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To qualify for an even earlier halt Entresto will need to show superiority on both the primary endpoint and cardiovascular death at a one-sided statistical significance level of 0.001 or less.īecause Novartis does not believe that Entresto will show a benefit on cardiovascular death at the interim look it expects the trial to proceed to final analysis in 2019, where the pill will need to show superiority below a one-sided statistical significance level of 0.025. The interim analysis will take place after about two thirds of the expected 1,847 cardiovascular events have occurred, which is due by the end of 2018.
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Secondary endpoints are all-cause mortality, change in New York Heart Association functional class, renal outcomes, and change in score on the Kansas City cardiomyopathy questionnaire. The trial has randomised 4,800 patients to treatment with either Entresto or Diovan, comparing the two on a composite endpoint of cardiovascular death or heart failure hospitalisation. Still, Paragon will have to clear a pretty high bar to be stopped this year. While expectations for an interim win in Paragon-HF are low, it should be remembered that Entresto’s first pivotal trial, in heart failure patients with reduced ejection fraction, was halted because it showed early superiority to Vasotec in keeping heart disease patients alive and out of hospital ( Novartis gets surprise heart failure win as ACC data roll in, March 31, 2014). Still, Novartis executives and investors expect the study to continue to a final readout in 2019 the company believes that the new indication could add $1bn in annual sales. The Paragon-HF trial in patients with preserved ejection fraction is due for an interim analysis sometime in the next few months, and if Entresto beats Diovan with a high level of statistical significance the trial could be halted for efficacy. One month's treatment at the target dosage costs $583.00.Entresto’s painfully sluggish launch has at last started to gain momentum, and expansion into a less severe form of heart failure could add some thrust to Novartis’s biggest growth driver.
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Entresto is not recommended for patients with severe hepatic impairment. In patients who had not been taking an ACE inhibitor or an ARB, or in those with severe renal impairment (eGFR <30 mL/min/1.73 m 2) or moderate hepatic impairment, the recommended starting dosage of Entresto is 24/26 mg twice daily. ACE inhibitor treatment should be discontinued 36 hours before starting Entresto. The dose should be doubled every 2-4 weeks as tolerated to reach a final dose of 97/103 mg. 2 Although statistical significance was narrowly missed, subgroup analyses suggested that sacubitril/valsartan showed benefit in patients with LVEF 45-57% and in women.ĭOSAGE - The recommended starting dosage of sacubitril/valsartan in adults is 49/51 mg twice daily. After a median follow-up of 35 months, there were 894 primary events in 526 patients randomized to receive sacubitril/valsartan 97/103 mg twice daily and 1009 primary events in 557 patients randomized to receive valsartan 160 mg twice daily (RR 0.87 95% CI 0.75-1.01). The primary endpoint was a composite of total hospitalizations for heart failure and cardiovascular death. TYPES OF HF - Almost half of all patients with heart failure have HFrEF, almost half have heart failure with preserved ejection fraction (HFpEF LVEF ≥50%), and the rest have heart failure with mid-range ejection fraction (HFmrEF LVEF 41-49%).ĬLINICAL STUDY - FDA approval of the expanded indication for Entresto was based on the results of a double-blind trial (PARAGON-HF) in 4822 patients with NYHA class II-IV heart failure, LVEF ≥45%, elevated levels of natriuretic peptides, and structural heart disease.
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Entresto is the first drug to be approved in the US for this indication. 1 The indication has now been expanded to include patients with chronic heart failure with any LVEF the label specifies that benefits are most clearly evident in patients with LVEF below normal. The oral fixed-dose combination of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker (ARB) valsartan ( Entresto – Novartis) was approved by the FDA in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction (HFrEF LVEF <40%).