Across 46 European CTIS heart-failure Phase II and Phase III trial records authorised in 2024–2026, the most frequent endpoint family was heart-failure hospitalisation, HF events, urgent HF visits, or clinical worsening, measured in 30 records (65.2%). Mortality or cardiovascular death appeared in 28 records (60.9%), while KCCQ/quality-of-life and safety/tolerability endpoints each appeared in 21 records (45.7%). Phase III trials were dominated by hard clinical outcomes, while Phase II trials relied more on safety, NT-proBNP, imaging, functional capacity, and exploratory biomarker packages.
HF hospitalisation, HF events, urgent visits, or clinical worsening appeared in 30 of 46 records (65.2%). Mortality, cardiovascular death, or all-cause death appeared in 28 of 46 records (60.9%), ahead of KCCQ/quality of life and safety/tolerability, each present in 21 of 46 records (45.7%).
For European CTIS heart-failure submissions, the most reusable endpoint architecture is still outcomes-first: HF hospitalisation/clinical worsening plus death/CV death. Patient-reported health status, safety, natriuretic peptides, renal function, and imaging are frequent but usually supportive rather than dominant.
Primary endpoints most often measured mortality/CV death in 23 of 46 records (50.0%) and HF event or clinical-worsening outcomes in 22 of 46 records (47.8%). Secondary endpoints repeated these outcomes but added KCCQ in 19 records (41.3%), safety in 15 records (32.6%), imaging in 15 records (32.6%), and NT-proBNP/BNP in 14 records (30.4%).
| Endpoint family | Primary | Secondary | Exploratory / other |
|---|---|---|---|
| Mortality / CV death | 23 / 46 | 24 / 46 | 0 / 46 |
| HF event / worsening | 22 / 46 | 22 / 46 | 1 / 46 |
| KCCQ / quality of life | 5 / 46 | 19 / 46 | 1 / 46 |
| Safety / tolerability | 10 / 46 | 15 / 46 | 1 / 46 |
| NT-proBNP / BNP | 5 / 46 | 14 / 46 | 0 / 46 |
| Renal function | 7 / 46 | 14 / 46 | 2 / 46 |
| Cardiac imaging | 6 / 46 | 15 / 46 | 1 / 46 |
For CTIS protocol design, mortality/CV death and HF events are the most defensible primary endpoint anchors. KCCQ, NT-proBNP, imaging, renal function, NYHA class, and 6MWD are more often used to support mechanism, health status, and clinical relevance rather than carry the primary claim.
Among 18 Phase II records, safety/tolerability was the leading endpoint family at 12 of 18 records (66.7%), followed by NT-proBNP/BNP in 9 of 18 (50.0%) and cardiac imaging in 8 of 18 (44.4%). Among 28 Phase III records, HF event/clinical-worsening endpoints appeared in 24 of 28 (85.7%) and mortality/CV death in 23 of 28 (82.1%).
The operational burden shifts sharply between phases. Phase II submissions need dense safety, biomarker, imaging, and functional-readout capture, while Phase III submissions need adjudicated event workflows, hospitalisation capture, mortality follow-up, and KCCQ/renal support endpoints.
The most common sub-disease group was generic or unspecified heart failure in 21 of 46 records (45.7%), followed by HFpEF in 10 records (21.7%), HFrEF in 9 records (19.6%), and HFmrEF in 6 records (13.0%). HFpEF records split between HF outcomes and KCCQ at 5 of 10 each (50.0%), HFrEF most often used KCCQ in 6 of 9 (66.7%), and HFmrEF most often used HF events, mortality, and KCCQ at 4 of 6 each (66.7%).
| Subgroup | Records | Top endpoint family | Frequency |
|---|---|---|---|
| Generic / unspecified HF | 21 | HF events and mortality | 14 / 21 each |
| HFpEF | 10 | HF events and KCCQ | 5 / 10 each |
| HFrEF | 9 | KCCQ | 6 / 9 |
| HFmrEF | 6 | HF events, mortality, KCCQ | 4 / 6 each |
HFpEF and HFmrEF programs retain heavy health-status endpoint use, while HFrEF records in this cohort frequently combine KCCQ with HF events and mortality. The smaller acute HF, pulmonary hypertension, obesity, CKD, and LV-hypertrophy subsets were visible but not large enough for robust endpoint-pattern comparison.
Small molecules were the only large modality group, appearing in 31 of 46 records (67.4%). In small-molecule records, HF event/clinical-worsening endpoints appeared in 23 of 31 (74.2%) and mortality/CV death in 22 of 31 (71.0%). Peptide/protein/enzyme records were smaller at 5 of 46 (10.9%) and were led by safety endpoints in 3 of 5 records (60.0%).
Small molecules define the core European HF endpoint benchmark in this cohort. Advanced modalities such as gene therapy, cell therapy, RNA, and oligonucleotides appeared, but their record counts were too small for stable modality-specific endpoint benchmarking.
The 46 CTIS heart-failure records were distributed across 2024, 2025, and 2026 authorisation-year slices: 24 records in 2024 (52.2%), 17 in 2025 (37.0%), and 5 in 2026 (10.9%). Phase III represented 28 of 46 records (60.9%) and carried the strongest need for hospitalisation, death, recurrent-event, and adjudicated cardiovascular outcome capture.
| Year | Phase II | Phase III | Total |
|---|---|---|---|
| 2024 | 9 | 15 | 24 |
| 2025 | 7 | 10 | 17 |
| 2026 | 2 | 3 | 5 |
For EU/CTIS submissions, Phase III heart-failure protocols should pre-specify event definitions, hospitalisation logic, death classification, recurrent-event handling, adjudication, and KCCQ timing clearly. Phase II protocols should justify biomarker, imaging, 6MWD, NYHA, PK/PD, and safety schedules because those endpoint families drive the early-signal package.
HF event endpoints include heart-failure hospitalisation, urgent HF visit, clinical worsening, total HF events, first HF event, or recurrent HF events. KCCQ means Kansas City Cardiomyopathy Questionnaire. NT-proBNP/BNP means natriuretic-peptide biomarker endpoints. 6MWD/6MWT means six-minute walk distance/test. NYHA means New York Heart Association functional class. MACE means major adverse cardiovascular events, usually including cardiovascular death, myocardial infarction, stroke, and related ischemic events.