By Van Selby, MD
Assistant Professor of Medicine, UCSF Cardiology Division, Advanced Heart Failure Section, San Francisco
Dr. Selby reports no financial relationships relevant to this field of study.
SOURCE: Fiuzat M, et al. Heart rate or beta-blocker dose? Association with outcomes in ambulatory heart failure patients with systolic dysfunction: Results from the HF-ACTION trial. JACC Heart Fail 2015. doi:10.1016/j.jchf.2015.09.002.
Beta-blockers reduce both morbidity and mortality in chronic heart failure with reduced ejection fraction (HFrEF). More recently, heart rate (HR) reduction has been associated with better outcomes in HFrEF. Fiuzat et al aimed to determine whether higher beta-blocker doses or reduced HR has a greater impact on outcomes in chronic HFrEF.
To compare the relative effects of HR reduction and higher beta-blocker dose, they performed a secondary analysis of the HF-ACTION trial. HF-ACTION randomized 2331 patients with ambulatory NYHA functional class II-IV heart failure and left ventricular ejection fraction < 35% to exercise training vs usual care. Patients were on stable doses of heart failure therapies for at least 6 weeks prior to study enrollment, with 94.5% receiving beta-blockers. Secondary analysis patients were categorized as either high (≥ 25 mg/day of carvedilol equivalent) or low beta-blocker dose and high (≥ 70 bpm) or low HR. The primary endpoint was the composite of death and all-cause hospitalization, and median follow-up was 2.5 years.
In unadjusted analyses, both higher beta-blocker dose and lower HR were associated with reduced risk of death or hospitalization. However, after adjusting for other predictors, only higher beta-blocker dose was significantly associated with the primary outcome (hazard ratio 0.77; P = 0.03). Higher beta-blocker dose was associated with improved outcomes regardless of the achieved HR. There was no increased risk of bradycardia among patients on higher doses of beta-blockers. The authors concluded that in HFrEF, titrating beta-blocker doses may confer a greater benefit than reducing HR.
COMMENTARY
Multiple large randomized trials have shown that treatment with beta-blockers leads to symptomatic improvement, reduced hospitalization, and increased survival in HFrEF. These trials generally targeted high doses, and as a result current guidelines recommend treatment with moderate to high doses of beta-blockers in HFrEF. However, evidence of a strong dose-response relationship for beta-blockers is somewhat limited, and one meta-analysis found no association between beta-blocker dose and outcome. The findings from the current analysis show that patients with higher beta-blocker doses have a lower risk of hospitalization or death, even after adjusting for other clinical predictors, and support the current recommendations.
Despite clear guideline recommendations, multiple studies have found that most patients with HFrEF are not titrated to target doses. There are many reasons for this, including concern for side effects, health system barriers that prevent easy medication titration, and possibly a lack of clear evidence that outcomes improve at higher doses. With the recent FDA approval of ivabradine, clinicians may be tempted to keep beta-blockers at lower doses and instead initiate ivabradine to achieve HR goals in patients with HFrEF. Ivabradine effectively lowers HR without many of the side effects associated with beta-blockers, and does not affect blood pressure. The findings of Fiuzat and others remind us that such practices are unacceptable for patients with HFrEF. Beta-blockers have beneficial effects in HFrEF beyond lowering HR, and titrating to target doses must be considered the first-line treatment.
This was a post-hoc analysis with several limitations. It is possible that patients on lower doses of beta-blockers were sicker, and therefore unable to tolerate target doses. The authors adjusted for many clinical characteristics, but residual confounders are a possibility. Furthermore, this study did not evaluate the strategy of using a non-beta-blocking medication such as ivabradine to lower HR; rather, it studied the association between baseline HR and outcomes.
Certain strategies can help reach target beta-blocker doses, and there are published guidelines to help increase the chance of successful up-titration. Always start with low doses (i.e., carvedilol 3.125 mg twice per day), and there should be minimal or no evidence of fluid retention when beta-blockers are initiated or up-titrated. Patients should be instructed to check their weight every morning after every dose increase to identify worsening fluid retention, and they should be advised that any initiation or dose increase may be associated with mild worsening of heart failure symptoms that often resolves after several weeks.
A growing body of literature shows the importance of reaching target doses of beta-blockers in HFrEF. It can be difficult at times, and may require close monitoring. Nevertheless, given the clear benefit this must be the goal for all HFrEF patients. The approval of ivabradine will be a useful addition for a small portion of HFrEF patients, but absolutely cannot substitute for higher beta-blocker doses in those patients who can tolerate it.
