HFrEF patients with low SBP do tolerate target dose of ARNI

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

Literature - Senni M, McMurray JJV, Wachter R, et al. - Eur J Heart Fail 2017; published online ahead of print


Treatment with sacubitril/valsartan, at target doses, significantly reduces CV death, HF hospitalization, and all-cause mortality compared with enalapril, in patients with HFrEF [1]. Due to its dual mode of action, the sacubitril/valsartan combination induces greater BP reductions compared with ACEIs and ARBs, which may restrict its routine use in HFrEF patients with low SBP. Low SBP is associated with a poor prognosis and in a recent analysis from the Systolic Heart Failure Treatment trial, every 10-mmHg lower baseline SBP was associated with a 12% higher risk for all-cause mortality in patients with chronic HFrEF [2-4].

In this post hoc analysis of the TITRATION study [5], the relationship between SBP at screening and successful initiation and up-titration of sacubitril/valsartan was evaluated in HFrEF patients. Randomized patients were divided in the following 4 SBP groups at screening: 100–110 mmHg; 111–120 mmHg; 121–139 mmHg; and ≥140 mmHg. In each SBP group, treatment success was defined as the proportion of patients achieving and maintaining the sacubitril/valsartan target dose of 97 mg/103 mg twice per day without any dose interruption or down-titration for 12 weeks. Moreover, the tolerability success was defined as the proportion of patients that tolerated sacubitril/valsartan 97 mg/103 mg twice per day for at least the final 2 weeks leading to study completion, regardless of previous dose interruption or down-titration.

Main results

  • Treatment success was highest in the two groups with SBP >120 mmHg, in which >80% of patients achieved and maintained the target dose of sacubitril/valsartan without any dose interruption or down-titration for 12 weeks. 76.1% of patients with SBP of 111–120 mmHg, and 72.7% of patients with SBP of 100–110 mmHg, achieved this target.
  • 80.0% of patients with SBP ≤120 mmHg achieved treatment success with gradual up-titration, and 68.9% of patients with a more rapid up-titration regimen did.
  • 85.2% of patients in the total cohort treated with sacubitril/valsartan achieved tolerability success. Tolerance was highest in patients with SBP in the range of 121–139 mmHg, among whom 90.6% achieved the target. 75.8% of patients with SBP of 100–110 mmHg, and 78.4% of patients with SBP of 111–120 mmHg achieved tolerability success.
  • In both the SBP 100–110 mmHg and SBP 111–120 mmHg patient groups, the rate of successful tolerance was higher (approximately 82.0%) with gradual up-titration, while the great majority of patients with SBP of >120 mmHg achieved tolerability success regardless of the up-titration regimen.
  • Patients in the lowest SBP category had the highest incidences of hypotension-related AEs.
  • After 12 weeks, SBP was lower in all groups and in both up-titration regimens, with greater reductions in patients with higher SBP at screening. In patients with baseline SBP of 100–110 mmHg and gradual up-titration, the mean reduction in SBP at 12 weeks was 1.4±11.2 mmHg, and in those with more rapid up-titration it was 7.0±15.0 mmHg.


In a post hoc analysis of the TITRATION study, the majority of patients with low SBP levels at screening tolerated the initiation/up-titration to target dose level of sacubitril/valsartan using a gradual up-titration regimen. These findings suggest that low screening SBP levels should not prevent clinicians from considering the initiation of sacubitril/valsartan.


1. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004.

2. Ambrosy AP, Vaduganathan M, Mentz RJ, et al. Clinical profile and prognostic value of low systolic blood pressure in patients hospitalized for heart failure with reduced ejection fraction: insights from the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial. Am Heart J 2013;165:216–225.

3. Banach M, Bhatia V, Feller MA, et al. Relation of baseline systolic blood pressure and long-term outcomes in ambulatory patients with chronic mild to moderate heart failure. Am J Cardiol 2011;107:1208–1214.

4. Komajda M, Bohm M, Borer JS, et al; SHIFT Investigators. Efficacy and safety of ivabradine in patients with chronic systolic heart failure according to blood pressure level in SHIFT. Eur J Heart Fail 2014;16:810–816.

5. Senni M, McMurray JJ, Wachter R, et al. Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail 2016;18:1193–1202.

Find this article online at Eur J Heart Fail

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free