Safety of COPD Medications: Current Evidence

COPD is one of the most common lung ailments seen in the primary care setting. Current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend treatment based on lung function tests, exacerbations, and respiratory symptoms. During the 2015 ACCP (CHEST 2015) meeting in Montreal, a panel that included Dr. Nicola Hanania MD from Baylor College of Medicine, Dr. Robert Weiss MD from Johns Hopkins and Dr. Mark Dransfield MD from University of Alabama, reviewed the current evidence on the safety of the commonly used medications for management of COPD.

Inhaled corticosteroids (ICS): 50% to 70% of patients diagnosed with COPD are on ICS; most patients have been using the medication for several years and often for inappropriate indications. The adverse effects of ICS include hyperglycemia, osteoporosis, pneumonia, skin thinning, cataracts, and dysphonia. A study looking at the use of ICS found that they led to a 34% increase in risk of new onset diabetes and a 34% increase in progression of diabetics to insulin dependence. Bone heath can be affected with long term use of steroids. In the TORCH trial,¹ which lasted for 3 years, there was not an increased incidence of decreased bone density or fractures. Observational data, however, have consistently shown an increased risk which is dose related. In a meta-analysis, an increased risk of fractures was found (odds ratio 1.27). Bottom line: patients on long-term ICS should be screened for, and where indicated, treated for osteoporosis. An increased risk of pneumonia was noted in patients on ICS in the TORCH trial.¹ Factors associated with the increased risk included lower FEV₁, smoking, previous pneumonias, and lower BMI. Another study comparing fluticasone and budesonide, found higher pneumonia risk in the fluticasone group. Interestingly, studies have found that even though the risk of pneumonia increased in patients on ICS, the risk of death related to pneumonia and exacerbations is lower in the ICS group.

Long-acting ß-agonists (LABA): potential adverse effects include hypokalemia, hyperglycemia, hypoxemia, tremors, and arrhythmias. Potential factors leading to increased adverse effects include advanced age, comorbidities, and poor compliance with medication instructions as well as systemic bioavailability and intrinsic efficacy. The safety of LABAs in COPD patients has been established in several clinical trials. In the TORCH trial,¹ the all-cause mortality was lower in the LABA group; the rate of cardiovascular events and ischemic events was not increased. LABAs have also not been found to be associated with increased mortality or CV events in COPD patients in large meta-analyses and a Cochrane review.

Anticholinergic agents: short- and long-acting antimuscarinic agents (LAMA) have been used in COPD for several years. In 2008, a meta-analysis² raised concerns over increased cardiovascular death risk (RR 1.26) in patients receiving LAMAs, leading to an FDA warning. The UPLIFT trial³ soon followed, which was a randomized controlled clinical trial looking at tiotropium hand inhalers in COPD patients, but did not show any increased risk of CV deaths in the LAMA group. This led to the FDA withdrawal in 2011 of the warning against tiotropium use in COPD patients. A different form of delivery, the tiotropium Respimat® (inhalation spray) has also been extensively studied. The Respimat delivery form was associated with an increased risk of death in a Cochrane review and meta-analysis, but the TIOSPIR clinical trial⁴ that looked specifically at the Respimat inhaler and risk of death, did not show any increased mortality. Thus while meta-analysis and population studies have raised concerns about cardiovascular safety with tiotropium, randomized trials have not supported this finding.

As with everything in medicine effective pharmacotherapy for COPD is a balancing act between the potential risks and the benefits. In the primary care setting we should follow treatment guidelines (especially when prescribing ICS, to prevent insulin resistance and osteoporosis) and individualize care based on the patient’s situation and medication side effects.

Hanania N, Weiss R, Dransfield M. Safety of COPD medications. Presentation at: American College of Chest Physicians annual meeting (CHEST 2015); October 27, 2105; Montreal, Canada.

References:

1. Calverley PMA, Anderson JA, Celli B, et al for the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356:775-789. DOI: 10.1056/NEJMoa063070. http://www.nejm.org/doi/full/10.1056/NEJMoa063070#t=articleTop

2. Singh S, Loke YK, Furberg DC. Inhaled Anticholinergics and Risk of Major Adverse Cardiovascular Events in Patients With Chronic Obstructive Pulmonary DiseaseA Systematic Review and Meta-analysis. JAMA. 2008;300:1439-1450. doi:10.1001/jama.300.12.1439. http://jama.jamanetwork.com/article.aspx?articleid=1028648

3. Tashkin DP, Celli B, Senn S et al for the UPLIFT Study Investigators. A 4-Year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543-1554. DOI: 10.1056/NEJMoa0805800. http://www.nejm.org/doi/full/10.1056/NEJMoa0805800#t=article

4. Wise RA, Anzueto A, Calverley P, et al. The Tiotropium Safety and Performance in Respimat Trial (TIOSPIR), a large scale, randomized, controlled, parallel-group trial-design and rationale. Respir Res. 2013;14:40. doi: 10.1186/1465-9921-14-40. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621103/