Skip to main content
SpringerLink
Log in

Efficacy and Safety of Low-Dose Prasugrel Versus Clopidogrel in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: a Systematic Review and Meta-analysis

  • Original Article
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

To assess the efficacy and safety of low-dose prasugrel compared to clopidogrel based on the occurrence of major adverse cardiac events (MACEs) and major bleeding in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI).

Methods

The PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were systematically searched up to May 2020 to identify relevant randomized controlled trials (RCTs) and observational studies. A meta-analysis was conducted using a random effects model to estimate relative risks (RRs) with 95% confidence intervals (CIs). The primary efficacy and safety endpoints were MACE and major bleeding, respectively.

Results

Three RCTs (n = 2884) and five observational studies (n = 30,117) were included. A meta-analysis of RCTs revealed no significant differences in terms of MACE (RR 0.92, 95% CI 0.74 to 1.16) or major bleeding (RR 0.97, 95% CI 0.57 to 1.65) between low-dose prasugrel and clopidogrel. A meta-analysis of observational studies revealed no significant difference in terms of MACE (RR 1.13, 95% CI 0.82 to 1.55) between the two groups, but low-dose prasugrel was associated with a significantly increased risk of major bleeding (RR 1.33, 95% CI 1.02 to 1.72).

Conclusions

We found that low-dose prasugrel was not associated with changes in MACE or major bleeding compared with clopidogrel in RCTs. However, analysis of data from observational studies revealed that low-dose prasugrel was associated with an increased risk of major bleeding compared with clopidogrel.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials.

References

  1. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, 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. J Am Coll Cardiol. 2016;68(10):1082–115.

    Article  Google Scholar 

  2. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, et al. 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(3):213–60.

    Article  Google Scholar 

  3. Collet JP, Thiele H, Barbato E, Barthélémy O, Bauersachs J, Bhatt DL, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021;42(14):1289–367.

  4. Sibbing D, Aradi D, Alexopoulos D, Ten Berg J, Bhatt DL, Bonello L, et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y(12) receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019;12(16):1521–37.

    Article  Google Scholar 

  5. Savi P, Herbert JM. Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis. Semin Thromb Hemost. 2005;31(2):174–83.

    Article  CAS  Google Scholar 

  6. Michelson AD, Frelinger AL, Braunwald E, Downey WE, Angiolillo DJ, Xenopoulos NP, et al. Pharmacodynamic assessment of platelet inhibition by prasugrel vs. clopidogrel in the TRITON-TIMI 38 trial. European Heart Journal. 2009;30(14):1753–63.

    Article  CAS  Google Scholar 

  7. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001–15.

    Article  CAS  Google Scholar 

  8. Park KH, Jeong MH, Kim HK, Ahn TH, Seung KB, Oh DJ, et al. Comparison of prasugrel versus clopidogrel in Korean patients with acute myocardial infarction undergoing successful revascularization. J Cardiol. 2018;71(1):36–43.

    Article  Google Scholar 

  9. Yun JE, Kim YJ, Park JJ, Kim S, Park K, Cho MS, et al. Safety and effectiveness of contemporary P2Y(12) inhibitors in an East Asian population with acute coronary syndrome: a nationwide population-based cohort study. J Am Heart Assoc. 2019;8(14): e012078.

    Article  CAS  Google Scholar 

  10. Kimura K, Kimura T, Ishihara M, Nakagawa Y, Nakao K, Miyauchi K, et al. JCS 2018 Guideline on diagnosis and treatment of acute coronary syndrome. Circ J. 2019;83(5):1085–196.

    Article  CAS  Google Scholar 

  11. Roe MT, Goodman SG, Ohman EM, Stevens SR, Hochman JS, Gottlieb S, et al. Elderly patients with acute coronary syndromes managed without revascularization: insights into the safety of long-term dual antiplatelet therapy with reduced-dose prasugrel versus standard-dose clopidogrel. Circulation. 2013;128(8):823–33.

    Article  CAS  Google Scholar 

  12. Saito S, Isshiki T, Kimura T, Ogawa H, Yokoi H, Nanto S, 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(7):1684–92.

    Article  CAS  Google Scholar 

  13. Akita K, Inohara T, Yamaji K, Kohsaka S, Numasawa Y, Ishii H, et al. Impact of reduced-dose prasugrel vs. standard-dose clopidogrel on in-hospital outcomes of percutaneous coronary intervention in 62 737 patients with acute coronary syndromes: a nationwide registry study in Japan. Eur Heart J Cardiovasc Pharmacother. 2020;6(4):231–8.

    Article  Google Scholar 

  14. Shoji S, Sawano M, Sandhu AT, Heidenreich PA, Shiraishi Y, Ikemura N, et al. Ischemic and bleeding events among patients with acute coronary syndrome associated with low-dose prasugrel vs standard-dose clopidogrel treatment. JAMA Netw Open. 2020;3(4): e202004.

    Article  Google Scholar 

  15. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7): e1000100.

    Article  Google Scholar 

  16. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12.

    Article  CAS  Google Scholar 

  17. Wongsalap Y, Kengkla K, Saokaew S. Efficacy and safety of low-dose prasugrel in patients with coronary artery diseases: a systematic review and meta-analysis. Prospero. 2020.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020188261.

  18. TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. N Engl J Med. 1985;312(14):932–6.

  19. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736–47.

    Article  Google Scholar 

  20. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366: l4898.

    Article  Google Scholar 

  21. Sterne JA, Hernan MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355: i4919.

    Article  Google Scholar 

  22. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editors. Cochrane Handbook for Systematic Reviews of Interventions version 6.2. Cochrane. 2021. http://www.training.cochrane.org/handbook.

  23. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

    Article  CAS  Google Scholar 

  24. Borenstein M, Hedges LV, Higgins JP, Rothstein HR. A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods. 2010;1(2):97–111.

    Article  Google Scholar 

  25. Shor E, Roelfs D, Vang ZM. The “Hispanic mortality paradox” revisited: meta-analysis and meta-regression of life-course differentials in Latin American and Caribbean immigrants’ mortality. Soc Sci Med. 2017;186:20–33.

    Article  Google Scholar 

  26. Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343: d4002.

    Article  Google Scholar 

  27. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.

    Article  Google Scholar 

  28. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94.

    Article  Google Scholar 

  29. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al. Grading quality of evidence and strength of recommendations. BMJ. 2004;328(7454):1490.

    Article  Google Scholar 

  30. Savonitto S, Ferri LA, Piatti L, Grosseto D, Piovaccari G, Morici N, et al. Comparison of reduced-dose prasugrel and standard-dose clopidogrel in elderly patients with acute coronary syndromes undergoing early percutaneous revascularization. Circulation. 2018;137(23):2435–45.

    Article  CAS  Google Scholar 

  31. Kitano D, Takayama T, Fukamachi D, Migita S, Morikawa T, Tamaki T, et al. Impact of low-dose prasugrel on platelet reactivity and cardiac dysfunction in acute coronary syndrome patients requiring primary drug-eluting stent implantation: a randomized comparative study. Catheter Cardiovasc Interv. 2020;95(1):E8–16.

    Article  Google Scholar 

  32. Ohya M, Shimada T, Osakada K, Kuwayama A, Miura K, Murai R, et al. In-hospital bleeding and utility of a maintenance dose of prasugrel 2.5 mg in high bleeding risk patients with acute coronary syndrome. Circ J. 2018;82(7):1874–83.

    Article  CAS  Google Scholar 

  33. Tokimasa S, Kitahara H, Nakayama T, Fujimoto Y, Shiba T, Shikama N, et al. Multicenter research of bleeding risk between prasugrel and clopidogrel in Japanese patients with coronary artery disease undergoing percutaneous coronary intervention. Heart Vessels. 2019;34(10):1581–8.

    Article  Google Scholar 

  34. Yasuda S, Honda S, Takegami M, Nishihira K, Kojima S, Asaumi Y, et al. Contemporary antiplatelet therapy and clinical outcomes of japanese patients with acute myocardial infarction - results from the prospective Japan acute myocardial infarction registry (JAMIR). Circ J. 2019;83(8):1633–43.

    Article  CAS  Google Scholar 

  35. Schüpke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wöhrle J, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med. 2019;381(16):1524–34.

    Article  Google Scholar 

  36. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57.

    Article  CAS  Google Scholar 

  37. Chen HB, Zhang XL, Liang HB, Liu XW, Zhang XY, Huang BY, et al. Meta-analysis of randomized controlled trials comparing risk of major adverse cardiac events and bleeding in patients with prasugrel versus clopidogrel. Am J Cardiol. 2015;116(3):384–92.

    Article  CAS  Google Scholar 

  38. Bavishi C, Panwar S, Messerli FH, Bangalore S. Meta-analysis of comparison of the newer oral P2Y12 inhibitors (prasugrel or ticagrelor) to clopidogrel in patients with non-ST-elevation acute coronary syndrome. Am J Cardiol. 2015;116(5):809–17.

    Article  CAS  Google Scholar 

  39. Bellemain-Appaix A, Brieger D, Beygui F, Silvain J, Pena A, Cayla G, et al. New P2Y12 inhibitors versus clopidogrel in percutaneous coronary intervention: a meta-analysis. J Am Coll Cardiol. 2010;56(19):1542–51.

    Article  CAS  Google Scholar 

  40. Kim HK, Tantry US, Smith SC Jr, Jeong MH, Park SJ, Kim MH, et al. The East Asian paradox: an updated position statement on the challenges to the current antithrombotic strategy in patients with cardiovascular disease. Thromb Haemost. 2021;121(4):422–32.

    Article  Google Scholar 

  41. Jakubowski JA, Erlinge D, Alexopoulos D, Small DS, Winters KJ, Gurbel PA, et al. The rationale for and clinical pharmacology of prasugrel 5 mg. Am J Cardiovasc Drugs. 2017;17(2):109–21.

    Article  CAS  Google Scholar 

  42. Dworeck C, Redfors B, Angerås O, Haraldsson I, Odenstedt J, Ioanes D, et al. Association of pretreatment with P2Y12 receptor antagonists preceding percutaneous coronary intervention in non-ST-segment elevation acute coronary syndromes with outcomes. JAMA Netw Open. 2020;3(10): e2018735.

    Article  Google Scholar 

  43. Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay JF, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013;369(11):999–1010.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Adam Joseph Osman Dede (Research specialist, School of Pharmaceutical Sciences, University of Phayao) for proofreading and English language review.

Funding

The study was supported by a grant from the Unit of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN) Grant number: FF64-UoE003, School of Pharmaceutical Sciences, University of Phayao. The funding source had no role in the study design, collection, analysis, and interpretation of data.

Author information

Authors and Affiliations

  1. School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand

    Yuttana Wongsalap, Supakorn Ungsriwong, Wanalee Kumtep, Surasak Saokaew & Kirati Kengkla

  2. Division of Pharmacy Practice, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand

    Yuttana Wongsalap, Surasak Saokaew & Kirati Kengkla

  3. Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, 56000, Thailand

    Yuttana Wongsalap, Surasak Saokaew & Kirati Kengkla

  4. Unit of Excellence On Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand

    Yuttana Wongsalap, Surasak Saokaew & Kirati Kengkla

  5. Biofunctional Molecule Exploratory Research Group, Biomedicine Research Advancement Centre, School of Pharmacy, Monash University Malaysia, Selangor Darul Ehsan, Bandar Sunway, Malaysia

    Surasak Saokaew

  6. Novel Bacteria and Drug Discovery Research Group, Microbiome and Bioresource Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Selangor DarulEhsan, Bandar Sunway, Malaysia

    Surasak Saokaew

  7. Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

    Vichai Senthong

Authors
  1. Yuttana Wongsalap
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Supakorn Ungsriwong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wanalee Kumtep
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Surasak Saokaew
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vichai Senthong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kirati Kengkla
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Yuttana Wongsalap: design, data collection, analysis, interpretation, writing the manuscript, critical revision, and final approval. Supakorn Ungsriwong: data collection. Wanalee Kumtep: data collection. Surasak Saokaew: data collection, critical revision, and final approval. Vichai Senthong: critical revision and final approval. Kirati Kengkla: design, data collection, analysis, interpretation, writing the manuscript, critical revision, and final approval.

Corresponding author

Correspondence to Kirati Kengkla.

Ethics declarations

Ethics Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 2449 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wongsalap, Y., Ungsriwong, S., Kumtep, W. et al. Efficacy and Safety of Low-Dose Prasugrel Versus Clopidogrel in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: a Systematic Review and Meta-analysis. Cardiovasc Drugs Ther 36, 991–1000 (2022). https://doi.org/10.1007/s10557-021-07202-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-021-07202-1

Keywords

Search

Navigation