Abstract
OBJECTIVE:
To evaluate the safety and cardiovascular benefits of β-blocker therapy in patients with chronic obstructive pulmonary disease (COPD).
DATA SOURCES:
Clinical literature was accessed through MEDLINE (1966–February 2003). Key search terms included chronic obstructive pulmonary disease and adrenergic β-antagonists.
DATA SYNTHESIS:
β-Blockers are often avoided in patients with COPD because of fear of bronchoconstriction, despite the known cardiovascular mortality benefits. A review of studies evaluating the use of β-blockers in COPD was undertaken.
CONCLUSIONS:
The literature supports the safety and mortality benefits of using β-blockers in COPD. Patients with mild to moderate COPD should receive cardioselective β-blocker therapy when a strong indication exists.
REQUEST
Should patients with a diagnosis of chronic obstructive pulmonary disease (COPD), which is a relative contraindication to β-blocker therapy, receive a β-blocker when a strong indication exists?
RESPONSE
BACKGROUND
β-Blockers have several beneficial effects in cardiovascular disease. They improve post-myocardial infarction (MI) mortality, perioperative mortality, mortality in congestive heart failure, mortality in hypertension, and symptoms and exercise tolerance in stable angina and are used in the treatment of arrhythmias.1–9 Despite these numerous benefits, clinicians are often hesitant to prescribe these agents to patients with COPD because of fear of bronchoconstriction. 10
COPD is characterized by airflow limitation that is not fully reversible, is usually progressive, and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases. 11 Patients with COPD are at risk of disease exacerbation when exposed to agents, such as β-blockers, that alter breathing by constricting the bronchioles.
Cardioselective β-blockers (acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol) competitively block the response to β-adrenergic stimulation and selectively block β1 receptors, with little or no effect on β2 receptors except at high doses. Cardioselective β-blockers have >20 times more affinity for β1 receptors than for β2 receptors and significantly reduce the risk of bronchoconstriction compared with nonselective β-blockers. 10 However, COPD is listed in many tertiary literature sources as a relative contraindication to β-blocker therapy because of the risk of bronchoconstriction. This is based largely on case reports of acute bronchospasm developing after administration of a noncardioselective β-blocker. 10
COPD is the fourth leading cause of death worldwide; the percent change in death rates has recently increased significantly and is expected to continue to increase. 11 Studies have shown that death in COPD patients is often not due to COPD alone, but to comorbid disease states such as cardiovascular disease. A study in Finland was conducted to determine the cause of death after a patient's first hospital admission for COPD. 12 The study group consisted of 2237 patients aged 65–69 years who had been initially hospitalized during 1986–1990 according to the national discharge register. Survival and causes of death were analyzed using data contained in the national mortality statistics. Thirty percent of patients died from COPD alone and 37.3% died from cardiovascular events. Another study examined participants from the Multiple Risk Factor Intervention Trial and found that the primary cause of death in patients with COPD was cardiovascular for 37% of patients and COPD -related for 34% of patients. 13
Studies have linked symptoms of chronic bronchitis and acute respiratory tract infections with the development of cardiovascular events, independent of the known major cardiovascular risk factors. A 13-year cohort study involving 19 444 randomly selected Finnish men and women evaluated patients with long-lasting symptoms of chronic bronchitis. 14 An increase in risk ratios of both coronary disease and coronary death was seen in women (1.34; 95% CI 1.04 to 1.74, and 1.41; 95% CI 0.92 to 2.16, respectively) and in men (1.36; 95% CI 1.17 to 1.56, and 1.55; 95% CI 1.26 to 1.90, respectively). A large, population-based, case—control study involving patients >75 years of age with no history of clinical risk factors and a first-time diagnosis of acute MI found that an acute MI was significantly associated with an acute respiratory tract infection in the 10 days before the index date (RR 2.7; 95% CI 1.6 to 4.7). 15
Pharmacologic treatment of COPD has also been shown to be associated with cardiovascular events in some cases. A nested, case—control study involved 630 patients with unstable angina or acute MI hospitalized in various Veterans Affairs Medical Centers. 16 The investigators determined that patients who had filled a β-agonist prescription (compared vs. those who had not filled a β-agonist prescription in 90 d) had an increased risk of experiencing acute coronary syndrome. A dose—response relationship was also seen when comparing the number of metered-dose inhaler (MDI) canisters of β-agonist used. The use of 3–5 MDI canisters had an odds ratio of 1.57 (95% CI 1.01 to 2.46), and the use of ≥6 MDI canisters had an odds ratio of 1.93 (95% CI 1.23 to 3.03). In addition, subjects who had received β-blockers and β-agonists in combination had no increase in acute coronary syndromes unless they had filled ≥6 β-agonist MDI canisters (OR 3.83; 95% CI 2.02 to 7.29).
These data establish the fact that many COPD patients have significant cardiac risk and might benefit from the cardioprotective properties of selective β1-blockers if they could be administered without adverse effects on COPD outcomes.
LITERATURE REVIEW
Safety
A recent meta-analysis of randomized, blinded, controlled trials examined the effects of cardioselective β-blockers on forced expiratory volume in 1 second (FEV1) or incidence of symptoms in patients with COPD. 17 It also evaluated the FEV1 response to β2-agonists after treatment with β1-blockers or placebo.
Trials were included if they reported FEV1 measured at rest or reported symptoms related to the study drug and placebo; were randomized, controlled, and single- or double-blind; and if they only included subjects with COPD, demonstrated by a baseline FEV1 of <80% normal predicted value or as defined by the guidelines of the American Thoracic Society. Trials were excluded if they only evaluated nonselective β-blockers, had previously been reported, were not randomized, were not blinded, did not provide FEV1 data or placebo controls, or were reviews of other trials. Outcome measures were the change in FEV1 from baseline in response to study group or placebo, FEV1 response to β2-agonist administered after placebo or study drug, and reported symptoms during the trial for study drug or placebo. 17
Nineteen trials were identified that met inclusion criteria, of which 11 gave information on single-dose studies and 8 provided information on treatments of longer duration. Longer-duration trials ranged from 2 days to 3 months (mean 1.1 mo). For the single-dose trials, β-block-ers were not associated with a change in FEV1 compared with placebo (weighted mean difference [WMD] −2.05%; 95% CI −6.05 to 1.96), and no increased respiratory symptoms were seen with β-blockers compared with placebo (risk difference [RD 0.0; 95% CI −0.03 to 0.03)]. In addition, there was no significant change in net treatment effect with the measured FEV1 response to an inhaled β2-agonist after treatment or placebo (WMD −1.21%; 95% CI −10.97 to 8.56). For the trials of longer duration, β-blockers were not associated with a change in FEV1 compared with placebo (WMD −2.55%; 95% CI −5.94 to 0.84). One patient in both the treatment group and the placebo group experienced increased respiratory symptoms. There was no significant difference in treatment effect with the measured FEV1 response to an inhaled β2-agonist after treatment or placebo (WMD −2.0%; 95% CI −13.77 to 9.77). Subgroup analyses were performed for patients with severe COPD, patients with reversible airway obstruction, and patients with comorbid cardiovascular conditions such as hypertension or angina. In all 3 groups, there was not a significant difference in FEV1 changes or symptoms. 17
This meta-analysis has several limitations. Most of the studies were small, some did not include a placebo group, and some were single- rather than double-blind. Also, the duration of treatment was short, even for the longer-duration trials; therefore, it is unclear whether longer β-blocker use would result in clinically important adverse effects.
A small clinical study reviewed the acute effects of esmolol on ventilatory function in 50 patients. 18 Patients were included if they had active cardiac disease (angina, recent MI, arrhythmia, or hypertension) and COPD. Patients were excluded if they had decompensated congestive heart failure, a history of asthma, second- or third-degree heart block, or a previous outpatient trial of a β-blocker. Esmolol was infused intravenously in a titrated dosage of 8, 16, and 24 mg/min at 10-minute intervals. Hemody-namic and spirometric measurements were performed at the end of each dosage period. Titration was continued only if no predetermined hemodynamic or pulmonary endpoints had been reached. None of the patients reported wheezing or dyspnea, and decreases in FEV1 were found in 3 patients (6%). The study concluded that there is little risk of bronchospasm when esmolol is used acutely in patients with COPD and cardiac disorders for β-blockade. A small patient population and a short duration of treatment with an intravenous β-blocker limit the results of this study. Extrapolation of the results to long-term use of an oral β-blocker may not be appropriate.
Effectiveness
A large, nonrandomized, retrospective study using data from the CCP (Cooperative Cardiovascular Project) evaluated the use and effectiveness of β-blocker therapy after an acute MI for elderly patients with COPD or asthma. 19 Patients were stratified into 3 groups (mild, moderate, and severe COPD or asthma) and were compared with patients without a diagnosis of COPD or asthma. The primary outcome measures for the study included the likelihood of receiving a prescription for a β-blocker at discharge, death within 1 year of discharge, and hospital readmission with a primary discharge diagnosis of COPD or asthma within 6 months of discharge.
A total of 54 962 patients were considered candidates for β-blocker therapy at discharge, including 12.1% with mild COPD or asthma, 5.2% with moderate COPD or asthma, 2.7% with severe COPD or asthma, and 80% without chart-documented COPD or asthma or who were not hospitalized for COPD or asthma in the year before the admission for the acute MI. Only 46.4% of eligible patients were prescribed β-blockers at discharge, and the rate of β-blocker use declined as COPD or asthma severity increased (p < 0.001). Over 91% of patients discharged on β-blockers were prescribed cardioselective agents. After adjusting for demographic and clinical factors, patients with COPD or asthma continued to be less likely to be prescribed β-blocker therapy compared with patients without pulmonary disease: mild COPD or asthma (OR 0.65; 95% CI 0.62 to 0.69), moderate COPD or asthma (OR 0.38; 95% CI 0.34 to 0.41), and severe COPD or asthma (OR 0.17; 95% CI 0.14 to 0.20). 19
β-Blocker use was significantly associated with a decreased 1-year mortality in patients without COPD or asthma (p < 0.001), with mild COPD or asthma (p < 0.001), and with moderate COPD or asthma (p = 0.02). In the adjusted analyses, a reduced mortality risk was significant in patients with mild COPD or asthma (RR 0.86; 95% CI 0.73 to 1.00; p = 0.048) and without COPD or asthma (RR 0.86; 95% CI 0.81 to 0.92). In the unadjusted analyses, patients with severe COPD or asthma who received β-block-ers had significantly lower readmission rates than patients who did not receive β-blockers (10% vs. 18.5%; p < 0.01); however, these findings were not significant in the adjusted analyses. 19 A previous study, which also used the CCP database, did not stratify by disease severity and suggested that β-blocker use in all COPD or asthma patients reduced mortality. 20 These studies combined data gathered from both COPD and asthma patients, making it difficult to draw definitive conclusions for COPD patients alone.
Underutilization
The most recent guidelines established by the American College of Cardiology and the American Heart Association suggest that β-blocker therapy after acute MI is appropriate for many patients with COPD or other relative contraindications. 21 Despite these updated guidelines, clinicians still rarely prescribe these agents.
A study using data from insurance claims found that cardiologists prescribed β-blockers for <50% of their patients despite no strong contraindication after MI. 22 Another study that examined outpatient prescription data from 1987 to 1992 found that only 21% of post-MI patients with no strong contraindication received a β-blocker. 23 Those who did receive these medications had a 43% lower mortality rate. In a study examining post-MI β-blocker use by year from 1994 to 1997, use increased during this time, but was strongly and inversely associated in patients with COPD or other respiratory diseases, with odds ratios ranging from 0.32 to 0.52. 24
SUMMARY
β-Blocker therapy for cardiovascular indications is underutilized in patients with COPD, perhaps because of fear of bronchoconstriction. Mortality benefits are seen in patients with mild to moderate COPD who receive cardioselective β-blockers compared with those who do not receive this therapy. Short-term studies of cardioselective β-blocker use in patients with COPD have shown no major adverse events on FEV1, respiratory symptoms, or response to β2-agonists. Patients with mild to moderate COPD should receive cardioselective β-blocker therapy when a strong indication exists.