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REPORT 212
Ivabradine for the treatment of
moderate to severe chronic heart
failure in subjects with heart rate ≥ 70
bpm and who tolerate less than 50%
of the recommended target dose of
beta-blockers
Ordinance no. 19/2016 – Published on 05/24/2016
EXECUTIVE SUMMARY
Technology: Ivabradine hydrochloride (Procoralan®)
Indication: Treatment of chronic heart failure
Applicants: Servier® and Fundação Zerbini – Instituto do Coração – Hospital das Clínicas of Medicine School of
Universidade de São Paulo (INCOR – HCFMUSP).
Background: Chronic heart failure is a complex and progressive systemic syndrome characterized by impaired
tissue perfusion, with typical symptoms of dyspnea, fatigue, in addition to worsened quality of life. This
syndrome is related to high mortality and hospitalization rates. Ivabradine is a prototype drug acting in heart
rate and which has been recently approved for the treatment of chronic heart failure associated with betablockers in subjects in the later stages of the disease and who keep a high heart rate even on treatment with the
maximum tolerated doses of these drugs.
Question: “Is the combination of ivabradine and conventional treatment with beta-blockers efficient and safe
for the treatment of patients with chronic heart failure when compared with the treatment with beta-blockers?”
Scientific evidence: Fifteen studies were evaluated, among those a double-blind, randomized, placebocontrolled clinical trial in which 6,500 subjects with chronic heart failure NYHA functional classification II to IV
and heart rate ≥ 70 bpm were enrolled. The treatment with ivabradine at an average dose of 6 mg twice daily
combined to beta-blockers for 23 months reduced the risk of hospitalization due to a worsening in heart failure
of 26%, to which a NNT of 20 (CI 95% 15 to 31) is associated. The drug has not shown effect in primary outcome
of mortality due to cardiovascular causes, as a reduction in all-cause mortality risk was not observed either. A
reduction in mortality risk due to heart failure, the secondary outcome, was noted, although this was associated
to an important inaccuracy due to low event rates and the wide confidence interval (NNT 83, CI 95% 52 to 333).
Through other studies, it is suggested the drug has effects in reversing the cardiac remodeling associated with
disease progression, reducing the heart failure-related biomarkers and diminishing the cardiac afterload,
improving the ventricular functioning and atrioventricular coupling, however without interfering in renal
function. Effects in heart rate lowering and heart frequency variation were identified. The use of the drug is
associated with a NNH of 58 (in a two-year period) in relation to atrial fibrillation outcome in subjects with a
heart rate higher than 70 bpm.
Economic evaluation: The applicant has submitted a cost-effective analysis in SUS perspective by the Markov
model, which compared the progression of subjects with chronic heart failure and heart rate over 75 bpm
treated for 15 years with ivabradine (7.5 mg twice daily) combined with beta-blockers or beta-blockers at the
maximum tolerated doses. For the outcome of life years saved, the RCEI was BRL 9,571.62 per year of life saved.
For this outcome, the technology is more efficient but also more expensive. The RCEI for the secondary outcome
of total hospitalizations was BRL 18,015.51 per hospitalization avoided.
Budget Impact Analysis: The budget impact of a potential incorporation of ivabradine to SUS was estimated for
three scenarios with different treatment access rates. In the first and lower scenario, the impact would be of 13
million for 2015 and 430 million for all the five years. In the second and third scenarios (intermediate and high),
the values for the first year would be BRL 13 million and BRL 80 million and, for five years, would be BRL 540 and
BRL 800 million, respectively.
Discussion: The main benefit of the drug, whose effect was evaluated by high quality evidence, is to avoid
hospitalizations due to worsening in heart failure. The relative effect is a reduction of 26% when compared with
the use of beta-blockers alone. However, even for the outcome of higher benefit, the absolute effect is still too
low, achieving a reduction of 4.9% only. For other hospitalization outcomes, the absolute effect is even lower
and more imprecise. There was no effect in mortality, since the use of the drug had no effect in the outcomes of
all-cause mortality and mortality due to cardiovascular causes. The statistically significant effect observed for a
reduction in heart failure mortality has emerged from a low quality measure and, therefore, an effect of low
reliability and quite liable to change in future works. The drug increases the risk of atrial fibrillation, with a NNH
of 83. The economic analysis results are fragile and arise from imprecise information, mainly on the quantitative
estimate of population eligible to treatment with ivabradine.
CONITEC’s Recommendation: CONITEC members present at the 43rd meeting of the plenary session held on
March 02 and 03, 2016 have appreciated the proposal and, based on the evidence submitted, the drug effect
has shown to be too minimal and limited to a reduction in hospitalizations with an increased risk of atrial
fibrillation. Therefore, the plenary session has unanimously decided on the preliminary recommendation
unfavorable to incorporation. The subject matter will be made available in a Public Consultation with preliminary
recommendation unfavorable.
Public Consultation: Public consultation No. 5 of March 11, 2016, regarding the proposal of incorporation in the
Unified Health System of ivabradine for the treatment of moderate to severe chronic heart failure in subjects
with heart rate ≥ 70 bpm and who tolerate less than 50% of the recommended target dose of beta-blockers,
submitted by Laboratório Servier® do Brasil Ltda. and, with some changes, by the Hospital das Clínicas of the
Medicine School of USP in case records MS/SIPAR no. 25000.137272/2015-80 and MS/SIPAR no.
25000.181434/2015-17, respectively, was made between 03/14/2016 and 04/04/2016. Altogether 20
contributions were received, with 15 of those being “experience or opinion” form and 5 of “Technical-scientific
knowledge” form. Only the public consultation contributions submitted in the period stipulated and through the
CONITEC website in its own form were considered. The contributions were evaluated and described in such
report.
Final Resolution: The CONITEC members present at the plenary session meeting held on 04/07/2016 have
unanimously decided to recommend the non-incorporation of ivabradine combined with beta-blockers for the
treatment of moderate to severe chronic heart failure in subjects with heart rate ≥ 70 bpm and who tolerate less
than 50% of the recommended target dose of beta-blockers. The Registration of Resolution no. 182/2016 was
signed.
Decision: Do not incorporate ivabradine for the treatment of moderate to severe chronic heart failure in
subjects with heart rate ≥ 70 bpm and who tolerate less than 50% of the recommended target dose of betablockers, in the scope of the Unified Health System – SUS. Ordinance no. 19 dated May 24, 2016, was published.