Importance of Clinical Worsening of Heart Failure Treated in the Outpatient Setting: Evidence From the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF).

Many episodes of worsening of heart failure (HF) are treated by increasing oral therapy or temporary intravenous treatment in the community or emergency department (ED), without hospital admission. We studied the frequency and prognostic importance of these episodes of worsening in the 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 (PARADIGM-HF). Outpatient intensification of HF therapy was added to an expanded composite outcome with ED visits, HF hospitalizations, and cardiovascular deaths. In an examination of first nonfatal events, 361 of 8399 patients (4.3%) had outpatient intensification of HF therapy without a subsequent event (ie, ED visit/HF hospitalizations) within 30 days; 78 of 8399 (1.0%) had an ED visit without previous outpatient intensification of HF therapy or a subsequent event within 30 days; and 1107 of 8399 (13.2%) had HF hospitalizations without a preceding event. The risk of death (in comparison with no-event patients) was similar after each manifestation of worsening: outpatient intensification of HF therapy (hazard ratio, 4.8; 95% confidence interval, 3.9-5.9); ED visit (hazard ratio, 4.5; 95% confidence interval, 3.0-6.7); HF hospitalizations (hazard ratio, 5.9; 95% confidence interval, 5.2-6.6). The expanded composite added 14% more events and shortened time to accrual of a fixed number of events. The benefit of sacubitril/valsartan over enalapril was similar to the primary outcome for the expanded composite (hazard ratio, 0.79; 95% confidence interval, 0.73-0.86) and was consistent across the components of the latter. Focusing only on HF hospitalizations underestimates the frequency of worsening and the serious implications of all manifestations of worsening. For clinical trials conducted in an era of heightened efforts to avoid HF hospitalizations, inclusion of episodes of outpatient treatment intensification (and ED visits) in a composite outcome adds an important number of events and shortens the time taken to accrue a target number of end points in an event-driven trial. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Okumura N ，Jhund PS ，Gong J ，Lefkowitz MP ，Rizkala AR ，Rouleau JL ，Shi VC ，Swedberg K ，Zile MR ，Solomon SD ，Packer M ，McMurray JJ ，PARADIGM-HF Investigators and Committees* ... -  《-》

Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (

The angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696) reduced cardiovascular morbidity and mortality compared with enalapril in patients with heart failure (HF) and reduced ejection fraction (EF) in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. We evaluated the influence of EF on clinical outcomes and on the effectiveness of sacubitril/valsartan compared with enalapril. Eight thousand three hundred ninety-nine patients with New York Heart Association class II to IV HF with reduced EF [left ventricular EF (LVEF) ≤40%] were randomized to sacubitril/valsartan 97/103 mg twice daily versus enalapril 10 mg twice daily and followed for a median of 27 months. The primary study end point was cardiovascular death or HF hospitalization. LVEF was assessed at the sites and recorded on case report forms. We related LVEF to study outcomes and assessed the effectiveness of sacubitril/valsartan across the LVEF spectrum. The mean LVEF in PARADIGM-HF, reported by sites, was 29.5 (interquartile range, 25-34). The risk of all outcomes increased with decreasing LVEF. Each 5-point reduction in LVEF was associated with a 9% increased risk of cardiovascular death or HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.05-1.13; P<0.001), a 9% increased risk for CV death (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14), a 9% increased risk in HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 1.04-1.14) and a 7% increased risk in all-cause mortality (hazard ratio, 1.07; 95% confidence interval, 1.03-1.12) in adjusted analyses. Sacubitril/valsartan was effective across the LVEF spectrum, with no evidence of heterogeneity, when modeled either in tertiles (P interaction=0.87) or continuously (P interaction=0.95). In patients with HF and reduced EF enrolled in PARADIGM-HF, LVEF was a significant and independent predictor of all outcomes. Sacubitril/valsartan was effective at reducing cardiovascular death and HF hospitalization throughout the LVEF spectrum. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Solomon SD ，Claggett B ，Desai AS ，Packer M ，Zile M ，Swedberg K ，Rouleau JL ，Shi VC ，Starling RC ，Kozan Ö ，Dukat A ，Lefkowitz MP ，McMurray JJ ... -  《-》

Effects of Sacubitril/Valsartan in the PARADIGM-HF Trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) According to Background Therapy.

In 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. We 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. The 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. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Okumura N ，Jhund PS ，Gong J ，Lefkowitz MP ，Rizkala AR ，Rouleau JL ，Shi VC ，Swedberg K ，Zile MR ，Solomon SD ，Packer M ，McMurray JJ ，PARADIGM-HF Investigators and Committees* ... -  《-》

Understanding the early mortality benefit observed in the PARADIGM-HF trial: considerations for the management of heart failure with sacubitril/valsartan.

This review aims to elucidate the optimal dosing of angiotensin receptor-neprilysin inhibitor (ARNI) therapy in the heart failure (HF) treatment paradigm through examination of the trial population characteristics and the mortality benefit observed in the Prospective Comparison of ARNI with angiotensin-converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF; NCT01035255) trial. Considerations regarding the initiation and titration of sacubitril/valsartan, a first-in-class ARNI, will also be addressed. The approval of sacubitril/valsartan heralded the first novel pharmacological class in over a decade for the treatment of heart failure with reduced ejection fraction (HFrEF). The PARADIGM-HF trial showed that treatment with valsartan/valsartan reduced the risk of first occurrence of either cardiovascular death or HF-related hospitalization (composite primary endpoint) by 20% compared with enalapril in patients with HFrEF. The incremental benefits of treatment with valsartan/valsartan over enalapril demonstrated in the PARADIGM-HF trial led to strong recommendations for its use over ACEIs or angiotensin receptor blockers to further reduce morbidity and mortality in the 2016 and 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America updates to the guidelines for the management of HF. Although the optimal timing for the initiation of valsartan/valsartan has yet to be determined, its early use is likely to have a positive impact on patient outcomes.

Sokos GG ，Raina A 《-》

Estimated 5-Year Number Needed to Treat to Prevent Cardiovascular Death or Heart Failure Hospitalization With Angiotensin Receptor-Neprilysin Inhibition vs Standard Therapy for Patients With Heart Failure With Reduced Ejection Fraction: An Analysis of Dat

Srivastava PK ，Claggett BL ，Solomon SD ，McMurray JJV ，Packer M ，Zile MR ，Desai AS ，Rouleau JL ，Swedberg K ，Fonarow GC ... -  《-》