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May 3, 2022 Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 e930

CLINICAL STATEMENTS AND GUIDELINES neurohormonal, and clinical effects consistent with those expected after interference with the renin-angiotensin system.17,18 Unlike ACEi, ARB do not inhibit kininase and are associated with a much lower incidence of cough and angioedema, although kininase inhibition by ACEi may produce beneficial vasodilatory effects. Patients who are intolerant to ACEi because of cough or angioedema should be started on an ARB. ARB should be started at low doses and titrated upward, with an attempt to use doses shown to reduce the risk of cardiovascular events in clinical trials. ARB should be given with caution to patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium (>5.0 mEq/L). Although ARB are alternatives for patients with ACEi-induced angioedema, caution is advised because some patients have also developed angioedema with ARB. For those patients for whom an ACEi or ARNi is inappropriate, use of an ARB remains advised. 4.	 Several cost-effectiveness analyses consistently found that ACEi therapy provides high value for patients with chronic HF. A model-based analysis, using generic ACEi costs, found ACEi therapy was high value.19 Previous analyses also found ACEi therapy was high value despite previously higher ACEi costs.19,21,22,24,25 This includes a trial-based analysis of SOLVD (Studies of Left Ventricular Dysfunction) that modeled long-term outcomes.21 Previous analyses included a range of clinical scenarios including asymptomatic LV dysfunction24 and LV dysfunction after MI,25 with ACEi therapy providing high value in each. There are limited data on the cost-effectiveness of ARBs from 2 clinical trials—a within-trial analysis of Val-HeFT (Valsartan Heart Failure Trial)23 and an analysis of the ELITE (Evaluation of Losartan in the Elderly) study20— which both suggested ARB therapy is high value. The high value of ARB therapy is also supported by its similar efficacy as ACEi therapy and the low-cost generic availability for both medication classes. 5.	 Patients with chronic stable HFrEF who tolerate ACEi and ARB should be switched to ARNi. In patients with mild-to-moderate HF who were able to tolerate both a target dose of enalapril (10 mg twice daily) and then subsequently an ARNi (sacubitril-valsartan; 200 mg twice daily, with the ARB component equivalent to valsartan 160 mg), hospitalizations and mortality were significantly decreased with the valsartan-sacubitril compound compared with enalapril.1 Another RCT and metaanalysis showed improvement in LV remodeling parameters with ARNi compared with enalapril.4,5

6.	 Multiple model-based analyses evaluated the economic value of ARNi therapy compared with ACEi therapy using the results of PARADIGM-HF.26–29,41 Three high-quality analyses26,28,29 consistently found costs per QALY <$60 000, which provides high value according to the benchmarks adopted for the current clinical practice guideline. These results were robust to the range of sacubitril-valsartan costs currently seen in care. These results were sensitive to the estimated mortality reduction and duration of treatment effectiveness. ARNi would need to maintain effectiveness beyond the PARADIGM-HF study period (mean, 27 months) to be considered high value.29 If clinical benefit were limited to 27 months, ARNi would be intermediate value. One additional analysis, based on the PIONEER-HF trial, found that inpatient initiation of ARNi was also high value compared with delayed initiation postdischarge.27

7.	 Oral neprilysin inhibitors, used in combination with ACEi, can lead to angioedema, and concomitant use is contraindicated and should be avoided. A medication that represented a neprilysin inhibitor and an ACEi—omapatrilat—was studied in hypertension and HF, but its development was terminated because of an unacceptable incidence of angioedema.30,31 and associated significant morbidity. This adverse effect was thought to occur because ACEi and neprilysin break down bradykinin, which can directly or indirectly cause angioedema31,32 An ARNi should not be administered within 36 hours of switching from or to an ACEi. 8.	 Omapatrilat, a neprilysin inhibitor (as well as an ACEi and aminopeptidase P inhibitor), was associated with a higher frequency of angioedema than that seen with enalapril in an RCT of patients with HFrEF.30 In a very large RCT of hypertensive patients, omapatrilat was associated with a 3-fold increased risk of angioedema compared with enalapril.31 Black patients and patients who smoked were particularly at risk. The high incidence of angioedema ultimately led to cessation of the clinical development of omapatrilat.33,34 Because of these observations, angioedema was an exclusion criterion in the first large trial assessing ARNi therapy in patients with hypertension35 and then in the large trial that showed clinical benefit of ARNi therapy in HFrEF.1 The rates of angioedema were numerically higher in patients treated with ARNi than in patients treated with ACEi in PARADIGM-HF, although this difference did not reach significance.1 ARNi therapy should not be administered in patients with a history of angioedema because of the concern that it will increase the risk of a recurrence of angioedema. 9.	 Angioedema attributable to ACEi is thought to result from defective degradation of the vasoactive peptides bradykinin, des-Arg9-BK (a metabolite

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