Rspiratory

A New Treatment for COPD

د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2012

Roflumilast With Long Acting Beta2 Agonists for COPD: Influence of Exacerbation History

Study Summary
Roflumilast is a phosphodiesterase 4 (PDE4) inhibitor that was approved in late 2011 with the indication of reducing acute exacerbations in patients with (COPD). Two large pivotal trials were performed to obtain approval from the US Food and Drug Administration, each with about 1500 patients; many important and clinically useful outcomes can be found on closer examination of these trials.

One question that arose is whether roflumilast would reduce exacerbations in patients who were also receiving a long-acting beta-2 agonist (LABA), as LABAs have also been shown to reduce exacerbation frequency. The data from the pivotal trials were re-examined to address this issue.

Approximately half the patients in the pooled trial received concomitant LABA. In these, the relative risk for exacerbations was 0.79 in those in the roflumilast arms vs 0.85 for those receiving LABA but not roflumilast. The difference was statistically significant (P < .039). The time to first exacerbation was similarly prolonged by roflumilast, particularly in patients who had frequent exacerbations.
The conclusion was that roflumilast was effective and reduced the rate of exacerbations even in patients who were receiving a LABA.

Viewpoint

This finding is interesting because the patients for whom roflumilast is recommended have severe or very severe COPD and are thus very likely to already be receiving all recommended COPD therapies, including long-acting bronchodilators. The present report reassures clinicians that despite the use of a LABA, roflumilast will still have its intended effect and further reduce the risk for an acute exacerbation.


Acute exacerbations are very serious events in the long-term course of COPD. They are extremely debilitating and can persist for weeks or months. They can also be fatal in 5%-20% of cases. They contribute to a more rapid decline in lung function and quality of life and are also very expensive events, particularly if the patient requires hospitalization. Therefore, a reduction in the frequency and severity of acute exacerbations of COPD is an important goal of therapy, and roflumilast contributes to that goal.

It should also be mentioned that roflumilast represents the first new class of agents for COPD in almost 3 decades. It is a PDE4 inhibitor, the enzyme PDE4 being thought to contribute to both bronchoconstriction and to inflammation in the COPD airways. If so, this would contribute to our need for an anti-inflammatory agent that was active against neutrophilic inflammation -- the type that is present in COPD airways and that is poorly responsive to corticosteroids.

Other features of roflumilast are that it has a small but not clinically meaningful bronchodilator effect, so it should not be used as a bronchodilator. Some patients report that they feel better when they take it, but the majority do not; the motivation for continued use should be the expected reduction in acute exacerbations. The ideal candidates are those with severe or very severe COPD with a bronchitic component, particularly those who have experienced at least 1 previous acute exacerbation.

Adverse events include gastrointestinal disturbance. Nausea and diarrhea occur in 10% to 20% of patients, usually within the first month of treatment, and these symptoms will prevent some patients from taking roflumilast on a long-term basis. Weight loss occurred in 7.5% of patients, again mostly in the first few months of use. Average weight loss was 4-5 lb at the end of 12 months. There are warnings of neuropsychiatric effects such as insomnia, anxiety, depression, and suicidal ideation.

The only contraindication due to concomitant disorder is liver impairment (Child-Pugh B or C). Use by nursing mothers is not recommended. Concomitant use with drugs that enhance the P450 system is not recommended; these are rifampin, carbamazepine, phenytoin, and phenobarbital. Roflumilast is compatible with all drugs commonly used for COPD. There is only 1 dosage strength, 500 mg, and no dose adjustment is required with concomitant medications or renal impairment.

Effect of beta blockers in treatment of chronic obstructive pulmonary disease

Abstract
Commentary on: Short PM, Lipworth SI, Elder DH, et al. Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. BMJ 2011;342:d2549.

Context

(COPD) is currently recognised as an inflammatory disease associated with significant extrapulmonary effects and important comorbidities, including ischaemic heart disease and heart failure.[1] Despite ample evidence of the benefits of β-blockers in hypertension, ischaemic heart disease and congestive heart failure, use of β-blockers is >50% lower in heart failure patients with than without COPD,[2] probably because of concern regarding the possibility of bronchospasm provoked by β-blockers in patients with underlying obstructive lung disease, despite evidence to the contrary.[3]

In view of the compelling evidence demonstrating beneficial effects of β-blockers in cardiovascular disease (CVD), including improved survival, failure to prescribe these agents in patients with COPD and concomitant CVD denies these benefits to such patients. A recent observational cohort study of patients with COPD demonstrated a favourable effect of β-blockers in reducing all-cause mortality, as well as exacerbations of COPD, irrespective of the presence or absence of overt CVD, suggesting 'dual cardiopulmonary protective properties' of β-blockers.[4]

The report by Short and colleagues seeks to extend these findings by investigating the effect of β-blockers added to specific treatment regimens for COPD across the spectrum of disease severity.


Methods
Short and colleagues performed a 9-year retrospective cohort study using a Scottish respiratory disease-specific database comprising nearly 6000 COPD patients >50 years of age to examine the effect of treatment with β-blockers (vs no β-blockers) when added to existing therapy for COPD of varying stages of severity defined by Global Initiative for Chronic Obstructive Lung Disease guidelines.

The authors implemented Cox regression models to derive HRs for the association of β-blocker use with all-cause mortality, adjusting for relevant covariates including age, gender, smoking, lung function (marker of COPD severity), cardiac disease history and use of various cardiac drugs. Subgroup analyses were performed based on particular COPD severity-related treatment regimens. Outcomes included lung function, all-cause mortality, cardiac or respiratory mortality and COPD exacerbations defined by emergency oral steroid prescriptions and hospitalisations for COPD.

Findings

Results failed to reveal any deleterious effect of β-blockers on lung function when added to any of the various treatment regimens for COPD and also demonstrated a significant reduction in all-cause mortality (HR 0.78) and death because of myocardial infarction or COPD within most of the COPD treatment categories. Benefits of β-blockers were also observed for reducing exacerbations and hospitalisations for COPD.

Commentary

The limitations of the study include those common to most retrospective observational cohort studies, including the inability to completely adjust for all possible confounders and, in particular, the potential for confounding by indication, in this case, the indication for prescribing β-blockers. Although the authors took into account overt CVD, they were unable to adjust for undiagnosed CVD. It is also possible that congestive heart failure, for example, may have accounted for some of the so-called exacerbations and hospitalisations attributed to COPD.

Together with previously published results, the current findings have important clinical implications. Physicians need to carefully assess their patients with COPD for clinical evidence of cardiovascular comorbidity to which they are already predisposed by their underlying COPD and their history of smoking. It is crucial to correct the misperception that cardioselective β-blockers are harmful in COPD or that they compromise the benefits of β-agonist therapy.

Particularly interesting about the findings from this and an earlier study[4] are the apparent benefits of β-blockers in COPD patients independent of coexisting CVD, particularly, the reductions in COPD exacerbations and hospitalisations for COPD. The mechanism of this apparent lung-specific benefit is unclear. Although the authors suggest that upregulation of β-receptors may account for the benefit by improving bronchodilator responsiveness to β-agonists, this potential mechanism remains speculative. Additional studies are warranted to investigate the mechanism of the apparent beneficial effects of β-blockers on COPD-specific outcomes.