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Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 May 3, 2022 e971 CLINICAL STATEMENTS AND GUIDELINES the 6-minute walk test, and QOL of 459 outpatients with chronic HF who received weekly intravenous ferric carboxymaltose until iron repletion.1 The improvement was independent of the presence of anemia. These findings were confirmed in 2 more recent trials.2,3 The IRONOUT HF (Iron Repletion Effects on Oxygen Uptake in Heart Failure) trial, however, showed no such improvement with oral iron supplementation.28 This is attributed to the poor absorption of oral iron and inadequacy of oral iron to replete the iron stores in patients with HF. Therefore, oral iron is not adequate to treat iron deficiency anemia in patients with HF. Although these trials were underpowered to detect reductions in hard clinical endpoints, 2 meta-analyses have suggested intravenous iron is associated with a reduction in cardiovascular death and hospitalizations.27,29 Most recently, the AFFIRM-AHF multicenter trial, which included 1132 patients with EF <50% hospitalized for HF, showed a decrease in hospitalization for HF with intravenous ferric carboxymaltose compared to placebo (RR, 0.74; 95% CI, 0.58–0.94) but no reduction in cardiovascular death.4 2. Anemia in patients with HF is associated with impaired erythropoietin production, with low levels found to be associated with worse long-term outcomes.30,31 Although small studies examining the use of erythropoietin-stimulating agents for the treatment of anemia in patients with HF have suggested a trend toward improvement in functional capacity and reduction in hospitalization, a high-quality randomized trial of darbepoetin alpha in 2278 patients showed no benefit and an increase in thrombotic events, including stroke.5,6,32 A meta-analysis of 13 trials supports these findings.6 Accordingly, erythropoietin-stimulating agent therapy is not recommended for the treatment of anemia in patients with HF. Hypertension 3. Clinical trials assessing the impact of goal blood pressure reduction on outcomes in patients with HFrEF and concomitant hypertension are lacking. The optimal blood pressure goal and antihypertensive regimen are not known. Antihypertensive therapy is associated with a decrease in the risk of incident HF in the general population,33,34 notably with the more stringent SBP target <120 mm Hg.35 However, low blood pressure, not as a part of an antihypertensive treatment, has been associated with poor outcomes in patients with HFrEF.7,8 This observation may reflect the association between low cardiac output and low blood pressure, rather than the effects of treatment for hypertension. Nevertheless, hypertension in patients with HFrEF represents an opportunity to maximize GDMT to goal blood pressures defined by the ACC/AHA hypertension guidelines.36 Sleep Disorders 4. In patients with HF, daytime sleepiness—typically a feature of obstructive sleep apnea—may not reflect the degree of underlying sleep-disordered breathing.37 Hence, the decision to refer a patient for a sleep study should be based on clinical judgment. Because the treatment of obstructive sleep apnea and central sleep apnea differ, and because obstructive sleep apnea and central sleep apnea can co-occur,9,11,12 sleep studies can inform clinical decision-making in patients with HF. 5. In patients with HF and central sleep apnea, continuous positive airway pressure is associated with better sleep quality and nocturnal oxygenation9 but has not been shown to affect survival.38 In adults with HFrEF and sleep-disordered breathing, meta-analyses of RCTs have shown that positive airway pressure therapy results in a moderate reduction in BNP39 and improvement in blood pressure and LVEF.40 6. Adaptive servo-ventilation was associated with increased mortality in 2 RCTs involving patients with HFrEF and central sleep apnea.11,12 Metaanalyses have supported these results.41,42 The weight of evidence does not support the use of adaptive servo-ventilation for central sleep apnea in HFrEF. Diabetes 7. The American Diabetes Association guidelines recommend the use of SGLT2i as first-line agent for the treatment of hyperglycemia in patients with diabetes with HF or at high risk of HF.43 SGLT2i are the first class of glucose-lowering agents to receive approval from the FDA for the treatment of HFrEF. Treatment of patients with type 2 diabetes with SGLT2i, including canagliflozin, dapagliflozin, empagliflozin, and sotagliflozin, is associated with a reduction in major adverse cardiovascular events, including hospitalization for HF and cardiovascular death.44 The mechanisms underlying the improvement in cardiovascular outcomes attributed to SGLT2i are, however, unknown but appear to be only partially related to the glucosuric effect.45 Two RCTs totaling 8474 patients with NYHA class II, III, or IV HF and EF ≤40%—DAPA-HF assessing dapagliflozin and EMPEROR-Reduced assessing empagliflozin—showed significant reductions in the relative risk of all-cause death (13%), cardiovascular Downloaded from http://ahajournals.org by on October 7, 2026