• Heart Failure Clinical Trials

• Heart Failure
• Cardiology
• Cardiology Clinical Trials

Clinical outcomes, including mortality, are improved with the use of a dual angiotensin receptor blocker-neprilysin inhibitor (ARNI), LCZ696, compared with the existing gold standard in the treatment of patients with chronic heart failure (CHF). John McMurray, MD, discussed findings and insights from a study that evaluated the efficacy and safety of LCZ696 vs enalapril on the morbidity and mortality of patients with CHF-namely, the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial [PARADIGM-HF; McMurray JJV et al. N Engl J Med. 2014].

The finding represents a new way to attack the physiologic basis of CHF, according to Dr McMurray. The current treatment strategy targets inhibition of harmful neurohumoral pathways to slow progression of heart failure (HF) through the use of drugs that inhibit the renin-angiotensin-aldosterone system and the sympathetic nervous system. In addition to harmful neurohumoral systems in CHF, other neurohumoral pathways promote sodium and water excretion and have growth-inhibiting properties. The new paradigm in CHF treatment lies in inhibiting detrimental neurohumoral pathways while augmenting the potentially beneficial neurohumoral pathways. The ARNI LCZ696 does both, inhibiting the renin-angiotensin-aldosterone system while augmenting natriuretic peptides and other vasoactive substances, such as bradykinin and substance P.

In PARADIGM-HF, 8442 patients with class NYHA II to IV symptoms, an elevated level of plasma brain-type natriuretic peptide or N-terminal fragment of the prohormone brain-type natriuretic peptide, and an ejection fraction ≤ 40% were randomized in a 1:1 ratio to either LCZ696 (200 mg, BID) or enalapril (10 mg, BID) in addition to other standard CHF therapy. Enalapril was chosen because it was the angiotensin-converting enzyme inhibitor demonstrated to reduce mortality and hospitalization of patients with CHF with reduced ejection fraction in the SOLVD-T trial [SOLVD Investigators. N Engl J Med. 1991].

The trial was scheduled to conclude around October 2014, but the Data Monitoring Committee recommended stopping it in March 2014 because of an overwhelmingly statistically significant benefit in favor of LCZ696 on (1) the primary composite end point of death from cardiovascular (CV) causes or first hospitalization for HF and (2) the major secondary end point of CV mortality. After a median follow-up of 27 months, the primary composite outcome had occurred in 21.8% of the LCZ696 group and 26.5% of the enalapril group (HR, 0.80; 95% CI, 0.73 to 0.87; P = .0000004).

Compared with enalapril, LCZ696 reduced the risk of death from CV causes by 20% (P < .001) and the risk of hospitalization for HF by 21% (P < .001). The rate of all-cause mortality was reduced from 19.8% with enalapril to 17.0% with LCZ696, a 16% reduction (P < .001). The effect of LCZ696 vs enalapril on mortality was larger than the effect that enalapril had when compared with placebo in SOLVD-T.

LCZ696 had a significantly favorable effect over enalapril on other end points, including all hospital admissions, CV-related hospital admissions, the number of emergency room visits, the need for device implantation, and the number of patients developing renal dysfunction. Patients randomized to LCZ696 who were admitted to the hospital were less likely than hospitalized enalapril patients to be admitted to an intensive care unit.

Patients randomized to LCZ696 had more symptomatic hypotension when compared with those randomized to enalapril (P < .001), but hypotension rarely required discontinuation of LCZ696. Fewer patients in the LCZ696 group vs the enalapril group stopped their study medication due to an adverse event (10.7% vs 12.3%; P = .03). Unlike the combination of a neprilysin inhibitor and an angiotensin-converting enzyme inhibitor, known to cause serious angioedema, there was no increased risk of serious angioedema with the ARNI when compared with enalapril.

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