Titration of Medical Therapy Linked with Clinical Outcomes in Patients With HFrEF

Beta Blocker Use in PCI
Beta Blocker Use in PCI
Researchers sought to assess clinical factors and outcomes related to changes in ACE inhibitor and β-blocker therapy in patients with HFrEF.

In patients with chronic heart failure with reduced ejection fraction (HFrEF), characteristics such as blood pressure and recent hospitalization status are associated with a likelihood of escalation and de-escalation of angiotensin-converting enzyme (ACE) inhibitor and β-blocker therapy. These titration findings were published in the American Heart Journal.

An analysis was conducted and included patients enrolled in the international, multicenter, randomized controlled Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial. Recognizing that patient characteristics related to dose titration and clinical outcomes subsequent to dose titration remain poorly understood among patients with HFrEF, the researchers sought to examine the utilization and dosing of ACE inhibitors and β-blockers in these individuals at baseline and at 6-month follow-up.

At baseline and at 6 months, medication dosing of both ACE inhibitors and evidence-based β-blockers for each participant was categorized relative to target dose specified in HF clinical management guidelines. The dosing groups were patients not receiving any medication, patients receiving 1% to 49% of the target dose, patients receiving 50% to 99% of the target dose, or patients receiving 100% or more of the target dose.

The patients were then categorized into 4 dose trajectory groups for each class of medication, based on the change in dose category between baseline and 6 months. These trajectory groups were stable subtarget-dosing (the dose category remained constant and less than target, including patients who remained on no medication); stable target-dosing group (the dose category remained constant and at target); dose  escalation group (increase in dose category, including medication initiation); and dose de-escalation group (decrease in dose category, including discontinuation). All of the participants were assigned to separate dose trajectory groups for both ACE inhibitors and β-blockers, independent of the other medication class.

The analysis had 3 prespecified coprimary endpoints: all-cause mortality, a composite of cardiovascular mortality or hospitalization for HF, and a composite of all-cause mortality and all-cause hospitalization. The study was designed as 2 identical parallel analyses, 1 for ACE inhibitors and 1 for β-blocker therapy.

A total of 1999 participants from the HF-ACTION trial were included in both the ACE inhibitor and β-blocker trajectory analyses. The majority of patients were treated with stable subtarget ACE inhibitor doses (59.4%), compared with the stable target group (25.6%), the dose escalation group (6.3%), and the dose de-escalation group (8.7%).

The majority of patients were treated with β-blocker doses that were stable subtarget β-blocker doses (50.1%), compared with the stable target group (29.2%), the dose escalation group (12.7%), and the dose de-escalation group (8.1%).

Results of the study showed that with both ACE inhibitor and β-blocker therapy, hospitalization for HF in the 6 months before enrollment was associated with dose escalation (odds ratio [OR], 2.32; 95% CI, 1.58-3.42 with ACE inhibitors and OR, 1.42; 95% CI, 1.05-1.90 with β-blockers). Further, higher systolic blood pressure per 1-mm Hg increase was associated with dose escalation as well (OR, 1.01; 95% CI, 1.00-1.03 with ACE inhibitors and OR, 1.01; 95% CI, 1.00-1.02 with β-blockers).

Hospitalization for any cause at 6 months prior to enrollment, which included both HF and non-HF causes, was associated with dose de-escalation (OR, 1.60; 95% CI, 1.14-2.25 with ACE inhibitors and OR, 1.67; 95% CI, 1.20-2.33 with β-blockers).

Following adjustment for patient characteristics, when compared with stable target dosing, dose de-escalation of either medication was associated with greater all-cause mortality (adjusted hazard ratio [aHR], 1.64; 95% CI, 1.11-2.42 with ACE inhibitors and aHR, 1.62; 95% CI, 1.04-2.53 with β-blockers). Compared with stable target dosing, both dose de-escalation of β-blockers (aHR, 1.98; 95% CI, 1.36-2.87) and stable subtarget dosing of β-blockers (aHR, 1.49; 95% CI, 1.18-1.87) were associated with greater cardiovascular mortality or hospitalization for HF.

Limitations of the study include the fact that since it used the HF-ACTION clinical trial cohort, the results may not reflect real-world clinical practice. Additionally, “this observational study cannot definitely determine cause-effect relationships.”

The researchers concluded that future studies are needed to develop targeted interventions to prevent de-escalation of guideline-directed medical therapy for patients with HFrEF, especially among individuals at high risk for medication discontinuation who are at a particularly high risk for the occurrence of clinical events. “Likewise, in cases where [guideline-directed medical therapy] is appropriately de-escalated due to development of contraindications or true intolerance, added consideration of advanced heart failure therapies or palliative care may be warranted,” the researchers wrote.

Disclosure: One of the study authors has declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of the author’s disclosures. 


Pierce JB, Mentz RJ, Sun JL, et al. Titration of medical therapy and clinical outcomes among patients with heart failure with reduced ejection fraction: findings from the HF-ACTION trial. Am Heart J. Published online May 29, 2022. doi:10.1016/j.ahj.2022.05.018