New drug LCZ696 superior to enalapril in heart failure treatment

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Findings from the PARADIGM-HF trial have found that the investigational medicine LCZ696 (Novartis) cuts cardiovascular deaths by 20% compared to ACE inhibitor enalapril in heart failure patients with reduced ejection fraction. The trial also found reduced heart failure hospitalisations (21%) and reduced risk of all-cause mortality (16%) with LCZ696.

The results, presented by Milton Packer, co-primary investigator of the study, (University of Texas Southwestern Medical Center, Dallas, USA) at the European Society of Cardiology congress (ESC; Barcelona, Spain, 30 August – 3 September), were simultaneously published in the New England Journal of Medicine.

Packer told delegates that these results “are extraordinarily powerful and compelling; they are destined to change the management of patients with chronic heart failure for years to come.”


LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNI), has already been granted Fast Track status by the United States Food and Drug Administration (FDA)-a designation which can expedite the review of new medicines intended to treat serious or life-threatening conditions. Fast Track designation also allows for rolling submission in the USA, which Novartis said it expects to complete by the end of 2014. The company said it aims to file in Europe in early 2015.


PARADIGM-HF (Prospective comparison of ARNI with angiotensin converting-enzyme inhibitors (ACEI) to determine impact on global mortality and morbidity in heart failure), the largest heart failure study ever done, randomised 8,399 patients with class II to IV heart failure and an ejection fraction of 40% or less to either LCZ696 200mg twice daily (n=4,187), or enalapril 10mg twice daily (n=4,212), in addition to recommended therapy.

“Given the survival advantage of LCZ696 over currently available drugs, once this drug becomes available, it would be difficult to understand why physicians would continue to use traditional angiotensin converting-enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) for the treatment of heart failure,” said Packer.

“The magnitude of the advantage of LCZ696 over enalapril on cardiovascular mortality was at least as large as that of enalapril over placebo during long-term treatment,” Packer reported. “This robust finding provides strong support for using this new approach instead of ACE inhibitors or ARBs in the treatment of chronic heart failure.”

Compared to enalapril, LCZ696 reduced the risk of death from cardiovascular causes by 20% (13.3% vs 16.5%; HR 0.80; p<0.0001), and the risk of hospitalisation for heart failure by 21% (12.8% vs 15.6%; HR 0.79; p<0.0001), noted Packer. This effect was consistent across all prespecified subgroups.

Secondary outcomes were also significantly improved by LCZ696, including all-cause mortality (17.0% vs 19.8%; HR 0.84; p<0.001) and symptoms and physical limitations of heart failure measured on the Kansas City Cardiomyopathy Questionnaire (p=0.001).

Analysis of the safety data from PARADIGM-HF showed that fewer patients on LCZ696 discontinued study medication for any adverse event compared to those on enalapril (10.7% vs 12.3%, respectively, p=0.03). The LCZ696 group had more hypotension although this did not lead to greater discontinuation of therapy. The LCZ696 group had less renal impairment, hyperkalemia and cough than the enalapril group. There was no statistically significant difference in angioedema between the two groups.


Michel Komajda (Université Pierre & Marie Curie Hôpital Pitié-Salpêtrière, ICAN Institute, Paris, France), discussant of the study at ESC, questioned whether based on the results of this trial a major change will occur in the international guidelines for the management of chronic heart failure. “This trial is the first to propose a substitution rather than an add-on strategy in chronic heart failure,” he noted.

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