Intensified NT BNPguided Therapy might be Beneficial among Patients aged less than 75 Years: Results from the TIME-CHF Trial
August 31, 2008 By Vijayalakshmi Kunadian MBBS MD MRCP 
ESC 2008-Munich, Germany: Researchers from Switzerland demonstrated that an intensified NT-BNP guided treatment of heart failure did not improve overall outcome but did reduce hospitalization and death among patients aged 60-74 years.
The results of the Trial of Intensified (BNP-guided) versus standard (symptom-guided) Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) was presented by Dr. Hans Brunner-La Rocca of Switzerland at the European Society of Cardiology Congress 2008 in Munich, Germany today with commentary by Dr Kenneth Dickstein of Norway.
It is not clear if outcomes can be improved among heart failure patients with intensified BNP-guided treatment compared with standard, symptom-guided management and if there is a difference among patients aged < 75 and ≥ 75 years of age. Researchers from Switzerland explored this further in the TIME-CHF trial among 499 systolic heart failure patients with ejection fraction <45%. Patients were randomized to an NT-BNP-guided (n=251) or a symptom-guided treatment strategy (n=248) and stratified into two age groups: 1. patients aged ≥75 years and 2. patients aged 60-74years.
Patients with shortness of breath belonging to NYHA class ≥II, heart failure hospitalizations within one year and NT-BNP levels >400 pg/ml among patients aged 60-74 years or 800pg/ml among patients aged ≥75 years were included in the trial. The treatment was optimized according to guidelines with the intention of reducing heart failure symptoms to NYHA <II or additionally NT-BNP-levels below the above mentioned levels. The following patients were excluded: patients with dyspnea not mainly caused by chronic heart failure, significant uncorrected valvular heart disease, acute coronary syndrome within 10 days, angina pectoris due to ischemia, percutaneous coronary intervention within 1 month, coronary artery bypass grafting within 3 months, body mass index >35 kg/m2, serum creatinine >3 mg/dl and life-expectancy <3 years unrelated to cardiovascular causes.
The primary endpoint of this trial consisted of survival free of all-cause hospitalizations up to 18 months and quality of life. The secondary endpoints consisted of survival and heart failure hospitalization-free survival.
Patients received the following medications: angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) (95%), beta-blockers (79%), diuretic (93%), and mineralocorticoid antagonists (41%). The causes of heart failure included ischemic cardiomyopathy (58%), hypertension (21%), and dilated cardiomyopathy (17%). The mean ejection fraction (EF) was 30%, and there was no difference in the median NT-BNP between the two arms at randomization (4657 pg/ml vs. 3998 pg/ml, p = 0.12). Overall, around 55% of the patients had pre-existing renal disease, and 73% had two or more comorbidities (79% among those aged ≥75 years). Quality of life, as assessed by the Minnesota scale, was similar in the two arms.
Over 90% of patients in the intensive treatment group received ACE inhibitors, ARBs, and beta-blockers compared to 55% in the standard therapy group. There was also a significant reduction in NT-BNP levels in both arms at the end of follow-up compared with the baseline, but there was no difference between the two arms themselves.
The main results of this trial are as follows: There was no significant difference in the primary endpoint between the two treatment groups [Hazard ratio (HR) 0.92, p=0.46]. However, the intensified treatment did improve the more disease-specific endpoint of survival free of heart failure hospitalizations (HR 0.66, p=0.008). Furthermore, the intensified therapy also reduced total mortality (HR 0.38, p=0.01) and improved survival free of heart failure hospitalizations (HR 0.41, p=0.002) among younger patients. However, this improvement in outcomes was not demonstrated among patients aged ≥75years.
Further analysis of this study demonstrated 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 aged 60-74 years. There was no difference in the quality of life between the two treatment groups among patients aged <75 years. However, in older patients, the change in quality of life from baseline was better among patients randomized to the standard therapy arm compared with the intensive therapy arm, using both Minnesota and SF-12 physical tools (p < 0.05).
The investigators concluded that intensified heart failure treatment did not significantly improve overall outcome compared to standard treatment. However, it improved survival free of heart failure hospitalizations overall and reduced mortality among patients <75 years of age. This benefit however was not demonstrated among patients aged ≥75 years.