1Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
2Cancer Research Institute, Seoul National University, Seoul, Korea
3Interdisciplinary Program in Cancer Biology Major, Seoul National University College of Medicine, Seoul, Korea
4Division of Cardiology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
5Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
6Department of Preventive Medicine, Korea University College of Medicine, Seoul, Korea
7Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Korea
Copyright © 2020 The Korean Society for Preventive Medicine
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
CONFLICT OF INTEREST
The authors have no conflicts of interest associated with the material presented in this paper.
FUNDING
This study was funded by the Korean Foundation for Cancer Research (grant No. CB-2017-A-2).
AUTHOR CONTRIBUTIONS
Conceptualization: SM, HYL, SKP. Data curation: SM, SKP. Formal analysis: SM. Funding acquisition: SKP. Methodology: SM, SKP, JJ. Project administration: SM, SKP. Visualization: SM. Writing – original draft: SM. Writing – review & editing: SM, HYL, SKP, JJ.
Characteristics |
Cohort data before IPTW |
ASD |
Cohort data after IPTW |
ASD | ||
---|---|---|---|---|---|---|
ARB users (n = 21 619) | CCB users (n = 38 850) | ARB users (n = 20 614)1 | CCB users (n = 38 395)1 | |||
Women | 9807 (45.4) | 17 898 (46.1) | 0.014 | 9623 (46.7) | 17 624 (45.9) | 0.016 |
Income level2 | 0.109 | 0.025 | ||||
Lowest | 3218 (14.9) | 6875 (17.7) | 3349 (16.2) | 6521 (17.0) | ||
Intermediate | 6250 (28.9) | 11 826 (30.4) | 6176 (30.0) | 11 409 (29.7) | ||
Highest | 7644 (35.4) | 11 999 (30.9) | 6834 (33.2) | 12 417 (32.3) | ||
Smoking | 0.130 | 0.027 | ||||
Never | 13 925 (64.4) | 25 859 (66.6) | 13 618 (66.1) | 25 373 (66.1) | ||
Past or current | 6959 (32.2) | 11 271 (29.0) | 6183 (30.0) | 11 471 (29.9) | ||
Missing | 735 (3.4) | 1720 (4.4) | 812 (3.9) | 1551 (4.0) | ||
Alcohol (times/wk) | 0.109 | 0.022 | ||||
Never | 13 548 (62.7) | 25 809 (66.4) | 13 591 (65.9) | 24 995 (65.1) | ||
1-2 | 4728 (21.9) | 5887 (17.7) | 3918 (19.0) | 7336 (19.1) | ||
≥3 | 3036 (14.0) | 5452 (14.0) | 2764 (13.4) | 5416 (14.1) | ||
Missing | 307 (1.4) | 702 (1.8) | 341 (1.7) | 649 (1.7) | ||
Exercise (times/wk) | 0.092 | 0.006 | ||||
Never | 10 949 (50.6) | 21 139 (54.4) | 10 960 (53.2) | 20 379 (53.1) | ||
1-2 | 5393 (24.9) | 8736 (22.5) | 4788 (23.2) | 8945 (23.3) | ||
≥3 | 4861 (22.5) | 8001 (20.6) | 4408 (21.4) | 8185 (21.3) | ||
Missing | 416 (1.9) | 974 (2.5) | 458 (2.2) | 887 (2.3) | ||
Antihypertensive medication | ||||||
ACE inhibitors | 285 (1.3) | 2923 (7.5) | 0.305 | 691 (3.4) | 2066 (5.4) | 0.099 |
Beta-blockers | 1344 (6.2) | 5720 (14.7) | 0.281 | 2056 (10.0) | 4607 (12.0) | 0.065 |
Diuretics | 9773 (45.2) | 7343 (18.9) | 0.587 | 5909 (28.7) | 10 595 (27.6) | 0.024 |
Others | 74 (0.3) | 246 (0.6) | 0.042 | 82 (0.4) | 216 (0.6) | 0.019 |
No. of drugs | 0.386 | 0.050 | ||||
Monotherapy | 11 085 (51.3) | 25 688 (66.1) | 13 083 (63.5) | 23 543 (61.3) | ||
Combination therapy | 10 534 (48.7) | 13 162 (33.9) | 7531 (36.5) | 14 852 (38.7) | ||
Comorbidity | ||||||
COPD | 3681 (17.0) | 6146 (15.8) | 0.033 | 3445 (16.7) | 6226 (16.2) | 0.013 |
CCI (≥1) | 1104 (5.1) | 1332 (3.4) | 0.083 | 929 (4.5) | 1512 (3.9) | 0.028 |
Diabetes mellitus | 4607 (21.3) | 4789 (12.3) | 0.242 | 3317 (16.1) | 5750 (15.0) | 0.031 |
Dyslipidemia | 5545 (25.6) | 6245 (16.1) | 0.237 | 4239 (20.6) | 7320 (19.1) | 0.038 |
MI or stroke | 1390 (6.4) | 2389 (6.1) | 0.042 | 1367 (6.6) | 2457 (6.4) | 0.018 |
Congestive heart failure | 697 (3.2) | 798 (2.1) | 0.073 | 571 (2.8) | 966 (2.5) | 0.016 |
Chronic kidney diseases | 689 (3.2) | 604 (1.6) | 0.107 | 450 (2.2) | 740 (1.9) | 0.018 |
Comedication | ||||||
Metformin | 2696 (12.5) | 1771 (4.6) | 0.286 | 1603 (7.8) | 2592 (6.8) | 0.040 |
Sulfonylurea | 2597 (12.0) | 2545 (6.6) | 0.189 | 1835 (8.9) | 3127 (8.1) | 0.027 |
Insulin | 120 (0.6) | 49 (0.1) | 0.074 | 67 (0.3) | 74 (0.2) | 0.026 |
Thiazolidinedione | 365 (1.7) | 177 (0.5) | 0.120 | 199 (1.0) | 299 (0.8) | 0.020 |
NSAIDs | 4385 (20.3) | 8500 (21.9) | 0.039 | 4331 (21.0) | 8244 (21.5) | 0.011 |
Aspirin | 4466 (20.7) | 8241 (21.2) | 0.014 | 4379 (21.2) | 8103 (21.1) | 0.003 |
Statin | 4908 (22.7) | 5248 (13.5) | 0.240 | 3714 (18.0) | 6247 (16.3) | 0.046 |
Age (y) | 58.5±8.7 | 60.0±9.3 | 0.159 | 59.2±8.9 | 59.6±9.3 | 0.046 |
BMI (kg/m2) | 24.7±2.9 | 24.7±2.9 | 0.016 | 24.7±2.9 | 24.7±2.9 | 0.004 |
SBP (mmHg) | 138.3±16.7 | 141.8±18.4 | 0.200 | 139.8±16.9 | 140.7±18.2 | 0.053 |
DBP (mmHg) | 85.8±11.2 | 87.5±11.9 | 0.142 | 86.5±11.2 | 86.9±11.8 | 0.038 |
FBS (mg/dL) | 105.6±35.9 | 100.8±31.0 | 0.146 | 102.6±31.2 | 102.0±33.2 | 0.019 |
Cholesterol (mg/dL) | 206.2±38.1 | 205.9±38.6 | 0.009 | 205.9±37.5 | 206.1±38.9 | 0.004 |
AST (U/L) | 27.2±16.0 | 27.6±16.0 | 0.024 | 27.3±17.2 | 27.5±15.6 | 0.010 |
ALT (U/L) | 27.0±19.4 | 26.7±20.5 | 0.017 | 26.8±20.4 | 26.8±20.0 | 0.003 |
γ-GTP (U/L) | 42.6±55.4 | 41.9±55.5 | 0.013 | 41.6±56.5 | 42.3±56.1 | 0.012 |
No. of doctor visits (/y) | 17.3±16.0 | 14.8±14.2 | 0.161 | 16.3±14.8 | 15.7±15.9 | 0.039 |
Values are presented as number (%) or mean±standard deviation.
ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; IPTW, inverse probability treatment weighting; ASD, absolute standardized mean difference; ACE, angiotensin converting enzyme; COPD, chronic obstructive pulmonary disease; CCI, Charlson Comorbidity Index; MI, myocardial infarction; NSAID, non-steroidal anti-inflammatory drugs; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBS, fasting blood sugar level; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, gamma-glutamyl transferase.
1 The number of subjects is given as a weighted number rounded to the first decimal place.
2 The intermediate group included the lower group, and the highest group included the upper-middle group.
Group | Person-years | Lung cancer cases (n)1 | HR (95% CI)2 |
---|---|---|---|
Cohort data before IPTW | |||
CCB | 286 256 | 366 | 1.00 (reference) |
ARB | 122 005 | 110 | 0.74 (0.60, 0.92)3 |
Cohort data after IPTW | |||
CCB | 286 256 | 357 | 1.00 (reference) |
ARB | 122 005 | 108 | 0.75 (0.59, 0.96) |
Censored at drug discontinuation or change4 | |||
CCB | 140 747 | 136 | 1.00 (reference) |
ARB | 66 359 | 29 | 0.50 (0.32, 0.77) |
Monotherapy5 | |||
CCB | 155 793 | 169 | 1.00 (reference) |
ARB | 49 614 | 42 | 0.81 (0.57, 1.15) |
1-Year lag | |||
CCB | 285 775 | 335 | 1.00 (reference) |
ARB | 121 396 | 105 | 0.80 (0.62, 1.03) |
2-Year lag | |||
CCB | 301 796 | 292 | 1.00 (reference) |
ARB | 127 790 | 85 | 0.74 (0.54, 1.02) |
ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; HR, hazard ratio; CI, confidence interval; IPTW, inverse probability treatment weighting.
1 The numbers of cases were weighted numbers rounded to the first decimal place except the cohort before IPTW.
2 Adjusted by IPTW, except for the cohort data before IPTW.
3 Crude HR.
4 CCB users were censored when they stopped CCB or were prescribed ARB, or vice versa.
5 CCB-only users and ARB-only users without any other antihypertensive medication at baseline.
Group | Person-years | Lung cancer cases (n)1 | HR (95% CI)2 |
---|---|---|---|
Men | |||
CCB | 154 018 | 264 | 1.00 (reference) |
ARB | 66 768 | 88 | 0.83 (0.62, 1.09) |
Women | |||
CCB | 132 238 | 93 | 1.00 (reference) |
ARB | 55 236 | 20 | 0.56 (0.34, 0.93) |
Age <60 | |||
CCB | 148 888 | 76 | 1.00 (reference) |
ARB | 76 246 | 31 | 0.87 (0.55, 1.40) |
Age ≥60 | |||
CCB | 137 368 | 289 | 1.00 (reference) |
ARB | 45 759 | 71 | 0.78 (0.58, 1.04) |
Subjects without COPD | |||
CCB | 242 953 | 263 | 1.00 (reference) |
ARB | 102 086 | 79 | 0.75 (0.56, 1.00) |
Subjects with COPD | |||
CCB | 43 303 | 91 | 1.00 (reference) |
ARB | 19 918 | 31 | 0.80 (0.50, 1.29) |
Never-smokers3 | |||
CCB | 191 596 | 132 | 1.00 (reference) |
ARB | 80 054 | 33 | 0.64 (0.42, 0.99) |
Ever-smokers3,4 | |||
CCB | 81 192 | 172 | 1.00 (reference) |
ARB | 36 822 | 52 | 0.73 (0.51, 1.02) |
Non-drinkers3 | |||
CCB | 192 980 | 216 | 1.00 (reference) |
ARB | 79 992 | 62 | 0.69 (0.49, 0.97) |
Drinkers (≥1/wk)3 | |||
CCB | 87 699 | 131 | 1.00 (reference) |
ARB | 39 839 | 49 | 0.89 (0.62, 1.28) |
Subjects without metformin | |||
CCB | 274 025 | 336 | 1.00 (reference) |
ARB | 107 704 | 89 | 0.72 (0.54, 0.94) |
Subjects with metformin | |||
CCB | 12 231 | 16 | 1.00 (reference) |
ARB | 14 301 | 59 | 1.51 (0.81, 2.80) |
The weights were recalculated in each stratified group.
ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; HR, hazard ratio; CI, confidence interval; COPD, chronic obstructive pulmonary disease.
1 The numbers of cases are weighted numbers rounded to the first decimal place.
2 Adjusted by inverse probability of treatment weighting.
3 Subjects with missing values were excluded.
4 Subjects included past and current smokers.
Characteristics | Cohort data before IPTW |
ASD | Cohort data after IPTW |
ASD | ||
---|---|---|---|---|---|---|
ARB users (n = 21 619) | CCB users (n = 38 850) | ARB users (n = 20 614) |
CCB users (n = 38 395) |
|||
Women | 9807 (45.4) | 17 898 (46.1) | 0.014 | 9623 (46.7) | 17 624 (45.9) | 0.016 |
Income level |
0.109 | 0.025 | ||||
Lowest | 3218 (14.9) | 6875 (17.7) | 3349 (16.2) | 6521 (17.0) | ||
Intermediate | 6250 (28.9) | 11 826 (30.4) | 6176 (30.0) | 11 409 (29.7) | ||
Highest | 7644 (35.4) | 11 999 (30.9) | 6834 (33.2) | 12 417 (32.3) | ||
Smoking | 0.130 | 0.027 | ||||
Never | 13 925 (64.4) | 25 859 (66.6) | 13 618 (66.1) | 25 373 (66.1) | ||
Past or current | 6959 (32.2) | 11 271 (29.0) | 6183 (30.0) | 11 471 (29.9) | ||
Missing | 735 (3.4) | 1720 (4.4) | 812 (3.9) | 1551 (4.0) | ||
Alcohol (times/wk) | 0.109 | 0.022 | ||||
Never | 13 548 (62.7) | 25 809 (66.4) | 13 591 (65.9) | 24 995 (65.1) | ||
1-2 | 4728 (21.9) | 5887 (17.7) | 3918 (19.0) | 7336 (19.1) | ||
≥3 | 3036 (14.0) | 5452 (14.0) | 2764 (13.4) | 5416 (14.1) | ||
Missing | 307 (1.4) | 702 (1.8) | 341 (1.7) | 649 (1.7) | ||
Exercise (times/wk) | 0.092 | 0.006 | ||||
Never | 10 949 (50.6) | 21 139 (54.4) | 10 960 (53.2) | 20 379 (53.1) | ||
1-2 | 5393 (24.9) | 8736 (22.5) | 4788 (23.2) | 8945 (23.3) | ||
≥3 | 4861 (22.5) | 8001 (20.6) | 4408 (21.4) | 8185 (21.3) | ||
Missing | 416 (1.9) | 974 (2.5) | 458 (2.2) | 887 (2.3) | ||
Antihypertensive medication | ||||||
ACE inhibitors | 285 (1.3) | 2923 (7.5) | 0.305 | 691 (3.4) | 2066 (5.4) | 0.099 |
Beta-blockers | 1344 (6.2) | 5720 (14.7) | 0.281 | 2056 (10.0) | 4607 (12.0) | 0.065 |
Diuretics | 9773 (45.2) | 7343 (18.9) | 0.587 | 5909 (28.7) | 10 595 (27.6) | 0.024 |
Others | 74 (0.3) | 246 (0.6) | 0.042 | 82 (0.4) | 216 (0.6) | 0.019 |
No. of drugs | 0.386 | 0.050 | ||||
Monotherapy | 11 085 (51.3) | 25 688 (66.1) | 13 083 (63.5) | 23 543 (61.3) | ||
Combination therapy | 10 534 (48.7) | 13 162 (33.9) | 7531 (36.5) | 14 852 (38.7) | ||
Comorbidity | ||||||
COPD | 3681 (17.0) | 6146 (15.8) | 0.033 | 3445 (16.7) | 6226 (16.2) | 0.013 |
CCI (≥1) | 1104 (5.1) | 1332 (3.4) | 0.083 | 929 (4.5) | 1512 (3.9) | 0.028 |
Diabetes mellitus | 4607 (21.3) | 4789 (12.3) | 0.242 | 3317 (16.1) | 5750 (15.0) | 0.031 |
Dyslipidemia | 5545 (25.6) | 6245 (16.1) | 0.237 | 4239 (20.6) | 7320 (19.1) | 0.038 |
MI or stroke | 1390 (6.4) | 2389 (6.1) | 0.042 | 1367 (6.6) | 2457 (6.4) | 0.018 |
Congestive heart failure | 697 (3.2) | 798 (2.1) | 0.073 | 571 (2.8) | 966 (2.5) | 0.016 |
Chronic kidney diseases | 689 (3.2) | 604 (1.6) | 0.107 | 450 (2.2) | 740 (1.9) | 0.018 |
Comedication | ||||||
Metformin | 2696 (12.5) | 1771 (4.6) | 0.286 | 1603 (7.8) | 2592 (6.8) | 0.040 |
Sulfonylurea | 2597 (12.0) | 2545 (6.6) | 0.189 | 1835 (8.9) | 3127 (8.1) | 0.027 |
Insulin | 120 (0.6) | 49 (0.1) | 0.074 | 67 (0.3) | 74 (0.2) | 0.026 |
Thiazolidinedione | 365 (1.7) | 177 (0.5) | 0.120 | 199 (1.0) | 299 (0.8) | 0.020 |
NSAIDs | 4385 (20.3) | 8500 (21.9) | 0.039 | 4331 (21.0) | 8244 (21.5) | 0.011 |
Aspirin | 4466 (20.7) | 8241 (21.2) | 0.014 | 4379 (21.2) | 8103 (21.1) | 0.003 |
Statin | 4908 (22.7) | 5248 (13.5) | 0.240 | 3714 (18.0) | 6247 (16.3) | 0.046 |
Age (y) | 58.5±8.7 | 60.0±9.3 | 0.159 | 59.2±8.9 | 59.6±9.3 | 0.046 |
BMI (kg/m2) | 24.7±2.9 | 24.7±2.9 | 0.016 | 24.7±2.9 | 24.7±2.9 | 0.004 |
SBP (mmHg) | 138.3±16.7 | 141.8±18.4 | 0.200 | 139.8±16.9 | 140.7±18.2 | 0.053 |
DBP (mmHg) | 85.8±11.2 | 87.5±11.9 | 0.142 | 86.5±11.2 | 86.9±11.8 | 0.038 |
FBS (mg/dL) | 105.6±35.9 | 100.8±31.0 | 0.146 | 102.6±31.2 | 102.0±33.2 | 0.019 |
Cholesterol (mg/dL) | 206.2±38.1 | 205.9±38.6 | 0.009 | 205.9±37.5 | 206.1±38.9 | 0.004 |
AST (U/L) | 27.2±16.0 | 27.6±16.0 | 0.024 | 27.3±17.2 | 27.5±15.6 | 0.010 |
ALT (U/L) | 27.0±19.4 | 26.7±20.5 | 0.017 | 26.8±20.4 | 26.8±20.0 | 0.003 |
γ-GTP (U/L) | 42.6±55.4 | 41.9±55.5 | 0.013 | 41.6±56.5 | 42.3±56.1 | 0.012 |
No. of doctor visits (/y) | 17.3±16.0 | 14.8±14.2 | 0.161 | 16.3±14.8 | 15.7±15.9 | 0.039 |
Group | Person-years | Lung cancer cases (n) |
HR (95% CI) |
---|---|---|---|
Cohort data before IPTW | |||
CCB | 286 256 | 366 | 1.00 (reference) |
ARB | 122 005 | 110 | 0.74 (0.60, 0.92) |
Cohort data after IPTW | |||
CCB | 286 256 | 357 | 1.00 (reference) |
ARB | 122 005 | 108 | 0.75 (0.59, 0.96) |
Censored at drug discontinuation or change |
|||
CCB | 140 747 | 136 | 1.00 (reference) |
ARB | 66 359 | 29 | 0.50 (0.32, 0.77) |
Monotherapy |
|||
CCB | 155 793 | 169 | 1.00 (reference) |
ARB | 49 614 | 42 | 0.81 (0.57, 1.15) |
1-Year lag | |||
CCB | 285 775 | 335 | 1.00 (reference) |
ARB | 121 396 | 105 | 0.80 (0.62, 1.03) |
2-Year lag | |||
CCB | 301 796 | 292 | 1.00 (reference) |
ARB | 127 790 | 85 | 0.74 (0.54, 1.02) |
Group | Person-years | Lung cancer cases (n) |
HR (95% CI) |
---|---|---|---|
Men | |||
CCB | 154 018 | 264 | 1.00 (reference) |
ARB | 66 768 | 88 | 0.83 (0.62, 1.09) |
Women | |||
CCB | 132 238 | 93 | 1.00 (reference) |
ARB | 55 236 | 20 | 0.56 (0.34, 0.93) |
Age <60 | |||
CCB | 148 888 | 76 | 1.00 (reference) |
ARB | 76 246 | 31 | 0.87 (0.55, 1.40) |
Age ≥60 | |||
CCB | 137 368 | 289 | 1.00 (reference) |
ARB | 45 759 | 71 | 0.78 (0.58, 1.04) |
Subjects without COPD | |||
CCB | 242 953 | 263 | 1.00 (reference) |
ARB | 102 086 | 79 | 0.75 (0.56, 1.00) |
Subjects with COPD | |||
CCB | 43 303 | 91 | 1.00 (reference) |
ARB | 19 918 | 31 | 0.80 (0.50, 1.29) |
Never-smokers |
|||
CCB | 191 596 | 132 | 1.00 (reference) |
ARB | 80 054 | 33 | 0.64 (0.42, 0.99) |
Ever-smokers |
|||
CCB | 81 192 | 172 | 1.00 (reference) |
ARB | 36 822 | 52 | 0.73 (0.51, 1.02) |
Non-drinkers |
|||
CCB | 192 980 | 216 | 1.00 (reference) |
ARB | 79 992 | 62 | 0.69 (0.49, 0.97) |
Drinkers (≥1/wk) |
|||
CCB | 87 699 | 131 | 1.00 (reference) |
ARB | 39 839 | 49 | 0.89 (0.62, 1.28) |
Subjects without metformin | |||
CCB | 274 025 | 336 | 1.00 (reference) |
ARB | 107 704 | 89 | 0.72 (0.54, 0.94) |
Subjects with metformin | |||
CCB | 12 231 | 16 | 1.00 (reference) |
ARB | 14 301 | 59 | 1.51 (0.81, 2.80) |
Values are presented as number (%) or mean±standard deviation. ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; IPTW, inverse probability treatment weighting; ASD, absolute standardized mean difference; ACE, angiotensin converting enzyme; COPD, chronic obstructive pulmonary disease; CCI, Charlson Comorbidity Index; MI, myocardial infarction; NSAID, non-steroidal anti-inflammatory drugs; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBS, fasting blood sugar level; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GTP, gamma-glutamyl transferase. The number of subjects is given as a weighted number rounded to the first decimal place. The intermediate group included the lower group, and the highest group included the upper-middle group.
ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; HR, hazard ratio; CI, confidence interval; IPTW, inverse probability treatment weighting. The numbers of cases were weighted numbers rounded to the first decimal place except the cohort before IPTW. Adjusted by IPTW, except for the cohort data before IPTW. Crude HR. CCB users were censored when they stopped CCB or were prescribed ARB, or vice versa. CCB-only users and ARB-only users without any other antihypertensive medication at baseline.
The weights were recalculated in each stratified group. ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; HR, hazard ratio; CI, confidence interval; COPD, chronic obstructive pulmonary disease. The numbers of cases are weighted numbers rounded to the first decimal place. Adjusted by inverse probability of treatment weighting. Subjects with missing values were excluded. Subjects included past and current smokers.