Annotation G

OBJECTIVE

Ensure that all patients with LV dysfunction are on optimal doses of pharmacological therapies with proven morbidity and mortality benefits.

(See CHF guideline at www.vapbm.org)

ANNOTATION

In patients with moderate to severe CHF symptoms, beta-blockers have been shown to improve symptoms, New York Heart Association (NYHA) class, and overall morbidity and mortality (Lechat et al., 1998). Thus far, studies support use of carvedilol, metoprolol, and bisoprolol for this indication. Before using beta-blockers, all patients should be on optimal doses of an ACE inhibitor, as in the clinical trials. Beta-blockers should not be used in uncompensated CHF and should be used with great caution in patients with Class IV CHF. Early termination of the COPERNICUS trial, which studied carvedilol in the setting of severe CHF, may alter this practice in the near future.

ACE-inhibitors should be given to all patients, in the absence of recognized contraindications, with CHF or evidence for LV systolic dysfunction (EF <0.40), and all attempts should be made to have patients on at least 20 mg of enalapril, or its equivalent, a day.

Multiple trials have convincingly demonstrated the benefit of ACE-inhibitor therapy in patients with CHF, due to LV systolic dysfunction (both ischemic and non-ischemic dysfunction). Clinical benefits include less dyspnea, improved exercise tolerance, reduced need for emergency care for heart failure, and improved survival. In both the SOLVD (1991) trial and the Veterans Heart Failure Trial (V-HeFTII) (Cohn et al., 1991), patients with reduced LVEF and symptoms of heart failure had improved survival with enalapril. In another trial in asymptomatic patients after MI with documented LV dysfunction, captopril reduced mortality and ischemic events compared with a placebo (Rutherford et al., 1994). A meta-analysis of 32 random control trials (RCTs) of ACE-inhibitors for symptomatic heart failure found an overall decrease in mortality of 28% (absolute risk reduction, 6.1%, NNT=16). The greatest benefit was found for NYHA class IV failure, LVEF <25%, and CHF due to IHD (Garg & Yusuf, 1995).

Moderate to high doses of ACE-inhibitors were used in all the trials. In the ATLAS study (1999), patients with moderate to severe heart failure were randomized to either a low dose (2.5 mg to 5 mg/day) or high dose (32.5 mg to 35 mg/day) of lisinopril. Those patients randomized to the higher-dose regimen had a 12% lower risk of death or hospitalization at 3 to5 years of follow-up. In a more recent study, patients with moderate CHF were randomized between moderate- (20 mg/day) and high-dose (60 mg/day) enalapril (Nanas, 2000). Following 12 months of therapy, there were differences in survival or other clinical variables. In patients intolerant of ACE-inhibitors, an angiotensin II receptor blocker (ARB) should be prescribed (Pitt et al., 1997; Pitt et al., 2000).

Results from a recent large-scale, randomized, placebo-controlled clinical trial suggest that all patients with IHD, irrespective of EF, may benefit from routine treatment with an ACE-inhibitor (i.e., ramipril) (HOPE Study Investigators, 2000). If these results are confirmed by other ongoing trials involving other ACE inhibitors, and in patients under the age of 55, treatment with an ACE-inhibitor will likely become the standard of care for all patients with IHD, irrespective of LV function. Pending the outcome of these trials, no firm recommendations can be made at this time for the routine use of ACE-inhibitors in all patients with IHD. Therefore, the decision to use ACE-inhibitor therapy in IHD patients with normal (>0.40) EF should be individualized and left to the discretion of the provider.

A randomized trial using a relatively low dose of spironolactone demonstrated significant improvement in outcomes in patients with severe CHF (i.e., Functional Class 3 to 4) who were already on ACE inhibitor therapy (Pitt et al., 1999). Remarkably, in this trial, the incidence of hyperkalemia was not increased with this dose of spironolactone. The effect of spironolactone in patients with less severe CHF is unknown.

The VA DIG Study (1997) showed no benefit in terms of mortality, but some reduction in frequency of hospitalization with the use of digoxin in patients with CHF. Discontinuing digoxin in patients with compensation heart failure results in worsening of symptoms.

While there is no evidence supporting mortality benefit of diuretics in patients with heart failure, diuretics are useful in the management of symptomatic volume overload (ACTION-HF, 1999).

EVIDENCE

Table 4. Medical Therapies For IHD Patients With LV Dysfunction
	Decision Criteria	Sources of Evidence	QE	R
1	ACE-inhibitors improve morbidity and mortality in patients with CHF or low EF.	Garg & Yusuf, 1995	I	A
2	Asymptomatic patients, but with low EF, experience survival benefit from ACE-inhibitors.	Rutherford et al., 1994 SOLVD Investigators, 1991	I	B
3	Doses of ACE-inhibitors should be optimized to obtain greatest benefit.	ATLAS Study, 1999	I	A
4	Beta-blockers should be considered for all patients with NYHA class II or III CHF, and EF<0.40, after stabilization on ACE-inhibitors.	Lechat et al., 1998	I	A
5	Addition of spironolactone to ACE-inhibitors and diuretics in patients with severe heart failure improves morbidity and mortality.	Pitt et al., 1999	I	A
6	Digoxin use in heart failure (EF<0.45) does not affect mortality, but decreases hospitalization due to heart failure.	DIG Study, 1997	II	A
7	Diuretics improve symptoms of volume overload.	ACTION-HF, 1999	III	A

QE = Quality of Evidence; R = Recommendation (See Introduction)