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Impact of Diabetes Mellitus on the Pharmacodynamic Effects of Ticagrelor Versus Clopidogrel in Troponin-Negative Acute Coronary Syndrome Patients Undergoing Ad Hoc Percutaneous Coronary Intervention.

ABSTRACT: Diabetes mellitus (DM) is associated with enhanced platelet reactivity and impaired response to oral antiplatelet therapy, including clopidogrel. This post hoc analysis investigated the pharmacodynamic effects of ticagrelor versus clopidogrel loading dose (LD) in troponin-negative acute coronary syndrome patients with or without DM undergoing percutaneous coronary intervention in the Ad Hoc PCI study.Patients randomized (1:1) to receive ticagrelor 180 mg LD or clopidogrel 600 mg LD were assessed by diabetic status. Platelet reactivity (P2Y12 reaction units [PRU] on VerifyNow® assay) was measured pre-LD, at 0.5, 2, and 8 hours post-LD, and at the end of the percutaneous coronary intervention. The primary endpoint was PRU levels 2 hours post-LD; secondary endpoints included rates of high on-treatment platelet reactivity (PRU?208). Of 100 randomized patients, 51 received ticagrelor (DM, n=20; non-DM, n=31) and 49 clopidogrel (DM, n=16; non-DM, n=33). At 2 hours post-LD, mean (SD) PRU levels in DM patients were 130.1 (111.7) with ticagrelor versus 287.6 (71.9) with clopidogrel (mean [95%CI] difference -157.5 [-225.3, -89.8]; P<0.001); in non-DM patients, they were 75.3 (75.7) versus 243.0 (72.4) (mean difference -167.7 [-207.1, -128.3]; P<0.001). High on-treatment platelet reactivity rates at 2 hours post-LD were also significantly (P<0.001) reduced with ticagrelor versus clopidogrel in DM and non-DM patients. Between-treatment differences for PRU and high on-treatment platelet reactivity were not significant at earlier time points but were at 8 hours post-LD (P<0.001).Compared with clopidogrel, ticagrelor achieved faster, enhanced platelet inhibition and reduced high on-treatment platelet reactivity rates, in DM and non-DM patients.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603082.

SUBMITTER: Sweeny JM

PROVIDER: S-EPMC5533039 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Impact of Diabetes Mellitus on the Pharmacodynamic Effects of Ticagrelor Versus Clopidogrel in Troponin-Negative Acute Coronary Syndrome Patients Undergoing Ad Hoc Percutaneous Coronary Intervention.

Sweeny Joseph M JM Angiolillo Dominick J DJ Franchi Francesco F Rollini Fabiana F Waksman Ron R Raveendran Ganesh G Dangas George G Khan Naeem D ND Carlson Glenn F GF Zhao Yonggang Y Teng Renli R Mehran Roxana R

Journal of the American Heart Association 20170329 4

<h4>Background</h4>Diabetes mellitus (DM) is associated with enhanced platelet reactivity and impaired response to oral antiplatelet therapy, including clopidogrel. This post hoc analysis investigated the pharmacodynamic effects of ticagrelor versus clopidogrel loading dose (LD) in troponin-negative acute coronary syndrome patients with or without DM undergoing percutaneous coronary intervention in the Ad Hoc PCI study.<h4>Methods and results</h4>Patients randomized (1:1) to receive ticagrelor 1 ...[more]

PMID: 28356282

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Project description:BackgroundPotent P2Y12 inhibitors such as ticagrelor and prasugrel are superior to clopidogrel in acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI). Whether this benefit extends to a patient population with chronic coronary syndromes (CCS) is unclear.AimsWe sought to compare the safety and efficacy of prasugrel and ticagrelor versus clopidogrel in patients undergoing PCI for CCS.MethodsConsecutive patients undergoing PCI for CCS at a tertiary centre between 2014 and 2019 who were discharged on prasugrel or ticagrelor were compared with those on clopidogrel. The primary endpoint was the composite of death and myocardial infarction (MI), with secondary outcomes including rates of bleeding, stroke, and target vessel revascularisation at 1 year.ResultsOverall, 11,508 patients were included in the study (ticagrelor/prasugrel n=2,860 [24.9%], clopidogrel n=8,648 [75.1%]) with an increasing frequency of potent P2Y12 inhibitor use over the study period (ptrend<0.001). Clopidogrel was used more frequently in patients with multimorbid risk factors, whereas anatomical or procedural complexity was associated with ticagrelor/prasugrel use (left main PCI, bifurcation PCI, number of lesions, rotational atherectomy). No difference in the incidence of death or MI was noted across the groups (ticagrelor/prasugrel vs clopidogrel: 2.7% vs 3.1%, adjusted hazard ratio [adjHR] 0.86, 95% confidence interval [CI]: 0.62-1.17; p=0.33) or secondary outcomes including bleeding (adjHR 0.75, 95% CI: 0.46-1.21; p=0.23) on propensity score stratification analysis. Additionally, no difference in the primary outcome was observed across subgroups, including those undergoing complex PCI.ConclusionsTicagrelor and prasugrel are increasingly used in patients with CCS undergoing PCI with similar 1-year efficacy and safety when compared to clopidogrel. Whether use of these agents can be beneficial in patients undergoing PCI for CCS with a high thrombotic and low bleeding risk warrants further study.

Project description:ImportanceGuidelines currently recommend ticagrelor over clopidogrel for patients with acute coronary syndrome (ACS) based on randomized clinical trial data in which ticagrelor reduced major adverse coronary events (MACE) vs clopidogrel but increased bleeding and dyspnea.ObjectiveTo compare the risk of MACE with ticagrelor vs clopidogrel in patients with ACS treated with percutaneous coronary intervention (PCI), to compare major bleeding and dyspnea, and to evaluate the association between P2Y12 inhibitor adherence and MACE.Design, setting, and participantsPopulation-based cohort study using data of patients discharged alive after PCI for ACS from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry from April 1, 2012, to March 31, 2016, with follow-up to 1 year. Analysis began April 2018.ExposuresOutpatient prescription for ticagrelor or clopidogrel within 31 days after PCI. Adherence was defined as a medication refill adherence value of 80% or higher.Main outcomes and measuresMajor adverse coronary events, a composite of all-cause death, hospitalization for ACS, unplanned coronary revascularization, or stent thrombosis within 365 days after index PCI. Secondary outcomes included hospitalization for major bleeding and emergency department visit for dyspnea.ResultsOf 11 185 individuals who underwent PCI, the median (interquartile range) age was 61 (54-71) years, and 2760 (24.7%) were women. Ticagrelor users (4076 [36.4%]) were generally younger and had fewer cardiac and noncardiac comorbidities than clopidogrel users. Ticagrelor was not associated with lower risk of MACE (adjusted hazard ratio [aHR], 0.97; 95% CI, 0.85-1.10); however, it was associated with an increased risk of major bleeding (aHR, 1.51; 95% CI, 1.29-1.78) and dyspnea (aHR, 1.98; 95% CI, 1.47-2.65). A total of 3328 ticagrelor users (81.6%) were adherent during the study vs 5256 of clopidogrel users (73.9%) (P < .001; χ2 = 86.4). In the full cohort, adherence was associated with a lower MACE risk (aHR, 0.79; 95% CI, 0.69-0.90 for adherence of ≥80% vs <80%). Differences in other secondary outcomes were not statistically significant. Sensitivity and subgroup analyses were consistent with primary analyses.Conclusions and relevanceIn this population-based cohort study of patients with ACS who underwent PCI, outpatient use of ticagrelor was not associated with a statistically significant reduction in MACE vs clopidogrel; however, it was associated with more major bleeding and dyspnea.

Project description:ImportanceCurrent guidelines recommend ticagrelor as the preferred P2Y12 platelet inhibitor for patients with acute coronary syndrome (ACS), primarily based on a single large randomized clinical trial. The benefits and risks associated with ticagrelor vs clopidogrel in routine practice merits attention.ObjectiveTo determine the association of ticagrelor vs clopidogrel with ischemic and hemorrhagic events in patients undergoing percutaneous coronary intervention (PCI) for ACS in clinical practice.Design, setting, and participantsA retrospective cohort study of patients with ACS who underwent PCI and received ticagrelor or clopidogrel was conducted using 2 United States electronic health record-based databases and 1 nationwide South Korean database from November 2011 to March 2019. Patients were matched using a large-scale propensity score algorithm, and the date of final follow-up was March 2019.ExposuresTicagrelor vs clopidogrel.Main outcomes and measuresThe primary end point was net adverse clinical events (NACE) at 12 months, composed of ischemic events (recurrent myocardial infarction, revascularization, or ischemic stroke) and hemorrhagic events (hemorrhagic stroke or gastrointestinal bleeding). Secondary outcomes included NACE or mortality, all-cause mortality, ischemic events, hemorrhagic events, individual components of the primary outcome, and dyspnea at 12 months. The database-level hazard ratios (HRs) were pooled to calculate summary HRs by random-effects meta-analysis.ResultsAfter propensity score matching among 31 290 propensity-matched pairs (median age group, 60-64 years; 29.3% women), 95.5% of patients took aspirin together with ticagrelor or clopidogrel. The 1-year risk of NACE was not significantly different between ticagrelor and clopidogrel (15.1% [3484/23 116 person-years] vs 14.6% [3290/22 587 person-years]; summary HR, 1.05 [95% CI, 1.00-1.10]; P = .06). There was also no significant difference in the risk of all-cause mortality (2.0% for ticagrelor vs 2.1% for clopidogrel; summary HR, 0.97 [95% CI, 0.81-1.16]; P = .74) or ischemic events (13.5% for ticagrelor vs 13.4% for clopidogrel; summary HR, 1.03 [95% CI, 0.98-1.08]; P = .32). The risks of hemorrhagic events (2.1% for ticagrelor vs 1.6% for clopidogrel; summary HR, 1.35 [95% CI, 1.13-1.61]; P = .001) and dyspnea (27.3% for ticagrelor vs 22.6% for clopidogrel; summary HR, 1.21 [95% CI, 1.17-1.26]; P < .001) were significantly higher in the ticagrelor group.Conclusions and relevanceAmong patients with ACS who underwent PCI in routine clinical practice, ticagrelor, compared with clopidogrel, was not associated with significant difference in the risk of NACE at 12 months. Because the possibility of unmeasured confounders cannot be excluded, further research is needed to determine whether ticagrelor is more effective than clopidogrel in this setting.

Project description:BackgroundIt is still unknown whether diabetes mellitus (DM) affects the relative safety and efficacy of ticagrelor vs clopidogrel in East Asian patients with acute coronary syndrome (ACS).ObjectivesThe authors sought to assess the safety and efficacy of ticagrelor vs clopidogrel according to the diabetic status of East Asian patients with ACS undergoing invasive management.MethodsThis prespecified analysis of the TICA KOREA (Clinically Significant Bleeding With Ticagrelor Versus Clopidogrel in Korean Patients With Acute Coronary Syndromes Intended for Invasive Management) trial included 800 Korean patients. The primary safety endpoint was clinically significant bleeding (PLATO [Platelet Inhibition and Clinical Outcomes] major or minor bleeding) at 12 months; the efficacy endpoint was major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke).ResultsOf 800 patients, 216 (27.0%) had DM. The incidence of clinically significant bleeding within 12 months was significantly higher with ticagrelor than clopidogrel in the nondiabetic group (10.2% vs 4.3%; HR: 2.45; 95% CI: 1.27-4.70; P = 0.007) and tended to be higher in the diabetic group (13.8% vs 8.0%; HR: 1.87; 95% CI: 0.54-4.36; P = 0.15); there was no significant interaction between treatment-arm and DM (P for interaction = 0.64). The incidences of major adverse cardiovascular events were not significantly different after ticagrelor or clopidogrel both in the diabetic group (10.8% vs 6.0%; HR: 1.90; 95% CI: 0.71-5.07; P = 0.20) and in the nondiabetic group (8.5% vs 5.7%; HR: 1.51; 95% CI: 0.81-2.81; P = 0.19) without significant interaction (P-for-interaction = 0.71).ConclusionsIn Korean ACS patients undergoing early invasive management, diabetes status did not affect the relative safety and efficacy of ticagrelor and clopidogrel. (Safety and Efficacy of Ticagrelor Versus Clopidogrel in Asian/Korean Patients With Acute Coronary Syndromes Intended for Invasive Management [TICA KOREA]; NCT02094963).

Dataset Information

Impact of Diabetes Mellitus on the Pharmacodynamic Effects of Ticagrelor Versus Clopidogrel in Troponin-Negative Acute Coronary Syndrome Patients Undergoing Ad Hoc Percutaneous Coronary Intervention.

Publications

Impact of Diabetes Mellitus on the Pharmacodynamic Effects of Ticagrelor Versus Clopidogrel in Troponin-Negative Acute Coronary Syndrome Patients Undergoing Ad Hoc Percutaneous Coronary Intervention.

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