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Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 May 3, 2022 e935 CLINICAL STATEMENTS AND GUIDELINES

or diabetes with risk factors to 2 g of icosapent ethyl (a highly purified EPA) twice daily or placebo and showed a reduced risk for the composite of cardiovascular death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina.3 In reported studies, omega-3 PUFA therapy has been well tolerated. Recent studies have reported that in patients with cardiovascular risk treated with omega-3 fatty acid, there may be a dose-related risk of AF.3,15,16 2.	 Hyperkalemia is common in HF as a result of the syndrome itself, comorbidities (diabetes, CKD), and use of RAASi, and can increase the risk for ventricular arrhythmias and mortality.11 Hyperkalemia results in dose reductions or discontinuation of RAASi, compromising their cardiorenal benefit in HF.12 Two newer gastrointestinal potassium binders—patiromer (RLY5016) and sodium zirconium cyclosilicate (SZC)—remove potassium by exchanging cations (calcium for patiromer, and sodium and hydrogen for SZC), leading to increased fecal excretion. Both agents have been FDA approved for treatment of hyperkalemia for patients receiving RAASi. In the PEARL-HF (Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder in patients with chronic heart failure) trial, patiromer led to lower potassium levels, less hyperkalemia, and a higher proportion of patients able to increase spironolactone dose to 50 mg daily compared with placebo.5 The HARMONIZE (Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance) trial included 94 patients (out of 258 total) with HF (87 of whom entered the double-blind phase).6,13 The SZC groups achieved lower potassium levels overall compared with placebo, and a higher proportion maintained normokalemia (potassium levels, <5.1 mEq/L). Whether patiromer or SZC improve clinical outcomes is under investigation. Adverse effects for the newer potassium binders include hypomagnesemia (for patiromer) and edema (for SZC). 3.	 In several retrospective analyses, the risk of thromboembolic events was not lower in patients with HF taking warfarin than in patients not treated with antithrombotic drugs.17–19 The use of warfarin was associated with a reduction in major cardiovascular events and death in patients with HF in some studies but not in others.20–22 An RCT that compared the outcome of patients with HFrEF assigned to aspirin, warfarin, or clopidogrel found that no therapy was superior.7 Another trial that compared aspirin with warfarin in patients with reduced LVEF, sinus rhythm, and no cardioembolic source showed no difference in either the primary outcome of death, stroke, or intracerebral hemorrhage, and no difference in the combined outcome of death, ischemic stroke, intracerebral hemorrhage, MI, or HF hospitalization.8 There was a significant increase in major bleeding with warfarin. A trial of rivaroxaban in patients with HFrEF, CAD, and normal sinus rhythm showed no difference in mortality, MI, and stroke compared with placebo.9 Therefore, there is no evidence of benefit for anticoagulation in HF patients without a specific indication (eg, VTE, AF, a previous thromboembolic event, or a cardioembolic source).

7.3.7 Drugs of Unproven Value or That May Worsen HF

Recommendations for Drugs of Unproven Value or Drugs That May Worsen HF Referenced studies that support the recommendations are summarized in the Online Data Supplements.

COR LOE Recommendations

3: No Benefit A 1.	 In patients with HFrEF, dihydropyridine calcium channel-blocking drugs are not recommended treatment for HF.1,2

3: No Benefit B-R 2.	 In patients with HFrEF, vitamins, nutritional supplements, and hormonal therapy are not recommended other than to correct specific deficiencies.3–9

3: Harm A 3.	 In patients with HFrEF, nondihydropyridine calcium channel-blocking drugs are not recommended.10–13

3: Harm A 4.	 In patients with HFrEF, class IC antiarrhythmic medications and dronedarone may increase the risk of mortality.14–16

3: Harm A 5.	 In patients with HFrEF, thiazolidinediones increase the risk of worsening HF symptoms and hospitalizations.17–21

3: Harm B-R 6.	 In patients with type 2 diabetes and high cardiovascular risk, the dipeptidyl peptidase-4 (DPP-4) inhibitors saxagliptin and alogliptin increase the risk of HF hospitalization and should be avoided in patients with HF.22–24

3: Harm B-NR 7.	 In patients with HFrEF, NSAIDs worsen HF symptoms and should be avoided or withdrawn whenever possible.25–28

Synopsis Although there is strong evidence for benefit with selected medications for HFrEF as outlined in Section 7.3, “Pharmacological Treatment for HF With Reduced Ejection Fraction (HFrEF),” there remain several classes of medications that have either unproven value or potential for harm (Table 13). These recommendations are not exhaustive but focus on the most relevant and commonly encountered medications in the management of patients with HFrEF: calcium channel blockers; antiarrhythmic agents; NSAIDs; medications for treatment of type 2 diabetes including thiazolidinediones and DPP-4 inhibitors; and vitamins, hormones, and nutritional supplements.

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