Warfarin to prevent stroke trial
For certain types of heart disease , the main risk is stroke. This condition occurs when a blood clot forms in the left atrium, causing the embolism to cause a stroke or transient ischemic attack (TIA). To address this problem, drugs that inhibit clot formation, warfarin, were developed and tested. Forty-five warfarin clinical trials conducted in the 1980s were primarily designed to evaluate the impact of warfarin on stroke prevention in participants with atrial fibrillation (AF).
The first study was the Danish single-center trial AFASAK. Participants were randomly assigned to the warfarin group, the aspirin group, and the placebo group, and the incidence of thromboembolic events in each group was compared. At the fourth interim analysis, the trial was terminated due to more thromboembolic events in the aspirin and placebo groups.
Subsequently, the Anticoagulation in Atrial Fibrillation Trial (BAATAF) and Stroke Prevention in Atrial Fibrillation (SPAF) trials were launched to evaluate the safety and effectiveness of warfarin and aspirin compared with placebo in preventing ischemic stroke or systemic embolism. And due to the obvious early benefit of SPAF, SPAF was discontinued.
These three trials provide consistent supporting evidence for warfarin in preventing stroke. This "pattern change" is the main reason why the CAFA research on and the SPINAF research on were terminated prematurely in April 1990 and March 1991 respectively.
CAFA compared warfarin with placebo in preventing systemic thromboembolism. When the primary results of AFASAK and SPAF were published, the target number of enrolled patients had reached 60%. Therefore, it was decided to terminate the CAFA study.
SPINAF also evaluated the efficacy of warfarin in preventing ischemic stroke. An interim analysis showed that the relative risk reduction for the primary endpoint was 79%, with warfarin superior to placebo. This information, along with the results of AFASAK, SPAF, and BAATAF, supported the DSMB's decision to terminate the SPINAF study in 1991.
Was it the right decision to terminate the trial?
CAPRICORN trial of carvedilol in patients with myocardial infarction
While it may be simple to make decisions about early discontinuation based on external information from a warfarin trial, this is far from the norm. The CAPRICORN (Carvedilol Survival in Patients with Left Ventricular Dysfunction After Myocardial Infarction) trial is another example of a clinical trial. In this trial, decisions to modify the study protocol based on external information may not have been correct.
The trial plans to conduct four interim analyzes focusing on all-cause mortality. After the third was completed, however, problems emerged with slow recruitment and the results of two clinical trials testing the efficacy of beta-blockers in patients with heart failure.
CIBIS-II (Cardiac Insufficiency-Bisoprolol Study) and MERIT-HF (Metoprolol C/XL Randomized Intervention Trial in Congestive Heart Failure) both evaluated the effects of beta-blockers in chronic heart failure. While both studies consistently demonstrated the benefit of beta-blockers, this highlights the concerns of members of the CAPRICORN Steering Committee and the DSMB that patient recruitment will decrease as these drugs become available in routine care.
Without having seen any unblinded study data, the DSMB decided to modify the protocol to add a co-primary endpoint: a composite endpoint of all-cause mortality or cardiovascular hospitalization . At the end of the study, the primary analysis showed a benefit for carvedilol in reducing the incidence of the co-primary endpoint.
Hydroxychloroquine in hospitalized patients with COVID-19 - ORCHID trial
The ORCHID (Outcomes Related to Hydroxychloroquine in Hospitalized Patients with Symptomatic COVID-19) trial was a multicenter, placebo-controlled trial of adult patients hospitalized with SARS-CoV-2 infection. The primary hypothesis is that hydroxychloroquine treatment will improve clinical status at 14 days compared with placebo.
Meanwhile, another trial provides outside information on hydroxychloroquine. The RECOVERY (Randomized Evaluation of COVID-19 Therapies) trial, , is an open-label platform trial comparing the impact of multiple potential therapies with usual care on the primary outcome of 28-day mortality.
In a prespecified interim analysis, the difference between the two groups in the primary outcome was small, and the data monitoring committee recommended discontinuing enrollment in the HCQ group due to lack of efficacy. In addition, FDA and the British Medicines and Healthcare products Regulatory Agency also oppose the use of hydroxychloroquine. However, an observational study claimed that hydroxychloroquine was toxic (later retracted by the Lancet due to fraud), and an observational study claiming that hydroxychloroquine was beneficial (the study was severely criticized). These political and media pressures, supported by peer-reviewed literature, have left researchers deeply confused and anxious. Well-designed trials such as
RECOVERY report no evidence of benefit or harm from using hydroxychloroquine in hospitalized patients with COVID-19. The termination of the trial based on media reports poses serious challenges to participant recruitment efforts and data monitoring, even for trials of other potential uses of HCQ in COVID-19 treatment, such as outpatient treatment and disease prevention.
Discussion
In summary, whether it is the warfarin trial, the CAPRICORN study, the ORCHID trial, and the COVID-19 vaccine trial are examples of how external information can influence the DSMB's monitoring of clinical trials and related decisions . While recommendations to stop a clinical trial on the basis of efficacy, safety or futility can be obtained through statistical stopping guidelines, as highlighted by the CAPRICORN and ORCHID studies, making a decision on whether to stop a trial based on external information may not be as straightforward.
As well as recommendations around efficacy, safety and futility, there are concerns about the continued balanced and ethical treatment of study participants, and how recruitment and trial integrity are maintained, which may be affected by outside information. The DSMB's primary role and responsibility is to ensure that trial participants are protected and the sacrifices they make to participate in the trial are respected by upholding the scientific mission of the trial. The DSMB's important job is to weigh the evidence and information and make the right choices for research participants based on the DSMB's thinking at the time.
The results of other clinical trials or the emergence of new effective treatment options can affect the scientific relevance and ethical acceptability of ongoing clinical trials. With the primary goal of protecting trial participants, DSMBs should carefully consider this information when making recommendations about continuing, stopping, or modifying ongoing clinical trials. Based on the COVID-19 vaccine example at the beginning of this article, Since we need more vaccines to protect against COVID-19, it makes sense that most vaccine trials are not terminated and new trials are being started.
