Platelet Inhibition in Patients With Systolic Heart Failure

Platelet Reactivity With Clopidogrel Versus Prasugrel 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.

Study Overview

• Status: Completed
• Conditions: Systolic Heart Failure
• Intervention / Treatment: Drug: Prasugrel 10 mg daily x 2 weeks; Drug: Clopidogrel 75 mg daily x 2 weeks

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 Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebaska Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Prasugrel; Prasugrel oral 10 mg once daily for 2 weeks	Drug: Prasugrel 10 mg daily x 2 weeks
Active Comparator: Clopidogrel; Clopidogrel oral 75 mg once daily for 2 weeks	Drug: Clopidogrel 75 mg daily x 2 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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, Change From Baseline at Week 2 Reported

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: University of Nebraska
• Collaborators: Eli Lilly and Company; Daiichi Sankyo, Inc.
• Investigators: Principal Investigator: Paul P Dobesh, PharmD, University of Nebraska

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2013
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 28, 2015

Study Registration Dates

• First Submitted: December 12, 2012
• First Submitted That Met QC Criteria: January 9, 2013
• First Posted (Estimated): January 10, 2013

Study Record Updates

• Last Update Posted (Estimated): October 9, 2023
• Last Update Submitted That Met QC Criteria: September 26, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Heart failure; Prasugrel; Clopidogrel; Platelet aggregation; Antiplatelet therapy
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Murmurs; Heart Failure; Systolic Murmurs; Heart Failure, Systolic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Clopidogrel; Prasugrel Hydrochloride
• Other Study ID Numbers: 0574-11-FB

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No