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Patients With HFrEF May Benefit From Alternate Method of Sac/Val Dose Titration


In this study, Italian investigators evaluated how sacubitril/valsartan (Sac/Val) dose titration among older patients with heart failure with reduced ejection fraction (HFrEF) might affect reverse cardiac remodeling and if the success of up-titration can be predicted.

Clinicians may want to consider alternative methods of dose titration for sacubitril/valsartan (Sac/Val) among patients who have heart failure with reduced ejection fraction (HFrEF), according to the results of a new study published in ESC Heart Failure. In particular, patients with right ventricular (RV) dysfunction who have a tricuspid annulus plane systolic excursion (TAPSE) below 16 mm may most benefit from treatment initiation with the lowest dose and extended observation prior to up-titration.

“Sac/Val is demonstrated to be superior to enalapril in reducing hospitalizations, cardiovascular mortality, and all-cause mortality in patients with ambulatory HFrEF in particular when it is maximally up-titrated,” the authors wrote. “Unfortunately, the target dose is achieved in less than 50% of HFrEF patients. We aimed to evaluate the role of Sac/Val and its titration dose on reverse cardiac remodeling and determine which echocardiographic index best predicts the up-titration success.”

In particular, they highlight the results seen from a post-hoc analysis of the PARADIGM-HF trial, which established that a high target dose of Sac/Val (97/103 mg) vs an intermediate (49/51 mg) or a low (24/26) dose leads to less risk of CV death or rehospitalization for HF.

Ninety-five patients (median age, 65.6 [range, 59.1-72.8) years; 84.2% male) receiving care for HFrEF at 5 Italian hospitals and who were prescribed Sac/Val were retrospectively identified between January 2020 and June 2021. Their primary outcome was Sac/Val high-dose tolerability, which the authors defined as “the ability of the patient to achieve and stably tolerate the maximum dose.” Independent predictors of dose tolerance were identified, and echocardiograms and left ventricular (LV) and RV strain analysis were performed.

By the 6-month mark after dose optimization, more study participants were continuing on the high Sac/Val dose (37.9%) compared with the lowest dose (34.7%) or the intermediate dose (27.4%). The most common comorbidity among them was hypertension (82.1%), most had started the study taking a beta-blocker (97.9%), and a majority had New York Heart Association (NYHA) class II disease (58%).

The most common reason for intolerance to the highest dose of Sac/Val were symptomatic hypotension in 41% and gastrointestinal symptoms in 12.6%.

During the follow-up period, notable reductions were seen in systolic and diastolic blood pressures, and patients with NYHA class III disease dropped from 41% to 14% as those with NHYA class II disease increased from 58% to 74%.

Also at the 6-month mark, overall LV and RV function had significantly improved, as seen by these results (all P < .001):

  • Left ventricular ejection fraction (LVEF) improved from 28.8% to 35%
  • Left ventricular end-systolic volume decreased 15.5%, from 135 to 114 mL
  • Peak systolicpulmonaryarterypressure decreased 10%, from 35 to 31.5 mm Hg
  • Left ventricular global longitudinal strain (LVgLS) improved 23.6%, from –7.4% to –9.15%
  • Right ventricular global longitudinal strain (RVgLS) improved 17.3%, from –13.3% to ­–15.6%
  • RV free wall longitudinal strain (RV-FW-LS) improved 20.3%, from –17.7% to –20%

Among those in whom the maximum Sac/Val dose was reached (n = 36), the following measures were superior vs those who did not reach the maximum dose (n = 59):

  • LV end-diastolic volume decreased 20 vs 9 mL
  • LV end-systolic volume decreased 25.5 vs 15.6 mL
  • LVgLS decreased 2% vs 1.5%
  • LVEF improved 7.75% vs 5.0%
  • RVgLS decreased 1.9% vs 1%
  • RV-FW-LS decreased 2% vs 1%
  • Fractional area change was 4.75% vs 4%
  • TAPSE decreased 2 vs 1 mm
  • Tricuspid annular S’ velocity increased 1.5 vs 1 cm/s

The authors note that their findings are especially strong because they not only echo the PARADIGM-HF finding that close to 38% of patients with HFrEF can achieve their target dose, but they improve on those findings because the present patient population was not specifically chosen for their ability to tolerate the maximum dose.

“Due to emerging data indicating that higher doses of Sac/Val are associated with improved outcomes, investigations on mechanisms related to dose titration in the community are eagerly awaited,” they concluded. “To the best of our knowledge, our study is the first to analyze the potential role of echocardiography in predicting Sac/Val maximum dose tolerability. We confirmed the ability of Sac/Val to improve, during follow-up, several parameters related to both LV and RV function.”


Wu H-X, Liu K-K, Li B-N, Lie S, Jin J-C. Efficacy and safety of sacubitril/valsartan in the treatment of middle-aged and elderly patients with hypertension: a systematic review and meta-analysis of randomized controlled trials. Ann Pall Med. 2022;11(5):1811-1825. doi:10.21037/apm-22-503

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