Whether or not stable (1 month or greater) beta-blocker therapy should be stopped during acutely decompensated heart failure (ADHF) exacerbations during hospitalization.
During an acute decompensated heart failure exacerbation leading to hospitalization, continuation of beta-blocker therapy is not associated with delayed or lesser clinical improvement.
There has been much clinical uncertainty in the continuation of beta-blocker therapy during a hospitalization for patient's with acute decompensated heart failure. This belief was rooted in the understanding that the negative inotropic effect of beta-blockers decreases cardiac output and increases left ventricular filling pressures potentially worsening a patient's heart failure exacerbation leading to cardiogenic shock. Prospective randomized trials in patients with chronic systolic heart failure have consistently concluded that beta-blocker therapy improved survival, QOL, and decreases hospitalization rate indeterminate of the etiology, sex, other associated therapy and age. This trial attempted to determine whether physician's should deem it appropriate to continue a patient's beta-blocker dose when hospitalized for acute decompensated heart failure.
Patient's were randomized to either continue their chronic (1 month or greater of stable dosing) beta-blocker therapy or discontinue it for 3 days upon hospitalization. Level of dyspnea and general well-being was rated on a 5-point Likert scale by the patient and a blinded physician at Day 3 and Day 8. No difference was found between groups at these time intervals. The study's secondary outcome of determining if these groups of patients would remain on beta-blocker therapy 3 months from hospitalization yielded a significant result; patient's who did not discontinue their beta-blocker during hospitalization were more likely to still be on the therapy 3 months following their hospitalization. Therefore for patients who meet the inclusion criteria for the trial could have their beta-blocker dose continued during their hospitalization for acute decompensated heart failure.
- Multicenter, double-blind, parallel-group, randomized, controlled trial
- N= 147
- Keeping Beta-blockade (n=69)
- Stopping Beta-blockade (n=78)
- Setting: Thirty-six Cardiology centers in France
- Enrollment: October 2004 - October 2008
- Mean follow-up: 8 days of hospitalization (or less if discharged prior to Day 8); 3 months following hospital discharge
- Analysis: Non-inferiority
- Primary outcome: Percentage of patients whose both general well-being and dyspnea had improved at 3 days according to the blinded physician.
- Secondary outcomes:
- Percentage of patients whose both general well-being and dyspnea had improved (i) at 3 days according to the patient, (ii) at day 8 according to the blinded physician, (iii) at day 8 according to the patient; BNP plasma levels at day 3; duration of hospitalization; re-hospitalization rate at 3 months; death rate at 3 months; proportion of patients receiving a beta-blocker at 3 months; mean dose of beta-blocker therapy at 3 months expressed as percent of recommended dosage.
- Aged 18 years or older
- Received beta-blocker therapy at a stable dosage for more than 1 month.
- Hospitalized for acute heart failure with pulmonary oedema (including dyspnea and pulmonary rales, or radiological evidence of oedema).
- RR had to be >24/min at some point during the ADHF episode or at time of inclusion.
- LVEF in the preceding 12 months lower than 40%
- Acute ST-elevation myocardial infarction
- Clinical indications for Dobutamine (According to practicing physician at entry; Use of PDE inhibitor not a contraindication)
- Second or Third degree AV Block
- HR < 50 BPM
- Patient in uptitration phase of beta-blocker therapy
- Participation in another research protocol
- Mean age: 72.3 (+/- 11.9) years
- 65% of the patients were male
- 39.5% were diabetic
- 64.6% Hypertensive
- Majority of the patient's had labelled ischemic etiology to their Heart Failure at 60.5% (either previous MI (27%) or significant stenosis noted on coronary angiography (73%))
- Lack of adherence to therapy was the most common reason for acute exacerbation (20%), undetermined was 42%
- Randomized to keeping beta-blockade (n=69) and stopping beta-blockade (n=78) for at least three days.
- Everyday during the first 8 days or until hospital discharge, if earlier, clinical data in the form of HR, BP, RR, O2 saturation, presence of pulmonary rales, lower limb oedema, hepatomegaly, jugular venous distension or hepato-jugular reflux were measured.
- BNP plasma levels were measured at entry and after 3 days
- After both 3 days and 8 days, two identical questionnaires were filled in, one by a physician unaware of the therapy of the patient (blinded physician) and one by the patient.
- Dyspnea and general well-being were quoted as worsened or improved compared with entry using a 5-point Likert scale
- After 3 months, patients were contacted (usually by telephone) to determine their clinical status (Alive or deceased, Re-hospitalized status, Dose of current beta-blocker if still prescribed).
Comparisons are keeping beta-blockage vs. stopping beta blockade.
- Improvements in both dyspnea and general well-being after 3 days according to blinded investigator
- 92.8% vs. 92.3% (95% CI -7.6-6.6%, unilateral upper limit of 6.6% indicating equivalence)
- Improvements in both dyspnea and general well-being after 3 days according to the patient
- 88.4% vs. 82.7% (Upper limit of unilateral 95% CI 3.8%, indicating equivalence)
- Improvements in both dyspnea and general well-being after 8 days according to the physician
- 95.2% vs. 95.4% (Upper limit of unilateral 95% CI 6.3%)
- Improvements in both dyspnea and general well-being after 8 days according to the patient
- 94.8% vs. 95.2% (Upper limit of unilateral 95% CI 6.9%)
- BNP plasma levels at day 3
- 1314 +/- 1214 pg/mL to 882+/- 950 pg/mL vs. 1387 +/- 1124 pg/mL to 876 +/-1382 pg/mL
- Duration of Hospitalization (days)
- 11.5 +/- 8.3 vs. 10.4 +/- 9.7 (p-value 0.2)
- Re-hospitalization rate at 3 months
- 40% vs. 47% (p-value 0.43)
- Death rate at 3 months
- 9% vs. 8% (p-value 0.83)
- Proportion of patients receiving a beta-blocker at 3 months
- 90% vs. 76% (p-value 0.04)
- An open allocation and low recruitment rate (only 169 patients, and further exclusion to 147) from twenty-eight centers in 4 years could suggest a selection bias and resulted in an under-powered trial - of particular importance for a non-inferiority trial.
- Patients included in the trial were hospitalized with pulmonary oedema, which by prior literature tends to represent approximately 25% of ADHF and patients also failed to show high severity clinical features (Low oxygen saturation, high respiratory rate and low blood pressure at baseline) which may explain the low three month mortality rate of 6% versus 15% in similarly studied populations
- The only significant difference between groups was a secondary outcome, the rate of beta-blocker prescription at 3 months.
- There was no reported validation of the 5-point Likert scale used to measure the variables of Dyspnea and General well-being which the trial is based on.
Funding was supported by the French Ministry of Health (Programme Hospitalier de Recherche Clinique).
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