利用健保資料庫探討藥物不良反應的風險

高雅慧

國立成功大學醫學院

臨床藥學研究所

藥物不良反應的代價

英國的研究

– 4%的病床年使用率– 四億六千六百萬英磅的健保(NHS)年度費用– 因藥物不良反應住院者，死亡率為2%美國的研究

– 6.7%的住院與嚴重的藥物不良反應有關– 死亡率為0.32%– 住院病人16%發生藥物不良反應– 門診病人25%有藥物不良反應的經驗

The history of drug regulation in the United States is a history of political responses to epidemics of adverse drug reactions, each adverse reaction of sufficient public health importance to lead to political pressure for regulatory change.

~ Brian L. Strom, Preface of pharmacoepidemiology4th ed. 2005

臨床試驗不足以釐清藥物不良反應

試驗族群均質性：單純病況

排除特定族群：孕婦、老年人、小孩

試驗人數不足以觀察到機率較低的不良反應

試驗期間較短

不足以預測醫療的臨床實境

併用藥品的交互作用

評估藥物不良反應的風險

發生率多高？

危險因素是什麼？

作用機轉是什麼？

和別的藥品是否有交互作用？

第二型選擇性環氧酶抑制劑(Coxibs)及傳統NSAIDs與老年人發生心衰竭之相關性-加拿大世代追蹤研究

加拿大安大略省資料庫

Health-care Databases包含130 萬≥ 65 歲

安大略省藥品申報系統Drug Benefit Program (ODB)

包含藥局調配記錄

定義世代追蹤族群病史評估定義心衰竭結果

Rofecoxib (退化性關節炎)Celecoxib (退化性及風濕性關節炎)

1. 使用傳統NSAIDs治療失敗或無法耐受副作者

2. 具有胃腸道出血或潰瘍病史者

加拿大醫事機構出院摘要資料庫Canadian Institute for Health Information

Discharge Abstract Database包含住院記錄

基本特質(如性別、年齡) 治療過程資訊 (如檢查項目)住院及出院診斷 (ICD-9428)

給付規範

Mamdani M et al. Lancet 2004; 363: 1751-6

世代追蹤族群之基本特質Study cohort (28% dispensing rate)

Non-NSAID users

Celecoxibusers

Rofecoxibusers

Non-selective NSAIDs users

No. (women;%)

100 000 (55458, 55%)

18 908 (13266, 70%)

14 583 (10473, 72%)

11 606 (7027, 61%)

Age (mean, SD) 75.4 (7.3) 76.5 (6.8) 76.5 (6.9) 75.9 (7.0)Residence in long-tern care facility (%)

4060 (4%) 810 (4%) 652 (4%) 930 (8%)

Low income status (%)

21065 (21%) 5673 (30%) 4445 (30%) 3943 (34%)

Admissions in past year (%)

11589 (12%) 3651 (19%) 2900 (20%) 2091 (18%)

No. of prescription drugs in past year (mean, SD)

5.4 (5.5) 9.5 (6.4) 9.9 (6.6) 8.3 (6.4)

處方celecoxib及rofecoxib以女性居多各組患者在過去病史沒有差異(data not show)

Mamdani M et al. Lancet 2004; 363: 1751-6

Non-selective NSAIDs users: Diclofenac + misoprostol 49%, naproxen 17%, ibuprofen 12%, diclofenac 10%

心衰竭不良反應Study cohort (55 000 person-years follow-up, 654 admissions)Non-NSAID

usersCelecoxib

users

Days of follow-up(Mean, SD)

139 (77)

Unadjusted (95% CI) 1.0 1.5 (1.2-1.8) 2.7 (2.2-3.3) 1.7 (1.2-2.3)

NNT n/a n/a 402 882

170 (97) 146 (90) 94 (70)

Rofecoxibusers

Non-selective NSAIDs users

348 116 143 47

Total follow-up (person-years)

38 099 8801 5846 2993

Crude CHF rate per 1000 person-years 9.1 13.2 24.5 15.7

Model-based RR

Adjusted (95% CI) 1.0 1.0 (0.8-1.3) 1.8 (1.5-2.2) 1.4 (1.0-1.9)

No. of admission

1.5 (1.1-2.1)

Rofecoxib 明顯增加心衰竭住院之機率

一般族群使用NSAIDs發生首次因心肌梗塞住院之危險性-芬蘭病例對照研究

芬蘭出、住院登記資料庫Hospital Discharge Register

2000.1~2003.12

芬蘭處方登錄資料系統Finnish Prescription Register

一般社區民眾之基本特質定義病例組(case)及對照組(control )定義藥品使用(NSAIDs)

目前用藥者 Current users 最近用藥者 Recent users 過去用藥者 Past users 沒有用藥者 Non-users

芬蘭申報系統Special Reimbursement Register

包含申報之藥品及診斷藥品為ATC/DDD代碼疾病為ICD-9代碼

目前用藥者：發生首次因心肌梗塞住院時仍在使用NSAIDs患者最近用藥者：發生首次因心肌梗塞住院時前1至30天內使用NSAIDs患者過去用藥者：發生首次因心肌梗塞住院時前大於30天有使用NSAIDs患者

Helin-Salmivaara A et al. Euro Heart J 2006; 27: 1657-63

病例組及對照組之基本特質Cases (%)n= 33 309

Controls (%)n= 138 949

Age (years)(0.4) (0.5)

(3.4)(13.9)(21.0)(28.3)(25.1)(7.8)(37.3)(5.8)(2.7)(24.0)(10.2)

(21.0)(10.3)(5.4)(0.1)

(2.9)(12.0)(18.5)(27.1)(28.3)(10.8)(39.6)(14.5)(4.3)(34.2)(47.7)

(35.0)(14.6)(3.9)(0.3)Clopidogrel 96 76

≤ 35 131 64536-45 966 4 750

66-75 9 014 39 318

≧ 86 3 601 10 825

Diabetes mellitus 4 820 8 091

Hypertension 11 406 33 304CAD 15 897 14 104Other medication

β-blocker 11 664 29 161HMG-CoA-reductase inhibitor 4 885 14 331HRT 1 306 7 508

3 9876 173

9 437

13 181

1 434

46-55 19 35056-65 29 213

76-85 34 848

Females 51 835

Rheumatoid arthritis 3 747

病例及對照組之比例為1比5Helin-Salmivaara A et al. Euro Heart J 2006; 27: 1657-63

個別NSAIDs發生首次因心肌梗塞危險之機率-1

(Aceclofenac, mefenamic acid,tenoxicam, tiaprofenic acid)

個別NSAIDs發生首次因心肌梗塞危險之機率-2

結論

所有的NSAIDs皆增加患者發生首次因心肌梗塞住院之機率

發生首次因心肌梗塞危險之機率與藥品使用期間長短有關

停藥時間較長患者，使用NSAIDs與因心肌梗塞而住院的相關性較低

Helin-Salmivaara A et al. Euro Heart J 2006; 27: 1657-63

臺灣藥物不良反應通報中心

通報次數( 佔總通報次數比例%) 藥品92年度 93年度 94年度

Ketoprofen 74 (2.64) 78 (2.49) (1.16)(2.24) (2.12)

(2.63)

(1.03)

(1.85)(1.22)

(1.85)(1.28)

55Diclofenac 52 70 101Ketorolac 36 58 125

Mefenamicacid

- - 49Ibuprofen - 39 -

在各年度通報排名前二十名之NSAIDs

蘇純慧，碩士論文2006.7

NSAIDs不良反應之通報藥品 不良反應

Ketoprofen Eyelid oedema、rash、eye swelling、angioneuroticoedema、hypersensitivity、pruritis、dyspnoea、urticaria、face oedema、flushing etc.Rash、eyelid oedema、eye swelling、pruritus、dyspnoea、angioneurotic oedema、hypersensitivity、swelling face、rash pruritic、urticaria etc.Rash、eyelid oedema、eys swelling、pruritus、angioneurotic oedema、dyspnoea、swelling face、rash pruritic、urticaria、hypersensitivity etc.Eyelid oedema、hypersensitivity

Stevens-Johnson syndrome

Diclofenac

Ketorolac

IbuprofenMefenamicacid

蘇純慧，碩士論文2006.7

在臺灣，非類固醇抗發炎劑與心血管不良反應的相關性？

全民健康保險學術研究資料庫

處方醫令明細檔 (OO &DO)– 識別碼

– 醫令類別

– 藥品代號 –健保藥品代碼

– 藥品用量 – 藥品一次之劑量– 藥品使用頻率

– 單價

– 總量

– 金額

What drug?

How used? What cost?

健保藥品代碼

A 0 1 2 3 4 5 1 0 0

許可證別A,B,J,K,N,P,R,S

劑型碼1,2,3,

4,5

許可證號碼 規格碼

ATC Classification

Anatomical Therapeutic Chemical ClassificationWHO Collaborating Center for Drug Statistics Methodology established in Oslo, 1982WHO International Working Group for Drug Statistics Methodology– Established by the WHO Division of Drug

Management and Polices in 1996– Consists of 13 experts in clinical pharmacology,

drug utilization, drug regulation, drug evaluation, statistics and medicine

The main groups (I)A Alimentary tract and metabolismB Blood and blood forming organsC Cardiovascular systemD DermatologicalsG Genito-urinary system and sex

hormoneH Systemic hormonal preparations,

excl. sex hormone J General anti-infectives for systemic

use

The main groups (II)

L Antineoplastic and immnomodulating agents

M Musculo-skeletal systemN Nervous systemP Antiparasitic products, insecticides

and repellentsR Respiratory systemS Sensory organV Various

ExampleA Alimentary tract and metabolism

(1st level, anatomical main group)A10 Drugs used in diabetes

(2nd level, therapeutic main group)A10B Oral blood glucose lowering drugs

(3rd level, therapeutic/pharm. group)A10B F Alpha glucosidase inhibitors

(4th level, chem./therap./pharm. group)A10B F01 Acarbose

(5th level, subgroup for chemical substance)

Pharmaceutical Products in NHI (2005)Class Category Products (%)

B Blood and blood forming organsA Alimentary tract and metabolism 1,995 (12.76)

N Nervous system 1,572 (10.05)M Musculo-skeletal system 1,397 (8.93)

DermatologicalsRespiratory systemGeneral antiinfectives for systemic use

Cardiovascular systemGenito-urinary system and sex hormonesSystemic hormonal preparations, excl. sex hormn.Sensory organsAntineoplastic and immunomodulating agentsAntiparasitic products, insecticides and repellentsVarious

2,260 (14.45)

D 1,873 (11.98)R 1,859 (11.89)J 1,754 (11.21)

C 1,032 (6.60)G 553 (3.54)H 477 (3.05)S 414 (2.65)L 289 (1.85)P 114 (0.73)V 51 (0.33)

Availability of Medicines, 1998Country No. of API No. of ProductAustria 1727 8643Belgium 1483 6118Denmark 1016 1915France 1514 4089Germany 1974 18554Italy 1693 5070Sweden 1041 1954UK 1366 3635Taiwan (2000) 1553 19865

Folino-Gallo, P et al. EJCP, 2001;57:441-6

列入研究的NSAIDsCoxib Celecoxib, RofecoxibNon-selective Diclofenac, Ibuprofern, Naproxen Other selective Etodolac, Meloxicam, Nabumetone,

NimesulideOther non-selective(23項)

Acemetacin, Alclofenac, Alminoprofen,Benzydamine, Epinizole, Fenbufen, Fenoprofen, Flurbiprofen, Flufenamic acid, Indomethacin, Ketorolac, Ketoprofen, Meclofenamic acid, Mefenamic acid, Niflumic acid, Phenylbutazone, Piroxicam, Sulindac, Tenoxicam, Tiaprofenic acid, Tiaramide, Tolfenamic acid, Tolmetin

Frequency of NSAIDs

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1998 1999 2000 2001 2002 2003

OthersRofecoxibEtodolacCelecoxibMeloxicamTiaprofenic acidAcemetacinIndomethacinFlurbiprofenNabumetonePiroxicamSulindacNaproxenIbuprofenMefenamic acidDiclofenac

Consumption DDD of NSAIDs

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1998 1999 2000 2001 2002 2003

OthersRofecoxibNimesulideCelecoxibFenbufenEtodolacIndomethacinKetoprofenAcemetacinFlurbiprofenTiaprofenic acidIbuprofenSulindacNaproxenDiclofenac

NSAIDs的處方使用率Study drug Patient number PercentageCelecoxib 25,179 3.19Rofecoxib 14,539 1.84Naproxen 25,281 3.22Ibuprofen 82,609 10.54Diclofenac 227,209 29.00Other selective NSAIDs 59,102 7.52

Other non-selective 348,535 44.49

Total 782,472 100.00

>60 y/o exposure group: 644,326人, unexposure group: 541,982人

Other selective: Nabumetone, Meloxicam, Etodolac, NimesulideOther non-selective: Phenylbutazone, Indometacin, Sulindac, Tolmetin, Alclofenac, Acemetacin,

Ketorolac, Piroxicam, Tenoxicam, Ketoprofen, Fenoprofen, Fenbufen, Flubiprofen, Tiaprofenic acid, Alminoprofen, Mefenamic acid, Tolfenamic acid, Flufenamic acid, Meclofenamic acid, Niflumic acid, Benzydamine, Tiaramide, Epinizole

Risk of Acute Myocardial Infarction among NSAIDs

Group AMI(n)Non-AMI

(n)Adjusted

OR Adjusted 95% CI

Control 2,208 539,774 1.00 -

0.80 )

)

)

)

)

)

)

0.62

0.87

0.67

0.76

0.75

0.81

Celecoxib 109 23,860 0.97 ( - 1.17

Rofecoxib 56 13,784 0.81 ( - 1.06

Naproxen 82 20,435 1.08 ( - 1.35

Ibuprofen 174 65,404 0.79 ( - 0.92

Diclofenac 550 182,629 0.84 ( - 0.92

Other selective 216 54,720 0.87 ( - 1.00

Other non-selective 903 281,404 0.87 ( - 0.94

Risk of Stroke among NSAIDs

Group Stroke(n)Non-stroke

(n)Adjusted

OR Adjusted 95% CI

Control 7,468 534,514 1.00 -

0.90 )

)

)

)

)

)

)

1.15

0.92

0.78

0.86

0.99

0.88

Celecoxib 394 23,575 0.99 ( - 1.10

Rofecoxib 308 13,532 1.30 ( - 1.46

Naproxen 260 20,257 1.04 ( - 1.18

Ibuprofen 620 64,958 0.85 ( - 0.93

Diclofenac 1,945 181,234 0.90 ( - 0.95

Other selective 914 54,022 1.06 ( - 1.14

Other non-selective 3,112 279,195 0.92 ( - 0.95

藥物的風險管理

藥物研發與製造

藥物許可證核發、適應症、警語

上市、行銷

醫院、藥局藥物審議委員會醫藥品查驗中心

醫師、藥師、護理人員

藥物不良反應通報系統

藥害救濟

藥物流行病學Pharmacoepidemiology

The study of the use of and the effects of drugs in large numbers of peopleBetter quantitation of the incidence of known adverse and beneficial effects– In patients not studied prior to marketing– As modified by other drugs and other illnesses– Relative to other drugs used for the same indication

Discovery of previously undetected adverse and beneficial effects

Goya, 1746-1828

Primum, Non Nocere~ Hippocrates, 400s BC

Alte fürst-erzbischöfliche Hofapotheke, Salzburg, Since 1591

http://www.birds.org.tw/diary/showdiary.php?diary_id=14

利用健保資料庫探討藥物不良反應的風險藥物不良反應的代價臨床試驗不足以釐清藥物不良反應評估藥物不良反應的風險第二型選擇性環氧酶抑制劑(Coxibs)及傳統NSAIDs與老年人發生心衰竭之相關性-加拿大世代追蹤研究世代追蹤族群之基本特質心衰竭不良反應一般族群使用NSAIDs發生首次因心肌梗塞住院之危險性-芬蘭病例對照研究病例組及對照組之基本特質個別NSAIDs發生首次因心肌梗塞危險之機率-1結論臺灣藥物不良反應通報中心NSAIDs不良反應之通報全民健康保險學術研究資料庫健保藥品代碼ATC ClassificationThe main groups (I)The main groups (II)ExamplePharmaceutical Products in NHI (2005)Availability of Medicines, 1998列入研究的NSAIDsFrequency of NSAIDsConsumption DDD of NSAIDsNSAIDs的處方使用率Risk of Acute Myocardial Infarction among NSAIDsRisk of Stroke among NSAIDs藥物的風險管理藥物流行病學 Pharmacoepidemiology