Economic impact of switching to fixed-dose combination therapy for Japanese hypertensive patients: a retrospective cost analysis
© Akazawa and Fukuoka; licensee BioMed Central Ltd. 2013
Received: 19 October 2012
Accepted: 25 March 2013
Published: 3 April 2013
The prescription of fixed-dose combinations (FDC) of antihypertensive drugs has increased rapidly since the relaxation of the prescription-term restriction.
In this study, we used the opportunity of this policy change in Japan as an instrument to assess the causal impact of switching to FDC on hypertensive treatment costs.
Claims data from 64 community pharmacies located in Tokyo were used to identify hypertensive patients under continuous treatment with angiotensin-receptor blockers (ARBs). Patients switching to FDC between December 2010 and April 2011 were compared to patients who did not receive FDC (control group). Changes in annual antihypertensive drug costs were compared using a difference-in-differences approach to adjust for patient characteristics and use of concomitant medication. Subpopulation analyses were also performed, taking into account pre-index treatment patterns and prescribers’ characteristics.
There were 542 patients who switched to FDC and 9664 patients in the control group. No significant differences were observed between the 2 groups, except for antihypertensive drug use patterns before the policy change and prescribers’ characteristics. The switch to FDC was associated with an annual saving of 10,420 yen (US$112.0) in antihypertensive drug costs. Approximately 20% of the FDC patients, however, switched from ARB alone, and their drug costs increased by 2376 yen (US$25.5).
For hypertensive patients who required ARB-based combination therapy, switching to FDC drugs had a significant cost-saving effect. However, the policy change of relaxing the prescription-term restriction could encourage aggressive treatment, i.e., switching to a combination therapy from monotherapy, regardless of medical conditions. Further research is required to evaluate the possible negative aspects of FDC drugs.
KeywordsAntihypertensive drug Fixed-dose combination Economic benefit Drug costs Social experiment Switching
Aggressive antihypertensive treatment using a combination therapy that includes drugs with different mechanisms of action has been recommended as a means of achieving better blood pressure control [1–3]. Reflecting the clinical evidence, including the findings of the ACCOMPLISH study , an angiotensin-receptor blocker (ARB) together with a calcium-channel blocker (CCB) is the combination most frequently prescribed to Japanese hypertensive patients [5, 6]. For patients who have comorbidities such as hyperlipidemia, diabetes, and chronic renal disease, more aggressive treatment, with the addition of thiazide diuretics (i.e., hydrochlorothiazide or HCTZ) is provided to achieve therapeutic goals . Because those patients need to take multiple medications in a day, the complex regimen often affects the patients’ adherence to the treatments. Thus, fixed-dose combination (FDC) therapy becomes one option. Many studies suggested that simplifying drug regimens by reducing the number of pills may improve patient adherence, lower blood pressures, and save health service use and costs [8–15]. From the Canadian perspective, for example, a yearly estimated cost-saving of $27 to $45 million could be made when 60–100% of patients who had received 2 separate antihypertensive drugs switched to FDC products . On the other hand, many antihypertensive drugs are available as generic formulations, while most FDC products are available as brand-name drugs alone. In the United States, where generics have the biggest market share in the world, observational studies using various databases indicated that the pharmacy cost of treating hypertension would increase after a switch to FDC products [11, 14, 17]. This increase cannot be ignored from the patients’ perspective, because their out-of-pocket costs vary according to their insurance status .
NHI price list of antihypertensive drugs
Listed price as of April 2012
Listed date of FDC drugs
losartan (50 mg) + hydrochlorothiazide (6.25 mg)
valsartan (80 mg) + hydrochlorothiazide (6.25 mg)
candesartan (8 mg) + hydrochlorothiazide (6.25 mg)
telmisartan (40 mg) + hydrochlorothiazide (6.25 mg)
valsartan (80 mg) + amlodipine (5 mg)
olmesartan (20 mg) + azelnidipine (16 mg)
candesartan (8 mg) + amlodipine (5 mg)
telmisartan (40 mg) + amlodipine (5 mg)
losartan (50 mg)
valsartan (80 mg)
candesartan (8 mg)
telmisartan (40 mg)
olmesartan (20 mg)
hydrochlorothiazide (25 mg)
amlodipine (5 mg)
azelnidipine (16 mg)
In Japan, newly listed drugs can be prescribed only in quantities sufficient for 14 days’ treatment ; therefore, patients have to visit their doctors repeatedly to get their prescriptions. This dispensing-day restriction is removed 1 year after launch, except for narcotic and psychotropic drugs. In a survey of 490 Japanese doctors, over 80% responded that the 14-day dispensing rule influences their choice of treatment . Considering their patients’ inconvenience, doctors often hesitate to prescribe new medications if there are other options, especially when they are treating conditions that require continuous management, such as hypertension. Thus, the market penetration of new drugs can be somewhat limited by this restriction. In the case of FDC drugs, however, Japan’s Central Social Insurance Medical Council (Chuikyo) decided that, because the clinical experience of each individual drug was sufficient, the14-day dispensing rule could be relaxed  and long-term prescriptions of all FDC antihypertensive drugs, even those newly listed, have been allowed since December 10, 2010. This policy change appeared likely to influence doctors’ prescribing behavior, so that the number of prescriptions of FDC drugs would increase rapidly immediately after this restriction was removed. In some cases, doctors might switch antihypertensive drugs regardless of medical conditions that required more aggressive treatments to control blood pressure.
In many previous studies that evaluated the benefits of FDC drugs, annual medical and drug costs were compared in patients who used FDC drugs and those without FDC drugs. To minimize potential selection bias, patient background characteristics were adjusted using propensity score and/or multivariable regression techniques [9, 13, 15, 17]. Because limited information is available in healthcare databases, unobservable confounding cannot be eliminated. Therefore, using this policy change in Japan as an instrument that would be endogenous for doctor preference and patient case-mix, we tested the hypothesis that switching to FDC drugs actually reduces antihypertensive drug costs, using a real world prescription record in Japan.
Nihon Chouzai is a large community pharmacy chain that has 457 dispensing pharmacies throughout Japan. We used its pharmacy claims database to extract data for patients who were prescribed ARBs continuously (i.e., who had dispensing records of an ARB at least every 4 months between December 2009 and March 2012) from pharmacies located in the Tokyo area (64 branches). The information stored in the database includes anonymous identification codes of patients, pharmacies, and institutions; patients’ age and gender; dispensing date; drug name (brand and general names, and unique identification code, called the “YJ code”); and drug price, dose, and duration (dispensing days).
Study population and design
The main outcomes of interests were the annual antihypertensive drug costs before and after the index date. The drug costs were summed over the 1-year interval prior to the index date (as pre-index costs) and over the 1-year interval after the index date (as post-index costs), including all prescriptions dispensed within the respective intervals. The annual costs were then calculated by adjusting for differences between 365 days and the actual follow-up days from which the costs were derived. Antihypertensive drugs included were ARBs, angiotensin-converting enzyme (ACE) inhibitors, dihydropyridine CCBs, thiazide diuretics (HCTZ), beta-blockers, alpha-beta blockers, and the FDC drugs. The study design is illustrated in Figure 1, which shows an example of how the timeframe was defined. Information about gender, age categories (≤64 years, 65–74 years, and ≥75 years), the number of drugs taken (use of ≥7 drugs), use of a diabetes drug, and use of a hyperlipidemia drug was extracted from the prescription records during the 4-month time window to create variables that would represent the patients’ background characteristics. As for prescribers’ characteristics, institutions where the prescriptions at the index date were issued were classified into 2 and variables indicating clinic (no bed) or hospital, as well as cardiovascular specialists or others, were created.
The prescription pattern of the FDC drugs was summarized as the ratio of the FDC prescriptions per month to the total ARB prescriptions (including FDC drugs) per month. A comparison of the patient characteristics (χ2 test) and annual antihypertensive drug costs (t-test) was made between the FDC drug users and the controls. Among the FDC drug users, the patients who switched from ARBs alone, those who had been taking both ARB and CCB in separate forms, those whose drugs were prescribed by doctors at clinics, and those whose drugs were prescribed by cardiovascular specialists, were selected as subgroups to compare the changes in antihypertensive drug costs. Because the dispensing fees paid to doctors by the NHI are based on the number of drugs prescribed, we evaluated the association between taking ≥7 drugs and switching to FDC drugs. Dispensing fees are discounted when ≥7 drugs are prescribed at the same time, as a disincentive to polypharmacy .
Estimated costs were expressed in yen (1 US$ = 93 yen as of February 14, 2013).
The impact of patient characteristics, including gender, age categories, number of concomitant drugs taken, diabetes treatment, and hyperlipidemia treatment, was adjusted using a multivariable regression method. The level of statistical significance was set at 5%. All statistical analyses were performed using SAS software version 9.3 (SAS Institute Inc., 2012, Cary NC USA). The study was approved by the Institutional Review Board at Meiji Pharmaceutical University (study number 2305) and was conducted in compliance with the Japanese Ethical Guidelines for Epidemiological Research, as updated in December 2008 .
With fixed-dose combination drugs (cases)
Without fixed-dose combination drugs (controls)
p (χ2 tests)
Number of patients
Drug use before index
ARB and CCB combination
Number of concomitant drugs
7 or more
Doctors at clinics (no bed)
Results of DID estimations of antihypertensive drug costs
Total patients n = 10,206
ARB and CCB combination before index n = 5674
ARB alone before index n = 4042
Prescribed by doctors at clinics n = 1104
Prescribed by cardiovascular specialists n = 2629
This study provides evidence that switching to FCD drugs reduces the annual cost of antihypertensive treatments. In particular, for patients treated with a combination of ARB and CCB in separate forms, the estimated annual savings are of the order of 12,800 yen. On the other hand, one-fifth of the patients switched from a single ARB pill to the FDC drug during the time window. This suggests that relaxing the 14-day dispensing rule may trigger more aggressive treatment to achieve better blood pressure control and could increase annual drug costs in such cases by 2400 yen.
A number of studies have indicated that switching to FDC drugs improves medication adherence [10, 28–30]. However, we could not confirm this benefit using pharmacy claims data in Japan. Because patients visited the doctor’s office regularly and received medications according to a schedule, the medication possession ratio (MPR) —which is defined as the total days of supply of drugs during the study period divided by the length of the follow-up period and is often used to measure adherence in claims-based studies  —was almost 100% for most patients, regardless of whether they actually took the medications as indicated or not. In April 2012, the NHI reimbursement rule for dispensing fees was revised in order to increase the pharmacists’ responsibility for checking for unused drugs and adjusting the quantity of drugs dispensed [25, 32]. When patients receive medications only as necessary, the MPR method can be used to monitor their medication adherence using the claims.
We assumed that doctors might have an incentive to use the FDC drugs so as to reduce the number of medications. According to Japan’s NHI reimbursement rule, doctor’s prescription fees are 400 yen for prescribing ≥7 drugs compared with 680 yen for prescribing ≤6 drugs. We identified 12% of the study population who had a prescription for ≥7 drugs. A sub-analysis targeting only those patients (data not shown) showed that the proportion who switched to FDC drugs and the impact on drug costs were almost the same as in the total study population. This finding suggests that doctors do not care about prescription fees; therefore, the switch may occur regardless of the number of medications that are prescribed at the same time.
The change in the dispensing rule encouraged the use of an FDC drug. Due to the NHI pricing rule for ARB combination drugs (approximately 80% of the individual drugs), for most patients the switch resulted in a cost saving. However, some cases switched from treatment with ARB alone, resulting in an increased cost. If these prescription changes occurred due to promotion of the new drugs, rather than to medical need, the economic benefits of switching need to be examined with care. It should also be noted that a generic version of the ARB losartan was introduced in June 2012 at prices 45% below those of the corresponding branded medication (45.3 yen for 20 mg, 86.0 yen for 50 mg, and 129.0 yen for 100 mg). Under Japanese dispensing rules, generics can be dispensed by pharmacists without the doctor’s permission, unless the prescription form specifies that there should be no generic substitution . However, once a patient has switched to an FDC, a further change to generics is unlikely, because the pharmacist would need to ask the doctor to rewrite the prescription to show the ARB and other medication separately before dispensing the generic substitutions—a rather unrealistic scenario. Thus, as our estimates suggest that the maximum cost saving from switching to FDC drugs was 17%, greater savings can be expected if patients continue to use separate ARB and CCB medications and switch to the generic forms when they become available. These effects need to be monitored constantly using pharmacy claims.
This social experiment examined the economic impact of switching to FDC antihypertensive treatment in terms of the benefit to the patient. However, because some patients actually switched to the aggressive treatment because of their medical needs, the effects we observed could be biased toward either direction. In addition, we had access only to prescription records at community pharmacies, whereas no clinical information, such as diagnosis and blood pressure, was available. Thus, the results should be adjusted for lifestyle diseases that might influence the treatment costs, incorporating variables corresponding to the use of drugs for diabetes and hyperlipidemia. Furthermore, patients may visit different pharmacies to obtain their medications and this would not have been apparent from the available pharmacy data. However, because the MPR was calculated as 100% for many patients, these misclassifications might be negligible. The DID approach was used to evaluate the effect of policy changes using claims data . In addition, we could adopt a time-series approach, using monthly records of claims to compensate for the inherent limitation of unmeasured variables, especially targeting cases who switched from ARB alone to the FDC drugs .
There are economic benefits from using combination pills when the switch occurs from combination therapy with the same drugs in separate forms. However, the introduction of the combination pills may result in aggressive but unnecessary treatment. Further research is needed to evaluate the economic impact of the combination pills by considering the introduction of antihypertensive generics in the future market.
Medication possession ratio
National health insurance
This study was conducted as a research project in a community pharmacy research group of the Japanese Society for Applied Therapeutics. We would like to thank Dr. Hiroyasu Ogata, chairperson of the society, for his contributions to obtaining data and providing technical advice for this research project. A research grant from the Ministry of Health, Labour and Welfare was used for a part of this study.
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