| Eligibility criteria |
Inclusion criteria should reflect pathophysiologically distinct patient populations, for example
Require echocardiographic evidence of diastolic dysfunction for therapies expected to impact cardiac structure or function Require reduced VO2 max or moderate limitation in 6 minute walk distance for therapies expected to improve exercise tolerance or patient-reported outcomes Use biomarker criteria to identify high-risk patients, or patients with evidence of a pathophysiological process (e.g. galectin-3 and cardiac fibrosis) Use the diagnostic potential of an (echo) stress test Require a higher LVEF threshhold (e.g. LVEF ≥50%) to avoid the confounding effects of HF-REF
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| Investigational intervention (device or drug) |
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| Sample size |
Targeted therapy may
Result in a greater treatment effect, or Reduce ‘noise’ of no effect, or Result in less variation on the treatment effect
These factors may decrease the required sample size, but little experience has accumulated regarding event rate or anticipated treatment effects in pathophysiologically distinct subgroups Phase II proof-of-concept studies will inform assumptions needed to determine sample size Proof-of-concept studies to identify the pathophysiological target other than clinical endpoints (e.g. resolving the thrombus in acute myocardial infarction) Adaptive designs that prospectively plan interim analyses with the purpose of determining whether aspects of study design require modification (e.g. sample size)168 may also be considered
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| Endpoint selection |
Consider cardiovascular-specific endpoints as primary (e.g. cardiovascular mortality) Consider repeat (HF) hospitalizations Consider all-cause endpoints for safety Symptom relief, quality of life, and other patient-reported outcomes should be a key primary or secondary endpoint in HF-PEF trials Improvement in measures of exercise capacity Consider changes in biomarkers with known information on severity of disease and outcome
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