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Supplementary Table 1. High-dimensional Propensity Score Model Results of Probability of Using Angiotensin II receptor blockers.

95% CI

Parameter Estimate Odds Ratios Lower Upper P value

Age, per year -0.0018 0.998 0.993 1.004 0.5223

Year of Index Date

2000 1

2001 2.6212 13.752 8.717 21.695 <.0001

2002 4.4398 84.76 54.296 132.319 <.0001

2003 5.5934 268.65 172.227 419.057 <.0001

2004 6.1126 451.5 289.306 704.624 <.0001

2005 6.1388 463.505 296.526 724.513 <.0001

2006 6.4302 620.274 396.265 970.917 <.0001

2007 6.5696 713.08 454.773 >999.999 <.0001

2008 7.0899 >999.999 763.88 >999.999 <.0001

2009 7.1333 >999.999 795.925 >999.999 <.0001

Month of Index Date

January 1

February -0.0177 0.982 0.886 1.09 0.7372

March -0.0058 0.994 0.899 1.099 0.9101

April 0.1564 1.169 1.055 1.296 0.003

May 0.215 1.24 1.117 1.377 <.0001

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June 0.1698 1.185 1.069 1.314 0.0013

July 0.1331 1.142 1.027 1.271 0.0146

August 0.1823 1.2 1.074 1.341 0.0013

September 0.225 1.252 1.119 1.401 <.0001

October 0.3569 1.429 1.278 1.597 <.0001

November 0.3663 1.442 1.288 1.615 <.0001

December 0.4429 1.557 1.397 1.736 <.0001

Male -0.2786 0.757 0.718 0.798 <.0001

Outpatient Visits, in the past one year

010 visits -0.066 0.936 0.863 1.015 0.1097

1120 visits -0.1287 0.879 0.804 0.961 0.0047

2130 visits -0.1604 0.852 0.769 0.943 0.002

3140 visits -0.2839 0.753 0.675 0.84 <.0001

>40 visits -0.066 0.936 0.863 1.015 0.1097

Outpatient Visits of nephrologist, in the past one year

0 visits 1

15 visits 0.0196 1.02 0.95 1.095 0.5877

610 visits 0.1803 1.198 1.033 1.388 0.0168

>10 visits 0.1216 1.129 0.93 1.371 0.2187

Outpatient Visits of cardiologist, in the past one year

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0 visits 1

15 visits 0.2095 1.233 1.164 1.306 <.0001

610 visits 0.3201 1.377 1.27 1.493 <.0001

>10 visits 0.205 1.227 1.099 1.371 0.0003

Outpatient Visits of Metabolism

&Endocrinology, in the past one year

0 visits 1

15 visits 0.1933 1.213 1.116 1.319 <.0001

610 visits 0.1979 1.219 1.039 1.429 0.0149

>10 visits 0.1528 1.165 0.964 1.408 0.1132

Outpatient Visits of neurologist, in the past one year

0 visits 1

15 visits 0.0539 1.055 0.984 1.131 0.1287

610 visits 0.2049 1.227 1.077 1.399 0.0021

>10 visits 0.1241 1.132 0.954 1.344 0.1555

Hospital level of first prescription of ARB or ACEI

Level I (Medical center) 1.6005 4.956 4.594 5.346 <.0001

Level II 1.2602 3.526 3.282 3.788 <.0001

Level III 1.2157 3.373 3.156 3.605 <.0001

Level IV (Local medical clinics) 1

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Monthly income, NT$

Dependent 1

0–19,100 -0.1661 0.847 0.799 0.898 <.0001

19,100–42,000 -0.1716 0.842 0.793 0.894 <.0001

> 42,000 0.3068 1.359 0.996 1.855 0.053

Urbanization level^*

1 1

2 -0.0975 0.907 0.863 0.953 0.0001

3 0.0108 1.011 0.928 1.101 0.8053

4 0.035 1.036 0.876 1.224 0.6817

Charlson comorbidity index score^† -0.00916 0.991 0.955 1.028 0.6249 Anti-hypertensive drug

Number of anti-HTN drug

1 1

2 -0.1396 0.87 0.821 0.922 <.0001

3 -0.0974 0.907 0.812 1.014 0.0865

> 4 -0.00161 0.998 0.78 1.279 0.9898

Alpha-blocker -0.0606 0.941 0.827 1.071 0.3573

Beta-blocker -0.0759 0.927 0.822 1.045 0.2157

Calcium channel blocker 0.2162 1.241 0.538 2.863 0.6122

Diuretics -0.2173 0.805 0.739 0.876 <.0001

Other anti-hypertensive drug -0.4167 0.659 0.547 0.794 <.0001 Other concomitant medications

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Antiplatelet agent^‡ 0.024 1.024 0.955 1.099 0.5017

Warfarin -0.0723 0.93 0.732 1.182 0.5532

Steroid -0.0858 0.918 0.834 1.01 0.0799

Dipyridamole -0.0659 0.936 0.862 1.017 0.1171

Nitrate -0.2785 0.757 0.682 0.84 <.0001

NSAID -0.018 0.982 0.923 1.045 0.569

PPI 0.0545 1.056 0.887 1.257 0.5406

Statin 0.1691 1.184 1.086 1.292 0.0001

Estrogen or progesterone 0.0735 1.076 0.836 1.385 0.5678 Anti-hyperglycemic drug -0.0884 0.915 0.841 0.997 0.0413 Comorbidities

Diabetes mellitus -0.2417 0.785 0.682 0.904 0.0007

Coronary artery disease 0.000237 1 0.947 1.056 0.9932 Chronic pulmonary disease 0.0291 1.03 0.963 1.1 0.391

Asthma 0.0364 1.037 0.964 1.116 0.3306

Dementia 0.0114 1.011 0.86 1.189 0.8905

Heart failure -0.1432 0.867 0.795 0.944 0.0011

Peripheral vascular disease -0.0622 0.94 0.837 1.055 0.2933 Peptic ulcer disease 0.0376 1.038 0.977 1.103 0.2239

Liver disease -0.0423 0.959 0.894 1.027 0.2321

Chronic kidney disease 0.0877 1.092 0.986 1.209 0.0929

Atrial fibrillation -0.1143 0.892 0.787 1.01 0.0723

Dyslipidemia 0.1007 1.106 1.05 1.165 0.0002

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Valvular heart disease -0.0961 0.908 0.843 0.979 0.0115

Drug abuse -0.1249 0.883 0.658 1.185 0.4058

Cancer 0.0699 1.072 0.959 1.199 0.2184

AIDS -0.2277 0.796 0.242 2.621 0.7079

Plegia 0.1489 1.161 0.865 1.557 0.3211

Autoimmune disease 0.0822 1.086 0.936 1.26 0.2783

*Urbanization levels in Taiwan are divided into four strata according to the Taiwan National Health Research Institute publications. Level 1 designates the most urbanized areas, and level 4 designates the least urbanized areas.

†Charlson Comorbidity Index (CCI) score is used to determine overall systemic health. With each increased level of CCI score, there are stepwise increases in the cumulative

mortality.‡Including aspirin, clopidogrel, ticlopidine and cilostazol

Abbreviations: CI, confidence interval; ARB, angiotensin II receptor blocker; ACEI, angiotensin-converting-enzyme inhibitor;NT$, new Taiwan dollars; HTN, hypertension;

NSAID, Non-steroidal anti-inflammatory drug; PPI, proton pump inhibitors; AIDS, Acquired Immune Deficiency Syndrome.

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Supplementary Table 2.Intention-To-Treat Analysis of Incidence and Risk of MACE, All-Cause Mortality and Adverse Effects among Elderly Patients Using ACEIs andARBs before High-dimensional Propensity Score-Matching.

ARB user ACEI user (As reference) Crude Adjusted^†

No. of

Event Person-years Incidence rate*

No. of

Hazard Ratio

(95% CI) P value Hazard Ratio

(95% CI) P value Intention-To-Treat

yocardial infarction1,091 172,909 6.31 2,012 295,514 6.81 0.95 (0.88-1.02) 0.138 0.92 (0.81-1.04) 0.174

schemic Stroke3,050 166,952 18.27 5,786 283,022 20.44 0.90 (0.86-0.94) <0.001 0.93 (0.87-1.00) 0.060

ll-cause mortality9,484 174,785 54.26 18,656 299,497 62.29 0.90 (0.88-0.92) <0.001 0.88 (0.84-0.92) <0.001

ospitalization for heart failure1,034 147,275 7.02 1,901 256,810 7.40 0.98 (0.91-1.06) 0.633 0.92 (0.80-1.05) 0.215

ospitalization for acute kidney injury2,281 171,926 13.27 3,691 294,742 12.52 1.11 (1.05-1.17) <0.001 0.93 (0.85-1.03) 0.152

ospitalization for hyperkalemia904 173,374 5.21 1,512 296,809 5.09 1.06 (0.98-1.15) 0.167 0.97 (0.84-1.12) 0.706

* per 10³ person-years.

† Adjusted for high-dimensional propensity score.

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Abbreviations: MACE, major adverse cardiovascular events; ACEIs,angiotensin-converting-enzyme inhibitors; ARBs,Angiotensin II receptor blockers; CI, confidence interval.

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Supplementary Table 3.As-Treated Analysis of Incidence and Risk of MACE, All-Cause Mortality and Adverse Effects among Elderly Patients Using ACEIs andARBs before High-dimensional Propensity Score-Matching.

ARB user ACEI user (As reference) Adjusted^† Competing Risk

No. of

Hazard Ratio

(95% CI) P value Hazard Ratio

(95% CI) P value As Treated

yocardial infarction386 90,100 4.28 518 101,169 5.12 0.75 (0.60-0.93) 0.011 1.10 (0.91-1.34)^‡ 0.315

schemic Stroke1,269 88,553 14.33 1,847 99,695 18.53 0.75 (0.67-0.85) <0.001 1.07 (0.97-1.19)^‡ 0.165

ll-cause mortality905 90,713 9.98 1,209 101,845 11.87 0.74 (0.64-0.85) <0.001 1.03 (0.91-1.17)^§ 0.676

ospitalization for heart failure640 89,720 7.13 884 100,898 8.76 0.75 (0.63-0.89) 0.001 1.07 (0.92-1.25)^‡ 0.385

ospitalization for acute kidney injury560 89,930 6.23 503 101,311 4.96 0.94 (0.76-1.16) 0.561 0.95 (0.77-1.18)^|| 0.664

ospitalization for hyperkalemia274 90,237 3.04 290 101,470 2.86 1.01 (0.76-1.33) 0.970 1.02 (0.77-1.35)^|| 0.900

* per 10³ person-years.

† Adjusted for high-dimensional propensity score.

‡ Death and discontinuing drug were calculated as a competing risk and adjusted for high-dimensional propensity score.

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§ Discontinuing drug were calculated as a competing risk and adjusted for high-dimensional propensity score.

|| Death was calculated as a competing risk and adjusted for high-dimensional propensity score.

Abbreviations: MACE, major adverse cardiovascular events; ACEIs, angiotensin-converting-enzyme inhibitors; ARBs, Angiotensin II receptor blockers; CI, confidence interval.

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Supplementary Table 4.Subgroup analysis of Risk of Myocardial infarction among Patients Using ACEIs and ARBs

Characteristic Hazard Ratio

(95% CI) P value Interaction

P value Gender

Male 0.874 (0.718-1.063) 0.178 0.654

Female 0.934 (0.752-1.161) 0.539

Age

70-80 years 0.857 (0.710-1.035) 0.109 0.428

> 81 years 0.964 (0.767-1.213) 0.756

Charlson Comorbidity Index score

4-5 0.933 (0.801-1.088) 0.377 0.356

6-7 0.779 (0.441-1.374) 0.388

8-9 0.468 (0.180-1.219) 0.120

>10 0.342 (0.036-3.298) 0.354

Diabetes mellitus

Yes 0.909 (0.738-1.120) 0.372 0.941

No 0.897 (0.732-1.100) 0.297

Chronic kidney disease

Yes 0.716 (0.492-1.041) 0.080 0.189

No 0.939 (0.801-1.100) 0.433

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Heart failure

Yes 0.845 (0.626-1.141) 0.272 0.633

No 0.916 (0.775-1.081) 0.300

Coronary artery disease

Yes 0.897 (0.736-1.093) 0.283 0.998

No 0.898 (0.725-1.114) 0.329

Using other anti-hypertensive agent

Yes 0.935 (0.748-1.168) 0.552 0.666

No 0.875 (0.721-1.060) 0.172

* ACEI cohort as reference group

Abbreviations:ACEIs,angiotensin-converting-enzyme inhibitors; ARBs,Angiotensin II receptor blockers;CI, confidence interval.

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Supplementary Table 5.Subgroup analysis of Risk of Ischemic Stroke among Patients Using ACEIs and ARBs

P value Gender

Male 0.992 (0.878-1.122) 0.900 0.504

Female 0.937 (0.828-1.061) 0.306

Age

70-80 years 0.938 (0.838-1.049) 0.259 0.458

> 81 years 1.004 (0.873-1.154) 0.956

4-5 0.975 (0.889-1.070) 0.599 0.644

6-7 0.806 (0.593-1.095) 0.168

8-9 1.038 (0.625-1.723) 0.885

>10 1.228 (0.455-3.315) 0.685

Yes 0.954 (0.835-1.090) 0.489 0.809

No 0.974 (0.868-1.093) 0.654

Yes 1.029 (0.833-1.270) 0.794 0.506

No 0.952 (0.865-1.048) 0.318

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Heart failure

Yes 0.806 (0.740-1.111) 0.343 0.506

No 0.977 (0.887-1.076) 0.638

Yes 0.977 (0.863-1.107) 0.715 0.771

No 0.952 (0.843-1.076) 0.432

Yes 1.038 (0.910-1.184) 0.582 0.150

No 0.911 (0.811-1.023) 0.116

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Supplementary Table 6. Subgroup analysis of Risk of Heart Failureamong Patients Using ACEIs and ARBs

P value Gender

Male 0.798 (0.670-0.950) 0.011 0.043

Female 1.019 (0.868-1.197) 0.817

Age

70-80 years 0.887 (0.752-1.045) 0.151 0.662

> 81 years 0.934 (0.789-1.107) 0.432

4-5 0.919 (0.809-1.044) 0.196 0.659

6-7 0.844 (0.583-1.221) 0.368

8-9 1.181 (0.608-2.292) 0.623

>10 0.612 (0.241-1.555) 0.302

Yes 0.966 (0.801-1.166) 0.721 0.443

No 0.879 (0.755-1.022) 0.094

Yes 0.882 (0.680-1.144) 0.343 0.811

No 0.919 (0.805-1.049) 0.213

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Heart failure

Yes 0.792 (0.663-0.947) 0.010 0.041

No 1.004 (0.858-1.176) 0.958

Yes 0.995 (0.851-1.162) 0.945 0.093

No 0.809 (0.675-0.969) 0.021

Yes 0.869 (0.711-1.063) 0.172 0.568

No 0.934 (0.808-1.081) 0.360

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Supplementary Table 7.Subgroup analysis of Risk of All-cause Mortality among Patients Using ACEIs and ARBs

P value Gender

Male 0.883 (0.827-0.943) <0.001 0.619

Female 0.906 (0.843-0.973) 0.006

Age

70-80 years 0.910 (0.950-0.974) 0.007 0.364

> 81 years 0.971 (0.813-0.933) <0.001 Charlson Comorbidity Index score

4-5 0.896 (0.850-0.944) <0.001 0.935

6-7 0.853 (0.727-1.002) 0.053

8-9 0.899 (0.680-1.189) 0.455

>10 0.958 (0.670-1.370) 0.816

Yes 0.951 (0.881-1.027) 0.202 0.040

No 0.858 (0.806-0.914) <0.001

Yes 0.908 (0.813-1.014) 0.087 0.770

No 0.891 (0.844-0.941) <0.001

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Heart failure

Yes 0.857 (0.778-0.945) 0.002 0.309

No 0.903 (0.854-0.955)

Yes 0.895 (0.834-0.960) 0.002 0.950

No 0.892 (0.834-0.954) 0.001

Yes 0.907 (0.841-0.977) 0.010 0.589

No 0.883 (0.829-0.941) <0.001

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Supplementary Table 8.Subgroup analysis of Risk of Acute Kidney Injury among Patients Using ACEIs and ARBsInhibitors

P value Gender

Male 0.932 (0.814-1.066) 0.305 0.422

Female 1.013 (0.868-1.182) 0.869

Age

70-80 years 0.950 (0.827-1.090) 0.461 0.753

> 81 years 0.981 (0.844-1.140) 0.806

4-5 0.977 (0.874-1.091) 0.677 0.947

6-7 0.889 (0.651-1.215) 0.461

8-9 0.930 (0.557-1.554) 0.783

>10 1.071 (0.523-2.192) 0.851

Yes 1.056 (0.908-1.229) 0.480 0.129

No 0.901 (0.786-1.034) 0.138

Yes 1.011 (0.829-1.232) 0.915 0.624

No 0.955 (0.848-1.075) 0.442

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Heart failure

Yes 0.947 (0.774-1.158) 0.595 0.421

No 0.870 (0.863-1.091) 0.613

Yes 1.010 (0.871-1.171) 0.897 0.340

No 0.929 (0.808-1.068) 0.301

Yes 1.026 (0.875-1.204) 0.752 0.168

No 0.927 (0.813-1.058) 0.261

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Supplementary Table 9. Subgroup analysis of Risk of Hyperkalemia among Patients Using ACEIs and ARBsInhibitors

(95% CI) P value Interaction P value Gender

M

ale 0.986 (0.785-1.238) 0.901 0.852

F

emale 1.018 (0.807-1.283) 0.882

Age

7

0-80 years 0.991 (0.795-1.235) 0.935 0.919

>

81 years 1.007 (0.791-1.281) 0.956

4

-5 0.953 (0.796-1.142) 0.605 0.193

6

-7 1.329 (0.813-2.171) 0.256

8

-9 1.513 (0.774-2.957) 0.226

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>

10 0.433 (0.112-1.676) 0.226

Y

es 1.234 (0.975-1.563) 0.081 0.017

N

o 0.931 (0.663-1.042) 0.109

Y

es 0.999 (0.756-1.322) 0.997 0.938

N

o 1.011 (0.828-1.235) 0.914

Heart failure

Y

es 0.977 (0.697-1.369) 0.892 0.244

N

o 1.007 (0.836-1.212) 0.944

Y

es 0.903 (0.711-1.148) 0.405 0.998

N

o 1.095 (0.877-1.367) 0.422

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Y

es 1.153 (0.889-1.494) 0.283 0.168

N

o 0.914 (0.741-1.126) 0.398

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