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Triple Antiplatelet Therapy with Cilostazol and Favorable Early Clinical Outcomes after Acute Myocardial Infarction Compared to Dual Antiplatelet Therapy with Standard or Potent P2Y12 Inhibitors.

ABSTRACT: Current guidelines for the management of acute myocardial infarction (AMI) recommend potent P2Y12 inhibitors rather than clopidogrel to prevent ischemic events. However, their ischemic benefits are offset by an increased major bleeding risk. We compared the efficacy and safety of triple antiplatelet therapy with cilostazol in the first month after AMI. This study investigated 16,643 AMI patients who received percutaneous coronary intervention (PCI) with drug-eluting stents (DES) in nationwide, real-world, multicenter registries in Korea. Patients were divided into DAPT (aspirin and clopidogrel, n = 11,285), Triple (aspirin, clopidogrel and cilostazol, n = 2547), and Potent (aspirin and ticagrelor/prasugrel, n = 2811) groups. The primary outcomes were net adverse clinical events (NACE), a composite of death from any cause, myocardial infarction (MI), stroke, and TIMI major bleeding one month after AMI. After adjusting for covariates, there were no statistically significant differences in the risk of death from any cause, MI, or stroke between the three groups. However, the risk of TIMI major bleeding was significantly greater in the Potent group than in the DAPT and Triple groups (p < 0.001). Accordingly, NACE was significantly higher in the DAPT (HR 1.265; 95% CI 1.006−1.591, p = 0.044) and Potent groups (HR 1.515; 95% CI 1.142−2.011, p = 0.004) than in the Triple group. Triple antiplatelet therapy with cilostazol was associated with an improved net clinical outcome in the first month after AMI without increasing the risk of bleeding compared to potent or standard P2Y12 inhibitor-based DAPT.

SUBMITTER: Byun S

PROVIDER: S-EPMC9693255 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Triple Antiplatelet Therapy with Cilostazol and Favorable Early Clinical Outcomes after Acute Myocardial Infarction Compared to Dual Antiplatelet Therapy with Standard or Potent P2Y12 Inhibitors.

Byun Sungwook S Lee Su Nam SN Lim Sungmin S Choo Eun Ho EH Choi Ik Jun IJ Kim Chan Joon CJ Moon Donggyu D Park Mahn-Won MW Park Chul Soo CS Ahn Youngkeun Y Jeong Myung-Ho MH Chang Kiyuk K

Journal of clinical medicine 20221121 22

Current guidelines for the management of acute myocardial infarction (AMI) recommend potent P2Y12 inhibitors rather than clopidogrel to prevent ischemic events. However, their ischemic benefits are offset by an increased major bleeding risk. We compared the efficacy and safety of triple antiplatelet therapy with cilostazol in the first month after AMI. This study investigated 16,643 AMI patients who received percutaneous coronary intervention (PCI) with drug-eluting stents (DES) in nationwide, r ...[more]

PMID: 36431333

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Project description:Compared with standard dual antiplatelet therapy, adjunctive cilostazol to dual antiplatelet therapy ('triple antiplatelet therapy') has a potential to reduce ischemic event occurrence after percutaneous coronary intervention. The pharmacokinetic and pharmacodynamic effects of clopidogrel have been significantly influenced by the enzyme activity of the ABCB1 C3435T and the CYP2C19 system. •?For the pharmacokinetics of cilostazol, genetic polymorphisms of the CYP3A5 and CYP2C19 have been associated with the substantial interindividual variability in healthy volunteers.Loss-of-function polymorphism of the CYP2C19 gene, but not the ABCB1 C3435T and CYP3A5*3 genes, affects the antiplatelet effect of triple antiplatelet therapy. Most of extensive and intermediate East Asian metabolizers (0 or 1 CYP2C19 loss-of-function allele) show adequate platelet inhibition when treated with triple antiplatelet therapy after percutaneous coronary intervention. However, carriage of 2 CYP2C19 loss-of-function alleles is still associated with the risk of high platelet reactivity (defined by by 5?µM ADP-induced maximal platelet aggregation >46%), which clinical impact needs to be validated in future clinical trials. AIMS Although adjunctive cilostazol to dual antiplatelet therapy can reduce the risks of clinical events after percutaneous coronary intervention (PCI), whether genetic polymorphism can influence the pharmacodynamics of this regimen has not been evaluated.One hundred and twenty-seven patients treated with PCI and taking triple antiplatelet therapy (?1?month) were enrolled. Platelet reactivity was assessed by conventional aggregometry and the VerifyNow P2Y12 assay. High on-treatment platelet reactivity (HPR) was defined as 5?µm ADP-induced maximal platelet reactivity (Agg(max) ) >46%. CYP3A5*3, CYP2C19*2/*3 and ABCB1 3435C > T were genotyped.CYP3A5*3 and ABCB1 3435C > T variants did not affect the antiplatelet effect of triple antiplatelet therapy. For non-carriers, one and two carriers of the CYP2C19 loss-of-function (LOF) allele, Agg(max) consecutively increased after the addition of 5?µm[mean (95% confidence intervals): 24.6% (20.8 to 28.5%) vs. 28.7% (25.4 to 32.0%) vs. 32.3% (25.8 to 38.7%), P?=?0.062, respectively] and 20?µm ADP [34.2% (29.3 to 39.0%) vs. 41.7% (37.8 to 45.6%) vs. 44.9% (37.9 to 51.9%), P?=?0.007, respectively]. Likewise, late platelet reactivity and P2Y12 reaction units proportionally changed according to the number of CYP2C19 LOF alleles. HPRs were observed in 9.2% of subjects: 6.3%, 7.4% and 20.0% with 0, 1 and 2 carriers of CYP2C19 LOF allele(s) (P?=?0.099). In multivariate analysis, carriage of two CYP2C19 LOF alleles was a significant predictor for the prevalence of HPR (odds ratio 5.78, 95% CI 1.21, 27.78, P?=?0.028).Among PCI-treated patients, the effect of triple antiplatelet therapy is influenced by the CYP2C19 LOF allele. Its clinical benefit needs to be validated according to the CYP2C19 metabolic phenotype in future clinical trials. [Adjunctive Cilostazol Versus High Maintenance dose ClopidogrEL in Acute Myocardial Infarction Patients According to CYP2C19 Polymorphism (ACCEL-AMI-2C19), NCT00915733 and Adjunctive Cilostazol Versus High Maintenance-dose Clopidogrel According to Cytochrome 2C19 Polymorphism (ACCEL-2C19), NCT01012193].

Project description:Introduction Dual antiplatelet therapy (DAPT) including prasugrel or ticagrelor is recommended in patients with acute coronary syndromes (ACS) treated with coronary intervention (PCI). Acknowledging the importance of bleeding, multiple trials tested abatement schemes including uniform or guided de-escalation from the potent P2Y12 inhibitor (P2Y12-De) or P2Y12 inhibitor monotherapy (P2Y12-Mo) with heterogeneous results. We aimed to perform a systematic review and network meta-analysis of the impact of DAPT abatement strategies in patients with PCI. Methods Electronic databases were searched for relevant randomized clinical studies evaluating clinical outcomes of patients after PCI. The rate of adverse events was evaluated using a frequentist network metanalysis. The random-effects model was used to combine risk estimates across trials and risk ratio (RR) with 95% confidence intervals (95% CIs) served as summary statistics. The primary endpoints of interest were the rate of major cardiac adverse events (MACE, defined as the composite of cardiovascular mortality, myocardial infarction and stroke) and bleeding. Results Ten studies were identified randomizing 42511 patients. 6359 switched to the P2Y12-De and 13062 switched to the P2Y12-Mo. The risk of MACE, reflected a 24% reduction in the P2Y12-De and a 14% in the P2Y12-Mo in comparison with the DAPT strategy using potent P2Y12 inhibitors (RR: 0.76 [0.62, 0.94], and RR: 0.86 [0.75, 0.99], p < 0.05 both). A 35% risk reduction of major bleeding was seen with monotherapy (RR: 0.65 [0.46, 0.91],) contrasting the de-escalation trials where this effect was not significant (RR: 0.84 [0.57, 1.22]). All bleeding and minor bleeding events were reduced with both strategies. Indirect P2Y12-Mo versus P2Y12-De comparisons exhibited them as similar alternatives without significant differences. Conclusion Our analysis suggests that both P2Y12-De and P2Y12-Mo reduce ischemic events and bleeding among PCI-treated ACS patients. Ischemic benefit was more expressed with P2Y12-De, however, reduction of major bleeding was only significant with P2Y12-Mo strategy. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021258502, identifier CRD42021258502.

Project description:Background and purposeAlthough dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the recurrence of ischemic stroke while significantly increasing the bleeding events compared with monotherapy, the CSPS.com trial (Cilostazol Stroke Prevention Study combination) showed that DAPT using cilostazol was more effective without the bleeding risk. In the CSPS.com trial, aspirin or clopidogrel was used as the underlying antiplatelet drug. The effectiveness and safety of each combination were examined and clarified.MethodsIn the CSPS.com trial, a multicenter, open-label, randomized controlled study, patients with high-risk, noncardioembolic ischemic stroke 8 to 180 days after onset treated with aspirin or clopidogrel alone at the discretion of the physician in charge were recruited. Patients were randomly assigned to receive either monotherapy or DAPT using cilostazol and followed for 0.5 to 3.5 years. The primary efficacy outcome was first recurrence of ischemic stroke. The safety outcome was severe or life-threatening bleeding. The analysis was based on the underlying antiplatelet agents.ResultsA total of 763 patients taking aspirin and 1116 taking clopidogrel were included in the intention-to-treat analysis. Although the clopidogrel group had more risk factors than the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the 2 groups. In the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the DAPT group and the aspirin-monotherapy group. In the clopidogrel group, the primary end point occurred at a rate of 2.31 per 100 patient-years in the DAPT group and 5.19 per 100 patient-years in the clopidogrel-monotherapy group (hazard ratio, 0.447 [95% CI, 0.258–0.774]). Safety outcome did not differ significantly between groups (0.51 per 100 patient-years versus 0.71 per 100 patient-years, respectively; hazard ratio, 0.730 [95% CI, 0.206–2.588]).ConclusionsThe combination of cilostazol and clopidogrel significantly reduced the recurrence of ischemic stroke without increasing the bleeding risk in noncardioembolic, high-risk patients.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012180.

Dataset Information

Triple Antiplatelet Therapy with Cilostazol and Favorable Early Clinical Outcomes after Acute Myocardial Infarction Compared to Dual Antiplatelet Therapy with Standard or Potent P2Y12 Inhibitors.

Publications

Triple Antiplatelet Therapy with Cilostazol and Favorable Early Clinical Outcomes after Acute Myocardial Infarction Compared to Dual Antiplatelet Therapy with Standard or Potent P2Y12 Inhibitors.

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