% in nonsmokers.
Review scope
Source of funding: No external funding.
Included studies evaluated clopidogrel, prasugrel, or ticagrelor and reported clinical outcomes separately for smokers and nonsmokers. Primary outcome was a composite of cardiovascular (CV) death, myocardial infarction, or stroke.
For correspondence: Dr. J.J. Gagne, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA. E-mail [email protected]. ■
Review methods MEDLINE, EMBASE/Excerpta Medica (both to Jul 2013), CINAHL, CAB Abstracts, Google Scholar, cardiology conference abstracts (American Heart Association, American College of Cardiology, European Society of Cardiology, and Heart Rhythm Society), systematic reviews, and reference lists were searched for randomized controlled trials (RCTs). 9 RCTs (n = 109 793, 31% smokers, follow-up range 30 d to 3 y) met selection criteria. Studies compared clopidogrel with aspirin (1 RCT); double-dose clopidogrel with standard-dose (1 RCT); and clopidogrel plus aspirin with aspirin alone (4 RCTs), with prasugrel plus aspirin (2 RCTs), and with ticagrelor plus aspirin (1 RCT). Risk for bias was low for all trials: 7 had adequate randomization; 8 had concealed allocation; all had blinded patients, personnel, and outcome assessments; and all reported adequate follow-up. Indirect analyses compared prasugrel and ticagrelor with the control groups from the 6 clopidogrel trials, and prasugrel with ticagrelor by smoking status.
Main results The main results are in the Table.
Conclusions Clopidogrel reduces a composite of cardiovascular death, myocardial infarction, or stroke more in smokers than in nonsmokers. Comparisons of antiplatelet therapies for reducing a composite of cardiovascular death, myocardial infarction, or stroke in smokers and nonsmokers* Direct comparisons
Number of trials (n)
RRR/RRI (95% CI) at 30 d to 3 y Smokers
Nonsmokers† RRR 8% (2 to 13)
Clopidogrel‡ vs control§
6 (74 498)
RRR 25% (17 to 33)
Prasugrel vs clopidogrel
2 (20 788)
RRR 29% (8 to 39)
Ticagrelor vs clopidogrel
1 (14 507)
RRR 17% (0 to 32)
RRR 11% (0 to 21)
Prasugrel vs control§
RRR 47% (36 to 56)
RRR 15% (5 to 24)
Ticagrelor vs control§
RRR 38% (22 to 50)
RRR 18% (7 to 28)
Prasugrel vs ticagrelor
RRR 15% (−9 to 33)
RRR 8% (−1 to 17)
Indirect comparisons||
RRI 3% (−12 to 20)
*Abbreviations defined in Glossary. RRR, RRI, and CI calculated from relative risks in article using a fixed-effect model. All patients received concurrent aspirin therapy in all but 1 clopidogrel-only group. †Never and former smokers. ‡Clopidogrel with or without aspirin. §Aspirin alone or lower dose of clopidogrel plus aspirin. ||Indirect analyses based on Bucher’s method for the 3 pairwise comparisons.
JC6
© 2014 American College of Physicians
Commentary Dual-antiplatelet therapy with aspirin and such P2Y12-receptor inhibitors as clopidogrel is an important component of treatment for patients with CV diseases (1). Smoking is a known CV risk factor that increases platelet reactivity. The meta-analysis by Gagne and colleagues supports prior observations that the benefit of clopidogrel in reducing CV events was seen primarily in smokers, with little benefit in nonsmokers. This supports the theory that smoking induces cytochrome P450 isoenzyme 1A2, increasing production of the active metabolite of clopidogrel, thereby increasing its efficacy in smokers (2). 1 study reported a gradient of increased risk for bleeding from nonsmokers to former and current smokers with clopidogrel (3). Several points are important for clinical practice. First, although the magnitude of benefit was lower in nonsmokers, clopidogrel still reduced the composite outcome (relative risk 0.92, 95% CI 0.87 to 0.98) in this group. Second, patients having percutaneous coronary intervention should receive dual-antiplatelet therapy for 1 to 12 months regardless of smoking status (4). Third, given increased efficacy and higher bleeding among smokers receiving clopidogrel, dosage adjustments may optimize outcomes, although no prospective data exist to support such adjustments. Prospective clinical studies with enrolment stratified by smoking status are needed to evaluate the impact of smoking on the efficacy and safety of varying dosages of P2Y12 inhibitors. For now, there are no indications to deprive nonsmokers of the benefits of P2Y12 inhibitors or to make any dose adjustments in smokers. It seems reasonable to counsel active smokers about the higher risk for bleeding with clopidogrel and urge them to stop smoking. Debabrata Mukherjee, MD, MS Texas Tech University El Paso, Texas, USA References 1. Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012;60:645-81. 2. Gurbel PA, Nolin TD, Tantry US. Clopidogrel efficacy and cigarette smoking status. JAMA. 2012;307:2495-6. 3. Berger JS, Bhatt DL, Steinhubl SR, et al; CHARISMA Investigators. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation. 2009;120:2337-44.19933933 4. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124:e574-651. 21 January 2014 | ACP Journal Club | Volume 160 • Number 2
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/929674/ by a Tufts University User on 07/31/2017
Review: Antiplatelet therapies are more effective in smokers than nonsmokers
Gagne JJ, Bykov K, Choudhry NK, et al. Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison. BMJ. 2013;347:f5307.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★✩✩ Question What are the relative efficacies of clopidogrel and newer antiplatelet agents in smokers and nonsmokers?
Overall, antiplatelet therapies, compared with control, reduce the composite outcome by 25% to 47% in smokers and by 8% to 18% in nonsmokers.
Review scope
Source of funding: No external funding.
Included studies evaluated clopidogrel, prasugrel, or ticagrelor and reported clinical outcomes separately for smokers and nonsmokers. Primary outcome was a composite of cardiovascular (CV) death, myocardial infarction, or stroke.
For correspondence: Dr. J.J. Gagne, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA. E-mail [email protected]. ■
Review methods MEDLINE, EMBASE/Excerpta Medica (both to Jul 2013), CINAHL, CAB Abstracts, Google Scholar, cardiology conference abstracts (American Heart Association, American College of Cardiology, European Society of Cardiology, and Heart Rhythm Society), systematic reviews, and reference lists were searched for randomized controlled trials (RCTs). 9 RCTs (n = 109 793, 31% smokers, follow-up range 30 d to 3 y) met selection criteria. Studies compared clopidogrel with aspirin (1 RCT); double-dose clopidogrel with standard-dose (1 RCT); and clopidogrel plus aspirin with aspirin alone (4 RCTs), with prasugrel plus aspirin (2 RCTs), and with ticagrelor plus aspirin (1 RCT). Risk for bias was low for all trials: 7 had adequate randomization; 8 had concealed allocation; all had blinded patients, personnel, and outcome assessments; and all reported adequate follow-up. Indirect analyses compared prasugrel and ticagrelor with the control groups from the 6 clopidogrel trials, and prasugrel with ticagrelor by smoking status.
Main results The main results are in the Table.
Conclusions Clopidogrel reduces a composite of cardiovascular death, myocardial infarction, or stroke more in smokers than in nonsmokers. Comparisons of antiplatelet therapies for reducing a composite of cardiovascular death, myocardial infarction, or stroke in smokers and nonsmokers* Direct comparisons
Number of trials (n)
RRR/RRI (95% CI) at 30 d to 3 y Smokers
Nonsmokers† RRR 8% (2 to 13)
Clopidogrel‡ vs control§
6 (74 498)
RRR 25% (17 to 33)
Prasugrel vs clopidogrel
2 (20 788)
RRR 29% (8 to 39)
Ticagrelor vs clopidogrel
1 (14 507)
RRR 17% (0 to 32)
RRR 11% (0 to 21)
Prasugrel vs control§
RRR 47% (36 to 56)
RRR 15% (5 to 24)
Ticagrelor vs control§
RRR 38% (22 to 50)
RRR 18% (7 to 28)
Prasugrel vs ticagrelor
RRR 15% (−9 to 33)
RRR 8% (−1 to 17)
Indirect comparisons||
RRI 3% (−12 to 20)
*Abbreviations defined in Glossary. RRR, RRI, and CI calculated from relative risks in article using a fixed-effect model. All patients received concurrent aspirin therapy in all but 1 clopidogrel-only group. †Never and former smokers. ‡Clopidogrel with or without aspirin. §Aspirin alone or lower dose of clopidogrel plus aspirin. ||Indirect analyses based on Bucher’s method for the 3 pairwise comparisons.
JC6
© 2014 American College of Physicians
Commentary Dual-antiplatelet therapy with aspirin and such P2Y12-receptor inhibitors as clopidogrel is an important component of treatment for patients with CV diseases (1). Smoking is a known CV risk factor that increases platelet reactivity. The meta-analysis by Gagne and colleagues supports prior observations that the benefit of clopidogrel in reducing CV events was seen primarily in smokers, with little benefit in nonsmokers. This supports the theory that smoking induces cytochrome P450 isoenzyme 1A2, increasing production of the active metabolite of clopidogrel, thereby increasing its efficacy in smokers (2). 1 study reported a gradient of increased risk for bleeding from nonsmokers to former and current smokers with clopidogrel (3). Several points are important for clinical practice. First, although the magnitude of benefit was lower in nonsmokers, clopidogrel still reduced the composite outcome (relative risk 0.92, 95% CI 0.87 to 0.98) in this group. Second, patients having percutaneous coronary intervention should receive dual-antiplatelet therapy for 1 to 12 months regardless of smoking status (4). Third, given increased efficacy and higher bleeding among smokers receiving clopidogrel, dosage adjustments may optimize outcomes, although no prospective data exist to support such adjustments. Prospective clinical studies with enrolment stratified by smoking status are needed to evaluate the impact of smoking on the efficacy and safety of varying dosages of P2Y12 inhibitors. For now, there are no indications to deprive nonsmokers of the benefits of P2Y12 inhibitors or to make any dose adjustments in smokers. It seems reasonable to counsel active smokers about the higher risk for bleeding with clopidogrel and urge them to stop smoking. Debabrata Mukherjee, MD, MS Texas Tech University El Paso, Texas, USA References 1. Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012;60:645-81. 2. Gurbel PA, Nolin TD, Tantry US. Clopidogrel efficacy and cigarette smoking status. JAMA. 2012;307:2495-6. 3. Berger JS, Bhatt DL, Steinhubl SR, et al; CHARISMA Investigators. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation. 2009;120:2337-44.19933933 4. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124:e574-651. 21 January 2014 | ACP Journal Club | Volume 160 • Number 2
Downloaded From: https://annals.org/pdfaccess.ashx?url=/data/journals/aim/929674/ by a Tufts University User on 07/31/2017
