Should inhaled steroids remain a cornerstone of COPD therapy? Or do the drugs make the condition worse? by Deborah Gesensway
Published in the August 2008 issue of Today's Hospitalist
New strategies that focus on combining different drugs have revolutionized treatment of chronic obstructive pulmonary disease (COPD) and its exacerbations. But do one of the mainstays of treatment—inhaled corticosteroids—really help?
At the American Thoracic Society (ATS) meeting in Toronto in June, some of the world’s leaders on COPD research and treatment debated that point. While there was little in the way of consensus, the debate should interest hospitalists for several reasons.
COPD is one of the 10 leading causes of hospitalization among adults in the U.S., a figure that should get any hospitalist’s attention.
“It doesn’t look like you are making things worse by using corticosteroids.”
–Peter Calverley, MD University of Liverpool
Furthermore, COPD is frequently seen in patients with other chronic diseases, such as diabetes, hypertension and heart disease. But perhaps just as importantly, researchers are beginning to study how well COPD patients are cared for once they are hospitalized.
While it’s true that hospitalists have little control over the causes of COPD exacerbations that bring patients to the hospital, data suggest that many of these inpatients receive less than optimal care. Researchers in the June 20, 2006, Annals of Internal Medicine, for example, reported great variation in practice across 360 U.S. hospitals for patients admitted for acute COPD exacerbations. In some hospitals, only 10% of patients received care that followed national guidelines.
One of the weakest links in hospital care of COPD, the study found, was the use of steroids. While virtually all patients received a chest X-ray, supplemental oxygen and a bronchodilator, as few as 70% of patients received steroids.
The debate over inhaled steroids is also something hospitalists should keep in mind when discharging patients. Here’s a look at the latest thinking about the pros and cons of managing COPD with inhaled steroids.
When it comes to inhaled corticosteroids for COPD, Peter Calverley, MD, professor of respiratory medicine at the University of Liverpool, England, said there is no arguing with the results of the most comprehensive clinical trial of COPD.
The TORCH trial followed patients with moderate to severe COPD for three years. Researchers found that subjects treated with a combination of salmeterol (50 mcg) and fluticasone propionate (500 mcg) had higher forced expiratory volume in one second (FEV1) values than those treated with either the long-acting bronchodilator, the steroid alone or a placebo.
The study found several positive outcomes. For one, there was “a trend” toward reduced mortality, although Dr. Calverley noted it was not statistically significant. Researchers also found a reduction in the number of exacerbations and improvement in lung function. (Dr. Calverley is one of the TORCH study’s co-authors.)
He and his colleagues concluded that until further investigation shows otherwise, “data support the use of salmeterol plus fluticasone propionate in the clinical management of COPD.” The main research article was published in the Feb. 22, 2007, issue of the New England Journal of Medicine.
TORCH was not alone in taking a favorable view of steroids. The INSPIRE trial, published in the Jan. 1, 2008, American Journal of Respiratory and Critical Care Medicine, also concluded that inhaled steroids have a place in COPD treatment.
INSPIRE researchers found that combining salmeterol and fluticasone propionate produced the same number of exacerbations among patients with severe COPD as treatment with an inhaled anticholinergic agent, tiotropium.
Moreover, patients receiving the salmeterol/fluticasone combination were less likely to withdraw from treatment, had better health status and had better survival than those taking tiotropium.
Yet another study—a Canadian trial published in the Apr. 17, 2007, Annals of Internal Medicine—concluded that adding steroids to tiotropium improved “lung function, quality of life and hospitalization rates,” although steroids didn’t “statistically influence rates of COPD exacerbation.”
Dr. Calverley noted that steroids don’t appear to work as well alone as in combination. However, he said that they do work better than a placebo at improving patients’ quality of life and reducing symptoms. Moreover, he added, patients taking inhaled steroids are less likely to be prescribed a course of either oral steroids or antibiotics during an exacerbation, which is a good thing.
The con side
Taking the other side of the debate during the ATS meeting, Peter Barnes, MD, professor of thoracic medicine and head of airway disease at the National Heart and Lung Institute in London, urged physicians to avoid steroids for COPD patients. In stark contrast to asthma, he said, the inflammation produced by COPD is “steroid-resistant.”
According to Dr. Barnes, some COPD patients respond to steroids because they also have asthma; the steroids improve the asthma, not the COPD. As evidence, he says that COPD patients treated either with bronchodilators or with corticosteroids alone experience the same—usually about 20%—reduction in exacerbations. “My conclusion is that the steroid adds no benefit to the bronchodilator,” he explained.
Dr. Barnes said that the TORCH study’s finding that combination therapy slows long-term disease progression is so small that it is statistically insignificant, which he said was no better than just “flipping a coin.” Moreover, he said, a Cochrane meta-analysis of a number of COPD treatment studies “confirmed that there is no effect on mortality.”
“I believe all the effect seen in the TORCH study can be attributed to salmeterol,” Dr. Barnes said, “and none to fluticasone.” The findings of TORCH and other recent COPD studies “may mean that steroids are doing something else to make people feel better, but they are not affecting their lung function.” That leads him to conclude that inhaled steroids probably don’t work.
Another point that Dr. Barnes made is that no one has ever demonstrated a dose response with steroids for COPD. In contrast, with asthma, higher doses do improve lung function more than lower doses. “It’s hard to show a dose response,” he said, “when there is no response.”
Dr. Barnes explained that he takes such an adamant stance against inhaled corticosteroids for COPD not just because he thinks that they’re ineffective, but that they can be harmful.
“These drugs can make you worse,” he said. “The side effects of inhaled steroids are well-known, especially with high doses. High doses are always used because people don’t respond on low doses, so doctors increase the dose.”
In addition, he said, people with COPD are “particularly vulnerable” to the systemic side effects of inhaled steroids. “They are elderly, immobile and have a lot of comorbid diseases like diabetes, hypertension, depression, and peptic ulceration,” Dr. Barnes pointed out, “that can be worsened by steroids.”
While Dr. Calverley acknowledged that the known side effects of steroids—ranging from increased rates of osteoporosis to greater susceptibility to pneumonia—can be an issue. He noted that the drugs should be given in lower than usual doses, but he argued that concerns about side effects may be overstated.
The TORCH study, for example, showed that the rate of deterioration in bone mineral density “was just the same as with placebo.” Because COPD alone increases risks of osteoporosis, he explained, “it doesn’t look like you are making things worse by using corticosteroids.”
The increased rates of pneumonia are worrisome, but they need to be put into perspective. “Contracting pneumonia is much less common than the occurrence of an exacerbation,” Dr. Calverley said.
Because people with moderate to severe COPD “feel better” when they are on corticosteroids and “have a better mortality,” Dr. Calverley said, “I believe corticosteroids have a role in COPD until something better comes along to replace them.”
He emphasized that the new studies, including TORCH, are concluding that combination therapy improves survival, reduces severe exacerbations and maybe lessens inflammation for COPD patients better than treatment with one class of drugs—either long acting beta-agonists or inhaled corticosteroids—alone.
Dr. Barnes countered that inhaled corticosteroids may have a place in COPD treatment, but only if scientists can figure out why steroids are not working now and then determine how they can “reverse steroid resistance” in COPD. “The future is to convert people with COPD to asthmatics,” he explained, “and then treat them with low-dose corticosteroids.”
The middle ground
While experts disagree about the best therapy for COPD, another speaker at the meeting pointed to this good news: Everyone agrees that treatment is better than doing nothing. That wasn’t always the case with COPD.
“We can now talk about how to treat patients with COPD,” said Antonio Anzueto, MD, professor of medicine, pulmonary and critical care at the University of Texas Health Science Center, San Antonio. “We used to be happy if we found that our patients could walk five more feet, and now we are talking about having an impact on mortality and quality of life.”
Regarding steroids for COPD, Dr. Anzueto urged physicians to embrace moderation. “Patients with severe disease should have combination therapy,” but at “the lowest possible doses to mitigate against potential side effects.”
And while long-acting bronchodilators should probably be the mainstay of treatment, Dr. Anzueto said, they should be combined with not only inhaled steroids, but long acting anticholinergics like tiotropium. Combinations of drugs seem to result in “a higher response and a further improvement in quality and life and exercise capacity,” he said.
Dr. Anzueto also urged physicians treating COPD to look beyond drug therapy and to consider pulmonary rehabilitation, including exercise training. Current guidelines on treating exacerbations requiring hospitalization suggest there is a place for systemic steroids during treatment.
Reconsidering the disease
Now that experts are optimistic that COPD patients can live better and longer, the next fronts in battling the disease, according to Dr. Anzueto, are figuring out when to start patients with mild to moderate COPD on long-term treatment and how to prevent exacerbations at all.
That broader discussion is part of a wholesale reconsideration of the disease itself. The newest thinking holds that perhaps COPD is not just a respiratory illness, but instead a manifestation of a systemic condition caused by chronic inflammation. The focus on steroids—long considered an anti inflammatory therapy—is related to this rethinking.
Leonardo M. Fabbri, MD, from the department of oncology, hematology and pulmonology at the University of Modena & Reggio Emilia in Modena, Italy, suggested that the disease’s name may change from “chronic obstructive pulmonary disease” to “chronic systemic inflammatory syndrome.” He explained that the move would make sense considering that more than 15% of COPD occurs in people who have never smoked, and that it is not entirely a disease of the elderly.
Advocates of this new interpretation point out that chronic systemic inflammation affects cardiovascular disease, osteoporosis and depression in addition to COPD. Studies have found that patients with COPD—and asthma to a lesser extent—are more at risk than the general population to also be diagnosed with angina, cataracts, bone fractures, osteoporosis, pneumonia and respiratory infections.
As a result, COPD is being put into the bigger picture. “If you see an FEV1 lower than normal,” Dr. Fabbri said, “don’t think only of the lung. There is strong evidence that the combination of airflow limitation and chronic inflammation are major risk factors for cardiovascular disease, maybe as important as cholesterol or blood pressure. We have to get out of the model that focuses on the lung and address the other comorbidities that develop along, with the respiratory component.”
His hope is that this reconsideration of COPD—as more than a lung disease—will eventually lead to new, more effective treatments that include ways of “remodeling the lung,” much like cardiologists now do with the heart when they remove plaque from the heart and coronary vessels.
After all, Dr. Fabbri reminded attendees, “People who smoke do not die only of respiratory disease, but they mostly die of myocardial infarction or cancer or cerebrovascular disease. From the lung, you have systemic consequences.”
Deborah Gesensway is a freelance writer who reports on U.S. health care from Toronto, Canada.