Systematic review and meta-analysis of optimal P2Y12 blockade in dual antiplatelet therapy for patients with diabetes with acute coronary syndrome

Jennifer A Rossington, Oliver I Brown, Angela Hoye, Jennifer A Rossington, Oliver I Brown, Angela Hoye

Abstract

Background: Patients with diabetes are at increased risk of acute coronary syndromes (ACS) and their mortality and morbidity outcomes are significantly worse following ACS events, independent of other comorbidities. This systematic review sought to establish the optimum management strategy with focus on P2Y12 blockade in patients with diabetes with ACS.

Methods: MEDLINE (1946 to present) and EMBASE (1974 to present) databases, abstracts from major cardiology conferences and previously published systematic reviews were searched to June 2014. Relevant randomised control trials with clinical outcomes for P2Y12 inhibitors in adult patients with diabetes with ACS were scrutinised independently by 2 authors with applicable data was extracted for primary composite end point of cardiovascular death, myocardial infarction (MI) and stroke; enabling calculation of relative risks with 95% CI with subsequent direct and indirect comparison.

Results: Four studies studied clopidogrel in patients with diabetes, with two (3122 patients) having primary outcome data showing superiority of clopidogrel against placebo with RR0.84 (95% CI 0.72-0.99). Irrespective of management strategy, the newer agents prasugrel (2 studies) and ticagrelor (1 study) had a lower primary event rate compared with clopidogrel; RR 0.80 (95% CI 0.66 to 0.97) and RR 0.89 (95% CI 0.77 to 1.02), respectively. When ticagrelor was indirectly compared with prasugrel, there was a trend to an improved primary outcome with prasugrel (RR 1.11 (95% CI 0.94 to 1.31)) particularly in those managed with percutaneous coronary intervention (PCI) (RR 1.23 (95% CI 0.95 to 1.59)). Prasugrel demonstrated a statistical superiority with prevention of further MI with RR 1.48 (95% CI 1.11 to 1.97). This was not at the expense of increased major thrombolysis in MI (TIMI) bleeding rates RR 0.94 (95% CI 0.59 to 1.51).

Conclusions: This meta-analysis shows the addition of a P2Y12 inhibitor is superior to placebo, with a trend favouring the use of prasugrel in patients with diabetes with ACS, particularly those undergoing PCI.

Keywords: CORONARY ARTERY DISEASE.

Figures

Figure 1
Figure 1
Comparison of outcomes in patients with versus patients without diabetes; primary outcome event rate (CV death, non-fatal MI and non-fatal CVA) as a percentage of the population in TRITON-TIMI 38 (prasugrel) and PLATO (ticagrelor) studies, exploring effects of presence of diabetes and nature of management. CV, cardiovascular; CVA, CV accident; MI, myocardial infarction; TIMI, thrombolysis in myocardial infarction.
Figure 2
Figure 2
Clopidogrel versus placebo; risk ratio with 95% CIs for the primary composite end point of CV death, non-fatal MI and non-fatal CVA in the diabetes population comparing clopidogrel versus placebo in addition to aspirin. CV, cardiovascular; CVA, CV accident; MI, myocardial infarction; PCI, percutaneous coronary intervention.
Figure 3
Figure 3
Prasugrel versus clopidogrel; risk ratio with 95% CIs for the primary composite end point of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke in the diabetic population comparing prasugrel versus clopidogrel in addition to aspirin.
Figure 4
Figure 4
Prasugrel and ticagrelor versus clopidogrel; risk ratio with 95% CIs for the primary composite end point of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Also, major bleeding in the diabetic populations managed with and without insulin; comparing prasugrel and ticagrelor versus clopidogrel in addition to aspirin. Event rate percentage of newer agent versus clopidogrel. DM, diabetes mellitus.
Figure 5
Figure 5
Ticagrelor versus prasugrel; risk ratio with 95% CIs for the primary composite end point, primary composite end point in those undergoing PCI, myocardial infarction, definite/probable stent thrombosis and major bleeding (TIMI classification) in the diabetes population, indirectly comparing ticagrelor versus prasugrel in addition to aspirin. MI, myocardial infarction; PCI, percutaneous coronary intervention; TIMI, thrombolysis in MI.
Figure 6
Figure 6
P2Y12 blockade versus placebo; risk ratio with 95% CIs for the primary composite end point of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke in the diabetes population, comparing P2Y12 blockade versus placebo in addition to aspirin.

References

    1. Yeghiazarians Y, Braunstein JB, Askari A et al. . Unstable angina pectoris. N Engl J Med 2000;342:101–14. 10.1056/NEJM200001133420207
    1. Sethi SS, Akl EG, Farkouh ME. Diabetes mellitus and acute coronary syndrome: lessons from randomized clinical trials. Curr Diabetes Rep 2012;12:294–304. 10.1007/s11892-012-0272-9
    1. Hall HM, Banerjee S, Mcguire DK. Variability of clopidogrel response in patients with type 2 diabetes mellitus. Diabetes Vasc Dis Res 2011;8:245–53. 10.1177/1479164111420890
    1. Sagel J, Colwell JA, Crook L et al. . Increased platelet aggregation in early diabetes mellitus. Ann Intern Med 1975;82:733–8. 10.7326/0003-4819-82-6-733
    1. Colwell JA, Halushka P, Sarji K et al. . Altered platelet function in diabetes mellitus. Diabetes 1976;25:826–31.
    1. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E et al. . Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005;54:2430–5. 10.2337/diabetes.54.8.2430
    1. Wiviott SD, Braunwald E, McCabe CH et al. , TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–15. 10.1056/NEJMoa0706482
    1. Sabatine MS, Cannon CP, Gibson CM et al. , Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 2005;294:1224–32. 10.1001/jama.294.10.1224
    1. Goodman SG, Huang W, Yan AT et al. , Expanded Global Registry of Acute Coronary Events (GRACE2) Investigators. The expanded Global Registry of Acute Coronary Events: baseline characteristics, management practices, and hospital outcome of patients with acute coronary syndromes. Am Heart J 2009;158:193–201. 10.1016/j.ahj.2009.06.003
    1. Daida H, Miyauchi K, Ogawa H et al. , PACIFIC investigators. Management and two-year long-term clinical outcome of acute coronary syndrome in Japan: prevention of atherothrombotic incidents following ischemic coronary attack (PACIFIC) registry. Circ J 2013;77:934–43. 10.1253/circj.CJ-13-0174
    1. Annual report SWEDEHEART 2012. Scand Cardiovasc J. 2014;48(Suppl 63):2–133.
    1. Donahoe SM, Stewart GC, McCabe CH et al. . Diabetes and mortality following acute coronary syndromes. JAMA 2007;298:765–75. 10.1001/jama.298.7.765
    1. Roberts AC, Porter KE. Cellular and molecular mechanisms of endothelial dysfunction in diabetes. Diabetes Vasc Dis Res 2013;10:472–82. 10.1177/1479164113500680
    1. Patti G, Proscia C, Sciascio G. Antiplatelet therapy in patients with diabetes mellitus and acute coronary syndrome. Circ J 2014;78:33–41. 10.1253/circj.CJ-13-0742
    1. Saucedo JF. Antiplatelet therapy for patients with diabetes mellitus and acute coronary syndrome. Prim Care Diabetes 2012;6:167–77. 10.1016/j.pcd.2012.02.001
    1. National Institute for Health and Care Excellence. Unstable angina and NSTEMI The early management of unstable angina and non-ST-segment-elevation myocardial infarction (clinical guideline 94) 2013. (accessed 14 Oct 2014).
    1. Hamm CW, Bassand JP, Agewall S et al. , ESC Committee for Practice Guidelines. 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 of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999–3054. 10.1093/eurheartj/ehr236
    1. Mehta SR, Yusuf S, Peters RJ et al. , Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527–33. 10.1016/S0140-6736(01)05701-4
    1. Cannon CP. Effectiveness of clopidogrel versus aspirin in preventing acute myocardial infarction in patients with symptomatic atherothrombosis (CAPRIE trial). Am J Cardiol 2002;90:760–2. 10.1016/S0002-9149(02)02606-1
    1. Brandt JT, Payne CD, Wiviott SD et al. . 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.e9–16. 10.1016/j.ahj.2006.10.010
    1. Erlinge D, Varenhorst C, Braun OO et al. . Patients with poor responsiveness to thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, but their platelets respond normally to active metabolite added ex vivo. J Am Coll Cardiol 2008;52:1968–77. 10.1016/j.jacc.2008.07.068
    1. Roe MT, Armstrong PW, Fox KAA et al. , TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012;367:1297–309. 10.1056/NEJMoa1205512
    1. Wallentin L, Becker RC, Budaj A et al. . Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. 10.1056/NEJMoa0904327
    1. Moher D, Liberati A, Tetzlaff J et al. . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535 10.1136/bmj.b2535
    1. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration, 2011. .
    1. Song F. What is indirect comparison? 2009. (accessed 16 Jul 2014).
    1. James S, Angiolillo DJ, Cornel JH et al. . Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2010;31:3006–16. 10.1093/eurheartj/ehq325
    1. Murphy SA, Antman EM, Wiviott SD et al. . Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON-TIMI 38 trial. Eur Heart J 2008;29:2473–9. 10.1093/eurheartj/ehn362
    1. Wiviott SD, Braunwald E, Angiolillo DJ et al. , TRITON-TIMI 38 Investigators. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction TIMI 38. Circulation 2008;118:1626–36. 10.1161/CIRCULATIONAHA.108.791061
    1. Wiviott SD, Desai N, Murphy SA et al. . Efficacy and safety of intensive antiplatelet therapy with prasugrel from TRITON-TIMI 38 in a core clinical cohort defined by worldwide regulatory agencies. Am J Cardiol 2011;108:905–11. 10.1016/j.amjcard.2011.05.020
    1. Wiviott SD, Braunwald E, McCabe CH et al. . Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 2008;371:1353–63. 10.1016/S0140-6736(08)60422-5
    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 syndrome without ST-segment elevation. N Engl J Med 2001;345:494–502. 10.1056/NEJMoa010746
    1. Mehta SR, Tanguay JF, Eikelboom JW et al. . Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010;376:1233–43. 10.1016/S0140-6736(10)61088-4
    1. Mehta SR, Bassand JP, Chrolavicius S et al. . Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010;363:930–42. 10.1056/NEJMoa0909475
    1. Cannon CP, Harrington RA, James S et al. , PLATelet inhibition and patient Outcomes Investigators. 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. 10.1016/S0140-6736(09)62191-7
    1. Storey RF, Becker RC, Harrington RA et al. . Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J 2011;32:2945–53. 10.1093/eurheartj/ehr231
    1. Bhatt DL, Marso SP, Hirsch AT et al. . Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 2002;90:625–8. 10.1016/S0002-9149(02)02567-5
    1. Salisbury AC, Wang K, Cohen DJ et al. . Selecting antiplatelet therapy at the time of percutaneous intervention for an acute coronary syndrome: weighing the benefits and risks of prasugrel versus clopidogrel. Circ Cardiovasc Qual Outcomes 2013;6:27–34. 10.1161/CIRCOUTCOMES.112.965624
    1. Gresner P, Dolník M, Waczuliková I et al. . Increased blood plasma hydrolysis of acetylsalicylic acid in type 2 diabetic patients: a role of plasma esterases. Biochim Biophys Acta 2006;1760:207–15. 10.1016/j.bbagen.2005.11.018
    1. Angiolillo DJ, Badimon JJ, Saucedo JF et al. . 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;32:838–46. 10.1093/eurheartj/ehq494
    1. Angiolillo DJ, Jakubowski JA, Ferreiro JL et al. . Impaired responsiveness to the platelet P2Y12 receptor antagonist clopidogrel in patients with type 2 diabetes and coronary artery disease. J Am Coll Cardiol 2014;64:1005–14. 10.1016/j.jacc.2014.06.1170
    1. Benko B. Influence of Diabetes on Cytochrome P450 Enzyme Mediated Drug Metabolism—Case Studies on Diclofenac and K-48. 2008. (accessed 14 Oct 2014).
    1. Angiolillo DJ, Bernardo E, Sabaté M et al. . Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2007;50:1541–7. 10.1016/j.jacc.2007.05.049
    1. Angiolillo DJ, Shoemaker SB, Desai B et al. . Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation 2007;115:708–16. 10.1161/CIRCULATIONAHA.106.667741
    1. Gurbel PA, Bliden KP, Butler K et al. . Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009;120:2577–85. 10.1161/CIRCULATIONAHA.109.912550
    1. Gurbel PA, Bliden KP, Butler K et al. . Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation 2010;121:1188–99. 10.1161/CIRCULATIONAHA.109.919456
    1. Angiolillo DJ, Bernardo E, Ramírez C et al. . Insulin therapy is associated with platelet dysfunction in patients with type 2 diabetes mellitus on dual oral antiplatelet treatment. J Am Coll Cardiol 2006;48:298–304. 10.1016/j.jacc.2006.03.038
    1. Deharo P, Bassez C, Bonnet G et al. . Prasugrel versus ticagrelor in acute coronary syndrome: a randomized comparison. Int J Cardiol 2013;170:e21–2. 10.1016/j.ijcard.2013.10.043
    1. Alexopoulos D, Galati A, Xanthopoulou I et al. . Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study. J Am Coll Cardiol 2012;60:193–9. 10.1016/j.jacc.2012.03.050
    1. 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. 10.1161/CIRCINTERVENTIONS.112.972323
    1. Alexopoulos D, Xanthopoulou I, Mavronasiou E et al. . Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with diabetes. Diabetes Care 2013;36:2211–16. 10.2337/dc12-2510
    1. Collet JP, Cuisset T, Rangé G et al. , ARCTIC Investigators. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012;367:2100–9. 10.1056/NEJMoa1209979
    1. Schulz S, Angiolillo DJ, Antoniucci D et al. , Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 Trial Investigators. 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. 10.1007/s12265-013-9527-3
    1. 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;33:2569–619. 10.1093/eurheartj/ehs215
    1. Amsterdam EA, Wenger NK, Brindis RG et al. . 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014:130:e344–426. (accessed 27 Oct 2014). 10.1161/CIR.0000000000000134
    1. 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:e362–425. 10.1161/CIR.0b013e3182742cf6
    1. Ryden L, Grant PJ, Anker SD et al. . Authors/Task Force Members. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 2013;34:3035–87. 10.1093/eurheartj/eht108
    1. National Institute for Health and Care Excellence. Prasugrel with percutaneous coronary intervention for treating acute coronary syndromes (review of technology appraisal guidance 182) 2014. (accessed 14 Oct 2014).

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