Physicians' Academy for Cardiovascular Education

New expanded composite endpoint is suggested for HF studies

Okumura N, et al. Circulation 2016


Importance of Clinical Worsening of Heart Failure Treated in the Outpatient Setting
Evidence From the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF)


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

Background

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)


Conclusion

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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References

1. Ahmed A, Allman RM, Fonarow GC, et al. Incident heart failure hospitalization and subsequent mortality in chronic heart failure: a propensity-matched study. J Card Fail. 2008;14:211–218.
2. McMurray JJ, Petrie MC, Murdoch DR, et al. Clinical epidemiology of heart failure: public and private health burden. Eur Heart J.1998;19(suppl P):P9–16.
3. Zannad F, Garcia AA, Anker SD, et al. Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document. Eur J Heart Fail. 2013;15:1082–1094.
4. Vidic A, Chibnall JT, Hauptman PJ. Heart failure is a major contributor to hospital readmission penalties. J Card Fail. 2015;21:134–137.
5. Huesch MD, Ong MK, Fonarow GC. Measuring heart failure care by 30-day readmission: rethinking the quality of outcome measures. Am Heart J. 2013;166:605–610.e2.
6. Ezekowitz JA, Kaul P, Bakal JA, et al. Trends in heart failure care: has the incident diagnosis of heart failure shifted from the hospital to the emergency department and outpatient clinics? Eur J Heart
Fail. 2011;13:142–147.
7. Blecker S, Ladapo JA, Doran KM, et al. Emergency department visits for heart failure and subsequent hospitalization or observation unit admission. Am Heart J. 2014;168:901–8.e1.
8. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Committees and Investigators. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail. 2013;15:1062–1073.
9. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.
10. Packer M, McMurray JJ, Desai AS; PARADIGM-HF Investigators and Coordinators. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131:54–61.