1. CHEST 2013; 144(3):758-765 R3 김유진 / Prof. 장나은

2. Introduction 2  Cardiovascular diseases  common, serious comorbid conditions in patients with COPD cardiac arrhythmia, venous thromboembolic disorders, myocardial infarction (MI), and stroke cardiovascular death, heart failure, and hospitalizations for cardiovascular diseases  Low-grade systemic inflammation has been proposed as a possible link between COPD and systemic comorbid diseases, such as cardiovascular disease.

3. Introduction 3  Roflumilast  newly registered, selective, oral, once-daily phosphodiesterase 4 (PDE- 4) inhibitor  antiinflammatory activity  reductions in the rates of acute exacerbations in patients with severe to very severe COPD  Retrospective assessment of cardiovascular events pooled from the entire clinical database of placebo-controlled roflumilast COPD trials of >12 weeks  The focus of the analysis was on the incidence of major adverse cardio-vascular events (MACEs), as defined previously, with roflumilast and its placebo comparator

4. MATERIALS AND METHODS

5. Clinical Studies and Protocol 5  inclusion criteria. (1) Compared randomized trials with a parallel group design, (2) one treatment arm of roflumilast >250 ug 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.  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 ug] FEV1/FVC ratio of< 70%).

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7. Assessments for Cardiovascular End Points 7  The primary analysis in the present study was based on MACEs  MACE End points sought from the database (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.

8. Statistical Analysis 8  The baseline characteristics in the entire cohort were summarized with descriptive statistics for roflumilast and placebo groups.  Analyses of MACEs were performed for all patients from studies comparing roflumilast (250- and 500- mg doses were combined) with placebo.  A Cox proportional hazard model was used to analyze the time to first event.  The hazard ratio (HR) : the ratio of roflumilast to placebo with 95% CIs and P values for statistical testing of the null hypothesis that HR = 1.0.

9. RESULTS

10. 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 mg total daily dose,  and 5,491 were randomized to placebo 10

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12. Primary Cardiovascular Events (Composite) for Controlled Trials  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). 12

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14. Cardiovascular Event Rates According to Cardiovascular Disorders at Baseline  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. 14

15. 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 b-agonist use.  However, reductions in MACEs were significant in patients with severe COPD stage III 15

16. Cardiovascular Event Rates According to COPD Exacerbations 16  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 with-out MACEs, the proportions experiencing exacerbations were similar (43.2% and 42.1%, respectively).

17. DISCUSSION

18.  Severe and moderate COPD  evidence of systemic inflammation  elevated circulating levels of tumor necrosis factor, IL-6, and C-reactive protein  an important link exists between systemic inflammation in COPD and cardiac injury  The oral PDE-4 inhibitor roflumilast  reduce airway inflammation in COPD as assessed by sputum neutrophil and eosinophil counts  reduce exacerbations of COPD 18

19. Conclusion 19  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.