Pragmatic approaches to the next generation of clinical trials in heart failure

The randomized controlled trial (RCT) is critical to establishing treatment efficacy and a foundation for regulatory approval, guideline recommendations, payer reimbursement, and clinical implementation of new interventions. In heart failure (HF), since the early mechanical circulatory support devices in the 1960s and the first heart transplantation in 1967, 50 years of clinical research and a growing number of well-conducted HF RCTs have delivered interventions providing dramatic improvements in quality of life and outcomes for patients with heart failure with reduced ejection fraction (HFrEF). However, clinical trials in cardiovascular disease and HF in particular are becoming increasingly large, complex, inefficient, and expensive. The next generation of RCTs in HF must adapt to changing clinical care and research settings, emerging health technologies, changing demographics, and increasing costs of both trials and the treatments they deliver. One opportunity to address these challenges is the concept of the pragmatic clinical trial, which offer numerous advantages over conventional trials. Data: The emergence of electronic health records, quality registries, and administrative and claims-based registries can be harnessed to integrate clinical trial conduct and design into routine care. The European Union General Data Protection Regulation is designed to protect personal privacy and security and has been viewed as cumbersome for big data research, but actually clarifies and standardizes EU regulations and facilitates compliant data curation, management, storage, and access. In traditional trials, these immense data repositories are not harnessed for trial design, patient enrolment, or baseline or outcome data collection. Pragmatic trials utilize these data sources for numerous aspects of trial design and conduct. Patients: In traditional trials, inclusion and exclusion criteria are determined by extrapolation from previous trials and expert opinion. Once a trial is underway, pre-screening, screening, and enrolment are manual, opportunistic, and arbitrary. In pragmatic trials, existing data platforms are harnessed to characterize future trial participants, estimate power, and to assess feasibility. Once trials are underway, pre-screening, screening, and enrolment are automated and efficient. Endpoints: In traditional trials, endpoints are collected by local investigators by manual patient contact and chart review. In pragmatic trials, endpoints are collected automatically in routine care. Most endpoints require independent adjudication also in pragmatic trials, but triggering endpoints for review can be automated and efficient. There are opportunities for collaborative pragmatic clinical trials in Europe. The Swedish cardiovascular registries pioneered the registry-based randomized clinical trial (RRCT) concept, where existing registries serve as platforms for patient screening and enrolment and data collection. Figure 1 describes the properties of conventional trials and of registries, and how these are combined into the RRCT concept.1 The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure With Preserved Ejection Fraction (SPIRRIT-HFpEF) is a Swedish-US pragmatic trial of mineralocorticoid receptor antagonists (MRAs, spironolactone, or eplerenone) vs. usual care in patients with HFpEF (ClinicalTrials.gov Identifier: NCT02901184). SPIRRIT-HFpEF is built on the Swedish Heart Failure Registry (SwedeHF)2 in Sweden and on a pragmatic data platform in the USA. Mineralocorticoid receptor antagonists are generic inexpensive drugs that are effective in HFrEF. Heart failure with preserved EF (HFpEF) and mid-range or mildly reduced EF (HFmrEF) has no evidence-based therapy. SPIRRIT-HFpEF tests new use of an existing intervention, or re-purposing of a drug known to be effective in HFrEF, for potential use also in HFmrEF and HFpEF. Combining randomization and registries into the RRCT [from Lund et al.1 originally published under Creative Commons Attribution license (CC BY; https://creativecommons.org/licenses/by/3.0/); no changes made to figure]. Combining randomization and registries into the RRCT [from Lund et al.1 originally published under Creative Commons Attribution license (CC BY; https://creativecommons.org/licenses/by/3.0/); no changes made to figure]. A new initiative, EuroHeart, is aimed at standardizing cardiovascular registries throughout Europe, in part built on the Swedish model, and ultimately provide a platform for European wide collaborative pragmatic trials.3 Pragmatic trials are especially suitable for trials of novel treatment strategies and for re-purposing of existing interventions for novel indications (new use of existing interventions), such as in SPIRRIT-HFPEF, and for ‘hard’ more objective endpoints. However, a pragmatic design is not suitable for all trial. Early phase trials or trials with complex and/or high-risk chronic interventions and trials focusing on ‘softer’ or patient-reported outcomes may be less suitable. But regardless of trial setting, the next generation of trials will need to be more efficient. Conflict of interest: None related to the present work. L.H.L. reports personal fees from Merck, personal fees from Sanofi, grants and personal fees from Vifor-Fresenius, grants and personal fees from AstraZeneca, grants and personal fees from Relypsa, personal fees from Bayer, grants from Boston Scientific, grants and personal fees from Novartis, personal fees from Pharmacosmos, personal fees from Abbott, grants and personal fees from Mundipharma, personal fees from Medscape, personal fees from Myokardia, grants and personal fees from Boehringer Ingelheim, outside the submitted work.