Physicians' Academy for Cardiovascular Education

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:


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

Impact of accelerating up-titration and changing drug sequencing

Impact of initiating two therapies simultaneously


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.


Show references

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

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