Several new drugs developed for the treatment of a variety of cardiovascular diseases are currently in the pharmaceutical pipeline. The following findings were presented at the 2009 annual meeting of the American Heart Association (AHA).
Antiplatelet Agents in Pipeline Pitted against Clopidogrel
Potential competitors to clopidogrel (Plavix) are lining up in the pharmaceutical pipeline. Two investigational antiplatelet drugs—cangrelor and ticagrelor— were compared with clopidogrel in phase 3 trials of patients undergoing percutaneous coronary intervention (PCI). The results indicate that cangrelor before PCI was not superior to clopidogrel in this setting, whereas ticagrelor prevented more deaths and ischemic events than clopidogrel in patients with an ST-elevation myocardial infarction (MI) who underwent PCI.
Cangrelor is a rapid and reversible blocker of the P2Y12 receptor, the same receptor that clopidogrel inhibits to exert its antiplatelet effect, but cangrelor must be given intravenously. This new agent was compared with clopidogrel in 2 studies presented at the AHA meeting. Both studies were stopped early, after interim analyses found no differences in the primary end point between the 2 treatments.
In one study, CHAMPION PCI, a composite end point of death, heart attack, or the need for revascularization procedures over 48 hours, the primary end point of the study, occurred with equal frequency in the 48 hours after PCI in patients with high-risk acute coronary syndromes (ACS) who were treated with either cangrelor or clopidogrel.
The 8820 patients in CHAMPION PCI were randomized to cangrelor starting 30 minutes before PCI and continued for at least 2 hours; at the end of the procedure they received 600 mg of clopidogrel. Patients randomized to clopidogrel received a 600-mg loading dose followed by a maintenance dose of 75 mg/day given with aspirin for at least 30 days thereafter. The primary end point occurred in 7.1% of the clopidogrel group and 7.5% of the cangrelor group, reported Lead Investigator Robert A. Harrington, MD, Director, Duke Clinical Research Institute, Durham, NC. Thirty-day outcomes were also not different between the 2 groups.
Minor and mild bleeding were significantly more frequent at 48 hours in cangrelor-treated patients, and there was a trend toward more major bleeding in the cangrelor group as well.
A companion trial that compared cangrelor and clopidogrel, CHAMPION PLATFORM, included 5362 patients with ACS who were randomized to intravenous cangrelor infusion started at the beginning of PCI or oral clopidogrel (600 mg) started immediately after PCI.
The primary end point, which was the same as in CHAMPION PCI, was 7.0% in cangrelor recipients and 8.0% in clopidogrel recipients, which was not a significant difference, said Deepak Bhatt, MD, MPH, Chief of Cardiology, VA Boston Healthcare System. However, compared with clopidogrel, cangrelor did significantly reduce the incidence of death (0.7% vs 0.2%) and stent thrombosis (0.6% vs 0.2%) at the 48-hour follow-up.
David Faxon, MD, Professor of Medicine, Cardiology, Brigham and Women's Hospital, Boston, found the reduction in death and stent thrombosis with cangrelor in CHAMPION PLATFORM to be encouraging for cangrelor. "We cannot ignore those findings," he said. He added that the duration of the infusion—2.1 hours—may have been too short to assess benefit, and the crossover from cangrelor to clopidogrel may have left patients vulnerable to inadequate platelet inhibition for a time.
Furthermore, he noted that cangrelor's onset is rapid, and it wears off rapidly, making it a good option for very ill patients in whom rapid platelet inhibition is desired, but who may need to go to the operating room.
Ticagrelor and clopidogrel went head-to-head in the PLATO trial, in which 8430 patients with ST-elevation MI who were to undergo planned PCI were randomized to ticagrelor or 300 mg of clopidogrel followed by 75 mg/day for 6 to 12 months.
The primary composite end point of cardiovascular death, MI, or stroke at 1 year was experienced by 11.0% of patients in the clopidogrel group and only 9.3% in the ticagrelor group, said Lead Investigator Philippe Gabriel Steg, MD, of Hôpital Bichat-Claude Bernard in Paris. All-cause death and definite stent thrombosis were also significantly less frequent in the ticagrelor group.
The incidence of major bleeding was equivalent between the 2 groups.
New CETP Inhibitor Raises HDL, Lowers LDL
The investigational CETP (cholesteryl ester transfer protein) inhibitor anacetrapib increased high-density lipoprotein (HDL) cholesterol by up to 43.4% with the highest dose—300 mg—while decreasing low-density lipoprotein (LDL) cholesterol by 15.1% at this same dose in a placebo-controlled randomized study of 539 hypercholesterolemic patients.
In the same study, when given in addition to 20 mg of atorvastatin (Lipitor), 300 mg anacetrapib raised HDL cholesterol by 41.8% and further reduced LDL cholesterol by 11.9%. Anacetrapib is in phase 3 trials.
Development of a previous CETP inhibitor—torcetrapib— was discontinued after clinical studies showed it increased the risk of major cardiovascular events despite significantly raising HDL cholesterol.
Thrombin Inhibitor Has Acceptable Rate of Bleeding
The oral direct thrombin inhibitor dabigatran, a potential alternative to warfarin (Coumadin), is associated with an acceptable rate of bleeding when used in addition to clopidogrel and aspirin.
In a placebo-controlled, dose-ranging study of 1861 patients who had had an acute heart attack, and for which they were being treated with aspirin and clopidogrel, major bleeding complications occurred at a rate of 0% to 2.0% in the patients who were randomized to dabigatran, 50 to 150 mg/day, for 6 months, reported researchers at Uppsala University Hospital, Sweden. Major bleeding occurred in 0.3% to 0.5% of the group randomized to placebo.
Dabigatran is already approved in several countries and is awaiting US Food and Drug Administration approval.