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New expanded composite endpoint is suggested for HF studies

Literature - Okumura N, et al. Circulation 2016

Okumura N, Jhund PS, Gong J, et al.
Circulation. 2016;133:2254-2262


The deterioration of heart failure (HF) symptoms and signs and the subsequent need for hospitalisation indicates a higher risk of hospital readmission and death, and is related with high costs for patients and the health care system [1,2]. Numbers related to 30-day HF rehospitalisation are used as clinical trial end points and consist a quality measure of care and reimbursement in the US [3-5]. As a result, episodes of worsening HF are also treated in the community or in non-ward-based settings without hospitalisation, although the frequency and the prognostic implications of such care are not known [6,7]. 
In this study, the occurrence and significance of non-hospitalised worsening HF was evaluated in the PARADIGM-HF (Prospective Comparison of angiotensin-receptor-neprilysin inhibitor with angiotensin-converting enzyme inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial [8-10]. Moreover, the potential value of non-hospitalised worsening HF events (intensification of therapy or ED visit) in an expanded composite endpoint for future clinical trials was investigated.

Main results

Out of the 8399 patients randomised:
  • 1124 (13.4%) were treated in an outpatient setting
  • 250 (3.0%) visited an emergency department (ED)
  • 1195 (14.2%) were hospitalised for worsening HF
  • 1251 (14.9%) died of a cardiovascular (CV) event
  • 1546 (18.4%) died of any cause
  • 763 (9.1%) died of a CV event without previous hospitalisation, ED visit, or intensification of therapy
  • 361 patients (4.3%) had intensification of therapy without a subsequent ED visit, hospital admission for HF, or CV death within 30 days
  • 78 (1.0%) visited an ED, with no previous intensification of therapy or subsequent hospital admission for worsening HF or CV death within 30 days
  • 1107 patients (13.2%) had worsening HF requiring hospitalisation without a previous ED visit or intensification of therapy
Examining mutually exclusive first nonfatal events, the number of patients without a subsequent nonfatal HF event or CV death during the trial period, were:
  • 223 (62% of 361) who had intensification of therapy
  • 52 (67% of 78) who experienced an ED visit
The number of patients who not experienced a nonfatal HF event or death of any cause was:
  • 203 (56% of 361) for those having intensification of therapy
  • 48 (62% of 78) for those having ED visits
The risk of death (in comparison with no-event patients after adjustment for treatment and region only) was similar after each of the 3 manifestations of worsening:
  • intensification of therapy (HR: 5.2; 95% CI: 4.2–6.3)
  • ED visit (HR: 4.5; 95% CI: 3.0–6.7)
  • hospitalisation for worsening HF (HR: 6.1; 95% CI: 5.4–6.8).
After adjustment, the risk of death remained 3 - 5 times higher in patients experiencing some manifestation of worsening, in comparison with those who did not.

Adding intensification of therapy and ED visits to the primary composite outcome (CV death or HF hospitalisation) of PARADIGM-HF resulted in approximately 14% additional primary events corresponding to:
  • 177 patients at 1 year of follow-up
  • 248 patients at 2 years of follow-up
  • 269 patients at 3 years of follow-up
The 1- and 2-year Kaplan–Meier event rates for the primary end point were 14.2% and 24.0%, respectively, in comparison with 16.5% and 27.5%, respectively, for the expanded composite.

Sacubitril/valsartan was superior to enalapril in reducing the risk of:
  • the primary composite outcome (HR: 0.80; 95% CI: 0.73–0.87)
  • CV death (HR: 0.80; 95% CI: 0.71–0.89)
  • hospitalisation for HF (HR: 0.79; 95% CI: 0.71–0.89).
  • the expanded composite end point (HR: 0.79; 95% CI: 0.73–0.86)


In the PARADIGM-HF trial, the HF hospitalisation endpoint underestimated the frequency of clinically worsening HF, since non-hospitalised worsening, including outpatient events and emergency department visits, were not taken into account as end points. These non-hospitalised worsening HF events were associated with a risk of subsequent death similar to that following HF hospitalisation, and should be included in primary end points of relevant clinical trials. The benefit of sacubitril/valsartan over enalapril for the expanded composite end point was similar to the primary outcome.

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