eFigure 1. The prescription frequency of statin in mild-to-moderate Alzheimer’s disease patients with and without early statin use during the period of one year before and after index date. A) Prevalent rate; B) Cumulative rate.

Supplementary Appendix

This appendix is provided by the authors to give readers additional information about this manuscript.

Early Statin Therapy Ameliorates the Progression of Alzheimer’s Disease: A Nationwide Population-Based Study

Feng-Cheng Lin, MD*; Yun-Shiuan Chuang, MS*; Hui-Min Hsieh, Ph.D., Kuei-Fen Chiu, MS; Ching-Kuan Liu, MD, PhD; Ming-Tsang Wu, MD, ScD

eTable 1. List of catastrophic diseases in the Taiwan National Health Insurance catastrophic illness registry file.

ICD-9-CM, 2001

Diseases

Effective Period

140-208

1. Malignant neoplasm

5 years

　

2. Congenital coagulopathy

Permanent

286

(1)Congenital factor Ⅷ disorder

286.1

(2)Congenital factor Ⅸ disorder

286.2

(3)Congenital factor XI deficiency

286.3

(4)Congenital deficiency of other clotting factors

　

3. Severe hemolytic, aplastic anemia

5 years

282

(1)Hereditary hemolytic anemias

283

(2)Acquired hemolytic anemias

284

(3)Aplastic anemias

　

4. Uremia

　

585

(1)Chronic renal failure (End-stage renal disease)

Permanent: Definite chronic dialysis

403.01, 403.11, 403.91

(2)Hypertensive renal disease with renal failure

3 months: Unsure chronic dialysis

404.02, 404.03, 404.12, 404.13, 404.92, 404.93

(3)Hypertensive heart and renal disease with renal failure

　

5. Autoimmune diseases

Permanent

710

(1)Systemic lupus erythematosus

710.1

(2)Systemic sclerosis

714

(3)Rheumatoid arthritis

714.30-714.33

Rheumatoid arthritis juvenile

710.4

(4)Polymyositis

710.3

(5)Dermatomyositis

　

(6)Vasculitis

446

(a)Polyarteritis nodosa

446.2

(b)Hypersensitivity angiitis

446.4

(c)Wegener’s granulomatosis

446.5

(d)Giant cell arteritis

443.1

(e)Thromboangiitis obliterans (Buerger’s disease)

446.7

(f)Takayasu’s disease

446.1

(g)Kawasaki disease

136.1

(h)Behçet’s disease

694.4

(7)Pemphigus

710.2

(8)Sjögren’s syndrome

555

(9)Crohn’s disease

556.0-556.6, 556.8-556.9

(10)Ulcerative colitis

　

6. Chronic psychotic disorders

　

290

(1)Senile and presenile organic psychotic conditions

Permanent for disease status, but prescription of any acetylcholinerase inhibitors (donepezil, rivastigmine, or galantamine) is evaluated every year.

293.1

(2)Subacute delirium

6 months (Re-evaluate every 6 months)

294

(3)Other organic psychotic conditions (chronic)

2 years for the first time

Permanent for renewal

295

(4)Schizophrenic disorders

Permanent

296

(5)Affective psychoses

2 years for the first time

Permanent for renewal

297

(6)Paranoid states

2 years for the first time

Permanent for renewal

299

(7)Psychoses with origin specific to childhood

299

(a)Infantile autism

5 years for the first time

Permanent for renewal

299.1

(b)Disintegrative psychoses

5 years for the first time

Permanent for renewal

299.8

(c)Other specified early childhood psychoses

5 years for the first time

Permanent for renewal

299.9

(d)Psychoses with origin specific to childhood unspecified

3 years for the first time

5 years for the second time

5 years for the third time

Permanent for the fourth time

　

7. Hereditary metabolic disorders

Permanent

243

(1)Congenital hypothyroidism

250.01, 250.03, 250.11, 250.13, 250.21, 250.23, 250.31, 250.33, 250.41, 250.43, 250.51, 250.53, 250.61, 250.63, 250.71, 250.73, 250.81, 250.83, 250.91, 250.93

(2)Type I diabetes mellitus

253.5

(3)Diabetes insipidus

255.2

(4)Congenital adrenal hyperplasia

270

(5)Disorders of amino-acid transport and metabolism

271

(6)Glycogen storage disease

271.1

(7)Galactosemia

272.1

(8)Pure hyperglyceridemia

272.6

(9)Lipodystrophy

272.7

(10)Lipidoses

272.9

(11)Disorders of lipoid metabolism

275.1

(12)Disorders of copper metabolism

275.40-275.42, 275.49

(13)Disorders of calcium metabolism

277.2

(14)Other disorders of purine and pyrimidine metabolism

277.5

(15)Mucopolysaccharidosis

277.8

(16)Other specified disorders of metabolism

277.9

(17)Disorders of metabolism

　

8. Congenital chromosome abnormality of heart, lung, gastrointestine, kidney, nerve or bone

　

740

(1)Anencephalus and similar anomalies

Permanent

742

(2)Other congenital anomalies of nervous system

3 years

745-746

(3)Bulbus cordis anomalies and anomalies of cardiac septal closure or other congenital anomalies of heart

3 years

747

(4)Other congenital anomalies of circulatory system

3 years

748.4

(5)Congenital cystic lung disease

Permanent

748.5

(6)Agenesis, hypoplasia and dysplasia of lung

Permanent

748.6

(7)Other anomalies of lung

Permanent

751

(8)Other congenital anomalies of digestive system

Permanent

753

(9)Renal agenesis and dysgenesis

Permanent

753.1

(10)Cystic kidney disease

Permanent

753.20-753.23, 753.29

(11)Obstructive defects of renal pelvis and ureter

Permanent

753.3

(12)Other specified anomalies of kidney

Permanent

756.4

(13)Chondrodystrophy

Permanent

758

(14)Chromosomal anomalies

Permanent

749.01-749.04

(15)Congenital cleft palate and cleft lip

3 years

749.11-749.14

　

9. Burning area over 20% of the total body-surface area or facial burning with facial dysfunction

1 year

948.2-948.9

(1)Burn of >20% of total body surface

　

(2)Facial burning

940

(a)Burn confined to eye and adnexa

941.5

(b)Burn of face and head, deep necrosis of underlying tissue (deep third degree) with loss of a body part

　

10. Organ transplant

　

V42.0

(1)Kidney replaced by transplant

Permanent

V42.1

(2)Heart replaced by transplant

Permanent

V42.6

(3)Lung replaced by transplant

Permanent

V42.7

(4)Liver replaced by transplant

Permanent

V42.81-V42.82

(5)Bone marrow replaced by transplant

5 years

V42.83

(6)Pancreas replaced by transplant

Permanent

996.81

(7)Complication of transplanted kidney

Permanent

996.82

(8)Complication of transplanted liver

Permanent

996.83

(9)Complication of transplanted heart

Permanent

996.84

(10)Complication of transplanted lung

Permanent

996.85

(11)Complication of transplanted bone marrow

5 years

996.86

(12)Complication of transplanted pancreas

Permanent

　

11. Poliomyelitis, cerebral palsy

Permanent

045.1

(1)Acute poliomyelitis with other paralysis

343

(2)Infantile cerebral palsy

344＋138

(3)Other paralytic syndromes (Late effect of acute poliomyelitis )

959.99

12. Major trauma rated 16 or above on the severity scale

1 year for the first time

Injury severity score 16

3 years for renewal

518.85

13. Long-term mechanical ventilation, defined as one of the following:

42 days for the first time

　

(1)Invasive mechanical ventilation for 21 or more days.

3 months for the second time

　

(2)Invasive mechanical ventilation followed by non-invasive ventilation, with a total duration of 21 or more days.

1 year after the second time

　

(3)Invasive mechanical ventilation followed by negative pressure ventilation, with a total duration of 21 or more days.

　

　

(4)Specific diseases, e.g., end stage heart failure, chronic pulmonary diseases, primary neuromuscular diseases, chronic hypoventilation syndrome, which require non-invasive ventilation for 21 or more days.

　

　

14. Severe malnutrition

　

261

(1)Patients suffering from severe malnutrition due to major enterectomy, intestinal failure already on a fully intravenous diet for 30 days, and unable to obtain sufficient nutrition through an oral diet

3 months for the first time

261.1

(2)Patients suffering from severe malnutrition due to other chronic disease already on a fully intravenous diet for 30 days, and unable to obtain sufficient nutrition through an oral diet

3 years for renewal

　

15. Respiratory, circulatory, or neurological sequel of decompression sickness

　

993.3

(1)Decompression sickness

Permanent

958

(2)Air embolism

3 years

358

16. Myasthenia gravis

3 years

　

17. Hereditary immunity deficiency

5 years

279.00, 279.06

(1)Hypogammaglobulinemia

279.08

(2)Selective immunoglobulin deficiency combined with repeated related infection

279.1

(3)Deficiency of cell-mediated immunity

279.2

(4)Combined immunity deficiency

279.3

(5)Phagocyte deficiency (chronic granulomatous disease )

279.8

(6)Other specified disorder of immune mechanism

　

18. Neurological, muscular, skin, bone, cardiopulmonary, urological and gastrointestinal complication of spinal cord injury

Permanent

806

(1)Fracture of vertebral column with spinal cord injury

952

(2)Spinal cord injury without evidence of spinal bone injury

336

(3)Other disease of spinal cord

　

19. Occupational disease

　

　

　

3 years for the first time

Permanent for renewal

500

(1)Coal workers’ pneumoconiosis

501

(2)Asbestosis

502

(3)Pneumoconiosis due to other silica or silicates

503

(4)Pneumoconiosis due to other inorganic dust

505

(5)Pneumoconiosis

　

20. Cerebrovascular disease (acute stage)

1 month

430

(1)Subarachnoid hemorrhage

431, 432

(2)Intracerebral hemorrhage

433, 434

(3)Cerebral infarction

435-437

(4)Other cerebrovascular disease

340

21. Multiple sclerosis

5 years

359.0, 359.1

22. Congenital muscular dystrophy

Permanent

　

23. Congenital anomalies integument

Permanent

757.39

(1)Congenital epidermolysis bullosa

757.9

(2)Congenital anomalies of the integument

757.1

(3)Ichthyosis congenita

030

24. Leprosy (Hansen’s disease)

Permanent

571.2, 571.5, 571.6

25. Liver cirrhosis with complication

5 years

　

(1)Ascites with poor control

　

(2)Esophageal or gastric varicosis bleeding

　

(3)Hepatic coma or liver decompensated

　

26. Premature infant

　

765.9

(1)Neurological, muscular, skeletal, cardiac or pulmonary complications due to premature infants to have admission care within three months birth.

765.99

(2)Neurological, muscular, skeletal, cardiac or pulmonary complications due to premature infants certified to have moderate impairments three months of age.

3 years

985.1

27. Toxic effect of arsenic and its compounds (black foot disease)

Permanent

335.2

28. Motor neuron disease

Permanent

046.1

29. Jakob -Creutzfeldt disease

Permanent

30. Rare diseases published by Taiwan Ministry of Health and Welfare

Permanent

Supplementary Appendix

eTable 2. ICD-9-CM diagnosis codes for comorbidities.

Diseases

ICD-9-CM Codes

Hypertension

401.xx

Diabetes mellitus

250.xx

Ischemic stroke

432.xx-438.xx

Intracerebral hemorrhage

430.xx-431.xx

Cardiac dysrhythmia

427.xx

Congestive heart failure

428.xx

Peripheral artery disease

443.8x, 443.9x

Peptic ulcer

531.x, 532.x

Ischemic heart disease

410.x-414.x

Supplementary Appendix

eTable 3. Frequency of statin use and number of decimals in Alzheimer’s disease patients with and without early statin use.

　

AD patients with early statin use (N = 719)

　

　

AD patients without early statin use

(N = 719)

　

N

%

Mean

SD

Median

Min

Max

　

N

%

Statin, cDDDs

93.7

91.4

65.3

2.0

726.0

1.00-28.00

171

23.78

-

28.01-61.67

178

24.76

-

61.68-120.00

185

25.73

-

> 120.00

185

25.73

-

Lipophilic, cDDDs1

91.2

88.5

63.0

2.0

726.0

1.00-28.00

148

21.83

-

28.01-61.67

140

20.65

-

61.68-120.00

146

21.53

-

> 120.00

147

21.68

-

Lipophilic agents2

Lovastatin

438

11.64

Simvastatin

797

21.18

Atorvastatin

1522

40.45

Fluvastatin

509

13.53

Hydrophilic, cDDDs1

86.0

89.1

58.7

2.3

512.0

1.00-28.00

22

3.24

-

28.01-61.67

29

4.28

-

61.68-120.00

27

3.98

-

> 120.00

19

2.80

-

Hydrophilic agents2

Pravastatin

327

8.69

Rosuvastatin

170

4.52

Pitavastatin

0

0.00

Propensity score probability

10 decimals

21

0.03

21

0.03

9 decimals

0

0.00

0

0.00

8 decimals

1

0.00

1

0.00

7 decimals

1

0.00

1

0.00

6 decimals

2

0.00

2

0.00

5 decimals

71

0.10

71

0.10

4 decimals

290

0.40

290

0.40

3 decimals

249

0.35

249

0.35

2 decimals

75

0.10

75

0.10

1 decimal

9

0.01

　

　

　

　

　

　

9

0.01

Abbreviation: AD = Mild-to-moderate Alzheimer’s disease; cDDD = cumulative defined daily dose; SD = standard deviation.

1N = 678 (Excluded 46 patients with early prescription of both lipophilic and hydrophilic statin).

2Some subjects were prescribed 2 different lipophilic or 2 different hydrophilic agents of statin during the period of one year before the index date and at index date.

Supplementary Appendix

eTable 4. Demographics and clinical characteristics of mild-to-moderate Alzheimer’s diseases patients with and without early statin use before and after propensity-score matching and after the exclusion of 46 patients with prescription of both hydrostatic and lipophilic statin between one year before index date and at index date.

　

AD with early statin use

(N = 678)

　

AD without early statin use

(N = 5707)

　

AD without early statin use1 (N = 678)

　

N

%

　

N

%

p value2

　

N

%

p value2

Age (yrs)

<0.0001

0.6743

50-59

99

14.60

785

13.76

88

12.98

60-69

355

52.36

2472

43.32

365

53.83

70-79

224

33.04

2450

42.93

225

33.19

Gender

<0.0001

0.8995

Male

165

24.34

2147

37.62

167

24.63

Female

513

75.66

3560

62.38

511

75.37

Comorbidity

Hypertension

562

82.89

3541

62.05

<0.0001

571

84.22

0.5097

Diabetes

382

56.34

1728

30.28

<0.0001

373

55.01

0.6227

Ischemic stroke

341

50.29

2544

44.58

0.0047

345

50.88

0.8280

Intracerebral hemorrhage

19

2.80

173

3.03

0.7413

13

1.92

0.2831

Cardiac dysrhythmia

150

22.12

1162

20.36

0.2828

143

21.09

0.6442

Congestive heart failure

92

13.57

635

11.13

0.0584

96

14.16

0.7533

Peripheral artery disease

28

4.13

119

2.09

0.0008

29

4.28

0.8924

Peptic ulcer

164

24.19

1247

21.85

0.1653

165

24.34

0.9495

Ischemic heart disease

365

53.83

2059

36.08

<0.0001

366

53.98

0.9566

Other medication

Aspirin

303

44.69

1171

20.52

<0.0001

308

45.43

0.7849

Corticosteroid

147

21.68

1090

19.10

0.1078

138

20.35

0.5486

NSAID

462

68.14

3485

61.07

0.0003

455

67.11

0.6845

Antidepressant

77

11.36

433

7.59

0.0006

85

12.54

0.5030

Anticoagulant

9

1.33

51

0.89

0.2684

7

1.03

0.6150

Benzodiazepine

303

44.69

　

2195

38.46

0.0017

　

313

46.17

0.5855

Abbreviation: AD = Mild-to-moderate Alzheimer’s disease patients; NSAID = non-steroidal anti-inflammatory drug.

1Matching as 1:1 with AD patients with early statin use by propensity score.

2Chi-square or Fischer’s exact measure, whichever appropriate.

Supplementary Appendix

eTable 5. Deterioration of mild-to-moderate Alzheimer’s diseases patients according to early statin use or not in a Cox regression model (N = 678).1

Parameters

Estimate

SE

p value

HR

95% CI

Model 1

　

　

　

　

　

AD without early statin use

1

AD with early statin use2

-0.21

0.06

0.0005

0.81

0.72

0.91

Model 2

AD with early statin use3

-0.22

0.06

0.0003

0.80

0.71

0.90

Model 3

AD with early statin use4

-0.24

0.06

<0.0001

0.79

0.70

0.89

Age (yrs)

50-59

1

60-69

-0.20

0.09

0.0300

0.82

0.69

0.98

70-79

0.02

0.10

0.8263

1.02

0.85

1.23

Gender

Female

1

Male

0.14

0.07

0.0410

1.16

1.01

1.33

Comorbidity

Hypertension

-0.05

0.08

0.5206

0.95

0.80

1.12

Diabetes

0.00

0.06

0.9817

1.00

0.88

1.13

Ischemic stroke

0.07

0.06

0.2497

1.08

0.95

1.22

Intracerebral hemorrhage

0.31

0.19

0.1017

1.37

0.94

1.99

Cardiac dysrhythmia

0.24

0.08

0.0026

1.27

1.09

1.48

Congestive heart failure

0.26

0.09

0.0045

1.30

1.08

1.55

Peripheral artery disease

0.29

0.15

0.0575

1.33

0.99

1.79

Peptic ulcer

-0.06

0.07

0.4113

0.94

0.81

1.09

Ischemic heart disease

-0.03

0.07

0.6555

0.97

0.85

1.11

Other medication

Aspirin

-0.07

0.06

0.2826

0.93

0.82

1.06

Corticosteroid

0.09

0.08

0.2390

1.09

0.94

1.27

NSAID

-0.04

0.07

0.5208

0.96

0.84

1.09

Antidepressant

0.13

0.10

0.1615

1.14

0.95

1.38

Benzodiazepine

-0.06

0.06

0.3624

0.94

0.83

1.07

Anticoagulant

-0.45

0.31

0.1484

0.64

0.35

1.17

Abbreviation: AD = Alzheimer’s diseases; CI = confidence interval; HR = hazard ratio; NSAID = non-steroidal anti-inflammatory drugs.

1Exclude 46 patients with prescription of both lipophilic and hydrophilic statin.

2Crude HR.

3Adjusted for age, gender, hypertension, and diabetes.

4Adjusted for all variables listed in this Table.