Do evidence-based treatments provide incremental benefits to patients with congestive heart failure already receiving angiotensin-converting enzyme inhibitors? A secondary analysis of one-year outcomes from the Assessment of Treatment with Lisinopril and Survival (ATLAS) study

Background: In patients with congestive heart failure (CHF), use of submaximal doses of angiotensin-converting enzyme (ACE) inhibitors (ie, low-dose ACE inhibitors) represents usual care in routine clinical practice, whereas high-dose ACE inhibitors, beta-blockers, and digoxin have each been shown to improve outcomes. Objective: We examined whether treatment with high dose-ACE inhibitors, beta-blockers, and digoxin would each provide incremental benefits over that achieved with usual care and whether concurrent use of high-dose ACE inhibitors, beta-blockers, and digoxin would provide maximal benefits. Methods: We conducted a secondary analysis of a randomized, controlled, active-comparator trial. Specifically, we studied 1-year outcomes data from the Assessment of Treatment with Lisinopril and Survival trial (ATLAS), which assessed high-dose ACE inhibitors (mean dosage, 33.2 mg daily lisinopril) versus low-dose ACE inhibitors (mean dosage, 4.5 mg daily lisinopril) in patients of any age with advanced CHF in 287 centers in 19 countries in the 1990s. In our analysis, patients were classified by their use of low-dose or high-dose ACE inhibitors, beta-blockers, and/or digoxin at the time of randomization. The primary outcome of interest was the ATLAS composite end point of all-cause mortality or hospitalization for any reason at 1 year. Multiple logistic regression analyses were used to adjust for baseline differences in patient characteristics. Results: The 3164 patients in the ATLAS study had a mean (SD) age of 64 (10) years; 2516 patients (80%) were men and 648 (20%) were women; mean (SD) left-ventricular ejection fraction was 23% (6%); and 2671 patients (84%) had New York Heart Association class III or IV symptoms. At 1 year, the mortality rate was 13% (408 patients); 43% (1369 patients) had ≥1 hospitalization; and the composite end point of mortality or hospitalization was 47% (1489 patients). Most patients (2873; 91%) remained on their initial treatment regimen. Compared with low-dose ACE inhibitors (n = 471), the composite end point decreased incrementally with the use of high-dose ACE inhibitors (n = 475) (adjusted odds ratio [aOR], 0.93; P = NS), high-dose ACE inhibitors plus beta-blockers (n = 72) (aOR, 0.89; P = NS), and high-dose ACE inhibitors plus beta-blockers plus digoxin (n = 77) (aOR, 0.47; P = 0.006). In absolute proportions, patients receiving high-dose ACE inhibitors plus beta-blockers plus digoxin for 1 year had 12% fewer deaths and hospitalizations than patients receiving low-dose ACE inhibitors alone. Conclusions: Compared with usual care for patients with CHF, in this analysis, an evidence-based strategy that incorporated high-dose ACE inhibitors plus beta-blockers plus digoxin was associated with incrementally greater reductions in morbidity and mortality. These findings support treatment guidelines that recommend the concurrent use of all available proven efficacious treatments in patients with advanced CHF.