Review Article
Bronchodilators in Heart Failure Patients With COPD: Is It Time for a Clinical Trial?

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Abstract

Chronic heart failure (HF) and chronic obstructive pulmonary disease (COPD) commonly coexist, and patients with both diseases fare worse than those with either disease alone. Several factors may contribute to worse outcomes, including an increased burden of care related to greater disease complexity, an overlap of symptoms resulting in misapplication of therapy, and the adverse effects of treatment for one disease on the symptoms and outcomes related to the other. For example, there are conflicting data about the cardiovascular risks of bronchodilators in HF patients who may experience worse outcomes with inhaled beta-2 agonists via arrhythmogenesis, ischemia, and/or attenuation of beta-blocker benefits. In contrast, the long-acting anticholinergic class of bronchodilators has a more reassuring safety profile. Anticholinergic bronchodilators may be the preferred first-line agents for COPD patients with comorbid HF, yet data supporting these recommendations are limited. Therapeutic trials in COPD patients have generally excluded patients with significant HF and vice-versa. This paper reviews bronchodilator therapy in HF and proposes a randomized trial designed to enroll patients with significant COPD and HF to determine the risks and/or benefits of adding a long-acting beta-2 agonist to patients currently taking a long-acting anticholinergic agent.

Section snippets

Factors Contributing to Worse Outcomes With Comorbid COPD and HF

Diagnostic difficulties and the overlapping signs and symptoms between HF and COPD contribute to worse outcomes in this patient population. Lung hyperinflation in COPD can hinder auscultation of rales or an S3, mask radiographic pulmonary edema, and impede acoustic windows on echocardiography, resulting in underestimation of the contribution of HF to the clinical presentation.2 Similarly, HF can reduce lung volumes and obscure the presence of airflow limitation on pulmonary function testing in

Bronchodilator Therapies

The guidelines for COPD management recommend medical therapy based on the degree of airflow obstruction (Fig. 1).32, 33 Treatment for mild obstruction (1-s forced expiratory volume [FEV1] ≥80% of predicted) includes short-acting bronchodilators, and moderate (FEV1 50%–80%) to severe (FEV1 <50%) obstruction warrants regular therapy with long-acting bronchodilators and consideration of inhaled corticosteroids and long-acting beta-agonists as combination therapy (Table 1).34, 35 Current guidelines

Bronchodilators in HF

The impact of inhaled bronchodilators on outcomes has never been prospectively evaluated in HF patients. Limited observational data exist regarding outcomes related to the use of bronchodilators in HF (Table 2). Because worse outcomes with bronchodilators in the studies may be attributed to confounding by indication or may reflect COPD severity rather than an adverse effect of therapy, the results should be viewed as exploratory. Two studies showed that in HF patients (including those with17

B2As

In this review we focus on the effects of B2As via the inhaled route, because data from a moderate-size randomized trial (n = 516) demonstrated increased mortality with an oral B2A in HF patients40 and current COPD clinical practice guidelines favor inhaled bronchodilators.32 The TORCH study investigated a large randomized sample of COPD patients treated with inhaled B2As with or without inhaled steroid compared with placebo.10 That study of 6,112 patients documented that the overall mortality,

Rationale for a Clinical Trial

Few of the observational studies and none of the RCTs of bronchodilators have adequately investigated their use in HF patients.36, 41 More recently, there has been a tendency to favor ACh over B2As in this population18; however, there are little data specifically in HF patients that demonstrate safety and efficacy of an ACh-based regimen. Recent studies excluded HF patients, were not designed to investigate CV events, lacked CV end point adjudication and strict intention-to-treat analysis, and

Proposed Trial

We propose a multicenter double-blind RCT of long-acting ACh therapy with or without long-acting B2A therapy in outpatients with stable HF and COPD. Given the significant heterogeneity of this population, there will be strict inclusion and exclusion criteria (Table 3) designed to focus the investigation on patients with significant systolic dysfunction (ie, beta-blocker requirement) and moderate-severe COPD (ie, bronchodilator requirement) as documented on pulmonary function tests (PFTs; FEV1

Conclusion

COPD is present in up to one-third of HF patients. These patients commonly receive bronchodilator therapies for which safety concerns have not been systematically evaluated. Overall, long-acting AChs have more reassuring cardiovascular safety profiles than B2As and may be the preferred first-line agents for COPD patients with comorbid HF, but these considerations need to be evaluated in a randomized trial before broad clinical application. We have provided the framework for a large-scale

Disclosures

None.

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