3.42 General discussion 197 Next, contemporary trials often require optimization of background HF medical and device therapy to demonstrate incremental benefit of new treatments. We showed that half of HFrEF trials registered in Clinicaltrials.gov required patients to be on ‘standard’ or ‘optimal’ medical therapy of which a quarter specifically mentioned RAS antagonists and beta-blockers and ten percent required background MRA regimen. The fact that majority do not explicitly define optimal therapy in the inclusion criterion signals the difficulty of identifying a single standard treatment. Doses aside, RAS antagonists and BB are widely implemented in practice with almost 90% of patients who are treated with double therapy.38 However, optimization to target doses has been exceedingly challenging, illustrated by futility of the GUIDE-IT trial for HF treatment intensification.57 Despite a protocol-driven approach by experienced HF cardiologists, only 15.5% of patients were optimized on GDMTs at 6 months.57 Reasons for not adjusting therapy include clinical stability and maximally tolerated therapy achieved, which raises the question of whether present GDMT goals were unrealistic to implement.57 In view of variations in availability, affordability and tolerability between populations, it is therefore time to re-think whether mandating background treatment, for instance a four-drug class approach58 is overly idealistic;59 especially when uptake of newer therapies such as sacubitril/valsartan and SGLT2i have been slow.60 Rather than restricting eligibility based on an ambiguous criterion of ‘standard background GDMT’, trial designers can measure the extent of background treatment on a scale such as one defined by the Heart Failure Collaboratory58 and model this information in the analysis as a probability for the outcome or trial membership or both.28 Data framework and analytic methods: the means to reach generalizable evidence Large collaborative consortia such as the Innovative Medicines Initiative BigData@Heart consortium facilitated sharing of individual-level HFrEF clinical trial data across multiple industry partners, setting in motion collaborations historically impeded by conflicts of commercial interest.61–63 Within this partnership, researchers from an academic university, UMC Utrecht formed the analytic center for pooled individual-level analyses of data from six pharmaceutical and academic partners. Target population data can be derived from patient registries, electronic health records (EHR) and administrative claims or billing databases. HF registries including
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