treatment-na?ve HFrEF)InterventionLCZ696 (TD 200 mg twice daily)Aim for TD br / Avoid co-prescription with ACEIComparatorEnalapril (TD 10 mg twice daily)Consistent with current best practiceOutcome20% RRR CV death br / 21% RRR HF hospitalisationRobust and clinically relevant outcomes br / Consistent benefit across subgroups br / Symptom/quality-of-life benefits Open in a separate window ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin Inhibitor; BNP = B-type natriuretic peptide; CV = cardiovascular; HF = heart failure; HFrEF = heart failure with reduced left ventricular ejection fraction; LVEF = left ventricular ejection fraction; NTproBNP = N-terminal pro B-type natriuretic peptide; PARADIGM-HF = Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; PICO = population, intervention, comparator, outcome; RRR = relative risk reduction; TD = target dose

treatment-na?ve HFrEF)InterventionLCZ696 (TD 200 mg twice daily)Aim for TD br / Avoid co-prescription with ACEIComparatorEnalapril (TD 10 mg twice daily)Consistent with current best practiceOutcome20% RRR CV death br / 21% RRR HF hospitalisationRobust and clinically relevant outcomes br / Consistent benefit across subgroups br / Symptom/quality-of-life benefits Open in a separate window ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin Inhibitor; BNP = B-type natriuretic peptide; CV = cardiovascular; HF = heart failure; HFrEF = heart failure with reduced left ventricular ejection fraction; LVEF = left ventricular ejection fraction; NTproBNP = N-terminal pro B-type natriuretic peptide; PARADIGM-HF = Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; PICO = population, intervention, comparator, outcome; RRR = relative risk reduction; TD = target dose. The patients were generally well treated with high levels of evidence-based pharmacological therapies including beta-blockers (93 %) and mineralocorticoid receptor antagonists (60 %60 %). The intervention evaluated in the PARADIGM-HF study was dual blockade of the reninCangiotensin system and neprilysin.[29] This study was not designed to test whether the benefit of LCZ696 was dose related, nor whether the relative effect on these neurohormonal systems varied at different doses. 10 mg twice daily)Consistent with current best practiceOutcome20% RRR CV death br / 21% RRR HF hospitalisationRobust and clinically relevant outcomes br / Consistent benefit across subgroups br / Symptom/quality-of-life benefits Open in a separate window ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor-neprilysin Inhibitor; BNP = B-type natriuretic peptide; CV = cardiovascular; HF = heart failure; HFrEF = heart failure with reduced left ventricular ejection fraction; LVEF = left ventricular ejection fraction; NTproBNP = N-terminal pro B-type natriuretic peptide; PARADIGM-HF = Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure; PICO = population, intervention, comparator, outcome; RRR = relative risk reduction; TD = target dose. The patients were generally well treated with high levels of evidence-based pharmacological therapies including beta-blockers (93 %) and mineralocorticoid receptor antagonists (60 %60 %). The intervention evaluated in the PARADIGM-HF study was dual blockade of the reninCangiotensin system and neprilysin.[29] This study was not designed to test whether the benefit of LCZ696 was dose related, nor whether the relative effect on these neurohormonal systems varied at different doses. In other words, we cannot assume that superiority over an ACEI (presumably related to the additional effect of neprilysin inhibition) will be maintained at low doses of LCZ696. It is therefore important that when clinicians prescribe LCZ696, they aim for the target dose tested in the PARADIGM-HF study. An ACEI was chosen as the comparator in the PARADIGM-HF study, given its robust evidence for safety and clinical effectiveness in HFrEF, and that ACEIs are recommended as first-line therapy in all major HF clinical guidelines.[11,12] Enalapril was specifically chosen because it has been Thioridazine hydrochloride shown to reduce mortality rates in patients with chronic HFrEF; and the target dose of 10 mg twice daily was the same as that in the SOLVD-T study.[3,29] Indeed, the mean daily dose achieved in the PARADIGM-HF study was 18.9 mg, which was higher compared with that in previous HF studies.[2,3] The outcome measures chosen in PARADIGM-HF study were robust and clinically relevant, including beneficial effects on symptoms, quality of life, rates of hospitalisation and other health resource utilisation, and mortality rates.[29,30] Furthermore, there were no subgroups where the point estimate HR was 1.0. The only pre-specified subgroup with a nominally significant interaction for the primary endpoint (unadjusted for multiple comparisons) Thioridazine hydrochloride was New York Heart Association class; however, there was no significant interaction effect for cardiovascular death. The benefits were observed on top of background therapy with 93 % of patients receiving beta-blockers at the time of randomisation. Although only 55 % of patients were receiving a mineralocorticoid receptor antagonist at the time of randomisation, significant reductions in the primary endpoint and cardiovascular death were observed in patients with or without prior mineralocorticoid receptor antagonist therapy.[29] Furthermore, significant reductions in sudden death rates were observed in both patients with and without an implantable defibrillator device.[31] Only 7 % of patients had a cardiac resynchronisation therapy device at the time of randomisation; however, the benefits of LCZ696 and Thioridazine hydrochloride cardiac resynchronisation therapy should be maintained in patients who meet the inclusion criteria for these treatments, including a persistent moderate to severe reduction in LVEF. Limitations of the Evidence for Angiotensin ReceptorCneprilysin Inhibitors in Heart Failure The PARADIGM-HF study is the only one supporting the use of ARNI over ACEI in patients with HFrEF. It is nonetheless a Rabbit Polyclonal to IkappaB-alpha large study that was primarily powered to detect a difference in cardiovascular mortality rates. Indeed, the P value achieved for the primary endpoint was equivalent to at least four trials with a P value 0.05.[32] On this basis, it would appear unethical to conduct a similar study to confirm the PARADIGM-HF findings. The most appropriate population to receive ARNI in clinical practice would match those who were studied in the PARADIGM-HF study, namely patients with symptomatic HFrEF despite appropriate doses of ACEI (or ARB) and beta-blockers. Although a clinical trial investigator may argue that the inclusion criteria for a clinical trial should be applied in clinical practice, one should also consider whether this allows clinicians to identify those patients most likely to benefit. For example, the patients enrolled in the PARADIGM-HF study had elevated BNP/NTproBNP levels; however, there was no significant interaction effect.