Prognostic value of worsening renal function in outpatients with chronic heart failure

Introduction and objectives: Renal function impairment predicts poor survival in heart failure. Attention has recently shifted to worsening renal function, based mostly on serum creatinine and estimated glomerular filtration rate. We assessed the prognostic effect of worsening renal function in ambulatory heart failure patients. Methods: Data from 306 ambulatory patients were abstracted from medical files. Worsening renal function was based on the change in estimated glomerular filtration rate, serum creatinine and urea within 6 months of referral. Prognosis was assessed by the composite endpoint all-cause death or heart failure hospitalization, censored at 2 years. Hazard ratios were estimated for worsening renal function, adjusted for sex, age, diabetes, New York Heart Association class, left ventricular systolic dysfunction, medications and baseline renal function. Results: The agreement among definitions was fair, with kappa coefficients generally not surpassing 0.5. Worsening renal function was associated with poor outcome with adjusted hazard ratios (95% confidence interval) of 3.2 (1.8–5.9) for an increase of serum creatinine > 0.3 mg/dl; 2.2 (1.3–3.7) for an increase in serum urea > 20 mg/dl and 1.9 (1.1–3.3) for a decrease in estimated glomerular filtration rate > 20%, independent of baseline renal function. The 2-year risk of death/heart failure hospitalization was approximately 50% in patients with an increase in serum creatinine or in serum urea; this positive predictive value was higher than for decreasing estimated glomerular filtration rate. Conclusions: In conclusion, worsening renal function was significantly associated with a worse outcome. Different definitions identified different patients at risk and increasing creatinine/urea performed better than decreasing estimated glomerular filtration rate

ARNIs: balancing “the good and the bad” of neuroendocrine response to HF

Background: A new class of drugs—angiotensin receptor, neprylisin inhibitors, ARNI—has shown to be prognostic superior in HFrEF to the sole inhibition of the renin–angiotensin axes with enalapril. The ultimate mechanism of action of ARNIs is unknown. Aim: We have considered that ARNI exerts a positive modulation of the neuroendocrine balance, with enhancement of the physiological diuresis and dilatation due to neprylisin inhibition by sacubitril. This represents a shift in HF medical therapy always directed to counteract (with inhibitors of the renin–angiotensin system, beta blockers or inhibitors of aldosterone) the so-called “bad” neuroendocrine response. Development of ARNI, on the contrary, has led to consider the neuroendocrine response to HFrEF from a different angle, which is to say that the activation is not always deleterious, but it could also be beneficial. This concept is highlighted by the enhancement of the activity of atrial natriuretic peptide, induced by sacubitril/valsartan in the PARADIGM trial, and found as proof from early studies on untreated patients with constrictive pericarditis. The possibility that sacubitril inhibition of neprylisin acts by enhancing substance P and gene-related calcitonin peptide is also considered, as well as the negative effect of neprylisin inhibition. Conclusions: The beneficial effects of ARNI are related, in part at least, to a positive modulation of the neuroendocrine response to the disease, resulting in an increase of physiological diuresis and dilatation

NT-proBNP Response to Sacubitril/Valsartan in Hospitalized Heart Failure Patients With Reduced Ejection Fraction: TRANSITION Study

Objectives: This study examined the effects of sacubitril/valsartan on N-terminal pro\u2013B-type natriuretic peptide (NT-proBNP) levels and determined patient characteristics associated with favorable NT-proBNP reduction response. Background: NT-proBNP levels reflect cardiac wall stress and predict event risk in patients with acute decompensated heart failure (ADHF). Methods: Post-hoc analysis of the TRANSITION (Comparison of Pre- and Post-discharge Initiation of Sacubitril/Valsartan Therapy in HFrEF Patients After an Acute Decompensation Event) study, including stabilized ADHF patients with reduced ejection fraction, randomized to open-label sacubitril/valsartan initiation in-hospital (pre-discharge) versus post-discharge. NT-proBNP was measured at randomization (baseline), discharge, and 4 and 10 weeks post-randomization. A favorable NT-proBNP response was defined as reduction to 641,000 pg/ml or >30% from baseline. Results: In patients receiving sacubitril/valsartan in-hospital, NT-proBNP was reduced by 28% at discharge, with 46% of patients obtaining favorable NT-proBNP reduction response compared with a 4% reduction and 18% favorable response rate in patients initiated post-discharge (p < 0.001). NT-proBNP was reduced similarly in patients initiating sacubitril/valsartan pre- and post-discharge (reduction at 4 weeks: 25%/22%; 10 weeks: 38%/34%) with comparable favorable response rates (46%/42% and 51%/48% at 4 and 10 weeks, respectively). NT-proBNP favorable response at 4 weeks was associated with lower risk of first heart failure (HF) rehospitalization or cardiovascular death through 26 weeks (hazard ratio: 0.57; 95% confidence interval [CI]: 0.38 to 0.86; p = 0.007). Predictors of a favorable response at 4 weeks were starting dose 6549/51 mg twice daily, higher baseline NT-proBNP, lower baseline serum creatinine, de novo HF, no atrial fibrillation, angiotensin-converting enzyme inhibitor\u2013naive or angiotensin receptor blocker\u2013naive, and no prior myocardial infarction. Conclusions: In-hospital initiation of sacubitril/valsartan produced rapid reductions in NT-proBNP, statistically significant at discharge. A favorable NT-proBNP response over time was associated with a better prognosis and predicted by higher starting dose and predisposing clinical profile. (Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event [TRANSITION]; NCT02661217

Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study

Aims: To assess tolerability and optimal time point for initiation of sacubitril/valsartan in patients stabilised after acute heart failure (AHF). Methods and results: TRANSITION was a randomised, multicentre, open-label study comparing two treatment initiation modalities of sacubitril/valsartan. Patients aged ≥ 18 years, hospitalised for AHF were stratified according to pre-admission use of renin–angiotensin–aldosterone system inhibitors and randomised (n = 1002) after stabilisation to initiate sacubitril/valsartan either ≥ 12-h pre-discharge or between Days 1–14 post-discharge. Starting dose (as per label) was 24/26 mg or 49/51 mg bid with up- or down-titration based on tolerability. The primary endpoint was the proportion of patients attaining 97/103 mg bid target dose after 10 weeks. Median time of first dose of sacubitril/valsartan from. the day of discharge was Day –1 and Day +1 in the pre-discharge group and the post-discharge group, respectively. Comparable proportions of patients in the pre- and post-discharge initiation groups met the primary endpoint [45.4% vs. 50.7%; risk ratio (RR) 0.90; 95% confidence interval (CI) 0.79–1.02]. The proportion of patients who achieved and maintained for ≥ 2 weeks leading to Week 10, either 49/51 or 97/103 mg bid was 62.1% vs. 68.5% (RR 0.91; 95% CI 0.83–0.99); or any dose was 86.0% vs. 89.6% (RR 0.96; 95% CI 0.92–1.01). Discontinuation due to adverse events occurred in 7.3% vs. 4.9% of patients (RR 1.49; 95% CI 0.90–2.46). Conclusions: Initiation of sacubitril/valsartan in a wide range of heart failure with reduced ejection fraction patients stabilised after an AHF event, either in hospital or shortly after discharge, is feasible with about half of the patients achieving target dose within 10 weeks. Clinical Trial Registration: ClinicalTrials.gov ID: NCT02661217. © 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology