Management of elderly patients with congestive heart failure—Design of the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF)

doi:10.1016/j.ahj.2005.10.022

American Heart Journal

Volume 151, Issue 5, May 2006, Pages 949-955

https://doi.org/10.1016/j.ahj.2005.10.022 Get rights and content

Background

Little is known about the management of elderly patients with congestive heart failure (CHF) although they represent the majority of the CHF population. Therefore, the TIME-CHF study was set up (1) to evaluate the medical management of very old patients (≥75 years) with CHF compared with younger patients (60-74 years), (2) to compare an intensified with a standard treatment approach, and (3) to differentiate between systolic and diastolic dysfunction (ejection fraction ≤45% vs >45%).

Methods

In a prospective single-blinded multicenter trial, 824 symptomatic patients, CHF hospitalization within the last year and elevated NT-BNP, are randomized to an intensified versus a standard medical therapy. Treatment strategies follow the published guidelines with the aim to reduce symptoms to NYHA class ≤II (standard) or, additionally, NT-BNP levels below twice the upper limit of normal (intensified). The primary end points are 18-month hospitalization-free survival and quality of life.

Results

By the end of 2004, 297 patients have been included, 147 randomized to intensified and 150 to standard therapy. Mean age in the older age group was 82 ± 4 years (n = 174) and 69 ± 4 years in the younger group (n = 123), respectively. Ejection fraction was >45% in 26% and 10%, respectively. Significant comorbidities were present in 93% of patients.

Conclusion

TIME-CHF will be the first prospective randomized trial to comprehensively study the management of elderly patients with CHF. It will provide unique information comparing two treatment strategies in two age groups irrespective of ejection fraction regarding prognosis, quality of life, as well as resource utilization and costs.

Section snippets

Aims of the study

To address these questions, TIME-CHF was initiated as a prospective randomized controlled multicenter trial. It addresses the management of patients with CHF ≥75 years of age and compares it with patients aged 60 to 74 years (aim 1). TIME-CHF compares an intensified approach with standard symptom-guided therapy. B-type natriuretic peptide levels are used to guide intensified therapy (aim 2). Patients are included irrespective of their left ventricular (LV) function and, therefore, are

Results

By the end of 2004, 297 patients have been included in the study. Preliminary baseline data are depicted in Table III. They indicate an overall ratio of male to female of 3:2. The average age in all patients was 77 ± 8 years. More patients with age ≥75 years were included (59%) versus 41% in the younger age group. Coronary artery disease was the most common underlying cause (59%), followed by hypertensive heart disease (23%) and dilated cardiomyopathy (13%). Most patients had systolic

Discussion

This project will be the first prospective trial to comprehensively study the therapeutic management in elderly patients with CHF. This is of particular importance because this is the largest, constantly growing, but also least-investigated patient population with CHF.⁸ There are several unique aspects of this protocol: (1) it compares two treatment strategies and not just single drug effects as done in most previous mortality trials in CHF; (2) the two strategies have clearly defined goals: to

References (30)

H. Ni
Prevalence of self-reported heart failure among US adults: results from the 1999 National Health Interview Survey
Am Heart J
(2003)
H. Krum et al.
Demographics and concomitant disorders in heart failure
Lancet
(2003)
J.L. Januzzi et al.
The N-terminal Pro-BNP Investigation of Dyspnea in the Emergency department (PRIDE) study
Am J Cardiol
(2005)
R.W. Troughton et al.
Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations
Lancet
(2000)
T.S. Rector et al.
Validity of the Minnesota Living with Heart Failure questionnaire as a measure of therapeutic response to enalapril or placebo
Am J Cardiol
(1993)
M.A. Hlatky et al.
A brief self-administered questionnaire to determine functional capacity (the Duke Activity Status Index)
Am J Cardiol
(1989)
V. Vaccarino et al.
Depressive symptoms and risk of functional decline and death in patients with heart failure
J Am Coll Cardiol
(2001)
E.F. Lewis et al.
Preferences for quality of life or survival expressed by patients with heart failure
J Heart Lung Transplant
(2001)
P.Y. Marie et al.
Exercise release of cardiac natriuretic peptides is markedly enhanced when patients with coronary artery disease are treated medically by beta-blockers
J Am Coll Cardiol
(2004)
Y. Takeda et al.
Effects of carvedilol on plasma B-type natriuretic peptide concentration and symptoms in patients with heart failure and preserved ejection fraction
Am J Cardiol
(2004)

J.W. Fung et al.

Effect of beta blockade (carvedilol or metoprolol) on activation of the renin-angiotensin-aldosterone system and natriuretic peptides in chronic heart failure

Am J Cardiol

(2003)

R. Pernenkil et al.

Course and prognosis in patients > or = 70 years of age with congestive heart failure and normal versus abnormal left ventricular ejection fraction

Am J Cardiol

(1997)

W.D. Dupont et al.

Power and sample size calculations. A review and computer program

Control Clin Trials

(1990)

M.M. Redfield et al.

Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic

JAMA

(2003)

K. MacIntyre et al.

Evidence of improving prognosis in heart failure: trends in case fatality in 66 547 patients hospitalized between 1986 and 1995

Circulation

(2000)

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Heart failure (HF) represents a major health and economic issue, with increasing morbidity and mortality in spite of novel therapeutic weapons. The disappointing results of HF management may be due to the current therapeutic approach based on the paradigm “one fits all”, that cannot apply to a complex and multifaceted syndrome as HF. At this regard, the European Union is developing policies to move from reductionism to precision medicine, in order to identify specific disease biomarkers and develop targeted therapeutic strategies. The institution of biobanks may represent the game changer in HF scenario, providing a collection of human biological materials with the related medical and epidemiological data fueling the development of personalized therapeutic approach and fostering current and/or future research projects.
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Cognitive impairment (CI) is common in patients with heart failure (HF) and impacts treatment adherence and other aspects of patient life in HF. Recognition of CI in patients with HF is therefore important. We aimed to develop a risk model with easily available patient characteristics, to identify patients with HF who are at high risk to be cognitively impaired and in need for further cognitive investigation.
The risk model was developed in 611 patients ≥ 60 years with HF from the TIME-CHF trial. Fifty-six (9 %) patients had CI (defined as Hodkinson Abbreviated Mental Test ≤ 7). We assessed the association between potential predictors and CI with least-absolute-shrinkage-and-selection-operator (LASSO) regression analysis. The selected predictors were: older age, female sex, NYHA class III or IV, Charlson comorbidity index ≥ 6, anemia, heart rate ≥ 70 bpm and systolic blood pressure ≥ 145 mmHg. A model that combined these variables had a c-statistic of 0.70 (0.63–0.78). The model was validated in 155 patients ≥ 60 years with HF from the ECHO study. In the validation cohort 51 (33 %) patients had CI (defined as a Mini Mental State Exam ≤ 24). External validation showed an AUC of 0.56 (0.46–0.66).
This risk model with easily available patient characteristics has poor predictive performance in external validation, which may be due to case-mix variation. These findings underscore the need for active screening and standardized assessment for CI in patients with HF.
Conformal Feature-Selection Wrappers and ensembles for negative-transfer avoidance
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Prognostic Significance of Longitudinal Clinical Congestion Pattern in Chronic Heart Failure: Insights From TIME-CHF Trial
2019, American Journal of Medicine
Citation Excerpt :
This is a post-hoc analysis of the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF). The design15 and main results16 were published previously. Briefly, TIME-CHF was a randomized, controlled multicenter trial that compared an N-terminal-pro B-type natriuretic peptide (NT-proBNP)-guided with a symptom-guided management in patients with chronic heart failure (n = 622), age ≥ 60 years, symptoms corresponding to New York Heart Association (NYHA) functional class ≥ II, hospitalization for heart failure within 12 months prior to inclusion, and NT-proBNP levels > 400 ng/L (< 75 years) or > 800 ng/L (≥ 75 years), respectively.
The relationship between longitudinal clinical congestion pattern and heart failure outcome is uncertain. This study was designed to assess the prevalence of congestion over time and to investigate its impact on outcome in chronic heart failure.
A total of 588 patients with chronic heart failure older than 60 years of age with New York Heart Association (NYHA) functional class ≥ II from the TIME-CHF study were included. The endpoints for this study were survival and hospitalization-free heart failure survival. Orthopnea, NYHA ≥ III, paroxysmal nocturnal dyspnea, hepatomegaly, peripheral pitting edema, jugular venous distension, and rales were repeatedly investigated and related to outcomes. These congestion-related signs and symptoms were used to design a 7-item Clinical Congestion Index.
Sixty-one percent of patients had a Clinical Congestion Index ≥ 3 at baseline, which decreased to 18% at month 18. During the median [interquartile range] follow-up of 27.2 [14.3-39.8] months, 17%, 27%, and 47% of patients with baseline Clinical Congestion Index of 0, 1-2, and ≥ 3 at inclusion, respectively, died (P < .001). Clinical Congestion Index was identified as an independent predictor of mortality at all visits (P < .05) except month 6 and reduced hospitalization-free heart failure survival (P < .05). Successful decongestion was related to better outcome as compared to persistent congestion or partial decongestion (log-rank P < 0.001).
The extent of congestion as assessed by means of clinical signs and symptoms decreased over time with intensified treatment, but it remained present or relapsed in a substantial number of patients with heart failure and was associated with poor outcome. This highlights the importance of appropriate decongestion in chronic heart failure.
Is the clinical presentation of chronic heart failure different in elderly versus younger patients and those with preserved versus reduced ejection fraction?
2018, European Journal of Internal Medicine
Citation Excerpt :
Therefore, using the database from TIME-CHF [14–16], the aims of this study were to assess the clinical characteristics and in particular prevalence of signs and symptoms of HF, comparing elderly versus younger patients and patients with HFpEF versus HFrEF and to develop a prediction rule for the differentiation of HFpEF and HFrEF based on clinical parameters. The design of the TIME-CHF study program [14] and the principal findings were reported previously [15, 16]. In short, TIME-CHF was a prospective randomized controlled multicenter trial addressing the management of elderly patients with HF comparing a standard symptom-guided therapy with an intensified, NT-proBNP guided medical therapy.
Whether the clinical presentation and in particular prevalence of symptoms and signs of heart failure (HF) is different in elderly versus younger patients and in those with reduced (HFrEF) versus preserved (HFpEF) left ventricular ejection fraction (LVEF) is a matter of ongoing debate.
To compare detailed clinical characteristics of these important subgroups and to develop a prediction rule for the differentiation of HFpEF and HFrEF based on clinical parameters.
The analysis was based on the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) comprising 622 patients ≥60 years with HF including the whole LVEF spectrum.
In the groups ≥75 years and with HFpEF typical symptoms and clinical signs of HF were more prevalent as compared to those <75 years or with HFrEF, respectively. The burden of comorbidities was higher in the older age group. HFrEF could not be differentiated from HFpEF by symptom history and clinical examination alone. However, a combination of age, presence of pulmonary rales, systolic blood pressure, cause of heart failure, osteoporosis, current smoking, NT-proBNP, haemoglobin, QRS width and heart rhythm allowed to identify HFrEF versus HFpEF with a sensitivity of 81% and specificity of 90% (c-statistics 0.91).
More symptoms and signs of HF were present both in the older age group and in patients with HFpEF. HFpEF versus HFrEF could be differentiated by a set of simple clinical, laboratory and ECG parameters but not by symptom history and physical examination alone.
N-Terminal Pro–B-Type Natriuretic Peptide–Guided Therapy in Chronic Heart Failure Reduces Repeated Hospitalizations—Results From TIME-CHF
2017, Journal of Cardiac Failure
Citation Excerpt :
The design and results of TIME-CHF study have been published in detail previously.25,27
Although heart failure (HF) patients are known to experience repeated hospitalizations, most studies evaluated only time to first event. N-Terminal B-type natriuretic peptide (NT-proBNP)–guided therapy has not convincingly been shown to improve HF-specific outcomes, and effects on recurrent all-cause hospitalization are uncertain. Therefore, we investigated the effect of NT-proBNP–guided therapy on recurrent events in HF with the use of a time-between-events approach in a hypothesis-generating analysis.
The Trial of Intensified Versus Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized 499 HF patients, aged ≥60 years, left ventricular ejection fraction ≤45%, New York Heart Association functional class ≥I,I to NT-proBNP–guided versus symptom-guided therapy for 18 months, with further follow-up for 5.5 years. The effect of NT-proBNP–guided therapy on recurrent HF-related and all-cause hospitalizations and/or all-cause death was explored. One hundred four patients (49 NT-proBNP–guided, 55 symptom-guided) experienced 1 and 275 patients (133 NT-proBNP–guided, 142 symptom-guided) experienced ≥2 all-cause hospitalization events. Regarding HF hospitalization, 132 patients (57 NT-proBNP–guided, 75 symptom-guided) experienced 1 and 122 patients (57 NT-proBNP–guided, 65 symptom-guided) experienced ≥2 events. NT-proBNP–guided therapy was significant in preventing 2nd all-cause hospitalizations (hazard ratio [HR] 0.83; P = .01), in contrast to nonsignificant results in preventing 1st all-cause hospitalization events (HR 0.91; P = .35). This was not the case regarding HF hospitalization events (HR 0.85 [P = .14] vs HR 0.73 [P = .01]) The beneficial effect of NT-proBNP–guided therapy was seen only in patients aged <75 years, and not in those aged ≥75 years (interaction terms with P = .01 and P = .03 for all-cause hospitalization and HF hospitalization events, respectively).
NT-proBNP–guided therapy reduces the risk of recurrent events in patients <75 years of age. This included all-cause hospitalization by mainly reducing later events, adding knowledge to the neutral effect on this end point when shown using time-to-first-event analysis only.
isrctn.org, identifier: ISRCTN43596477.

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: This study is sponsored by the Horten Foundation, Lugano, Switzerland, as well as by unrestricted grants from AstraZeneca Pharma, Menarini Pharma, Novartis Pharma, Pfizer Pharma, Servier (all Switzerland with equal contributions), Roche Diagnostics, Roche Pharma, and Merck Pharma, Switzerland.

^c: See Appendix A.

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Trial DesignManagement of elderly patients with congestive heart failure—Design of the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF)

Background

Methods

Results

Conclusion

Section snippets

Aims of the study

Results

Discussion

Am Heart J

Lancet

Am J Cardiol

Lancet

Am J Cardiol

Am J Cardiol

J Am Coll Cardiol

J Heart Lung Transplant

J Am Coll Cardiol

Am J Cardiol

Am J Cardiol

Am J Cardiol

Control Clin Trials

Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic

JAMA

Evidence of improving prognosis in heart failure: trends in case fatality in 66 547 patients hospitalized between 1986 and 1995

Circulation

Trial Design
Management of elderly patients with congestive heart failure—Design of the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF)