Advertisement

Meta-Analysis of Randomized Controlled Trials Comparing Risk of Major Adverse Cardiac Events and Bleeding in Patients With Prasugrel Versus Clopidogrel

      The use of prasugrel in patients with coronary artery disease (CAD) has been associated with decreased major adverse cardiac events (MACEs) compared with clopidogrel but with an increased risk of bleeding. However, it remains unclear if the risks of bleeding outweigh those of MACEs in patients on prasugrel treatment. We systematically reviewed randomized controlled trials comparing prasugrel with clopidogrel in patients with CAD. We performed a literature search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trial databases from inception to November 25, 2014, and reviewed the reference lists of retrieved articles. A comparative estimate was made for the combined rates of MACEs and bleeding from the same trials in the framework of this meta-analysis and expressed as odds ratios (ORs) and 95% confidence intervals (CIs) in both random- and fixed-effects models. Nine studies involving 25,214 patients were included in our meta-analysis. In both the random- and fixed-effects models, the risks of MACEs outweighed those of major bleeding (OR 7.48, 95% CI 3.75 to 14.94, p <0.0001, random effects) and of minor bleeding (OR 3.77, 95% CI 1.73 to 8.22, p = 0.009, random effects). Results were corroborated in a standard-dose clopidogrel subgroup analysis (OR 7.46, 95% CI 3.54 to 15.68, p <0.0001, and OR 6.44, 95% CI 2.80 to 14.80, p <0.0001, random effects, respectively). In conclusion, despite the increased risk of bleeding associated with prasugrel treatment compared with clopidogrel, the risk of MACEs far outweighed the risk of bleeding.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Jneid H.
        • Anderson J.L.
        • Wright R.S.
        • Adams C.D.
        • Bridges C.R.
        • Casey Jr., D.E.
        • Ettinger S.M.
        • Fesmire F.M.
        • Ganiats T.G.
        • Lincoff A.M.
        • Peterson E.D.
        • Philippides G.J.
        • Theroux P.
        • Wenger N.K.
        • Zidar J.P.
        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: 645-681
        • Kushner F.G.
        • Hand M.
        • Smith Jr., S.C.
        • King III, S.B.
        • Anderson J.L.
        • Antman E.M.
        • Bailey S.R.
        • Bates E.R.
        • Blankenship J.C.
        • Casey Jr., D.E.
        • Green L.A.
        • Hochman J.S.
        • Jacobs A.K.
        • Krumholz H.M.
        • Morrison D.A.
        • Ornato J.P.
        • Pearle D.L.
        • Peterson E.D.
        • Sloan M.A.
        • Whitlow P.L.
        • Williams D.O.
        2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
        J Am Coll Cardiol. 2009; 54: 2205-2241
        • Windecker S.
        • Kolh P.
        • Alfonso F.
        • Collet J.P.
        • Cremer J.
        • Falk V.
        • Filippatos G.
        • Hamm C.
        • Head S.J.
        • Juni P.
        • Kappetein A.P.
        • Kastrati A.
        • Knuuti J.
        • Landmesser U.
        • Laufer G.
        • Neumann F.J.
        • Richter D.J.
        • Schauerte P.
        • Uva M.S.
        • Stefanini G.G.
        • Taggart D.P.
        • Torracca L.
        • Valgimigli M.
        • Wijns W.
        • Witkowski A.
        2014 ESC/EACTS Guidelines on myocardial revascularization.
        Kardiol Pol. 2014; 72: 1253-1379
        • Yusuf S.
        • Zhao F.
        • Mehta S.R.
        • Chrolavicius S.
        • Tognoni G.
        • Fox K.K.
        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
        • Fernando H.
        • Dart A.M.
        • Peter K.
        • Shaw J.A.
        Proton pump inhibitors, genetic polymorphisms and response to clopidogrel therapy.
        Thromb Haemost. 2011; 105: 933-944
        • Gremmel T.
        • Panzer S.
        Clinical, genetic and confounding factors determine the dynamics of the in vitro response/non response to clopidogrel.
        Thromb Haemost. 2011; 106: 211-218
        • O'Donoghue M.
        • Wiviott S.D.
        Clopidogrel response variability and future therapies: clopidogrel: does one size fit all?.
        Circulation. 2006; 114: e600-e606
        • Wiviott S.D.
        • Braunwald E.
        • McCabe C.H.
        • Montalescot G.
        • Ruzyllo W.
        • Gottlieb S.
        • Neumann F.J.
        • Ardissino D.
        • De Servi S.
        • Murphy S.A.
        • Riesmeyer J.
        • Weerakkody G.
        • Gibson C.M.
        • Antman E.M.
        Prasugrel versus clopidogrel in patients with acute coronary syndromes.
        N Engl J Med. 2007; 357: 2001-2015
        • Wiviott S.D.
        • Antman E.M.
        • Braunwald E.
        Prasugrel.
        Circulation. 2010; 122: 394-403
        • Saito S.
        • Isshiki T.
        • Kimura T.
        • Ogawa H.
        • Yokoi H.
        • Nanto S.
        • Takayama M.
        • Kitagawa K.
        • Nishikawa M.
        • Miyazaki S.
        • Nakamura M.
        Efficacy and safety of adjusted-dose prasugrel compared with clopidogrel in Japanese patients with acute coronary syndrome: the PRASFIT-ACS study.
        Circ J. 2014; 78: 1684-1692
        • Wiviott S.D.
        • Antman E.M.
        • Winters K.J.
        • Weerakkody G.
        • Murphy S.A.
        • Behounek B.D.
        • Carney R.J.
        • Lazzam C.
        • McKay R.G.
        • McCabe C.H.
        • Braunwald E.
        Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial.
        Circulation. 2005; 111: 3366-3373
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        BMJ. 2009; 339: b2535
        • Higgins J.
        • Green S.
        Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0.
        Cochrane Collaboration, 2011 (Available at:)
        • Begg C.B.
        • Mazumdar M.
        Operating characteristics of a rank correlation test for publication bias.
        Biometrics. 1994; 50: 1088-1101
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • Minder C.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • Duval S.
        • Tweedie R.
        Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis.
        Biometrics. 2000; 56: 455-463
        • Alexopoulos D.
        • Dimitropoulos G.
        • Davlouros P.
        • Xanthopoulou I.
        • Kassimis G.
        • Stavrou E.F.
        • Hahalis G.
        • Athanassiadou A.
        Prasugrel overcomes high on-clopidogrel platelet reactivity post-stenting more effectively than high-dose (150-mg) clopidogrel: the importance of CYP2C19*2 genotyping.
        JACC Cardiovasc Interv. 2011; 4: 403-410
        • Angiolillo D.J.
        • Badimon J.J.
        • Saucedo J.F.
        • Frelinger A.L.
        • Michelson A.D.
        • Jakubowski J.A.
        • Zhu B.
        • Ojeh C.K.
        • Baker B.A.
        • Effron M.B.
        A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy in diabetes MellitUS (OPTIMUS)-3 Trial.
        Eur Heart J. 2011; 32: 838-846
        • Dridi N.P.
        • Johansson P.I.
        • Clemmensen P.
        • Stissing T.
        • Radu M.D.
        • Qayyum A.
        • Pedersen F.
        • Helqvist S.
        • Saunamaki K.
        • Kelbaek H.
        • Jorgensen E.
        • Engstrom T.
        • Holmvang L.
        Prasugrel or double-dose clopidogrel to overcome clopidogrel low-response—the TAILOR (Thrombocytes and IndividuaLization of ORal antiplatelet therapy in percutaneous coronary intervention) randomized trial.
        Platelets. 2014; 25: 506-512
        • Montalescot G.
        • Sideris G.
        • Cohen R.
        • Meuleman C.
        • Bal dit Sollier C.
        • Barthelemy O.
        • Henry P.
        • Lim P.
        • Beygui F.
        • Collet J.P.
        • Marshall D.
        • Luo J.
        • Petitjean H.
        • Drouet L.
        Prasugrel compared with high-dose clopidogrel in acute coronary syndrome. The randomised, double-blind ACAPULCO study.
        Thromb Haemost. 2010; 103: 213-223
        • Roe M.T.
        • Armstrong P.W.
        • Fox K.A.
        • White H.D.
        • Prabhakaran D.
        • Goodman S.G.
        • Cornel J.H.
        • Bhatt D.L.
        • Clemmensen P.
        • Martinez F.
        • Ardissino D.
        • Nicolau J.C.
        • Boden W.E.
        • Gurbel P.A.
        • Ruzyllo W.
        • Dalby A.J.
        • McGuire D.K.
        • Leiva-Pons J.L.
        • Parkhomenko A.
        • Gottlieb S.
        • Topacio G.O.
        • Hamm C.
        • Pavlides G.
        • Goudev A.R.
        • Oto A.
        • Tseng C.D.
        • Merkely B.
        • Gasparovic V.
        • Corbalan R.
        • Cinteza M.
        • McLendon R.C.
        • Winters K.J.
        • Brown E.B.
        • Lokhnygina Y.
        • Aylward P.E.
        • Huber K.
        • Hochman J.S.
        • Ohman E.M.
        Prasugrel versus clopidogrel for acute coronary syndromes without revascularization.
        N Engl J Med. 2012; 367: 1297-1309
        • Wiviott S.D.
        • Trenk D.
        • Frelinger A.L.
        • O'Donoghue M.
        • Neumann F.J.
        • Michelson A.D.
        • Angiolillo D.J.
        • Hod H.
        • Montalescot G.
        • Miller D.L.
        • Jakubowski J.A.
        • Cairns R.
        • Murphy S.A.
        • McCabe C.H.
        • Antman E.M.
        • Braunwald E.
        Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial.
        Circulation. 2007; 116: 2923-2932
        • Steiner S.
        • Moertl D.
        • Chen L.
        • Coyle D.
        • Wells G.A.
        Network meta-analysis of prasugrel, ticagrelor, high- and standard-dose clopidogrel in patients scheduled for percutaneous coronary interventions.
        Thromb Haemost. 2012; 108: 318-327
        • Chatterjee S.
        • Ghose A.
        • Sharma A.
        • Guha G.
        • Mukherjee D.
        • Frankel R.
        Comparing newer oral anti-platelets prasugrel and ticagrelor in reduction of ischemic events—evidence from a network meta-analysis.
        J Thromb Thrombolysis. 2013; 36: 223-232
        • Ye Y.
        • Xie H.
        • Zeng Y.
        • Zhao X.
        • Tian Z.
        • Zhang S.
        Optimal oral antithrombotic regimes for patients with acute coronary syndrome: a network meta-analysis.
        PLoS One. 2014; 9: e90986
        • Steinhubl S.R.
        • Berger P.B.
        • Mann III, J.T.
        • Fry E.T.
        • DeLago A.
        • Wilmer C.
        • Topol E.J.
        Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.
        JAMA. 2002; 288: 2411-2420
        • Brandt J.T.
        • Payne C.D.
        • Wiviott S.D.
        • Weerakkody G.
        • Farid N.A.
        • Small D.S.
        • Jakubowski J.A.
        • Naganuma H.
        • Winters K.J.
        A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation.
        Am Heart J. 2007; 153: 66.e9-66.e16
        • Weerakkody G.J.
        • Jakubowski J.A.
        • Brandt J.T.
        • Farid N.A.
        • Payne C.D.
        • Zhu J.
        • Warner M.R.
        • Naganuma H.
        • Winters K.J.
        Comparison of speed of onset of platelet inhibition after loading doses of clopidogrel versus prasugrel in healthy volunteers and correlation with responder status.
        Am J Cardiol. 2007; 100: 331-336
        • Asai F.
        • Jakubowski J.A.
        • Naganuma H.
        • Brandt J.T.
        • Matsushima N.
        • Hirota T.
        • Freestone S.
        • Winters K.J.
        Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: a single ascending dose study in healthy humans.
        Platelets. 2006; 17: 209-217