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Reduced Rate Of Major Adverse Cardiovascular Events (MACE) Observed In COPD Patients Treated With Daxas® (Roflumilast)

New data analysis published in CHEST journal indicates the lack of a cardiovascular safety signal when treating patients with COPD and suggests potential cardiovascular benefits of roflumilast when used as an add-on therapy

Chronic obstructive pulmonary disease (COPD) patients treated with bronchodilator with or without inhaled corticosteroids, may experience significantly fewer major adverse cardiovascular events (MACE) when roflumilast is used as an add-on therapy.[i] Roflumilast is an orally-administered highly selective phosphodiesterase 4 (PDE4) inhibitor, manufactured by Takeda Pharmaceutical Company Limited for the treatment of COPD-specific inflammation.

The new post-hoc data analysis published in CHEST was led by Professor William B. White, Professor of Medicine, Chief, Division of Hypertension and Clinical Pharmacology of the Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, Connecticut. It evaluated the effects of roflumilast on cardiovascular outcomes in moderate to very severe COPD patients and showed a 35% reduction of MACE in patients treated with roflumilast as an add-on therapy when compared to placebo (p = 0.019). The analysis, found significant reductions of MACE (non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) in patients treated with roflumilast compared to placebo, independent of age, gender, smoking status, use of concomitant COPD treatments, such as long-acting beta-agonists and inhaled corticosteroids and COPD exacerbations.[i]

“While limited data exist on the potential cardiovascular benefits of new COPD therapies, this analysis of MACE on roflumilast is important as it highlights the absence of a cardiovascular safety indicator when treating patients with COPD,” commented Professor Klaus F. Rabe, Professor of Pulmonary Medicine at the University of Kiel and Director of the Department of Pneumology at LungenClinic Grosshansdorf. “COPD often coexists with other diseases and this data underscores the need for physicians to take a holistic approach in the management of their patients when treating COPD.”

The prevalence of cardiac comorbidities within the COPD population is high,[ii] with various studies demonstrating the incidence of comorbid hypertension ranging between 28%[iii] and 40%,[iv] diabetes mellitus between 12%iv and 14%iii and depression between 22.8%[v] and 42%.[vi] The risk of developing incident cardiac arrhythmia, venous thromboembolic disorders, myocardial infarction and stroke are substantially greater in COPD patients than in healthy individuals.[vii],[viii] Additionally 40% of COPD patients have cardiovascular disease[ix] and patients are known to have higher rates of cardiovascular mortality and hospitalisations.[viii],[x],[xi],[xii]

Recent studies have shown that severe and moderate COPD patients have evidence of systemic inflammation;[xiii],[xiv],[xv],[xvi] this has been proposed as a link between COPD and systemic comorbidities, such as cardiovascular disease.[xvii] There is also an important link between systemic inflammation in COPD and cardiac injury in association with varying levels of airflow obstruction.xi

As a phosphodiesterase-4 (PDE4) inhibitor, roflumilast provides a wide range of anti-inflammatory actions in vitro[xviii] and in vivo[xix] and has been shown to reduce airway inflammation in COPD as assessed by sputum neutrophil and eosinophil counts,[xx] an anti-inflammatory benefit that may be associated with the drug’s ability to reduce exacerbations of COPD.[xxi] Thus, there is potential for the MACE reduction seen with roflumilast as an add-on therapy to be related in part to reductions in vascular inflammation induced by PDE-4 inhibition.[i]

“The outcomes of the MACE evaluation indicate the potential additional benefits of roflumilast treatment for COPD patients with cardiovascular comorbidities. In addition to reducing future risk in COPD patients, roflumilast may reduce cardiovascular risk factors by improving glucose and lipid homeostasis.[xxii],[xxiii] It is important to define the potential cardiovascular benefits of roflumilast in future controlled trials,” commented Ulrich Thienel, Vice President and Therapeutic Area Leader Immunology and Respiratory, Takeda.

Roflumilast, as an add-on to long acting bronchodilators, is approved for severe COPD associated with chronic bronchitis and a history of frequent exacerbations. It has a unique mode of action which targets COPD inflammation and has been shown to reduce exacerbations, with the ability to shift patients from the frequent to more stable infrequent exacerbator status, independent of concomitant therapy with all forms of bronchodilators and inhaled corticosteroids.[xxiv]

About Daxas®

Daxas® is the first anti-inflammatory treatment developed to target COPD-specific inflammation with a novel mode of action. Its active component, roflumilast, is a potent and selective inhibitor of the PDE4 enzyme.[xix]

Four large randomised placebo controlled trials have shown that roflumilast significantly reduces exacerbations and improves lung function when added to long acting bronchodilators. [xvi],[xxv],[xxvi]

Roflumilast is indicated in the EU for the maintenance treatment of severe COPD (FEV1 post-bronchodilator less than 50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations as an add-on to bronchodilator treatment.[xxvii]

Daxas is generally well tolerated. Pooled data from 14 randomised, double-blind, placebo-controlled studies of roflumilast in COPD patients (5,766 patients in total treated with roflumilast and 5,491 with placebo), showed the most frequent adverse events occurring more commonly with roflumilast versus placebo were diarrhoea (10.1% versus 2.6%), weight decrease (6.8% versus 1.8%), nausea (5.2% versus 1.4%), and headache (4.6% versus 2.0%). Apart from weight decrease, the majority of these adverse events resolved within 3 weeks.[xxviii] The majority of these adverse reactions were mild or moderate.


[i] White WB, et al. Cardiovascular Outcomes In Patients Receiving Roflumilast for the Treatment of Chronic Obstructive Pulmonary Disease. CHEST 2013. doi: 10.1378/chest.12-2332. (Accessed February 2013)

[ii]de Lucas-Ramos P, et al. Chronic obstructive pulmonary disease as a cardiovascular risk factor. Results of a case-control study. Int J Chron Obstruct Pulmon Dis 2012; 7: 679-86.

[iii]Sin, DD, et al. Mortality in COPD: role of comorbidities, Eur Respir J 2006; 28: 1245-57.

[iv]Mannino DM, et al. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J 2008; 32: 962-9.

[v]Ng T, et al. Co-morbid association of depression and COPD: a population-based study. Respiratory Medicine 2009; 103(6): 895-901.

[vi]Hill K, et al. Anxiety and depression in end-stage COPD. Eur Respir J 2008; 31: 667–677.

[vii]Rabe KF, et al. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007; 176: 532-55.

[viii]Feary JR, et al. Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care. Thorax 2010; 65: 956-962.

[ix]Eriksson B, et al. Association of heart diseases with COPD and restrictive lung function – Results from a population survey Berne. Respiratory Medicine 2013; 107: 98-106.

[x]Sidney S, et al. COPD and incident cardiovascular disease hospitalizations and mortality: Kaiser Permanente Medical Care Program. CHEST 2005; 128: 2068-75.

[xi]Sin DD, et al. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003; 107: 1514-19.

[xii]Lange P, et al. Prediction of the Clinical Course of Chronic Obstructive Pulmonary Disease, Using the New GOLD Classification – A Study of the General Population Peter. Am J Respir Crit Care Med. 2012; 186: (10) 975–981.

[xiii]Tashkin DP, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008; 359: 1543-54.

[xiv]Takabatake N, et al. The relationship between chronic hypoxemia, and activation of the tumor necrosis factor-alpha system in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161: 1179-84.

[xv]Eid AA, et al. Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164: 1414-18.

[xvi]Schols AM, et al. Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax 1996; 51: 819-824.

[xvii]Fabbri LM & Rabe KF. From COPD to chronic systemic inflammatory syndrome? The Lancet 2007; 370, 9589: 797-799.

[xviii]Hatzelmann A & Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther 2001; 297: 267-79.

[xix]Hatzelman A, et al. The preclinical pharmacology of roflumilast – A selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulmonary Pharmacology & Therapeutics 2010; 23: 235-256.

[xx]Grootendorst DC, et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007; 62: 1081-87.

[xxi]Calverley PM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. The Lancet 2009; 374: 685–694.

[xxii]Wouters EFM, et al. Effect of the Phosphodiesterase 4 Inhibitor Roflumilast on Glucose Metabolism in Patients with Treatment-Naive, Newly Diagnosed Type 2 Diabetes Mellitus. Journal of Clin Endocr & Metab 2012; 97: E1720-E1725.

[xxiii]Vollert S, et al. The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice. Diabetologia 2012; 55, 10: 2279-2788.

[xxiv]Wedzicha JA, et al. Efficacy Of Roflumilast In The Chronic Obstructive Pulmonary Disease Frequent Exacerbator Phenotype. CHEST 2012. doi:10.1378/chest.12-1489.

[xxv]Fabbri LM, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomised clinical trials. The Lancet 2009; 374: 695–703.

[xxvi]Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharm 2011; 163: 53–67.

[xxvii]EU Summary of Product Characteristics, Daxas®, May 2011

[xxviii]Calverley P, et al. Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol. Int J Chron Pulmon Dis 2012; 7: 375-382.

Source: Takeda Pharmaceuticals International GmbH