New use of long-term inhaled bronchodilators is associated with an early increase in the risk for cardiovascular disease (CVD), the findings of a new study suggest.
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, lead author, Meng-Ting Wang, PhD, and coauthors write in JAMA Internal Medicine.
The findings suggest that clinicians should “be very vigilant with regard to any cardiovascular symptoms within 30 days of initiating LABA or LAMA treatment for COPD,” they warn.
After those initial 30 days, however, the risk for CVD associated with the use of long-acting bronchodilators appeared to wane.
Dr Wang, from the School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China, and colleagues performed an observational, nested, case-control study using data from the Taiwan National Health Insurance Research Database (NHIRD). NHIRD encompasses the medical and pharmacy records of more than 99% of the Taiwanese population covered under the national health insurance program.
The cohort consisted of patients aged 40 years or older 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 outcome (coronary heart disease, cardiac arrhythmia, heart failure, or ischemic stroke), withdrawal from the National Health Insurance program, death, or the end of the study period on December 31, 2011.
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.
All patients and controls who had used long-acting bronchodilators were classified according to how recent that use was: current (use within 30 days or less), recent (use within 31 to 90 days), past (use within 91 to 180 days), or remote (use within more than 180 days). In each category, the members were further subdivided into “new” users (no record of any other use within the 31 to 365 days before their cardiovascular event), and “prevalent” users (everyone else).
Of the patients with severe CVD, 5987 (15.9%) were using LABA or LAMA, including 760 new users (12.5%). Of the controls, 21,196 (14.5%) were using long-acting bronchodilators, including 1733 (8.2%) who were new 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 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. The findings were not affected by the patients’ baseline CVD status and were replicated in a subsequent case-crossover design analysis.
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,” they state. Earlier studies may have missed this relationship because the investigators enrolled patients who had already used LABA or LAMA, or because those studies excluded people with severe CVD. “Both factors could have led to the inclusion of patients with tolerability to cardiovascular events” in those trials.
Study limitations include the possibility that worsening COPD may have prompted the use of long-acting bronchodilators and caused the observed CVD; a risk for selection bias or protopathic bias; confounding by patients’ baseline CVD status; and the inability to control for factors such as smoking and alcohol consumption, which can affect the risk for CVD.
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.
The authors have disclosed no relevant financial relationships.
JAMA Intern Med. Published online January 2, 2018. Abstract
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