Coronary Heart Disease (CHD) in Elderly Patients: Which Drug to Choose, Ticagrelor and Clopidogrel? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Mohammed Ahmed Akkaif, Abubakar Sha'aban, Nur Aizati Athirah Daud, Ismaeel Yunusa, Mei Li Ng, Muhamad Ali Sk Abdul Kader, Dzul Azri Mohamed Noor, Baharudin Ibrahim, Mohammed Ahmed Akkaif, Abubakar Sha'aban, Nur Aizati Athirah Daud, Ismaeel Yunusa, Mei Li Ng, Muhamad Ali Sk Abdul Kader, Dzul Azri Mohamed Noor, Baharudin Ibrahim

Abstract

Background: A new generation P2Y12 receptor inhibitor (ticagrelor) is recommended in current therapeutic guidelines to treat patients with coronary heart disease (CHD). However, it is unknown if ticagrelor is more effective than clopidogrel in elderly patients. Therefore, a systematic review was done to assess the effectiveness and safety of ticagrelor and clopidogrel in older patients with CHD to determine the appropriate antiplatelet treatment plan.

Methodology: We performed a systematic review of randomized controlled trials (RCTs) to compare the effectiveness and safety of ticagrelor vs. clopidogrel in elderly patients with CHD. We selected eligible RCTs based on specified study criteria following a systematic search of PubMed and Scopus databases from January 2007 to May 2021. Primary efficacy outcomes assessed were major adverse cardiovascular events (MACEs), myocardial infarction (MI), stent thrombosis (ST), and all-cause death. The secondary outcome assessed was major bleeding events. We used RevMan 5.3 software to conduct a random-effects meta-analysis and estimated the pooled incidence and risk ratios (RRs) with 95% confidence intervals (CIs) for ticagrelor and clopidogrel.

Results: Data from 6 RCTs comprising 21,827 elderly patients were extracted according to the eligibility criteria. There was no significant difference in the MACE outcome (incidence: 9.23% vs. 10.57%; RR = 0.95, 95% CI = 0.70-1.28, p = 0.72), MI (incidence: 5.40% vs. 6.23%; RR = 0.94, 95% CI= 0.69-1.27, p = 0.67), ST (incidence: 2.33% vs. 3.17%; RR = 0.61, 95% CI= 0.32-1.17, p = 0.13), and all-cause death (4.29% vs. 5.33%; RR = 0.86, 95% CI = 0.65-1.12, p = 0.25) for ticagrelor vs. clopidogrel, respectively. In addition, ticagrelor was not associated with a significant increase in the rate of major bleeding (incidence: 9.98% vs. 9.33%: RR = 1.37, 95% CI = 0.97-1.94, p = 0.07) vs. clopidogrel.

Conclusions: This study did not find evidence that ticagrelor is significantly more effective or safer than clopidogrel in elderly patients with CHD.

Keywords: clopidogrel; meta-analysis; randomized controlled trials; systematic review; ticagrelor.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flow chart of articles screening.
Figure 2
Figure 2
Graph of risk of bias.
Figure 3
Figure 3
The forest plots for (A): MACE; (B): MI; (C): stent thrombosis; (D): all-cause mortality in elderly patients treated with Ticagrelor versus clopidogrel.
Figure 4
Figure 4
The forest plots for major bleeding in elderly patients treated with Ticagrelor versus clopidogrel.

References

    1. Roth G.A., Mensah G.A., Johnson C.O., Addolorato G., Ammirati E., Baddour L.M., Barengo N.C., Beaton A.Z., Benjamin E.J., Benziger C.P. Global burden of cardiovascular diseases and risk factors, 1990–2019: Update from the GBD 2019 study. J. Am. Coll. Cardiol. 2020;76:2982–3021. doi: 10.1016/j.jacc.2020.11.010.
    1. Roth G.A., Abate D., Abate K.H., Abay S.M., Abbafati C., Abbasi N., Abbastabar H., Abd-Allah F., Abdela J., Abdelalim A. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1736–1788. doi: 10.1016/S0140-6736(18)32203-7.
    1. Roth G.A., Forouzanfar M.H., Moran A.E., Barber R., Nguyen G., Feigin V.L., Naghavi M., Mensah G.A., Murray C.J. Demographic and epidemiologic drivers of global cardiovascular mortality. N. Engl. J. Med. 2015;372:1333–1341. doi: 10.1056/NEJMoa1406656.
    1. Fox K.A., Dabbous O.H., Goldberg R.J., Pieper K.S., Eagle K.A., Van de Werf F., Avezum Á., Goodman S.G., Flather M.D., Anderson F.A. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: Prospective multinational observational study (GRACE) BMJ. 2006;333:1091. doi: 10.1136/bmj.38985.646481.55.
    1. Mehran R., Pocock S.J., Nikolsky E., Clayton T., Dangas G.D., Kirtane A.J., Parise H., Fahy M., Manoukian S.V., Feit F. A risk score to predict bleeding in patients with acute coronary syndromes. J. Am. Coll. Cardiol. 2010;55:2556–2566. doi: 10.1016/j.jacc.2009.09.076.
    1. Wallentin L., Becker R.C., Budaj A., Cannon C.P., Emanuelsson H., Held C., Horrow J., Husted S., James S., Katus H. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 2009;361:1045–1057. doi: 10.1056/NEJMoa0904327.
    1. Valgimigli M., Bueno H., Byrne R.A., Collet J.-P., Costa F., Jeppsson A., Jüni P., Kastrati A., Kolh P., Mauri L. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur. J. Cardio-Thorac. Surg. 2018;53:34–78. doi: 10.1093/ejcts/ezx334.
    1. Dhillon S. Ticagrelor: A review of its use in adults with acute coronary syndromes. Am. J. Cardiovasc. Drugs. 2015;15:51–68. doi: 10.1007/s40256-015-0108-5.
    1. Akkaif M.A., Daud N.A.A., Sha’aban A., Ng M.L., Sk Abdul Kader M.A., Noor D.A.M., Ibrahim B. The Role of Genetic Polymorphism and Other Factors on Clopidogrel Resistance (CR) in an Asian Population with Coronary Heart Disease (CHD) Molecules. 2021;26:1987. doi: 10.3390/molecules26071987.
    1. Yoon H.Y., Lee N., Seong J.M., Gwak H.S. Efficacy and safety of clopidogrel versus prasugrel and ticagrelor for coronary artery disease treatment in patients with CYP2C19 LoF alleles: A systemic review and meta-analysis. Br. J. Clin. Pharmacol. 2020;86:1489–1498. doi: 10.1111/bcp.14317.
    1. Biswas M., Kali M.S.K., Biswas T.K., Ibrahim B. Risk of major adverse cardiovascular events of CYP2C19 loss-of-function genotype guided prasugrel/ticagrelor vs. clopidogrel therapy for acute coronary syndrome patients undergoing percutaneous coronary intervention: A meta-analysis. Platelets. 2021;32:591–600. doi: 10.1080/09537104.2020.1792871.
    1. Husted S., James S., Becker R.C., Horrow J., Katus H., Storey R.F., Cannon C.P., Heras M., Lopes R.D., Morais J. Ticagrelor versus clopidogrel in elderly patients with acute coronary syndromes: A substudy from the prospective randomized PLATelet inhibition and patient Outcomes (PLATO) trial. Circ. Cardiovasc. Qual. Outcomes. 2012;5:680–688. doi: 10.1161/CIRCOUTCOMES.111.964395.
    1. Avezum A., Makdisse M., Spencer F., Gore J.M., Fox K.A., Montalescot G., Eagle K.A., White K., Mehta R.H., Knobel E. Impact of age on management and outcome of acute coronary syndrome: Observations from the Global Registry of Acute Coronary Events (GRACE) Am. Heart J. 2005;149:67–73. doi: 10.1016/j.ahj.2004.06.003.
    1. Gimbel M., Qaderdan K., Willemsen L., Hermanides R., Bergmeijer T., de Vrey E., Heestermans T., Gin M.T.J., Waalewijn R., Hofma S. Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome (POPular AGE): The randomised, open-label, non-inferiority trial. Lancet. 2020;395:1374–1381. doi: 10.1016/S0140-6736(20)30325-1.
    1. Szummer K., Montez-Rath M.E., Alfredsson J., Erlinge D., Lindahl B., Hofmann R., Ravn-Fischer A., Svensson P., Jernberg T. Comparison between ticagrelor and clopidogrel in elderly patients with an acute coronary syndrome: Insights from the SWEDEHEART registry. Circulation. 2020;142:1700–1708. doi: 10.1161/CIRCULATIONAHA.120.050645.
    1. Liberati A., Altman D.G., Tetzlaff J., Mulrow C., Gøtzsche P.C., Ioannidis J.P., Clarke M., Devereaux P.J., Kleijnen J., Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. J. Clin. Epidemiol. 2009;62:e1–e34. doi: 10.1016/j.jclinepi.2009.06.006.
    1. Guidelines E.C.f.P., Bax J.J., Baumgartner H., Ceconi C., Dean V., Deaton C., Fagard R., Funck-Brentano C., Hasdai D., Hoes A. Third universal definition of myocardial infarction. J. Am. Coll. Cardiol. 2012;60:1581–1598.
    1. Kikkert W.J., van Geloven N., van der Laan M.H., Vis M.M., Baan J., Koch K.T., Peters R.J., de Winter R.J., Piek J.J., Tijssen J.G. The prognostic value of bleeding academic research consortium (BARC)-defined bleeding complications in ST-segment elevation myocardial infarction: A comparison with the TIMI (Thrombolysis In Myocardial Infarction), GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), and ISTH (International Society on Thrombosis and Haemostasis) bleeding classifications. J. Am. Coll. Cardiol. 2014;63:1866–1875.
    1. Sterne J.A., Savović J., Page M.J., Elbers R.G., Blencowe N.S., Boutron I., Cates C.J., Cheng H.-Y., Corbett M.S., Eldridge S.M. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366 doi: 10.1136/bmj.l4898.
    1. Stare J., Maucort-Boulch D. Odds ratio, hazard ratio and relative risk. Metodoloski Zv. 2016;13:59.
    1. Higgins J.P., Thompson S.G., Deeks J.J., Altman D.G. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. doi: 10.1136/bmj.327.7414.557.
    1. Sterne J.A., Sutton A.J., Ioannidis J.P., Terrin N., Jones D.R., Lau J., Carpenter J., Rücker G., Harbord R.M., Schmid C.H. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343 doi: 10.1136/bmj.d4002.
    1. Guan W., Lu H., Yang K. Choosing between ticagrelor and clopidogrel following percutaneous coronary intervention: A systematic review and Meta-Analysis (2007–2017) Medicine. 2018;97:e12978. doi: 10.1097/MD.0000000000012978.
    1. Wang H., Wang X. Efficacy and safety outcomes of ticagrelor compared with clopidogrel in elderly Chinese patients with acute coronary syndrome. Ther. Clin. Risk Manag. 2016;12:1101. doi: 10.2147/TCRM.S108965.
    1. Tang X., Li R., Jing Q., Wang Q., Liu P., Zhang P., Liu Y. Assessment of ticagrelor versus clopidogrel treatment in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. J. Cardiovasc. Pharmacol. 2016;68:115–120. doi: 10.1097/FJC.0000000000000390.
    1. Park D.-W., Kwon O., Jang J.-S., Yun S.-C., Park H., Kang D.-Y., Ahn J.-M., Lee P.H., Lee S.-W., Park S.-W. Clinically significant bleeding with ticagrelor versus clopidogrel in Korean patients with acute coronary syndromes intended for invasive management: A randomized clinical trial. Circulation. 2019;140:1865–1877. doi: 10.1161/CIRCULATIONAHA.119.041766.
    1. Goto S., Huang C.-H., Park S.-J., 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;79:2452–2460. doi: 10.1253/circj.CJ-15-0112.
    1. Savi P., Nurden P., Nurden A., Levy-Toledano S., Herbert J.-M. Clopidogrel: A review of its mechanism of action. Platelets. 1998;9:251–255. doi: 10.1080/09537109876799.
    1. Wallentin L. P2Y12 inhibitors: Differences in properties and mechanisms of action and potential consequences for clinical use. Eur. Heart J. 2009;30:1964–1977. doi: 10.1093/eurheartj/ehp296.
    1. Birkeland K., Parra D., Rosenstein R. Antiplatelet therapy in acute coronary syndromes: Focus on ticagrelor. J. Blood Med. 2010;1:197.
    1. Akkaif M.A., Ng M.L., Kader M.A.S.A., Daud N.A.A., Sha’aban A., Ibrahim B. A review of the effects of ticagrelor on adenosine concentration and its clinical significance. Pharmacol. Rep. 2021:1–14. doi: 10.1007/s43440-021-00309-0.
    1. Akkaif M.A., Sha’aban A., Daud N.A.A., Ng M.L., Ibrahim B. Investigate the Strategy of Using Pharmacogenetics and Pharmacometabonomics to the Personalization of Ticagrelor Antiplatelet Therapy. Syst. Rev. Pharm. 2020;11:1100–1107.
    1. Kang H.-J., Clare R.M., Gao R., Held C., Himmelmann A., James S.K., Lim S.T., Santoso A., Yu C.-M., Wallentin L. Ticagrelor versus clopidogrel in Asian patients with acute coronary syndrome: A retrospective analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial. Am. Heart J. 2015;169:899–905.e891. doi: 10.1016/j.ahj.2015.03.015.
    1. Fujisaki T., Kuno T., Ando T., Briasoulis A., Takagi H., Bangalore S. Potent P2Y12 Inhibitors versus Clopidogrel in Elderly Patients with Acute Coronary Syndrome: Systematic Review and Meta-Analysis: P2Y12 inhibitors and elderly patients with ACS. Am. Heart J. 2021;237:34–44. doi: 10.1016/j.ahj.2021.03.009.
    1. Tarantini G., Ueshima D., D’Amico G., Masiero G., Musumeci G., Stone G.W., Brener S.J. Efficacy and safety of potent platelet P2Y12 receptor inhibitors in elderly versus nonelderly patients with acute coronary syndrome: A systematic review and meta-analysis. Am. Heart J. 2018;195:78–85. doi: 10.1016/j.ahj.2017.09.012.
    1. Crimi G., Morici N., Ferrario M., Ferri L.A., Piatti L., Grosseto D., Cacucci M., Mandurino Mirizzi A., Toso A., Piscione F. Time course of ischemic and bleeding burden in elderly patients with acute coronary syndromes randomized to low-dose prasugrel or clopidogrel. J. Am. Heart Assoc. 2019;8:e010956. doi: 10.1161/JAHA.118.010956.
    1. Cuisset T., Deharo P., Quilici J., Johnson T.W., Deffarges S., Bassez C., Bonnet G., Fourcade L., Mouret J.P., Lambert M. Benefit of switching dual antiplatelet therapy after acute coronary syndrome: The TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study. Eur. Heart J. 2017;38:3070–3078. doi: 10.1093/eurheartj/ehx175.
    1. Franchi F., Rollini F., Rivas Rios J., Rivas A., Agarwal M., Kureti M., Nagaraju D., Wali M., Shaikh Z., Briceno M. Pharmacodynamic effects of switching from ticagrelor to clopidogrel in patients with coronary artery disease: Results of the SWAP-4 study. Circulation. 2018;137:2450–2462. doi: 10.1161/CIRCULATIONAHA.118.033983.
    1. Li X.Y., Su G.H., Wang G.X., Hu H.Y., Fan C.J. Switching from ticagrelor to clopidogrel in patients with ST-segment elevation myocardial infarction undergoing successful percutaneous coronary intervention in real-world China: Occurrences, reasons, and long-term clinical outcomes. Clin. Cardiol. 2018;41:1446–1454. doi: 10.1002/clc.23074.
    1. Pourdjabbar A., Hibbert B., Chong A.-Y., Le May M.R., Labinaz M., Simard T., Ramirez F.D., Lugomirski P., Maze R., Froeschl M. A randomised study for optimising crossover from ticagrelor to clopidogrel in patients with acute coronary syndrome. Thromb. Haemost. 2017;117:303–310. doi: 10.1160/TH16-04-0340.

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