Platelet Inhibition in Patients With Systolic Heart Failure
Condition: Systolic Heart Failure
MeSH terms: Heart Failure; Heart Failure, Systolic; Systolic Murmurs
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Prasugrel 10 mg daily x 2 weeks; Clopidogrel 75 mg daily x 2 weeks
Intervention type(s): Drug; Drug
Intervention MeSH terms: Clopidogrel; Prasugrel Hydrochloride
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Heart failure; Antiplatelet therapy; Platelet aggregation; Clopidogrel; Prasugrel