hon p.1 [100%]YAKUGAKU ZASSHI 130(12) 1725―1736 (2010)  2010 The Pharmaceutical Society of Japan

1725―Regular Article―

Cost-eŠectiveness Analysis of Pre-seasonal Medication for Cedar Pollinosis in Japan
Kazuhiro TAMAYAMA,a,b Shu-Ling HOSHI,a Masahide KONDO,,a and Ichiro OKUBOa
aDepartment of Health Care Policy and Management, Graduate School of Comprehensive Human Sciences,

University of Tsukuba, 111 Tennoudai, Tsukuba, Ibaraki 3058577, Japan, and bHealth and Welfare
Division, Yokohama City Totsuka Public Health and Welfare Center, 1573 Totsuka-cho,
Totsuka-ku, Yokohama, Kanagawa 2440003, Japan(Received February 1, 2010; Accepted August 28, 2010)
Pre-seasonal medication is recommended for cases of cedar pollinosis that are expected to manifest severe symptoms during the season, according to the standard clinical guideline in Japan. This study aims to appraise the value formoney of additional costs that accompany the choice of pre-seasonal medication from payer's perspective. Based on the
12 reports of controlled clinical trials with Symptom Score (SS) and Medication Score (MS) comparing pre-seasonal
medication with intra-seasonal symptomatic medication, 15 incremental cost-eŠectiveness ratios (ICERs) and 4 integrated ICERs of each group of targeted agents are estimated. Incremental eŠects are estimated by reading SS charts,
and incremental costs are estimated by reading MS charts and using National Health Insurance Medical Fee Scheduleand National Health Insurance Drug Price Standard. Estimated ICERs range from ¥322,195 per quality-adjusted lifeyear (QALY) to ¥57,088,063 per QALY. Integrated ICERs are: ¥1,128,286 per QALY for 2nd generation histamine H1
receptor antagonists, ¥2,248,018 per QALY for leukotriene receptor antagonists, ¥2,692,911 per QALY for prostaglandin D2 and thromboxane A2 receptor antagonists, ¥1,150,943 per QALY for Th2 cytokine suppressors, and ¥1,291,341
per QALY for all agents. Pre-seasonal medication for cedar pollinosis is cost-eŠective regardless of the choice of theprophylactic agent among 2nd generation histamine H1 receptor antagonists, leukotriene receptor antagonists,
prostaglandin D2 and thromboxane A2 receptor antagonists, or Th2 cytokine suppressors, taking the suggested thresholdof ¥5,000,000 per 1 QALY gain in Japan. The use of 2nd generation histamine H1 receptor antagonists and Th2 cytokine
suppressors are found more favourable.
Key words―cedar pollinosis; cost-eŠectiveness; health care expenditure; pre-seasonal medication; seasonal allergic
rhinitis (SAR)

INTRODUCTION
Seasonal allergic rhinitis is one of the most prevalent diseases in Japan. The pollen of Japanese cedarthat scatters about in the air during the months ofJanuary to May is the most common allergen, causing
26.5％ of the nation to suŠer from cedar pollinosis
every year.1) A remarkably high morbidity raises concern about health care resources used in controllingthe disease. Health care expenditure for cedar pollinosis has been estimated at ¥198,600 million2) to¥286,000 million3) annually.
There are several coping strategies and treatment
modalities against allergic rhinitis such as patientcommunication, elimination or avoidance of allergen,
medication, speciˆc immunotherapy, and surgicaltreatment. According to the standard clinical guideline,4) pre-seasonal oral medication is recommended
for cases of cedar pollinosis that are expected toe-mail: mkondo＠md.tsukuba.ac.jp

manifest severe symptoms during the season. However, whereas better clinical outcomes are expected, taking pre-seasonal medication for prophylaxis implies aheavier total dose over the season compared to intraseasonal symptomatic medication.
From the viewpoint of health economics, it is imperative to appraise the value for money of additionalcosts that accompany pre-seasonal medication.
Therefore, we carry out a cost-eŠective analysis ofchoosing pre-seasonal medication instead of symptomatic medication in treating cedar pollinosis. The
results should inform us whether the choice of preseasonal medication is justiˆable as an e‹cient use of
ˆnite resources for health care. It would contribute torealise the e‹cient management of the disease, as well
as deepen our understanding of resource implicationsof preventive care.
MATERIALS AND METHODS
We conduct a cost-eŠectiveness analysis from thepayer's perspective based on the reports of clinical tri-hon p.2 [100%]1726

Vol. 130 (2010)

als of pre-seasonal medication for cedar pollinosis.
Social insurers and patients are regarded as payers.
Comparison
We compare the choice of preseasonal medication instead of intra-seasonal symptomatic medication with the incremental cost-eŠectiveness ratio (ICER).
Incremental_cost
ICER＝Incremental_eŠect
CostPre-seasonal_treatment－CostSymptomatic_treatment＝
EŠectPre-seasonal_treatment－EŠectSymptomatic_treatment
Controlled Clinical Trials
We carry out a systematic and deliberate literature search of electrical
databases: ``Japana Centra Revuo Medicina'' and``Medline'', with key words such as ``allergic rhinitis'', ``pollinosis'', ``prophylactic'', ``early phase'',or ``pre-seasonal'', which produce 142 reports of controlled clinical trials of medication for cedar pollinosis. Controlled trials comparing pre-seasonal oral
medication with intra-seasonal symptomatic oral
medication are included in our analysis if the results
are reported in a form of Symptom Score (SS) and
Medication Score/Symptom-Medication Score (MS/SMS) deˆned in the latest Japanese Guideline,4) since
SS corresponds to the clinical outcomes or MS/SMS
to the health care resource use.

Fig. 1.

Figure 1 is a ‰owchart showing the inclusion andexclusion of identiˆed reports of trials. Fifty six trials
in accordance with the Japanese Guideline ver. 2(1994) and earlier, in which SS and MS/SMS are
diŠerent from one in the latest Japanese guideline ver.
6 (2009) are excluded, since we plan to use SS/MS/
SMS in our outcomes estimation and costing. Twenty
six trials comparing between agents of pre-seasonal
medication or between agents of intra-seasonal symptomatic medication are excluded, since these comparisons are not under our consideration. Four trialsof nasal drops or eye drops only are excluded, since
only oral medications are recommended for preseasonal medication in the guideline. Twenty seventrials not employing SS as a measure of endpoint are
excluded from 56 remained trials. Sixteen trials arefurther excluded, because presented results are notsu‹cient for our further analysis. Finally, the exclusion of duplicated publication results in the inclusionof 12 trials reports into this study.
The use of SS as a measure of outcomes in the clinical study of cedar pollinosis is recommended in theguideline,4) and it is used in half of the trials comparing pre-seasonal oral medication with intra-seasonal
symptomatic oral medication (29/56: 52％). Al-

Inclusion of Reports of Controlled Clinical Trials

hon p.3 [100%]

No. 12though it is not shown in Fig. 1, about half of the trials not employing SS as a measure of endpoint reportsub-scores for SS such as Sneezing Fit Score, Runny
Nose Score, or Nasal Congestion Score. This means
three quarters of the trials use, or at least partiallyuse, the recommended SS/MS/SMS system. Therefore, we consider that our use of SS/MS/SMS as oneof the major inclusion criteria is acceptable, eventhough the number of ˆnally included reports, twelve,
is relatively small. The rest of the trials, about aquarter of all, employ Japanese Rhino-conjunctivitis
Quality of Life Questionnaire (JRQLQ),5) MOS
Short-Form 36-Item Health Survey (SF-36),6) etc. asa measure of outcomes.
Table 1 lists twelve identiˆed reports of trials.718)
All of them are non-randomised trials, while there is
no report of trials with random assignment. The assignment of patients is subject to the timing ofpatients' voluntary ˆrst visit to clinics only, i.e., before or during the season, except Shimizu et al.
(2005)15) and Hirata et al. (2004),17) which are threearm trials with two types of interventions. In Shimizu
et al. (2005),15) patients visiting the clinic before theseason are assigned to a combined therapy, ``withsteroid nasal drop'' group if they were heavily symptomatic in the previous year, or otherwise to a single
agent therapy, ``without steroid nasal drop'' group.
In Hirata et al. (2004),17) patients visiting the clinic
for more than two weeks before the season are assigned to a ``long course'' group, while those visiting
less than two weeks before the season are assigned toa ``short course'' group. And Hamajima et al.

Fig. 2.

1727(2006)13) report two comparisons, one in 2002 season
and another in 2006 season. Therefore, we estimate a
total of 15 ICERs for all comparisons.
Seven713) report the use of 2nd generation histamine H1 receptor antagonists; two14,15) report leukotriene receptor antagonists; one16) reports prostaglandin D2 and thromboxane A2 receptor antagonists;
and two17,18) report Th2 cytokine suppressors asprophylactic agents. As a prior meta-analysis of theeŠectiveness of pre-seasonal medication summarises
eŠect size by the type of agent,19) we also estimate integrated ICERs for each group of targeted agent andall agents.
Outcomes Estimation
SS is used for calculating
incremental eŠect in terms of quality-adjusted lifeyears (QALYs). The QALY is one of the recommended measures of outcomes in cost-eŠectivenessanalysis.20) Especially, its use can be justiˆed whenhealth related quality of life is the important outcome, such as treatment of arthritis, which is expected to have no impact on mortality.21) In the sameway, cedar pollinosis is not a lethal disease and alleviation of unpleasant symptoms is most important in
the treatment. Figure 2 illustrates the calculation ofincremental eŠect in terms of QALYs by reading SS
charts. Patients' health states during the season measured in SS are converted into utility weights according
to Tamayama et al. (2009).22) Outcomes gain ismeasured as areas between courses followed by the
pre-seasonal medication group and the control groupduring the season.
Incremental eŠects are integrated for each group of

Calculation of Incremental EŠect in Terms of QALYs

The right panel is an example of the result of a controlled trial presented with SS chart. Area A and area C show gains in outcomes and area B a loss by preseasonal medication. The left panel is a function converting SS to utility weights. We calculate the outcomes gain according to the deˆnition of QALYs: a sum of life
C in the right panel are measured after the conversion of SS to utility
years with certain levels of health related quality of life measured in utility weights. Areas A
weights based on the left panel as shown in-between the panels. SS; symptom score.

27 cases with pre-seasonal bepotastine besilate (dosage not stated)
37 cases with intra-seasonal symptomatic medication
44 cases with pre-seasonal bepotastine besilate (dosage not stated)
36 cases with intra-seasonal symptomatic medication

2003
2003
2003
2004
2002
2006

Hayashi et al.
(2004)9)

Yasumoto et al.
(2004)10)

Kawauchi et al.
(2003)11)

Ohta et al. (2006)12)

2005

2000
2002

Imai et al. (2005)16)

Hirata et al. (2004)17)

2005

2005

Shimuzu et al.
(2008)15)

2nd generation
histamine H1
receptor antagonists

67 cases with pre-seasonal suplatast tosilate 100 mg 3 times a day/200 mg twice a day
26 cases with intra-seasonal symptomatic medication

109 cases with pre-seasonal suplatast tosilate 100 mg 3 times a day (long course, 2 weeks)
57 cases with pre-seasonal suplatast tosilate 100 mg 3 times a day (short course, ＜2 weeks)
52 cases with intra-seasonal symptomatic medication

60 cases with pre-seasonal ramatroban 75 mg twice a day
41 cases with intra-seasonal symptomatic medication

26 cases with intra-seasonal symptomatic medication

Th2 cytokine
suppressors

Prostaglandin D2 andthromboxane A2 receptor antagonists

Leukotriene
receptor
54 cases with pre-seasonal suplatast tosilate 225 mg twice a day
13 cases with pre-seasonal suplatast tosilate 225 mg twice a day & steroid nasal drops (dosage not stated) antagonists

21 cases with pre-seasonal suplatast tosilate 225 mg twice a day
8 cases with intra-seasonal symptomatic medication

33 cases with pre-seasonal fexofenadine hydrochloride 60 mg twice a day
33 cases with intra-seasonal symptomatic medication

29 cases with pre-seasonal olopatadine hydrochloride 5 mg twice a day
75 cases with intra-seasonal symptomatic medication

15 cases with pre-seasonal olopatadine hydrochloride 5 mg twice a day
15 cases with intra-seasonal symptomatic medication

11 cases with pre-seasonal olopatadine hydrochloride 5 mg twice a day
6 cases with intra-seasonal symptomatic medication

Type of agent

1728

Inagawa et al.
(2007)18)

2005

Miyanohara et al.
(2009)14)

Hamajima et al.
(2006)13)

26 cases with pre-seasonal fexofenadine hydrochloride 60 mg twice a day
23 cases with intra-seasonal symptomatic medication

2002

Yamashita (2004)8)65 cases with pre-seasonal olopatadine hydrochloride 5 mg twice a day
72 cases with intra-seasonal symptomatic medication

2002

Itagaki et al. (2003)7)

Comparison

SeasonReports of Controlled Clinical Trials of Pre-seasonal Medication Adopted for Cost-eŠectiveness Analysis

ReportTable 1.

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hon p.5 [100%]

No. 12targeted agent and all agents. Since QALYs are derived from SS chart readings, neither sample level data
nor variables representing error are available, any
typical statistical model of meta-analysis such as
Mantel-Haenszel method, Peto method or DerSimonian-Laird method are not applicable. We calculate weighted averages based on the total numbers ofsamples enrolled in each study for the purpose of integration. Ninety ˆve ％ conˆdence intervals are also
reported.
Costing
In the context of this study, costs
borne by patients or third party payers such as social
insurers are considered. Direct payments to healthcare providers by them are calculated as costs, while
the other type of opportunity costs, such as productivity losses, are left uncounted.
Amounts of health care provided to patients are estimated by reading MS/SMS charts and descriptionsof treatments in the reported trials, which are supplemented with the standard treatment suggested by
the guidelines at the time of trial. SMS is converted
into MS using corresponding SS. Since no monetarydata are reported in the 12 reports of controlled clinical trials, we separately estimate unit costs for these
according to National Health Insurance Medical Fee
Schedule23) and National Health Insurance Drug
Price Standard.24)
Unit costs, which are multiplied by the amounts ofhealth care provided, are shown in Table 2. Medical
fee includes consultation and prescription, whichranges from ¥1,740 to ¥5,547 per consultation depending on the type of consultation and the prescription. For example, it includes the initial visit fee/follow up visit fee, examination fee such as speciˆc IgE
test, prescription fee at clinics, and dispensing fee at
pharmacies. Additionally, patients are assumed tomake a weekly visit for Yamashita (2004),8) Yasumoto et al. (2004),10) Hamajima et al. (2006),13) Imai etal. (2005),16) and a biweekly visit for Itagaki et al.
(2003),7) Hayashi et al. (2004),9) Kawauchi et al.
(2003),11) Ohta et al. (2006),12) Miyanohara et al.
(2009),14) Shimuzu et al. (2008),15) Hirata et al.
(2004),17) Inagawa et al. (2007)18) based on theirdescriptions in the reports. The proportion of out-ofhouse prescription is set at 55.1％ according to Surveyof Medical Care Activities in Public Health Insurance
2008.25)
Daily drug prices of targeted agents range from¥126 to ¥296. Prices for additional drugs are calculat-

1729

ed as averages of daily prices of possible agents usedbased on the description in the reports supplemented
with the guidelines by the MS/SMS, which range
from ¥53 to ¥253.
Incremental costs are integrated for each group of
targeted agent and all agents in the similar way as incremental eŠects. We calculate weighted averages
based on the total numbers of samples enrolled ineach study. Ninety ˆve ％ conˆdence intervals arealso reported.
Integrated ICERs
In addition to 15 ICERs for
all comparisons based on the 12 reports of controlled
clinical trials, we calculate integrated ICERs for eachgroup of targeted agent and all agents deˆned as below:
Integrated_ICER
Weighted_average_of_Incremental_costs＝
Weighted_average_of_Incremental_eŠect
Discounting
Since the time horizon of our analysis is one season of cedar pollinosis, which is lessthan half a year, both eŠects and costs are not discounted.
Sensitivity Analysis
In order to deal with theuncertainty of estimated outcomes and costs, stochastic sensitivity analyses are performed. Assuming thatoutcomes and costs are subject to triangle distributions, of which bases range ±30％ of the estimatedvalue for 15 comparisons and 95％ conˆdence intervals for integrated ICERs, Monte Carlo simulations
are carried out with 1,000 iterations.
EŠect of Pollen Scattering
The association between total pollen counts in the air during the season
measured by Durham method and incremental costs/
incremental eŠects/ICERs are also analysed, since it
is commonly known that the severity of symptoms
and outcomes of treatments depend on the pollen level during the season.13,17,26) 2nd generation histamine
H1 receptor antagonists and all agents are separately
analysed taking the diŠerence in targeted agents into
account.
RESULTS
Outcomes
Table 3 shows the estimated outcomes. Incremental eŠects in terms of QALYs are
consistently positive, which suggests pre-seasonal
medication is more eŠective compared to intraseasonal symptomatic medication. Outcome gains
range from 0.00007 to 0.00857 QALY. These are equivalent to gaining 37 minutes to 75 days of living inolopatadine hydrochloride 139

190
190
275

fexofenadine

fexofenadine

bepotastine besilate
pranlukast hydrate
pranlukast hydrate
pranlukast hydrate＋SN

Yasumoto et al. (2004)10)

Kawauchi et al. (2003)11)

Ohta et al. (2006)12)

Hamajima et al. (2006)13)

Miyanohara et al. (2009)14)

suplatast tosilate

suplatast tosilate

Hirata et al. (2004)17)

Inagawa et al. (2007)18)
156

156

296

126

178

―

AAN/AHE/CARE

SN/SE/PTA＋nSN/PTA＋nSE/
229
LA＋nSN/LA＋nSE

180

―

56

56

65

AAN/AHE/CARE/2AH
127/PTA/LA

SN/SE/Th2＋nSE/Th2＋nSN/
LA＋nSE/LA＋nSN

SN/SE

SN/SE

2AH＋CARE/2AH＋AHE/2AH＋AAN/SN/SE

210

126

117

117

117

117

117

SN/SE/PTA＋nSN/PTA＋nSE/
Th2＋nSN/Th2＋nSE/LA＋nSN/ 225
LA＋nSE

SN/AAN＋AHE/AAN＋CARE

SN/AAN＋AHE/AAN＋CARE

SN/AAN＋AHE/AAN＋CARE

SN/AAN＋AHE/AAN＋CARE

SN/AAN＋AHE/AAN＋CARE

Additional agent for MS＝3

SN/SE/2AH＋AAN/2AH＋AHE
65/2AH＋CARE

bepotastine besilate

68

68

AAN/AHE/CARE/2AH
AAN/AHE/CARE/2AH

79

53

71

71

71

71

71

71

epinastine hydrochloride

2AH/AAN/AHE/CARE

AAN/AHE/CARE

AAN/AHE/CARE

AAN/AHE/CARE

AAN/AHE/CARE

AAN/AHE/CARE

AAN/AHE/CARE

Additional agent for MS＝2

5,547
3,367

MS1

Unit Costs

―

―

―

―

―

―

―

―

―

―

―

2AH＋SN/OCAR＋SN/SN＋AHE/
SN＋CARE/SE＋AAN/OS/2AH＋
AAN＋AHE/OCAR＋AAN＋AHE 60/2AH＋AAN＋AHE/2AH＋AAN＋CARE/OCAR＋AAN＋CARE

―

―

―

―

―

2AH＋SN/OCAR＋SN/SN＋AHE/
SN＋CARE/AHN＋SE/SE＋
OCAR/OS/2AH＋AAN＋AHE/
253
OCAR＋AAN＋AHE/2AH＋AAN＋CARE/OCAR＋AAN＋OCAR

―

―

―

AAN＋SE/SN＋AHE/SN＋CARE/
OS/OCAR＋AAN＋AHE/OCAR＋ 131
SN/OCAR＋SE―

Additional agent for MS＝4

1730

MS: medication score. SN: steroid nasal drop. AAN: antiallergic nasal drop. AHE: antihistamine eyedrop. CARE: chemical mediator antireleaser eyedrop. 2AH: 2nd generation antihistamine. PTA: Prostaglandin D2 andthromboxane A2 receptor antagonist. LA: Leukotriene receptor antagonist. SE: steroid eyedrop. nSE: non-steroid eyedrop. nSN: non-steroid nasal drop. OS: oral steroid. OCAR: oral chemical mediator antireleaser. Th2: Th2
cytokine suppressor

ramatroban

Imai et al. (2005)16)

Shimuzu et al. (2008)15)

olopatadine hydrochloride 139

Hayashi et al. (2004)9)178

olopatadine hydrochloride 139

Yamashita (2004)8)

Targeted agent

3,980
1,800

olopatadine hydrochloride 139

3,920
1,740

MS2

Out-of-house prescription

Itagaki et al. (2003)7)

ReportDrug price per day (¥)

Initial consultation
Follow-up consultation

MS＝1

In-house prescription

Medical fee per consultation (¥)

Table 2.

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Vol. 130 (2010)

hon p.7 [100%]

No. 12

1731

Table 3.

ReportCost (¥)
Weight Pre-season Intra-season(week)(week)

Itagaki et al. (2003)7)

137

Yamashita (2004)8)17

Hayashi et al. (2004)9)30

Yasumoto et al. (2004)10)

104

Kawauchi et al. (2003)11)

66

Ohta et al. (2006)12)

49

Hamajima et al. (2006)13)(2002 season)(2006 season)

Results of Cost-eŠectiveness Analysis

64

80

5,024(2)11,459( 6)13,643( 6)5,388(4)11,511( 6)11,140( 6)4,955(1)11,470( 3)13,738( 3)2,478(1)8,281( 6)9,488( 6)7,810(4)11,386( 6)13,540( 6)7,810(4)11,357( 6)13,851( 6)5,261(3)8,511( 5)9,611( 5)8,132(5)9,924( 6)
11,047( 6)Weighted average of incremental cost & eŠect [95％ conˆdence
interval] and integrated ICER of 2nd generation histamine H1
receptor antagonists
Miyanohara et al. (2009)14)
Shimuzu et al. (2008)15)(with steroid nasal drop)(without steroid nasal drop)

29

39

80

4,916(4)5,760( 4)4,009( 4)7,833(4)7,247( 4)10,941( 4)8,056(4)8,803( 4)10,941( 4)Incremental
cost (¥)

Incremental eŠect(QALY)

Incremental cost eŠectivenessratio: ICER (¥/QALY)(2.5 percentile 97.5 percentile)

2,839

0.00423

671,739(cost-saving 1,952,966)

5,759

0.00080

7,219,096(1,084,614 14,019,492)

2,688

0.00230

1,167,904(cost-saving 3,640,438)

1,271

0.00262

485,695(cost-saving 1,824,704)

5,656

0.00578

977,897(cost-saving 2,079,316)

5,316

0.00455

1,168,498(cost-saving 2,564,530)

4,160

0.00007

57,088,063(2,075,451 126,499,194)

7,008

0.00465

1,505,702(468,257 2,727,413)

3,949
0.00350[3,787 4,112] [0.00336 0.00364]
6,666

0.00253

2,633,269(1,530,998 4,028,108)

5,918

0.00510

1,160,150(173,793 2,198,236)

4,139

0.00080

5,188,425(cost-saving 11,506,374)

5,103
Weighted average of incremental cost & eŠect [95％ conˆdence
0.00227
interval] and integrated ICER of leukotriene receptor antagonists [4,928 5,278] [0.00200 0.00257]
Imai et al. (2005)16)

101

5,532(3)15,115( 9)16,195( 9)4,4520.00165

Weighted average of incremental cost & eŠect [95％ conˆdence
4,452
0.00165
interval] and integrated ICER of prostaglandin D2 and throm[Not available] [Not available]
boxane A2 receptor antagonists
Hirata et al. (2004)17)(long course, 2 weeks)(short course, ＜2 weeks)
Inagawa et al. (2007)18)

109

161

93

4,983(2)17,225(10)19,445(10)7,814(4)17,240(10)19,445(10)10,806(6)11,742( 6)14,069( 6)1,128,286(1,076,143 1,179,304)

2,248,018(2,035,549 2,476,613)
2,692,911(cost-saving 6,564,557)
2,692,911(Not available)

2,763

0.00857

322,195(cost-saving 1,174,346)

5,609

0.00113

4,964,943(cost-saving 12,010,133)

8,479

0.00660

1,285,210(341,858 2,440,601)

Weighted average of incremental cost & eŠect [95％ conˆdence
interval] and integrated ICER of Th2 cytokine suppressors

5,490
0.00477[5,270 5,710] [0.00442 0.00511]

1,150,943(1,080,366 1,226,933)

Weighted average of incremental cost & eŠect [95％ conˆdence
interval] and integrated ICER of all agents

4,623
0.00358[4,510 4,736] [0.00344 0.00372]

1,291,341(1,245,606 1,338,728)

hon p.8 [100%]1732

Vol. 130 (2010)

perfect health. Weighted averages of each group of
targeted agents are: 0.00350 QALY for 2nd generation histamine H1 receptor antagonists, 0.00227 forleukotriene receptor antagonists, 0.00165 for prostaglandin D2 and thromboxane A2 receptor antagonists, 0.00477 for Th2 cytokine suppressors, and
0.00358 for all agents.
Costs
Table 3 also shows the estimated costs.
Incremental costs are consistently positive as anticipated, which suggests the pre-seasonal medication accompanies additional use of resources for health care.
Additional costs range from ¥1,271 to ¥8,479 per season. Weighted averages of each group of targeted
agents are: ¥3,949 for 2nd generation histamine H1
receptor antagonists, ¥5,103 for leukotriene receptor
antagonists, ¥4,452 for prostaglandin D2 and thromboxane A2 receptor antagonists, ¥5,490 for Th2
cytokine suppressors, and ¥4,623 for all agents.
Here, breakdowns of costs are also presented. In
regards to the costs during the season, costs of the
pre-medication group are lower than those of the control group, except for Yamashita (2004),8) Hayashi etal. (2004),9) and Miyanohara et al. (2009).14) Thesesuggest that the pre-seasonal medication tends toreduce resource use during the season.
Cost-eŠectiveness
Table 3 shows the estimatedICERs as well. They range from ¥322,195 per QALY
to ¥57,088,063 per QALY. Integrated ICERs of eachgroup of targeted agents are: ¥1,128,286 per QALY

Fig. 3.

for 2nd generation histamine H1 receptor antagonists,¥2,248,018 per QALY for leukotriene receptor
antagonists, ¥2,692,911 per QALY for prostaglandin
D2 and thromboxane A2 receptor antagonists,¥1,150,943 per QALY for Th2 cytokine suppressors,and ¥1,291,341 per QALY for all agents.
Figure 3 plots the results on a cost-eŠectivenessplane. A threshold line where ICER equals¥5,000,000 per 1 QALY gain is drawn according to
Shiroiwa et al. (2010),27) although there is no established threshold to judge cost-eŠectiveness in Japan.
Three ICERs, Yamashita (2004),8) Hamajima et al.
(2006)13) in the 2002 season, and Shimizu et al.
(2008)15) for ``without steroid drops'' are judged
cost-ineŠective, and the rest cost-eŠective. The ICER
of Hamajima et al. (2006)13) in the 2002 season,¥57,088,063 per QALY is remarkably high, which isdue to the smallest outcome gain of 0.00007 QALY.
If we take this threshold, the integrated ICERs of
2nd generation histamine H1 receptor antagonists,leukotriene receptor antagonists, prostaglandin D2
and thromboxane A2 receptor antagonists, and Th2
cytokine suppressors are all judged cost-eŠective.
And the integrated ICER of all agents is also judged
cost-eŠective, as well.
Stability of ICERs
Table 3 shows the results ofstochastic sensitivity analyses. 2.5 percentiles and97.5 percentiles of 1,000 ICERs obtained by Monte
Carlo Simulations are presented along with point esti-

Cost-eŠectiveness Planehon p.9 [100%]

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mates of ICER. They range from cost-saving, i.e.,
cost less and gain more, to ¥126,499,194 per QALY.
However, only 2 of 97.5 percentiles ICERs, Imai etal. (2005),16) and Hirata et al. (2004)17) for ``shortcourse'', go beyond the suggested threshold of¥5,000,000 per 1 QALY gain and becoming costineŠective by the sensitivity analysis in addition to 3
ICERs, Yamashita (2004),8) Hamajima et al.
(2006)13) in the 2002 season, and Shimizu et al.
(2008)15) for ``without steroid drops'', of which estimated ICERs in the base-case analyses have alreadybeen judged cost-ineŠective.
In regards to the stability of integrated ICERs, novalue of 2.5 percentiles results in cost-saving, while novalue of 97.5 percentile go beyond the suggested
threshold.
Pollen Counts and Incremental Costs/Incremental

Fig. 4.

EŠects/ICERs
Figure 4 shows the results of correlation analyses between total pollen counts in the air
during the season measured by Durham method andincremental costs/incremental eŠects/ICERs. The
scatter diagram in the upper panel illustrates the correlation between total pollen counts and the incremental costs of pre-seasonal medication. Squaresof Pearson's correlation coe‹cient are 0.523 for 2nd
generation histamine H1 receptor antagonists and0.299 for all agents, both of which are not statisticallysigniˆcant. Similarly, the scatter diagram in the middle panel illustrates the correlation between total
pollen counts and the incremental eŠects. Squares ofPearson's correlation coe‹cient are 0.088 for 2nd
generation histamine H1 receptor antagonists and0.057 for all agents, both of which are not statisticallysigniˆcant. And the scatter diagram in the lower panel

Correlation between Total Pollen Count and Outcomes/ICERs

ICER; incremental cost-eŠectiveness ratio.

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Vol. 130 (2010)

illustrates the correlation between total pollen counts
and the ICERs. Squares of Pearson's correlationcoe‹cient are 0.192 for 2nd generation histamine H1
receptor antagonists and 0.225 for all agents, both ofwhich are not statistically signiˆcant, as well.
DISCUSSION
We conduct a cost-eŠectiveness analysis of preseasonal medication for cedar pollinosis in Japan
based on 12 reports of clinical trials, in which not
only outcomes but also the resource use are presented. We compare the choice of pre-seasonal medication against intra-seasonal symptomatic treatment
with 15 ICERs. The estimated ICERs range from¥322,195 per QALY to ¥57,088,063 per QALY, andamong these, 12 ICERs are less than the suggested
threshold for judging cost-eŠectiveness, ¥5,000,000
per 1 QALY gain.27) Integrated ICERs of 2nd generation histamine H1 receptor antagonists of ¥1,128,286
per QALY is judged cost-eŠective, although 2 out of
8 ICERs are beyond the threshold. Those of leukotriene receptor antagonists of ¥2,248,018 per
QALY, prostaglandin D2 and thromboxane A2 receptor antagonists of ¥2,692,911 per QALY, Th2
cytokine suppressors of ¥1,150,943 per QALY, andall agents of ¥1,291,341 per QALY are judged costeŠective, as well. These results suggest that the choiceof pre-seasonal medication by patients and/or physicians is justiˆable as an e‹cient use of ˆnite resources
for health care regardless of the choice of agent. The
use of 2nd generation histamine H1 receptor antagonists and Th2 cytokine suppressors are foundmore favourable than the use of the other agents fromthe viewpoint of health economics. The former ismainly due to lower drug costs, and the latter to larger eŠect among the agents. These results are considered stable, since ranges of ICERs resulted fromstochastic sensitivity analyses do not pass beyond thethreshold.
Since the suggested threshold for judging costeŠectiveness, ¥5,000,000 per 1 QALY gain,27) is derived from a survey questioning willingness-to-pay inregards to life threatening diseases, the value may
diŠer for no life threatening disease like cedar pollinosis here. However, we quote this value in thisstudy, because no speciˆc threshold is available in theliterature to date and prior cost-eŠectiveness analysesof pollinosis in developed countries use a thresholdsimilar to ¥5,000,000 per 1 QALY gain.28,29)

Although we include only two three-arm trials considering prescription patterns, their results imply that
limiting target patients with more severe symptoms,
administering heavier medication, or prolonging theduration of pre-seasonal medication would make
ICERs even more favourable. However, prolonged
pre-seasonal medication is not necessary to result in
more favourable ICERs among the results based on
two-arm trials.
Whereas the association between total pollencounts in the air during the season and outcomes oftreatments is known in the literature,13,17,26) no correlation was found between total pollen counts and incremental costs/incremental eŠects/ICERs. Thesemay be due to the small number of included reports
out of identiˆed controlled clinical trials by our literature search, 12 out of 142, which may have a bias.
There are some points to note as to the method employed in this study. As mentioned above, reports oftrials included in this study are so limited that caution
is needed in interpreting the results. Arguably,
however, our inclusion criteria, reporting in SS and
MS/SMS, is one approach to make the most fromavailable knowledge to date in the literature in conducting a cost-eŠectiveness analysis under the context
of this study, since SS allow us to estimate incremental eŠect in terms of QALYs exactly subject to thedeˆnition. And there is no report of trial which
describe more detailed resource use than MS/SMS.
While it is admittable that estimation of unit costs in
our costing is rough, our approach of averaging daily
drug prices of possible choice of agents is a reasonably feasible one, and estimated incremental costs successfully re‰ect the diŠerence in resources used between pre-seasonal medication and symptomatic
medication.
Since the signiˆcance of productivity losses related
to cedar pollinosis has been pointed out,30,31) leaving
this uncounted from our scope of costing might aŠect
the results. Nevertheless, better outcomes by the
choice of pre-seasonal medication imply negative incremental productivity loss. Therefore, estimatedICERs might be overestimates.
In conclusion, pre-seasonal medication for cedar
pollinosis is cost-eŠective regardless of the choice ofprophylactic agent among 2nd generation histamine
H1 receptor antagonists, leukotriene receptor antagonists, prostaglandin D2 and thromboxane A2
receptor antagonists, or Th2 cytokine suppressors.

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1735

Acknowledgements
This study was ˆnanced bya grant from the University of Tsukuba.

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