Heart Failure in Patients With Reduced Ejection Fraction

ACE Inhibitors

Recommendation

7.1

ACE inhibitors are recommended for routine administration to symptomatic and asymptomatic patients with LVEF <= 40%. (Strength of Evidence = A)

ACE inhibitors should be titrated to doses used in clinical trials, as tolerated during concomitant up-titration of beta blockers. (Strength of Evidence = C).

Background

There is compelling evidence that ACE inhibitors should be used to inhibit the renin-angiotensin-aldosterone system (RAAS) in all HF patients with reduced LVEF, whether or not they are symptomatic (Table 7.1). A number of large clinical trials have demonstrated improvement in morbidity and mortality in HF patients with reduced LVEF, both chronically and post-myocardial infarction (MI).1-3 The mortality benefit is strongest across New York Heart Association (NYHA) class II-IV HF, but appears present in patients who are NYHA class I as well.4

The major side effects of ACE inhibitors in patients with HF are hypotension and azotemia. Both are usually well tolerated and do not indicate the need to lower the dose or discontinue the ACE inhibitor. The azotemia commonly is related to a relative volume-depleted state caused by diuretic therapy and may be improved by a reduction in diuretic dose. Moderate renal insufficiency should not be considered a contraindication to the use of ACE-inhibitors, although careful attention to serum potassium and creatinine levels is imperative.5 The major symptomatic side effect is a dry cough that usually does not require discontinuation of the drug. Care should be taken to distinguish between a cough that is ACE inhibitor-related and one that is due to worsening pulmonary congestion. If the cough impairs the patient's quality of life, alternative therapy, such as an ARB, is recommended.6

Recommendations

7.2

It is recommended that other therapy be substituted for ACE inhibitors in the following circumstances:

  • In patients who cannot tolerate ACE inhibitors due to cough, ARBs are recommended. (Strength of Evidence = A)
  • The combination of hydralazine and an oral nitrate may be considered in such patients not tolerating ARB therapy. (Strength of Evidence = C)
  • Patients intolerant to ACE inhibitors from hyperkalemia or renal insufficiency are likely to experience the same side effects with ARBs. In these cases, the combination of hydralazine and an oral nitrate should be considered. (Strength of Evidence = C)
7.3

ARBs are recommended for routine administration to symptomatic and asymptomatic patients with an LVEF <= 40% who are intolerant to ACE inhibitors for reasons other than hyperkalemia or renal insufficiency. (Strength of Evidence = A)

7.4

ARBs should be considered in patients experiencing angioedema while on ACE inhibitors based on their underlying risk and with recognition that angioedema has been reported infrequently with ARBs. (Strength of Evidence = B)

The combination of hydralazine and oral nitrates may be considered in this setting in patients who do not tolerate ARB therapy. (Strength of Evidence = C)

Background

Both ACE inhibitors and ARBs inhibit the RAAS, but by different mechanisms. ACE inhibitors block an enzyme responsible for converting angiotensin I to angiotensin II and for degrading various kinins. However, during chronic therapy, angiotensin II levels are not completely suppressed by ACE inhibitors for at least 2 reasons. Instituting an ACE inhibitor increases renin levels, resulting in higher levels of angiotensin I, which will tend by mass action to produce greater angiotensin II levels. Production of angiotensin II may also occur through non-ACE enzyme systems not blocked by inhibitors of this enzyme.7,8 Thus, despite treatment with ACE inhibitors in patients with chronic HF, angiotensin II levels may remain elevated and increase over time.9,10

ARBs block the effects of angiotensin II on the ATI receptor, independent of the source of angiotensin II production. Coupled with angiotensin II "escape," this led to the hypothesis that ARBs might be superior to ACE inhibitors in HF and that the addition of ARBs to ACE inhibitors in patients with chronic HF might provide additional blockade of the RAAS and greater therapeutic benefit. ACE inhibitors reduce the degradation of kinins, which may lead to important therapeutic benefits not provided by ARBs, making the potential combination of the two agents more attractive.11,12 Recommendations 7.13, 7.21, and 7.22 and the accompanying background discusses combination ACE-inhibitor and ARB therapy.

ACE inhibitors can have some troublesome side effects, including cough and angioedema, which may limit therapy with these agents. ARBs have been demonstrated to be well tolerated in randomized trials of patients judged to be intolerant of ACE inhibitors.13,14 Both drugs have similar effects on blood pressure, renal function, and potassium.13 The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Alternative trial prospectively tested the effect of an ARB in an ACE inhibitor intolerant population of patients with chronic HF and an LVEF <40%. The addition of candesartan in these patients resulted in a reduction in the composite endpoint of cardiovascular death or hospital admission for HF from 40% in the control group to 33% in the candesartan group over a mean follow-up of 34 months with a trend toward decreased all-cause mortality.13 Post-hoc subgroup analysis of a small number of patients in the Valsartan in Heart Failure Trial (Val-HeFT) also found that patients intolerant to ACE inhibitors had fewer HF hospitalizations and a trend toward improved mortality with the addition of valsartan.15 These data suggest that an ARB should be used in ACE inhibitor intolerant patients with chronic HF and LVEF <40%. ARBs should be titrated as tolerated, in conjunction with beta blocker therapy, to target doses used in clinical trials (Table 7.1). ARBs should be considered instead of ACE inhibitors primarily in patients who are intolerant of ACE inhibitors because of intractable cough or angioedema. ARBs appear as likely as ACE inhibitors to produce hypotension, worsening renal function, and hyperkalemia. See background to Recommendations 7.19-7.20 for information about isosorbide dinitrate/hydralazine as an alternative to ACE-inhibitor therapy in intolerant patients.

Angioedema and ARBs. Nearly three-quarters of patients in CHARM-Alternative were intolerant to ACE inhibitors primarily because of cough, but intolerance was also reported in 13% from symptomatic hypotension, 12% from renal dysfunction, and 4% from angioedema/anaphylaxis.13 In that study, 3 patients taking candesartan and none taking placebo had angioedema. None of the episodes were life-threatening and only 1 of the 3 patients discontinued candesartan. The 3 cases of angioedema all occurred in the 39 patients intolerant to ACE inhibitors because of angioedema. Thus, the risk of recurrent angioedema with ARBs in patients with angioedema from ACE inhibition appears to be acceptable, assuming careful instructions and patient monitoring.

Recommendation

7.5

Individual ARBs may be considered as initial therapy rather than ACE inhibitors for patients with the following conditions:

  • HF Post-MI (Strength of Evidence = A)
  • Chronic HF and reduced LVEF (Strength of Evidence = B)

Background

Support for the use of the ARB, valsartan, in patients post-MI is provided by The Valsartan in Acute Myocardial Infarction Trial (VALIANT), which randomized 14,703 patients 0.5 to 10 days post-MI to valsartan, valsartan plus captopril, or captopril alone. Patients enrolled had clinical or radiologic signs of HF, evidence of reduced LVEF, or both.16 The primary end point was all-cause mortality. There were no statistical differences among the 3 groups at a mean follow-up of 24.7 months. With monotherapy, hypotension and renal dysfunction were more common in the valsartan group, and cough, rash, and taste disturbance were more common in the captopril group. The authors concluded that monotherapy with valsartan was equivalent to monotherapy with captopril. The Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) study randomized 5477 patient with HF or reduced LVEF post-MI to captopril or losartan.17 The primary endpoint was all-cause mortality. There were 946 deaths during a mean follow-up of 2.7 years: 499 (18%) in the losartan group and 447 (16%) in the captopril group (relative risk 1.13 [95% CI 0.99-1.28], P=.07). Thus valsartan appears equivalent to captopril in patients with HF or reduced LVEF post-MI, but the data do not clearly support equivalence of losartan to captopril in these patients.

In patients with chronic HF and reduced LVEF, 2 reviews have addressed the equivalence of ARBs and ACE inhibitors.18,19 One meta-analysis concluded that ARBs should be considered "suitable alternatives" to ACE inhibitors. The Centers for Medicare and Medicaid Services has used this review to consider both ARBs and ACE inhibitors as acceptable to satisfy performance standards in patients with HF.20 A second review suggested that ACE-inhibitors remain first line therapy, whereas ARBs were recommended for ACE-intolerant patients.18

Table 7.1: ACE-inhibitor, Angiotensin Receptor Blocker, and Beta-Blocker Therapy in HF with Low LVEF

Generic Name Trade Name Initial Daily Dose Target Dose Mean Dose Achieved in Clinical Trials
ACE-inhibitors
Captopril Capoten 6.25 mg tid 50 mg tid 122.7 mg/day160
Enalapril Vasotec 2.5 mg bid 10 mg bid 16.6 mg/day42
Fosinopril Monopril 5-10 mg qd 80 mg qd n/a
Lisinopril Zestril, Prinivil 2.5-5 mg qd 20 mg qd *4.5 mg/day (low dose ATLAS)
33.2 mg/day (high dose ATLAS)161
Quinapril Accupril 5 mg bid 80 mg qd n/a
Ramipril Altace 1.25-2.5 mg qd 10 mg qd n/a
Trandolapril Mavik 1 mg qd 4 mg qd n/a
Angiotensin Receptor Blockers
Candesartan Atacand 4-8 mg qd 32 mg qd 24 mg/day162
Losartan Cozaar 12.5-25 mg qd 150 mg qd 129 mg/day163
Valsartan Diovan 40 mg bid 160 mg bid 254 mg/day164
Beta-blockers
Bisoprolol Zebeta 1.25 mg qd 10 mg qd 8.6 mg/day47
Carvedilol Coreg 3.125 mg bid 25 mg bid 37 mg/day165
Carvedilol Coreg CR 10 mg qd 80 mg qd
Metoprolol succinate CR/XL Toprol XL 12.5-25 mg qd 200 mg qd 159 mg/day48
Aldosterone Antagonists
Spironolactone Aldactone 12.5 to 25 mg qd 25 mg qd 26 mg/day60
Eplerenone Inspra 25 mg qd 50 mg qd 42.6 mg/day61
Other Vasodilators
Fixed dose Hydralazine/Isosorbide dinitrate BiDil 37.5 mg hydralazine/20 mg isosorbide dinitrate tid 75 mg hydralazine/40 mg isosorbide dinitrate tid 142.5 mg hydralazine/76 mg isosorbide dinitrate/day166
Hydralazine Apresoline 37.5 mg qid 75 mg qid 270 mg/day167
Isosorbide dinitrate Isordil 20 mg qid 40 mg qid 136 mg/day167

*No difference in mortality between high and low dose groups, but 12% lower risk of death or hospitalization in high dose group vs. low dose group.