7.3 Pharmacological Treatment^∗ for HFrEF

7.3.1 Renin-Angiotensin System Inhibition With ACEi or ARB or ARNi

Synopsis

Inhibition of the renin-angiotensin system is recommended to reduce morbidity and mortality for patients with HFrEF, and ARNi, ACEi, or ARB are recommended as first-line therapy (1-18). If patients have chronic symptomatic HFrEF with NYHA class II or III symptoms and they tolerate an ACEi or ARB, they should be switched to an ARNi because of improvement in morbidity and mortality (1-5). An ARNi is recommended as de novo treatment in hospitalized patients with acute HF before discharge given improvement in health status, reduction in the prognostic biomarker NT-proBNP, and improvement of LV remodeling parameters compared with ACEi/ARB. Although data are limited, the use of an ARNi may be efficacious as de novo treatment in patients with symptomatic chronic HFrEF to simplify management. ARB may be used as an alternative to ACEi in the setting of intolerable cough, or as alternatives to ACEi and ARNi in patients with a history of angioedema. If patients are switched from an ACEi to an ARNi or vice versa, there should be at least 36 hours between ACEi and ARNi doses.

Recommendation-Specific Supportive Text

1. An ARNi is composed of an ARB and an inhibitor of neprilysin, an enzyme that degrades natriuretic peptides, bradykinin, adrenomedullin, and other vasoactive peptides. In PARADIGM-HF (Prospective Comparison of ARNi with ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure), an RCT that compared the first approved ARNi, sacubitril-valsartan, with enalapril in symptomatic patients with HFrEF tolerating an adequate dose of either ACEi or ARB, sacubitril-valsartan significantly reduced the composite endpoint of cardiovascular death or HF hospitalization by 20% relative to enalapril (1). The benefit was observed to a similar extent for death and HF hospitalization and was consistent across prespecified subgroups (1). Use of an ARNi is more frequently associated with symptomatic hypotension and a comparable incidence of angioedema when compared with enalapril (1). Sacubitril-valsartan has been approved for patients with symptomatic HF. HF effects and potential off-target effects may be complex with inhibition of the neprilysin enzyme, which has multiple biological targets. Trial data have included ACEi/ARB-naïve patients before ARNi initiation (53% in the PIONEER-HF [Comparison of Sacubitril-Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode] trial and 24% in the TRANSITION [Comparison of Pre- and Post-discharge Initiation of Sacubitril/Valsartan Therapy in HFrEF Patients After an Acute Decompensation Event] trial) and have shown similar efficacy and safety in treatment-naïve patients (2,3). The PIONEER-HF trial showed that ARNi reduced NT-proBNP levels in patients hospitalized for acute decompensated HF without increased rates of adverse events (worsening renal function, hyperkalemia, symptomatic hypotension, angioedema) when compared with enalapril (3). Additional outcome analyses suggested reduction in all-cause mortality and rehospitalization for HF but were only hypothesis-generating as exploratory study endpoints. In the open-label TRANSITION trial, patients with HFrEF hospitalized with worsening HF were randomized to start ARNi either before or after discharge (2). Safety outcomes were similar for both arms, suggesting that early initiation may simplify management (rather than initiating and uptitrating ACEi first and then switching to ARNi) (2). ARNi should be initiated de novo in patients hospitalized with acute HFrEF before discharge in the absence of contraindications. ARNi may be initiated de novo in patients with chronic symptomatic HFrEF to simplify management, although data are limited. The PARADISE-MI (Prospective ARNi vs ACE Inhibitor Trial to DetermIne Superiority in Reducing Heart Failure Events After MI) trial (40) will provide information on whether sacubitril-valsartan will significantly reduce the rate of cardiovascular death, HF hospitalization or outpatient HF requiring treatment in patients after acute MI, with LVEF ≤40% and/or pulmonary congestion, and 1 of 8 additional risk-enhancing factors like AF, previous MI, diabetes, compared with the ACEi ramipril; and whether the safety and tolerability of sacubitril-valsartan was comparable to that of ramipril. Thus, at the present time, the efficacy of ARNi in patients with LV dysfunction, and HF in the early post-MI period, remains uncertain.

2. ACEi reduce morbidity and mortality in HFrEF. RCTs clearly establish the benefits of ACE inhibition in patients with mild, moderate, or severe symptoms of HF and in patients with or without CAD (6-11). Data suggest that there are no differences among available ACEi in their effects on symptoms or survival (12). ACEi should be started at low doses and titrated upward to doses shown to reduce the risk of cardiovascular events in clinical trials. ACEi can produce angioedema and should be given with caution to patients with low systemic blood pressures, renal insufficiency, or elevated serum potassium (>5.0 mEq/L). If maximal doses are not tolerated, intermediate doses should be tried; abrupt withdrawal of ACE inhibition can lead to clinical deterioration and should be avoided. Although the use of an ARNi in lieu of an ACEi for HFrEF has been found to be superior, for those patients for whom ARNi is inappropriate, continued use of an ACEi for all classes of HFrEF remains strongly advised.

3. ARB have been shown to reduce mortality and HF hospitalizations in patients with HFrEF in large RCTs (14-16). Long-term treatment with ARB in patients with HFrEF produces hemodynamic, 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 dysfunction (24) 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) study (20)—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 meta-analysis 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 analyses (26,28,29) 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 angioedema (31,32). 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 hypertension (35) 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 of bradykinin), and substance P (36,37). ACEi should not be administered to patients with any history of angioedema, but ARB do not interfere as directly with bradykinin metabolism and have been associated with low rates of angioedema (38,39).