Alternative drug therapy schedules to treat HFrEF could lead to fewer hospitalizations or deaths

Accelerated and personalized therapy for heart failure with reduced ejection fraction

Literature - Shen L, Jhund PS, Docherty KF, et al. - Eur Heart J. 2022 Apr 25;ehac210. doi: 10.1093/eurheartj/ehac210

Introduction and methods


The conventional approach to initiate therapy in patients with HFrEF involves a sequence that follows the chronological order in which the trials were conducted, with cautious up-titration of each treatment [1-3]. It remains unclear whether this approach is optimal, especially since different medications act independently, have additive effects and exhibit early benefit. This study explored whether alternative approaches and sequences may improve patient outcomes.

Aim of the study

The authors modeled the impact of more rapid up-titration of therapies used in a conventional order or in different orders on the frequency of HF hospitalization and death.


To estimate the treatment effects of 5 life-saving medications, data were collected from 6 RCTs conducted in HFrEF patients: SOLVD-Treatment (enalapril vs. placebo) [4], MERIT-HF (metoprolol vs. placebo) [5], EMPHASIS-HF (eplerenone vs. placebo) [6], PARADIGM-HF (sacubitril/valsartan vs. enalapril) [7], DAPA-HF (dapagliflozin vs. placebo) [8], and a combined cohort of patients randomized to the placebo arm in SOLVD-Treatment and CHARM-Alternative (candesartan vs. placebo) [9]. As patients in this combined cohort did not receive any of the 5 pharmacological therapies, they were regarded as a “treatment-naïve” HFrEF population; this data set was used to generate the event rates of the endpoints.

The following titration and drug sequencing schedules were examined:

  • Sequence 1: conventional titration and drug sequence, consisting of RAASi, beta-blocker, MRA, ARNI (switching from RAASi to ARNI), and SGLT2i (total up-titration time: 24 weeks).
  • Sequence 1a: accelerated approach to up-titration of Sequence 1 (total up-titration time: 16 weeks).
  • Sequence 1b: starting with ARNI instead of RAASi and up-titrating all drugs rapidly, as in Sequence 1a (total up-titration time: 12 weeks).
  • Sequences 2–5: various treatment sequences that were variations of Sequence 1b and had been found to be most advantageous over Sequence 1a, assuming each treatment exerted its full effect from halfway through its up-titration period (total up-titration time: 12 weeks).
  • Sequence duos 1–6: various combinations of all drugs except RAASi, whereby two drugs were started in combination followed by the two remaining drugs.


In this study, the main endpoints were a composite outcome of CV death or HF hospitalization, and all-cause death.

Main results

Impact of accelerating up-titration of conventional drug sequencing

  • Accelerating the titration timeline (Sequence 1a) was estimated to result in 23 fewer patients experiencing the composite outcome (HF hospitalization or CV death) and 7 fewer deaths from any cause per 1000 patients treated compared with the conventional approach (Sequence 1), in the first 12 months after starting treatment.

Impact of accelerating up-titration and changing drug sequencing

  • Comparison of Sequence 1b to Sequence 1a showed that starting with an ARNI rather than a RAASi was estimated to result in 8 fewer patients experiencing the composite outcome and 1 less death from any cause per 1000 treated after 12 months.
  • The most effective alternative approaches (Sequences 2–5 vs. Sequence 1b) resulted in further reductions in the rate of fatal and non-fatal events over 12 months.
  • The best sequence for reducing the composite outcome was Sequence 2 (SGLT2i initiated at t=0/MRA added at t=1 week/ARNI added at t=3 weeks/beta-blocker added at t=8 weeks; total up-titration time 12 weeks) . Compared with Sequence 1b, Sequence 2 prevented 17 patients from experiencing this outcome at 12 months.
  • When Sequence 2 was compared with Sequence 1, the additional number of patients avoiding the composite outcome event was 47 per 1000 patients treated.
  • The best alternative sequence for reducing all-cause mortality was Sequence 3 (SGLT2i started at t=0/MRA added at t=1 week/beta-blocker added at t=3 weeks/ARNI added at t=7 weeks; total up-titration time 12 weeks). Compared with Sequence 1b, Sequence 3 prevented 5 deaths per 1000 patients treated for 12 months.
  • When Sequence 3 was compared with Sequence 1, 14 patients avoided premature death per 1000 treated.

Impact of initiating two therapies simultaneously

  • The sequence duo starting with the combination of SGLT2i and MRA (initiated at t=0), followed by an ARNI (added at t=2 weeks), and then a beta-blocker (added at t=7 weeks) was most effective in reducing the composite outcome compared with Sequence 1b (22 fewer events per 1000 patients treated over 12 months). The total up-titration time of this sequence was 11 weeks.
  • The sequence duo that prevented the most deaths of any cause compared with Sequence 1b (7 fewer deaths per 1000 patients treated over 12 months) comprised an MRA plus beta-blocker (initiated at t=0), then an SGLT2i (added at t=4 weeks), and finally an ARNI (added at t=5 weeks), with a total up-titration time of 10 weeks.


Modeling of accelerated up-titration and optimized drug sequencing schedules suggested that at least 14 deaths and 47 patients experiencing HF hospitalization or CV death per 1000 HFrEF patients treated can be prevented in the first year after starting therapy compared with the conventional schedule. This indicates that standard treatment guidance in HFrEF may not lead to the best patient outcomes.

According to the authors, “if the effects of our life-saving therapies are mechanistically distinct, independent, and additive, the order in which treatments are added should not depend on which trial was done first but on other considerations, such as the size of the effect, speed of onset of benefit, and time taken to up-titrate to the target dose. This philosophy also argues for the implementation of as many effective therapies as possible, as rapidly as possible.”

Editorial comment

In their editorial comment, Jasper Tromp and Adriaan A. Voors start by interpreting some of the results found by Shen et al. The researchers found that up to half of the reduction in events could be primarily attributed to shortening the time to reach the target dose. Tromp and Voors believe this might partially explain why sequences starting with medications that have fewer up-titration steps (i.e., SGLT2is or MRAs) were associated with the largest reduction in events.

After highlighting some of the study’s strengths—using two large, well-characterized treatment-naïve populations to estimate the possible number of reduced events and the extensive modeling of various clinically relevant treatment combinations—Tromp and Voors address several limitations. One of their comments is that the authors modeled best-case scenarios but that “real-world” patients are commonly older and have more comorbidities, which often leads to discontinuation of HF drug therapy and leaves the question whether some of the rapid up-titration schedules are realistic in clinical practice. In the Discussion section of their article, Shen and coauthors do acknowledge they made several assumptions, including with regard to adherence rates. They also admit that maximum gains from the drugs examined are likely lower in real-world scenarios. Nonetheless, Tromp and Voors state that this study provides compelling evidence on using alternative treatment strategies to reduce the time to initiate and up-titrate therapy in patients with HFrEF.

Tromp and Voors also set out to expose the reasons that many HFrEF patients are still undertreated or treated at suboptimal drug doses. They believe “clinical inertia” and underappreciation of clinical risk might play an important role. According to these authors, clinical inertia may be merely a reflection of underlying structural issues, such as high medication co-payments and staff shortages. They end their contribution by offering different solutions addressing these barriers, for example by increasing HF medication insurance coverage and implementing nurse-led HF clinics.


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2. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Colvin MM, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2017;136:e137–e161.

3. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–3726.

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5. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–2007.

6. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21.

7. McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004.

8. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008.

9. Granger CB, McMurray JJV, Yusuf S, Held P, Michelson EL, Olofsson B, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772–776.

Find this article online at Eur Heart J.Find the editorial comment online at Eur Heart J.

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