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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Abstract

Background

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.

Methods and Results

Patients randomized (1:1) to receive ticagrelor 180 mg LD or clopidogrel 600 mg LD were assessed by diabetic status. Platelet reactivity (P2Y ₁₂ 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).

Conclusions

Compared with clopidogrel, ticagrelor achieved faster, enhanced platelet inhibition and reduced high on‐treatment platelet reactivity rates, in DM and non‐ DM patients.

Clinical Trial Registration

URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603082.

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Most cited references 27

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Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.

Alan R Shuldiner, Jeffrey R O'Connell, Kevin P Bliden … (2009)

Clopidogrel therapy improves cardiovascular outcomes in patients with acute coronary syndromes and following percutaneous coronary intervention by inhibiting adenosine diphosphate (ADP)-dependent platelet activation. However, nonresponsiveness is widely recognized and is related to recurrent ischemic events. To identify gene variants that influence clopidogrel response. In the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study (2006-2008), we administered clopidogrel for 7 days to 429 healthy Amish persons and measured response by ex vivo platelet aggregometry. A genome-wide association study was performed followed by genotyping the loss-of-function cytochrome P450 (CYP) 2C19*2 variant (rs4244285). Findings in the PAPI Study were extended by examining the relation of CYP2C19*2 genotype to platelet function and cardiovascular outcomes in an independent sample of 227 patients undergoing percutaneous coronary intervention. ADP-stimulated platelet aggregation in response to clopidogrel treatment and cardiovascular events. Platelet response to clopidogrel was highly heritable (h(2) = 0.73; P < .001). Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance (P = 1.5 x 10(-13) for rs12777823, additive model). The rs12777823 polymorphism was in strong linkage disequilibrium with the CYP2C19*2 variant, and was associated with diminished clopidogrel response, accounting for 12% of the variation in platelet aggregation to ADP (P = 4.3 x 10(-11)). The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention (P = .02). Furthermore, patients with the CYP2C19*2 variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death during 1 year of follow-up (hazard ratio, 2.42; 95% confidence interval, 1.18-4.99; P = .02). CYP2C19*2 genotype was associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes.

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Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.

Jessica Mega, Tabassome Simon, Jean-Philippe Collet … (2010)

Clopidogrel, one of the most commonly prescribed medications, is a prodrug requiring CYP450 biotransformation. Data suggest its pharmacologic effect varies based on CYP2C19 genotype, but there is uncertainty regarding the clinical risk imparted by specific genotypes. To define the risk of major adverse cardiovascular outcomes among carriers of 1 (≈ 26% prevalence in whites) and carriers of 2 (≈ 2% prevalence in whites) reduced-function CYP2C19 genetic variants in patients treated with clopidogrel. A literature search was conducted (January 2000-August 2010) in MEDLINE, Cochrane Database of Systematic Reviews, and EMBASE. Genetic studies were included in which clopidogrel was initiated in predominantly invasively managed patients in a manner consistent with the current guideline recommendations and in which clinical outcomes were ascertained. Investigators from 9 studies evaluating CYP2C19 genotype and clinical outcomes in patients treated with clopidogrel contributed the relevant hazard ratios (HRs) and 95% confidence intervals (CIs) for specific cardiovascular outcomes by genotype. Among 9685 patients (91.3% who underwent percutaneous coronary intervention and 54.5% who had an acute coronary syndrome), 863 experienced the composite end point of cardiovascular death, myocardial infarction, or stroke; and 84 patients had stent thrombosis among the 5894 evaluated for such. Overall, 71.5% were noncarriers, 26.3% had 1 reduced-function CYP2C19 allele, and 2.2% had 2 reduced-function CYP2C19 alleles. A significantly increased risk of the composite end point was evident in both carriers of 1 (HR, 1.55; 95% CI, 1.11-2.17; P = .01) and 2 (HR, 1.76; 95% CI, 1.24-2.50; P = .002) reduced-function CYP2C19 alleles, as compared with noncarriers. Similarly, there was a significantly increased risk of stent thrombosis in both carriers of 1 (HR, 2.67; 95% CI, 1.69-4.22; P < .0001) and 2 (HR, 3.97; 95% CI, 1.75-9.02; P = .001) CYP2C19 reduced-function alleles, as compared with noncarriers. Among patients treated with clopidogrel for percutaneous coronary intervention, carriage of even 1 reduced-function CYP2C19 allele appears to be associated with a significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis.

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Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack.

S Johnston, Pierre Amarenco, Gregory W Albers … (2016)

Ticagrelor may be a more effective antiplatelet therapy than aspirin for the prevention of recurrent stroke and cardiovascular events in patients with acute cerebral ischemia.

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Author and article information

Contributors

Joseph M. Sweeny: joseph.sweeny@mountsinai.org

Journal

Journal ID (nlm-ta): J Am Heart Assoc

Journal ID (iso-abbrev): J Am Heart Assoc

Journal ID (doi): 10.1002/(ISSN)2047-9980

Journal ID (publisher-id): JAH3

Journal ID (hwp): ahaoa

Title: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2047-9980

Publication date (Electronic): 30 March 2017

Publication date Collection: April 2017

Volume: 6

Issue: 4 ( doiID: 10.1002/jah3.2017.6.issue-4 )

Electronic Location Identifier: e005650

Affiliations

[ ¹ ] Icahn School of Medicine at Mount Sinai New York NY

[ ² ] University of Florida College of Medicine‐Jacksonville Jacksonville FL

[ ³ ] MedStar Washington Hospital Center Washington DC

[ ⁴ ] University of Minnesota Medical School Minneapolis MN

[ ⁵ ] AstraZeneca Wilmington DE

Author notes

[*] [* ] Correspondence to: Joseph M. Sweeny, MD, Icahn School of Medicine at Mount Sinai, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, NY 10029‐6574. E‐mail: joseph.sweeny@ 123456mountsinai.org

Article

Publisher ID: JAH32122

DOI: 10.1161/JAHA.117.005650

PMC ID: 5533039

PubMed ID: 28356282

SO-VID: b0f2c486-0413-489d-ad68-c41b6718d182

License:

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 25 January 2017

Date accepted : 16 February 2017

Page count

Figures: 5, Tables: 1, Pages: 10, Words: 6392

Funding

Funded by: AstraZeneca

Custom metadata

source-schema-version-number 2.0

component-id jah32122

cover-date April 2017

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.3 mode:remove_FC converted:11.07.2017

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: ad hoc percutaneous coronary intervention,clopidogrel,diabetes mellitus,platelet reactivity,ticagrelor,percutaneous coronary intervention,treatment

Data availability:

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: ad hoc percutaneous coronary intervention, clopidogrel, diabetes mellitus, platelet reactivity, ticagrelor, percutaneous coronary intervention, treatment

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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

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Abstract

Background

Methods and Results

Conclusions

Clinical Trial Registration

Related collections

Cardiovascular Innovations and Applications

Most cited references 27

Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.

Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.

Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack.

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Cited by 17

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