Contents · Supplementary material 8. Propensity score adjusted rate ratios of all outcomes without trimming band Outcomes by treatment duration No of patients No of events Rate ratio

1

Appendix: Cardiovascular outcomes associated with use of

clarithromycin: population based study

Contents Supplementary material 1: ICD-9 and ICD-10 codes for outcomes identification ...................................... 2

Supplementary material 2. Helicobacter pylori eradication therapy regimen containing clarithromycin

with appropriate doses ................................................................................................................................ 3

Supplementary material 3. List of covariates included in Propensity Score with ICD codes ...................... 4

Supplementary material 4. Distribution of propensity scores in 20 strata *† .............................................. 6

Supplementary material 5. Number of prescriptions for out-patient Helicobacter pylori treatment

containing-clarithromycin from 2003-2012 ................................................................................................ 7

Supplementary material 6. Baseline characteristics of trimmed cohort at index date in cohort analysis ..... 8

Supplementary material 7. Propensity score distributions before and after propensity score trimming .... 10

Supplementary material 8. Propensity score adjusted rate ratios of all outcomes without trimming band 11

Supplementary material 9. Rate ratios of all outcomes for current and recent use of clarithromycin versus

amoxicillin in sensitivity analysis ............................................................................................................. 15

Supplementary material 10. Subgroup analysis of risk of cardiovascular outcomes associated with current

use of clarithromycin versus amoxicillin .................................................................................................. 17

2

Supplementary material 1: ICD-9 and ICD-10 codes for outcomes identification

ICD-9 Codes

Myocardial Infarction 410

Arrhythmia 426.82, 427.0, 427.1, 427.2, 427.41, 427.42, 427.5, 427.60

Stroke 430, 431, 432, 433.01, 433.11, 433.21, 433.31, 433.81, 433.91, 434,

436, 437.0, 437.1

ICD-10 Codes

Cardiac death I11, I13, I20-25, I27, I30-52

3

Supplementary material 2. Helicobacter pylori eradication therapy regimen containing

clarithromycin with appropriate doses

Co-prescription of two antibiotics and one of the proton pump inhibitors:

Clarithromycin 500mg bd Amoxicillin 1000mg bd Esomeprazole 20mg bd

Lansoprazole 30mg bd

Omeprazole 20mg bd

Pantoprazole 40mg bd

Rabeprazole 20mg bd

Clarithromycin 250mg bd Metronidazole 400mg bd Esomeprazole 20mg bd

Lansoprazole 30mg bd

Omeprazole 20mg bd

Pantoprazole 40mg bd

Rabeprazole 20mg bd

4

Supplementary material 3. List of covariates included in Propensity Score with ICD codes

Parameters

Demographic factors

Calendar month at exposure

Medical history ICD9 Codes

Respiratory related disease

Chronic obstructive pulmonary disease or related 490-492, 494, 496

Endocrine and metabolic disorders

Obesity 278.0

Hyperlipidaemia 272.0-272.2, 272.4

Diabetes and related complications 249, 250

Thyroid disorders 242-244

Cardiovascular related disease

Hypertensive diseases 401-405

Coronary heart disease 410, 411, 412, 413, 414, 429.71, 429.79

Cerebrovascular diseases 430-437

Arterial disease 433.00, 433.10, 433.20, 433.30, 433.80, 433.90,

440-445, 447, 557

Cardiomyopathy 425

Heart failure 402.01, 402.11, 402.91, 404.01, 404.03, 404.11,

404.13, 404.91, 404.93, 428

Valve disorders 424

Arrhythmia and conduction disorders 426-427

Renal disease

Hypertensive renal disease 403-404

Renal failure 584-586

Liver disease

Esophageal varices 456.0, 456.1, 456.2

Hepatic failure, liver fibrosis and cirrhosis 570, 571

Psychiatric disease

Schizophrenia and psychosis 295, 297, 298.3, 298.4, 298.8, 298.9

Bipolar disorder 296.0, 296.1, 296.4-296.7, 296.80, 296.81

296.89

Depression 296.2, 296.3, 296.82, 298.0, 300.4, 311

Prescription drug used in past year

ARB/ACE-I

Calcium channel blockers

Loop diuretics

Other diuretics

Beta-blockers

Anti-arrhythmics class I and II

Digoxin

Nitrates

Platelet inhibitors

Anticoagulants

Peripheral vasodilator

Lipid lowering drugs

Insulin

Oral hypoglycemic agent

Antidepressants

Antipsychotics

Oral corticosteroids

NSAIDS

5

PPI/H-2 blocker

Number of drugs used

Health care use

Number of outpatients visits in past year

Number of inpatient stays in past year

Number of emergency visits in past year

6

Supplementary material 4. Distribution of propensity scores in 20 strata *†

Propensity

score

Clarithromycin users Amoxicillin users

N (%) Myocardial infarction (%) N (%) Myocardial infarction (%)

1 2356 (2.2) 13 (3.5) 13 984 (6.4) 61 (6.8)

2 3284 (3.0) 9 (2.5) 13 055 (6.0) 67 (7.5)

3 3061 (2.8) 18 (4.9) 13 278 (6.1) 85 (9.5)

4 2914 (2.7) 8 (2.2) 13 425 (6.2) 66 (7.4)

5 3074 (2.8) 18 (4.9) 14 344 (6.6) 46 (5.2)

6 2557 (2.4) 9 (2.5) 12 733 (5.9) 40 (4.5)

7 2677 (2.5) 5 (1.4) 13 669 (6.3) 41 (4.6)

8 2925 (2.7) 8 (2.2) 14 165 (6.5) 36 (4.0)

9 2745 (2.5) 7 (1.9) 12 806 (5.9) 35 (3.9)

10 4075 (3.7) 8 (2.2) 12 282 (5.6) 40 (4.5)

11 4935 (4.5) 13 (3.5) 11 638 (5.3) 39 (4.4)

12 6455 (5.9) 16 (4.4) 9634 (4.4) 21 (2.4)

13 5930 (5.4) 7 (1.9) 10 408 (4.8) 39 (4.4)

14 5838 (5.4) 21 (5.7) 10 500 (4.8) 49 (5.5)

15 6414 (5.9) 30 (8.2) 9925 (4.6) 40 (4.5)

16 7612 (7.0) 47 (12.8) 8727 (4.0) 53 (5.9)

17 8860 (8.1) 32 (8.7) 7479 (3.4) 53 (5.9)

18 10 520 (9.7) 32 (8.7) 5819 (2.7) 24 (2.7)

19 11 921 (10.9) 32 (8.7) 4418 (2.0) 27 (3.0)

20 10 835 (9.9) 34 (9.3) 5504 (2.5) 30 (3.4)

* 1 indicates smallest probability of receiving clarithromycin; 20 indicates highest probability of

receiving clarithromycin †Value in (%) was corrected to 1 decimal place

7

Supplementary material 5. Number of prescriptions for out-patient Helicobacter pylori

treatment containing-clarithromycin from 2003-2012

8

Supplementary material 6. Baseline characteristics of trimmed cohort at index date in

cohort analysis. Values are numbers (percentages) unless stated otherwise

Characteristics Clarithromycin users

(n=95 797)

Amoxicillin users

(n=198 305)

Median age (years) 59.0 60.0

Men 49 652 (51.8) 104 050 (52.5)

Calendar month at exposure

January 8247 (8.6) 17 928 (9.0)

February 8025 (8.4) 16 686 (8.4)

March 8996 (9.4) 18 885 (9.5)

April 8293 (8.7) 17 140 (8.6)

May 8269 (8.6) 17 268 (8.7)

June 7897 (8.2) 16 592 (8.4)

July 8023 (8.4) 16 469 (8.3)

August 8009 (8.4) 16 131 (8.1)

September 7452 (7.8) 15 425 (7.8)

October 7449 (7.8) 15 047 (7.6)

November 7401 (7.7) 15 008 (7.6)

December 7736 (8.1) 15 726 (7.9)

Medical history:

Chronic obstructive pulmonary disease 4324 (4.5) 5739 (2.9)

Obesity 231 (0.2) 351 (0.2)

Diabetes 8566 (8.9) 14 416 (7.3)

Thyroid disorders 1511 (1.6) 3002 (1.5)

Hyperlipidaemia 3567 (3.7) 5849 (3.0)

Hypertensive diseases 14 290 (14.9) 24 328 (12.3)

Coronary heart disease 6581 (6.9) 10 429 (5.3)

Cerebrovascular diseases 6981 (7.3) 11 459 (5.8)

Arterial disease 1666 (1.7) 2540 (1.3)

Cardiomyopathy 293 (0.3) 461 (0.2)

Heart failure 4078 (4.3) 5724 (2.9)

Valve disorders 537 (0.6) 997 (0.5)

Arrhythmia and conduction disorders 4999 (5.2) 8731 (4.4)

Hypertensive renal disease 296 (0.3) 383 (0.2)

Renal failure 1928 (2.0) 2581 (1.3)

Oesophageal varices 133 (0.1) 133 (0.1)

Hepatic failure, liver fibrosis and cirrhosis 1075 (1.1) 1472 (0.7)

Schizophrenia, delusional disorders and

psychosis

1739 (1.8) 3775 (1.9)

Bipolar disorder 190 (0.2) 429 (0.2)

Depression 2569 (2.7) 4720 (2.4)

Prescription in past year:

Angiotensin receptor blocker/angiotensin

converting enzyme inhibitor

13 791 (14.4) 24 758 (12.5)

Calcium channel blockers 18 619 (19.4) 35 205 (17.8)

Loop diuretics 7290 (7.6) 10 189 (5.1)

Other diuretics 7617 (8.0) 15 103 (7.6)

β blockers 16 658 (17.4) 31 485 (15.9)

Anti-arrhythmics class I and II 937 (1.0) 1380 (0.7)

Digoxin 2044 (2.1) 3203 (1.6)

Nitrates 7942 (8.3) 12 008 (6.1)

Platelet inhibitors 14 871 (15.5) 24 069 (12.1)

Anticoagulants 2977 (3.1) 4920 (2.5)

Peripheral vasodilators 775 (0.8) 1258 (0.6)

Lipid lowering drugs 8288 (8.7) 14 468 (7.3)

9

Insulin 2611 (2.7) 3629 (1.8)

Oral hypoglycemic agent 11 080 (11.6) 21 012 (10.6)

Antidepressants 4549 (4.8) 8091 (4.1)

Antipsychotics 3496 (3.7) 6598 (3.3)

Oral corticosteroids 6516 (6.8) 7796 (3.9)

Non-steroidal anti-inflammatory drugs 15 728 (16.4) 27 527 (13.9)

Proton pump inhibitors/H2 receptor

blockers

45 043 (47.0) 38 840 (19.6)

Median No (interquartile range) of

prescriptions used in past year

14 (4-38) 11 (2-29)

Health care use in past year:


outpatient visits

5 (1-10) 4 (1-9)


inpatient stays

1 (0-1) 0 (0-1)


emergency department visits

1 (0-2) 0 (0-1)

10

Supplementary material 7. Propensity score distributions before and after propensity score

trimming

11

Supplementary material 8. Propensity score adjusted rate ratios of all outcomes without

trimming band

Outcomes by treatment

duration No of patients No of events

Rate ratio

(95% CI)

Myocardial infarction*

Day 1-14

Clarithromycin 102 514 132

3.57

(2.78 to 4.57)

Amoxicillin 204 851 149 ---

Day 15-30


1.00

(0.48 to 2.08)


Day 31-90


1.11

(0.67 to 1.86)


Day 91-365


0.94

(0.70 to 1.27)


Day 366-730


1.17

(0.88 to 1.57)


Day 731-1095


1.03

(0.75 to 1.42)


Arrhythmia*

Day 1-14


2.30

(1.30 to 4.09)


Day 15-30


0.81

(0.33 to 1.97)


Day 31-90


0.79

(0.45 to 1.40)


Day 91-365


1.10

(0.74 to 1.63)


Day 366-730

Clarithromycin 55 081 36 1.13

12

(0.74 to 1.72)


Day 731-1095


1.14

(0.70 to 1.83)


Stroke*

Day 1-14


1.13

(0.83 to 1.54)


Day 15-30


1.13

(0.66 to 1.94)


Day 31-90


1.33

(0.99 to 1.78)


Day 91-365


1.04

(0.87 to 1.25)


Day 366-730


1.12

(0.93 to 1.34)


Day 731-1095


1.16

(0.96 to 1.40)


All-cause mortality*

Day 1-14


1.72

(1.61 to 1.83)

Amoxicillin 217 788 2562 ---

Day 15-30


0.89

(0.80 to 0.99)

Amoxicillin 213 275 1611 ---

Day 31-90


0.68

(0.62 to 0.75)

Amoxicillin 205 313 2283 ---

Day 91-365


0.89

(0.82 to 0.97)

Amoxicillin 191 066 2563 ---

13

Day 366-730


0.99

(0.89 to 1.11)

Amoxicillin 161 948 1544 ---

Day 731-1095


0.98

(0.84 to 1.13)


Cardiac mortality†

Day 1-14


1.71

(1.41 to 2.06)


Day 15-30


1.30

(0.94 to 1.80)


Day 31-90


0.78

(0.57 to 1.07)


Day 91-365


0.86

(0.66 to 1.11)


Day 366-730


0.96

(0.70 to 1.33)


Day 731-1095


0.77

(0.52 to 1.14)


Non-cardiac mortality*

Day 1-14


1.79

(1.67 to 1.92)

Amoxicillin 217 788 2067 ---

Day 15-30


0.89

(0.79 to 0.99)

Amoxicillin 213 275 1335 ---

Day 31-90


0.69

(0.62 to 0.76)

Amoxicillin 205 313 1808 ---

Day 91-365

Clarithromycin 65 875 655 0.92

14

(0.83 to 1.01)

Amoxicillin 191 066 1799 ---

Day 366-730


1.05

(0.92 to 1.20)

Amoxicillin 161 948 1052 ---

Day 731-1095


1.04

(0.87 to 1.25)


Days 1-14=current use; days 15-30=recent use; days 31-1095=past use.

* Analysis with adjustment for age, sex and propensity score †

Analysis with adjustment for age, sex, history of myocardial infarction and arrhythmia, and propensity score

15

Supplementary material 9. Rate ratios of all outcomes for current and recent use of

clarithromycin versus amoxicillin in sensitivity analysis

Before PS adjustment

Propensity scores

trimming 1st & 20th strata

Propensity scores

without trimming strata

Outcomes by

treatment duration

Rate ratio*

(95% CI)

Rate ratio‡

(95% CI)

Rate ratio‡

(95% CI)

Myocardial infarction

Day 1-7

Clarithromycin

2.51

(1.95 to 3.22)

3.47

(2.63 to 4.57)

3.34

(2.56 to 4.34)

Amoxicillin --- --- ---

Day 8-30

Clarithromycin

1.63

(1.01 to 2.64)

1.50

(0.82 to 2.73)

1.54

(0.92 to 2.58)


Outcomes by

treatment duration

Rate ratio*

(95% CI)

Rate ratio‡

(95% CI)

Rate ratio‡

(95% CI)

Arrhythmia

Day 1-7

Clarithromycin

2.96

(1.57 to 5.60)

3.52

(1.71 to 7.23)

3.41

(1.73 to 6.73)


Day 8-30

Clarithromycin

0.88

(0.44 to 1.76)

0.77

(0.35 to 1.72)

0.76

(0.36 to 1.58)


Outcomes by

treatment duration

Rate ratio*

(95% CI)

Rate ratio‡

(95% CI)

Rate ratio‡

(95% CI)

Stroke

Day 1-7

Clarithromycin

0.93

(0.67 to 1.29)

1.04

(0.72 to 1.50)

1.06

(0.75 to 1.49)


Day 8-30

Clarithromycin

1.22

(0.82 to 1.80)

1.11

(0.71 to 1.75)

1.10

(0.72 to 1.69)


Outcomes by

treatment duration

Rate ratio*

(95% CI)

Rate ratio‡

(95% CI)

Rate ratio‡

(95% CI)

All-cause mortality

Day 1-7

Clarithromycin

2.67

(2.48 to 2.88)

2.23

(2.04 to 2.43)

1.98

(1.83 to 2.15)


Day 8-30

Clarithromycin

1.58

(1.47 to 1.69)

1.17

(1.07 to 1.27)

1.04

(0.96 to 1.12)


16

Outcomes by

treatment duration

Rate ratio†

(95% CI)

Rate ratioa

(95% CI)

Rate ratioa

(95% CI)

Cardiac mortality

Day 1-7

Clarithromycin

1.83

(1.48 to 2.26)

1.62

(1.27 to 2.07)

1.62

(1.29 to 2.03)


Day 8-30

Clarithromycin

1.62

(1.29 to 2.03)

1.47

(1.13 to 1.92)

1.44

(1.13 to 1.83)


Outcomes by

treatment duration

Rate ratio*

(95% CI)

Rate ratio‡

(95% CI)

Rate ratio‡

(95% CI)

Non-cardiac mortality

Day 1-7

Clarithromycin

2.91

(2.68 to 3.15)

2.42

(2.20 to 2.67)

2.10

(1.93 to 2.30)


Day 8-30

Clarithromycin

1.64

(1.52 to 1.77)

1.20

(1.09 to 1.31)

1.04

(0.96 to 1.13)


Days 1-7=current use; days 8-30=recent use.

* Analysis with initial adjustment for age, sex † Analysis with initial adjustment for age, sex and history of myocardial infarction and arrhythmia

‡ Analysis with full adjustment for age, sex, and propensity score

a Analysis with full adjustment for age, sex, and history of myocardial infarction and arrhythmia and propensity

score

17

Supplementary material 10. Subgroup analysis of risk of cardiovascular outcomes

associated with current use of clarithromycin versus amoxicillin Rate ratio

(95%CI)*

Absolute risk difference per 1000

(95%CI)*

Cardiac death

Sex

Male 1.71 (1.31 to 2.23) 1.15 (0.50 to 1.98)

Female 1.62 (1.16 to 2.25) 0.75 (0.19 to 1.51)

Age

18-64 2.13 (1.07 to 4.23) 0.20 (0.01 to 0.57)

65-74 1.73 (1.05 to 2.84) 0.87 (0.06 to 2.19)

75+ 1.60 (1.25 to 2.03) 2.63 (1.10 to 4.52)

History of hypertensive diseases

No 1.53 (1.17 to 1.99) 0.57 (0.18 to 1.07)

Yes 1.90 (1.37 to 2.65) 3.47 (1.43 to 6.36)

History of diabetes mellitus

No 1.57 (1.24 to 1.99) 0.71 (0.30 to 1.24)

Yes 2.03 (1.32 to 3.12) 3.71 (1.15 to 7.63)

Myocardial infarction

Sex

Male 3.64 (2.57 to 5.15) 2.13 (1.27 to 3.35)

Female 3.74 (2.51 to 5.56) 1.68 (0.93 to 2.79)

Age

18-64 5.11 (2.63 to 9.90) 0.63 (0.25 to 1.37)

65-74 2.14 (1.19 to 3.86) 1.15 (0.19 to 2.89)

75+ 4.00 (2.89 to 5.54) 5.77 (3.63 to 8.73)


No 3.78 (2.73 to 5.23) 1.51 (0.94 to 2.29)

Yes 3.32 (2.15 to 5.12) 4.78 (2.37 to 8.49)


No 3.76 (2.79 to 5.07) 1.65 (1.07 to 2.43)

Yes 3.12 (1.82 to 5.35) 4.95 (1.91 to 10.15)

Arrhythmia

Sex

Male 2.40 (1.17 to 4.91) 0.30 (0.04 to 0.85)

Female 1.92 (0.64 to 5.75) 0.09 (-0.04 to 0.46)

Age

18-64 3.99 (1.10 to 14.50) 0.13 (0.00† to 0.60)

65-74 2.21 (0.53 to 9.32) 0.18 (-0.07 to 1.27)

75+ 1.92 (0.89 to 4.13) 0.40 (-0.05 to 1.36)


No 2.58 (1.26 to 5.27) 0.20 (0.03 to 0.55)

Yes 1.61 (0.55 to 4.75) 0.24 (-0.17 to 1.45)


No 2.49 (1.29 to 4.81) 0.21 (0.04 to 0.53)

Yes 1.25 (0.29 to 5.36) 0.11 (-0.31 to 1.89)

*Adjusted for propensity score with trimming 1st and 20

th strata

† Value was 0.004 when corrected to 3 decimal places.

18

Documents

Contents · Supplementary material 8. Propensity score adjusted rate ratios of all outcomes without trimming band Outcomes by treatment duration No of patients No of events Rate ratio