No new drug for systolic heart failure (HF) has been approved by the FDA for more than a decade; the last one being eplerenone (an aldosterone antagonist) which was approved in 2003. In 2005 a combination drug of hydralazine –isosorbide dinitrate was cleared for (HF) for African Americans who persisted with symptoms despite evidence based treatment. Finally after so many years of research a new combination tablet has made head lines across the globe for significant reduction in mortality in HF patients already on standard treatment including 10 mg twice a day of enalapril. The novel drug has been given the rather mundane name of LCZ696, and consists of a combination of a neprilysin inhibitor (sacubitril) and the angiotensin receptor blocker (ARB) valsartan (160 mg).
The PARADIGM-‐HF (Prospective Comparison of ARNI [Angiotensin Receptor-‐Neprilysin Inhibitor] with ACEI (Angiotensin-‐Converting-‐Enzyme-‐Inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial), randomized trial presented in the AHA Meeting of 2014 and simultaneously published in the New England Journal of Medicine, showed significant lowering of deaths from any cause and deaths from cardiovascular causes plus hospitalization for HF. There was also significant improvement in quality of life with the new drug. The PARADIGM-‐HF trial concluded after randomizing 8442 patients in NYHA class II, III, IV HF and a left ventricle ejection fraction (LVEF) of 40% or less to LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily) in addition to standard treatment, that LCZ696 was superior to enalapril in reducing the risks of death and hospitalization for HF. The trial had to in fact be stopped early after 27 months because of overwhelmingly better results with LCZ696.
Angiotensin converting enzyme inhibitors (ACEI) have been used for systolic HF patients with reduced LVEF for a quarter of a century since the CONSENSUS (1987) and SOLVD (1991) trials demonstrated a significant reduction in deaths in HF patients by a relative 16 to 40%. These land mark trials established the preeminent position of ACEI’s in the treatment of systolic HF Enalapril was found to be superior to the combination of hydralazine and isosorbide dinitrate in the V-‐HeFT II study (1991). Renin-‐angiotensin-‐ aldosterone system (RAAS) inhibitors such as ACEI and ARB produce vasodilatation, reduce cardiac hypertrophy, and myocardial fibrosis. Angiotensin receptor blockers interfere with angiotensin II leading to vasodilatation and have also been found useful in treatment of HF but as they have not been observed to be superior to ACEI’s; ARB’s are prescribed for patients who are intolerant to ACEI’s. Beta-‐blockers (metoprolol-‐1999/ bisoprolol 1999/carvedilol 2001) and mineralocorticoid-‐ receptor antagonists (spironolactone-‐1999/eplerenone-‐2011) were found to provide incremental decrease in HF deaths by 30-‐ 35% and 22-‐30% when added to ACEI’s. The US Carvedilol Heart Failure Study (1996) and the COPERNICUS trial (2001) demonstrated significant improvement in symptoms and lowering of mortality in HF patients with carvedilol. Spironolactone was found to reduce mortality by 30% in HF patients already taking an ACEI and a loop diuretic in the RALES trial (1999); whereas eplerenone another mineralocorticoid receptor antagonist (MRA) was found significantly effective in the EMPHASIS-‐HF trial (2011), which included patients with HF but mild symptoms. It is important to remember that milrinone, a positive inotrope (and a phosphodiesterase inhibitor) that intuitively appears beneficial, was actually seen to increase deaths by 28% in the large PROMISE trial (1991).
Digoxin discovered to be effective in HF by William Withering more than 200 years ago may be used specifically to reduce hospitalization for heart failure (by 28%) only; because digoxin does not reduce mortality. Nesiritide, a recombinant B-‐type natriuretic peptide (given as intravenous infusion) that produces vasodilatation was approved for acute HF in 2001 for treating dyspnea. The ASCEND-‐HF trial in 2011 however showed no benefit with nesiritide in lowering death or re-‐hospitalization. Furthermore there was no improvement in dyspnea. Cardiac resynchronization therapy (CRT) using a biventricular pacemaker has also shown to significantly lower mortality, raise LVEF, better symptoms, and improve quality of life in patients with moderately severe HF. Quite a few randomized studies using this device have demonstrated substantial salutatory effects in HF; COMPANION (2004), CARE-‐HF (2005), MADIT-‐CRT (2009) AND RAFT (2010). The MADIT-‐CRT trial showed that as compared to an ICD alone, CRT plus ICD significantly reduced deaths in patients of HF with mild symptoms (NYHA II-‐III) in the presence of left bundle branch block and a QRS complex of at least 130 msec.
The largest study on HF is the PARADIGM-‐HF trial , that has demonstrated 20% reduction in cardiovascular mortality and 16% lowering of all cause deaths. The neprilysin blocker (sacubitril) in LCZ696 results in higher levels of natriuretic peptides that produce vasodilatation, reduce salt and water retention, and also modify left ventricle hypertrophy/fibrosis. Natriuretic peptides also inhibit the RAAS and the sympathetic drive. LCZ696 is a fixed dose combination of valsartan and a neprilysin inhibitor (secubitral) in a 1:1 ratio. Twelve percent of patients in both groups of the PARADIGM-‐HF trial withdrew in the run in phase because of adverse effects; during the trial fewer patients on LCZ696 stopped study medication. Seventy two percent of patients were in NYHA class II and 23% were in NYHA class III. Ischemic cardiomyopathy was present in 60% patients and the mean LVEF was 29% only. Beta-‐ blockers were being used by 93%, diuretic by 80%, an MRA by 55%, but only 7% had a CRT device implanted in them. The low numbers of CRT device are understandable because the majority of patients were in NYHA class II and this symptomatic state was not standard indication for CRT when patients for PARADIGM-‐HF were being enrolled. Albeit it is not absolutely clear in which patient group LCZ696 will be most effective, as it is not still certain in which patients an ACEI or beta-‐blocker would be most beneficial, we have at our disposal a new class of drug for HF therapy that has proven efficacy and has been found to be as safe as enalapril. The PARADIGM-‐HF trial should provide hope for millions of HF patients across the globe who suffer on a daily basis despite being on standard therapy, because the evidence provided by this trial is more than reasonable. LCZ696 will certainly not be the best HF drug or the final word in HF therapy but it could be a small step in the right direction. Mortality was seen in 17% patients on LCZ606 versus 20% on enalapril; an absolute reduction of 3%. It is imperative that the manufacturer keeps the cost of the drug affordable for patients in developing nations.