Platelet Inhibition in Patients With Systolic Heart Failure
| Status: | Completed |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 19 - 75 |
| Updated: | 10/4/2017 |
| Start Date: | February 2013 |
| End Date: | December 28, 2015 |
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.
prasugrel achieve greater platelet inhibition compared to those treated with clopidogrel.
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.
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.
We found this trial at
1
site
Click here to add this to my saved trials
