Chest
Volume 144, Issue 3, September 2013, Pages 758-765
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Original Research
COPD
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Cardiovascular Safety in Patients Receiving Roflumilast for the Treatment of COPD

https://doi.org/10.1378/chest.12-2332Get rights and content

Background

Evaluation of cardiovascular safety for new therapies for COPD is important because of a high prevalence of cardiac comorbidities in the COPD population. Hence, we evaluated the effects of roflumilast, a novel oral phosphodiesterase 4 inhibitor developed for the treatment and prevention of COPD exacerbations, on major adverse cardiovascular events (MACEs).

Methods

Intermediate- and long-term placebo-controlled clinical trials of roflumilast in COPD were pooled and assessed for potential cardiovascular events. Studies comprised 14 12- to 52-week placebo-controlled trials in patients with moderate to very severe COPD. All deaths and serious nonfatal cardiovascular events were evaluated by an independent adjudication committee blinded to study and treatment. The MACE composite of cardiovascular death, nonfatal myocardial infarction, and stroke was analyzed according to treatment group.

Results

Of 6,563 patients receiving roflumilast, 52 experienced MACEs (14.3 per 1,000 patient-years), and of 5,491 patients receiving placebo, 76 experienced MACEs (22.3 per 1,000 patient-years). The MACE composite rate was significantly lower for roflumilast compared with placebo (hazard ratio, 0.65; 95% CI, 0.45-0.93; P = .019).

Conclusions

A lower rate of cardiovascular events was observed with roflumilast than with placebo in patients with COPD, indicating the lack of a cardiovascular safety signal when treating patients with COPD. Potential cardiovascular benefits of roflumilast should be evaluated in future controlled clinical trials.

Section snippets

Clinical Studies and Protocol

The prespecified approach by charter was to determine the incidence of MACE as previously defined9 (nonfatal MI, nonfatal stroke, and cardiovascular death) for roflumilast and placebo (or a combination of roflumilast and active agent vs placebo and active agent). All COPD clinical studies from the roflumilast drug safety database that met the following criteria were included in the analysis: (1) randomized trials with a parallel group design, (2) one treatment arm of roflumilast ≥ 250 μg per

Baseline Characteristics of the Treatment Groups

As shown in Table 2, 12,054 patients were included in the analysis; 6,563 patients were randomized to roflumilast 250 to 500 μg total daily dose, and 5,491 were randomized to placebo. Baseline patient characteristics in the comparisons between roflumilast and placebo were similar for age, sex, COPD severity, and concomitant cardiovascular and pulmonary medications. Similar proportions of the patients in the roflumilast and placebo treatment groups had cardiovascular risk factors of

Discussion

In an analysis of clinical trials involving > 12,000 patients, reductions in MACEs (nonfatal MI, nonfatal stroke, and cardiovascular death) were found in patients treated with the PDE-4 inhibitor roflumilast compared with patients who received placebo. Of note, subgroup analyses indicated that the risk reduction might be more prominent in patients with severe vs moderate COPD. Changes in MACEs for roflumilast relative to placebo were not altered substantially as a result of baseline

Conclusions

This cardiovascular safety analysis of data from randomized controlled trials of roflumilast in patients with COPD for up to 1 year demonstrates a lower incidence of cardiovascular events in those treated with roflumilast vs placebo. Further resolution of the absolute and relative cardiovascular effects of systemic PDE-4 inhibition will require purposefully designed prospective randomized trials of appropriate durations.

Acknowledgments

Author contributions: Dr White had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr White: contributed as principal investigator and chair of the cardiovascular adjudication committee to the conception and design of the analysis and drafting of the manuscript.

Dr Cooke: contributed as a member of the cardiovascular adjudication committee to the data interpretation and critical review of the manuscript.

Dr

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    For editorial comment see page 723

    Funding/Support: Funding was provided by Research and Development, Forest Research Institute Inc, a wholly owned subsidiary of Forest Laboratories, Inc, Jersey City, NJ, and Nycomed: a Takeda Company, Zurich, Switzerland.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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