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Cardiovascular Safety of Roflumilast
Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts: Dr MacNee has acted in an advisory capacity for GlaxoSmithKline plc; Pfizer, Inc; Novartis AG; and Almirall, SA. He has received payment from GlaxoSmithKline plc and Pfizer, Inc for research programs and clinical activities and has also received payments from Boehringer-Ingelheim GmbH, GlaxoSmithKline, AstraZeneca, Novartis AG, and Janssen Pharmaceuticals to travel to meetings and/or present at conferences. Dr Maclay has reported no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: John D. Maclay, MBChB MD, University of Edinburgh, Centre for Inflammation Research, 47 Little France Crescent, Edinburgh EH16 4SB, Scotland; e-mail: johnmaclay@ gmail.com © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-1352
References 1. Maclay JD, MacNee W. Cardiovascular disease in COPD: mechanisms. Chest. 2013;143(3):798-807. 2. Chang CL, Robinson SC, Mills GD, et al. Biochemical markers of cardiac dysfunction predict mortality in acute exacerbations of COPD. Thorax. 2011;66(9):764-768. 3. Yap LB, Mukerjee D, Timms PM, Ashrafian H, Coghlan JG. Natriuretic peptides, respiratory disease, and the right heart. Chest. 2004;126(4):1330-1336. 4. Pauriah M, Khan F, Lim TK, et al. B-type natriuretic peptide is an independent predictor of endothelial function in man. Clin Sci (Lond). 2012;123(5):307-312. 5. Maclay JD, McAllister DA, Mills NL, et al. Vascular dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;180(6):513-520.
Outcomes could have been adjusted, using person-years of exposure as a denominator. In conclusion, the study by White et al1 does not provide enough evidence to support the cardiovascular safety of roflumilast. More studies are needed to further investigate the cardiovascular safety of the drug. Yuji Oba, MD Nazir A. Lone, MD Columbia, MO Affiliations: From the University of Missouri-Columbia. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: Yuji Oba, MD, University of MissouriColumbia, 1 Hospital Dr, CE 412, Columbia, MO 65212; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-1036
References 1. White WB, Cooke GE, Kowey PR, et al. Cardiovascular safety in patients receiving roflumilast for the treatment of COPD. Chest. 2013;144(3):758-765. 2. Ferreira-González I, Busse JW, Heels-Ansdell D, et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ. 2007; 334(7597):786. 3. Oba Y, Lone NA. Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Ther Adv Respir Dis. 2013;7(1):13-24.
Cardiovascular Safety of Roflumilast To the Editor: In this issue of CHEST (see page 758), White et al1 report significantly lower major adverse cardiovascular events (MACEs) for roflumilast compared with placebo (hazard ratio, 0.65; 95% CI, 0.45-0.93; P 5 .019) from data in 12,054 patients with COPD. In addition to the studies analyzed not being designed or powered to examine cardiovascular outcomes, we would like to point out other limitations of the study. First, the incidence of nonfatal stroke was the only component of MACEs that showed a statistically significant difference. It may not be appropriate to use a composite outcome if the magnitude of treatment effects is not comparable across the outcome components.2 It may be fair to say that roflumilast could decrease cerebrovascular events but not cardiovascular events or mortality because roflumilast was not associated with a lower incidence of such MACE components compared with placebo. Second, the incidence of atrial fibrillation was not included in the study. Our recent meta-analysis showed that atrial fibrillation was significantly more frequent with roflumilast than with placebo (0.4% vs 0.2%; P 5 .02).3 The COPD safety pool White et al1 used included this information, and they should have incorporated it into the study. Third, the discontinuation rate because of adverse effects was significantly more frequent with roflumilast than with placebo (15% vs 9.2%, P , .0001).3 The imbalance of dropout rates between the two groups may have affected the study results. The results may have been quite different if all patients recruited for roflumilast continued to take the drug during the entire study period.
Response To the Editor: The intention of our study, reported in this issue of CHEST,1 was to evaluate the cardiovascular (CV) safety of roflumilast in . 12,000 patients with COPD using adjudicated major adverse CV events (MACEs) of CV death, nonfatal myocardial infarction, and nonfatal stroke. The results of our study showed that the hazard ratios for roflumilast relative to placebo were similar and in the same direction (, 1) for all three components of this MACE composite.1 Oba and Lone stated incorrectly that stroke was the only MACE component that was significantly different for roflumilast relative to placebo. In fact, none of the components met statistical significance for a reduction in CV events. We concluded that our large analysis demonstrated the lack of a CV safety concern for roflumilast in patients with moderate to severe COPD, and the results generated the hypothesis of potential benefit, particularly in those patients lacking CV comorbidities at baseline.1 The absolute and relative CV effects of roflumilast are currently being evaluated in purposefully designed, prospective randomized trials. William B. White, MD Farmington, CT on behalf of the coauthors Affiliations: From the Division of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center, University of Connecticut School of Medicine.
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Correspondence
References 1. Maclay JD, MacNee W. Cardiovascular disease in COPD: mechanisms. Chest. 2013;143(3):798-807. 2. Chang CL, Robinson SC, Mills GD, et al. Biochemical markers of cardiac dysfunction predict mortality in acute exacerbations of COPD. Thorax. 2011;66(9):764-768. 3. Yap LB, Mukerjee D, Timms PM, Ashrafian H, Coghlan JG. Natriuretic peptides, respiratory disease, and the right heart. Chest. 2004;126(4):1330-1336. 4. Pauriah M, Khan F, Lim TK, et al. B-type natriuretic peptide is an independent predictor of endothelial function in man. Clin Sci (Lond). 2012;123(5):307-312. 5. Maclay JD, McAllister DA, Mills NL, et al. Vascular dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;180(6):513-520.
Outcomes could have been adjusted, using person-years of exposure as a denominator. In conclusion, the study by White et al1 does not provide enough evidence to support the cardiovascular safety of roflumilast. More studies are needed to further investigate the cardiovascular safety of the drug. Yuji Oba, MD Nazir A. Lone, MD Columbia, MO Affiliations: From the University of Missouri-Columbia. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: Yuji Oba, MD, University of MissouriColumbia, 1 Hospital Dr, CE 412, Columbia, MO 65212; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-1036
References 1. White WB, Cooke GE, Kowey PR, et al. Cardiovascular safety in patients receiving roflumilast for the treatment of COPD. Chest. 2013;144(3):758-765. 2. Ferreira-González I, Busse JW, Heels-Ansdell D, et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ. 2007; 334(7597):786. 3. Oba Y, Lone NA. Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Ther Adv Respir Dis. 2013;7(1):13-24.
Cardiovascular Safety of Roflumilast To the Editor: In this issue of CHEST (see page 758), White et al1 report significantly lower major adverse cardiovascular events (MACEs) for roflumilast compared with placebo (hazard ratio, 0.65; 95% CI, 0.45-0.93; P 5 .019) from data in 12,054 patients with COPD. In addition to the studies analyzed not being designed or powered to examine cardiovascular outcomes, we would like to point out other limitations of the study. First, the incidence of nonfatal stroke was the only component of MACEs that showed a statistically significant difference. It may not be appropriate to use a composite outcome if the magnitude of treatment effects is not comparable across the outcome components.2 It may be fair to say that roflumilast could decrease cerebrovascular events but not cardiovascular events or mortality because roflumilast was not associated with a lower incidence of such MACE components compared with placebo. Second, the incidence of atrial fibrillation was not included in the study. Our recent meta-analysis showed that atrial fibrillation was significantly more frequent with roflumilast than with placebo (0.4% vs 0.2%; P 5 .02).3 The COPD safety pool White et al1 used included this information, and they should have incorporated it into the study. Third, the discontinuation rate because of adverse effects was significantly more frequent with roflumilast than with placebo (15% vs 9.2%, P , .0001).3 The imbalance of dropout rates between the two groups may have affected the study results. The results may have been quite different if all patients recruited for roflumilast continued to take the drug during the entire study period.
Response To the Editor: The intention of our study, reported in this issue of CHEST,1 was to evaluate the cardiovascular (CV) safety of roflumilast in . 12,000 patients with COPD using adjudicated major adverse CV events (MACEs) of CV death, nonfatal myocardial infarction, and nonfatal stroke. The results of our study showed that the hazard ratios for roflumilast relative to placebo were similar and in the same direction (, 1) for all three components of this MACE composite.1 Oba and Lone stated incorrectly that stroke was the only MACE component that was significantly different for roflumilast relative to placebo. In fact, none of the components met statistical significance for a reduction in CV events. We concluded that our large analysis demonstrated the lack of a CV safety concern for roflumilast in patients with moderate to severe COPD, and the results generated the hypothesis of potential benefit, particularly in those patients lacking CV comorbidities at baseline.1 The absolute and relative CV effects of roflumilast are currently being evaluated in purposefully designed, prospective randomized trials. William B. White, MD Farmington, CT on behalf of the coauthors Affiliations: From the Division of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center, University of Connecticut School of Medicine.
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Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 09/03/2013
Correspondence