Platelet Inhibition in Patients With Systolic Heart Failure

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.

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.