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Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 May 3, 2022 e937 CLINICAL STATEMENTS AND GUIDELINES

cardiomyopathy, diltiazem had no impact on mortality13 but, in HFrEF after acute MI, diltiazem was associated with a higher risk of recurrent HF.11,12 4.	 In the CAST (Cardiac Arrhythmia Suppression) trial, patients with asymptomatic ventricular arrhythmias post-MI on the class IC antiarrhythmics encainide or flecainide had increased mortality.14 The applicability of CAST to patients without recent MI or to other class I antiarrhythmic drugs is uncertain, but class IC antiarrhythmic agents are generally avoided in patients with structural heart disease. In ANDROMEDA (Antiarrhythmic Trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease Study), for the class III antiarrhythmic dronedarone, patients with HFrEF who were hospitalized had increased mortality.16 In the SWORD (Survival With ORal D-sotalol) trial of the class III antiarrhythmic sotalol, patients with HF post-MI had increased mortality.15 However, SWORD was published in 1996, and whether sotalol would be harmful in the current era of GDMT and ICDs is uncertain; sotalol may be used for refractory atrial-ventricular arrhythmias with close monitoring for decompensation. Amiodarone46,47 and dofetilide48,49 are the only antiarrhythmic agents with neutral effects on mortality in clinical trials of patients with HFrEF. Class IA antiarrhythmic agents such as quinidine and class IB agents such as mexiletine have not been studied and may be indicated for the management of refractory ventricular arrhythmias in the context of the individual patient’s risk benefit calculus and in conjunction with electrophysiology consultation. 5.	 Thiazolidinediones increase insulin sensitivity by activating nuclear peroxisome proliferator-activated receptor gamma (PPAR-γ). Expressed in virtually all tissues, PPAR-γ also regulates sodium reabsorption in the collecting ducts of the kidney. In observational cohort studies,17 meta-analysis,18 and clinical trials,19–21 thiazolidinediones have been associated with increased incidence of fluid retention and HF events in those patients with19,21or without18,20a previous history of HF. 6.	 DPP-4 is a cell-surface enzyme that deactivates several peptides include glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1. DPP-4 inhibitors affect glucose regulation through multiple mechanisms, including enhancement of glucose-dependent insulin secretion, slowed gastric emptying, and reduction of postprandial glucagon and of food intake. The impact of DPP-4 inhibitors on cardiovascular outcomes in patients with diabetes and high cardiovascular risk has been assessed in multiple RCTs. Saxagliptin increased the risk of hospitalization for HF,22 as did alogliptin in a post hoc analysis including only patients with no HF history,23,50 but sitagliptin51,52and linagliptin53–55 did not; these findings may have been a result of baseline differences in the use of metformin, thiazolidinediones, and insulin, which also affect HF risk. The FDA recommends discontinuation specifically of saxagliptin and alogliptin in patients who develop HF,56 and whether the risk of worsening HF is a class effect of DPP-4 inhibitors is unclear. 7.	 NSAIDs inhibit the synthesis of renal prostaglandins, which mediate vasodilation in the kidneys and directly inhibit sodium resorption in the thick ascending loop of Henle and collecting tubule. Hence, NSAIDs can cause sodium and water retention and blunt the effects of diuretics. Several observational cohort studies have revealed increased morbidity and mortality in patients with HF using either nonselective or selective NSAIDs.25–28

7.3.8 GDMT Dosing: Sequencing and Uptitration

Recommendations for GDMT Dosing: Sequencing and Uptitration Referenced studies that support the recommendations are summarized in the Online Data Supplements.

COR LOE Recommendations

1 A 1.	 In patients with HFrEF, titration of guidelinedirected medication dosing to achieve target doses showed to be efficacious in RCTs is recommended, to reduce cardiovascular mortality and HF hospitalizations, unless not well tolerated.1–10

2a C-EO 2.	 In patients with HFrEF, titration and optimization of guideline-directed medications as frequently as every 1 to 2 weeks depending on the patient’s symptoms, vital signs, and laboratory findings can be useful to optimize management.

Synopsis Clinical trials of ACEi, ARB, ARNi, beta blockers, and most other HFrEF medications had therapy initiated at low dose by trial protocol.1–9,11–14 If the initial dose was tolerated, the protocol would then direct the uptitration of medication dose over time to a specified target dose (Table 14), unless not well tolerated. Even if symptoms improved or other indicators of response were shown at lower doses, the medication dose would still be increased to the trial-defined target doses. Because these target doses were the ones that established the efficacy and safety of these medications in HFrEF and serve as the basis of the guideline recommendations (Table 15), use of these target doses is recommended, if tolerated.1–9,11–14 Use of all 4 drug classes has been estimated to reduce all-cause mortality by 73% compared with no treatment.15 If the target dose cannot be achieved or is not well tolerated, then the highest tolerated dose is recommended.

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