Accelerated and Personalized Therapy for HFrEF

Quick Takes

  • Modeling based on HFrEF clinical trials shows that compared to a conventional approach where GDMT is optimized over 24 weeks, an accelerated approach for GDMT initiation and up-titration was associated with lesser all-cause and cardiovascular death and HF hospitalizations within 1 year.
  • Regimens associated with least all-cause mortality and least CV death/HF hospitalizations included initiating two classes simultaneously followed by other two agents sequentially.

Study Questions:

What is the appropriate sequence of initiating and titrating guideline-directed medical therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF)?


Five trials conducted in patients with HFrEF were used to model the effects of GDMT initiated and titrated in various combinations. The control group was comprised of a placebo cohort from trials that did not receive any GDMT. Outcomes of interest included a composite of cardiovascular (CV) death, HF hospitalization, and all-cause death. The conventional regimen led to GDMT optimization with all four classes of agents (angiotensin-converting enzyme inhibitor [ACEi] switched to angiotensin receptor–neprilysin inhibitor [ARNI] + beta-blocker [BB] + mineralocorticoid receptor antagonist [MRA] + sodium–glucose cotransporter 2 inhibitor [SGLT-2i]) within 24 weeks, and the accelerated regimen led to optimization within 16 weeks. Additional titration regimens were evaluated including initiating with an ARNI upfront with medical optimization within 12 weeks and various combinations of two drugs simultaneously followed by the other two leading to up-titration within 8-12 weeks.


Compared to the conventional regimen, an accelerated regimen optimizing medications over 16 weeks led to fewer HF hospitalizations or CV deaths (-23 per 1,000 patients in 1 year) and all-cause mortality (-7 per 1,000 patients in 1 year). Initiation of ARNI upfront with medical optimization within 12 weeks led to additional lowering of all endpoints (-8 per 1,000 patients for HF hospitalizations or CV death and -1.4 per 1,000 patients for all-cause mortality) compared to the accelerated regimen. Evaluation of two agents simultaneously further lowered incidence of all endpoints. For lowering composite of HF hospitalizations or CV death, the most effective regimen was SGLT-2i plus MRA followed by ARNI and then BB (-21 per 1,000 compared to ARNI upfront). For all-cause mortality, the most effective regimen was MRA + BB followed by SGLT-2i and then ARNI (-7 per 1,000 patients compared to ARNI upfront).


In this study modeling various combinations of GDMT initiation and titration for HFrEF, shorter duration to achieve target doses was associated with reduced risk for all-cause mortality, CV death, and HF hospitalization.


For treatment of HFrEF, which agent should be initiated first and how rapidly should medications be titrated remains hotly debated. More recently, there has been an increased endorsement of accelerated approaches including simultaneous initiation of multiple classes together. In this study, the authors model various approaches and the overarching finding is that minimizing the time taken to achieve target doses of all four agents for HFrEF leads to lower risk for all-cause and CV death and HF hospitalization. While various combinations were modeled, it is difficult to draw interpretations on which combination is the best given the fact that these results are modeled off clinical trials and these regimens assume that one agent is maximally up-titrated prior to initiating the next class. Furthermore, initiating multiple agents in real-world practice comes with increased risk for adverse events such as hyperkalemia, renal injury, and hypotension. Regardless, these data support that rapid initiation and up-titration of GDMT for HFrEF leads to the best outcomes. In particular, upfront use of ARNI when feasible helps shorten time to achieve medication optimization.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Adrenergic beta-Antagonists, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Heart Failure, Hospitalization, Mineralocorticoid Receptor Antagonists, Neprilysin, Receptors, Angiotensin, Sodium-Glucose Transporter 2 Inhibitors, Stroke Volume, Treatment Outcome

< Back to Listings