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.