Generic placeholder image

Current Vascular Pharmacology

Author(s): Oliver Brown, Jennifer Rossington, Gill Louise Buchanan, Giuseppe Patti and Angela Hoye*

DOI: 10.2174/1570161116666180123092054

DownloadDownload PDF Flyer Cite As
Is there Sex-related Outcome Difference According to oral P2Y12 Inhibitors in Patients with Acute Coronary Syndromes? A Systematic Review and Meta-Analysis of 107,126 Patients

Page: [191 - 203] Pages: 13

  • * (Excluding Mailing and Handling)

Abstract

Background and Objectives: The majority of patients included in trials of anti-platelet therapy are male. This systematic review and meta-analysis aimed to determine whether, in addition to aspirin, P2Y12 blockade is beneficial in both women and men with acute coronary syndromes.

Methods: Electronic databases were searched and nine eligible randomised controlled studies were identified that had sex-specific clinical outcomes (n=107,126 patients). Risk Ratios (RR) and 95% Confidence Intervals (CI) were calculated for a composite of cardiovascular death, myocardial infarction or stroke (MACE), and a safety endpoint of major bleeding for each sex. Indirect comparison analysis was performed to statistically compare ticagrelor against prasugrel.

Results: Compared to aspirin alone, clopidogrel reduced MACE in men (RR, 0.79; 95% CI, 0.68 to 0.92; p=0.003), but was not statistically significant in women (RR, 0.88; 95% CI, 0.75 to 1.02, p=0.08). Clopidogrel therapy significantly increased bleeding in women but not men. Compared to clopidogrel, prasugrel was beneficial in men (RR, 0.84; 95% CI, 0.73 to 0.97; p=0.02) but not statistically significant in women (RR, 0.94; 95% CI, 0.83 to 1.06; p=0.30); ticagrelor reduced MACE in both men (RR, 0.85; 95% CI, 0.77 to 0.94; p=0.001) and women (RR, 0.84; 95% CI, 0.73 to 0.97; p=0.02). Indirect comparison demonstrated no significant difference between ticagrelor and prasugrel in either sex. Compared to clopidogrel, ticagrelor and prasugrel increased bleeding risk in both women and men.

Conclusion: In summary, in comparison to monotherapy with aspirin, P2Y12 inhibitors reduce MACE in women and men. Ticagrelor was shown to be superior to clopidogrel in both sexes. Prasugrel showed a statistically significant benefit only in men; however indirect comparison did not demonstrate superiority of ticagrelor over prasugrel in women.

Keywords: Sex, oral, P2Y12, inhibitors, ACS, CHD, MACE.

Graphical Abstract

[1]
Nichols M, Townsend N, Luengo-Fernandez R, et al. European Cardiovascular Disease Statistics 2012 European Heart Network, Brussels, European Society of Cardiology, Sophia Antipolis
[2]
Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: A report of the American college of cardiology foundation/American heart association. Circulation 2013; 127: 663-28.
[3]
Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569-19.
[4]
Hamm CW, Bassand J-P, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation. Eur Heart J 2011; 32: 2999-54.
[5]
O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: A report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation 2013; 127: 362-25.
[6]
Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-02.
[7]
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-39.
[8]
Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST- segment elevation. N Eng J Med 2005; 352: 1179-89.
[9]
Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: Randomised placebo-controlled trial. Lancet 2005; 366: 1607-21.
[10]
Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary sundromes. N Eng J Med 2009; 361: 1045-57.
[11]
Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndrome. N Eng J Med 2007; 357: 2001-15.
[12]
Moscucci M, Fox KAA, Cannon CP, et al. Predictors of major bleeding in acute coronary syndromes: The Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003; 24: 1815-23.
[13]
Breet NJ, Sluman MA, van Berkel JPJ, et al. Effect of gender difference on platelet reactivity. Neth Heart J 2011; 19: 451-7.
[14]
Wang TY, Angiolillo DJ, Cushman M, et al. Platelet biology and response to antiplatelet therapy in women: Implications for the development and use of antiplatelet pharmacotherapies for cardiovascular disease. J Am Coll Cardiol 2012; 59: 891-900.
[15]
James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design and baseline characteristics of the PLATelet inhibition andpatient Outcomes (PLATO) trial. Am Heart J 2009; 157: 599-605.
[16]
Chin CT, Roe MT, Fox KA, et al. Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non-ST-segment elevation myocardial infarction: The targeted platelet inhibition to clarify the optimal strategy to medically manage Acute Coronary Syndromes (TRILOGY ACS) trial. Am Heart J 2010; 160: 16-22.
[17]
Roe MT, Armstrong PW, Fox KAA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012; 367: 1297-309.
[18]
Lau ES, Braunwald E, Murphy SA, et al. Potent P2Y 12 inhibitors in men versus women. J Am Coll Cardiol 2017; 69: 1549-59.
[19]
Goto S, Huang C-H, Park S-J, et al. Ticagrelor vs. clopidogrel in Japanese, Korean and Taiwanese patients with acute coronary syndrome - randomized, double-blind, phase III PHILO study. Circ J 2015; 79: 2452-60.
[20]
Saito S, Isshiki T, Kimura T, et al. Efficacy and safety of adjusted-dose prasugrel compared with clopidogrel in Japanese patients with acute coronary syndrome. Circ J 2014; 78: 1684-92.
[21]
Higgins JPT, Altman DG, Sterne JAC. Assessing risk of bias in included studies In: Higgins JPT, Green S, Eds Cochrane Handbook for Systematic Reviews of Interventions Cochrane Collaboration, 2011.
[22]
Review Manager. (RevMan) [Computer program] Version 53 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
[23]
Song F. Song F What is indirect comparison? Oxford, UK: 2009 [cited 2017 April 25], Available from: http://www.medicine.ox.ac.uk/bandolier/painres/download/whatis/What_is_ind_comp. pdf
[24]
Wells G, Sultan S, Chen L, et al. Indirect evidence: Indirect treatment comparisons in meta-analysis. Ottawa: Canadian agency for drugs and technologies in health. 2009; 3-23.
[25]
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177-88.
[26]
Motovska Z, Hlinomaz O, Miklik R, et al. Prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary percutaneous coronary intervention: Multicenter randomized PRAGUE-18 study. Circulation 2016; 134: 1603-12.
[27]
Husted S, James SK, Bach RG, et al. The efficacy of ticagrelor is maintained in women with acute coronary syndromes participating in the prospective, randomized, PlAtelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2014; 35: 1541-50.
[28]
Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): A randomised double-blind study. Lancet 2010; 375: 283-93.
[29]
Tang X, Fan J, Ming J, et al. Impact of new oral or intravenous P2Y12 inhibitors and clopidogrel on major ischemic and bleeding events in patients with coronary artery disease: A meta-analysis of randomized trials. Atherosclerosis 2014; 233: 568-78.
[30]
Aradi D, Komócsi A, Vorobcsuk A, Serebruany VL. Impact of clopidogrel and potent P2Y12 inhibitors on mortality and stroke in patients with acute coronary syndrome or undergoing percutaneous coronary intervention. Thromb Haemost 2013; 109: 93-101.
[31]
Parodi G, Bellandi B, Valenti R, et al. Comparison of double (360 mg) ticagrelor loading dose with standard (60 mg) prasugrel loading dose in ST-elevation myocardial infarction patients: The Rapid Activity of Platelet Inhibitor Drugs (RAPID) primary PCI 2 study. Am Heart J 2014; 167: 909-14.
[32]
Alexopoulos D, Xanthopoulou I, Gkizas V, et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv 2012; 5: 797-804.
[33]
Schulz S, Angiolillo DJ, Antoniucci D, et al. Randomized comparison of ticagrelor versus prasugrel in patients with acute coronary syndrome and planned invasive strategy--design and rationale of the intracoronary stenting and antithrombotic regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT-5). J Cardiovasc Transl Res 2014; 7: 91-100.
[34]
Berger JS, Bhatt DL, Cannon CP, et al. The relative efficacy and safety of clopidogrel in women and men a sex-specific collaborative meta-analysis. J Am Coll Cardiol 2009; 54: 1935-45.
[35]
Patti G, De Caterina R, Abbate R, et al. Platelet function and long-term antiplatelet therapy in women: Is there a gender-specificity? A “state-of-the-art” paper. Eur Heart J 2014; 35: 2213-23.
[36]
Capodanno D, Angiolillo DJ. Impact of race and gender on antithrombotic therapy. Thromb Haemost 2010; 104: 471-84.
[37]
Andreotti F, Marchese N. Women and coronary disease. Heart 2008; 94: 108-16.
[38]
Lansky A, Hochman J, Ward P, et al. Percutaneous coronary intervention and adjunctive pharmacotherapy in women: A statement for healthcare professionals from the American Heart Association. Circulation 2005; 111: 940-53.
[39]
Chieffo A, Hoye A, Mauri F, et al. Gender-based issues in interventional cardiology: A consensus statement from the Women in Innovations (WIN) Initiative. Catheter Cardiovasc Interv 2010; 75: 145-52.
[40]
Mingo S, Goicolea J, Nombela L, et al. Primary percutaneous angioplasty. An analysis of reperfusion delays, their determining factors, and their prognostic implications. Rev Esp Cardiol 2009; 62: 15-22.
[41]
Akhter N, Milford-Beland S, Roe M, et al. Gender differences among patients with acute coronary syndromes undergoing percutaneous coronary intervention in the American College of Cardiology-National Cardiovascular Data Registry (ACC-NCDR). Am Heart J 2009; 157: 141-8.
[42]
Milcent C, Dormont B, Durand-Zaleski I, Steg P. Gender differences in hospital mortality and use of percutaneous coronary intervention in acute myocardial infarction. Circulation 2007; 115: 833-9.
[43]
Steg PG, Huber K, Andreotti F, et al. Bleeding in acute coronary syndromes and percutaneous coronary interventions: position paper by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J 2011; 32: 1854-64.
[44]
Alexander KP, Chen AY, Newby LK, et al. Sex differences in major bleeding with glycoprotein IIb/IIIa inhibitors: Results from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) initiative. Circulation 2006; 114: 1380-7.
[45]
Valgimigli M, Gagnor A, Calabró P, et al. Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: A randomised multicentre trial. Lancet 2015; 385: 2465-76.
[46]
Riesmeyer J, Salazar D, Weerakkody G, et al. Relationship between exposure to prasugrel active metabolite and clinical outcomes in the TRITON-TIMI 38 substudy. J Clin Pharmacol 2012; 52: 789-97.
[47]
Higgins JPT, Altman DG, Sterne JAC. Indirect comparisons and multiple-treatment meta-analysis In: Higgins JPT, Green S, Eds Cochrane Handbook for Systematic Reviews of Interventions Cochrane Collaboration, 2011.
[48]
Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials. Circulation 2011; 123: 2736-47.