Likelihood of Null Effects of Large NHLBI Clinical Trials Has Increased over Time

Abstract

Background: We explore whether the number of null results in large National Heart Lung, and Blood Institute (NHLBI) funded trials has increased over time.

Methods: We identified all large NHLBI supported RCTs between 1970 and 2012 evaluating drugs or dietary supplements for the treatment or prevention of cardiovascular disease. Trials were included if direct costs >$500,000/year, participants were adult humans, and the primary outcome was cardiovascular risk, disease or death. The 55 trials meeting these criteria were coded for whether they were published prior to or after the year 2000, whether they registered in clinicaltrials.gov prior to publication, used active or placebo comparator, and whether or not the trial had industry co-sponsorship. We tabulated whether the study reported a positive, negative, or null result on the primary outcome variable and for total mortality.

Results: 17 of 30 studies (57%) published prior to 2000 showed a significant benefit of intervention on the primary outcome in comparison to only 2 among the 25 (8%) trials published after 2000 (χ2=12.2,df= 1, p=0.0005). There has been no change in the proportion of trials that compared treatment to placebo versus active comparator. Industry co-sponsorship was unrelated to the probability of reporting a significant benefit. Pre-registration in clinical trials.gov was strongly associated with the trend toward null findings.

Conclusions: The number NHLBI trials reporting positive results declined after the year 2000. Prospective declaration of outcomes in RCTs, and the adoption of transparent reporting standards, as required by clinicaltrials.gov, may have contributed to the trend toward null findings.

Fig 1. Relative risk of showing benefit or harm of treatment by year of publication for large NHLBI trials on pharmaceutical and dietary supplement interventions.

Positive trials are indicated by the plus signs while trials showing harm are indicated by a diagonal line within a circle. Prior to 2000 when trials were not registered in clinical trials.gov, there was substantial variability in outcome. Following the imposition of the requirement that trials preregister in clinical trials.gov the relative risk on primary outcomes showed considerably less variability around 1.0.

Fig 2. Summary of results on the primary outcome in NHLBI trials on pharmaceutical and supplement interventions that were not pre-registered in clinical trials.gov (panel A) and pre-registered in clinical trials.gov (panel B).

Trials indicated by shading and black boxes had statistically significant effects of intervention while trials not shaded and represented by gray boxes had null effects.