P911Tolerability and safety of sacubitril/valsartan in high-risk subgroups

Abstract

Introduction: Current ESC guidelines recommend sacubitril/valsartan (SV) for patients (P) with ongoing symptomatic chronic heart failure with reduced ejection fraction, despite first line medical therapy. Experience regarding tolerability and safety in real world is less well described, mainly in high-risk subgroups. Purpose: To assess tolerability and success in achieving maximum SV dose in high-risk subgroups of a real world population. Methods: Retrospective and descriptive study extended to all P initiated and up-titrated on SV in a specialized HF unit since October 2016. P were stratified as high-risk if: systolic blood pressure (SBP) <110mmHg, pre-study low dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB), potassium (K) >5,0mmol/L, serum creatinine (Cr) >1,5mg/dL, glomerular filtration rate (GFR) <45mL/min/1.73m2. Data collected included demographics, initial dose, titration, discontinuation and adverse events. Clinical parameters were documented at each evaluation. Descriptive statistics were used for analysis. Results: Of 112P, at initiation visit 57P (75%male; 67+12years; 49%ischemic etiology; mean EF 30%; all NYHA II-III) had at least one high-risk criteria: 40% SBP<110mmHg, 44% K >5mmol/L, 19% Cr >1,5mg/dL, 25% GFR<45mL/min/1.73m2 and 26% low dose ACEI/ARB. 75,4% initiated on low doses (24/26mg) - mainly when low SBP (96% vs 62%) - and the remaining on 49/51mg. The up-titration phase lasted 46+19days. After a mean follow-up time of 275days (4-469), 44% achieved and remained on highest dose, 32% on medium dose and 12% on 24/26mg without tolerating dose increase (SBP<110mmHg 30 vs 26 vs 22%; Cr>1,5mg/dL 36 vs 27 vs 18%; GFR<45mL/min/1.73m2 29 vs 36 vs 7%; K>5,0mmol/L 52 vs 36 vs 8%; low dose ACEI/ARB 33 vs 20 vs 20%). The main reasons to not achieve the highest dose in all subgroups were dizziness/hypotension (48%; 3P with SBP<90mmHg) and hyperkalemia (44%; maximum 5,7mmol/L). 7P (12%) discontinued SV, 5 of them in titration phase. The commonest reason was a composite of hypotension/dizziness (n=4; 2P with SBP<90mmHg); other reasons included acute renal failure (n=1; decreasing 36% of GFR), gastrointestinal disturbance (n=1) and left ventricular assist device implantation (n=1). No episodes of angioedema. Regarding tolerance, SBP decreased 5mmHg (118+17 vs 114+17), Cr increased 0,06mg/dL (1,19+0,39 vs 1,25+0,44) and no changes on K (4,9+0,4 vs 4,9+0,4). Of those who had worsening of renal function, 5,3% (3P) had a decrease in eGFR>35% (maximum decrease of 42,6%). Conclusion: Our data suggests that SV appears to be well tolerated and has good safety even in patients with high-risk profile: low SBP, at least moderate renal dysfunction, borderline-high K level and those that did not tolerate more than low doses ACEI/ARB. True hypotension was the dominant cause for discontinuation. More gradual up-titration and rationalize other medications with anti-hypertensive side effects maximize attainment of higher doses of SV.