10.4081/btvb.2023.86
Not required
application/pdf
2785-5309
86
2
en
Marco Cattaneo
https://creativecommons.org/licenses/by-nc/4.0
Bleeding, Thrombosis and Vascular Biology
platelet function tests
Guided antiplatelet therapy in patients undergoing percutaneous coronary intervention
Text.Serial.Journal
https://www.btvb.org/btvb
2
Invited Editorials
2023-06-23
2023-05-31
2023-04-30
2023-06-27
Bleed Thromb Vascul Biol
Marco Cattaneo
2023/06/23
10.4081/btvb.2023.86
Fondazione Arianna Anticoagulazione, Bologna
2785-5309
2
platelet function tests
en
- 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(5):959-967.
Guided antiplatelet therapy in patients undergoing percutaneous coronary intervention
https://www.btvb.org/btvb/article/download/86/73
2
                                                                                                            INVITED EDITORIAL

Guided antiplatelet therapy in patients undergoing percutaneous
coronary intervention
Marco Cattaneo

Fondazione Arianna Anticoagulazione, Bologna, Italy




     Patients undergoing percutaneous coronary intervention (PCI)                It has been hypothesized that tailoring anti-P2Y12 treatment
are treated with dual antiplatelet therapy (DAPT) with aspirin plus         to individual patients would increase the clinical benefit of
an antagonist of the P2Y12 platelet receptor to reduce the risk of          DAPT.2 Randomized controlled trials (RCTs) have been per-
major adverse cardiovascular events (MACE).1 Clopidogrel,                   formed to test the safety and efficacy of guided therapy (GT)
which is a pro-drug and the most commonly used P2Y12 antag-                 based on the results of patient genotyping (genotype-GT) or
onist, does not adequately inhibit platelet function in about 1/3 of        platelet function tests (PFT-GT). Typically, patients were random-
treated patients, who display high on-treatment platelet reactivity         ized to GT or unguided therapy and the incidence of MACE and




                                                                                                        ly
(HTPR) and are insufficiently protected from MACE.2,3 Mutations             bleeding events was recorded during pre-defined follow-up peri-




                                                                                                on
of cytochrome-P450 (CYP) isoforms, which are responsible for                ods. Some RCTs, however, had a different design from the above:
the generation of the active metabolite, are associated with re-            all clopidogrel-treated patients underwent PFT and only those
sponse variability to clopidogrel, in combination with other vari-          with HTPR were randomized to continue on clopidogrel or switch




                                                                                          e
ables.2 Two alternative oral anti-P2Y12 drugs, prasugrel and                to alternative drugs: these RCTs (HTPR-therapy), therefore, did
ticagrelor, display more favorable pharmacokinetics than clopi-
dogrel, conferring more consistent inhibition of platelet function
and efficient prevention of thrombotic events, albeit at the expense
                                                                                  us
                                                                            not test the safety and efficacy of GT, but those of alternative ther-
                                                                            apies for patients with HTPR.
                                                                                 Meta-analyses of published studies gave contrasting results,
of higher incidence of bleeding complications.3
                                                                            al
                                                                            likely due to the heterogeneity of the included studies. Some meta-
                                                                            analyses lumped together RCTs, non-randomized intervention
                                                                  ci

                                                                            studies and observational studies. Meta-analyses that considered
                                                                            RCTs only, or analyzed the results of RCTs separately, included
                                                                er


  Correspondence: Marco Cattaneo, Fondazione Arianna Anticoa-
                                                                            both studies on PFT-GT and HTPR-therapy,4 genotype-GT and
  gulazione, via Paolo Fabbri 1/3, 40138 Bologna, Italy
                                                                            PFT-GT,5 genotype-GT, PFT-GT and HTPR-therapy.6 One meta-
                                                               m



  E-mail: marco.natale.cattaneo@gmail.com
                                                                            analysis included genotype-GT only,7 while none analyzed PFT-
                                                                            GT studies only. Additional meta-analyses of homogenous studies
                                                    om




  Citation: Cattaneo M. Guided antiplatelet therapy in patients un-
  dergoing percutaneous coronary intervention. Bleeding, Thrombo-           are necessary in order to evaluate the safety and efficacy of dif-
  sis, and Vascular Biology 2023;2:86.                                      ferent GT strategies. To this aim, Birocchi et al. recently elected
                                                                            to perform 3 separate systematic reviews and meta-analyses, each
                                             -c




  Key words: P2Y12, antiplatelet therapy, cardiovascular diseases,          one for each of the 3 different study designs of RCTs.8
  monitoring, genotype, platelet function tests.
                                    on




                                                                                 According to the meta-analysis by Birocchi et al.,8 genotype-
  Conflict of interest: the author declares no potential conflict of in-    GT did not affect the incidence of bleeding events, but reduced
  terest.                                                                   the incidence of MACE. However, most of the evidence of pro-
                              N




                                                                            tective effects of genotyping stemmed from RCTs that had been
  Funding: none.                                                            performed in China, because those performed elsewhere failed to
                                                                            show statistically significant benefit. This finding is compatible
  Received: 31 May 2023.                                                    with the marginal role of CYP2C19 mutations in the response to
  Accepted: 5 June 2023.
                                                                            clopidogrel among non-asiatic populations,9 while they bear
                                                                            greater influence among patients from East/South Asia, among
  Publisher’s note: all claims expressed in this article are solely those
  of the authors and do not necessarily represent those of their affili-    whom their prevalence is very high.9 The meta-analysis of the
  ated organizations, or those of the publisher, the editors and the re-    overall published RCTs on genotype-GT by Birocchi et al.8 sub-
  viewers. Any product that may be evaluated in this article or claim
  that may be made by its manufacturer is not guaranteed or endorsed
  by the publisher.
                                                                            Abbreviations
  ©
   Copyright: the Author(s), 2023                                           PCI, percutaneous coronary intervention
  Licensee PAGEPress, Italy                                                 DAPT, dual antiplatelet therapy
  Bleeding, Thrombosis and Vascular Biology 2023; 2:86                      MACE, major adverse cardiovascular events
  doi:10.4081/btvb.2023.86                                                  HTPR, high on-treatment platelet reactivity
                                                                            LTPR, low-on-treatment platelet reactivity
  This work is licensed under a Creative Commons Attribution-               GT, guided therapy
  NonCommercial 4.0 International License (CC BY-NC 4.0).                   PFT-GT, platelet function tests-guided therapy
                                                                            RCT, randomized controlled trial


                                              Bleeding, Thrombosis and Vascular Biology 2023; 2:86
                          Guided antiplatelet therapy in patients undergoing percutaneous coronary intervention                            29



stantially confirmed the results of a previous meta-analysis,7           Birocchi et al.,8 it is possible to conclude that most of the evidence
which, however, failed to differentiate between RCTs performed           of genotype-GT efficacy stems from RCTs in Chinese patients,
in East-Asia and elsewhere.                                              in whom PFT guidance also proved effective. Evidence from the
     The analysis of all published RCTs of PFT-GT revealed that          meta-analysis by Birocchi et al. indicates that, in patients from
it had no statistically significant effect on the incidence of both      countries outside East/South Asia, genotype guidance is of dubi-
major bleedings and MACE.8 However, a sub-analysis showed                ous efficacy and PFT guidance is ineffective.
that PFT-GT significantly reduced the incidence of MACE in Chi-
nese patients but not in non-asiatic patients.8 The explanation for
this difference is the same already given for the discrepancy ob-        References
served in these populations for genotype-GT. Overall, the data
suggested that PFT-GT is less effective than genotype-GT both             1. Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021
among Chinese patients and patients from other countries, likely             ACC/AHA/SCAI guideline for coronary artery revasculariza-
as a consequence of the unsatisfactory diagnostic accuracy of                tion: a report of the American College of Cardiology/Ameri-
PFTs and the lability of the platelet reactivity phenotype, which            can Heart Association Joint Committee on clinical practice
may switch from HTPR to normal platelet reactivity or low-on                 guidelines. Circulation 2022;145:e18-114.
treatment platelet reactivity (LTPR) and back to HTPR over time           2. Cattaneo M. Response variability to clopidogrel: is tailored
in a high proportion of patients,2 in contrast to the stability of the       treatment, based on laboratory testing, the right solution? J
CYP genotype.                                                                Thromb Haemost 2012;10:327-36.




                                                                                            ly
     The above interpretation is supported also by the results of         3. Cattaneo M. New P2Y(12) inhibitors. Circulation 2010;121:




                                                                                    on
the third meta-analysis by Birocchi et al., which focused on RCTs            171-9.
exploring the safety and efficacy of alternative treatment in pa-         4. Aluvilu A, Ferro A. Role of platelet function testing in acute
tients with HTPR on clopidogrel (HTPR-therapy).8 These RCTs                  coronary syndromes: a meta-analysis. Open Heart 2022;9:




                                                                              e
showed that alternative antiplatelet regimens significantly de-              e002129.
creased the risk of MACE in patients with HTPR, thus implying             5. Galli M, Benenati S, Capodanno D, et al. Guided versus stan-
that failure of PFT-GT is not accounted for by failure of alternative
regimens to reduce MACE, but rather by inadequate diagnostic
                                                                         us  dard antiplatelet therapy in patients undergoing percutaneous
                                                                             coronary intervention: a systematic review and meta-analysis.
accuracy of PFTs to identify patients with HTPR. RCTs of HTPR-               Lancet 2021;397:1470-83.
                                                                    al
therapy enrolled only patients with HTPR: all of them who had             6. Yamani N, Unzek S, Mankani MH, et al. Does individualized
                                                     ci

been randomized to the experimental arm could benefit from the               guided selection of antiplatelet therapy improve outcomes
administration of more effective anti-P2Y12 drugs, such as tica-             after percutaneous coronary intervention? A systematic re-
                                                   er


grelor or prasugrel. Therefore, these RCTs simply confirm that               view and meta-analysis. Ann Med Surg (Lond) 2022;79:
prasugrel and ticagrelor are more effective than clopidogrel, as it          103964.
                                                  m



had been previously shown by ad hoc RCTs.3 In contrast, only a            7. Tang B, Wang X, Wang X, et al. Genotype-guided antiplatelet
minority of enrolled patients in RCTs on PFT-GT were treated                 therapy versus standard therapy for patients with coronary ar-
                                       om




with these drugs, as patients with LTPR continued on clopidogrel.            tery disease: an updated systematic review and meta-analysis.
Misdiagnosis of HTPR in poor responders to clopidogrel in the                J Pharm Pharm Sci 2022;25:9-23.
experimental arm would preclude them from being treated with              8. Birocchi S, Rocchetti M, Minardi A, et al. Guided antiplatelet
                                 -c




more efficient regimens and, consequently, lead to underestima-              therapy with P2Y12 antagonists in patients undergoing per-
tion of the clinical benefit for the overall patient population. This        cutaneous coronary intervention: 3 systematic reviews with
                         on




interpretation is also supported by the observation that, at variance        meta-analyses of randomized controlled trials with homoge-
with genotype-GT and PFT-GT RCTs, the point estimates for rel-               neous design. medRxiv preprint doi: https://doi.org/10.1101/
                    N




ative risk of MACE were similar in HTPR-Therapy RCTs per-                    2023.05.25.23290520; May 29, 2023.
formed in China and elsewhere.8                                           9. Fricke-Galindo I, Céspedes-Garro C, Rodrigues-Soares F, et
     The 2022 Clinical Pharmacogenetics Implementation Con-                  al. Interethnic variation of CYP2C19 alleles, predicted phe-
sortium Guideline for CYP2C19 Genotype and Clopidogrel rec-                  notypes and measured metabolic phenotypes across world
ommends CYP2C19 genotyping of patients undergoing PCI,10                     populations. Pharmacogenomics J 2016;16:113-23.
principally based on the results of a meta-analysis,5 which, how-        10. Lee CR, Luzum JA, Sangkuhl K, et al. Clinical pharmacoge-
ever, analyzed together genotype-GT and PFT-GT, and did not                  netics implementation consortium guideline for CYP2C19
differentiate between studies performed in China and those per-              genotype and clopidogrel therapy: 2022 update. Clin Phar-
formed elsewhere. Based on the results of the meta-analysis by               macol Ther 2022;112:959-67.




                                           Bleeding, Thrombosis and Vascular Biology 2023; 2:86
