Cardiology trial results announced

Findings from the ARISTOTLE trial were among the highlights of the European Society of Cardiology’s annual congress. Apixaban was shown to be superior to warfarin in the prevention of stroke and systemic embolism, in patients with atrial fibrillation, and was also associated with less bleeding and lower mortality rates. When compared to warfarin, itself a very effective treatment to prevent stroke, apixaban resulted in an additional 21% relative reduction in stroke and systemic embolism. It also resulted in a 31% relative reduction in major bleeding, as well as an 11% relative reduction in overall mortality. The better prevention of stroke was statistically significant with P=0.011, the lower rate of major bleeding at P<0.001, and the lower mortality at P=0.047. Haemorrhagic stroke was reduced by about 50%. The drug also has major practical advantages over warfarin: it does not require monitoring and has few interactions with other medications or food. Apixaban was better tolerated than warfarin, with fewer discontinuations. The number of events prevented per 1,000 people, which indicate absolute risk reduction, were also impressive, said John Alexander, M.D., a study co-author and Duke University cardiologist. “Apixaban prevented six patients from having a stroke, 15 patients from having major bleeding, and eight patients from dying. The predominant effect on stroke prevention was on haemorrhagic stroke. Apixaban prevented four patients from having haemorrhagic stroke and two patients from having an ischaemic or uncertain type of stroke.” The results were presented by the co- chairs of the ARISTOTLE trial in two late breaking clinical trial sessions at the European Society of Cardiology in Paris, France, and the main trial results were published simultaneously online in the New England Journal of Medicine. The time in therapeutic range analysis was presented by Lars Wallentin, professor of cardiology and director of the Uppsala Clinical Research Center in Sweden. The main trial results were presented by Christopher B. Granger, professor of medicine at Duke University in Durham, North Carolina, US.

Effects of dalcetrapib on vascular function

Results of the phase IIb dal-VESSEL study show that dalcetrapib, an investigational molecule which acts on cholesteryl ester transfer protein (CETP), did not impair endothelial function (as indicated by flow-mediated dilatation) or increase blood pressure, and was generally well tolerated in patients with, or at risk of, coronary heart disease. “The results provide important information regarding the safety of this novel molecule,” said principal investigator Professor Thomas F. Lüscher from the University Hospital, Zurich, Switzerland. He added that dal-VESSEL was the largest multicentre trial ever performed with brachial flow-mediated dilatation measured as a marker of endothelial function and cardiovascular risk. Dal-VESSEL was an exploratory phase IIb randomised, double-blind, placebocontrolled trial in patients with coronary heart disease (CHD), or CHD risk equivalents, in which 476 patients with HDL-C levels <50 mg/dL were recruited. They received dalcetrapib 600 mg/day or placebo in addition to their existing treatments. The primary efficacy endpoint was change from baseline in brachial flow mediated dilation after 12 weeks. The primary safety endpoint was 24-hour ambulatory blood pressure monitoring assessed at week four. Patients were treated for a total period of 36 weeks. Results showed that dalcetrapib reduced CETP activity by almost 50% and increased high-density lipoprotein cholesterol (HDL-C) levels by 31% without changing nitric-oxide-dependent endothelial function or markers of inflammation and oxidative stress. No safety signals were observed during the whole study, and 23 pre-specified positively adjucated events occurred with an even distribution in both treatement arms (11 with dalcetrapib and 12 with placebo). Dalcetrapib raises functional HDL-C by modulating CETP activity through a mechanism which differs from other CETP inhibitors, and, in earlier experimental studies, promoted efflux of cholesterol from cells. The hypothesis that it will similarly remove cholesterol from atherosclerotic plaques in humans, potentially reducing the occurrence of cardiovascular events, is currently being tested in phase III studies. Results of a second phase 2b study of dalcetrapib, dal-PLAQUE, showed similarly ‘encouraging’ results in atherosclerotic disease progression – no evidence of pro-inflammatory effects as measured by positron emission tomography/computed tomography (PET/CT) at six months, nor on plaque progression measured by magnetic resonance imaging after 12 months. “High density lipoprotein removes cholesterol from atherosclerotic plaques,” said Prof. Lüscher, “so drugs which improve this functionality may slow the progression of atherosclerosis and prevent cardiovascular events. Results so far suggest that dalcetrapib does not have pro-inflammatory or pro-atherogenic effects, does not affect blood pressure and is generally well tolerated by patients treated for up to two years.”