Platelet Inhibition in Patients With Systolic Heart Failure

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by University of Nebraska
Sponsor:
Collaborators:
Daiichi Sankyo Inc.
Eli Lilly and Company
Information provided by (Responsible Party):
Paul Dobesh, PharmD, University of Nebraska
ClinicalTrials.gov Identifier:
NCT01765400
First received: December 12, 2012
Last updated: January 21, 2014
Last verified: January 2014
  Purpose

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 Intervention Phase
Systolic Heart Failure
Drug: Prasugrel 10 mg daily x 2 weeks
Drug: Clopidogrel 75 mg daily x 2 weeks
Phase 4

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by University of Nebraska:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 50
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)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   19 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01765400

Contacts
Contact: Paul P Dobesh, PharmD 402-559-3982 pdobesh@unmc.edu
Contact: Julie H Oestreich, PharmD, PhD 402-559-2916 joestreich@unmc.edu

Locations
United States, Nebraska
University of Nebaska Medical Center Recruiting
Omaha, Nebraska, United States, 68198
Contact: Paul P Dobesh, PharmD    402-559-3982    pdobesh@unmc.edu   
Contact: Julie H Oestreich, PharmD, PhD    402-559-2916    joestreich@unmc.edu   
Sponsors and Collaborators
University of Nebraska
Daiichi Sankyo Inc.
Eli Lilly and Company
Investigators
Principal Investigator: Paul P Dobesh, Pharm.D. University of Nebraska
  More Information

No publications provided

Responsible Party: Paul Dobesh, PharmD, Associate Professor of Pharmacy Practice, University of Nebraska
ClinicalTrials.gov Identifier: NCT01765400     History of Changes
Other Study ID Numbers: 574-11-FB
Study First Received: December 12, 2012
Last Updated: January 21, 2014
Health Authority: United States: Data and Safety Monitoring Board
United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by University of Nebraska:
Heart failure
Antiplatelet therapy
Platelet aggregation
Clopidogrel
Prasugrel

Additional relevant MeSH terms:
Heart Failure
Heart Failure, Systolic
Heart Diseases
Cardiovascular Diseases
Clopidogrel
Ticlopidine
Prasugrel
Platelet Aggregation Inhibitors
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Fibrinolytic Agents
Fibrin Modulating Agents
Cardiovascular Agents

ClinicalTrials.gov processed this record on August 28, 2014