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Am Fam Physician. 2005;71(6):1210-1215

Studies of angiotensin-converting enzyme (ACE) inhibitor therapy demonstrate that upward-dosing of ACE inhibitors is required to achieve survival benefit in patients with heart failure. No study has compared low dosing of ACE inhibitors with no therapy. It is important to evaluate the benefits of low-dose ACE inhibitor therapy, because many older patients are given low ACE inhibitor dosages because of a fear of adverse effects or because the higher dosages were not tolerated. Rochon and colleagues performed a large population-based study that examined the benefits of different dosing regimens.

Patients at least 66 years of age with a first diagnosis of heart failure who survived 45 days after hospital discharge were included in the study. The 16,539 patients in the cohort were divided into four groups: non-users of ACE inhibitors, and participants who were taking low doses (25 percent or less of trial dose), medium doses (25 to 99 percent of trial dose), or high doses (trial dose or higher) of ACE inhibitors, with the last category determined on the basis of the Agency for Healthcare Quality and Research’s recommendations. The study identified changes in dosage or discontinuation of the drug in its cohort, and accounted for patients with contraindications to ACE inhibitors and varying degrees of heart failure severity. Outcome measures were mortality, a composite outcome of mortality and rehospitalization, and mortality or all-cause hospitalization.

During the one-year follow-up, 25.3 percent of the study participants died, 37.4 percent died or were rehospitalized with heart failure, and 61.0 percent died or had other hospitalizations. Of the entire group, 65.3 percent were taking some dosage of ACE inhibitor at 45 days following their heart failure hospitalization, with 36.5 percent of these taking low doses.

Overall, taking an ACE inhibitor conferred a survival benefit, and not taking an ACE inhibitor was associated with increased mortality. Similarly, taking an ACE inhibitor had a positive effect on composite outcome compared with not taking an ACE inhibitor. Taking a low-dose ACE inhibitor in these two measures was better than no ACE inhibitor at all, but in the third outcome measure, one-year mortality or all-cause mortality, no ACE inhibitor and low-dose ACE inhibitor therapy were similar in benefit. In all outcome measures, high-dose ACE inhibitor therapy conferred a significantly improved benefit (see accompanying table).

Hazard ratio (CI)
Dose at day 45 (no. of patients)DeathDeath/heart failure hospitalizationDeath/all hospitalization
None (5,746)1.12 (1.02 to 1.22)1.08 (1.00 to 1.16)1.04 (0.98 to 1.10)
Low (3,935)*1.001.001.00
Medium (4,316)0.94 (0.86 to 1.03)0.95 (0.88 to 1.02)0.95 (0.89 to 1.00)
High (2,542)0.76 (0.68 to 0.85)0.87 (0.80 to 0.95)0.87 (0.81 to 0.93)

The authors conclude that high-dose ACE inhibitor therapy confers the greatest one-year survival benefit in older patients who have been hospitalized for heart failure. Mortality was reduced by more than 20 percent in patients receiving high-dose therapy compared with patients receiving low-dose therapy. This finding is particularly important because few of these patients receive high-dose treatment. Still, low-dose ACE inhibitor therapy in this setting is superior to no ACE therapy. Physicians treating these patients need to find a balance between tolerability and efficacy.

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