Physicians' Academy for Cardiovascular Education

PARAMOUNT: beneficial effects of ARNI inhibitor in Heart Failure pEF

Literature - Solomon SD et al; Lancet. 2012;380:1387-95

The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial.


Solomon SD, Zile M, Pieske B, et al; Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators.

Lancet. 2012;380:1387-95. doi: 10.1016/S0140-6736(12)61227-6.


Background:

Heart failure with preserved ejection fraction (HFpEF) is responsible for about half of the cases of heart failure and is associated with substantial morbidity and mortality [1-5]. Until now there was no treatment that improved clinical outcomes in this disease [6]. LCZ696 is the first angiotensin receptor neprisylin inhibitor that simultaneously inhibits the RAAS and increases the endogenous natriuretic peptide system, both of which may be beneficial in patients with heart failure.
The PARAMOUNT study is a phase II study in 301 patients from 13 countries in which the effects of the ARB valsartan LCZ696 on concentrations of natriuretic peptides were compared in patients with heart failure with preserved ejection fraction. The natriuretic peptide examined in this study, NT-proBNP, is a marker of left ventricular wall stress; levels are increased in patients with heart failure.


Results:

  • LCZ696 reduced the levels of NT-proBNP by 23% compared with valsartan (p = 0.005) (Fig. 1).
  • LCZ696 also reduced enlargement of the left atrium, another marker of adverse outcomes in heart failure, and improved the symptoms of heart failure (Fig. 2)
  • LCZ696 was well tolerated with fewer serious and overall adverse events than valsartan

Conclusion:

LCZ696 has potential beneficial effects in patients with heart failure with preserved ejection fraction; further research in these patients is recommended.

Figure 1.

NT-proBNP at 4, 12, and 36 weeks in the LCZ696 and valsartan groups

Figure 2

Changes in NYHA and clinical composite assessment showing percentage of patients who have worsened, remained unchanged, or improved for each measure.

NYHA=New York Heart Association


References

1. Fonarow GC, Stough WG, Abraham WT, et al; OPTIMIZE-HF Investigators and Hospitals. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol 2007; 50: 768–77.
2. Lam CS, Donal E, Kraigher-Krainer E, Vasan RS. Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur J Heart Fail 2011; 13: 18–28.
3. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006; 355: 260–69.
4. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355: 251–59.
5. Solomon SD, Anavekar N, Skali H, et al, Candesartan in Heart Failure Reduction in Mortality (CHARM) Investigators. Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients. Circulation 2005; 112: 3738–44.
6. Aurigemma GP, Gaasch WH. Clinical practice. Diastolic heart failure. N Engl J Med 2004; 351: 1097–105.


Abstract

Background:
Heart failure with preserved ejection fraction is associated with substantial morbidity and mortality, but effective treatments are lacking. We assessed the efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), in patients with this disorder.

Methods:
PARAMOUNT was a phase 2, randomised, parallel-group, double-blind multicentre trial in patients with New York Heart Association (NYHA) class II-III heart failure, left ventricular ejection fraction 45% or higher, and NT-proBNP greater than 400 pg/mL. Participants were randomly assigned (1:1) by central interactive voice response system to LCZ696 titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily, and treated for 36 weeks. Investigators and participants were masked to treatment assignment. The primary endpoint was change in NT-proBNP, a marker of left ventricular wall stress, from baseline to 12 weeks; analysis included all patients randomly assigned to treatment groups who had a baseline and at least one postbaseline assessment. This trial is registered at Clinicaltrials.gov, number NCT00887588.

Findings:
149 patients were randomly assigned to LCZ696 and 152 to valsartan; 134 in the LCZ696 group and 132 in the valsartan group were included in analysis of the primary endpoint. NT-proBNP was significantly reduced at 12 weeks in the LCZ696 group compared with the valsartan group (LCZ696: baseline, 783 pg/mL [95% CI 670-914], 12 weeks, 605 pg/mL [512-714]; valsartan: baseline, 862 pg/mL [733-1012], 12 weeks, 835 [710-981]; ratio LCZ696/valsartan, 0•77, 95% CI 0•64-0•92, p=0•005). LCZ696 was well tolerated with adverse effects similar to those of valsartan; 22 patients (15%) on LCZ696 and 30 (20%) on valsartan had one or more serious adverse event.

Interpretation:
In patients with heart failure with preserved ejection fraction, LCZ696 reduced NT-proBNP to a greater extent than did valsartan at 12 weeks and was well tolerated. Whether these effects would translate into improved outcomes needs to be tested prospectively.

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