• Cardiology Clinical Trials
• Cardiology
• Heart Failure

• Cardiology Clinical Trials
• Heart Failure

A greater reduction in cardiovascular (CV) death or heart failure (HF) hospitalization was achieved with an investigational drug, LCZ696, than with enalapril, an angiotensin-converting enzyme (ACE) inhibitor representing the gold standard treatment for HF that has been shown to reduce CV mortality in patients with HF with reduced ejection fraction (HFrEF) on top of optimal medical therapy in a large-scale, international, double-blind clinical trial. The trial was terminated early because of the improvement in CV death.

LCZ696 is an angiotensin receptor neprilysin inhibitor (ARNI), which combines a neprilysin inhibitor and the angiotensin receptor blocker (ARB) valsartan, to simultaneously counteract maladaptive mechanisms caused by degradation of vasoactive peptides by neprilysin and deficiencies in the endogenous adaptive elements in H F, stated Milton Packer, MD, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

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. Published online August 30, 2014] randomized patients with clinically stable NYHA class II to IV H F, left ventricular ejection fractions (LVEFs) ≤ 40%, and modestly increased levels of brain natriuretic peptide (≥ 150 pg/mL) after a 2-week run-in phase to LCZ696 200 mg BID (n = 4212) or enalapril 10 mg BID (n = 4187). During the run-in, patients were switched from their current ACE inhibitor or ARB to enalapril 10 mg BID for 2 weeks, and then, to ensure tolerance of both drugs, LCZ696 was added at escalating doses (100 mg BID for 2 weeks, then 200 mg BID for 2 weeks).

The median follow-up period was 27 months, and the average daily doses at the last visit were LCZ696 375 mg and enalapril 18.9 mg. The patients were representative of patients with HF seen in the general community. They were aged 63.8 years, 22% were women, 60% had ischemic cardiomyopathy, and the LVEF was ∼ 30%.

The results for the composite primary end point of CV death or HF hospitalization, for its components, and the secondary end point of all-cause mortality are detailed in Table 1. For all prespecified subgroups, LCZ696 was more effective than enalapril in reducing primary end point events and CV mortality.

Quality of life as measured by the Kansas City Cardiomyopathy Questionnaire at 8 months was significantly improved with LCZ696 versus enalapril (P = .001). There was no significant difference between the groups for new-onset atrial fibrillation (HR, 0.97; 95% CI, 0.72 to 1.31; P = .84) or protocol-defined decline in renal function (HR, 0.86; 95% CI, 0.65 to 1.13; P = .28).

Regarding safety, more patients in the enalapril group than the LCZ696 group discontinued treatment because of hypotension, hyperkalemia, or worsening renal function, and blinded, adjudicated angioedema was similar in the 2 groups (Table 2).

Dr Packer stated that LCZ696 was more effective than guideline-recommended doses of enalapril in patients with HFrEF to reduce all-cause mortality and CV death, the symptoms and physical limitations of HF, and the risk for HF hospitalization. LCZ696 was better tolerated and less likely to be discontinued because of an adverse event than enalapril. The rates of cough, hyperkalemia, and renal impairment were lower with LCZ696 than with enalapril, as was drug discontinuation for hypotension. The reduction in CV mortality with LCZ696 over enalapril was similar to that achieved when an ACE inhibitor is compared with placebo, indicating that LCZ696 doubles the effect of ACE inhibitors on CV death. These results provide robust support for using the novel drug instead of an ACE inhibitor or ARB, he stated.

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