Cardio-selective and non-selective beta-blockers in chronic obstructive pulmonary disease: effects on bronchodilator response and exercise. Detrimental effects of beta-blockers in COPD: a concern for nonselective beta-blockers. Bisoprolol in patients with heart failure and moderate to severe chronic obstructive pulmonary disease: a randomized controlled trial. Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH). The IPPPSH Collaborative Group. Beta-adrenoceptor blockers and terbutaline in patients with chronic obstructive lung disease. Effects and interaction after oral administration. Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial. Effect of beta-adrenergic blockade on hyperventilation and exercise tolerance in emphysema. Labetalol, beta blockers, and acute deterioration of chronic airway obstruction. The effect of beta-blockers on ventilatory function in chronic bronchitis.
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. beta-Blockers are known to worsen FEV(1) and airway hyperresponsiveness (AHR) in patients with asthma. Both characteristics determine the outcome of COPD, a disease with frequent cardiac comorbidity requiring beta-blocker treatment.
                To determine the effects of beta-blockers on AHR (provocative concentration of methacholine causing a 20% fall in FEV(1) [PC(20)]), FEV(1), and response to formoterol in patients with COPD.
                A double-blind, placebo-controlled, randomized, cross-over study.
                An ambulatory, hospital outpatient clinic of pulmonary diseases.
                Patients with mild-to-moderate irreversible COPD and AHR.
                Fifteen patients received propranolol (80 mg), metoprolol (100 mg), celiprolol (200 mg), or placebo for 4 days, followed by a washout period >/= 3 days. On day 4 of treatment, FEV(1) and PC(20) were assessed. Immediately hereafter, formoterol (12 microg) was administered and FEV(1) was measured for up to 30 min.
                PC(20) was significantly lower (p < 0.01) with propranolol and metoprolol treatment (geometric means, 2.06 mg/mL and 2.02 mg/mL, respectively) than with placebo (3.16 mg/mL) or celiprolol (3.41 mg/mL). FEV(1) deteriorated only after propranolol treatment (2.08 +/- 0.31 L) [mean +/- SD] compared with placebo (2.24 +/- 0.37 L). The fast bronchodilating effect of formoterol was hampered by propranolol (mean increase in FEV(1) at 3 min, 6.7 +/- 8.9%) but was unaffected by the other beta-blockers (16.9 +/- 9.8%, 22 +/- 11.6%, and 16.9 +/- 9.0% for placebo, metoprolol, and celiprolol, respectively).
                Pulmonary effects did not occur by celiprolol. Only propranolol reduced FEV(1) and the bronchodilating effect of formoterol. Both metoprolol and propranolol increased AHR. Thus, different classes of beta-blockers have different pulmonary effects. The anticipated beneficial cardiovascular effects of a beta-blocker must be weighted against the putative detrimental pulmonary effects, ie, effect on FEV(1), AHR, and response to additional beta(2)-agonists. Heart failure (HF) and chronic obstructive pulmonary disease (COPD) frequently coexist. No study has prospectively examined the effects of beta-blockade in those with both conditions.
                We randomized 27 patients with HF and coexistent moderate or severe COPD to receive bisoprolol or placebo, titrated to maximum tolerated dose over 4 months. The primary outcome was forced expiratory volume in 1 s (FEV(1)). The study is registered with ClinicalTrials.gov, number: NCT00702156. Patients were elderly and predominantly male. Cardiovascular comorbidity, smoking history, and pulmonary function were similar in each group (mean FEV(1) 1.37 vs. 1.26 L, P = 0.52). A reduction in FEV(1) occurred after 4 months following treatment with bisoprolol compared with placebo (-70 vs. +120 mL, P = 0.01). Reversibility following inhaled beta(2)-agonist and static lung volumes were not impaired by bisoprolol. All measures of health status exhibited a consistent non-significant improvement, including the Short Form 36 physical and mental component scores (2.6 vs. 0.5 and 0.8 vs. -0.3, respectively), Minnesota Living with Heart Failure Questionnaire (-2.5 vs. 3.5) and Chronic Respiratory Questionnaire (0.07 vs. -0.24). The mean number of COPD exacerbations was similar in the bisoprolol and placebo groups (0.50 and 0.31, respectively, P = 0.44).
                Initiation of bisoprolol in patients with HF and concomitant moderate or severe COPD resulted in a reduction in FEV(1). However, symptoms and quality of life were not impaired. Myocardial infarction, sudden cardiac death, cerebrovascular accidents, blood pressure control and treatment tolerability were studied in a randomized double-blind trial conducted in 6357 men and women aged 40-64 years with uncomplicated essential hypertension (diastolic blood pressures 100-125 mmHg). At the start of the trial 3185 patients received treatment based on a beta-blocker (oxprenolol), while in the remaining 3172 placebo replaced oxprenolol. Supplementary drugs, excluding beta-blockers, were used as necessary in both treatment groups, with the aim of reducing diastolic pressure to 95 mmHg or less. Patients were followed for 3-5 years, a total of 25 651 patient years at risk. In most respects the two groups fared equally well; sudden death (relative risk [RR] 1.08; 95% confidence interval [Cl] 0.68 and 1.72), myocardial infarction (RR 0.83; Cl 0.59 and 1.16) and cerebrovascular accident (RR 0.97; Cl 0.64 and 1.47) rates were similar. Beta-blocker based therapy was associated with significantly lower average blood pressures, earlier ECG normalization, less hypokalaemia and fewer withdrawals from double-blind treatment for uncontrolled hypertension. Doctor-elicited and patient-assessed unwanted effects demonstrated overall good tolerability. In smokers the cardiac event rate was doubled. We propose that beta-blocker treatment effects depend on smoking status, with a significant interaction benefiting non-smoking men. Lower blood pressures during treatment were associated with substantially lower rates for cardiac as well as cerebrovascular events. Proportional hazards analysis also underlines the importance of other cardiovascular risk factors. The IPPPSH stresses the need for a comprehensive approach to the management of blood pressure and other risk factors in hypertensive patients. We studied the effects of a combined treatment with beta 2-stimulating and beta-blocking drugs in 35 patients suffering from chronic obstructive lung disease (COLD) and ischemic heart disease, and/or arterial hypertension. The drugs used were equipotent repeated oral doses of metoprolol (100 mg twice daily [bid]), propranolol (80 mg bid), and a matching placebo for beta-adrenoceptor blockade given in a double-blind and crossover fashion. The intake period of each beta-blocker was two days with consecutive two-day-washout period; 2.5 mg terbutaline and beta-stimulator placebo, respectively, were given throughout the whole trial three times daily (tid). Propranolol alone caused severe deterioration of lung function. After 18 patients had been studied, this drug had to be excluded from the trial. When compared with placebo, metoprolol provoked increasing obstruction, too, but to a significantly lesser degree than propranolol. These negative effects on FEV1 and FRC were completely equalized by terbutaline. Predictive factors for the tolerability of beta-blockers in patients with COLD could not be found. Therefore, careful observations in the initial phase of the treatment with beta-selective blockers are necessary. 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. Ventilation, heart rate, and arterial blood gas tensions were measured at rest and during incremental exercise in 10 patients with emphysema after intravenous placebo or 7 mg metoprolol. Metoprolol reduced heart rate by 14% (P less than 0.001) and ventilation by 11% (P less than 0.01), but there was no significant difference in arterial O2 or CO2 tension (Pao2 and PaCO2, respectively). Metoprolol increased the time to exhaustion on a cycle ergometer (P less than 0.05) but did not improve the 12-min walking distance. A double-blind randomized crossover comparison of 4 wk treatment with atenolol (100 mg/day), metoprolol (100 mg/day), or matched placebo was performed in 12 patients with emphysema. Both beta-adrenoceptor antagonists reduced resting heart rate by 33% (P less than 0.001) and resting minute ventilation by 11% (P less than 0.025). There was no change in resting or exercise Pao2 or Paco2. During steady-state exercise on a cycle ergometer, atenolol and metoprolol reduced ventilation by 14 and 4%, respectively. This was accompanied by 11 and 5% reductions in O2 consumption (P less than 0.05) and 13 and 6% falls in CO2 production (P less than 0.05). There were no significant changes in tests of exercise tolerance, but forced expiratory volume in 1 s and forced vital capacity were reduced during beta 1-adrenergic blockade. beta 1-Blocking drugs reduce hyperventilation in emphysema by reducing pulmonary gas exchange without a change in arterial blood gas tensions. Increased airflow obstruction prevents this reduction being of therapeutic value. The effects on lung function of labetalol (a combined alpha and beta adrenergic receptor blocker) and three beta adrenergic receptor blockers (propranolol, atenolol, metoprolol) have been assessed in patients with chronic airflow obstruction using a double-blind trial. With the dosages used, all drugs produced an equivalent fall of blood pressure. Propranolol was the only drug that significantly increased airways obstruction (FEV1, specific airways resistance). Following salbutamol, labetalol was associated with a significantly greater improvement of airflow than either propranolol or metoprolol. On these acute studies, the order of preference for beta blocking drugs in management of hypertension in patients with obstructive airways disease, would be labetalol, (atenolol) or (metoprolol) and then propranolol. The effect of propranolol and atenolol on air-flow obstruction in patients with chronic bronchitis was evaluated by means of a double-blind, placebo-controlled cross-over trial. Fifteen patients with chronic bronchitis and mild air-flow obstruction, in whom there was no clinical suggestion of asthma, were studied. Two patients developed symptomatic increases in air-flow obstruction on propranolol and were withdrawn from the study. A symptomatically insignificant but statistically significant increase in air-flow obstruction was observed during treatment with both propranolol and atenolol.
Cardioselective beta-blockers, given to patients with COPD in the identified studies did not produce adverse respiratory effects. Given their demonstrated benefit in conditions such as heart failure, coronary artery disease and hypertension, cardioselective beta-blockers should not be routinely withheld from patients with COPD.