Cardiovascular · Clinical trials
Heart Failure with Preserved EF (HFpEF) Clinical Trials
Approved therapies, the pivotal-trial endpoints they were judged on, the magnitude of benefit — and the drugs that failed their endpoints, and why.
Indication overview
About heart failure with preserved ef (hfpef) — and why its trials are hard
Heart failure with preserved ejection fraction (HFpEF) is defined by signs and symptoms of heart failure with a left ventricular ejection fraction of 50% or higher (mildly reduced, 41-49%, is a related category). It accounts for roughly half of all heart failure and is driven by aging, hypertension, obesity, diabetes and atrial fibrillation, producing diastolic dysfunction and elevated filling pressures. For decades HFpEF was defined by therapeutic failure: renin-angiotensin blockers, mineralocorticoid antagonists and neprilysin inhibition all failed or narrowly missed their primary endpoints. The breakthrough came with SGLT2 inhibitors. EMPEROR-Preserved was the first trial to show a clear benefit, with empagliflozin reducing the composite of cardiovascular death or heart-failure hospitalization; DELIVER confirmed the class effect with dapagliflozin. These agents are now guideline-recommended across the ejection-fraction spectrum. Sacubitril/valsartan (PARAGON-HF) narrowly missed statistical significance but earned a broadened FDA indication. GLP-1 receptor agonists (semaglutide, STEP-HFpEF) show promise in obesity-related HFpEF. As the landmark first positive trial, EMPEROR-Preserved with empagliflozin holds precedence in this indication.
Approved therapies & pivotal evidence
What's been approved — and by how much it moved the endpoint
| Drug (brand) | Approved | Setting | Pivotal trial | Primary endpoint | Magnitude of benefit |
|---|---|---|---|---|---|
| Empagliflozin (Jardiance) | 2022 | HFpEF/heart failure across EF spectrum | EMPEROR-Preserved | Composite of CV death or hospitalization for heart failure | HR 0.79 (95% CI 0.69-0.90) vs placebo; benefit driven largely by reduced HF hospitalizations. First positive HFpEF outcome trial |
| Dapagliflozin (Farxiga) | 2023 | HFpEF/heart failure across EF spectrum | DELIVER | Composite of worsening heart failure or CV death | HR 0.82 (95% CI 0.73-0.92) vs placebo; consistent across EF and confirmed the SGLT2 class effect |
| Sacubitril/valsartan (Entresto) | 2021 | Broadened HF label including below-normal EF (mildly reduced/preserved) | PARAGON-HF | Composite of total HF hospitalizations and CV death | RR 0.87 (95% CI 0.75-1.01), narrowly missed significance (p=0.06); label expanded based on totality of evidence |
Where trials have failed
Drugs that missed their endpoint — and what contributed
The most instructive lessons in heart failure with preserved ef (hfpef) development come from programmes that failed the endpoint that mattered.
| Drug / trial | Endpoint outcome | What contributed |
|---|---|---|
| Spironolactone — TOPCAT | Missed the overall primary composite (CV death, aborted cardiac arrest, HF hospitalization) | Marked regional heterogeneity; benefit seen in the Americas but not in Russia/Georgia where drug-adherence and diagnosis were questioned, diluting the overall result |
| Irbesartan — I-PRESERVE | No reduction in death or CV hospitalization in HFpEF | ARB did not improve outcomes; reinforced that renin-angiotensin blockade alone is ineffective in HFpEF |
| Candesartan — CHARM-Preserved | Did not significantly reduce the primary CV death or HF hospitalization composite | Only a modest, non-significant effect on hospitalizations; underpowered for a definitive HFpEF benefit |
| Perindopril — PEP-CHF | Failed to show significant long-term benefit on the primary endpoint | High crossover to open-label ACE inhibitors and lower-than-expected event rates undermined power |
| Vericiguat — VITALITY-HFpEF | Did not improve physical limitation (KCCQ) or 6-minute walk distance | Soluble guanylate cyclase stimulation failed to improve symptoms in HFpEF despite benefit in reduced-EF (VICTORIA) |
Choosing the right endpoint
Primary endpoints that matter in heart failure with preserved ef (hfpef) trials
- Composite CV death or HF hospitalization — Primary endpoint in EMPEROR-Preserved and DELIVER; HF hospitalization typically drives the benefit
- Total (recurrent) HF hospitalizations — Captures repeat events; central to PARAGON-HF analysis
- KCCQ clinical summary score — Patient-reported health status; primary in symptom trials like VITALITY-HFpEF and STEP-HFpEF
- 6-minute walk distance — Functional capacity measure used as a co-primary in several HFpEF symptom studies
How iNGENū runs heart failure with preserved ef (hfpef) trials
Physician-led design, built for FDA submission
Endpoint & biomarker strategy
Board-certified specialists design endpoints and patient selection aligned to current FDA guidance for this indication.
FDA-ready data
Built to ICH-GCP and 21 CFR 312.120, with direct FDA submission — data accepted by the FDA, EMA and MHRA.
Faster, lower-cost delivery
~4-week ethics via the TGA CTN scheme, up to 43.5% R&D rebate, and 80–90% below US CRO cost.
Request a fixed-milestone proposal and a tailored endpoint & feasibility summary for this indication.
Frequently asked questions
Heart Failure with Preserved EF (HFpEF) clinical trials — FAQs
Which drug class finally worked in HFpEF?
Why is TOPCAT controversial?
Did Entresto succeed in HFpEF?
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