Обзор американских кардиологических журналов за неделю (ссылки)

[Chevychelov]

Drugmaker Pulls Plug on Oral Anticoagulant

By Peggy Peck, Executive Editor, Reviewed by
September 29, 2011

Review

Astellas Pharma has announced it is shutting down global development of darexaban maleate, a direct factor Xa inhibitor, after an acute coronary syndrome study revealed a higher bleeding risk associated with the drug.

The company said the ACS results reported at the European Society of Cardiology meeting last month in Paris, coupled with its inability to find a development partner for darexaban made further development impractical.

In the ACS study there was a significant dose-dependent increase in major bleeding and clinically relevant nonmajor bleeding at six months among patients treated with darexaban.

But darexaban is not the first direct factor Xa inhibitor to demonstrate safety concerns when used to treat ACS patients -- apixaban failed in phase III for that patient population. And a third factor Xa inhibitor, rivaroxaban (Xarelto), is currently being evaluated for ACS.

Earlier this year, Astellas abandoned plans to seek approval from the Japanese regulatory agency to market the drug for use after surgery.
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Featured Commentary

Issue No. 6, 2011
CETP inhibition in perspective

The sixth in a series of regular Commentaries highlighting topical issues relevant to EAS activities
Cholesteryl ester transfer protein (CETP) inhibition has been a ‘hot topic’ in recent news. At the European Society of Cardiology (ESC) Congress in Paris 27-31 August, two trials with dalcetrapib were presented –dal-PLAQUE and dal-VESSEL. Results and implications from these trials are discussed here.
Dal-PLAQUE
The findings from this small trial, presented as a poster at the ESC Paris, were subsequently published in The Lancet.1 Dal PLAQUE was designed to investigate the effects of dalcetrapib treatment on structural and inflammatory markers of plaque burden, using innovative multimodality imaging techniques.

In this phase IIb, double-blind trial 130 patients (mean age 63 years, 82% male and mean HDL cholesterol 1.2 mmol/L or 46 mg/dL at baseline) with coronary heart disease (CHD) or CHD risk equivalents and treated to a LDL cholesterol level of <2.6 mmol/L (mean 1.9 mmol/L or 74 mg/dL) were randomly allocated to treatment with dalcetrapib 600 mg/day or placebo for 24 months. The primary endpoints were indices of plaque burden from the carotid and abdominal aorta (total vessel area, wall area, wall thickness and normalised wall index) at 24 months measured using magnetic resonance imaging (MRI). Plaque inflammation was also assessed at 6 months using 18F fluoro-deoxyglucose uptake measured by positron emission tomography/computed tomography (FDG-PET/CT).

Treatment with dalcetrapib increased plasma levels of HDL cholesterol levels by 31%, consistent with previous phase II data.2

Dalcetrapib treatment was associated with reduction in structural markers of plaque burden at 24 months, as indicated by:
Significant reduction in total vessel area (absolute change from baseline corrected for placebo, -4.01 mm2, 90%CI -7.23 to -0.80, p=0.041)
A trend for reduction in average wall area (-2.20 mm2, 90%CI -4.54 to 0.13, p=0.12).
The dalcetrapib placebo-corrected changes in total vessel area, average wall area and normalised wall index were either below the pre-specified ‘no harm’ boundary, or the change was numerically lower in the dalcetrapib group than the placebo group.

FDG-PET/CT results showed no evidence of increased vascular inflammation with dalcetrapib at 6 months. The target to background ratio (TBR) for the most diseased segment decreased over 6 months in the dalcetrapib group but did not change in the placebo group (average absolute change 0.19, 90% CI -0.29 to -0.09, p=0.001 versus -0.043, 90% CI -0.14 to 0.06, p=0.51). Exploratory analyses showed that the change in HDL cholesterol level appeared to be inversely correlated with the change in TBR for the most diseased segment at 6 months. A 4.3% reduction in arterial inflammation was observed with each increase in HDL cholesterol tertile (p=0.04).

Dalcetrapib treatment was not associated with any increase in blood pressure. There were 15 adjudicated cardiovascular events (13 on dalcetrapib vs. 2 on placebo).

It is acknowledged that the study was exploratory and therefore no correction was made for multiple statistical analyses. Additionally, patients were only randomised if they had a sufficient PET signal at baseline. Despite these methodological limitations, the data support the hypothesis that HDL cholesterol raising associated with dalcetrapib treatment might reduce inflammation in turn leading to favourable changes in structural vascular changes.