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Prof. Stephen James Nicholls,
Prof. John Chapman,
All the Scientific resources on ESC Congress 365
By Stephen James NichollsOther authors: Dr Christie M Ballantyne (USA); Professor Philip J Barter (Australia); Dr Bryan Brewer (USA); Professor John JP Kastelein (The Netherlands); Dr Allan Gordon (USA); Dr Jan Johansson (USA); Dr Norman Wong (Canada); Dr Rishi Puri (USA); Ms Marilyn Borgman (USA); Ms Kathy Wolski (USA); Dr Steven Nissen (USA)Purpose:Considerable interest has focused on the development of therapies that target high-density lipoproteins (HDL) and reverse cholesterol transport. The ability to increase endogenous synthesis of the major protein carried on HDL, apolipoprotein A-I (apoA-I), results in dose-dependent increases in large HDL particles consistent with lipid mobilisation. The aim of this study was to evaluate the effect of the first oral agent that induces apoA-I synthesis (RVX-208) on progression of coronary atherosclerosis using intravascular ultrasound.
Study Design:A double-blind, randomized controlled trial of patients with angiographic coronary artery disease and low HDL cholesterol, treated for 26 weeks with RVX-208 200 mg or placebo, allocated in a 3:1 ratio.
Sample Size:Of 676 patients screened, 324 patients were randomized in 67 centers between November 2011 and October 2012.
Endpoints:The primary endpoint was the nominal change in percent atheroma volume in patients treated with RVX-208 compared to baseline. Additional objectives include comparisons with placebo, changes in total atheroma volume, lipid and biochemical measurements, in addition to safety and tolerability over the 26-week treatment period.
Power Calculations:It was estimated that 186 patients in the RVX-208 treatment group would be required to provide 85% power to detect regression of percent atheroma volume of ≥ 0.6%, assuming a standard deviation of 2.7%. It was assumed that 20% of patients would discontinue or have non-evaluable imaging, requiring randomization of at least 310 patients.
Conclusion:The last patient received their final dose of treatment in April 2013 and complete study results will be available before the ESC Scientific Sessions. This study provides the first opportunity to evaluate directly the effects of inducing apoA-I synthesis with RVX-208 on the rate of progression of coronary atherosclerosis.
Several aspects of the ASSURE trial merit discussion:1) The trial used Intravascular ultrasound imaging to evaluate the potential impact of RVX -208 on coronary atheroma; this methodology has been amply validated in previous intervention trials with a variety of agents, including statins and infusion of recombinant forms of high-density lipoproteins (HDL).2) The ASSURE trial was designed on the basis of results obtained in pre-clinical studies , in investigations in healthy volunteers, and in statin-treated patients with incident coronary disease investigating the effect of RVX208 on apoAI production, turnover, and circulating levels of apoAI and HDL-cholesterol. Overall, these findings suggested that at doses of up to 150 mg/day, RVX-208 induced an increase in apoAI and HDL-C of the order of 5 to 10%, and suggested that HDL efflux function may be enhanced. An increase in hepatic enzyme levels was also observed, thereby precluding further augmentation of the dose.3) As presented by Dr Nicholls, this agent did not produce changes in parameters of coronary atheroma, which were distinct from those observed in the placebo group. Several explanations may be formulated:
In summary, the impact of RVX208 treatment in coronary heart disease patients was not incremental over placebo in this trial. As a minimum, a trial of considerably greater duration would be required to more exhaustively evaluate RVX208; insights from HDL infusion trials however suggest that the low absolute magnitude of the increase in apoAI/HDL by this agent would remain largely inadequate to warrant its development as an anti-atherosclerotic agent.The ASSURE trial did not by any means directly evaluate the “HDL hypothesis”. The quest for agents that modulate apoAI/HDL metabolism and function in cardiometabolic disease must therefore be maintained, despite this setback.
ASSURE: Effect of an Oral Agent Inducing Apo A-I Synthesis on Progression of Coronary Atherosclerosis: Results of the ASSURE Study
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