Racial Differences in Ischaemia/Bleeding Risk Trade-Off during Anti-Platelet Therapy: Individual Patient Level Landmark Meta-Analysis from Seven RCTs

Abstract

Background Prolonged dual anti-platelet therapy (DAPT) is intended to reduce ischaemic events, at the cost of an increased bleeding risk in patients undergoing percutaneous coronary intervention (PCI). In this study, we evaluated whether race influences the ischaemia/bleeding risk trade-off.

Methods We searched for randomized clinical trials (RCTs) comparing DAPT duration after PCI. To compare the benefit or harm between DAPT duration by race, individual patient-level landmark meta-analysis was performed after discontinuation of the shorter duration DAPT group in each RCT. The primary ischaemic endpoint was major adverse cardiac events (MACEs), and the primary bleeding endpoint was major bleeding events (clinicaltrials.gov NCT03338335).

Results Seven RCTs including 16,518 patients (8,605 East Asians, 7,913 non-East Asians) were pooled. MACE occurred more frequently in non-East Asians (0.8% vs. 1.8%, p < 0.001), while major bleeding events occurred more frequently in East Asians (0.6% vs. 0.3%, p = 0.001). In Cox proportional hazards model, prolonged DAPT significantly increased the risk of major bleeding in East Asians (hazard ratio [HR], 2.843, 95% confidence interval [CI], 1.474–5.152, p = 0.002), but not in non-East Asians (HR, 1.375, 95% CI, 0.523–3.616, p = 0.523). East Asians had a higher median probability risk ratio of bleeding to ischaemia (0.66 vs. 0.15), and the proportion of patients with higher probability of bleeding than ischaemia was significantly higher in East Asians (32.3% vs. 0.4%, p < 0.001).

Conclusion We suggest that the ischaemia/bleeding trade-off may be different between East Asians and non-East Asians. In East Asians, prolonged DAPT may have no effect in reducing the ischaemic risk, while significantly increases the bleeding risk.

Keywords

dual anti-platelet therapy - race - East Asians - ischaemia/bleeding trade-off

• References

• 1 Mehran R, Giustino G, Baber U. DAPT duration after DES: what is the “mandatory” duration?. J Am Coll Cardiol 2015; 65 (11) 1103-1106
• 2 Udell JA, Bonaca MP, Collet JP. , et al. Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials. Eur Heart J 2016; 37 (04) 390-399
• 3 Mehran R, Pocock S, Nikolsky E. , et al. Impact of bleeding on mortality after percutaneous coronary intervention results from a patient-level pooled analysis of the REPLACE-2 (randomized evaluation of PCI linking angiomax to reduced clinical events), ACUITY (acute catheterization and urgent intervention triage strategy), and HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trials. JACC Cardiovasc Interv 2011; 4 (06) 654-664
• 4 Palmerini T, Della Riva D, Benedetto U. , et al. Three, six, or twelve months of dual antiplatelet therapy after DES implantation in patients with or without acute coronary syndromes: an individual patient data pairwise and network meta-analysis of six randomized trials and 11 473 patients. Eur Heart J 2017; 38 (14) 1034-1043
• 5 Gargiulo G, Windecker S, da Costa BR. , et al. Short term versus long term dual antiplatelet therapy after implantation of drug eluting stent in patients with or without diabetes: systematic review and meta-analysis of individual participant data from randomised trials. BMJ 2016; 355: i5483
• 6 Palmerini T, Benedetto U, Bacchi-Reggiani L. , et al. Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials. Lancet 2015; 385 (9985): 2371-2382
• 7 Levine GN, Jeong YH, Goto S. , et al. Expert consensus document: World Heart Federation expert consensus statement on antiplatelet therapy in East Asian patients with ACS or undergoing PCI. Nat Rev Cardiol 2014; 11 (10) 597-606
• 8 Jeong YH. “East Asian Paradox”: challenge for the current antiplatelet strategy of “one-guideline-fits-all races” in acute coronary syndrome. Curr Cardiol Rep 2014; 16 (05) 485
• 9 Mak KH, Bhatt DL, Shao M. , et al. Ethnic variation in adverse cardiovascular outcomes and bleeding complications in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study. Am Heart J 2009; 157 (04) 658-665
• 10 Cutlip DE, Windecker S, Mehran R. , et al; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007; 115 (17) 2344-2351
• 11 Feres F, Costa RA, Abizaid A. , et al; OPTIMIZE Trial Investigators. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013; 310 (23) 2510-2522
• 12 Colombo A, Chieffo A, Frasheri A. , et al. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol 2014; 64 (20) 2086-2097
• 13 Gwon HC, Hahn JY, Park KW. , et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012; 125 (03) 505-513
• 14 Valgimigli M, Campo G, Monti M. , et al; Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012; 125 (16) 2015-2026
• 15 Kim BK, Hong MK, Shin DH. , et al; RESET Investigators. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012; 60 (15) 1340-1348
• 16 Gilard M, Barragan P, Noryani AAL. , et al. 6- versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial. J Am Coll Cardiol 2015; 65 (08) 777-786
• 17 Lee CW, Ahn JM, Park DW. , et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014; 129 (03) 304-312
• 18 Giustino G, Baber U, Sartori S. , et al. Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol 2015; 65 (13) 1298-1310
• 19 Levine GN, Bates ER, Bittl JA. , et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: an update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation 2016; 134 (10) e123-e155
• 20 Valgimigli M, Bueno H, Byrne RA. , et al. ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018; 39 (03) 213-260
• 21 Capodanno D, Angiolillo DJ. Tailoring duration of DAPT with risk scores. Lancet 2017; 389 (10073): 987-989
• 22 Yeh RW, Secemsky EA, Kereiakes DJ. , et al; DAPT Study Investigators. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016; 315 (16) 1735-1749
• 23 Costa F, van Klaveren D, James S. , et al; PRECISE-DAPT Study Investigators. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet 2017; 389 (10073): 1025-1034
• 24 Jeong YH, Tantry US, Kim IS. , et al. Effect of CYP2C19*2 and *3 loss-of-function alleles on platelet reactivity and adverse clinical events in East Asian acute myocardial infarction survivors treated with clopidogrel and aspirin. Circ Cardiovasc Interv 2011; 4 (06) 585-594
• 25 Park KW, Kang J, Park JJ. , et al. Amlodipine, clopidogrel and CYP3A5 genetic variability: effects on platelet reactivity and clinical outcomes after percutaneous coronary intervention. Heart 2012; 98 (18) 1366-1372
• 26 Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol 2007; 50 (04) 309-315
• 27 Teng R, Butler K. Pharmacokinetics, pharmacodynamics, and tolerability of single and multiple doses of ticagrelor in Japanese and Caucasian volunteers. Int J Clin Pharmacol Ther 2014; 52 (06) 478-491
• 28 Goto S, Huang CH, Park SJ, Emanuelsson H, Kimura T. Ticagrelor vs. clopidogrel in Japanese, Korean and Taiwanese patients with acute coronary syndrome -- randomized, double-blind, phase III PHILO study. Circ J 2015; 79 (11) 2452-2460
• 29 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: the PRASFIT-ACS study. Circ J 2014; 78 (07) 1684-1692
• 30 Kang J, Han JK, Ahn Y. , et al; investigators for Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH). Third-generation P2Y12 inhibitors in East Asian acute myocardial infarction patients: a nationwide prospective multicentre study. Thromb Haemost 2018; 118 (03) 591-600