Principal Findings:

A total of 499 patients were randomized, 251 to the intensive therapy arm, and 248 to the standard therapy arm. Ischemic cardiomyopathy was the major cause of heart failure in about one-half of the patients (58%), followed by hypertension (21%), and dilated cardiomyopathy (17%). The mean ejection fraction (EF) was 30%, and the median NT-BNP was similar between the two arms at randomization (4657 pg/ml vs. 3998 pg/ml, p = 0.12). About 55% of the patients had pre-existing renal disease, and 73% had two or more comorbidities (79% in those ≥75 years of age). Quality of life was similar in the two arms.

Uptitration of therapy to reduce symptoms was recommended more frequently in the intensified therapy arm than the standard therapy at all time points studied (p

There was no difference between the intensive therapy and standard therapy arms in the incidence of all-cause hospitalization-free survival (41% vs. 40%, hazard ratio [HR] 0.91, 95% CI 0.72-1.14, p = 0.39), or total survival (84% vs. 78%, HR 0.68, 95% CI 0.45-1.02, p = 0.06). However, there was a significant reduction in the intensive therapy arm in the incidence of heart failure-related hospitalization-free survival (72% vs. 62%, HR 0.68, 95% CI 0.50-0.92, p = 0.01).

Subanalyses seemed to indicate that obese patients (body mass index >24.9), patients with one or no comorbidities, and younger patients (ages <75 years) did better with the intensive treatment compared with standard management. There was a statistically significant interaction between age and treatment groups, with a greater reduction in those ages 60-74 years.

Although the quality of life was significantly better than baseline in both groups, there was no difference in the quality of life between the two treatment groups over the duration of follow-up.

Although the overall incidence of adverse effects including hospitalization for hypotension and renal failure was similar between the two arms, noncompliance due to these two reasons was more common in the intensive therapy arm. Moreover, serious adverse events were noted to be more common in the intensive therapy arm in patients older than 75 years of age.

Long-term follow-up: Data were available for 329 patients (92%). There was no difference in hospitalization-free survival (HR 0.87, 95% CI 0.71-1.06, p = 0.16) and all-cause mortality (HR 0.85, 95% CI 0.64-1.13, p = 0.25) between the intensive therapy and standard therapy arms; HF hospitalization-free survival was improved in the intensive therapy arm (HR 0.70, 95% CI 0.55-0.90, p = 0.005). This effect was again more pronounced in the ages 60-74 years subgroup. Landmark analysis at 12 months showed attenuation of the benefit of intensive therapy on HF hospitalization-free survival (p = 0.10).