Effect of redundant clinical trials from mainland China evaluating statins in patients with coronary artery disease: cross sectional study

Abstract

Objective To identify redundant clinical trials evaluating statin treatment in patients with coronary artery disease from mainland China, and to estimate the number of extra major adverse cardiac events (MACEs) experienced by participants not treated with statins in those trials. Design Cross sectional study. Setting 2577 randomized clinical trials comparing statin treatment with placebo or no treatment in patients with coronary artery disease from mainland China, searched from bibliographic databases to December 2019. Participants 250 810 patients with any type of coronary artery disease who were enrolled in the 2577 randomized clinical trials. Main outcome measures Redundant clinical trials were defined as randomized clinical trials that initiated or continued recruiting after 2008 (ie, one year after statin treatment was strongly recommended by clinical practice guidelines). The primary outcome is the number of extra MACEs that were attributable to the deprivation of statins among patients in the control groups of redundant clinical trials—that is, the number of extra MACEs that could have been prevented if patients were given statins. Cumulative meta-analyses were also conducted to establish the time points when statins were shown to have a statistically significant effect on coronary artery disease. Results 2045 redundant clinical trials were identified published between 2008 and 2019, comprising 101 486 patients in the control groups not treated with statins for 24 638 person years. 3470 (95% confidence interval 3230 to 3619) extra MACEs were reported, including 559 (95% confidence interval 506 to 612) deaths, 973 (95% confidence interval 897 to 1052) patients with new or recurrent myocardial infarction, 161 (132 to 190) patients with stroke, 83 (58 to 105) patients requiring revascularization, 398 (352 to 448) patients with heart failure, 1197 (1110 to 1282) patients with recurrent or deteriorated angina pectoris, and 99 (95% confidence interval 69 to 129) unspecified MACEs. Conclusions Of more than 2000 redundant clinical trials on statins in patients with coronary artery disease identified from mainland China, an extra 3000 MACEs, including nearly 600 deaths, were experienced by participants not treated with statins in these trials. The scale of redundancy necessitates urgent reform to protect patients.

Assessment of redundant randomized clinical trials among patients with ST segment elevation myocardial infarction

“…Redundant RCTs could be defined by either CPGs or cumulative meta-analyses (CMAs), i.e., RCTs were considered redundant if conducted after the efficacy of routine therapies was confirmed by either CPGs or CMAs. We expected that CPGs would confirm the efficacy of routine therapies later than CMAs [ 12 ]. To be more conservative, we used CPGs in the primary analysis to define redundant RCTs.…”

“…An RCT was entirely redundant if its recruitment started 1 year after the experimental therapy was established as routine therapy by CPGs for the first time and remained so in the following updates [ 12 ]. The 1-year “grace period” allows researchers to learn about the CPGs and terminate their RCTs.…”

“…Since 2016, mainland China has been producing more scientific publications than any other country [ 9 ], but its fastest-growing output of biomedical research appears to include substantial redundancy [ 10 , 11 ]. For example, it has been estimated that between 2008 and 2019, more than 2000 redundant RCTs were conducted in mainland China [ 12 ]. Those RCTs compared statins, drugs already determined to be beneficial, with placebo or no treatment among patients with coronary artery disease.…”

“…Those RCTs compared statins, drugs already determined to be beneficial, with placebo or no treatment among patients with coronary artery disease. Patients in the control groups were denied statins and, as a result, may have suffered over 3000 unnecessary major cardiac adverse events (MACEs), including more than 500 deaths, that could have been prevented had they received statins [ 12 ].…”

Meta-research evaluating redundancy and use of systematic reviews when planning new studies in health research: a scoping review

“…the factor determining if a study would be considered to be redundant. A cutoff could also be used without performing a cumulative meta-analysis, but instead stating that "redundant clinical trials were defined as randomized clinical trials that initiated or continued recruiting after 2008" where a clinical guideline was published [21]. Different criteria were used for cut-off analyses, with four of them using cumulative meta-analysis (p-value, visual inspection of a forest plot, trial sequential analysis, and failsafe ratio), and the others either extended funnel plot, number of similar trials published after a trial is stopped early for benefit, number of studies published after established "high" certainty of evidence, or the number of studies published after established guidelines had established certainty of evidence (see also Supplementary Material 3).…”