title: Limitations of Sacubitril/Valsartan in the Management of Heart Failure.
abstract: BACKGROUND
  The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial was a double-blind trial that randomized 8442 patients with heart failure (HF) with reduced ejection fraction (HFrEF) to receive twice daily dosing of either 200 mg of LCZ696 or 10 mg of enalapril in addition to standard medical therapy for HF.
  Limitations of this trial include (1) sacubitril has not been tested by itself in the treatment of HFrEF; (2) the maximum recommended dose of valsartan for the treatment of HFrEF was used in this trial, but the maximum recommended dose of enalapril for the treatment of HFrEF was not used; (3) a run-in phase was used in this trial to test the tolerability of LCZ696, and patients who had adverse effects in this period were excluded from randomization; (4) the percent of blacks enrolled in this trial was only 5%; (5) LCZ696 caused a 14% incidence of hypotension; (6) neprilysin inhibition might favor the development of Alzheimer dementia, which was not assessed in the PARADIGM-HF trial; (7) patients with severe symptomatic HF were underrepresented in this trial; (8) major exclusions from this trial included an acute coronary event in the last 3 months, severe pulmonary disease, hepatic impairment, and an estimated glomerular filtration rate <30 mL per minute per 1.73 m.
  
  
  METHODS
  Review of the PARADIGM-HF trial.
  
  
  RESULTS
  At 27-month follow-up, the PARADIGM-HF trial showed that compared with enalapril, LCZ696 reduced the composite of cardiovascular death or hospitalization for HF 20% (absolute risk reduction 4.7%, P < 0.001).
  
  
  CONCLUSIONS
  The numerous limitations discussed under the areas of uncertainty should be considered when prescribing LCZ696 for the treatment of HFrEF.
authors: Cardiology Division, Department of Medicine, Westchester Medical Center, New York Medical College, Valhalla, NY.
authors: Srikanth
authors: S
authors: Yandrapalli
authors: Wilbert S
authors: WS
authors: Aronow
authors: Pratik
authors: P
authors: Mondal
authors: David R
authors: DR
authors: Chabbott
mesh_terms: D001741:Black or African American; D000544:Alzheimer Disease / Q000453:epidemiology; D000613:Aminobutyrates / Q000627:therapeutic use*; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D004338:Drug Combinations; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010352:Patient Dropouts; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D013777:Tetrazoles / Q000627:therapeutic use*; D000068756:Valsartan; D044465:White People
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination