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Original Research: COPD |

Cardiovascular Safety in Patients Receiving Roflumilast for the Treatment of COPDCardiovascular Safety of Roflumilast FREE TO VIEW

William B. White, MD; Glen E. Cooke, MD; Peter R. Kowey, MD; Peter M. A. Calverley, MD; Dirk Bredenbröker, MD; Udo-Michael Goehring, MD; Haiyuan Zhu, PhD; Hassan Lakkis, PhD; Hans Mosberg, MD; Paul Rowe, MD; Klaus F. Rabe, MD, PhD
Author and Funding Information

From the Calhoun Cardiology Center (Dr White), University of Connecticut School of Medicine, Farmington, CT; Ross Heart Hospital (Dr Cooke), College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Division of Cardiology (Dr Kowey), Lankenau Medical Center, and Jefferson Medical College, Philadelphia, PA; University Hospital Aintree (Dr Calverley), Liverpool, England; Respiratory Medicine (Drs Bredenbröker, Goehring, and Mosberg), Nycomed: a Takeda Company, Zurich, Switzerland; Forest Research Institute Inc (Drs Zhu, Lakkis, and Rowe), Jersey City, NJ; and University Kiel and Lung Clinic Grosshansdorf, members of the German Center for Lung Research (Dr Rabe), Grosshansdorf, Germany.

Correspondence to: William B. White, MD, Division of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center, University of Connecticut School of Medicine, 263 Farmington Ave, Farmington, CT 06030-3940; e-mail: wwhite@nso1.uchc.edu


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.


Chest. 2013;144(3):758-765. doi:10.1378/chest.12-2332
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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.

Figures in this Article

Cardiovascular diseases are common, serious comorbid conditions in patients with COPD. The risks for developing incident cardiac arrhythmia, venous thromboembolic disorders, myocardial infarction (MI), and stroke in patients with COPD are substantially greater than in healthy people.1,2 Additionally, COPD compounds the risk of cardiovascular death, heart failure, and hospitalizations for cardiovascular diseases when present as a comorbid condition in patients with underlying ischemic heart disease.3,4 The findings are less clear with regard to the impact of COPD on MI rates in patients with underlying heart disease3,5 and perhaps could be better classified through cluster analyses into distinct phenotypes according to the severity of each comorbidity.5

Low-grade systemic inflammation has been proposed as a possible link between COPD and systemic comorbid diseases, such as cardiovascular disease.6 Thus, whether specific therapies for pulmonary disease may have effects on cardiovascular outcomes in patients with COPD is of interest.

Roflumilast is a newly registered, selective, oral, once-daily phosphodiesterase 4 (PDE-4) inhibitor shown to have antiinflammatory activity7 and to produce effective reductions in the rates of acute exacerbations in patients with severe to very severe COPD.8 As part of the clinical development of roflumilast for the treatment of COPD, > 12,000 patients have participated in trials for 12 to 52 weeks.

In the present study, we performed a retrospective assessment of cardiovascular events pooled from the entire clinical database of placebo-controlled roflumilast COPD trials of ≥ 12 weeks (Table 1). The patient-level evaluation was performed by an expert committee blinded to treatment group and unaware of any study results at the time of the assessment. The focus of the analysis was on the incidence of major adverse cardiovascular events (MACEs), as defined previously,16 with roflumilast and its placebo comparator.

Table Graphic Jump Location
Table 1 —Summary of Studies Included in the COPD Safety Pool
a 

One patient each in studies FK1 103 and M2-124 was randomized twice.

b 

Study FK1 103 evaluated withdrawal of roflumilast after 12 wk of treatment vs continued treatment for 24 wk; the switch arm of the study (patients who received roflumilast for 12 wk then placebo for 12 wk) was not included in this pooled analysis.

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 day, (3) one treatment arm of placebo comparator or placebo and active agent, and (4) a planned double-blind treatment period of ≥ 12 weeks. Fourteen studies met these inclusion criteria. Comparisons presented in this article are roflumilast vs placebo or roflumilast plus salmeterol or tiotropium vs placebo plus salmeterol or tiotropium. Open-label trials, studies that assessed pharmacologic effects or drug-drug interactions rather than clinical outcomes, and single- or multiple-dose studies of roflumilast for disposition assessments were excluded from the analysis. This analysis was conducted with a pool of studies and multiple sites in different countries so that there is not one committee or approval number, but all sites had independent ethics committee or institutional review board approval prior to study start.

The 14 studies comprising this analysis are shown in Table 1. These studies included ambulatory adult patients aged > 40 years who had been given a clinical diagnosis of COPD (confirmed with postbronchodilator [albuterol 400 μg] FEV1/FVC ratio of ≤ 70%).

Patients were randomly assigned to oral roflumilast 250 or 500 μg once daily or to placebo. Patients could use short-acting β2-agonist inhalers as needed and short-acting anticholinergic drugs at stable doses. In some of the trials, they could continue treatment with long-acting β-agonists, long-acting anticholinergic drugs, or inhaled corticosteroids, although use of theophylline was not allowed in the studies. All studies were approved by local ethical committees, and informed consent was obtained prior to enrollment of patients.

Assessments for Cardiovascular End Points

The primary analysis in the present study was based on MACEs.16 These events were identified by extracting all deaths and all serious adverse cardiovascular events reported by investigators using the Medical Dictionary for Regulatory Activities, version 11.0. These events comprised the nonadjudicated dataset that was then assessed independently by a three-member cardiovascular adjudication committee (authors W. B. W., G. E. C., P. R. K.) with extensive expertise in cardiac and cerebrovascular end point assessment. All cardiovascular event adjudications were performed while blinded to both drug exposure and type of study to determine whether the cardiovascular events and deaths met the criteria for MACEs. End points sought from the database were (1) nonfatal cardiac events (nonfatal MI, myocardial ischemia, acute coronary syndrome, angina pectoris, resuscitated cardiac arrest, coronary revascularization); (2) all deaths, including from MI, stroke, heart failure, arrhythmia, sudden death or unexplained death, pulmonary embolism, and vascular emergencies (eg, aortic dissection); and (3) cerebrovascular events (ischemic or hemorrhagic stroke or transient ischemic attack). Noncardiovascular deaths were those that did not meet the cardiovascular death criteria.

The following definitions were used in the adjudicated diagnosis of a MACE end point. Acute MI was defined as the presence of two or more of the following criteria: (1) persistent chest pain; (2) cardiac biomarker (myocardial band fraction of creatine phosphokinase, cardiac troponins) levels above the upper limit of normal if spontaneous or more than three or five times the upper limits of normal if after percutaneous coronary intervention or coronary artery bypass graft surgery, respectively; and (3) myocardial injury pattern or development of Q waves in two contiguous ECG leads. Stroke was defined as ischemic or hemorrhagic with an acute, focal neurologic event lasting ≥ 24 h. Imaging studies (CT scan or MRI of the brain) were reviewed and nearly always available but were not mandatory for adjudication of the event. If an imaging study demonstrated an acute cerebrovascular injury that was not associated with a clinical neurologic deficit of > 24 h, the event was characterized as a stroke. Cardiovascular death was defined as that caused by MI, stroke, heart failure, arrhythmia, sudden or unexplained death, pulmonary embolism, or vascular emergencies, such as aortic dissection. The definitions of all events used in the adjudication process were well defined and prespecified in a committee charter.

If events adjudicated by the cardiovascular adjudication committee differed in diagnosis from that assigned by the original reporter, the event was reclassified according to the committee determination. If the data available were deemed insufficient by the committee to permit a definitive diagnosis, then the original reporter’s diagnosis was accepted. All events within 30 days of the last drug exposure were considered as exposure associated and included in the analyses. When two clinically linked events occurred within 2 weeks of each other, the more severe event was included in the analysis; for example, if a patient had a hemorrhagic stroke followed by a cardiovascular death 6 days later, cardiovascular death rather than nonfatal stroke would be the event included in the analysis.

Statistical Analyses

The baseline characteristics in the entire cohort were summarized with descriptive statistics for roflumilast and placebo groups. The times to MACE were analyzed in the entire cohort according to the treatment that patients received. In any individual patient, the first event (nonfatal MI, nonfatal stroke, or cardiovascular death) was used for the time-to-event calculations. The safety population was defined a priori in the various trial protocols as all patients who received one or more doses of assigned study medication and was used in all statistical analyses.

Analyses of MACEs were performed for all patients from studies comparing roflumilast (250- and 500-μg doses were combined) with placebo. A Cox proportional hazard model was used to analyze the time to first event. The hazard ratio (HR) of each respective event was expressed as the ratio of roflumilast to placebo with 95% CIs and P values for statistical testing of the null hypothesis that HR = 1.0. When the estimated HR was < 1, roflumilast had a more favorable cardiovascular event profile than the other treatment; the reverse was true if the estimated HR was > 1. All P values and 95% CIs were two sided. To assess the consistency of the treatment effect across various subgroups, similar analyses were performed for patients with and without baseline cardiovascular comorbid conditions, and additional analyses for composite MACE were performed for subgroups on the basis of age group, sex, baseline smoking status, COPD severity, concomitant inhaled corticosteroid use, and concomitant long-acting β-agonist use. Kaplan-Meier plots were generated for each category of events for the overall population.

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 hypertension, diabetes, hyperlipidemia, or ischemic heart disease at baseline (Table 2).

Table Graphic Jump Location
Table 2 —Baseline Characteristics of the COPD Population

Data are presented as median (range), mean ± SD, or No. (%). GOLD = Global Initiative for Chronic Obstructive Lung Disease; HMG-CoA = 5-hydroxy-3-methylglutaryl-coenzyme A.

Primary Cardiovascular Events (Composite) for Controlled Trials

The disposition of deaths and nonfatal cardiovascular deaths by the adjudication process is shown in Figure 1 according to treatment assignment. A total of 78 cardiovascular deaths and 51 nonfatal MACEs were adjudicated by the independent committee blinded to treatment assignment. For the primary analysis, results are from adjudicated MACEs. The HRs and 95% CIs based on the Cox proportional hazards model are presented in Table 3. A total of 129 adjudicated MACEs were confirmed in 128 of 12,054 patients in the analysis. Fifty-two MACEs were observed in 52 of 6,563 patients randomized to roflumilast (3,639 patient-years), and 77 MACEs were observed in 76 of 5,491 patients randomized to placebo (3,448 patient-years). For the roflumilast vs placebo adjudicated events comparison, a significant treatment difference was evident (HR, 0.65; 95% CI, 0.45-0.93; P = .019). The HRs for the individual cardiovascular events were < 1 for cardiovascular death, nonfatal MI, and nonfatal stroke for roflumilast vs placebo, but none were statistically significant. Correcting for exposure to treatment, the adjudicated roflumilast event rate was 14.3 per 1,000 patient-years compared with a placebo rate of 22.3 per 1,000 patient-years (Table 3).

Figure Jump LinkFigure 1. Disposition of the events following formal adjudication. All potential CV events were evaluated by a cardiovascular adjudication committee blinded to treatment assignment. Note that four subjects in each treatment group did not have sufficient data for determination of the primary cause of death. CV = cardiovascular; MACE = major adverse cardiovascular event; MI = myocardial infarction.Grahic Jump Location
Table Graphic Jump Location
Table 3 —Incidence Rates and HRs for MACEs

Data are presented as No. (%), unless otherwise indicated. CHF = congestive heart failure; CV = cardiovascular; HR = hazard ratio; MACE = major adverse cardiovascular event; MI = myocardial infarction.

a 

Calculated using the Cox proportional hazard model with terms for treatment, age, sex, smoking status, and country pool.

b 

Patients treated with roflumilast and placebo were exposed to study drug for 3,639 and 3,448 patient-y, respectively. Exposure-adjusted incidence rates per 1,000 patient-y were 14.3 (roflumilast) and 22.3 (placebo) for composite MACEs, 9.6 (roflumilast) and 12.5 (placebo) for CV death, 3.0 (roflumilast) and 6.4 (placebo) for nonfatal MI, and 1.6 (roflumilast) and 3.5 (placebo) for nonfatal stroke.

c 

Significant at P < .05.

Kaplan-Meier plots for the probability of experiencing MACEs and the various components are presented in Figure 2. These plots were truncated after 372 days. With the exception of nonfatal stroke, fatal and nonfatal cardiovascular events accrual began to separate between 90 and 150 days of exposure, with lower event rates for roflumilast than for placebo.

Figure Jump LinkFigure 2. Kaplan-Meier plots of time to event for MACEs in the roflumilast and placebo treatment groups. A, Probability of experiencing the composite MACEs. B, Cardiovascular death component. C, Nonfatal MI component. D, Nonfatal stroke component. See Figure 1 legend for expansion of abbreviation.Grahic Jump Location
Cardiovascular Event Rates According to Cardiovascular Disorders at Baseline

Risk factors recorded at baseline included the presence of hypertension, diabetes mellitus, hyperlipidemia, and a history of heart disease (Table 2). Adjudicated event rates were higher in patients with baseline cardiovascular risk factors than in those without baseline cardiovascular risk (Table 4). HRs for MACEs found in patients treated with roflumilast relative to placebo in patients without cardiovascular diseases or risk factors at baseline were lower than in those with cardiovascular comorbid conditions. Adjusting for cardiovascular risk factors at baseline did not materially affect the HR for MACEs. There were significantly fewer MACEs for roflumilast than for placebo in the subgroup of patients with COPD who did not have cardiovascular comorbid conditions at baseline (Table 4).

Table Graphic Jump Location
Table 4 —Incidence Rates and HRs for MACEs According to Baseline CV Comorbid Diseases

Data are presented as No. (%), unless otherwise indicated. See Table 3 legend for expansion of abbreviations.

a 

Calculated using Cox proportional hazard model with terms for treatment, age, sex, smoking status, and country pool.

b 

Includes ischemic heart disease, type 2 diabetes, dyslipidemia, and hypertension (see Table 2).

c 

Significant at P < .05.

Cardiovascular Event Rates According to Other Factors at Baseline

Adjudicated event rates according to age, sex, smoking status, COPD severity, and concomitant long-term pulmonary medication use are shown in Figure 3. HRs were similar across age, sex, and smoking status. There were no significant interactions for COPD severity, concomitant inhaled corticosteroid use, or long-acting β-agonist use. However, reductions in MACEs were significant in patients with severe COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stage III), in those using concomitant inhaled corticosteroids, and in those not using long-acting β-agonists and not in the corresponding subgroups.

Figure Jump LinkFigure 3. Hazard ratios and 95% CIs for the major adverse cardiac events composite depicted according to clinical and demographic subgroups of patients receiving roflumilast vs placebo. GOLD = Global Initiative for Chronic Obstructive Lung Disease; ICS = inhaled corticosteroid; LABA =long-acting β-agonist.Grahic Jump Location
Cardiovascular Event Rates According to COPD Exacerbations

Subanalyses of the four trials carried out for 1 year demonstrated that exacerbations of COPD were reduced significantly by roflumilast relative to placebo. Between patients with and without exacerbations, the proportions with MACEs were similar (1.7% and 1.6%, respectively). Between patients with and without MACEs, the proportions experiencing exacerbations were similar (43.2% and 42.1%, respectively).

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 cardiovascular risk factors. The cardiovascular effects of roflumilast appeared to be independent of age, sex, smoking status, use of concomitant COPD treatments such as long-acting β-agonists and inhaled steroids, and COPD exacerbations.

Patients with COPD are known to have higher rates of cardiovascular mortality and hospitalizations compared with age- and sex-matched control patients without COPD,2,17,18 and the rates of cardiovascular death and MI in the present analysis are similar to those previously published.1921 Of note, stroke rates typically are not reported in most studies evaluating cardiovascular event rates in trials or cohorts of COPD. The rates of cardiac death and MI vary substantially in analyses of COPD populations according to pulmonary and cardiovascular disease severity, the era in which the study was performed, and the duration of the observational period.35,2022 In the present study of > 12,000 patients with COPD in which about 17% had ischemic heart disease, the placebo MACE rate was 1.4%, and the roflumilast MACE rate was 0.8%. In contrast, in a VALIANT (Valsartan in Acute Myocardial Infarction Trial) substudy3 of 1,258 patients with COPD, all of whom had a very recent MI, the average rate of cardiovascular death, MI, and heart failure was about 15%. In a pooled analysis of 19 studies comparing tiotropium to placebo in 7,819 much-healthier patients with moderate to severe with COPD, the incidence of cardiovascular death was only 0.35%20 and likely reflects both the lower cardiovascular morbidity chosen for clinical trial participation and the much shorter observation time.

In the present study, patients with cardiovascular risk factors or disease at baseline had two to three times the MACE rate as patients without these at baseline. In both subgroups of patients, roflumilast conveyed a reduction in cardiovascular events, although the change appeared to be more substantial in patients without baseline cardiovascular diseases.

Studies have shown that patients with severe and moderate COPD also have evidence of systemic inflammation, including elevated circulating levels of tumor necrosis factor, IL-6, and C-reactive protein, compared with healthy people.18,2325 Additionally, Sin and Man18 showed that an important link exists between systemic inflammation in COPD and cardiac injury in association with varying levels of airflow obstruction. Unfortunately, proinflammatory markers were not obtained in all the studies used in the present pooled analysis of cardiovascular events. However, it is known that PDE-4 inhibition provides a wide range of antiinflammatory actions in vitro26 and in vivo.27 The oral PDE-4 inhibitor roflumilast has been shown to reduce airway inflammation in COPD as assessed by sputum neutrophil and eosinophil counts,7 an antiinflammatory benefit that may be associated with the ability of the drug to reduce exacerbations of COPD.8 Hence, the reduction in MACEs seen with roflumilast compared with placebo in the present analysis may be partly related to reductions in vascular inflammation induced by PDE-4 inhibition.

Few data exist with regard to potential cardiovascular benefits of therapies for COPD. Extensive analyses of the effects of long-acting β-agonists and inhaled corticosteroids on cardiovascular events have shown no harm,28,29 and a trend toward a mortality benefit for the combination of salmeterol and fluticasone proprionate has been observed in the TORCH (Toward a Revolution in COPD Health) trial.30 The long-term effects of the inhaled long-acting anticholinergic agent tiotropium on cardiovascular events was first reported in the UPLIFT (Understanding Potential Long-Term Impacts on Function With Tiotropium) trial19 and later reviewed in a pooled analysis of shorter-term placebo-controlled trials of the agent.31 In UPLIFT, the incidence rate of serious cardiac events was 16% lower for tiotropium than for placebo (P < .05), with an 11% reduction seen in all-cause mortality (P = .09).19 In a later pooled analysis of nearly 20,000 patients, the relative risk of mortality while receiving tiotropium was significantly reduced by 23%.31 In the present study of roflumilast in patients with COPD, the relative reduction in MACE compared with placebo was 35%, with all three components (cardiovascular death, nonfatal MI, and nonfatal stroke) showing a similar directional change that favored roflumilast.

Study Limitations

Although the studies included in this pooled analysis were not designed to assess the relative effects of roflumilast vs placebo on cardiovascular outcomes, the baseline characteristics of the population, including age, underlying cardiovascular risk factors, severity of COPD, and concomitant cardiac and pulmonary therapies were similar for the roflumilast and placebo treatment groups (Table 2). Furthermore, although the present sample size is quite large, the trials were for ≤ 1 year of observation, so the patient-years of exposure are relatively small compared with primary cardiovascular outcome studies. However, the event rates in the placebo-controlled trials analyzed here were similar to those in trials and analyses of cardiovascular events in patients with COPD.1719,29,31 Nevertheless, the description of absolute risk of MACEs for roflumilast relative to placebo must be interpreted with caution.

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.

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

Dr Calverley: contributed as a member of the steering committee for roflumilast studies to the data interpretation and critical review of the manuscript.

Dr Bredenbröker: contributed to the clinical operations for the conduct of the study, data acquisition, and critical review of the manuscript.

Dr Goehring: contributed to the clinical operations for the conduct of the study, data acquisition, and critical review of the manuscript.

Dr Zhu: contributed to the biometric analysis, data analysis, and critical review and editing of the manuscript.

Dr Lakkis: contributed to the biometric analysis, data analysis, and critical review and editing of the manuscript.

Dr Mosberg: contributed as a safety physician involved with the clinical study operations to the data acquisition and interpretation and critical review of the manuscript.

Dr Rowe: contributed as a safety physician involved with the clinical study operations to the data acquisition and interpretation and critical review of the manuscript.

Dr Rabe: contributed as a member of the steering committee for roflumilast studies to the data interpretation and critical review of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr White has research funding from the National Institutes of Health unrelated to the content of this article. He is the president of the American Society of Hypertension, Inc for 2012 to 2014. Dr White is a consultant regarding the cardiovascular safety of numerous noncardiac drugs and devices (steering committees, data safety monitoring committees, and cardiovascular end point committees) for companies that include Ardea Biosciences, Inc; AstraZeneca; Dendreon Pharmaceuticals; EMD Serono, Inc; Forest Research Institute, Inc; Eli Lilly and Company; Roche; Teva Pharmaceutical Industries, Ltd; and Takeda Global Research and Development Center, Inc. Drs Cooke and Kowey are prior members of the cardiovascular adjudication committee for roflumilast and are paid consultants to Nycomed. Drs Calverley and Rabe are members of the steering committee for roflumilast trials and are paid consultants to Nycomed. Drs Bredenbröker and Goehring are full-time employees of Nycomed. Drs Zhu, Lakkis, and Rowe are full-time employees of Forest Research Institute Inc. Dr Mosberg was a full-time employee of Nycomed until June 2012.

Role of sponsors: Nycomed: a Takeda company supplied the original data and source documents to the cardiovascular adjudication committee. All data in this analysis were available to all authors for review and assessment. None of the authors received any financial compensation for any aspect of manuscript preparation. No medical writer was involved in drafting the manuscript.

Other contributions: Morgan Hill, PhD, Prescott Medical Communications Group (Chicago, Illinois), provided assistance with the preparation of figures and tables, which was made possible by funding from Forest Research Institute Inc.

HR

hazard ratio

MACE

major adverse cardiovascular event

MI

myocardial infarction

PDE-4

phosphodiesterase 4

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Calverley PM, Anderson JA, Celli B, et al; TORCH Investigators. Cardiovascular events in patients with COPD: TORCH study results. Thorax. 2010;65(8):719-725. [CrossRef] [PubMed]
 
Calverley PM, Anderson JA, Celli B, et al; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789. [CrossRef] [PubMed]
 
Celli B, Decramer M, Leimer I, Vogel U, Kesten S, Tashkin DP. Cardiovascular safety of tiotropium in patients with COPD. Chest. 2010;137(1):20-30. [CrossRef] [PubMed]
 
Bredenbröker D, Syed J, Leichtl S, Rothgeb F, Wurst W. Safety of once-daily roflumilast, a new, orally active, selective phosphodiesterase 4 inhibitor, in patients with COPD [abstract]. Am J Respir Crit Care Med. 2002;165(595 pt 2):A595.
 
Bredenbröker D, Syed J, Leichtl S, Rathgeb F, Wurst W. Roflumilast, a new orally active phosphodiesterase 4 inhibitor, is effective in the treatment of chronic obstructive pulmonary disease [abstract]. Eur Respir J. 2002;20(suppl 38):374s.
 
Boszormenyi-Nagy G, Pieters WR, Steffen H, et al. The effect of roflumilast treatment and subsequent withdrawal in patients with COPD [abstract]. Proc Am Thorac Soc. 2005;2(abstracts issue):A544.
 
Rabe KF, Bateman ED, O’Donnell D, Witte S, Bredenbröker D, Bethke TD. Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2005;366(9485):563-571. [CrossRef] [PubMed]
 
Rennard SI, Calverley PM, Goehring UM, Bredenbröker D, Martinez FJ. Reduction of exacerbations by the PDE4 inhibitor roflumilast—the importance of defining different subsets of patients with COPD. Respir Res. 2011;12:18. [CrossRef] [PubMed]
 
Calverley PM, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176(2):154-161. [CrossRef] [PubMed]
 
Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al; M2-127 and M2-128 Study Groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009;374(9691):695-703. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Disposition of the events following formal adjudication. All potential CV events were evaluated by a cardiovascular adjudication committee blinded to treatment assignment. Note that four subjects in each treatment group did not have sufficient data for determination of the primary cause of death. CV = cardiovascular; MACE = major adverse cardiovascular event; MI = myocardial infarction.Grahic Jump Location
Figure Jump LinkFigure 2. Kaplan-Meier plots of time to event for MACEs in the roflumilast and placebo treatment groups. A, Probability of experiencing the composite MACEs. B, Cardiovascular death component. C, Nonfatal MI component. D, Nonfatal stroke component. See Figure 1 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 3. Hazard ratios and 95% CIs for the major adverse cardiac events composite depicted according to clinical and demographic subgroups of patients receiving roflumilast vs placebo. GOLD = Global Initiative for Chronic Obstructive Lung Disease; ICS = inhaled corticosteroid; LABA =long-acting β-agonist.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Summary of Studies Included in the COPD Safety Pool
a 

One patient each in studies FK1 103 and M2-124 was randomized twice.

b 

Study FK1 103 evaluated withdrawal of roflumilast after 12 wk of treatment vs continued treatment for 24 wk; the switch arm of the study (patients who received roflumilast for 12 wk then placebo for 12 wk) was not included in this pooled analysis.

Table Graphic Jump Location
Table 2 —Baseline Characteristics of the COPD Population

Data are presented as median (range), mean ± SD, or No. (%). GOLD = Global Initiative for Chronic Obstructive Lung Disease; HMG-CoA = 5-hydroxy-3-methylglutaryl-coenzyme A.

Table Graphic Jump Location
Table 3 —Incidence Rates and HRs for MACEs

Data are presented as No. (%), unless otherwise indicated. CHF = congestive heart failure; CV = cardiovascular; HR = hazard ratio; MACE = major adverse cardiovascular event; MI = myocardial infarction.

a 

Calculated using the Cox proportional hazard model with terms for treatment, age, sex, smoking status, and country pool.

b 

Patients treated with roflumilast and placebo were exposed to study drug for 3,639 and 3,448 patient-y, respectively. Exposure-adjusted incidence rates per 1,000 patient-y were 14.3 (roflumilast) and 22.3 (placebo) for composite MACEs, 9.6 (roflumilast) and 12.5 (placebo) for CV death, 3.0 (roflumilast) and 6.4 (placebo) for nonfatal MI, and 1.6 (roflumilast) and 3.5 (placebo) for nonfatal stroke.

c 

Significant at P < .05.

Table Graphic Jump Location
Table 4 —Incidence Rates and HRs for MACEs According to Baseline CV Comorbid Diseases

Data are presented as No. (%), unless otherwise indicated. See Table 3 legend for expansion of abbreviations.

a 

Calculated using Cox proportional hazard model with terms for treatment, age, sex, smoking status, and country pool.

b 

Includes ischemic heart disease, type 2 diabetes, dyslipidemia, and hypertension (see Table 2).

c 

Significant at P < .05.

References

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Calverley PM, Anderson JA, Celli B, et al; TORCH Investigators. Cardiovascular events in patients with COPD: TORCH study results. Thorax. 2010;65(8):719-725. [CrossRef] [PubMed]
 
Calverley PM, Anderson JA, Celli B, et al; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789. [CrossRef] [PubMed]
 
Celli B, Decramer M, Leimer I, Vogel U, Kesten S, Tashkin DP. Cardiovascular safety of tiotropium in patients with COPD. Chest. 2010;137(1):20-30. [CrossRef] [PubMed]
 
Bredenbröker D, Syed J, Leichtl S, Rothgeb F, Wurst W. Safety of once-daily roflumilast, a new, orally active, selective phosphodiesterase 4 inhibitor, in patients with COPD [abstract]. Am J Respir Crit Care Med. 2002;165(595 pt 2):A595.
 
Bredenbröker D, Syed J, Leichtl S, Rathgeb F, Wurst W. Roflumilast, a new orally active phosphodiesterase 4 inhibitor, is effective in the treatment of chronic obstructive pulmonary disease [abstract]. Eur Respir J. 2002;20(suppl 38):374s.
 
Boszormenyi-Nagy G, Pieters WR, Steffen H, et al. The effect of roflumilast treatment and subsequent withdrawal in patients with COPD [abstract]. Proc Am Thorac Soc. 2005;2(abstracts issue):A544.
 
Rabe KF, Bateman ED, O’Donnell D, Witte S, Bredenbröker D, Bethke TD. Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2005;366(9485):563-571. [CrossRef] [PubMed]
 
Rennard SI, Calverley PM, Goehring UM, Bredenbröker D, Martinez FJ. Reduction of exacerbations by the PDE4 inhibitor roflumilast—the importance of defining different subsets of patients with COPD. Respir Res. 2011;12:18. [CrossRef] [PubMed]
 
Calverley PM, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176(2):154-161. [CrossRef] [PubMed]
 
Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al; M2-127 and M2-128 Study Groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009;374(9691):695-703. [CrossRef] [PubMed]
 
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