Propranolol treatment of congestive heart failure in infants with congenital heart disease: The CHF-PRO-INFANT Trial. Congestive heart failure in infants treated with propanol. Cardio-selective and non-selective beta-blockers in chronic obstructive pulmonary disease: effects on bronchodilator response and exercise. Reduction in heart failure events by the addition of a clinical pharmacist to the heart failure management team: results of the Pharmacist in Heart Failure Assessment Recommendation and Monitoring (PHARM) Study. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. Quality of care for secondary prevention for patients with coronary heart disease: results of the Hastening the Effective Application of Research through Technology (HEART) trial. A randomized and controlled pilot trial of beta-blockers for the treatment of recurrent syncope in patients with a positive or negative response to head-up tilt test. Clinical reminders attached to echocardiography reports of patients with reduced left ventricular ejection fraction increase use of beta-blockers: a randomized trial. Comparison of a chronotherapeutically administered beta blocker vs. a traditionally administered beta blocker in patients with hypertension.
Infants with congenital heart disease and left-to-right shunts may develop significant clinical symptoms of congestive heart failure in spite of therapy with digoxin and diuretics. We investigated the effects of beta-blockade in infants with severe heart failure.
                We performed a prospective, randomized, open monocenter trial in infants treated with digoxin and diuretics (n=10) in comparison to 10 infants receiving additional beta-blocker therapy. After 17 days on average beta-blocker treated infants (propranolol:1,6 mg/kg/day) improved significantly with respect to Ross heart failure score (3.3+/-2.3 vs. 8.3+/-1.9, P=0.002), lower renin levels (338+/-236 vs. 704+/-490 microU/l, P=0.008) and lower mean heart rates in Holter ECG (118+/-10 vs. 142+/-11 beats/min, P<0.001). While digoxin and diuretic treated infants had unchanged mean heart rate (149+/-8 vs. 148+/-10 beats/min), less decrease of symptoms (Ross Score: 8.5+/-1.7 vs. 6.8+/-2.3, P=0.02) but a significant increase of renin levels (139+/-102 vs. 938+/-607 microU/l, P=0.001).
                Additional propranolol treatment but not digoxin and diuretics alone can effectively reduce clinical symptoms of heart failure in infants with congenital heart disease, who suffer from increased neurohormonal activation. Patients with chronic obstructive pulmonary disease (COPD) often have co-existing cardiovascular disease and may require beta-blocker treatment. There are limited data on the effects of beta-blockers on the response to inhaled beta2-agonists and exercise capacity in patients with COPD.
                To determine the effects of different doses of cardio-selective and non-selective beta-blockers on the acute bronchodilator response to beta-agonists in COPD, and to assess their effects on exercise capacity.
                A double-blind, randomized, three-way cross-over (metoprolol 95 mg, propranolol 80 mg, placebo) study with a final open-label high-dose arm (metoprolol 190 mg). After 1 week of each treatment, the bronchodilator response to salbutamol was measured after first inducing bronchoconstriction using methacholine. Exercise capacity was assessed using the incremental shuttle walk test.
                Eleven patients with moderate COPD were recruited. Treatments were well-tolerated although two did not participate in the high-dose metoprolol phase. The area under the salbutamol-response curve was lower after propranolol compared with placebo (P=0.0006). The area under the curve also tended to be lower after high-dose metoprolol (P=0.076). The per cent recovery of the methacholine-induced fall was also lower after high-dose metoprolol (P=0.0018). Low-dose metoprolol did not alter the bronchodilator response. Oxygen saturation at peak exercise was lower with all beta-blocker treatments (P=0.046).
                Non-selective beta-blockers and high doses of cardio-selective beta-blockers may inhibit the bronchodilator response to beta2-agonists in patients with COPD. Beta-blockers were also associated with lower oxygen saturation during exercise. The clinical significance of these adverse effects is uncertain in view of the benefits of beta-blocker treatment for cardiovascular disease. The multidisciplinary approach to managing heart failure has been shown to improve outcomes. The role of a clinical pharmacist in treating heart failure has not been evaluated.
                One hundred eighty-one patients with heart failure and left ventricular dysfunction (ejection fraction <45) undergoing evaluation in clinic were randomized to an intervention or a control group. Patients in the intervention group received clinical pharmacist evaluation, which included medication evaluation, therapeutic recommendations to the attending physician, patient education, and follow-up telemonitoring. The control group received usual care. The primary end point was combined all-cause mortality and heart failure clinical events. All clinical events were adjudicated by a blinded end point committee.
                Baseline characteristics were similar except for slightly higher age in the intervention group. Median follow-up was 6 months. All-cause mortality and heart failure events were significantly lower in the intervention group compared with the control group (4 vs 16; P= .005). In addition, patients in the intervention group received higher angiotensin-converting enzyme inhibitor doses as reflected by the median fraction of target reached (25th and 75th percentiles), 1.0 (0.5 and 1) and 0.5 (0.1875 and 1) in the intervention and control groups, respectively (P<.001). The use of other vasodilators in angiotensin-converting enzyme inhibitor-intolerant patients was higher in the intervention group (75% vs 26%; P= .02).
                Outcomes in heart failure can be improved with a clinical pharmacist as a member of the multidisciplinary heart failure team. This observation may be due to higher doses of angiotensin-converting enzyme inhibitors and/or closer follow-up. In the Thrombolysis in Myocardial Infarction (TIMI) Phase II trial, patients received intravenous recombinant tissue-type plasminogen activator (rt-PA) and were randomized to either a conservative or an invasive strategy. Within this study, the effects of immediate versus deferred beta-blocker therapy were also assessed in patients eligible for beta-blocker therapy, a group of 1,434 patients of which 720 were randomized to the immediate intravenous group and 714 to the deferred group. In the immediate intravenous group, within 2 hours of initiating rt-PA metoprolol was given (5 mg intravenously at 2-minute intervals over 6 minutes, for a total intravenous dose of 15 mg, followed by 50 mg orally every 12 hours in the first 24 hours and 100 mg orally every 12 hours thereafter). The patients assigned to the deferred group received metoprolol, 50 mg orally twice on day 6, followed by 100 mg orally twice a day thereafter. The therapy was tolerated well in both groups and the primary end point, resting global ejection fraction at hospital discharge, averaged 50.5% and was virtually identical in the two groups. The regional ventricular function was also similar in the two groups. Overall, there was no difference in mortality between the immediate intravenous and deferred groups, but in the subgroup defined as low risk there were no deaths at 6 weeks among those receiving immediate beta-blocker therapy in contrast to seven deaths among those in whom beta-blocker therapy was deferred. These findings for a secondary end point in a subgroup were not considered sufficient to warrant a recommendation regarding clinical use. There was a lower incidence of reinfarction (2.7% versus 5.1%, p = 0.02) and recurrent chest pain (18.8% versus 24.1%, p less than 0.02) at 6 days in the immediate intravenous group. Thus, in appropriate postinfarction patients, beta-blockers are safe when given early after thrombolytic therapy and are associated with decreased myocardial ischemia and reinfarction in the first week but offer no benefit over late administration in improving ventricular function or reducing mortality. Men aged 40-64 years with mild to moderate hypertension [diastolic blood pressure (DBP) 100-130 mmHg] were randomized to treatment with a diuretic (n = 3272) or a beta-blocker (n = 3297), with additional drugs if necessary, to determine whether a beta-blocker based treatment differs from thiazide diuretic based treatment with regard to the prevention of coronary heart disease (CHD) events and death. Patients with previous CHD, stroke or other serious diseases, or with contraindications to diuretics or beta-blockers were excluded. If normotension (DBP less than 95 mmHg) was not achieved by monotherapy, other antihypertensive drugs were added, but the two basic drugs were not crossed over. Patients were assessed at 6-monthly intervals. The mean follow-up for end-points was 45.1 months. Blood pressure (BP) side effects and end-points were recorded in a standardized manner. Entry characteristics and the BP reduction achieved were very similar in both treatment groups. All analyses were made on an intention-to-treat basis. The incidence of CHD did not differ between the two treatment groups. The incidence of fatal stroke tended to be lower in the beta-blocker treated group than in the diuretic treated group. Total mortality and the total number of end-points were similar in both groups. The percentage of patients withdrawn due to side effects was similar, whereas the number of reported symptoms, according to a questionnaire, was higher for patients on beta-blockers. The incidence of diabetes did not differ between the two groups. Subgroup analyses did not detect a difference in the effect of beta-blockers compared with diuretics in smokers as opposed to non-smokers, and beta-blockers also had the same effects as diuretics in the quartile with the highest predicted risk for CHD. Beta-blockers and thiazide diuretics were approximately equally well tolerated. The two drugs had a similar BP reducing effect although additional drugs had to be given more often in the diuretic group. Antihypertensive treatment based on a beta-blocker or on a thiazide diuretic could not be shown to affect the prevention of hypertensive complications, including CHD, to a different extent. Effective therapies for reducing mortality rates in persons with coronary heart disease (CHD) remain underused. We report the results of an effectiveness trial of a quality improvement effort to increase the use of 3-hydroxy-3methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors in patients with CHD in a network-model managed-care setting.
                Patients with CHD were identified by searching a claims database. The use of therapies was assessed by linkage with a pharmacy database. An intervention, consisting of a guideline summary, peer comparison performance feedback, and patient specific chart reminders was evaluated in a randomized, practice-based effectiveness trial.
                Data were available for >700 patients per year (1999-2002) in 131 practices. At baseline (1999), 55% of patients were receiving HMG CoA reductase inhibitors, 39% of patients were receiving beta-blockers, and 24% of patients were receiving ACE inhibitors. The use of all 3 types of medications increased steadily with time, with the exception of a decrease in the use of HMG CoA reductase inhibitors in the final year (2002). No difference in medication use was observed between randomized groups.
                The observed pattern of care supports the contention that the quality of outpatient care for secondary prevention of CHD improved from 1999 to 2002 in this setting. The basis for the inconsistent pattern of use of HMG CoA reductase inhibitors is not certain, but may relate to concerns about toxicity. Centralized mailings of guideline summaries, performance feedback reports, and chart reminders had no observable impact on quality of care in this setting. More intensive intervention may be required to improve the quality of outpatient care for the secondary prevention of CHD. The aim of this study was to assess the efficacy of lipophilic beta-blockers in preventing recurrent neurocardiogenic syncope and the value of head-up tilt test (HUT) in predicting response to therapy. The efficacy of beta-blockers in recurrent syncope is controversial. The value of HUT in predicting efficacy of therapy has not been investigated. Fifty-six patients (44+/-18 years, 36 women) with recurrent syncope (> 1 event in the last 6 months) of suspected neurocardiogenic origin were included in the study. Independent of the response to HUT, patients were randomized to receive metoprolol or propanolol at the maximal tolerated dose (28 patients, group A, 86+/-23 vs 98+/-29 mg/d) or no pharmacological therapy (28 patients, group B). The primary endpoint was the first recurrence of syncope. During the 1-year of follow-up, 20 patients of group A and 8 of group B had no recurrence. In group A, of 20 patients without recurrences 12 had a positive and 8 a negative HUT result while of 8 patients with recurrences 5 had a positive and 3 a negative response to HUT. In the group B, of 20 patients with recurrences 10 had a positive and 10 a negative HUT result while of 8 patients without recurrences 4 had a positive and 4 a negative response to HUT. In a multivariate Cox-regression analysis, medical therapy was the only independent factor for predicting recurrence of syncope (P = 0.004); HUT had no influence in this regard (P = 0.773). In conclusion, lipophilic beta-blockers appear efficacious in preventing recurrent syncope of suspected neurocardiogenic origin. The efficacy of therapy seems to be not predicted by HUT. Although beta-blockers are known to prolong survival for patients with reduced left ventricular ejection fraction, they are often underused. We hypothesized that a reminder attached to the echocardiography report would increase the use of beta-blockers for patients with reduced left ventricular ejection fraction.
                We randomized 1546 consecutive patients with a left ventricular ejection fraction <45% found on echocardiography at 1 of 3 laboratories to a reminder for use of beta-blockers or no reminder. Patients were excluded from analysis if they died within 30 days of randomization (n=89), did not receive medications through the Veterans Affairs system after 30 days (n=180), or underwent echocardiography at >1 laboratory (n=6). The primary outcome was a prescription for an oral beta-blocker between 1 and 9 months after randomization. The mean age of the 1271 included patients was 69 years; 60% had a history of heart failure, and 51% were receiving treatment with beta-blockers at the time of echocardiography. More patients randomized to the reminder had a subsequent beta-blocker prescription (74%, 458 of 621) compared with those randomized to no reminder (66%, 428 of 650; P=0.002). The effect of the reminder was not significantly different for subgroups based on patient location (inpatient versus outpatient) or prior use of beta-blockers.
                A reminder attached to the echocardiography report increased the use of beta-blockers in patients with depressed left ventricular systolic function. Increasing systolic blood pressure and heart rate during the early morning results in increased myocardial oxygen demand. The use of beta blockers during this period may decrease cardiac workload, particularly in beta-blocker sensitive patients. The impact of a new chronotherapeutic beta blocker was assessed in 44 hypertensive patients. Patients were randomized to delayed-release propranolol (INP) dosed at 10 p.m. or to traditionally dosed propranolol (ILA) dosed at 8 a.m. for 4 weeks, following which they were switched to the alternative formulation for 4 weeks. Thirty-four-hour ambulatory blood pressure monitoring and pharmacokinetic measurements were obtained. INP and ILA resulted in significant reductions in mean 24-hour blood pressure (-9.0/-6.9 mm Hg and -10.4/-7.7 mm Hg, respectively). The top 25% of responders to high-dose propranolol (sensitive patients) were compared on each formulation. Mean trough reductions were -8.0/-6.7 mm Hg and -7.6/-5.8 mm Hg, respectively. Mean blood pressure reductions in the beta-blocker sensitive patients (n = 11) between 6 a.m. and noon were -15.2/-11.9 mm Hg on INP and -8.0/-4.6 mm Hg on ILA. Heart rate reduction was -14.1 bpm and double product reduction was -3319 in the INP patients between 6 a.m. and 12 noon compared with -10.5 and -2209 in the ILA patients. This study suggests that INP and ILA are effective once-a-day beta blockers, but the use of delayed-release propanolol results in a greater reduction in double product between 6 a.m. and noon in beta-blocker sensitive patients than does traditionally dosed propranolol.
There are not enough data to recommend or discourage the use of beta-blockers in children with congestive heart failure. Further investigations in clearly defined populations with standardised methodology are required to establish guidelines for therapy. Pharmacokinetic investigations of beta-blockers in children are required to provide effective dosing in future trials.