Platelet Inhibition in Patients With Systolic Heart Failure
The investigators aim to determine if patients with systolic heart failure treated with prasugrel achieve greater platelet inhibition compared to those treated with clopidogrel.
Systolic Heart Failure
Drug: Prasugrel 10 mg daily x 2 weeks
Drug: Clopidogrel 75 mg daily x 2 weeks
|Study Design:||Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Platelet Reactivity With Clopidogrel Versus Prasugrel in Patients With Systolic Heart Failure|
- The change in platelet aggregation measured by the Accumetrics (VerifyNow P2Y12) assay between baseline and each antiplatelet medication [ Time Frame: Baseline, 2 weeks post clopidogrel, and 2 weeks post prasugrel ] [ Designated as safety issue: No ]
- The change in light transmission aggregometry (LTA)between baseline and each antiplatelet medication [ Time Frame: Baseline, 2 weeks post clopidogrel, and 2 weeks post prasugrel ] [ Designated as safety issue: No ]
- The change in platelet activation assay (VASP)between baseline and each antiplatelet medication [ Time Frame: Baseline, 2 weeks post clopidogrel, and 2 weeks post prasugrel ] [ Designated as safety issue: No ]
|Study Start Date:||February 2013|
|Estimated Study Completion Date:||July 2015|
|Estimated Primary Completion Date:||July 2015 (Final data collection date for primary outcome measure)|
Active Comparator: Prasugrel
Prasugrel 10 mg once daily for 2 weeks
|Drug: Prasugrel 10 mg daily x 2 weeks|
Active Comparator: Clopidogrel
Clopidogrel 75 mg once daily for 2 weeks
|Drug: Clopidogrel 75 mg daily x 2 weeks|
Thienopyridine antiplatelet agents are an important component of therapy for management of acute coronary syndrome (ACS). Dual antiplatelet therapy with a thienopyridine, most commonly clopidogrel, and aspirin is widely used in the management of ACS to prevent major adverse cardiovascular events. Despite the benefits of this regimen, many patients continue to develop atherothrombotic events while on this regimen. Various reasons including inter-patient variability, delayed onset of action, and the obtainable antiplatelet activity of clopidogrel have been described as potential causes of the limited efficacy in preventing recurrent events. The Trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel—thrombolysis in myocardial infarction (TRITON-TIMI 38) showed that patients with moderate-to-high-risk ACS scheduled for percutaneous coronary intervention (PCI) treated with prasugrel had decreased cardiovascular events compared to clopidogrel.
Clopidogrel is a prodrug that requires two hepatic conversion steps by the cytochrome (CYP)P450 enzyme system. The need for CYP450 involvement is known to contribute to the variable response of platelet inhibition demonstrated with clopidogrel. Although prasugrel is also a thienopyridine, it only requires hepatic CYP450 enzymes for one conversion step, and is converted to the active metabolite more efficiently. Therefore, prasugrel provides significantly more potent platelet inhibition compared to clopidogrel.
Patients with advanced systolic heart failure commonly have elevated hepatic venous pressures that can cause hepatic congestion and hypoperfusion resulting in impaired hepatic function. The elevated hepatic venous pressure predominantly affects the hepatic centrilobular cells which contain the highest concentration of cytochrome P-450 (CYP450) enzyme system. Hence patients with advanced heart failure may convert less clopidogrel to the active metabolite and subsequently produce less platelet inhibition compared to prasugrel.
Since prasugrel only requires the CYP450 system for one conversion step, the impact of hepatic congestion should be limited for heart failure patients treated with prasugrel. The phase 3, multi-center TRITON-TIMI 38 trial comparing clopidogrel and prasugrel showed that in an unselected patient population presenting with ACS, prasugrel achieved greater cardiovascular event reduction that was attributed to more robust platelet inhibition. Hence, we designed this trial to prospectively test the hypothesis that systolic heart failure patients with increased circulating catecholamines and possible abnormal functioning of CYP450 system treated with prasugrel will achieve greater platelet reactivity inhibition compared to those treated with clopidogrel.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01765400
|Contact: Paul P Dobesh, PharmDfirstname.lastname@example.org|
|Contact: Julie H Oestreich, PharmD, PhDemail@example.com|
|United States, Nebraska|
|University of Nebaska Medical Center||Recruiting|
|Omaha, Nebraska, United States, 68198|
|Contact: Paul P Dobesh, PharmD 402-559-3982 firstname.lastname@example.org|
|Contact: Julie H Oestreich, PharmD, PhD 402-559-2916 email@example.com|
|Principal Investigator:||Paul P Dobesh, Pharm.D.||University of Nebraska|