Long-term results of intensified, N-terminal-pro-B-type natriuretic peptide-guided versus symptom-guided treatment in elderly patients with heart failure: five-year follow-up from TIME-CHF.

BACKGROUND: Therapy guided by N-terminal-pro-B-type natriuretic peptide (NT-proBNP) levels may improve outcomes in patients with chronic heart failure (HF), especially in younger patients with reduced left ventricular ejection fraction. It remains unclear whether treatment effects persist after discontinuation of the NT-proBNP-guided treatment strategy. METHODS AND RESULTS: Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure randomized 499 patients with HF aged≥60 years with left ventricular ejection fraction≤45% to intensified, NT-proBNP-guided versus standard, symptom-guided therapy into prespecified age groups (60-74 and ≥75 years) during 18 months. A total of 329 patients (92%) alive at 18 months agreed to long-term follow-up. HF medication was intensified to a larger extent in the NT-proBNP-guided group. During long-term, NT-proBNP-guided therapy did not improve hospital-free (primary end point: hazard ratio, 0.87; 95% confidence interval, 0.71-1.06; P=0.16) or overall survival (hazard ratio, 0.85; 95% confidence interval, 0.64-1.13; P=0.25) but did improve HF hospitalization-free survival (hazard ratio, 0.70; 95% confidence interval, 0.55-0.90; P=0.005). Patients aged 60 to 74 years had benefit from NT-proBNP-guided therapy on the primary end point and HF hospitalization-free survival, whereas patients aged≥75 years did not (P<0.10 for interaction). In landmark analysis, there was no regression to the mean after cessation of the NT-proBNP-guided strategy. More intensified HF medication at month 12 was associated with better long-term HF hospitalization-free and overall survival. CONCLUSIONS: Intensified, NT-proBNP-guided therapy did not improve the primary end point compared with symptom-guided therapy but did improve HF hospitalization-free survival. Within the subgroup of patients aged 60 to 74 years, it improved clinical outcome including the primary end point. These effects did not disappear after cessation of the NT-proBNP-guided strategy on the long-term. This is possibly attributable to a more intensified HF medical therapy in the NT-proBNP-guided group. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.org. Unique identifier: ISRCTN43596477.

Safety and tolerability of intensified, N-terminal pro brain natriuretic peptide-guided compared with standard medical therapy in elderly patients with congestive heart failure: results from TIME-CHF.

AIMS: NT-proBNP-guided therapy results in intensification of medical heart failure (HF) therapy and is suggested to improve outcome. However, it is feared that an intensified, NT-proBNP-guided therapy carries a risk of adverse effects. Therefore, the safety and tolerability of NT-proBNP-guided therapy in the Trial of Intensified vs standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) was assessed. METHODS AND RESULTS: A total of 495 chronic HF patients, aged ≥60, with an LVEF ≤45%, NYHA class ≥II, randomized to NT-proBNP-guided or symptom-guided therapy and ≥1 month follow-up were included in the present safety analysis. All adverse events (AEs) were recorded during the 18-month trial period. A total of 5212 AEs were noted, 433 of them serious. NT-proBNP-guided therapy led to a higher up-titration of HF medication and was well tolerated, with a dropout rate (12% vs. 11%, P = 1.0) and AE profile [number of AEs/patient-year 4.7 (2.8-9.4) vs. 5.4 (2.7-11.4), P = 0.69; number of severe AEs/patient-year 0.7 (0-2.7) vs. 1.3 (0-3.9), P = 0.21] similar to that of symptom-guided therapy, although most subjects in both treatment groups (96% vs. 95%, P = 0.55) experienced at least one AE. Age and number of co-morbidities were associated with AEs and interacted with the safety profile of NT-proBNP-guided therapy: positive effects were more frequent in younger and less co-morbid patients whereas potential negative effects-although small and related to non-severe AEs only-were only seen in the older and more co-morbid patients. CONCLUSIONS: NT-proBNP-guided therapy is safe in elderly and highly co-morbid HF patients. Trial registration ISRCTN43596477.

Cost-effectiveness of N-terminal pro-B-type natriuretic-guided therapy in elderly heart failure patients: results from TIME-CHF (Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure).

OBJECTIVES: This study aimed to assess cost-effectiveness of N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided versus symptom-guided therapy in heart failure (HF) patients ≥60 years old. BACKGROUND: Cost-effectiveness of NT-proBNP guidance in HF patients is unclear. It may create additional costs with uncertain benefits. METHODS: In the TIME-CHF (Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure), patients with left ventricular ejection fraction (LVEF) of ≤45% were randomized to receive intensified NT-proBNP-guided therapy or standard, symptom-guided therapy. For cost-effectiveness analysis, 467 (94%) patients (age 76 ± 7 years, 66% male) were eligible. Incremental cost-effectiveness was calculated as incremental costs per gained life-year and quality-adjusted life-year (QALY) within the 18-month trial period, as defined per protocol. RESULTS: NT-proBNP-guided therapy was dominant (i.e., more effective and less costly) over symptom-guided therapy, saving $2,979 USD (2.5 to 97.5% confidence interval [CI]: $8,758 to $3,265) per patient, with incremental effectiveness of +0.07 life-years and +0.05 QALYs. The probability of NT-proBNP-guided therapy being dominant was 80%, and the probability of saving 1 life-year or QALY at a cost of $50,000 was 97% and 93%, respectively. Exclusion of residence costs resulted in an incremental cost-effectiveness ratio (ICER) of $5,870 per life-year gained. Cost-effectiveness of NT-proBNP-guided therapy was most pronounced in patients <75 years old and in those with <2 significant comorbidities, being dominant in all sensitivity analyses. In the worst-case scenario (excluding residence costs in those with ≥2 comorbidities), the ICER was $11,935 per life-year gained. CONCLUSIONS: NT-proBNP-guided therapy has a high probability of being cost effective in HF patients with reduced LVEF, particularly in patients age 60 to 75 years or with less than 2 comorbidities. (Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure [TIME-CHF]; ISRCTN43596477).

Incidence, clinical predictors, and prognostic impact of worsening renal function in elderly patients with chronic heart failure on intensive medical therapy.

BACKGROUND: Incidence, predictors, and prognostic impact of worsening renal function (WRF) in elderly patients with chronic heart failure (HF) undergoing intensive contemporary medical therapy are unknown. METHODS AND RESULTS: In 566 patients (age 77 ± 8 years) included in the TIME-CHF, serum creatinine (sCr) was repeatedly measured up to 6 months. Worsening renal function was classified as increase in sCr by 0.2 to 0.3 (WRFI), 0.3 to 0.5 (WRFII), or ≥0.5 mg/dL (WRFIII) within the first 6 months. Outcome events were assessed for 18 months. RESULTS: The incidence of WRF I, II, and III was 12%, 19%, and 22%, respectively. Worsening renal function III was associated with increased mortality (hazard ratio 1.98 [95% CI 1.27-3.07, P = .002] vs no WRF), whereas WRF I/II was not. History of renal failure, spironolactone treatment, higher baseline dose, and higher maximal increase in loop diuretic dose were independently associated with the occurrence of WRF III, whereas angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and ß-blocker use and allocation to N-terminal pro-B-type natriuretic peptide-guided management were not. Worsening renal function III was an independent predictor of death, death or hospitalization, and death or HF hospitalization also after adjusting for baseline characteristics. CONCLUSIONS: One fifth of elderly patients with chronic HF experienced WRF III on 6-month intensive HF treatment. These patients had higher mortality, whereas patients with smaller sCr rises did not. Occurrence of WRF III was associated with high doses of loop diuretics and spironolactone use but not with other treatments.

Closed loop stimulation and accelerometer-based rate adaptation: results of the PROVIDE study.

AIMS: We compared pacing rate adaptation based on closed loop stimulation (CLS) or accelerometer sensor (AS) during acute mental and physical stress in the same patient. METHODS AND RESULTS: One month after Protos (Biotronik, Germany) pacemaker implantation, 131 chronotropically incompetent patients were randomized to AS or CLS for 3 months with crossover. Arithmetic and 6 min walk tests were performed in the non-rate-adaptive mode and AS and CLS rate-adaptive modes, respectively. At the end, patients had to select the individually preferred pacemaker sensor. Heart rate during mental stress was higher (3.0 +/- 9.2 bpm) in the CLS than in the AS mode (P = 0.004). Benefit in the walking distance compared with non-rate-adaptive pacing was similar for the two modes: added 27 +/- 96 m (AS, P = 0.013) and 30 +/- 116 m (CLS, P = 0.025). At the end of the walk, heart rate was higher by 4.8 +/- 21.4 bpm in AS than in CLS (P = 0.049). Twice as many patients preferred CLS over AS (P < 0.01). CONCLUSION: The arithmetic test was associated with a significantly higher heart rate for CLS than for AS, showing a greater sensitivity of CLS-based rate adaptation to mental stress. Performance during physical stress was comparable. Patients preferred CLS.

Cost-effectiveness of invasive versus medical management of elderly patients with chronic symptomatic coronary artery disease. Findings of the randomized trial of invasive versus medical therapy in elderly patients with chronic angina (TIME).

AIM: To compare benefits and costs of invasive versus medical management in elderly patients with chronic angina. METHODS AND RESULTS: In a predefined subgroup of 188 patients of the Trial of Invasive versus Medical therapy in Elderly patients with chronic angina (TIME), one-year benefits were assessed as freedom from major events and improvements in symptoms and quality of live. Costs were determined as one-year costs of resource utilisation. Invasive patients had higher 30-day, but lower months 2-12 hospital and intervention costs than medical patients, resulting in somewhat higher one-year costs for invasive management (p=0.08). However, billing data available for a subgroup of patients showed higher practitioner's charges in the medical patients (adjusted p=0.0015). Incremental costs to prevent one major event by invasive management averaged CHF 10100 (95% CI: -800 to 28300) or 6965, ranging from average CHF 5100 (euro 3515) to CHF 11600 (euro 8000) in a best, compared to a worst, case scenario. CONCLUSIONS: Early increased costs of revascularization in invasive patients were balanced after one year by increased practitioners' charges and symptom-driven late revascularizations in medical patients. Therefore, the invasive strategy with improved clinical effectiveness at only marginally higher costs as medical management was cost-effective. Costs should not be an argument against invasive management of elderly patients with chronic angina.

Frequency and outcome of in-hospital resuscitation outside the ICU-setting.

BACKGROUND: Guidelines on performing cardiopulmonary resuscitation and its research have been published. Only few data concerning in-hospital resuscitation are available from Switzerland. The aim of our study was to evaluate the frequency and outcome of cardiopulmonary arrests in our hospital and to look for ways of improving our resuscitation management. METHODS: The prospective study was performed in the Kantonsspital Liestal, a primary care hospital with 360 beds, where about 24'300 in-patients were treated during the 2 year observation period. Only in-hospital resuscitations outside the ICU were included and recorded according to the Utstein criteria. RESULTS: Within a 24 months period, 61 emergency calls were registered. 25 patients needed cardiopulmonary resuscitation. Initial cardiac rhythms were available for all subjects: 8 patients had asystole, 7 ventricular fibrillation and 10 pulseless electrical activity. 12 of 25 resuscitated patients had a return of spontaneous circulation, 7 lived longer than 24 hours and 6 patients (24%) survived to hospital discharge, 4 of them in a very good or good neurological condition. After 12 months 3 patients (12%) were living independently at home, 2 patients had to be treated in a nursing home and 1 patient had died. CONCLUSIONS: Our data correspond to survival rates in larger studies from abroad but are limited by the number of patients investigated. Improvements are necessary in documentation of resuscitation efforts. Rapid defibrillation must be further stressed. The implementation of a multicentre study is suggested because quality control and further improvement of in-hospital resuscitation are needed in Switzerland.

Outcome of elderly patients with chronic symptomatic coronary artery disease with an invasive vs optimized medical treatment strategy: one-year results of the randomized TIME trial.

CONTEXT: The risk-benefit ratio of invasive vs medical management of elderly patients with symptomatic chronic coronary artery disease (CAD) is unclear. The Trial of Invasive versus Medical therapy in Elderly patients (TIME) recently showed early benefits in quality of life from invasive therapy in patients aged 75 years or older, although with a certain excess in mortality. OBJECTIVE: To assess the long-term value of invasive vs medical management of chronic CAD in elderly adults in terms of quality of life and prevention of major adverse cardiac events. DESIGN: One-year follow-up analysis of TIME, a prospective randomized trial with enrollment between February 1996 and November 2000. SETTING AND PARTICIPANTS: A total of 282 patients with Canadian Cardiac Society class 2 or higher angina despite treatment with 2 or more anti-anginal drugs who survived for the first 6 months after enrollment in TIME (mean age, 80 years [range, 75-91 years]; 42% women), enrolled at 14 centers in Switzerland. INTERVENTIONS: Participants were randomly assigned to undergo coronary angiography followed by revascularization (if feasible) (n = 140 surviving 6 months) or to receive optimized medical therapy (n = 142 surviving 6 months). MAIN OUTCOME MEASURES: Quality of life, assessed by standardized questionnaire; major adverse cardiac events (death, nonfatal myocardial infarction, or hospitalization for acute coronary syndrome) after 1 year. RESULTS: After 1 year, improvements in angina and quality of life persisted for both therapies compared with baseline, but the early difference favoring invasive therapy disappeared. Among invasive therapy patients, later hospitalization with revascularization was much less likely (10% vs 46%; hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.11-0.32; P<.001). However, 1-year mortality (11.1% for invasive; 8.1% for medical; HR, 1.51; 95% CI, 0.72-3.16; P =.28) and death or nonfatal myocardial infarction rates (17.0% for invasive; 19.6% for medical; HR, 0.90; 95% CI, 0.53-1.53; P =.71) were not significantly different. Overall major adverse cardiac event rates were higher for medical patients after 6 months (49.3% vs 19.0% for invasive; P<.001), a difference which increased to 64.2% vs 25.5% after 12 months (P<.001). CONCLUSIONS: In contrast with differences in early results, 1-year outcomes in elderly patients with chronic angina are similar with regard to symptoms, quality of life, and death or nonfatal infarction with invasive vs optimized medical strategies based on this intention-to-treat analysis. The invasive approach carries an early intervention risk, while medical management poses an almost 50% chance of later hospitalization and revascularization.