Several new drugs, currently at advanced stages of development, were featured during the annual meeting of the American College of Cardiology (ACC) in March 2009.
Prasugrel Awaits FDA Decision as New Evidence Show Resistance to Clopidogrel
The antiplatelet drug prasugrel remains in regulatory limbo after a US Food and Drug Administration advisory panel voted unanimously in February to recommend its approval. Prasugrel may take on added importance as 2 new studies presented at the ACC annual meeting demonstrate that approximately one third of patients have a genetic polymorphism that confers resistance to clopidogrel.
People who carry the cytochrome (CY) P450 2C19 (CYP2C19) genetic variant CYP2C19*2 have a diminished antiplatelet response to clopidogrel and suffer more ischemic events after angioplasty and stenting than those who do not carry the gene variant, according to Paul A. Gurbel, MD, director of cardiovascular research, Sinai Center for Thrombosis Research, Baltimore.
Among 227 patients undergoing angioplasty with a stent, 30% had the gene variant. “This common variant encodes a defective enzyme that likely fails to adequately convert clopidogrel to its active metabolite, leading to lesser inhibition of platelet function and diminished cardiovascular protection,” Dr Gurbel said. People with this gene variant were more than twice as likely as those with the wild type of the gene to have ischemic events at 1 year (21% versus 10%, respectively).
The CYP2C19*2 polymorphism also predicted a worse prognosis in young patients treated with clopidogrel after a heart attack, found Jean-Philippe Collet, MD, of Institut National de la Santé Et de la Recherche Médicale, Paris.
Prasugrel is metabolized more efficiently than clopidogrel and has superior bioavailability for faster activation and a more consistent antiplatelet effect, said Michelle O. Donoghue, MD, investigator in the TIMI Study Group at Brigham and Women’s Hospital. In a new analysis of a study known as TRITON-TIMI 38, which was conducted in patients scheduled for angioplasty and stenting, prasugrel maintained its advantage over clopidogrel in preventing cardiovascular events in patients taking other drugs metabolized by the CYP450 enzyme.
Compared with clopidogrel, prasugrel was associated with consistent reductions in adverse ischemic events in patients who were taking a lipophilic statin, those who were or were not using a proton pump inhibitor (PPI), and those taking amiodarone.
At last year’s meeting of the American Heart Association, a major study showed that concomitant use of PPIs with clopidogrel increased the risk of major cardiovascular events at 1 year in stented patients.
Dronedarone Reduces Cardiovascular Hospitalizations, Death
Dronedarone, a multichannel-blocking antiarrhythmic drug, was found to reduce hospitalizations for cardiovascular causes, and death from any cause, in a meta-analysis of 5 clinical trials totaling 6157 patients with atrial fibrillation or atrial flutter.
A 24% relative reduction in the risk of cardiovascular hospitalization or death was found in the placebo-controlled trials in those assigned to dronedarone compared with placebo.
Eprotirome, which Targets Thyroid Hormone, also Lowers LDL Cholesterol
Eprotirome, which targets thyroid hormone receptors, further improved the lipid profile in patients already taking statins.
Eprotirome acts selectively on the liver, mimicking the effects of thyroid hormone on lipids, without side effects in organs outside the liver, said Jens Kristensen, MD, PhD, vice president of clinical development for the Swedish pharmaceutical company Karo Bio. In 189 patients with elevated low-density lipoprotein cholesterol (LDL-C) despite statin therapy, eprotirome, which was used as add-on therapy, reduced LDL-C by 21% to 32% and triglycerides by 15% to 33%, depending on the dosage, after 12 weeks. The drug was well-tolerated and is ready for phase 3 study, said Dr Kristensen.