One lesson rings clear from the recent American Heart Association (AHA) scientific session and other conferences: It is really hard to successfully complete randomized controlled clinical trials these days.
A few of the late-breaking clinical trials presented Nov. 16-19 at the AHA meeting were terminated early. Slow recruitment and a lower than expected event rate hobbled ISAR-SAFE, which compared six months vs. 12 months of clopidogrel (Plavix, Brisotol Myers-Squibb/Sanofi Aventis) treatment after implantation of drug-eluting stents. The Japanese Primary Prevention Project trial, which assessed daily low-dose aspirin vs. no aspirin for reducing atherosclerotic events, also wrapped up early after an interim analysis pointed to futility.
These challenges aren’t isolated to the recent presentations. Panelists at the 2014 Transcatheter Cardiovascular Therapeutics’ ISAR-TRIPLE late-breaker voiced concern about the sample size and ability to confidently make conclusions in what might be an underpowered study. ISAR-TRIPLE randomized atrial fibrillation patients to six weeks or six months of clopidogrel plus concomitant aspirin and oral anticoagulation with vitamin K antagonists after implantation with a drug-eluting stent. Yet more than a quarter of patients in the six-week group continued clopidogrel after six weeks.
Some AHA trials that managed to maintain their might applied novel designs. For instance, ODYSSEY ALTERNATIVE researchers found a way to tease out patients who may not be statin-intolerant, an important factor in a study designed to evaluate the safety and effectiveness of a low-density lipoprotein cholesterol-lowering monoclonal antibody (alirocumab) in at-risk statin-intolerant patients.
The double-blind, double-dummy placebo-controlled study put patients who had a history of statin intolerance through a weeding stage of placebo subcutaneous injections and placebo pills. Those who reported muscle-related adverse events were excluded. The remaining 314 patients were randomized to alirocumab and a daily oral placebo or a placebo subcutaneous injection and daily oral ezetimibe or oral atorvastatin.
The DAPT study also broke ground with a design that enrolled patients through the Harvard Clinical Research Institute or one of four postmarketing surveillance studies involving four different drug-eluting stents. It, too, had a pre-randomization stage by making patients eligible to either dual antiplatelet therapy or aspirin alone only if they first remained DAPT tolerant for the prior 12 months. It is not perfect but the trial provided the statistical power to answer questions about risks and benefits with shorter and longer duration DAPT.
Congratulations to all presenters. All of these trials also offer insights, including ways to design a robust trial despite sometimes difficult circumstances.
Editor, Cardiovascular Business