The DUPLICATE initiative is building an empirical evidence base for using longitudinal insurance claims prospectively to achieve large-scale replication of randomized controlled trials. Dr. Wang, a codirector of the initiative, is an associate professor of medicine at Harvard Medical School and associate epidemiologist in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital.
PROACT Xa was a prospective, randomized clinical trial conducted to determine whether apixaban was noninferior to warfarin in preventing valve thrombosis or valve-related thromboembolism in patients with an On-X mechanical aortic valve. The trial’s pragmatic design features enabled the investigators to conduct the the trial successfully during the COVID-19 public health emergency.
Dr. Alexander is a cardiologist and professor of medicine in the Duke University School of Medicine and a faculty member in the Duke Clinical Research Institute.
The QUARTET USA trial tested a novel approach to lowering blood pressure compared with standard-dose monotherapy. The trial was embedded within a network of federally qualified healthcare centers in the Chicago metropolitan area. Ciolino is an associate professor of preventive medicine (biostatistics) and director of the master of science in biostatistics program in the Northwestern University Feinberg School of Medicine.
Dr. Meersch-Dini will discuss the results of the HandiCAP trial (Impact of Handover of Anesthesia Care on Adverse Postoperative Outcomes), a parallel-group, randomized clinical trial of intraoperative handover of anesthesia care in 12 centers in Germany.
Justin A. Ezekowitz, MBBCh, MSc
Professor of Medicine and Alberta Health Services Chair in Cardiac Sciences
Director, Cardiovascular Research
Co-Director, Canadian VIGOUR Centre
University of Alberta
Cardiologist, Mazankowski Alberta Heart Institute
Keywords
PCORnet; COVID-19; Electronic health record (EHR); Surveillance data
Key Points
Prior randomized controlled studies on dietary intake of sodium have shown no consistent or conclusive results.
SODIUM-HF is a pragmatic randomized trial of 806 patients in 6 countries with heart failure randomized to usual care or a low-sodium diet (≤1500 mg/day NA) and followed for 12 months. The primary outcome measures were mortality, hospitalizations, and emergency department (ED) visits.
Patients started out around 2200 mg of dietary sodium per day. The usual care group showed little reduction while the SODIUM intervention group saw a 28% reduction to around 1658 mg per day.
The intervention group did not have a statistically significant positive outcome for the primary endpoints of mortality, hospitalizations, or ED visits.
Patients reported a modestly higher quality of life after 6 and 12 months on the lower sodium diet as reported on the KCCQ quality of life questionnaire.
As part of an overall health strategy, clinicians may want to encourage a low sodium diet for patients with HF as a therapy to improve a patient’s quality of life.
Discussion Themes
– The top 3 challenges to the SODIUM-HF study were finding patients willing to change their diet, maintaining fidelity to the study intervention across multiple sites, and the impact of COVID on recruitment.
– No study sites were in the US due to cost restrictions.
– Efficacy trials are still very important and we need to get better at funding them and running them for longer periods.
The SODIUM-HF trial is open-label, randomized controlled trial conducted at 26 sites in Australia, Canada, Chile, Colombia, Mexico, and New Zealand to test whether reduction in dietary sodium reduces the incidence of future clinical events.
The SPIRRIT-HFpEF trial, conducted Sweden and the US, was a randomized pragmatic clinical trial of spironolactone or eplerenone in heart failure.
Death from heart disease is decreasing while death from Heart Failure is increasing.
The SPIRRIT-HFpEF trial focused on improving the trajectory for the growing heart failure population.
Patients treated with Spironolactone had a modest but not statistically significant improvement over placebo, but total hospitalizations were less.
Patients with a lower ejection fraction were more likely to benefit than patients with a higher ejection fraction.
The Swedish Heart Failure Registry (SwedeHF) has been collecting data from HF patients since 2000.’
Discussion Themes
The hardest aspect of a clinical trial is recruitment and enrollment. Patients are spread out over the health care system. The challenge is getting staff and personnel to do the work of screening and prescreening.
In the SPIRRIT-HFpEF, the drawbacks of not blinding were small and the costs of blinding would have been huge.
SPIRRIT-HFpEF is using a registry-based randomized clinical trial design to determine whether initiation of spironolactone plus usual care improves outcomes of patients with heart failure with preserved ejection fraction compared with usual care alone.
The Living Textbook has recently published materials that explore how randomized trials can be designed to promote both internal and external validity. The new contributions, from Drs. Merrick Zwarenstein, Ahmed Al-Jaishi, and Amit Garg, explain that consideration of the trial’s intention, whether pragmatic or explanatory, is the key to designing a trial that successfully answers its primary research question. While there is a contrast between pragmatic and explanatory intentions, there is not a dichotomy. Instead, trials will vary across the spectrum of design decisions leaning toward choices that match the trial’s purpose. The PRECIS-2 tool can help investigators design their trial to align with its intention. The authors illustrate these points in a new Living Textbook section, PRECIS-2 Case Study, which contrasts the design decisions made for two trials in a renal dialysis setting.
“The purpose should be decided before embarking on designing a trial, and each element of the trial design should be aligned to the chosen purpose.”– Zwarenstein et al. 2021
The Good Clinical Trials Collaborative has opened a 6-week public consultation period on its draft guidance for randomized controlled trials. The consultation period will last until September 15.
Launched in June 2020 with the support of Wellcome, the Bill & Melinda Gates Foundation, and the African Academy of Sciences, the Collaborative is developing guidance “to enable and promote informative, ethical, and efficient randomized controlled clinical trials.” The purpose of the guidance is to identify the fundamental principles of randomized controlled trials and enable their application to a wide range of healthcare settings and interventions.