国立保健医療科学院 保健医療経済評価研究センター
Center for Outcomes Research and EconomicEvaluation for Health (C2H), National Institute of
Public Health (NIPH) | URL: http://c2h.niph.go.jp

June 1st, 2021

[C2H1906] Summary of cost-effectiveness evaluationof Ivabradine (Coralan)
1. Indications
Chronic heart failure with resting heart rate 75 and above at the time of initialadministration
2. Price of drug
Ivabradine was reimbursed from November 2019 for JPY 82.9 (2.5 mg), JPY 145.4(5 mg), and JPY 201.9 (7.5 mg) as of May 2021. The price was calculated using asimilar efficacy comparison method, with a usefulness premium of 35%. This productwas designated as an H2 cost-effectiveness evaluation item.
3. Scope of cost-effectiveness evaluation
This product is a hyperpolarization-activated cyclic nucleotide–gated (HCN) channel
blocker and has indications for patients with chronic heart failure who receive
standard drug therapy including β blockers. The first session of the Expert Committeeof Cost-Effectiveness Evaluation (ECCEE) determined that the target population
should be chronic heart failure patients receiving β blockers, angiotensin-converting
enzyme(ACE)inhibitors,

orangiotensin

receptor

blockers(ARBs)

andmineralocorticoid receptor antagonists (MRAs). As ivabradine is used as an add-on to
the standard therapy, only standard therapy (placebo) was selected as a comparator.

Targetpopulation
Comparator

Chronic heart failure patients receiving β blockers, ACE inhibitors
or ARBs and MRAs. Their left ventricular ejection fraction is 35%
and below, and resting heart rate is 75 and above
Only standard therapy (placebo)4. Evaluation of additional benefits
The manufacturer identified eight clinical trials which evaluated the efficacy andsafety of ivabradine by systematic review (SR). Six trials were excluded because
they were abstracts for academic conferences. Only the literature on the SHIFT trial
and J-SHIFT trial was included. The academic group extended the SR search period
and researched based on the manufacturer’s submission. As a result, 23 publications
were detected, of which 22 publications were based on the SHIFT trial and post-hoc
analysis of the SHIFT trial, and one was related to the J-SHIFT trial. The analysis ofthe academic group was consistent with the manufacturer’s submission.
According to the J-SHIFT trial, 66% (82/124) and 73% (90/123) of patients
received 15 mg of ivabradine per day, 4 weeks and 6 weeks after randomization,respectively. In comparison, in the actual clinical setting, more than half of all
patients received only 2.5 mg or 5 mg of ivabradine per day, as estimated by theNational Claims Database. The dose was much lower than that of the clinical trial.
Therefore, the academic group questioned whether the clinical trial data can beextrapolated to calculate effectiveness in the actual clinical setting.
DoseNumber of patients

2.5 mg505 mg341

7.5 mgLess than 1010 mg

186

12.5 mg

Less than 1015 mg

4320 mg

Less than 10The SHIFT trial and J-SHIFT trial showed that ivabradine reduced the risk of cardiac
death. However, further consideration of the applicability of the clinical trial is needed
if the actual dose is significantly different from the dose administered in the clinical
trial. After the completion of this evaluation, monitoring of the dose should becontinued and the product should be reevaluated if necessary.
5. Result of cost-effectiveness analysis
The manufacturer estimated cost-effectiveness using the Markov model. Theacademic group insisted that this analysis should be revised based on the followingcomments. The third session of the ECCEE agreed with the academic group.

･ The manufacturer used 59.59 as the age of the target population based on theSHIFT trial. However, it is possible that patients enrolled in the clinical trial wereyounger than actual patients. The academic group estimated the actual age to be
68.76 through the National Claims Database. Therefore, this age was used for thecost-effectiveness analysis.
･ The manufacturer assumes that the administration of ivabradine improves qualityof life (QOL) even if it does not recover cardiac function. As this is not clinicallysupported, it is possible that this assumption leads to an overestimation of costeffectiveness. Therefore, this effect should be regarded as zero, and costeffectiveness recalculated based on this setting.
The result of the cost-effectiveness analysis reflecting these comments fromthe academic group is shown below.
Comparator

ICER (JPY/QALY)

Only standard therapy (placebo)

3,568,905

However, if the dose of ivabradine is significantly different between clinical trials andthe actual clinical setting, and it raises questions about the applicability of the clinical
trial data, the above ICER is not guaranteed.