Therapy with angiotensin converting enzyme (ACE) inhibitors has been shown to reduce the rate of hospitalization in patients with congestive heart failure (CHF), and these medications are recommended as first-line agents by the Agency for Health Care Policy and Research (AHCPR). Recent surveys, however, show that these agents are prescribed in only 40 to 70 percent of patients with CHF. Moreover, data indicate that daily dosages are often below the recommended equivalent of 20 mg or more of enalapril. Luzier and associates conducted a retrospective study to investigate whether the dosing recommendations of the AHCPR are effective in routine clinical practice and to test the impact of these drugs on the rate of rehospitalization in patients with CHF.
A total of 314 patients admitted at least twice during a 36-month period because of CHF were included in the study. For the purposes of analysis, ACE inhibitor dosages were converted to enalapril-equivalent dosages according to target daily doses recommended in the AHCPR guidelines. These dosages were 20 mg of enalapril, 150 mg of captopril and 20 mg of lisinopril daily.
Most of the patients received combination therapy, with nearly one half receiving the full regimen of a diuretic, digoxin and an ACE inhibitor. However, ACE inhibitor doses were consistent with the AHCPR guidelines in only 45 of 209 patients (22 percent) receiving an ACE inhibitor or 45 of 314 patients (14 percent) overall.
Diuretic therapy was found to be associated with a decrease in time to readmission, whereas digoxin had no effect. The ACE inhibitor dose was a significant covariant of the 90-day readmission rate. Daily dosages of 2.5 mg and 5 mg of enalapril were not associated with a significant reduction in the relative risk of readmission. In contrast, 10 mg of enalapril reduced the relative risk of readmission to 0.55, and 20 mg of enalapril further reduced the relative risk of readmission to 0.44. This dose-response relationship appeared to be unrelated to the severity of CHF.
A clear dose-response relationship was found, with increasing ACE inhibitor doses lowering the probability of readmission. Using the modeled function, it was possible to estimate the maximum ACE inhibitor effect and to identify the extrapolated maximum benefit that could be derived. Achievement of 90 to 95 percent of the theoretic maximum benefit would require an enalapril dosage of 100 to 200 mg daily.
The authors conclude that ACE inhibitor dosages higher than those currently in general use are required to achieve optimal effect in patients with CHF. At a minimum, clinicians should prescribe the dosages recommended by the AHCPR for the management of CHF.
editor's note: ACE inhibitors change the balance between the properties of angiotensin II and bradykinin, causing vasodilation and natriuresis. Metabolism of other vasoactive substances may also be altered. This decrease in systemic vascular resistance occurs without an increase in the heart rate. ACE inhibitors have been shown to decrease mortality in patients with CHF and in patients with left ventricular dysfunction after myocardial infarction and to delay progression of diabetic nephropathy in patients with diabetes. Adequate dosage is important to achieve the desired effects in these populations. Future research may determine that ACE inhibitor dosages even larger than those currently recommended may decrease mortality and morbidity in specific populations.—r.s.