A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: Results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial

University of Florida College of Medicine-Jacksonville, 655 W. Eighth Street, Jacksonville, FL 32209, USA.
European Heart Journal (Impact Factor: 15.2). 04/2011; 32(7):838-46. DOI: 10.1093/eurheartj/ehq494
Source: PubMed


Patients with diabetes mellitus (DM) have increased platelet reactivity and reduced platelet response to clopidogrel compared with patients without DM. Prasugrel, a more potent antiplatelet agent, is associated with greater reductions in ischaemic events compared with clopidogrel, particularly in patients with DM. The aim of this study was to perform serial pharmacodynamic assessments of prasugrel with high-dose clopidogrel in patients with DM.
Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 was a prospective, randomized, double-blind, crossover study in patients with type 2 DM and coronary artery disease (CAD). Patients (n= 35) were randomly assigned to either prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD) or clopidogrel 600 mg LD/150 mg MD over two 1-week treatment periods separated by a 2-week washout period. Platelet function was assessed by VerifyNow® P2Y12 assay, light transmission aggregometry, and vasodilator-stimulated phosphoprotein phosphorylation at 0, 1, 4, and 24 h and 7 days. Greater platelet inhibition by VerifyNow® P2Y12 was achieved by prasugrel compared with clopidogrel at 4 h post-LD (least squares mean, 89.3 vs. 27.7%, P< 0.0001; primary endpoint). The difference in platelet inhibition between prasugrel and clopidogrel was significant from 1 h through 7 days (P < 0.0001). Similar results were obtained using all other platelet function measures. Prasugrel resulted in fewer poor responders at all time points irrespective of definition used.
In patients with type 2 DM and CAD, standard-dose prasugrel is associated with greater platelet inhibition and better response profiles during both the loading and maintenance periods when compared with double-dose clopidogrel.

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    • "P < 0.0001) and this was also seen for the MD at 7 days (61.8% vs. 44.2%; P < 0.0001) [25]. The superior antiplatelet effect of prasugrel was further demonstrated in the phase II PRINCIPLE-TIMI (prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation — TIMI) 44 trial, which compared a 60 mg dose of prasugrel with a 600 mg LD of clopidogrel. "
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    ABSTRACT: Effective antagonism of the P2Y(12) platelet receptor is central to the treatment of acute coronary syndrome (ACS) patients, especially in the setting of percutaneous coronary intervention and stenting. According to consensus guidelines, early revascularization and intensive antiplatelet therapy are key to reducing the complications that arise from myocardial ischaemia and the recurrence of cardiovascular events. Until recently, clopidogrel was the key P2Y(12) antagonist advocated, but due to several limitations as an antiplatelet agent, newer drugs with more predictable, rapid and potent effects have been developed. Prasugrel and ticagrelor are now the recommended first-line agents in patients presenting with non-STsegment elevation ACS and ST-segment elevation ACS, due to large-scale randomized trials that demonstrated net clinical benefit of these agents over clopidogrel, as stated in the European guidelines. Although no study has directly compared the two agents, analysis of the data to date suggests that certain patient types, such as diabetics, those with ST-segment elevation myocardial infarction or renal failure and the elderly may have a better outcome with one agent over the other. Further studies are needed to confirm these differences and answer pending questions regarding the use of these drugs to optimize efficacy while minimizing adverse events, such as bleeding. The aim of this review is to provide an overview of the current P2Y(12). receptor antagonists in the treatment of ACS, with a focus on issues of appropriate agent selection, timing of treatment, bleeding risk and the future role of personalized treatment using platelet function and genetic testing.
    Archives of cardiovascular diseases 03/2014; 107(3). DOI:10.1016/j.acvd.2014.01.009 · 1.84 Impact Factor
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    • "Prasugrel and ticagrelor are newer and more potent than clopidogrel antiplatelet agents, which have been introduced recently into our armamentarium while treating ACS patients undergoing PCI (9,10). In the Prasugrel Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS-3) study, in patients with DM and coronary artery disease (CAD), prasugrel provided a higher inhibitory platelet activity than high-dose clopidogrel (11). A prespecified, subgroup analysis of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) showed that prasugrel significantly reduced the incidence of the composite of cardiovascular death, myocardial infarction, and stroke compared with clopidogrel (12.2 and 17.0%, respectively, HR 0.70; P < 0.001) among DM patients, although without significant DM status-by-treatment interaction (12). "
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    ABSTRACT: OBJECTIVE It has been postulated that prasugrel might be the preferred treatment option in diabetes mellitus (DM) patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). We aimed to compare the pharmacodynamic action of ticagrelor versus prasugrel.RESEARCH DESIGN AND METHODS In a prospective, single-center, single-blind, crossover study, 30 consecutive ACS patients with DM who had been pretreated with clopidogrel were randomized to either 90 mg ticagrelor twice daily or 10 mg prasugrel once daily with a 15-day treatment period. Platelet reactivity (PR) was assessed with the VerifyNow P2Y12 function assay, measured in P2Y12 reaction units (PRU).RESULTSPR was significantly lower after ticagrelor (45.2 PRU [95% CI 27.4-63.1]) compared with prasugrel (80.8 PRU [63.0-98.7]), with a least squares mean difference of -35.6 PRU (-55.2 to -15.9, P = 0.001). High PR rate was 0% for ticagrelor and 3.3% for prasugrel (P = 1.0).CONCLUSIONS In DM patients with ACS who had been pretreated with clopidogrel and who undergo PCI, ticagrelor achieves a significantly higher platelet inhibition than prasugrel. Both antiplatelet agents effectively treat high PR. The relevance of these findings to the clinical efficacy and safety of ticagrelor and prasugrel in DM patients needs further elucidation.
    Diabetes care 03/2013; 36(8). DOI:10.2337/dc12-2510 · 8.42 Impact Factor
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    • "There are polymorphisms in the genes coding for CYP enzymes, with common alleles in CYP2C19 having reduced function resulting in lower clopidogrel active metabolite concentrations. The newly thienopyridine, prasugrel effects are associated with a higher reduction in ischaemic events (compared to clopidogrel), particularly in patients with diabetes mellitus [125]. Moreover, prasugrel has better efficacy than clopidogrel in modulating heterotypic aggregation and Pselectin expression, in ADP-stimulated platelets from subjects with atherosclerosis treated with the two different thienopyridines [126]. "
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    ABSTRACT: Cardiovascular diseases are one of the leading causes of morbidity and mortality in industrialized countries, and although many processes play a role in the development of vascular disease, thrombosis is the primary event that precipitates stroke and acute coronary syndromes. The blood platelets are of significant importance in medicine. These cells are involved in many physiological processes, particularly haemostasis through their ability to aggregate and form clots in response to activation. In addition, these dynamic cells display activities that extend beyond thrombosis, including an important role in initiating and sustaining vascular inflammation. The expansion of knowledge from basic and clinical research has highlighted the critical position of platelets in several inflammatory diseases such as arthritis and atherosclerosis. Platelets are emerging as important mediators of inflammation and provide important signals to mediate phenotype of other blood and vascular cells. The important role of platelets in arterial thrombosis and the onset of acute myocardial infarction after atherosclerotic plaque rupture make inhibition of platelet aggregation a critical step in preventing thrombotic events associated with stroke, heart attack, and peripheral arterial thrombosis. However, the use of platelet inhibitors for thrombosis prevention must seek a delicate balance between inhibiting platelet activation and an associated increased bleeding risk. The aim of this review is to up-date the knowledge on platelets physiology and dysfunction in pathologies, such as diabetes mellitus, hypercholesterolemia, and hypertension, emphasizing the link between platelets and the inflammation-related atherosclerosis. The review evaluates the opportunities offered by the novel platelet inhibitors to efficiently alleviate the thrombotic events.
    Thrombosis Research 02/2012; 129(2):116-26. DOI:10.1016/j.thromres.2011.09.026 · 2.45 Impact Factor
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