Studies of ACE-inhibitor dosage and tolerability
Two trials may help to illustrate this prob lem: the Assessment of Treatment with Lisinopril And Survival (ATLAS), and the Network of General Practitioners and Hospital Physicians Involved in the Study of Low Versus High Doses of Enalapril in Patients With Heart Failure (NETWORK). The ATLAS patients received low-dose or high-dose lisinopril with
2.5 mg to 5.0 mg daily, or 32.5 mg to 35 mg daily. Of the 405 patients not previously receiving an angiotensin-converting enzyme (ACE) inhibitor, only 4.2% could not be titrated to the mean doses required for randomization, due to hypotensive symptoms (2.0%) or renal dysfunction and/or hyperkalemia (2.3%). Doses in over 90% of randomized patients in the low-dose and high-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Dizziness, hypotension, worsening renal function, and hyperkalemia were observed more frequendy in the high-dose group, but the two groups were similar in the number of patients requiring discontinuation of the study medication. Subgroups with presumed risk factors for ACE-inhibitor intolerance (blood pressure <120 mm Hg; creatinine, >1.5 mg/dL; age, >70 years; diabetes) generally tolerated the high-dose strategy. These findings demonstrate that ACE-inhibitor therapy in most heart failure patients can be successfully titrated to, and maintained at, high doses, and that more aggressive use of these agents is warranted.
When compared with the low-dose group, the high-dose group had a nonsignificant 8% lower risk of death, but a significant 12% lower risk of death or hospitalization for any reason. Retrospective analysis of the ATLAS database showed that high-dose lisinopril delayed the time to all-cause mortality and hospitalization for heart failure by 7.1 months. This analysis tested the hypothesis that vascular and arrhythmic events are not only major precipitants of sudden death, but also contribute to heart failure progression. Decreased vascular events, as well as ventricular remodeling benefits, could thus account for the decrease in death and hospitalization with high-dose lisinopril.
In analyzing the prognostic impact of predefined high-dose vs low-dose ACE inhibition at entry into an elective heart transplantation program, Berger et al found 47% of patients on high doses (captopril 75 mg, enalapril 20 mg, lisinopril 20 mg, or ramipril 5 mg daily) and 53% on low doses. Concomitant nitrate, 13-blocker, and amiodarone therapy was more frequent in the high-dose group, together with higher furosemide doses and higher serum y-glutamyltranspeptidase levels. High-dose vs low-dose ACE-inhibitor therapy at program entry was the strongest independent single predictor of mortality, with only blood pressure, alanine transaminase and left ventricular end-diastolic diameter providing additional prognostic information. In this study, transplant candidates receiving suboptimal ACE inhibitor doses for whatever reason were at increased mortality risk.