Risk and risk reduction in trials of heart failure with reduced ejection fraction: absolute or relative?
Bibliographic record
Abstract
Randomized clinical trials (RCTs) of heart failure with reduced ejection fraction (HFrEF) typically recruit patients at high risk of clinical outcomes during the follow-up period by including those with severe symptoms, comorbidities, elevated cardiac biomarkers, or a recent hospitalization. 1 By recruiting patients who will likely respond to the intervention and commonly experience outcomes without it, trials can demonstrate treatment efficacy with smaller sample sizes or shorter periods of follow-up.For example, in the CONSENSUS RCT of enalapril in patients with severe symptoms, 253 enrolled patients demonstrated a 40% relative risk reduction (RRR) in 6-month mortality.2 In contrast, in the SOLVD trial of enalapril in younger patients with less severe symptoms, 2569 patients were enrolled to demonstrate a 16% RRR in 4-year mortality 3 (Table 1).Some have argued that recruiting high-risk patients in an RCT can have drawbacks -patients may be too advanced in their disease trajectory for treatment to improve physiologic and clinical endpoints.4 Another concern is that higher-risk patients may experience adverse effects more commonly.The VICTO-RIA trial showed that vericiguat caused a 10% RRR [hazard ratio (HR) 0.90; 95% confidence interval (CI) 0.82, 0.98] in the composite endpoint of cardiovascular death or heart failure hospitalization.5 VICTORIA enrolled higher-risk patients (37.8 events/100 patient-years) than a majority of pharmacotherapy trials in patients with HFrEF, a reason proposed by some to explain its modest effect; the absolute risk reduction (ARR) (3.0%) and RRR were lower than in the PARADIGM-HF trial, which recruited lower-risk patients (13.2 events/100 patient-years) and demonstrated that sacubitril-valsartan caused a RRR of 20% (HR 0.80; 95% CI 0.73, 0.87) and ARR of 4.7 vs. enalapril on the same composite endpoint.6 Furthermore, subgroup analysis in a few HFrEF trials demonstrated the possibility of attenuated treatment effect in higher-risk patients.[6][7][8] To some, this evidence represents the possibility of a risk threshold within RCTs beyond which pharmacotherapies may provide minimal incremental benefit.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.098 | 0.159 |
| Meta-epidemiology (narrow) | 0.003 | 0.002 |
| Meta-epidemiology (broad) | 0.013 | 0.015 |
| Bibliometrics | 0.003 | 0.003 |
| Science and technology studies | 0.001 | 0.003 |
| Scholarly communication | 0.005 | 0.006 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.006 | 0.009 |
| Insufficient payload (model declined to judge) | 0.009 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".