New use of long-term inhaled bronchodilators is associated with an early increase in the risk for cardiovascular disease (CVD), according to a study published in the journal JAMA Internal Medicine.

In a large observational study, the risk for CVD in people with chronic obstructive pulmonary disease (COPD) was increased approximately 1.5-fold during the first 30 days after starting therapy with long-acting β2 agonists (LABAs) or long-acting muscarinic antagonists (LAMAs) compared with ongoing or more prolonged use, the researchers said.

Dr Wang, from the School of Pharmacy, National Defense Medical Center, Taipei, and team performed an observational, nested, case-control study, which enrolled the patients (age ≥40), who had made two outpatient visits or one inpatient visit for COPD within 1 year between January 1, 2008, and June 30, 2011, and had filled at least one prescription for a COPD medication at each visit.

Participants were followed until their first CVD outcomes such as coronary heart disease, cardiac arrhythmia, heart failure, or ischemic stroke, withdrawal from the National Health Insurance program, death.

The authors used conditional logistic regression analysis to calculate the odds ratio (OR) of CVD associated with LABA or LAMA use. Covariates accounted for in the analysis included CVD risk factors (such as hypertension, diabetes, hyperlipidemia, and prior CVD) and proxy indicators of COPD severity (such as outpatient visits for COPD accompanied by prescriptions for corticosteroids or respiratory antibiotics).

The final sample consisted of 37,719 patients who had been diagnosed with severe CVD. Each patient was matched with 4 randomly selected patients without CVD, according to disease risk score (±0.01) and cohort entry date, for a total of 146,139 controls.

The participants were classified into "new" users and "prevalent" users. On adjusted regression analysis, new use of LABA was associated with an OR of CVD of 1.5 (95% confidence interval [CI], 1.35 – 1.67;P < .001) compared with nonuse. New use of LAMA was associated with an adjusted OR of 1.52 (95% CI, 1.28 – 1.80; P < .001); new use of LABA and LAMA together was associated with an adjusted OR of 2.03 (95% CI, 1.42 – 2.91; P < .001).

However, use of LABA within 91 to 180 days (past use) was associated with an adjusted OR for  CVD of 0.97 (95% CI, 0.83 – 0.99; P = .03); use of LAMA, with an adjusted OR of 0.86 (95% CI, 0.74 – 1.00; P = .06); and of LABA and LAMA combined, 0.95 (95% CI, 0.76 – 1.20; P = .69).

Overall, the authors write, "the cardiovascular risks peaked at around the 30th day after new initiation of LABA or LAMA therapy, waned from 31 to 60 days of therapies, and reduced to a level even lower than the baseline risk from 71 to 240 days" compared with nonuse.

This is the first evidence suggesting that "new use and duration since initiation of inhaled long-acting bronchodilators are associated with the therapy-related risk of CVD in patients with COPD," researchers stated. "Both factors could have led to the inclusion of patients with tolerability to cardiovascular events" in those trials.

Nevertheless, on the basis of these findings, the authors recommend that, before prescribing LABAs or LAMAs in this patient population, physicians carefully assess for cardiovascular risk and, if necessary, consider a course of preventive therapy for CVD during initial treatment with inhaled long-acting bronchodilators.