Study highlights COPD drug risks

AUSTRALIAN experts have questioned the significance of research showing an increased risk of cardiovascular events in older patients with chronic obstructive pulmonary disease who start taking long-acting beta-agonists and anticholinergics.

The observational population-based study of more than 190 000 patients aged 66 years or more with COPD, published in JAMA Internal Medicine, found patients newly prescribed inhaled long-acting beta-agonists (LABAs) and long-acting anticholinergics (LAAs) were at increased risk of cardiovascular events when compared with those not using the medications. (1)

It found no significant difference in risk between the two medications and that the risk of cardiovascular event was highest in the 2–3 weeks after the medication was prescribed.

Professor Haydn Walters, director of the NHMRC Centre for Research Excellence for Chronic Respiratory Disease and Lung Ageing, said the study’s message — to take care when starting these medications in elderly patients with COPD and a history of heart disease — was valuable, but the absolute difference in risk of a cardiac event was still very small (about 0.4 percentage points) and from a low baseline risk.

“It’s not to say that we should ignore [the research]. It’s a very large population study, so therefore it’s very strong evidence”, he said.

However, he said the study population was elderly, with an average age of 79 years, and in Australia patients were more likely to present with COPD and start on drug therapy at a younger age.

Professor Bill Musk, a respiratory physician and clinical professor of medicine and population health at the University of WA, agreed that the risk of cardiovascular events was small, but he said the findings were still concerning, particularly because many COPD patients had been smokers and were already at increased cardiovascular risk.

“We do need to treat their COPD and the long-acting agents are the best agents we have, so we need to use them when they are helpful”, Professor Musk told MJA InSight.

“We should be prepared to discontinue them when they don’t appear to be helping, but the assessment of that can be quite difficult”, he said. “We need to be vigilant for any signs that suggest cardiovascular side effects.”

However, Professor Musk said one problem with the study was that it did not set out the basis for COPD diagnosis. “We don’t know that [the patients] actually had COPD … it could be that the symptoms that prompted the prescription of the LABAs and LAAs were due to heart disease rather than lung disease”, he said.

Professor Walters said the study also raised questions about the underuse of cardioselective beta-blockers in a population with a high prevalence of heart disease.

“Only 30% [of study cases] were on beta-blockers and one of the questions which I think needs to be addressed is to what extent would cardioselective beta-blockers [protect] people with heart disease from these deleterious effects?”

While Professor Walters said the very high rates of asthma in the study population may have tempered the use of these drugs, Australian research had identified underuse of beta-blockade in COPD patients more generally. (2)

An invited commentary in the same issue of JAMA Internal Medicine said although the study authors had recommended that “subjects should be monitored closely”, a firm recommendation on what that monitoring should be could not be made. (3)

“Monitoring, of course, is the responsibility of an informed treating physician. The main contribution of this study is to highlight that responsibility”, the commentary said.

In another study on COPD, published in JAMA, researchers found that short-term steroid therapy in patients with acute exacerbations of COPD is just as effective as conventional therapy in reducing re-exacerbations. (4)

The randomised trial compared a 5-day course of 40 mg of prednisone daily with a 14-day course, with respect to re-exacerbation. The researchers found no difference between the short-term and conventional therapy groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function

Professor Walters welcomed the study. He said there was good Cochrane Collaboration evidence that steroids were effective in exacerbations of COPD, but given the toxicity of these drugs to an older, vulnerable population with frequent comorbidities, “the less you can effectively give, the better”. (5)

Professor Musk said the study was important and validated his long-term practice of prescribing a limited course of steroids for COPD exacerbations and discontinuing the medication before discharge.

“We don’t want people to be left on steroids because of all the side effects they carry with them.”

1. JAMA Int Med 2013; Online 20 May
2. Intern Med J 2012; 42: 786-793
3. JAMA Int Med 2013; Online 20 May
4. JAMA 2013; Online 21 May
5. The Cochrane Library 2009; Online 21 January