Platelet Inhibition in Patients With Systolic Heart Failure

Sponsor

University of Nebraska (Other)

Overall Status

Completed

CT.gov ID

NCT01765400

Collaborator

Daiichi Sankyo, Inc. (Industry), Eli Lilly and Company (Industry)

Enrollment

Location

Arms

34.8

Actual Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The investigators aim to determine if patients with systolic heart failure treated with prasugrel achieve greater platelet inhibition compared to those treated with clopidogrel.

Condition or Disease	Intervention/Treatment	Phase
Systolic Heart Failure	Drug: Prasugrel 10 mg daily x 2 weeks Drug: Clopidogrel 75 mg daily x 2 weeks	Phase 4

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Platelet Reactivity With Clopidogrel Versus Prasugrel in Patients With Systolic Heart Failure

Actual Study Start Date :

Feb 1, 2013

Actual Primary Completion Date :

Dec 1, 2015

Actual Study Completion Date :

Dec 28, 2015

Arms and Interventions

Arm	Intervention/Treatment
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

Arm

Intervention/Treatment

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

Outcome Measures

Primary Outcome Measures

The change in platelet aggregation measured by the Accumetrics (VerifyNow P2Y12) assay between baseline and each antiplatelet medication [Baseline, 2 weeks post clopidogrel, and 2 weeks post prasugrel]

Secondary Outcome Measures

The change in light transmission aggregometry (LTA)between baseline and each antiplatelet medication [Baseline, 2 weeks post clopidogrel, and 2 weeks post prasugrel]
The change in platelet activation assay (VASP)between baseline and each antiplatelet medication [Baseline, 2 weeks post clopidogrel, and 2 weeks post prasugrel]

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients 19 to 74 years of age.
Patients with a left ventricular ejection fraction <35% by echocardiogram, SPECT myocardial perfusion study, cardiac MRI, cardiac computerized tomographic angiogram or invasive left ventricular angiogram within the last 6 months.
Patients with NYHA Class III-IV heart failure at the time of enrollment.

Exclusion Criteria:

Recent hospitalization within 30 days
Patients expected to undergo major surgery or PCI in the next 30 days
Patients taking clopidogrel, prasugrel, ticagrelor, ticlopidine, or cilostazol
Patients listed for heart transplantation or having left ventricular assist device placement
Patients with known allergy to either medication
Patients with prior history of stroke or transient ischemic attack
Patients with known intracranial neoplasm, aneurysm, or arteriovenous malformation
Patients with a history of bleeding requiring hospitalization for treatment
Patients taking oral anticoagulants
Patients with body weight <60 kg
Women who are pregnant or breastfeeding
Patients with hemoglobin <10 mg/dl or platelet count <100,000/ul at baseline
Patients with known clotting or platelet disorders
Patients with a baseline INR > 1.4
Patients with liver function tests (AST or ALT) > 2 times normal
Patients with a suspected change in their use of aspirin during the study (starting, stopping, or changing dose of aspirin)
Patients unwilling to consent to CYP2C19 genetic testing.