{"doi":"10.1002/ejhf.1816","title":"With Great Power Comes Great … Reliability","abstract":"This article refers to ‘Mega-trials in heart failure: effects of dilution in examination of new therapies’ by B.A. Davison et al., published in this issue on pages 1698–1707. The sheer number of medical ailments that afflict humans far surpasses our ability to effectively alter the natural course of most diseases. Yet, modern evidence-based medicine has catapulted remarkable gains for both the prevention and chronic management of cardiovascular diseases. The recognition of smoking, hypertension, diabetes, and dyslipidaemia as strong modifiable atherosclerotic risk factors has slowly decreased rates of cardiovascular diseases and in turn have contributed to the overall improvement in population health. Nowhere is this more evident than in the management of chronic heart failure with reduced ejection fraction (HFrEF), where we now have over a dozen therapeutic options to improve quality of life and reduce morbidity and mortality1 (Figure 1). While a number of medical therapies – even after potentially promising signals in Phase II studies – failed to demonstrate benefits in large-scale trials in HFrEF, the benefits demonstrated in successful trials for chronic HFrEF have been reproduced in subsequent trials using other agents in the same pharmacologic class. These evidence-based medical therapies provide sequential incremental clinical benefits without noted heterogeneity across a multitude of subgroups of patients based on demographics, comorbidities, or severity of disease, enrolled in the landmark trials.1, 2 Treatment benefits stratified by severity estimated using validated risk scores report relative risk reductions of similar magnitude for treatment compared to placebo without important heterogeneity.3, 4 Although clinical trials may enrol a selective HFrEF patient population than those in routine clinical practice, similar relative risk reductions are observed in clinical effectiveness studies of registry populations with guideline-directed medical therapies, despite higher baseline risk and comorbidity burdens.5 In contrast to the success in demonstrating benefits with multiple medications for HFrEF, there has been consistent failure to identify therapies which improve outcomes for patients hospitalized with acute heart failure (AHF) or heart failure with preserved ejection fraction (HFpEF). Several theories have been put forth to explain these trends. For AHF, some of the early failures were attributed to initiating study medications too late after initial presentation, allowing patients with lower blood pressure to be enrolled, not identifying optimal doses of study medications, or using unreliable survey instruments to measure changes in symptoms. Subsequent trials attempting to target more defined patient populations and administer treatment soon after presentation were also unsuccessful. Questions have been raised as to whether AHF represents a distinct entity that requires acute intervention beyond intravenous diuretics and whether any short-term infusion of medication could meaningful improve clinical outcomes.6 In this respect, it is interesting to note that initiating chronic guideline-directed medical therapy sacubitril/valsartan in AHF patients with HFrEF did result in improved post-discharge outcomes. For HFpEF trials, the lack of success has been attributed to the incomplete understanding of the pathophysiology of the disease state, marked heterogeneity among patients, inadequate phenotyping, unreliable surrogate markers, trials which may have enrolled patients that did not actually have HFpEF, as well as having not yet tested therapies with sufficient efficacy to improve outcomes. In this issue of the Journal, Davison et al.7 theorize that larger and larger trial sizes have led to the ‘dilution of statistical power.’ Furthermore, the lack of success of medical treatments for HFpEF and AHF may be secondary to these trial design decisions. They then use study simulations to examine the probability that a pos","journal":"European Journal of Heart Failure","year":2020,"id":129365,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":49613,"name":"Javed Butler","orcid":"0000-0001-7683-4720","position":1,"is_corresponding":false},{"id":97058,"name":"Gregg C. Fonarow","orcid":"0000-0002-3192-8093","position":2,"is_corresponding":false},{"id":256542,"name":"Boback Ziaeian","orcid":"0000-0001-9787-3649","position":0,"is_corresponding":true}],"reference_count":19,"raw_metadata":null,"created_at":"2026-07-18T23:15:45.920615Z","pmid":"32301141","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}