Supplementary appendix: Additional material. Figure S1. Flow-chart of inclusion/exclusion criteria.

Transcription

1 Supplementary appendix: Additional material Figure S1. Flow-chart of inclusion/exclusion criteria. 1

2 Table S1. Codes considered to identify heart failure patients by the included databases. Coding system Database (Country) Codes/term ICD-9-CM a SISR (IT) OSSIFF (IT) PHARMO (NL) , , , , , , , , , , 428, 428.0, 428.1, ICD-10-GM b GePaRD (GER) I11.0, I11.00, I11.01, I13.0, I13.00, I13.01, I13.2, I13.20, I13.21, I50, I50.0, I50.00, I50.01, I50.1, I50.11, I50.12, I50.13, I50.14, I50.19, I50.9 READ c v2 THIN (UK) 14A6.00, G1yz100, G21z100, G232.00, G234.00, G58..00, G58..11, G580.00, G580.11, G580.12, G580.13, G580.14, G580000, G580100, G580200, G580300, G581.00, G581.11, G581.12, G581.13, G581000, G582.00, G58z.00, G58z.11, G58z.12 a International Classification of Diseases, 9th revision, clinical modification [ int/classifications/icd/en] b International Classification of Diseases, 10th revision, German modification c READ clinical classification system [Chisholm J. The Read clinical classification. BMJ 1990;300:1092] 2

3 Table S2. Odds ratios (ORs) and p-values for the association between current use of individual NSAIDs and HF risk from the main analysis. Column (a): raw p-values: Column (b): Bonferroni- Holm adjusted p-values. Individual NSAIDs OR (a) Raw p- value (b) Bonferroni- Holm adjusted p- value Ketorolac 1.83 <0.001 <0.001 Etoricoxib 1.51 <0.001 <0.001 Rofecoxib 1.36 <0.001 <0.001 Diclofenac 1.19 <0.001 <0.001 Nimesulide 1.18 <0.001 <0.001 Piroxicam 1.27 <0.001 <0.001 Ibuprofen 1.18 <0.001 <0.001 Indometacin 1.51 <0.001 <0.001 Naproxen 1.16 < Celecoxib Dexibuprofen Sulindac Oxaprozin Nabumetone Etodolac Ketoprofen Valdecoxib Acemetacin Meloxicam Aceclofenac Diclofenac, combinations Tenoxicam Lornoxicam Dexketoprofen Tiaprofenic acid Flurbiprofen Proglumetacin

4 Table S3. Odds ratios for the association between current use of individual NSAIDs and HF risk in comparison with current use of celecoxib (active comparator). Individual NSAIDs OR* 95% Confidence Interval Oxaprozin 0.83 (0.57, 1.20) Dexketoprofen 0.87 (0.42, 1.84) Etodolac 0.89 (0.65, 1.22) Flurbiprofen 0.99 (0.69, 1.43) Proglumetacin 1.03 (0.62, 1.69) Meloxicam 1.04 (0.96, 1.13) Aceclofenac 1.04 (0.93, 1.17) Diclofenac combinations 1.04 (0.94, 1.15) Ketoprofen 1.05 (0.97, 1.13) Lornoxicam 1.07 (0.81, 1.43) Tenoxicam 1.08 (0.81, 1.43) Tiaprofenic Acid 1.09 (0.56, 2.13) Nabumetone 1.15 (0.90, 1.47) Valdecoxib 1.15 (0.83, 1.60) Naproxen 1.19 (1.09, 1.29) Ibuprofen 1.20 (1.14, 1.27) Dexibuprofen 1.20 (0.90, 1.61) Nimesulide 1.20 (1.15, 1.26) Diclofenac 1.21 (1.16, 1.27) Acemetacin 1.24 (0.74, 2.06) Piroxicam 1.29 (1.20, 1.38) Sulindac 1.35 (0.81, 2.25) Rofecoxib 1.38 (1.29, 1.47) Etoricoxib 1.53 (1.42, 1.65) Indometacin 1.53 (1.35, 1.74) Ketorolac 1.84 (1.67, 2.04) *Odds Ratio for the association between current use of individual NSAIDs and risk of HF with respect to current use of celecoxib. 4

5 Table S4. Clinical features and other selected characteristics of case patients hospitalized for heart failure and matched controls included into each database. THE NETHERLANDS - PHARMO (PHARMO Institute for Drug Outcomes Research) (N=8,250) (N=653,466) Men 4,646 (60.46%) 426,158 (62.33%) Age at cohort entry: mean (SD) 78 (10) 77 (11) Comorbidities and other characteristics* Acute Myocardial Infarction 73 (0.88%) 2130 (0.33%) Alcohol Abuse 16 (0.19%) 500 (0.08%) Asthma 9 (0.11%) 199 (0.03%) Atrial Fibrillation and Flutter 127 (1.54%) 2803 (0.43%) Chronic Liver Disease 8 (0.10%) 334 (0.05%) Chronic Respiratory Disease 1949 (23.62%) (13.22%) Diabetes 1611 (19.53%) (8.01%) Heart Failure 134 (1.62%) 2131 (0.33%) Hyperlipidemia 1843 (22.34%) (13.98%) Hypertension 702 (8.51%) (5.65%) Iron Deficiency Anemia 361 (4.38%) (1.90%) Ischemic Heart Disease 231 (2.80%) 7376 (1.13%) Kidney Failure Obesity 16 (0.19%) 948 (0.15%) Osteoarthritis 157 (1.90%) (1.66%) Other Cardiovascular Disease 519 (6.29%) (1.75%) Rheumatoid Arthritis and Inflammatory Polyarthritis 18 (0.22%) 506 (0.08%) Smoking 9 (0.11%) 279 (0.04%) Stroke Confounder 26 (0.32%) 625 (0.10%) Valvular Disease and Endocarditis 24 (0.29%) 403 (0.06%) Concomitant use of other drugs** ACE Inhibitor/AT-II Antagonists 3861 (50.24%) (28.14%) Anticoagulants 1909 (24.84%) (6.57%) Aspirin 1466 (19.08%) (8.28%) Beta Blockers 3854 (50.15%) (29.53%) Calcium Channel Blockers 2255 (29.34%) (17.10%) Cardiac Glycosides 1193 (15.52%) (3.43%) Cyp2C9 Inducers 6 (0.07%) 113 (0.02%) Cyp2C9 Inhibitors 496 (6.01%) 8132 (1.24%) Diuretics 4256 (55.38%) (16.56%) Glucorticoids 801 (10.42%) (4.84%) Nitrates 1163 (15.13%) (4.90%) Platelet Aggregation Inhibitor 629 (8.18%) (2.74%) Vasodilators 520 (6.77%) (2.25%) * Assessed in the 12 months preceding cohort entry. ** Assessed in the 14 days preceding the index HF hospitalization. : not available 5

6 ITALY SISR (Sistema Informativo Sanitario Regionale) (N=34,773) (3,312,454) Men 14,140 (40.66%) 1,338,754 (40.42%) Age at cohort entry: mean (SD) 78 (10) 78 (10) Comorbidities and other characteristics* Acute Myocardial Infarction 956 (2.75%) 22,591 (0.68%) Alcohol Abuse 73 (0.21%) 2,704 (0.08%) Asthma 79 (0.23%) 3,499 (0.11%) Atrial Fibrillation and Flutter 1,596 (4.59%) 35,072 (1.06%) Chronic Liver Disease 378 (1.09%) 15,486 (0.47%) Chronic Respiratory Disease 5,584 (16.06%) 327,712 (9.89%) Diabetes 8,139 (23.41%) 371,582 (11.22%) Heart Failure 3,833 (11.02%) 91,385 (2.76%) Hyperlipidemia 7,334 (21.09%) 526,980 (15.91%) Hypertension 10,215 (29.38%) 854,865 (25.81%) Iron Deficiency Anemia Ischemic Heart Disease 2,300 (6.61%) 62,802 (1.90%) Kidney Failure 133 (0.38%) 3,460 (0.10%) Obesity 438 (1.26%) 9,758 (0.29%) Osteoarthritis 646 (1.86%) 48,086 (1.45%) Other Cardiovascular Disease 5,644 (16.23%) 188,134 (5.68%) Rheumatoid Arthritis and Inflammatory Polyarthritis 157 (0.45%) 7,153 (0.22%) Smoking Stroke Confounder 414 (1.19%) 21,469 (0.65%) Valvular Disease and Endocarditis 510 (1.47%) 10,053 (0.30%) Concomitant use of other drugs** ACE Inhibitor/AT-II Antagonists 16,991 (48.86%) 974,943 (29.43%) Anticoagulants 6,999 (20.13%) 189,656 (5.73%) Aspirin 12,786 (36.77%) 759,562 (22.93%) Beta Blockers 7,627 (21.93%) 435,123 (13.14%) Calcium Channel Blockers 12,617 (36.28%) 861,069 (25.99%) Cardiac Glycosides 5,470 (15.73%) 144,214 (4.35%) Cyp2C9 Inducers Cyp2C9 Inhibitors 3,999 (11.50%) 90,114 (2.72%) Diuretics 17,507 (50.35%) 556,149 (16.79%) Glucorticoids 3,062 (8.81%) 130,582 (3.94%) Nitrates 10,567 (30.39%) 338,230 (10.21%) Platelet Aggregation Inhibitor 4,033 (11.60%) 189,748 (5.73%) Vasodilators * Assessed in the 12 months preceding cohort entry. ** Assessed in the 14 days preceding the index HF hospitalization. : not available 6

7 ITALY OSSIFF (Osservatorio Interaziendale per la Farmacoepidemiologia e la Farmacoeconomia) (N=23,753) (N=2,159,548) Men 9,924 (41.78%) 884,886 (40.98%) Age at cohort entry: mean (SD) 78 (10) 77 (10) Comorbidities and other characteristics* Acute Myocardial Infarction 569 (2.40%) 14,425 (0.67%) Alcohol Abuse 58 (0.24%) 2,334 (0.11%) Asthma 61 (0.26%) 2,396 (0.11%) Atrial Fibrillation and Flutter 859 (3.62%) 19,174 (0.89%) Chronic Liver Disease 233 (0.98%) 9,287 (0.43%) Chronic Respiratory Disease 3,963 (16.68%) 226,000 (10.47%) Diabetes 3,899 (16.41%) 153,790 (7.12%) Heart Failure 1,504 (6.33%) 36,585 (1.69%) Hyperlipidemia 2,864 (12.06%) 193,743 (8.97%) Hypertension 5,241 (22.06%) 408,379 (18.91%) Iron Deficiency Anemia 625 (2.63%) 28,750 (1.33%) Ischemic Heart Disease 1,304 (5.49%) 36,591 (1.69%) Kidney Failure 46 (0.19%) 913 (0.04%) Obesity 130 (0.55%) 2120 (0.10%) Osteoarthritis 521 (2.19%) 31,274 (1.45%) Other Cardiovascular Disease 2,921 (12.30%) 92,517 (4.28%) Rheumatoid Arthritis and Inflammatory Polyarthritis 100 (0.42%) 3,890 (0.18%) Smoking Stroke Confounder 307 (1.29%) 14,341 (0.66%) Valvular Disease and Endocarditis 245 (1.03%) 4,907 (0.23%) Concomitant use of other drugs** ACE Inhibitor/AT-II Antagonists 8,279 (34.85%) 439,870 (20.37%) Anticoagulants 4,520 (19.03%) 121,319 (5.62%) Aspirin 7,275 (30.63%) 398,196 (18.44%) Beta Blockers 3,223 (13.57%) 183,367 (8.49%) Calcium Channel Blockers 7,146 (30.08%) 434,902 (20.14%) Cardiac Glycosides 4,159 (17.51%) 111,664 (5.17%) Cyp2C9 Inducers 18 (0.08%) 673 (0.03%) Cyp2C9 Inhibitors 2,567 (10.81%) 56,793 (2.63%) Diuretics 11,539 (48.58%) 339,377 (15.72%) Glucorticoids 1,895 (7.98%) 77,641 (3.60%) Nitrates 6,850 (28.84%) 205,666 (9.52%) Platelet Aggregation Inhibitor 2,201 (9.27%) 92,327 (4.28%) Vasodilators * Assessed in the 12 months preceding cohort entry. ** Assessed in the 14 days preceding the index HF hospitalization. : not available 7

8 GERMANY GePaRD (German Pharmacoepidemiological Research Database) (N=7,685) (N=683,663) Men 3,937 (47.72%) 303,716 (46.48%) Age at cohort entry: mean (SD) 75 (11) 73 (11) Comorbidities and other characteristics* Acute Myocardial Infarction 1,239 (16.12%) 37,070 (5.42%) Alcohol Abuse 229 (2.98%) 7,702 (1.13%) Asthma 610 (7.94%) 36,198 (5.29%) Atrial Fibrillation and Flutter 1,735 (22.58%) 45,724 (6.69%) Chronic Liver Disease 1,166 (15.17%) 72,751 (10.64%) Chronic Respiratory Disease 1,371 (17.84%) 65,990 (9.65%) Diabetes 1,944 (25.30%) 71,867 (10.51%) Heart Failure 2,767 (36.01%) 77,676 (11.36%) Hyperlipidemia 2,506 (32.61%) 149,564 (21.88%) Hypertension 2,439 (31.74%) 150,496 (22.01%) Iron Deficiency Anemia 257 (3.34%) 7,362 (1.08%) Ischemic Heart Disease 3,341 (43.47%) 149,100 (21.81%) Kidney Failure 1,176 (15.30%) 34,817 (5.09%) Obesity 1,737 (22.60%) 76,194 (11.14%) Osteoarthritis 2,233 (29.06%) 187,447 (27.42%) Other Cardiovascular Disease 3,233 (42.07%) 152,755 (22.34%) Rheumatoid Arthritis and Inflammatory Polyarthritis 337 (4.39%) 23,174 (3.39%) Smoking Stroke Confounder 970 (12.62%) 42,198 (6.17%) Valvular Disease and Endocarditis 1,500 (19.52%) 52,696 (7.71%) Concomitant use of other drugs** ACE Inhibitor/AT-II Antagonists 3,861 (50.24%) 192,401 (28.14%) Anticoagulants 1,909 (24.84%) 44,910 (6.57%) Aspirin 1,466 (19.08%) 56,614 (8.28%) Beta Blockers 3,854 (50.15%) 201,893 (29.53%) Calcium Channel Blockers 2,255 (29.34%) 116,932 (17.10%) Cardiac Glycosides 1,193 (15.52%) 23,416 (3.43%) Cyp2C9 Inducers 5 (0.07%) 64 (0.01%) Cyp2C9 Inhibitors 496 (6.01%) 8,132 (1.24%) Diuretics 4,256 (55.38%) 113,224 (16.56%) Glucorticoids 801 (10.42%) 33,115 (4.84%) Nitrates 1,163 (15.13%) 33,499 (4.90%) Platelet Aggregation Inhibitor 629 (8.18%) 18,744 (2.74%) Vasodilators 520 (6.77%) 15,409 (2.25%) * Assessed in the 12 months preceding cohort entry. ** Assessed in the 14 days preceding the index HF hospitalization. : not available 8

9 UNITED KINGDOM THIN (The Health Improvement Network) (N=17,702) (N=1, ) Men 9,005 (50.87%) 718,051 (49.96%) Age at cohort entry: mean (SD) 76 (11) 74 (11) Comorbidities and other characteristics* Acute Myocardial Infarction 226 (1.28%) 5,006 (0.35%) Alcohol Abuse 1,566 (8.85%) 115,631 (8.05%) Asthma 272 (1.54%) 14,787 (1.03%) Atrial Fibrillation and Flutter 289 (1.63%) 7,444 (0.52%) Chronic Liver Disease 30 (0.17%) 904 (0.06%) Chronic Respiratory Disease 3,323 (18.77%) 164,379 (11.44%) Diabetes 2,295 (12.96%) 75,752 (5.27%) Heart Failure 115 (0.65%) 1,348 (0.09%) Hyperlipidemia 4,246 (23.99%) 198,906 (13.84%) Hypertension 1,308 (7.39%) 64,314 (4.47%) Iron Deficiency Anemia 916 (5.17%) 35,370 (2.46%) Ischemic Heart Disease 1,230 (6.95%) 39,117 (2.72%) Kidney Failure 87 (0.49%) 1,849 (0.13%) Obesity 2,234 (12.62%) 92,084 (6.41%) Osteoarthritis 3,359 (18.98%) 206,083 (14.34%) Other Cardiovascular Disease 738 (4.17%) 18,969 (1.32%) Rheumatoid Arthritis and Inflammatory Polyarthritis 124 (0.70%) 5,546 (0.39%) Smoking 155 (0.88%) 7,876 (0.55%) Stroke Confounder 152 (0.86%) 6,476 (0.45%) Valvular Disease and Endocarditis 104 (0.59%) 2,587 (0.18%) Concomitant use of other drugs* ACE Inhibitor/AT-II Antagonists 5,842 (33.00%) 230,435 (16.03%) Anticoagulants 2,252 (12.72%) 41,931 (2.92%) Aspirin 8,665 (48.95%) 398,457 (27.72%) Beta Blockers 3,948 (22.30%) 231,473 (16.11%) Calcium Channel Blockers 4,638 (26.20%) 225,130 (15.66%) Cardiac Glycosides 2,414 (13.64%) 39,332 (2.74%) Cyp2C9 Inducers 9 (0.05%) 299 (0.02%) Cyp2C9 Inhibitors 731 (4.13%) (0.77%) Diuretics 11,433 (64.59%) 414,726 (28.86%) Glucorticoids 2,077 (11.73%) 74,559 (5.19%) Nitrates 4,286 (24.21%) 106,775 (7.43%) Platelet Aggregation Inhibitor 1,613 (9.11%) 48,153 (3.35%) Vasodilators 614 (3.47%) 14,098 (0.98%) * Assessed in the 12 months preceding cohort entry. ** Assessed in the 14 days preceding the index HF hospitalization. : not available 9

10 Table S5. Database-specific distributions of NSAIDs use status among case and control. THE NETHERLANDS - PHARMO (PHARMO Institute for Drug Outcomes Research) NSAIDs exposure (N=8,250) (N=653,466) Current Use of: Aceclofenac 3 (0.04%) 261 (0.04%) Acemetacin Azapropazone 2 (0.02%) 58 (0.01%) Celecoxib 47 (0.57%) 2,825 (0.43%) Dexibuprofen 2 (0.02%) 90 (0.01%) Dexketoprofen 0 (0.00%) 7 (0.00%) Diclofenac 380 (4.61%) 21,456 (3.28%) Diclofenac, combinations 144 (1.75%) 8,273 (1.27%) Etodolac Etoricoxib 69 (0.84%) 2,363 (0.36%) Fenbufen Fenoprofen Fentiazac Flurbiprofen 0 (0.00%) 87 (0.01%) Ibuprofen 171 (2.07%) 10,700 (1.64%) Ibuprofen, combinations Indometacin 32 (0.39%) 992 (0.15%) Ketoprofen 6 (0.07%) 441 (0.07%) Ketoprofen, combinations Ketorolac Lonazolac Lornoxicam Lumiracoxib Meclofenamic acid Mefenamic acid Meloxicam 93 (1.13%) 5,574 (0.85%) Mofebutazone Morniflumate Nabumetone 17 (0.21%) 919 (0.14%) Naproxen 137 (1.66%) 7,303 (1.12%) Naproxen and esomeprazole Niflumic acid Nimesulide Oxaprozin Parecoxib Phenylbutazone 1 (0.01%) 13 (0.00%) Prioxicam 18 (0.22%) 873 (0.13%) Proglumetacin Rofecoxib 111 (1.35%) 5,234 (0.80%) Sulindac 13 (0.16%) 331 (0.05%) Tenoxicam 0 (0.00%) 15 (0.00%) Tiaprofenic acid 2 (0.02%) 219 (0.03%) Tolfenamic acid 0 (0.00%) 7 (0.00%) Valdecoxib 0 (0.00%) 31 (0.00%) Recent Use of any NSAID 1,725 (20.91%) 142,047 (21.74%) : not available 10

11 ITALY SISR (Sistema Informativo Sanitario Regionale) NSAIDs exposure (N=34,773) (3,312,454) Current Use of: Aceclofenac 224 (0.64%) 21,005 (0.63%) Acemetacin 0 (0.00%) 10 (0.00%) Azapropazone Celecoxib 532 (1.53%) 59,505 (1.80%) Dexibuprofen 32 (0.09%) 2,294 (0.07%) Dexketoprofen 0 (0.00%) 1 (0.00%) Diclofenac 1,010 (2.90%) 74,937 (2.26%) Diclofenac, combinations 68 (0.20%) 7,133 (0.22%) Etodolac Etoricoxib 411 (1.18%) 30,116 (0.91%) Fenbufen Fenoprofen Fentiazac 1 (0.00%) 47 (0.00%) Flurbiprofen 13 (0.04%) 1224 (0.04%) Ibuprofen 514 (1.48%) 31,834 (0.96%) Ibuprofen, combinations Indometacin 95 (0.27%) 5262 (0.16%) Ketoprofen 483 (1.39%) 44,291 (1.34%) Ketoprofen, combinations 0 (0.00%) 1 (0.00%) Ketorolac 239 (0.69%) 9,993 (0.30%) Lonazolac Lornoxicam 34 (0.10%) 3,046 (0.09%) Lumiracoxib Meclofenamic acid 0 (0.00%) 13 (0.00%) Mefenamic acid 0 (0.00%) 84 (0.00%) Meloxicam 214 (0.62%) 21,162 (0.64%) Mofebutazone Morniflumate 1 (0.00%) 10 (0.00%) Nabumetone 18 (0.05%) 1,967 (0.06%) Naproxen 121 (0.35%) 11,748 (0.35%) Naproxen and esomeprazole Niflumic acid 0 (0.00%) 1 (0.00%) Nimesulide 1,770 (5.09%) 128,443 (3.88%) Oxaprozin 16 (0.05%) 2,440 (0.07%) Parecoxib Phenylbutazone Prioxicam 531 (1.53%) 41,483 (1.25%) Proglumetacin 8 (0.02%) 873 (0.03%) Rofecoxib 394 (1.13%) 27,740 (0.84%) Sulindac 1 (0.00%) 132 (0.00%) Tenoxicam 32 (0.09%) 2,907 (0.09%) Tiaprofenic acid 2 (0.01%) 203 (0.01%) Tolfenamic acid Valdecoxib 23 (0.07%) 1,787 (0.05%) Recent Use of any NSAID 12,916 (37.14%) 1,213,352 (36.63%) : not available 11

12 ITALY OSSIFF (Osservatorio Interaziendale per la Farmacoepidemiologia e la Farmacoeconomia) NSAIDs exposure (N=23,753) (N=2,159,548) Current Use of: Aceclofenac 62 (0.26%) 6,757 (0.31%) Acemetacin 0 (0.00%) 21 (0.00%) Azapropazone Celecoxib 374 (1.57%) 33,872 (1.57%) Dexibuprofen 9 (0.04%) 876 (0.04%) Dexketoprofen Diclofenac 592 (2.49%) 42,466 (1.97%) Diclofenac, combinations 47 (0.20%) 4,767 (0.22%) Etodolac Etoricoxib 194 (0.82%) 10,370 (0.48%) Fenbufen Fenoprofen Fentiazac 0 (0.00%) 23 (0.00%) Flurbiprofen 15 (0.06%) 1,117 (0.05%) Ibuprofen 186 (0.78%) 11,194 (0.52%) Ibuprofen, combinations 0 (0.00%) 1 (0.00%) Indometacin 53 (0.22%) 2,942 (0.14%) Ketoprofen 251 (1.06%) 21,191 (0.98%) Ketoprofen, combinations Ketorolac 210 (0.88%) 7,462 (0.35%) Lonazolac Lornoxicam 15 (0.06%) 1,200 (0.06%) Lumiracoxib Meclofenamic acid Mefenamic acid 0 (0.00%) 23 (0.00%) Meloxicam 121 (0.51%) 11,721 (0.54%) Mofebutazone Morniflumate 0 (0.00%) 31 (0.00%) Nabumetone 8 (0.03%) 1,173 (0.05%) Naproxen 96 (0.40%) 7,413 (0.34%) Naproxen and esomeprazole Niflumic acid 0 (0.00%) 38 (0.00%) Nimesulide 947 (3.99%) 68,944 (3.19%) Oxaprozin 13 (0.05%) 1207 (0.06%) Parecoxib Phenylbutazone Prioxicam 376 (1.58%) 28,903 (1.34%) Proglumetacin 7 (0.03%) 431 (0.02%) Rofecoxib 412 (1.73%) 29,140 (1.35%) Sulindac 2 (0.01%) 26 (0.00%) Tenoxicam 18 (0.08%) 1,655 (0.08%) Tiaprofenic acid 1 (0.00%) 122 (0.01%) Tolfenamic acid Valdecoxib 12 (0.05%) 617 (0.03%) Recent Use of any NSAID 7,657 (32.24%) 690,164 (31.96%) : not available 12

13 GERMANY GePaRD (German Pharmacoepidemiological Research Database) NSAIDs exposure (N=7,685) (N=683,663) Current Use of: Aceclofenac 1 (0.01%) 262 (0.04%) Acemetacin 14 (0.18%) 818 (0.12%) Azapropazone Celecoxib 20 (0.26%) 1,268 (0.19%) Dexibuprofen 3 (0.04%) 328 (0.05%) Dexketoprofen 6 (0.08%) 425 (0.06%) Diclofenac 692 (9.00%) 48,954 (7.16%) Diclofenac, combinations 13 (0.17%) 994 (0.15%) Etodolac Etoricoxib 80 (1.04%) 2,733 (0.40%) Fenbufen Fenoprofen Fentiazac Flurbiprofen Ibuprofen 507 (6.60%) 28,337 (4.14%) Ibuprofen, combinations Indometacin 21 (0.27%) 996 (0.15%) Ketoprofen 2 (0.03%) 206 (0.03%) Ketoprofen, combinations Ketorolac Lonazolac 0 (0.00%) 5 (0.00%) Lornoxicam 1 (0.01%) 78 (0.01%) Lumiracoxib 0 (0.00%) 87 (0.01%) Meclofenamic acid Mefenamic acid Meloxicam 25 (0.33%) 1,249 (0.18%) Mofebutazone 0 (0.00%) 3 (0.00%) Morniflumate Nabumetone 1 (0.01%) 55 (0.01%) Naproxen 19 (0.25%) 898 (0.13%) Naproxen and esomeprazole Niflumic acid Nimesulide Oxaprozin Parecoxib 0 (0.00%) 10 (0.00%) Phenylbutazone 1 (0.01%) 113 (0.02%) Prioxicam 25 (0.33%) 1,301 (0.19%) Proglumetacin 1 (0.01%) 97 (0.01%) Rofecoxib Sulindac Tenoxicam Tiaprofenic acid 1 (0.01%) 44 (0.01%) Tolfenamic acid Valdecoxib 0 (0.00%) 62 (0.01%) Recent Use of any NSAID 2,531 (32.93%) 224,101 (32.78%) : not available 13

14 UNITED KINGDOM THIN (The Health Improvement Network) NSAIDs exposure (N=17,702) (N=1,437,272) Current Use of: Aceclofenac 6 (0.03%) 473 (0.03%) Acemetacin 2 (0.01%) 130 (0.01%) Azapropazone 1 (0.01%) 213 (0.01%) Celecoxib 280 (1.58%) 21,455 (1.49%) Dexibuprofen 1 (0.01%) 80 (0.01%) Dexketoprofen 2 (0.01%) 95 (0.01%) Diclofenac 554 (3.13%) 53,979 (3.76%) Diclofenac, combinations 181 (1.02%) 16,125 (1.12%) Etodolac 40 (0.23%) 3,578 (0.25%) Etoricoxib 81 (0.46%) 4,457 (0.31%) Fenbufen 3 (0.02%) 214 (0.01%) Fenoprofen 0 (0.00%) 35 (0.00%) Fentiazac Flurbiprofen 2 (0.01%) 353 (0.02%) Ibuprofen 634 (3.58%) 53,880 (3.75%) Ibuprofen, combinations 1 (0.01%) 171 (0.01%) Indometacin 66 (0.37%) 3364 (0.23%) Ketoprofen 7 (0.04%) 821 (0.06%) Ketoprofen, combinations 0 (0.00%) 4 (0.00%) Ketorolac Lonazolac Lornoxicam 0 (0.00%) 31 (0.00%) Lumiracoxib Meclofenamic acid Mefenamic acid 4 (0.02%) 802 (0.06%) Meloxicam 176 (0.99%) 14,785 (1.03%) Mofebutazone Morniflumate Nabumetone 22 (0.12%) 1,184 (0.08%) Naproxen 217 (1.23%) 15,035 (1.05%) Naproxen and esomeprazole 0 (0.00%) 1 (0.00%) Niflumic acid Nimesulide Oxaprozin Parecoxib Phenylbutazone 0 (0.00%) 1 (0.00%) Prioxicam 24 (0.14%) 1,862 (0.13%) Proglumetacin Rofecoxib 296 (1.67%) 16,816 (1.17%) Sulindac 0 (0.00%) 150 (0.01%) Tenoxicam 1 (0.01%) 139 (0.01%) Tiaprofenic acid 3 (0.02%) 246 (0.02%) Tolfenamic acid 0 (0.00%) 21 (0.00%) Valdecoxib 3 (0.02%) 304 (0.02%) Recent Use of any NSAID 3,818 (21.57%) 305,801 (21.28%) : not available 14

15 Table S6. Database-specific adjusted Odds Ratio (ORs), with 95% Confidence Intervals (95% CI), measuring the association between current use of individual NSAIDs (compared with past use of any NSAID) and risk of a hospitalization for heart failure. PHARMO (NL) SISR (IT) OSSIFF (IT) GEPARD (GER) THIN (UK) OR 95% CI OR 95% CI OR 95% CI OR 95% CI OR 95% CI Aceclofenac 1.10 (0.96, 1.25) 0.82 (0.64, 1.06) Acemethacin 1.27 (0.73, 2.20) Celecoxib 1.13 (0.84, 1.52) 0.90 (0.83, 0.98) 0.99 (0.89, 1.10) 1.20 (0.76, 1.90) 0.98 (0.87, 1.11) Diclofenac 1.35 (1.21, 1.50) 1.27 (1.19, 1.35) 1.25 (1.14, 1.36) 1.33 (1.21, 1.45) 0.92 (0.84, 1.01) Diclofenac, combinations 1.34 (1.12, 1.59) 0.92 (0.72, 1.17) 0.94 (0.71, 1.26) 0.93 (0.53, 1.64) 0.93 (0.80, 1.08) Etodolac 0.85 (0.62, 1.17) Etoricoxib 2.23 (1.73, 2.88) 1.34 (1.21, 1.48) 1.62 (1.40, 1.88) 2.04 (1.61, 2.59) 1.41 (1.13, 1.77) Ibuprofen 1.36 (1.16, 1.60) 1.20 (1.09, 1.31) 1.23 (1.06, 1.43) 1.46 (1.32, 1.61) 1.01 (0.93, 1.10) Indomethacin 2.28 (1.58, 3.28) 1.40 (1.13, 1.72) 1.33 (1.01, 1.76) 1.67 (1.07, 2.62) 1.54 (1.20, 1.98) Ketoprofen 1.05 (0.96, 1.15) 1.01 (0.89, 1.15) Ketorolac 1.74 (1.52, 1.98) 1.99 (1.72, 2.30) Meloxicam 1.15 (0.93, 1.42) 1.02 (0.89, 1.17) 1.00 (0.83, 1.20) 1.54 (1.02, 2.32) 0.92 (0.79, 1.07) Nabumetone 1.46 (0.88, 2.40) 1.50 (0.97, 2.31) Naproxen 1.39 (1.16, 1.66) 0.90 (0.75, 1.07) 1.15 (0.94, 1.41) 1.51 (0.94, 2.42) 1.23 (1.07, 1.42) Nimesulide 1.20 (1.14, 1.26) 1.17 (1.09, 1.25) Piroxicam 1.88 (1.16, 3.04) 1.27 (1.16, 1.39) 1.24 (1.12, 1.38) 1.70 (1.12, 2.57) 1.01 (0.67, 1.52) Rofecoxib 1.61 (1.31, 1.96) 1.43 (1.29, 1.59) 1.26 (1.13, 1.39) 1.30 (1.15, 1.46) Sulindac 1.89 (1.06, 3.38) Recent use of any NSAID 0.98 (0.92, 1.04) 0.98 (0.96, 1.01) 0.98 (0.95, 1.01) 1.03 (0.97, 1.09) 1.09 (1.05, 1.14) Current use of any NSAID 1.41 (1.31, 1.51) 1.19 (1.16, 1.23) 1.22 (1.17, 1.27) 1.41 (1.32, 1.52) 1.02 (0.97, 1.07) : not available 15

16 Table S7. Distributions cases and controls along the categories of the current prescribed dose (in DDD equivalents and corresponding daily amount of active principle in mg) of selected individual NSAIDs. Data obtained by pooling PHARMO and THIN databases NSAIDs exposure Daily amount of active principle (N=25,179) (N=2,028,106) Celecoxib Low 160 mg 25 (9.3%) 1,459 (7.2%) Medium mg 212 (78.8%) 16,735 (82.8%) High mg 7 (2.6%) 403 (2.0%) Very High 401 mg 25 (9.3%) 1,609 (8.0%) Diclofenac Low 80 mg 59 (8.1%) 3,541 (6.3%) Medium mg 215 (29.3%) 16,904 (30.1%) High mg 408 (55.7%) 34,060 (60.7%) Very High 201 mg 51 (7.0%) 1,613 (2.9%) Diclofenac, combinations Low 80 mg 16 (5.7 %) 1,032 (5.2%) Medium mg 131 (48.0%) 10,366 (51.8%) High mg 122 (44.7%) 8,493 (42.4%) Very High 201 mg 4 (1.5%) 133 (0.7%) Etoricoxib Low 48 mg 2 (1.7%) 165 (3.1%) Medium mg 57 (47.5%) 2,646 (49.3%) High mg 40 (33.3%) 1,898 (35.4%) Very High 121 mg 21 (17.5%) 655 (12.2%) Ibuprofen Low 960 mg 107 (19.6%) 7,659 (17.9%) Medium mg 383 (70.0%) 28,960 (67.7%) High mg 52 (9.5%) 5,901 (13.8%) Very High 2401 mg 5 (0.9%) 250 (0.6%) Indometacin Low 80 mg 9 (13.4%) 471 (16.0%) Medium mg 35 (52.2%) 1,462 (49.6%) High mg 21 (31.3%) 954 (32.4%) Very High 201 mg 2 (3.0%) 62 (2.1%) Naproxen Low 400 mg 11 (4.0%) 703 (4.2%) Medium mg 59 (21.7%) 3,677 (21.9%) High mg 47 (17.3%) 2,707 (16.1%) Very High 1001 mg 155 (57.0%) 9,711 (57.8%) Piroxicam Low 16 mg 4 (11.1%) 177 (8.1%) Medium mg 28 (77.8%) 1,796 (82.6%) High mg 1 (2.8%) 57 (2.6%) Very High 41 mg 3 (8.3%) 145 (6.7%) Rofecoxib Low 20 mg 107 (33.8%) 5,963 (36.3%) Medium mg 197 (62.2%) 9,977 (60.7%) High mg 3 (1.0%) 106 (0.7%) Very High 51 mg 10 (3.2%) 381 (2.3%) Recent Use of any NSAID 5,463 (21.7%) 442,216 (21.8%) The dose currently prescribed dose of each NSAID was categorized as low ( 0.8 daily dose equivalents), medium (from 0.9 to 1.2), high (from 1.3 to 1.9) and very high dose ( 2 defined daily dose equivalents). Only patients for which the prescribed daily dose of current NSAIDs use was recorded in the corresponding database of membership were retained in this analysis. Daily amounts of active principles are based on the DDD/amount conversion factors from (accessed December 2015). 16