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Benefit of new HF agent over existing treatment consistent across ages

Literature - Jhund PS et al., Eur Heart J. 2015

Jhund PS, Fu M, Bayram E et al., PARADIGM-HF Investigators and Committees
Eur Heart J. 2015 Jul 31. pii: ehv330. [Epub ahead of print]


While heart failure (HF) is generally considered a condition of the elderly in Western societies, patients with HF in for instance Asia and Latin America are often much younger. This partly explains why patients with HF in large international trials are often a decade or more younger than patients in clinical practice in the northern hemisphere. In addition, comorbidities may cause elderly patients to be excluded from trial enrolment.
This analysis studied outcomes according to age in the Prospective comparison of angiotensin receptor neprilysin inhibitor (ARNI) with angiotensin converting enzyme inhibitor to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). In PARADIGM, 8399 patients aged 18-96 years old (mean age 63.8 years), from 47 countries, were randomised to treatment with enalapril 10 mg twice daily or the ARNI LCZ696 (sacubitril-valsartan) 200 mg twice daily  [1-3]. The following age categories were distinguished: <55, 55-64, 65-74 and >75 years.

Main results

  • The effect of LCZ696 vs. enalapril on the unadjusted incidence of the primary composite outcome of CV death or hospitalisation for HF (HFH) did not show a significant interaction with age category (P-interaction=0.94, with HR: 0.78 (95%CI: 0.64-0.96), HR: 0.76 (0.65-0.90), HR: 0.80 (0.68-0.93), and HR: 0.86 (0.71-1.04) for the respective age categories).
  • The effect of LCZ696 on rate of CV death as compared with enalapril was consistent across the age spectrum (P-interaction=0.94), as was its effect on HFH (P-interaction=0.81).
  • All-cause mortality was relatively high in the youngest group. In the other age categories, rate of death increased with increasing age. The effect of LCZ696 vs. enalapril was consistent with age.
  • Fractional polynomial analysis of the effect of LCZ696 vs. enalapril with age as a continuous variable, showed that risks in LCZ696-treated patients was lower than in the enalapril group across the age spectrum, except for CV mortality and the composite of CV mortality and HFH in the eldest group (95%CIs were wide).
  • The benefit of LCZ696 vs. enalapril in preventing worsening of Kansas City Cardiomyopathy Questionnaire score was consistent across the age groups (P-interaction=0.90).
  • Adverse effects of treatment generally were more common with increasing age, but the gradient was modest. Although symptomatic hypotension occurred more often in the LCZ696 group than the enalapril group, study drug discontinuation due to hypotension was uncommon. Adverse event reasons for discontinuation were not related to age. 


In PARADIGM-HF, the benefit of ARNI LCZ696 over enalapril was consistent across all age categories examined, although the rate of death and hospitalisation for HF increased with age and while older patients differed in many ways from their younger counterparts.

Find this article online at Eur Heart J


1. 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.
2. 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.
3. Packer M, McMurray JJ, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation 2015;131:54–61.

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