Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction

Abstract

Heart failure patients are classified by ejection fraction (EF) into distinct groups: heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF). Although patients with heart failure commonly have multiple comorbidities that complicate management and may adversely affect outcomes, their role in the HFpEF and HFrEF groups is not well-characterized. This review summarizes the role of noncardiac comorbidities in patients with HFpEF versus HFrEF, emphasizing prevalence, underlying pathophysiologic mechanisms, and outcomes. Pulmonary disease, diabetes mellitus, anemia, and obesity tend to be more prevalent in HFpEF patients, but renal disease and sleep-disordered breathing burdens are similar. These comorbidities similarly increase morbidity and mortality risk in HFpEF and HFrEF patients. Common pathophysiologic mechanisms include systemic and endomyocardial inflammation with fibrosis. We also discuss implications for clinical care and future HF clinical trial design. The basis for this review was discussions between scientists, clinical trialists, and regulatory representatives at the 10th Global CardioVascular Clinical Trialists Forum.

Keywords: comorbidities; ejection fraction; heart failure.

Figure 1. Clinical Trial Considerations Related to Comorbidities

Trial protocols should consider feasibility of encouraging the inclusion of patients with comorbidities (as able). Trial sites should be selected on the basis, in part, of the comorbidity burden of the patient populations. Intensified safety monitoring may be needed in the context of comorbidities. Study entry criteria may need to be adjusted to acknowledge differences in biomarker thresholds in the context of comorbidities such as obesity and/or renal function. Exclusionary biomarker criteria (e.g., renal biomarkers) may offer mechanisms to support patient safety. As able, consider targeting comorbidities as a primary intervention and include comorbidity-specific trial endpoints (e.g., dyspnea relief and beta-blocker usage in context of COPD). Trialists should also take into account regional differences in the prevalence of comorbidities when performing sample size calculations and designing trials (e.g., differential event rates in the presence of comorbid diseases).

Figure 2. Central Illustration. Associations Between Heart Failure and Comorbidities

Pathways linking several common comorbidities to disease progression in both HFpEF and HFrEF are presented and factors exacerbating other comorbid conditions are highlighted. These comorbidities are interrelated by several common mechanisms, including inflammation and worsening congestion, as well as by sympathetic and renin-angiotensin aldosterone system activation. Heart failure influences each of the comorbidities, demonstrating the bidirectional association. Abbreviations: COPD = chronic obstructive pulmonary disease; CV = cardiovascular; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LV = left ventricular; RAAS = renin-angiotensin-aldosterone system; RV = right ventricular.