The comparative effectiveness of differing dosages of guideline-directed medical therapy
(GDMT) for heart failure with reduced ejection fraction (HFrEF) on clinical and patient-reported
outcomes in clinical practice in the United States is unknown. This study sought to
characterize associations between the dosing of GDMT and outcomes for patients with
HFrEF in U.S. clinical practice.
This analysis included 4832 outpatients who had chronic HFrEF across 150 practices
in the U.S. in the Change the Management of Patients with Heart Failure (CHAMP-HF)
registry with no contraindication and available dosing data for at least 1 GDMT at
baseline. Baseline dosing of angiotensin-converting enzyme (ACEI)/angiotensin II receptor
blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and
mineralocorticoid receptor antagonist (MRA) therapies were examined. For each medication
class, multivariable models assessed associations between medication dosing and clinical
outcomes over 24 months (all-cause mortality, HF hospitalization) and patient-reported
outcomes at 12 months (change in the Kansas City Cardiomyopathy Questionnaire Overall
Summary score [KCCQ-OS]).
After adjustment, compared with target dosing, lower dosing was associated with higher
all-cause mortality for ACEIs/ARBs/ARNIs (50% to < 100% target dosage, HR 1.16 [95%
CI 0.87–1.55]; < 50% target dosage, HR 1.37 [95% CI 1.05–1.79]; none, HR 1.75 [95%
CI 1.32–2.34; overall P< 0.001) and beta-blockers (50% to < 100% target dosage, HR 1.30 [95% CI 1.00–1.69];
< 50% target dosage, HR 1.41 [95% CI 1.11–1.79; none, HR 1.24 [95% CI 0.92–1.67];
overall P= 0.042). Lower dosing of ACEIs/ARBs/ARNIs was independently associated with higher
risk of HF hospitalization (50% to < 100% target dosage, HR 1.08 [95% CI 0.90–1.30];
< 50% target dosage, HR 1.23 [1.04–1.47]; none, HR 1.29 [1.04–1.60]; overall P= 0.046), but beta-blocker dosing was not (overall P= 0.085). Target dosing of MRAs was not associated with risk of mortality or HF hospitalization.
For each GDMT, compared with target dosing, lower dosing was not associated with change
in the KCCQ-OS at 12 months, with the potential exception of worsening KCCQ-OS scores
with lower dosing of ACEIs/ARBs/ARNIs.
In this contemporary U.S. outpatient HFrEF registry, target dosing of ACEI/ARB/ARNI
and beta-blocker therapy was associated with reduced mortality and was variably associated
with HF hospitalization and patient-reported outcomes. MRA dosing was not associated
with outcomes. The totality of these findings support the benefits of target dosing
of GDMT in routine practice, as tolerated, with unmeasured differences among patients
receiving differing dosages potentially explaining the differing results seen here
compared with randomized clinical trials.