Severity of heart failure and dosage of angiotensin converting enzyme inhibitors

Patients, methods, and results

We examined the drug regimens of 157 patients seen by two consultants in a specialist clinic for chronic heart failure. Chronic heart failure was diagnosed from the finding of impaired left ventricular function on echocardiography, radionuclide ventriculography, or cardiac catheterisation. All patients underwent exercise testing with metabolic gas exchange measurements. All had been reviewed at least once while taking their current angiotensin converting enzyme inhibitor and had had no change in drug treatment in the previous six weeks.

The dose of angiotensin converting enzyme inhibitor was standardised to the lowest target dose shown to improve mortality: captopril 25 mg twice daily,2 enalapril 10 mg twice daily,1 lisinopril 10 mg daily,4 and ramipril 5 mg twice daily.3 We also chose a clinical scale of equivalence based on drug datasheets: 12.5 mg captopril three times a day was assumed to be equivalent to 5 mg enalapril twice daily and to 5 mg lisinopril once daily.

Forty three patients were not taking any angiotensin converting enzyme inhibitor; 47 were taking captopril, 47 enalapril, 17 lisinopril, one ramipril, one fosinopril, and one perindopril (table). The diagnosis was dilated cardiomyopathy in 66 patients and ischaemic heart disease in 91. Diagnosis was not related to angiotensin converting enzyme inhibitor usage, and 85 patients were taking doses lower than the optimum suggested by the results of survival trials. Captopril was most likely to be given in dosages associated with improved mortality: 13 out of 47 were taking it twice daily and the remaining 34 three times daily. Thirty three of the 47 patients taking enalapril were taking the drug once daily.

There was no difference between the groups of patients in usage of alternative vasodilators. Patients taking an angiotensin converting enzyme inhibitor had more severe heart failure as judged by mean left ventricular ejection fraction (26.0% (SD 12.7%) v 34.6% (18.6%), 95% confidence interval for difference 5.84 to 11.46; P<0.01) and daily dosage of diuretic (85.6 (70.6) v 39.1 (36.2) mg frusemide equivalent, 41.4 to 51.7; P<0.001). Patients taking angiotensin converting enzyme inhibitor had lower mean serum sodium concentrations (138.2 (1.8) v 139.5 (2.7) mmol/l, −1.07 to −1.61; P=0.03) and higher mean concentrations of urea (8.35 (3.56) v 6.10 (1.91) mmol/l, 1.96 to 2.55; P<0.001) and creatine (121.06 (39.49) v 98.82 (17.39) μmol/l, 19.03 to 25.44; P<0.001). There was no correlation between the dosage of angiotensin converting enzyme inhibitor and ejection fraction, blood pressure, peak oxygen consumption, or serum concentrations of urea and electrolytes. There was a good correlation between the two scales of angiotensin converting enzyme inhibition (r=0.86, P<0.001).

Comment

Angiotensin converting enzyme inhibition improves survival of patients with chronic heart failure. As yet, a minority of patients are treated with angiotensin converting enzyme inhibitors.5 Two trials to determine the relation between dose and benefit (NETWORK (studying enalapril) and assessment of treatment with lisinopril and survival (ATLAS)) are in progress. We found that even in hospital based care of chronic heart failure a wide range of different angiotensin converting enzyme inhibitor regimens is used. Clinical variables seem not to influence the dosage used. Only those patients taking captopril were likely to be receiving the drug in the range associated with a beneficial effect on mortality.

Until the results of studies comparing high and low doses of angiotensin converting enzyme inhibitors are known, the aim of treatment should be to reach a dosage associated with improved mortality.