Meta-Analysis of Potent P2Y12-ADP Receptor Antagonist Therapy Compared to Clopidogrel Therapy in Acute Coronary Syndrome Patients with Chronic Kidney Disease

Abstract

Background The clinical benefit of anti-platelet agents in patients with chronic kidney disease (CKD) is uncertain. In addition, the risk–benefit ratio of potent oral P2Y12-adenosine diphosphate (ADP) receptor antagonists (PPAs), namely, prasugrel and ticagrelor, compared with clopidogrel in CKD patients suffering from acute coronary syndrome (ACS) remains unknown.

Objective We performed a meta-analysis of all studies comparing the clinical outcomes of PPA and clopidogrel therapy in CKD patients suffering from ACS.

Methods We searched PubMed, the Cochrane library, Google Scholar, Clinical trial.org and the abstracts of international cardiology congresses from April 2000 to October 2017. Clinical studies comparing PPA with clopidogrel in ACS patients with CKD were selected. Our literature research identified five studies which were included in the meta-analysis. The primary endpoint was a composite of major adverse cardiovascular events (MACEs) at the latest follow-up available. Secondary endpoint included bleedings.

Results We included data from three sub-group analysis of randomized clinical trials and two prospective observational studies (n = 31,234). Overall, PPAs were associated with lower rates of major cardiovascular events, with a pooled hazard ratio (pHR) of 0.88 (95% confidence interval [CI]: 0.79–0.99; p = 0.03), without increased bleedings (pHR = 1.10) (95% CI: 0.95–1.27; p = 0.18). In a sensitivity analysis restricted to studies enrolling invasively managed patients, the benefit of PPA on MACE was maintained (pHR = 0.85) (95% CI: 0.77–0.93; p < 0.001), including a reduction in mortality (pHR = 0.82) (95% CI: 0.7–0.96; p = 0.016).

Conclusion Compared with clopidogrel, PPAs were associated with a reduced rate of MACE without increased bleedings in CKD patients with ACS. Among invasively managed patients, this benefit from PPA included a reduction in mortality.

Keywords

acute coronary syndrome - anti-platelet - chronic kidney failure - outcome - percutaneous coronary intervention

Authors' Contributions

Laurent Bonello, Marc Laine, Gilles Lemesle, Etienne Puymirat: Contribution to the concept and design and writing of the manuscript. Thibaut Dabry: Data analysis and data interpretation. Franck Thuny, Franck Paganelli: Data interpretation and critical revising of the intellectual content. Daniel Aradi: Critical revising of the intellectual content. Stéphane Burtey: Writing and revising of the intellectual content. Dirk Sibbing: Writing and revising of the intellectual content. Corinne Frere, Julien Mancini: Data analysis and interpretation.

• References

• 1 Goldenberg I, Subirana I, Boyko V. , et al. Relation between renal function and outcomes in patients with non-ST-segment elevation acute coronary syndrome: real-world data from the European Public Health Outcome Research and Indicators Collection Project. Arch Intern Med 2010; 170 (10) 888-895
• 2 El-Menyar A, Zubaid M, Sulaiman K. , et al. In-hospital major clinical outcomes in patients with chronic renal insufficiency presenting with acute coronary syndrome: data from a Registry of 8176 patients. Mayo Clin Proc 2010; 85 (04) 332-340
• 3 Szummer K, Lundman P, Jacobson SH. , et al; SWEDEHEART. Influence of renal function on the effects of early revascularization in non-ST-elevation myocardial infarction: data from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). Circulation 2009; 120 (10) 851-858
• 4 Laine M, Burtey S, Puymirat E, Lemesle G, Bonello L. Research and therapeutic nihilisms in chronic kidney disease. JACC Cardiovasc Interv 2017; 10 (22) 2343-2344
• 5 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 2017; DOI: 10.1093/eurheartj/ehx419.
• 6 Wallentin L, Becker RC, Budaj A. , et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11) 1045-1057
• 7 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 (20) 2001-2015
• 8 Palmer SC, Di Micco L, Razavian M. , et al. Effects of antiplatelet therapy on mortality and cardiovascular and bleeding outcomes in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med 2012; 156 (06) 445-459
• 9 Shamseer L, Moher D, Clarke M. , et al; PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 2015; 350: g7647
• 10 Sugidachi A, Asai F, Ogawa T, Inoue T, Koike H. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol 2000; 129 (07) 1439-1446
• 11 Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials. BMJ 2011; 343: 5928
• 12 Wells G, Shea B, O'Connell D. , et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses; 2009. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm . Accessed August 9, 2018
• 13 Roe MT, Armstrong PW, Fox KA. , et al; TRILOGY ACS Investigators. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012; 367 (14) 1297-1309
• 14 James S, Budaj A, Aylward P. , et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2010; 122 (11) 1056-1067
• 15 Edfors R, Sahlen AS, Szummer KS. Outcomes in patients treated with ticagrelor versus clopidogrel after acute myocardial infarction in relation to renal function: 1-year SWEDEHEART registry data. Paper presented at: European Society of Cardiology Congress, September 2017; Barcelona, Spain. European Heart Journal, Volume 38, Issue suppl_1, 1 August 2017, ehx493.6011. Available at: https://doi.org/10.1093/eurheartj/ehx493.6011 . Accessed August 9, 2018
• 16 Baber U, Chandrasekhar J, Sartori S. , et al. Associations between chronic kidney disease and outcomes with use of prasugrel versus clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a report from the PROMETHEUS study. JACC Cardiovasc Interv 2017; 10 (20) 2017-2025
• 17 Keltai M, Tonelli M, Mann JF. , et al; CURE Trial Investigators. Renal function and outcomes in acute coronary syndrome: impact of clopidogrel. Eur J Cardiovasc Prev Rehabil 2007; 14 (02) 312-318
• 18 Roffi M, Patrono C, Collet JP. , et al; ESC Scientific Document Group. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37 (03) 267-315
• 19 Barragan P, Sainsous J, Silvestri M. , et al. Ticlopidine and subcutaneous heparin as an alternative regimen following coronary stenting. Cathet Cardiovasc Diagn 1994; 32 (02) 133-138
• 20 Morel O, El Ghannudi S, Jesel L. , et al. Cardiovascular mortality in chronic kidney disease patients undergoing percutaneous coronary intervention is mainly related to impaired P2Y12 inhibition by clopidogrel. J Am Coll Cardiol 2011; 57 (04) 399-408
• 21 Bonello L, Laine M, Baumstarck K. , et al. A randomized trial of platelet reactivity monitoring-adjusted clopidogrel therapy versus prasugrel therapy to reduce high on-treatment platelet reactivity. Int J Cardiol 2013; 168 (04) 4244-4248
• 22 Jeong KH, Cho JH, Woo JS. , et al. Platelet reactivity after receiving clopidogrel compared with ticagrelor in patients with kidney failure treated with hemodialysis: a randomized crossover study. Am J Kidney Dis 2015; 65 (06) 916-924