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Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 May 3, 2022 e951 CLINICAL STATEMENTS AND GUIDELINES

Fibrillation (AF) in HF,” for HF specific recommendations for AF). Although beta blockers and nondihydropyridine calcium channel blockers are often considered as first-line agents for heart rate control in patients with HFpEF, a recent smaller openlabel trial, RATE-AF in elderly patients with AF and symptoms of HF (most with preserved LVEF), compared the use of the beta blocker, bisoprolol, to digoxin.32 At 6 months, the primary endpoint of QOL was similar between the 2 groups. However, several secondary QOL endpoints, functional capacity, and reduction in NT-proBNP favored digoxin at 12 months. There was a similar heart rate reduction in both groups. Of note, more adverse events such as higher rates of dizziness, lethargy, and hypotension occurred with beta blockers than digoxin. The comprehensive care of AF is beyond the scope of these guidelines. AF-specific care recommendations can be found in separate ACC/AHA clinical practice guidelines.33,34 4.	 MRAs improve diastolic function in patients with HFpEF.35 The TOPCAT trial investigated the effects of spironolactone in patients with HFpEF. The small reduction (HR, 0.89) in the composite of death, aborted cardiac death, and HF hospitalization was not statistically significant, although HF hospitalization was reduced (HR, 0.83); adverse effects of hyperkalemia and increasing creatinine levels were more common in the treatment group.5 A post hoc analysis6 showed efficacy in the Americas (HR 0.83) but not in Russia-Georgia (HR 1.10). A sample of the Russia-Georgia population in the active treatment arm had nondetectable levels of a spironolactone metabolite. Post hoc analyses have limitations, but they suggest a possibility of benefit in appropriately selected patients with symptomatic HFpEF (LVEF ≥45%, elevated BNP level or HF admission within 1 year, eGFR >30 mL/min/1.73 m2, creatinine <2.5 mg/dL, and potassium <5.0 mEq/L). Furthermore, another post hoc analysis suggested that the potential efficacy of spironolactone was greatest at the lower end of the LVEF spectrum.7 Careful monitoring of potassium, renal function, and diuretic dosing at initiation and follow-up are key to minimizing the risk of hyperkalemia and worsening renal function. 5.	 Although RAAS inhibition strategies have been successful in the treatment of HFrEF, and RAAS activation is suggested in HFpEF,36,37 clinical trials with RAAS inhibition have not showed much benefit in patients HFpEF. In the CHARM- Preserved (Candesartan in patients with chronic HF and preserved left-ventricular ejection fraction) trial, patients with LVEF >40% were randomized to an ARB, candesartan, or to placebo.38 The primary endpoint (cardiovascular death or HF hospitalization) was not significantly different between the 2 groups (HR, 0.89; 95% CI, 0.77–1.03, P=0.118; covariate-adjusted HR, 0.86; P=0.051). Cardiovascular mortality was identical in the 2 groups; HF hospitalizations were lower in the candesartan arm, with borderline statistical significance on the covariate-adjusted analysis only (HR, 0.84; 95% CI, 0.70–1.00; P=0.047; unadjusted P=0.072). The number of individuals hospitalized for HF (reported by the investigator) was lower in the candesartan group than placebo (230 versus 279; P=0.017). A post hoc analysis of the CHARM trials showed that improvement in outcomes with candesartan was greater at the lower end the LVEF spectrum.39 In a meta-analysis of 7694 patients with HFpEF in 4 trials evaluating ARB, there was no signal for benefit on cardiovascular mortality (HR, 1.02), all-cause mortality (HR, 1.02), or HF hospitalization (HR, 0.92; 95% CI, 0.83–1.02).40,41

6.	 In the PARAMOUNT-HF (Prospective Comparison of ARNi With ARB on Management of Heart Failure With Preserved Ejection Fraction) trial, a phase II RCT in patients with HFpEF (LVEF ≥45%), sacubitril-valsartan resulted in a lower level of NT-proBNP after 12 weeks of treatment compared with the ARB, valsartan.42 In the PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure and Preserved Left Ventricular Ejection Fraction) trial, in 4822 patients with HFpEF (LVEF ≥45%, HF admission within 9 months or elevated natriuretic peptide levels, and eGFR ≥30 mL/min/m2), sacubitril-valsartan compared with valsartan did not achieve a significant reduction in the primary composite endpoint of cardiovascular death or total (first and recurrent) HF hospitalizations (rate ratio, 0.87; 95% CI, 0.75-1.01; P=0.06).10 Given the primary outcome was not met, other analyses are exploratory. There was no benefit of sacubitrilvalsartan on cardiovascular death (HR, 0.95) or total mortality (HR, 0.97). There was a signal of benefit for the ARNi for HF hospitalizations (rate ratio, 0.85; 95% CI, 0.72–1.00; P=0.056). The occurrence of hyperkalemia and the composite outcome of decline in renal function favored sacubitril-valsartan, but it was associated with a higher incidence of hypotension and angioedema. In prespecified subgroup analyses, a differential effect by LVEF and sex was noted. A benefit of sacubitrilvalsartan compared with valsartan was observed in patients with LVEF below the median (45%–57%; rate ratio, 0.78; 95% CI, 0.64–0.95), and in women (rate ratio, 0.73; 95% CI, 0.59–0.90).10,43,44 7.	 Nitrate therapy can reduce pulmonary congestion and improve exercise tolerance in patients

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