Recommendations for Stage C HFpEF

CORLOERecommendationsComment/Rationale
IBSystolic and diastolic blood pressure should be controlled in patients with HFpEF in accordance with published clinical practice guidelines to prevent morbidity (164,165).2013 recommendation remains current.
ICDiuretics should be used for relief of symptoms due to volume overload in patients with HFpEF.2013 recommendation remains current.
IIaCCoronary revascularization is reasonable in patients with CAD in whom symptoms (angina) or demonstrable myocardial ischemia is judged to be having an adverse effect on symptomatic HFpEF despite GDMT.2013 recommendation remains current.
IIaCManagement of AF according to published clinical practice guidelines in patients with HFpEF is reasonable to improve symptomatic HF.2013 recommendation remains current (Section 9.1 in the 2013 HF guideline).
IIaCThe use of beta-blocking agents, ACE inhibitors, and ARBs in patients with hypertension is reasonable to control blood pressure in patients with HFpEF.2013 recommendation remains current.
IIbB-RIn appropriately selected patients with HFpEF (with EF ≥45%, elevated BNP levels or HF admission within 1 year, estimated glomerular filtration rate >30 mL/min, creatinine <2.5 mg/dL, potassium <5.0 mEq/L), aldosterone receptor antagonists might be considered to decrease hospitalizations (83,166,167).NEW: Current recommendation reflects new RCT data.
See Online Data Supplement C.
Mechanistic studies have suggested that mineralocorticoid receptor antagonists can improve measures of diastolic function in patients with HFpEF, possibly by a similar effect on remodeling (83,168).
The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial (166) investigated the effects of spironolactone on a combined endpoint of death, aborted cardiac death, and HF hospitalization in patients with HFpEF. A small reduction (HR=0.89) in this composite endpoint did not reach statistical significance, although HF hospitalization was reduced (HR=0.83); known side effects of hyperkalemia and rising creatinine were seen more commonly in the treatment group (166). An unusual amount of regional variation was seen in this trial, prompting a post-hoc analysis (167) that showed that rates of the primary endpoint were 4-fold lower in Russia/Georgia than in North America and South America (the Americas). Rates in the Americas were comparable to those in other HFpEF trials (169,170). The post-hoc analysis showed efficacy in the Americas (HR=0.83) but not in Russia/Georgia (HR=1.10). Moreover, a sample of the Russia/Georgia population, despite having been in the active treatment arm, had nondetectable levels of the metabolite of spironolactone. These post-hoc analyses have significant limitations, but they suggest that in appropriately selected patients with symptomatic HFpEF (with ejection fraction [EF] ≥45%, elevated BNP level or HF admission within 1 year, estimated glomerular filtration rate >30 mL/min creatinine <2.5 mg/dL, and potassium <5.0 mEq/L), particularly in those with elevated BNP levels, use of spironolactone might be considered with close monitoring of potassium and renal function. Confirmatory studies are required.
With regard to the use of mineralocorticoid receptor antagonists, creatinine should be <2.5 mg/dL in men or <2.0 mg/dL in women (or estimated glomerular filtration rate >30 mL/min) and potassium should be <5.0 mEq/L. Careful monitoring of potassium, renal function, and diuretic dosing represents best practices at initiation and during follow-up thereafter to minimize risk of hyperkalemia and worsening renal function.
IIbBThe use of ARBs might be considered to decrease hospitalizations for patients with HFpEF (169).2013 recommendation remains current.
III: No BenefitB-RRoutine use of nitrates or phosphodiesterase-5 inhibitors to increase activity or QoL in patients with HFpEF is ineffective (171,172).NEW: Current recommendation reflects new data from RCTs.
See Online Data Supplement C.
Nitrate therapy can reduce pulmonary congestion and improve exercise tolerance in patients with HFrEF. However, the NEAT-HFpEF (Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction) trial (171) randomized 110 patients with EF ≥50% on stable HF therapy, not including nitrates, and with activity limited by dyspnea, fatigue, or chest pain, to either isosorbide mononitrate or placebo and found no beneficial effects on activity levels, QoL, exercise tolerance, or NT-proBNP levels. On the basis of this trial, routine use of nitrates in patients with HFpEF is not recommended. This recommendation does not apply to patients with HFpEF and symptomatic CAD for whom nitrates may provide symptomatic relief. Phosphodiesterase-5 inhibition augments the nitric oxide system by upregulating cGMP activity. The RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) trial (172) randomized 216 patients with EF ≥50% on stable HF therapy and with reduced exercise tolerance (peak observed Vo2 <60% of predicted) to phosphodiesterase-5 inhibition with sildenafil or placebo. This study did not show improvement in oxygen consumption or exercise tolerance.
III: No BenefitCRoutine use of nutritional supplements is not recommended for patients with HFpEF.2013 recommendation remains current.