Impact of systolic blood pressure on the safety and tolerability of initiating and up‐titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study

• Published in: European journal of heart failure 2018-03, Vol.20 (3), p.491-500
• Main Authors: Senni, Michele, McMurray, John J.V., Wachter, Rolf, McIntyre, Hugh F., Anand, Inder S., Duino, Vincenzo, Sarkar, Arnab, Shi, Victor, Charney, Alan
• Format: Article
• Language: English
• Subjects: Aged; Aminobutyrates - administration & dosage; Angiotensin Receptor Antagonists - administration & dosage; Blood pressure; Blood Pressure - drug effects; Cause of Death - trends; Double-Blind Method; Drug Combinations; Drug Tolerance; Europe - epidemiology; Female; Follow-Up Studies; Heart failure; Heart Failure - drug therapy; Heart Failure - mortality; Heart Failure - physiopathology; Humans; Hypotension; LCZ696; Male; Middle Aged; Neprilysin; Sacubitril/valsartan; Stroke Volume - physiology; Survival Rate - trends; Systole; Tetrazoles - administration & dosage; Titration; Tolerability; Treatment Outcome; United States - epidemiology
• ISSN: 1388-9842; 1879-0844
• DOI: 10.1002/ejhf.1054

Aims The TITRATION trial investigated two strategies to initiate and up‐titrate sacubitril/valsartan (LCZ696) to the same target dose, over a condensed (3‐week) or conservative (6‐week) period, in patients with heart failure with reduced ejection fraction (HFrEF) and systolic blood pressure (SBP) of ≥100 mmHg. This post hoc analysis examined the relationship between baseline SBP at screening and achievement of the target dose of sacubitril/valsartan of 97 mg/103 mg (also termed ‘LCZ696 200 mg’) twice per day during the study. Methods and results Patients (n = 498) were categorized in four groups based on SBP at screening: 100–110 mmHg (n = 70); 111–120 mmHg (n = 93); 121–139 mmHg (n = 168) and ≥140 mmHg (n = 167). Overall, 72.7%, 76.1%, 85.6% and 82.9%, respectively, of patients in these SBP categories achieved and maintained the target dose of sacubitril/valsartan without down‐titration/dose interruption over 12 weeks (‘treatment success’). Compared with patients with SBP of 100–110 mmHg, rates of treatment success among patients in the higher SBP groups [111–120 mmHg (P = 0.96); 121–139 mmHg (P = 0.06) and ≥140 mmHg (P = 0.25)] did not differ significantly. A higher percentage of patients with lower SBP (100–110 mmHg) achieved treatment success with gradual up‐titration (6 weeks) (∼80%) than with rapid up‐titration (∼69%). Similar findings were observed with regard to ‘tolerability success’ (maintenance of the target dose for at least the final 2 weeks prior to study completion). Hypotension occurred more frequently in patients with lower SBP. Conclusions The majority of patients (>80%) with SBP of ≥100 mmHg achieved and maintained the target dose of sacubitril/valsartan if the treatment was titrated gradually. These findings suggest that low SBP should not prevent clinicians from considering the initiation of sacubitril/valsartan.