Thromb Haemost 2024; 124(05): 482-496
DOI: 10.1055/a-2149-4344
Atherosclerosis and Ischaemic Disease

Guided Anti-P2Y12 Therapy in Patients Undergoing PCI: Three Systematic Reviews with Meta-analyses of Randomized Controlled Trials with Homogeneous Design

Simone Birocchi
1   Divisione di Medicina Generale II, Dipartimento di Scienze della Salute, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
,
Matteo Rocchetti
2   Divisione di Cardiologia, Dipartimento di Scienze della Salute, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
,
Alessandro Minardi
2   Divisione di Cardiologia, Dipartimento di Scienze della Salute, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
,
Gian Marco Podda
1   Divisione di Medicina Generale II, Dipartimento di Scienze della Salute, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
,
3   Research Center on Thromboembolic Disorders and Antithrombotic Therapies, ASST Lariana, University of Insubria, Como, Italy
,
Marco Cattaneo
1   Divisione di Medicina Generale II, Dipartimento di Scienze della Salute, ASST Santi Paolo e Carlo, Università degli Studi di Milano, Milan, Italy
4   Fondazione Arianna Anticoagulazione, Bologna, Italy
› Author Affiliations


Abstract

Background The value of guided therapy (GT) with anti-P2Y12 drugs in percutaneous coronary intervention (PCI) is unclear. Meta-analyses lumped together randomized controlled trials (RCTs) with heterogeneous designs, comparing either genotype-GT or platelet function test (PFT)-GT with unguided therapy. Some meta-analysis also included RCTs that did not explore GT, but included the effects of switching patients with high on-treatment platelet reactivity (HTPR) to alternative therapies (HTPR-Therapy). We performed three distinct systematic reviews/meta-analyses, each exploring only RCTs with homogeneous design.

Methods MEDLINE, Embase, and Central databases were searched for RCTs testing genotype-GT, PFT-GT, or HTPR-Therapy in PCI-treated patients, through October 1, 2022. Two reviewers extracted the data. Risk ratios (RRs) (95% confidence intervals) were calculated. Primary outcomes were major bleedings (MBs) and major adverse cardiovascular events (MACE).

Results In seven genotype-GT RCTs, RRs were: MB, 1.06 (0.73–1.54; p = 0.76); MACE, 0.65 (0.47–0.91; p = 0.01), but significant risk reduction was observed in RCTs performed in China (0.30, 0.16–0.54; p < 0.0001) and not elsewhere (0.75, 0.48–1.18; p = 0.21). In six PFT-GT RCTs, RRs were: MB, 0.91 (0.64–1.28, p = 0.58); MACE, 0.82 (0.56–1.19; p = 0.30): 0.62 (0.42–0.93; p = 0.02) in China, 1.08 (0.82–1.41; p = 0.53) elsewhere. In eight HTPR-Therapy RCTs, RRs were: MB, 0.71 (0.41–1.23; p = 0.22); MACE, 0.57 (0.44–0.75; p < 0.0001): 0.56 (0.43–0.74, p < 0.0001) in China, 0.58 (0.27–1.23, p = 0.16) elsewhere.

Conclusion No GT strategy affected MB. Overall, genotype-GT but not PFT-GT reduced MACE. However, genotype-GT and PFT-GT reduced MACE in China, but not elsewhere. PFT-GT performed poorly compared to HTPR-Therapy, likely due to inaccurate identification of HTPR patients by PFT.

Supplementary Material



Publication History

Received: 14 June 2023

Accepted: 06 August 2023

Accepted Manuscript online:
07 August 2023

Article published online:
05 September 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Lawton JS, Tamis-Holland JE, Bangalore S. et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022; 145 (03) e18-e114
  • 2 Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost 2007; 5 (Suppl. 01) 230-237
  • 3 Cattaneo M. Response variability to clopidogrel: is tailored treatment, based on laboratory testing, the right solution?. J Thromb Haemost 2012; 10 (03) 327-336
  • 4 Mega JL, Close SL, Wiviott SD. et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 2010; 376 (9749) 1312-1319
  • 5 Brar SS, ten Berg J, Marcucci R. et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data. J Am Coll Cardiol 2011; 58 (19) 1945-1954
  • 6 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
  • 7 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
  • 8 Cattaneo M. New P2Y(12) inhibitors. Circulation 2010; 121 (01) 171-179
  • 9 Xie X, Ma YT, Yang YN. et al. Personalized antiplatelet therapy according to CYP2C19 genotype after percutaneous coronary intervention: a randomized control trial. Int J Cardiol 2013; 168 (04) 3736-3740
  • 10 Notarangelo FM, Maglietta G, Bevilacqua P. et al. Pharmacogenomic approach to selecting antiplatelet therapy in patients with acute coronary syndromes: the PHARMCLO trial. J Am Coll Cardiol 2018; 71 (17) 1869-1877
  • 11 Claassens DMF, Vos GJA, Bergmeijer TO. et al. A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI. N Engl J Med 2019; 381 (17) 1621-1631
  • 12 Pereira NL, Farkouh ME, So D. et al. Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: the TAILOR-PCI randomized clinical trial. JAMA 2020; 324 (08) 761-771
  • 13 Tuteja S, Glick H, Matthai W. et al. Prospective CYP2C19 genotyping to guide antiplatelet therapy following percutaneous coronary intervention: a pragmatic randomized clinical trial. Circ Genom Precis Med 2020; 13 (01) e002640
  • 14 Al-Rubaish AM, Al-Muhanna FA, Alshehri AM. et al. Bedside testing of CYP2C19 vs. conventional clopidogrel treatment to guide antiplatelet therapy in ST-segment elevation myocardial infarction patients. Int J Cardiol 2021; 343: 15-20
  • 15 Shi X, Zhang Y, Zhang Y. et al. Personalized antiplatelet therapy based on CYP2C19 genotypes in Chinese ACS patients undergoing PCI: a randomized controlled trial. Front Cardiovasc Med 2021; 8: 676954
  • 16 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 (22) 2100-2109
  • 17 Hazarbasanov D, Velchev V, Finkov B. et al. Tailoring clopidogrel dose according to multiple electrode aggregometry decreases the rate of ischemic complications after percutaneous coronary intervention. J Thromb Thrombolysis 2012; 34 (01) 85-90
  • 18 Xu L, Wang L, Yang X. et al. Platelet function monitoring guided antiplatelet therapy in patients receiving high-risk coronary interventions. Chin Med J (Engl) 2014; 127 (19) 3364-3370
  • 19 Zhu HC, Li Y, Guan SY. et al. Efficacy and safety of individually tailored antiplatelet therapy in patients with acute coronary syndrome after coronary stenting: a single center, randomized, feasibility study. J Geriatr Cardiol 2015; 12 (01) 23-29
  • 20 Cayla G, Cuisset T, Silvain J. et al; ANTARCTIC investigators. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet 2016; 388 (10055): 2015-2022
  • 21 Zheng YY, Wu TT, Yang Y. et al. Personalized antiplatelet therapy guided by a novel detection of platelet aggregation function in stable coronary artery disease patients undergoing percutaneous coronary intervention: a randomized controlled clinical trial. Eur Heart J Cardiovasc Pharmacother 2020; 6 (04) 211-221
  • 22 Price MJ, Berger PB, Teirstein PS. et al; GRAVITAS Investigators. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011; 305 (11) 1097-1105
  • 23 Ari H, Ozkan H, Karacinar A, Ari S, Koca V, Bozat T. The EFFect of hIgh-dose ClopIdogrel treatmENT in patients with clopidogrel resistance (the EFFICIENT trial). Int J Cardiol 2012; 157 (03) 374-380
  • 24 Trenk D, Stone GW, Gawaz M. et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) study. J Am Coll Cardiol 2012; 59 (24) 2159-2164
  • 25 Samardzic J, Krpan M, Skoric B, Pasalic M, Petricevic M, Milicic D. Serial clopidogrel dose adjustment after platelet function testing improves outcome of acute coronary syndrome patients undergoing percutaneous coronary intervention with high on-treatment platelet reactivity. J Thromb Thrombolysis 2014; 38 (04) 459-469
  • 26 Li Y, Han Y, Guan S. et al. Optimal- vs. standard-antiplatelet therapy on platelet function and long-term clinical outcomes in patients with high on-treatment platelet reactivity: 2-year outcomes of the multicentre, randomized Optimal-antiPlatelet Therapy (OPT) trial. Eur Heart J Suppl 2015; 17: B23-B31
  • 27 Tang YD, Wang W, Yang M. et al; CREATIVE Investigators. Randomized comparisons of double-dose clopidogrel or adjunctive cilostazol versus standard dual antiplatelet in patients with high posttreatment platelet reactivity: results of the CREATIVE trial. Circulation 2018; 137 (21) 2231-2245
  • 28 You J, Li H, Guo W. et al. Platelet function testing guided antiplatelet therapy reduces cardiovascular events in Chinese patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention: the PATROL study. Catheter Cardiovasc Interv 2020; 95 (Suppl. 01) 598-605
  • 29 Ying L, Wang J, Li J. et al. Intensified antiplatelet therapy in patients after percutaneous coronary intervention with high on-treatment platelet reactivity: the OPTImal Management of Antithrombotic Agents (OPTIMA)-2 trial. Br J Haematol 2022; 196 (02) 424-432
  • 30 Aluvilu A, Ferro A. Role of platelet function testing in acute coronary syndromes: a meta-analysis. Open Heart 2022; 9 (02) e002129
  • 31 Yamani N, Unzek S, Mankani MH. et al. Does individualized guided selection of antiplatelet therapy improve outcomes after percutaneous coronary intervention? A systematic review and meta-analysis. Ann Med Surg (Lond) 2022; 79: 103964
  • 32 Wang X, Wang S, Yang J, Yu X, Liu L. Genotype-guided antiplatelet therapy compared with standard therapy for patients with acute coronary syndromes or undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Thromb Res 2020; 193: 130-138
  • 33 Tang B, Wang X, Wang X, Liu L, Ma Z. Genotype-guided antiplatelet therapy versus standard therapy for patients with coronary artery disease: an updated systematic review and meta-analysis. J Pharm Pharm Sci 2022; 25: 9-23
  • 34 Sibbing D, Aradi D, Jacobshagen C. et al; TROPICAL-ACS Investigators. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet 2017; 390 (10104): 1747-1757
  • 35 Galli M, Benenati S, Capodanno D. et al. Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Lancet 2021; 397 (10283): 1470-1483
  • 36 Gurbel PA, Mahla E, Tantry US. Peri-operative platelet function testing: the potential for reducing ischaemic and bleeding risks. Thromb Haemost 2011; 106 (02) 248-252
  • 37 Siller-Matula JM, Jilma B. Why have studies of tailored anti-platelet therapy failed so far?. Thromb Haemost 2013; 110 (04) 628-631
  • 38 Bauer T, Bouman HJ, van Werkum JW, Ford NF, ten Berg JM, Taubert D. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ 2011; 343: d4588
  • 39 Fricke-Galindo I, Céspedes-Garro C, Rodrigues-Soares F. et al. Interethnic variation of CYP2C19 alleles, ‘predicted’ phenotypes and ‘measured’ metabolic phenotypes across world populations. Pharmacogenomics J 2016; 16 (02) 113-123
  • 40 Biswas M, Jinda P, Sukasem C. Pharmacogenomics in Asians: differences and similarities with other human populations. Expert Opin Drug Metab Toxicol 2023; 19 (01) 27-41
  • 41 Sorich MJ, Rowland A, McKinnon RA, Wiese MD. CYP2C19 genotype has a greater effect on adverse cardiovascular outcomes following percutaneous coronary intervention and in Asian populations treated with clopidogrel: a meta-analysis. Circ Cardiovasc Genet 2014; 7 (06) 895-902
  • 42 Biswas M, Sukasem C, Khatun Kali MS, Ibrahim B. Effects of the CYP2C19 LoF allele on major adverse cardiovascular events associated with clopidogrel in acute coronary syndrome patients undergoing percutaneous coronary intervention: a meta-analysis. Pharmacogenomics 2022; 23 (03) 207-220
  • 43 Hochholzer W, Ruff CT, Mesa RA. et al. Variability of individual platelet reactivity over time in patients treated with clopidogrel: insights from the ELEVATE-TIMI 56 trial. J Am Coll Cardiol 2014; 64 (04) 361-368
  • 44 Podda GM, Grossi E, Palmerini T. et al. Prediction of high on-treatment platelet reactivity in clopidogrel-treated patients with acute coronary syndromes. Int J Cardiol 2017; 240: 60-65
  • 45 Kozinski M, Bielis L, Wisniewska-Szmyt J. et al. Diurnal variation in platelet inhibition by clopidogrel. Platelets 2011; 22 (08) 579-587
  • 46 Paniccia R, Antonucci E, Gori AM. et al. Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients. J Thromb Haemost 2007; 5 (09) 1839-1847
  • 47 Nakahara H, Sarker T, Dean CL. et al. A sticky situation: variable agreement between platelet function tests used to assess anti-platelet therapy response. Front Cardiovasc Med 2022; 9: 899594
  • 48 Parodi G, Marcucci R, Valenti R. et al. High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA 2011; 306 (11) 1215-1223
  • 49 Hao PP, Zhang MX, Li RJ. et al. Clopidogrel 150 vs. 75 mg day(-1) in patients undergoing percutaneous coronary intervention: a meta-analysis. J Thromb Haemost 2011; 9 (04) 627-637
  • 50 Lee CR, Luzum JA, Sangkuhl K. et al. Clinical pharmacogenetics implementation consortium guideline for CYP2C19 genotype and clopidogrel therapy: 2022 update. Clin Pharmacol Ther 2022; 112 (05) 959-967