Gaps in Treatment of Co-morbidities
Common non-cardiac co-morbidities, such as anaemia, lung disease, kidney disease, diabetes and depression, likely play important roles in progression of HF and may interfere with diagnosis and therapy. Anaemia and chronic obstructive pulmonary disease (COPD) may confound the diagnosis of worsening HF. Depression may interfere with a patient’s ability to self-manage. Kidney disease often limits the use of ACEI/ARB, and severe lung disease may limit the use of beta-blocker. Frailty, cancer, gout, obesity and other co-morbidities may also directly affect HF therapy. The long-term safety and efficacy of many treatments for these co-morbidities in patients with HF are unknown. Moreover, as HF trials commonly exclude patients with significant co-morbidities, it is not clear whether GDMT have differential effects in these particular patients.63
Chronic obstructive pulmonary disease (COPD) can co-exist and confound the diagnosis of HF. Unfortunately, patients with severe COPD are often excluded from HF trials, so data are limited in this population.64 Despite concern about beta-blockers exacerbating COPD, it has been shown that even non-selective beta-blockers, such as carvedilol, are not associated with worse outcomes in patients with chronic HF and COPD.65 However, in the setting of an acute COPD exacerbation, the role of beta-blockers remains unknown. Additionally, the use of beta-2 agonist bronchodilators have been implicated in worsening HF, though this finding is limited by the observational nature of the data.66
Anaemia is a common finding in patients with HF and is independently associated with increased mortality risk.67 However, It is unclear whether anaemia is simply a marker of disease severity or a direct mediator of poor outcomes. Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF), the largest RCT to evaluate erythropoiesis-stimulating agents in patients with HFrEF and anaemia, showed no difference in death or HF hospitalisation but increased thromboembolic events in the darbepoetin alfa group (13.5 % versus 10.0 %, p=0.009).68 In patients with HF and iron deficiency, however, the Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial showed that Intravenous (IV) ferric carboxymaltose improved NYHA class, six-minute walk distance and quality of life.69 A multicentre RCT evaluating oral iron in patients with HFrEF and iron deficiency is expected to start soon (NCT02188784).
Diabetes mellitus (DM) is highly associated with poor clinical status in patients with HF.70 The interaction between these two clinical syndromes is complex, and patients with DM have been shown to respond differently to HFrEF therapy compared with non-diabetics.71 From a DM therapy standpoint, while thiazolidinedione has clearly been shown to increase HF, the safety of newer therapies for DM – glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT-2) inhibitors – are unknown for patients with HF. Even insulin, an established treatment, has been associated with higher mortality in patients with advanced HF, though this may be more related to severity of diabetes.72
Chronic kidney disease (CKD) and the associated cardiorenal syndrome portend poorer prognosis and significantly impact management of HF patients.73 Significant renal dysfunction may preclude the use of ACEIs, ARBs and mineralocorticoids in patients with HFrEF. In addition, patients with advanced kidney disease (stage 4 and stage 5 CKD) and end-stage renal disease are frequently excluded from HF trials.74 In the setting of ADHF, no effective therapy for cardiorenal syndrome has been found, perhaps mirroring the lack of progress in ADHF care in the last decade.
Depression is also highly prevalent in patients with HF and independently predicts increased hospitalisation and mortality.75 However, there has been surprisingly little work done on defining the interaction between the two diseases and finding effective therapy. Although data have contested conventional wisdom that beta-blocker is associated with depression, beta-blocker’s effect on patients with concomitant HF and depression is unclear.76 While tricyclic antidepressants should be avoided in patients with HF due to known risks of QT interval prolongation and ventricular arrhythmia, the ideal antidepressant in HF patients is unknown. Sertraline Against Depression and Heart Disease in Chronic Heart Failure (SADHART-CHF), one of the few RCTs to date on this topic, found no benefit with sertraline in patients with HF and depression.77
Finally, pulmonary hypertension (PH) is a common complication of HF and is independently associated with poor prognosis.78 Unfortunately, there is no validated treatment for PH due to left heart disease. Perhaps due to patient heterogeneity, clinical trials have not shown benefits with prostanoids, endothelin-1 antagonists or guanylate cyclase stimulators in patients with HFrEF.79 For patients with HFpEF and PH, one small placebo-controlled trial showed that sildenafil increased exercise capacity and improved haemodynamic status.80 However a larger trial, Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX), evaluated sildenafil in HFpEF and showed no difference in clinical outcomes compared to placebo.81 Ongoing trials are evaluating the role of sildenafil (NCT01616381) and tadalafil (NCT01910389) in patients with PH and HFrEF, and the role of riociguat in patients with PH and HFpEF (NCT01172756). Neither the ACCF/AHA nor the ESC Guideline specifically addresses patients with HF and PH.