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Platelet Inhibition in Patients With Systolic Heart Failure

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ClinicalTrials.gov Identifier: NCT01765400
Recruitment Status : Completed
First Posted : January 10, 2013
Last Update Posted : October 2, 2017
Sponsor:
Collaborators:
Daiichi Sankyo, Inc.
Eli Lilly and Company
Information provided by (Responsible Party):
Paul Dobesh, PharmD, University of Nebraska

Tracking Information
First Submitted Date  ICMJE December 12, 2012
First Posted Date  ICMJE January 10, 2013
Last Update Posted Date October 2, 2017
Actual Study Start Date  ICMJE February 2013
Actual Primary Completion Date December 1, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 9, 2013)
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 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01765400 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 9, 2013)
  • 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 ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Platelet Inhibition in Patients With Systolic Heart Failure
Official Title  ICMJE Platelet Reactivity With Clopidogrel Versus Prasugrel in Patients With Systolic Heart Failure
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Systolic Heart Failure
Intervention  ICMJE
  • Drug: Prasugrel 10 mg daily x 2 weeks
  • Drug: Clopidogrel 75 mg daily x 2 weeks
Study Arms  ICMJE
  • Active Comparator: Prasugrel
    Prasugrel 10 mg once daily for 2 weeks
    Intervention: Drug: Prasugrel 10 mg daily x 2 weeks
  • Active Comparator: Clopidogrel
    Clopidogrel 75 mg once daily for 2 weeks
    Intervention: Drug: Clopidogrel 75 mg daily x 2 weeks
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 28, 2017)
30
Original Estimated Enrollment  ICMJE
 (submitted: January 9, 2013)
50
Actual Study Completion Date  ICMJE December 28, 2015
Actual Primary Completion Date December 1, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01765400
Other Study ID Numbers  ICMJE 574-11-FB
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Paul Dobesh, PharmD, University of Nebraska
Study Sponsor  ICMJE University of Nebraska
Collaborators  ICMJE
  • Daiichi Sankyo, Inc.
  • Eli Lilly and Company
Investigators  ICMJE
Principal Investigator: Paul P Dobesh, Pharm.D. University of Nebraska
PRS Account University of Nebraska
Verification Date September 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP