TIME-CHF Questions Treatment of Heart Failure to Natriuretic-Peptide Targets

August 31, 2008

August 31, 2008 (Munich, Germany) — The use of natriuretic-peptide levels rather than symptoms alone to guide the medical management of heart failure, a strategy that's been tested in several trials with mixed results, failed to influence the primary end point of hospitalization-free survival over 18 months in a randomized heart-failure trial reported here today at the European Society of Cardiology Congress 2008 [1].

The natriuretic-peptide–based approach did appear to improve survival free from heart-failure hospitalizations, a secondary but more conventional end point, among the prospectively defined subgroup of patients who were younger than 75 years. Interestingly, in this trial, according to lead investigator Dr Hans Peter Brunner–La Rocca (University Hospital Basel, Switzerland), patients 75 years and older--a group that has been greatly underrepresented in heart-failure drug trials, he observed--didn't show any outcome difference between the two management strategies.

In the study, called the Trial of Intensified versus Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF), "intensified" therapy guided by levels of N-terminal brain-type natriuretic peptide (NT-proBNP) led to higher dosages of ACE inhibitors, beta blockers, and other standard heart-failure meds independently of age.

In the younger patients, those who were 65 to 74 years old, intensive therapy and standard symptom-guided management were associated with similar improvements in quality-of-life scores (on, for example, the Minnesota Living with Heart Failure Questionnaire), Brunner-La Rocca reported. The older patients, however, didn't show as big a jump in quality-of-life scores on intensified therapy as they did on standard management (p<0.05 for the difference between strategies in the older group).

That, he told heartwire , suggests that intensified medical therapy may represent too much of a good thing for some elderly patients--that is, those 75 or older--who in general and as occurred in TIME-CHF, tend to be sicker than younger patients. In this trial, he said, the older group "did quite well" with standard medical therapy, "but if we push it to the limits, and uptitrate the doses too much, then we may cause some harm in the elderly patients, at least those who are fragile with a lot of comorbidities."

It also suggests that lessons from the HF trials on which treatment guidelines are based may not apply to the elderly with heart failure, he observed. "There is a difference in [treatment] response between those being represented in the large trials and those not being represented in the large trials, and I think this is something that we should be looking at in the future." Pointing to the greater number of comorbidities in the older group, he said "The evidence in the guidelines we have is based, probably, on about 15% to 20% of the population that we actually treat."

TIME-CHF randomized 499 patients with heart failure of NYHA class 2 or worse despite medical therapy, who had an LVEF of <45%, an HF hospitalization within the previous year, and an NT-proBNP level at least twice the upper limit of normal to natriuretic-peptide–guided or symptom-guided management. Patients, though not clinicians, were blinded to treatment group.

Standard therapy meant treating to an NYHA class no higher than 2. Therapy in the natriuretic-peptide treatment group was aimed at achieving levels <400 pg/mL for patients aged 60 to 74 years or <800 pg/mL for those >75 years in addition to a NYHA class of 2 or better. Medical therapy was according to European guidelines and included either ACE inhibitors or angiotensin receptor blockers, beta blockers, and, for patients in NYHA class 3 or worse, spironolactone or eplerenone.

Hazard Ratio (95% CI) for 18-Month Outcomes, Standard Therapy vs Natriuretic Peptide-Guided Therapy, Overall and by Age Group

End Point Overall, n=499 Age <75, n=210 Age >75, n=289
Survival free of any
0.92 (0.73-1.15) 0.76 (0.53-1.09) 1.06 (0.79-1.43)
Survival 0.68 (0.46-1.01) 0.38 (0.18-0.80)c 0.92 (0.57-1.49)
Survival free of heart-failure hospitalization 0.66 (0.49-0.90)b 0.41 (0.23-0.72)d 0.86 (0.59-1.24)

a. primary end point b. p=0.008 c. p=0.01 d. p=0.002

Dr Kenneth Dickstein (University of Bergen, Stavanger, Norway), the discussant for Brunner-La Rocca's presentation, said the study indeed suggests that HF patients older than 75 respond differently to heart-failure therapies compared with younger patients, so "clearly we need trials targeting older patients."

But Dickstein cautioned against reading too much into clinical-end-point reductions in the younger group. "The sample size for this trial was based on the entire population for detecting a difference between NT-proBNP-guided and standard therapy." Therefore, even though the age groups were prospectively defined, their outcomes "essentially represent subgroup findings."

He also highlighted one of the study's other findings that stood out: natriuretic-peptide–guided therapy and standard management both significantly reduced NT-proBNP levels from baseline to six months (p<0.001), but to similar degrees--that is, using NT-proBNP as a treatment target didn't, overall, produce steeper declines in NT-proBNP levels. That, Dickstein said, questions the need for taking other than a baseline natriuretic-peptide level.

Dickstein pointed out that the two age-based groups were defined by far more than age itself. "These are different populations," he said, with the elderly group having significantly more coronary disease and comorbidities, lower LVEF, more symptoms, and other indications that they were more fragile than the younger patients.

Baseline Differences Between the Younger and Elderly Patient Groups in TIME-CHF

Feature Age 60-74, n=210 Age >75 n=289 p
Mean age (y) 69 89 <0.001
Female (%) 25 41 <0.001
CAD heart-failure etiology (%) 49 64 <0.001
LVEF (%) 28 10 <0.001
NYHA class >3 (%) 66 81 <0.001
≥2 comorbidities (%) 64 79 <0.001
Creatinine (µm/L) 111 121 0.004

Brunner-La Rocca said TIME-CHF was primarily funded by a nonprofit foundation but also supported by "unrestricted grants" from AstraZeneca, Novartis, Menarini, Pfizer, Servier, Roche Diagnostics, and Merck.

  1. Brunner-La Rocca HP. Trial of intensified (BNP-guided) versus standard (symptom-guided) medical therapy in elderly patients with congestive heart failure: TIME-CHF. European Society of Cardiology Congress 2008; August 31, 2008; Munich, Germany. Hot line 1.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.


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