Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure - TIME-CHF

Description:

While earlier studies have suggested that B-type natriuretic peptide (BNP)-guided therapy may have a beneficial role in the management of chronic heart failure, there are very little data on this topic in elderly patients. Accordingly, the goal of this trial was to investigate the efficacy of intensive BNP-guided therapy compared with standard symptom-guided therapy in patients with heart failure, with the specific inclusion of patients ≥75 years of age.

Hypothesis:

Intensive BNP-guided therapy would be associated with a significant reduction in all-cause hospitalization-free survival in patients with heart failure, including the elderly, compared with standard symptom-guided therapy.

Study Design

  • Randomized
  • Parallel
  • Stratified

Patients Screened: 739
Patients Enrolled: 499
NYHA Class: III/IV 74%
Mean Follow Up: 18 months
Mean Patient Age: 76 years
Female: 35
Mean Ejection Fraction: 30%

Patient Populations:

  • Symptomatic heart failure (NYHA ≥II, despite therapy)
  • Heart failure hospitalization within the last year
  • Age ≥60 years
  • NT-BNP >2 x ULN (as known in 2002)
    • >400 pg/ml (60-74 years of age)
    • >800 pg/ml (≥75 years of age)

Exclusions:

  • 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 >2.5 mg/dl
  • Life-expectancy <3 years unrelated to cardiovascular causes

Primary Endpoints:

  • All-cause hospitalization-free survival
  • Quality of life

Secondary Endpoints:

  • Survival
  • Heart failure hospitalization-free survival

Drug/Procedures Used:

Patients randomized to the intensified therapy arm received medical therapy specifically targeted to reduce the NT-BNP to <400 pg/ml (2 x upper limit of normal [ULN]) in patients 60-74 years of age, and <800 pg/ml (4 x ULN) in those ages 75 or older, as well as to keep symptoms at New York Heart Association (NYHA) class II or lower. Patients in the standard therapy arm received symptom-guided management, to keep symptoms at NYHA class II or lower.

Concomitant Medications:

Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) (95%), beta-blockers (79%), diuretic (93%), and mineralocorticoid antagonists (41%)

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).

Interpretation:

The results of the TIME-CHF trial indicate that intensified BNP-guided therapy does not reduce the incidence of all-cause hospitalization-free survival in patients with chronic heart failure, although it does reduce the incidence of heart failure, hospitalization-free survival. This effect appears to be sustained on long-term follow-up. There is significant effect modification by age, with younger patients (ages 60-74 years) responding more favorably than older patients (≥75 years), and older patients possibly having more serious adverse effects as well.

It is noteworthy that irrespective of the treatment strategy, the final reduction in NT-BNP is similar between the two arms, suggesting that BNP may not be necessary to longitudinally follow in outpatients with chronic heart failure, as long as it is measured at baseline. Further studies specifically targeting the elderly, which comprise an increasing subset of patients with heart failure, are necessary, since studies like these demonstrate that results obtained in younger patients cannot be extrapolated to elderly populations.

References:

Sanders-van Wijk, Maeder MT, Nietlispach F, et al. Long-Term Results of Intensified, NT-proBNP-Guided Versus Symptom-Guided Treatment in Elderly Patients With Heart Failure: 5-Year Follow-up From TIME-CHF. Circ Heart Fail 2013;Dec 18:[Epub ahead of print].

Pfisterer M, Buser P, Rickli H, et al. BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial. JAMA 2009;301:383-92.

TIME-CHF First Results on Systolic LV Dysfunction. Presented by Dr. H.P. Brunner-La Rocca at the European Society of Cardiology Congress, Munich, Germany, August/September 2008.

Clinical Topics: Anticoagulation Management, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Hypertension

Keywords: Renal Insufficiency, Follow-Up Studies, Body Mass Index, Quality of Life, Heart Failure, Comorbidity, Peptide Fragments, Hypotension, Hypertension, Cardiomyopathy, Dilated, Natriuretic Peptide, Brain


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