Redundant trials in China lead to more MACEs, deaths in control participants

More than 2,000 redundant clinical trials on statins in patients with coronary artery disease (CAD) have been identified from mainland China, resulting in an extra 3,000 major adverse cardiac events (MACEs), including nearly 600 deaths, among participants who were not treated with statins in these trials, according to a cross-sectional study.

“The scale of redundancy necessitates urgent reform to protect patients,” the researchers said.

This study searched bibliographic databases through December 2019 and identified 2,577 randomized controlled trials (RCTs) comparing statin treatment with placebo or no treatment in a total of 250,810 CAD patients from mainland China.

Redundant clinical trials were defined as RCTs initiating or continuing recruitment after 2008 (ie, 1 year after statin treatment was strongly recommended by clinical practice guidelines). The number of extra MACEs that were attributable to the deprivation of statins among patients in the control groups was the primary outcome.

Of the RCTs, 2,045 were published between 2008 and 2019, comprising 101,486 control patients not treated with statins for 24,638 person-years. [BMJ 2021;372:n48]

A total of 3,470 extra MACEs (95 percent confidence interval [CI], 3,230–3,619) were reported. This included 559 deaths (95 percent CI, 506–612), 973 patients with new or recurrent myocardial infarction (95 percent CI, 897–1,052), 161 patients with stroke (95 percent CI, 132–190), 83 patients requiring revascularization (95 percent CI, 58–105), 398 patients with heart failure (95 percent CI, 352–448), 1,197 patients with recurrent or deteriorated angina pectoris (95 percent CI, 1,110–1,282), and 99 unspecified MACEs (95 percent CI, 69–129).

The occurrence of multiple system failures led to these large-scale redundant trials, according to researchers, noting how investigators were untrained to consider existing evidence before initiating clinical trials.

“We did not formally assess how the authors justified their trials, but, as others have reported, we noticed that few redundant trials cited systematic reviews or previous trials, suggesting a lack of appreciation about previous evidence,” they noted. [Ann Intern Med 2011;154:50-55; J Clin Epidemiol 2016;69:174-178; J Clin Epidemiol 2021;129:151-157; J Clin Epidemiol 2021;129:158-166]

Clinical practitioners were also under pressure to publish a research paper. This explains why only 20 percent of included trials reported clinical events, “because it is easier and faster to conduct clinical trials on surrogate laboratory outcomes.” [Lancet 2013;381:e4; Nature 2010;463:142-143]

In addition, committees reviewing trial protocols did not check the scientific foundation and protect participants from enrolling in harmful trials; some journal editors failed to evaluate the scientific value of publications properly; not all trials reported their funding source; and none of them were registered in trial registries. [Chest 2015;148:1148-1155; JAMA 2003;290:516-523]

Worse, these findings might only cover a fraction of the problem as nearly 80 percent of eligible trials did not report clinical events, even with follow-up of many years, and those with limited follow-up might not capture the long-term benefits of statins. Additionally, evidence on publication rate of clinical trials in mainland China was insufficient, and the current study was limited to only one drug class, one disease condition, one type of comparator, and RCTs.

“Future studies are needed to evaluate the existence of research redundancy over the entire clinical trial community and the general biomedical research in mainland China,” the researchers said.