• Naoki Okumura, Pardeep S Jhund, Jianjian Gong, Martin P Lefkowitz, Adel R Rizkala, Jean L Rouleau, Victor C Shi, Karl Swedberg, Michael R Zile, Scott D Solomon, Milton Packer, John J V McMurray, and PARADIGM-HF Investigators and Committees*.
• From the BHF Cardiovascular Research Centre, University of Glasgow, United Kingdom (N.O., P.S.J., J.J.V.M.); Novartis Pharmaceutical Corporation, East Hanover, NJ (J.G., M.P.L., A.R.R., V.C.S.); Institut de Cardiologie de Montréal, Université de Montréal, Quebec, Canada (J.L.R.); Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden (K.S.); National Heart and Lung Institute, Imperial College, London, United Kingdom (K.S.); Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston (M.R.Z.); Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (S.D.S.); and Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.).
• Circ Heart Fail. 2016 Sep 1; 9 (9).

BackgroundIn the PARADIGM-HF trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), the angiotensin receptor neprilysin inhibitor sacubitril/valsartan was more effective than the angiotensin-converting enzyme inhibitorenalapril in patients with heart failure and reduced ejection fraction. We examined whether this benefit was consistent irrespective of background therapy.Methods And ResultsWe examined the effect of study treatment in the following subgroups: diuretics (yes/no), digitalis glycoside (yes/no), mineralocorticoid receptor antagonist (yes/no),and defibrillating device (implanted defibrillating device, yes/no). We also examined the effect of study drug according to β-blocker dose (≥50% and <50% of target dose) and according to whether patients had undergone previous coronary revascularization. We analyzed the primary composite end point of cardiovascular death or heart failure hospitalization, as well as cardiovascular death. Most randomized patients (n=8399)were treated with a diuretic (80%) and β-blocker (93%); 47% of those taking a β-blocker were treated with ≥50% of the recommended dose. In addition, 4671 (56%) were treated with a mineralocorticoid receptor antagonist, 2539 (30%) with digoxin, and 1243 (15%) had a defibrillating device; 2640 (31%) had undergone coronary revascularization. Overall, the sacubitril/valsartan versus enalapril hazard ratio for the primary composite end point was 0.80 (95% confidence interval,0.73-0.87;P<0.001) and for cardiovascular death was0.80 (0.71-0.89;P<0.001). The effect of sacubitril/valsartan was consistent across all subgroups examined. The hazard ratio for primary end point ranged from 0.74 to 0.85 and for cardiovascular death rangedfrom 0.75 to 0.89, with no treatment-by-subgroup interaction.ConclusionsThe benefit of sacubitril/valsartan, over an angiotensin-converting enzyme inhibitor, was consistent regardless of background therapy and irrespective of previouscoronary revascularization or β-blocker dose.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.© 2016 American Heart Association, Inc.

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