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      Roflumilast in COPD: a Brazilian perspective

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          Dear editor We would like to discuss the use of roflumilast in Brazil and its perspectives, based on the data currently available. This medication is underused in Brazil, probably due to its high cost in the public health care system. Of the approximately 21,000 patients who have a condition which could be treated with roflumilast (personal communication, Takeda Pharmaceutical Company, 2014), only 14% are currently using it. Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition that currently affects between 3 and 7 million Brazilian citizens. As per DATA-SUS (Department of Data Analysis of the Brazilian Public Health System), COPD in 2010 led to 141,994 hospitalizations, 778,428 hospitalization days, a total cost of US$30.4 million, and led to 7,937 deaths directly related to COPD, which ranks 5th as cause of death in Brazil.1 According to the PLATINO study, the prevalence of COPD in Brazil is 15.8% in adults over the age of 40 years.2 Patients with severe and very severe COPD usually suffer at least one exacerbation per year. COPD patients with chronic bronchitis for example, have twice as many exacerbations per year as patients without chronic bronchitis, and these patients are at an increased risk of hospitalization and death. Each exacerbation can last from a few days to several weeks, longer including the recovery period.3 COPD exacerbation enhances the systemic effects of inflammation, which increases the risk of cardiovascular and cerebrovascular events by up to 2.27 times during the first 5 days after an exacerbation. Thus, a reduction in the frequency of exacerbations brings an additional positive effect on reducing cardiovascular risk.4,5 Data from recent studies have clearly demonstrated the life-threatening potential of this condition.3 Suissa et al showed using a large retrospective cohort of COPD patients, that the median time between consecutive severe exacerbations declined with every new episode, and that a 50% mortality rate following the first hospitalization for severe exacerbation was 3.6 years.3 Despite the high mortality observed after an COPD exacerbation episode (23%), exacerbations do not raise the same concerns as myocardial infarction which presents a mortality rate of 9.6% after 1 year.6 Persistent systemic inflammation has been recognized in patients with stable COPD, as well as its relationship in the risk of exacerbations, which in turn further aggravate systemic inflammation, possibly contributing to the increased risk of myocardial infarction and stroke. This data suggests that preventing exacerbations with strategies directly targeting inflammation may have the potential to impact morbidity in patients with COPD.7 Roflumilast is an innovative oral anti-inflammatory drug with a unique mechanism to treat severe, and very severe COPD associated with chronic bronchitis in adult patients with recurrent episodes of exacerbations. This may contribute to a decrease in the consumption of various health resources, such as hospital admissions, examinations, and additional medication. Roflumilast is used as an add-on drug with a bronchodilator, having an adjuvant effect in this group of patients. The intended effect of roflumilast to-date is to reduce the risk of exacerbation in COPD patients. Based on its anti-inflammatory effects, the drug has a mild indirect effect on improving lung function. Due to its oral use, roflumilast is distributed to the lungs via systemic circulation and therefore may be able to reach lower airway inflammation, which can be out of range from inhaled medications, particularly in patients with a high degree of obstruction and mucus production. Roflumilast, due to being an oral treatment taken on a daily basis, may have an added favorable impact on the overall adherence to therapy of COPD.8 A meta-analysis of eleven clinical trials (N=9,675 COPD patients) in which roflumilast was compared to a placebo (with or without other pharmacological therapies), and whose primary endpoint also included exacerbation rates, found that roflumilast significantly decreased the mean exacerbation rate by 23%.9 Phase II (AURA) and Phase III (HERMES) clinical trials reported that treatment with roflumilast in order to prevent one moderate or severe exacerbation per year was 5.29 and 3.64, respectively (NNT, number of patients needed to treat to prevent one exacerbation),10 a lower value than the NNT for statins in the secondary prevention setting, which ranges from 8 to 28 in a timeframe of 5 years.11 However, further studies are necessary to increase the robustness of these observed findings. The React study showed that roflumilast reduced exacerbations and hospital admissions in patients with severe COPD and chronic bronchitis, who were at risk for frequent and severe exacerbations, despite undergoing inhaled corticosteroid and long-acting β2-agonist therapy, even in combination with tiotropium.12 That approximately 5 million Brazilians over a 40 year period have COPD, and that the public health system only provides treatment for 319,166 patients,2 emphasizes the under treatment of COPD in Brazil. According to this estimate, the number of severe to very severe patients eligible for roflumilast in Brazil would be approximately 21,449 patients.13 Sales data obtained indicate that 106,462 units of roflumilast were sold from June 2011 (launching) to November 2014 (personal communication, Takeda Pharmaceutical Company, 2014), to the approximately 3,000 patients treated during this period. Considering that the roflumilast target in Brazil is 21,449 patients, approximately 14% of the targeted population are being treated so far. Other drugs available for the treatment of stable COPD, which are provided free of charge through the Brazilian public health system so long as a patient meets the clinical protocol are: ipratropium bromide, salmeterol, formoterol, budesonide, and fluticasone. Roflumilast and long-acting anti-muscarinic drugs are not on the list of medicines provided free through the public health system. Patients with the exacerbator phenotype are treated with the combination of inhaled corticosteroids and long-acting β2-agonists. This explains why only 14% of patients who would benefit from taking roflumilast in Brazil are utilizing this drug. In addition, the relatively high price (US$35.00; 8% of minimum monthly wage), which is expensive for the average Brazilian population, and the gastrointestinal side effects that some patients have,9 collaborate to its underutilization. We may conclude that one of the reasons for the low rate of roflumilast use in Brazil may be that it has not yet been included on the formal public health system list for free drug distribution.14 In addition, the relatively high cost of the drug in regards to the average Brazilian’s income may also be another reason. However, there is high potential for its use, in light of the significant percentage of the exacerbator phenotype among the severe and very severe COPD patients in the Brazilian population.

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          Most cited references 10

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          From COPD to chronic systemic inflammatory syndrome?

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            Chronic obstructive pulmonary disease is an independent predictor of death but not atherosclerotic events in patients with myocardial infarction: analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT).

            Chronic obstructive pulmonary disease is an independent predictor of mortality in patients with myocardial infarction (MI). However, the impact on mode of death and risk of atherosclerotic events is unknown. We assessed the risk of death and major cardiovascular (CV) events associated with chronic obstructive pulmonary disease in 14 703 patients with acute MI enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) trial. Cox proportional hazards models were used to evaluate the relationship between chronic obstructive pulmonary disease and CV outcomes. A total of 1258 (8.6%) patients had chronic obstructive pulmonary disease. Over a median follow-up period of 24.7 months, all-cause mortality was 30% in patients with chronic obstructive pulmonary disease, compared with 19% in those without. The adjusted hazard ratio (HR) for mortality was 1.14 (95% confidence interval 1.02-1.28). This reflected increased incidence of both non-CV death [HR 1.86 (1.43-2.42)] and sudden death [HR 1.26 (1.03-1.53)]. The unadjusted risk of all pre-specified CV outcomes was increased. However, after multivariate adjustment, chronic obstructive pulmonary disease was not an independent predictor of atherosclerotic events [MI or stroke: HR 0.98 (0.77-1.23)]. Mortality was significantly lower in patients receiving beta-blockers, irrespective of airway disease. In high-risk patients with acute MI, chronic obstructive pulmonary disease is associated with increased mortality and non-fatal clinical events (both CV and non-CV). However, patients with chronic obstructive pulmonary disease did not experience a higher rate of atherosclerotic events.
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              Acute coronary syndromes in the GUSTO-IIb trial: prognostic insights and impact of recurrent ischemia. The GUSTO-IIb Investigators.

              Recurrent ischemia after an acute coronary syndrome portends an unfavorable outcome and has major resource-use implications. This issue has not been studied systematically among the spectrum of patients with acute coronary presentations, encompassing those with and without ST-segment elevation. We assessed the 1-year prognosis of the 12 142 patients enrolled in the GUSTO-IIb trial by the presence (n=4125) or absence (n=8001) of ST-segment elevation. This latter group was further categorized into those with baseline myocardial infarction (n=3513) or unstable angina (n=4488). We also assessed the incidence of recurrent ischemia and its impact on outcomes. Recurrent ischemia was significantly rarer in those with ST-segment elevation (23%) than in those without (35%; P<0.001). Mortality at 30 days was greater among patients with ST-segment elevation (6.1% versus 3.8%; P<0.001) but less so at 6 months; by 1 year, mortality did not differ significantly (9.6% versus 8.8%). Patients with non-ST-segment-elevation infarction had higher rates of reinfarction at 6 months (9.8% versus 6.2%) and higher 6-month (8.8% versus 5.0%) and 1-year mortality rates (11.1% versus 7.0%) than such patients who had unstable angina. Refractory ischemia was associated with an approximate doubling of mortality among patients with ST-segment elevation and a near tripling of risk among those without ST elevation. This study highlights not only the substantial increase in late mortality and reinfarction with non-ST-segment-elevation infarction but also the opportunities for better triage and application of therapeutic strategies for patients with recurrent ischemia.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                08 September 2015
                : 10
                : 1853-1855
                [1 ]Department of Respiratory Diseases, Santa Casa School of Medical Sciences in São Paulo, Federal University of São Paulo, HospitalSão Paulo, São Paulo, Brazil
                [2 ]Departmentof Respiratory Diseases, Escola Paulista de Medicina, Federal University of São Paulo, HospitalSão Paulo, São Paulo, Brazil
                Author notes
                Correspondence: Roberto Stirbulov, Department of Respiratory Diseases, Santa Casa School of Medical Sciences in São Paulo, Rua Dr José Ferraz de Oliveira 100, São Paulo 04645-010, Brazil, Email stirbulov@
                © 2015 Stirbulov and Jardim. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.


                Respiratory medicine


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