Supplementary materials. Evidence of potential bias in a comparison of β-blockers and calcium channel

Transcription

1 Supplementary materials Evience of potential bias in a comparison of β-blockers an calcium channel blockers in patients with chronic obstructive pulmonary isease an acute coronary synrome: results of a multi-national stuy Article type: Research Authorship: Yaa-Hui Dong, Matthew Alcusky, Vittorio Maio, Jun Liu, Mengan Liu, Li-Chiu Wu, Chia- Hsuin Chang *, Mei-Shu Lai, Joshua J. Gagne *Corresponence to Chia-Hsuin Chang Department of Internal Meicine, National Taiwan University Hospital 7, Chung-Shan South Roa, Taipei, 10002, Taiwan Tel: ; Fax: ; chiahsuin123@yahoo.com.tw 1

2 Table of Contents METHODS Data source Definitions of continuous enrollment Stuy population an stuy rugs Outcomes an follow-up Table S1. Anatomical Therapeutic Chemical (ATC) Classification System Coes Use To Ientify P4 P5 P5 P6 P7 Carioselective BB or Non-DHP CCB Initiators Table S2. International Classification of Diseases, 9 th Revision, Clinical Moification (ICD-9-CM) P8 Diagnostic or Proceure Coes or Current Proceure Terminology, 4 th Revision (CPT) Coes Use To Ientify Baseline Comorbiities for Carioselective BB or Non-DHP CCB Initiators Table S3. Anatomical Therapeutic Chemical (ATC) Classification System Coes Use To Ientify P10 RESULTS Baseline Meication Use for Carioselective BB or Non-DHP CCB Initiators Table S4. Summary of the Stuy Cohort Assembly, By Database Table S5a-S5e. Baseline Demographics, Comorbiities, Meication Use, an P11 P12 Resource Utilization Between Carioselective BB or Non-DHP CCB Initiators in Iniviual Databases Table S6 Distribution of Propensity Scores Table S7. Follow-up an Iniviual Outcome Event Rates for Carioselective BB or Non- P27 P28 DHP CCB Initiators Table S8. Risk of CV Hospitalizations Due To Iniviual Outcomes Comparing P29 Carioselective BB Versus Non-DHP CCB Initiators Table S9a-S9c Comparison of Characteristic Balance in Different Sensitivity Analyses in P30 Iniviual Databases Table S10 Results of Subgroup Analyses Comparing Carioselective BB versus Non- P39 2

3 DHP CCB Initiators in three US Databases 3

4 METHODS Data source The US Optum Research Database (Optum) comprises ata for health insurance beneficiaries enrolle in commercial UniteHealth Group-affiliate health plans. The atabase inclues ata for approximately 14 million patients on a yearly basis an 60 million patients in total, representing a large geographically iverse population across the US. The Pennsylvania Pharmaceutical Assistance Contract for the Elerly (PACE) an the New Jersey Pharmaceutical Assistance to the Age an Disable (PAAD) programs assist low-income resients of Pennsylvania an New Jersey age 65 years or oler with prescription rug coverage. These programs cover virtually all prescription meications for their beneficiaries, requiring iniviuals to pay only a small copayment. The pharmacy claims recors for each beneficiary were linke to Meicare Part A an Part B ata through the Centers for Meicare an Meicai Services. The Italian National Health Service provies universal health insurance coverage for all Italian citizens. The Regione Emilia-Romagna (RER) atabase, a population-base longituinal health care atabase, captures claims for care provie to iniviuals in Emilia-Romagna, a northeastern Italian region with approximately 4 million resients. The Taiwan National Health Insurance (NHI) Aministration has execute a single-payer an compulsory NHI program in Taiwan since 1995, with an enrollment rate of 99% by The Taiwan NHI atabase comprises approximately 99% of the total Taiwanese population of 4

5 approximately 23 millions of iniviuals. All these atabases inclue comprehensive information on emographic an enrollment recors, hospital amissions, pharmacy ispensing claims ata from outpatient clinics, an vital status. The RER atabase oes not contain information on outpatient resource utilization an ays supply of meications for each pharmacy ispensing. Data from each ataset coul be linke via anonymize unique patient ientifiers within iniviual atabases. In general, these five atabases cover wiely geographically, socioeconomically, an clinically iverse iniviuals, which facilitates the generalizability of this stuy. Definition of continuous enrollment For Optum, PACE, an PAAD atabases, continuous enrollment was operationally efine as having no insurance coverage gap of greater than 30 ays uring the 180 ays before the inex hospitalization amission. For the RER atabase, continuous enrollment was efine as having an at least 180-ay resiency in Emilia-Romagna. For the Taiwan NHI atabase, continuous enrollment was efine as having >=1 hospital amission or outpatient visit uring this perio. Stuy population an stuy rugs ACS hospitalization was efine as an inpatient stay for acute myocarial (MI) or unstable angina using International Classification of Diseases, 9th Revision, Clinical moification (ICD- 9-CM) coes 410.x0, 410.x1, 411.xx in any position on an inpatient claim. The COPD iagnosis was efine as any inpatient or outpatient ICD-9-CM coes 491.xx, 492.xx, or 496.xx in any position (except for the RER atabase, in which information was available only from inpatient iagnosis files). 5

6 Outcomes an follow-up CV hospitalizations were efine as first hospitalization for a composite CV event, incluing acute MI, unstable angina, an congestive heart failure (CHF) (ICD-9-CM coes 410.x0, 410.x1, 411.xx, 428.xx base on the primary iagnosis) following the inex ate. COPD hospitalization was the first hospitalize event (ICD-9-CM coes 491.xx, 492.xx, 496.xx, base on the primary iagnosis) following the inex ate. 6

7 Table S1. Anatomical Therapeutic Chemical (ATC) Classification System Coes Use To Ientify Carioselective BB or Non-DHP CCB Initiators Meication ATC Classification System Coes Define Daily Dose a Carioselective BBs Practolol C07AB g Metoprolol C07AB g Atenolol C07AB03 75 mg Acebutolol C07AB g Betaxolol C07AB05 20 mg Bevantolol C07AB g Bisoprolol C07AB07 10 mg Celiprolol C07AB g Epanolol C07AB g s-atenolol C07AB11 50 mg Nebivolol C07AB12 5 mg Talinolol C07AB g Metoprolol, combinations C07AB g b Bisoprolol, combinations C07AB57 10 mg b Metoprolol an thiazies C07BB g b Atenolol an thiazies C07BB03 75 mg b Acebutolol an thiazies C07BB g b Bevantolol an thiazies C07BB g b Bisoprolol an thiazies C07BB07 10 mg b Nebivolol an thiazies C07BB12 5 mg b Metoprolol an thiazies, 0.15 g b C07BB52 combinations Metoprolol an other 0.15 g b C07CB02 iuretics Atenolol an other iuretics C07CB03 75 mg b Atenolol an other iuretics, 75 mg b C07CB53 combinations Atenolol, thiazies an other 75 mg b C07DB01 iuretics Metoprolol an other 0.15 g b C07FB02 antihypertensives Atenolol an other 75 mg b C07FB03 antihypertensives Bisoprolol an other 10 mg b C07FB07 antihypertensives Non-DHP CCBs Verapamil C08DA g Verapamil, combinations C08DA g b Diltiazem C08DB g Abbreviations: BBs, β-blockers; DHP CCBs, ihyropyriine calcium channel blockers. a The efine aily ose was establishe by the expert committee of Worl Health Organization as the average maintenance ose per ay for a rug use for its main inication in aults ( accesse Feb, 2015). b The efine aily ose of combination is base on the ingreients of carioselective BB or non-dhp CCB. 7

8 Table S2. International Classification of Diseases, 9 th Revision, Clinical Moification (ICD-9-CM) Diagnostic or Proceure Coes or Current Proceure Terminology, 4 th Revision (CPT) Coes Use To Ientify Baseline Comorbiities a for Carioselective BB or Non-DHP CCB Initiators Comorbiities ICD-9-CM Diagnostic Coes Other Coes Assessment Perio 1: Before the ACS Hospitalization Amission Date MI b PTCA b Stent b CABG b Coronary revascularization b, Hemorrhagic stroke b Ischemic heart isease b TIA b Assessment Perio 2: Between the ACS Hospitalization Amission Date an the Inex Date 410.xx, 412.xx 430.xx, 431.xx, 432.xx 433.x1, 434.x1, 436.xx 435.xx 8 ICD-9-CM Proceure Coe: 00.66, 36.01, 36.02, 36.05, CPT Coes: 92973, 92982, 92984, 92995, ICD-9-CM Proceure Coe: 36.06, CPT Coes: 92980, ICD-9-CM Proceure Coe: 36.1x, 36.2x CPT Coes: , , 33530, , 33545, Specific for Taiwan NHI atabase 68023A,68023B, 68024A,68024B,68025A, 68025B,83064A1, 97901K, 97902A, 97903B, 97906K, 97907A, 97908B, 97911K, 97912A, 97913B,97916K, 97917A, 97918B, 33076A, 33076B, 33077A, 33077B, 33078A, 33078B, 97511K, 97512A, 97513B, 97516K, 97517A, 97518B, 97521K, 97522A, 97523B Assessment Perio: Before The Inex Date Hypertension b 401.xx-405.xx (iagnosis-relate group: 134) Angina b 411.xx IHD b 413.xx, 414.xx Cariac ysrhythmia b 427.xx Atrial fibrillation b CHF b 428.xx, , , , , , , , , , Cereborvascular isease b 430.xx-438.xx PVD b 443.xx, 445.xx, 442.0x, 442.2x, 442.3x CPT Coes: 35256, 35286, 35351, 35355, 35361, 35363, 35371, 35372, 35381, 35454, 35456, 35459, 35470, 35473, 35474, 35482, 35483, 35485, 35492, 35493, 35495, 35521, 35533, 35541, 35546, 35548, 35549, 35551, 35556, 35558, 35563, 35565, 35566, 35571, 35621, 35623, 35641, 35646, 35647, 35650, 35651, 35654, 35656, 35661, 35663, 35666, 35671, 27590, 27591, 27592, 27594, 27596, 27880, 27881, 27882, 27884, 27886, 27888

9 Disorers of lipi metabolism 272.xx Diabetes mellitus 250.xx Thyroi isease COPD c 491.xx, 492.xx, 494.xx, 496.xx Asthma c 493.xx Pneumonia, influenza, an acute 480.xx-487.xx, 466.xx bronchitis c Chronic liver isease 571.xx Gastric bleeing 531.0x, 531.2x, 531.4x, 531.6x, 532.0x, 532.2x, 532.4x, 532.6x, 533.0x, 533.2x, 533.4x, 533.6x, 534.0x, 534.2x, 534.4x, 534.6x, ICD-9-CM Proceure Coes: CPT Coes: Chronic kiney isease or enstage renal isease xx, 404.xx, 585.xx Rheumatoi arthritis / 710.x,714.xx, 715.xx, 720.xx Osteoarthritis Osteoporosis 733.0x Any cancer other than lung 140.xx-161.xx, 163.xx-208.xx cancer Lung cancer 162.x Dementia 290.0x-290.4x, 291.2, 294.1x, 331.0x-331.2x, ICD-9-CM Proceure Coes: 39.95, CPT Coes: , 90999, 99512, Seizure 345.xx, 780.3x Psychiatric isorer , 296.2x, 296.3x, , , 298.0, 300.4, 309.0, 309.1, , 311, 300.0x x, 300.5x-300.9x, 295.xx, 297.xx- 299.xx, 290.8, 290.9, 780.1, 296.0x, 296.1x, 296.4x-296.9x Abbreviations: ACS, acute coronary synromes; BBs, β-blockers; CABG, Coronary Artery Bypass Graft Surgery; CHF, Congestive heart failure; COPD, chronic obstructive pulmonary isease; DHP CCBs, ihyropyriine calcium channel blockers; IHD, Ischemia heart isease; MI, myocarial infarction; NHI, national health insurance; PTCA, percutaneous transluminal coronary angioplasty; Peripheral vascular isease, PVD; TIA, Transient ischemic attack. a Comorbiities were measure base on any iagnosis positions in inpatient an outpatient iagnosis files. b Cariovascular episoes inclue: MI, coronary revascularization (PTCA, stent, CABG), hemorrhagic stroke, ischemic stroke, TIA, hypertension, angina, IHD, cariac ysrhythmia, atrial fibrillation, CHF, cerebrovascular isease, an PVD. c Respiratory -relate episoes inclue COPD, asthma, pneumonia, influenza, an acute bronchitis. Base on Taiwan NHI service claims coes ( accesse October, 2013). 9

10 Table S3. Anatomical Therapeutic Chemical (ATC) Classification System Coes Use To Ientify Baseline Meication Use for Carioselective BB or Non-DHP CCB Initiators Meication ATC Classification System Coes Assessment Perio 1: Before the ACS Hospitalization Amission Date Assessment Perio 2: Between the ACS Hospitalization Amission Date an the Inex Date ACEIs / ARBs / Reinin inhibitors C09 Non-carioselective BB C07AA, C07AG, C07BA, C07BG, C07CA, C07CG, C07DA, C07EA, C07FA DHP CCB C08C, C08E, C08G Diuretics C03, C07B, C07C, C07D, C08G Other anti-hypertensive agents C02 Nitrates C01DA Anti-arrhythmic agents C01B Digoxin C01AA Anti-platelet agents B01AC Anti-coagulants B01AA Fibrates / statins C10AA, C10AB Assessment Perio: Before the Inex Date Anti-iabetic agents A10A, A10B Thyroi-therapy rugs H03 Inhale short-acting bronchoilators R03AC02, R03AC03, R03AC04, R03AC06, R03BB01 Inhale long-acting bronchoilators R03AC12, R03AC13, R03AC16, R03AC18, R03AK06, R03AK07, R03BB04 ICS R03BA, R03AK06, R03AK07 Oral corticosterois H02AB, H02BX Oral bronchoilators R03CC02, R03CC03, R03CC04, R03CC05, R03CC08, R03CC09, R03CC12, R03CC13, R03CC91 R03DA04, R03DA05 Antibiotics J01 Histamine 2 antagonists / PPIs A02BA, A02BC COX-2 selective NSAIDs M01AH COX-2 nonselective NSAIDs M01AA, M01AB, M01AC, M01AE, M01AG, M01AX Anti-epileptics N03 Anti-psychiatric rugs N06A, N05B, N05C, N05A Abbreviations: ACEIs, angiotensin converting enzyme inhibitors; ACS, acute coronary synromes; ARBs, angiotensin Ⅱ receptor blockers; BBs, β-blockers; Cox, cyclooxygenase; DHP CCBs, ihyropyriine calcium channel blockers; ICS, inhale corticosterois; NSAIDs, non-steroial anti-inflammatory rugs; PPIs, proton pump inhibitors. 10

11 Table S4. Summary of the Stuy Cohort Assembly, By Database Inclusion / Exclusion Criteria Patient episoes with an ACS hospitalization in the iniviual atabases uring the stuy perio Exclue ue to * Lack of continuous enrollment for 180 ays before the ACS hospitalization amission ate * No COPD iagnosis before the ACS hospitalization ischarge ate Patient episoes with ACS an COPD uring the stuy perio Exclue ue to * No prescription of carioselective BBs or non-dhp CCBs within 90 ays after ACS hospitalization ischarge Patient episoes with use of carioselective BBs or non-dhp CCBs Exclue ue to * Age less than 20 (or 65) years, more than 120 years, or unetermine * Unetermine sex * Use of carioselective BBs or non-dhp CCBs before the inex ate * Receipt of both carioselective BBs an non-dhp CCBs on the inex ate US Optum (2004/ /12) No of patient episoes = 175,939 * No of patient episoes = 25,149 * No of patient episoes = 117,511 No of patient episoes = 33,279 * No of patient episoes = 16,112 No of patient episoes = 17,167 * No of patient episoes = 0 * No of patient episoes = 0 * No of patient episoes = 10,322 * No of patients = 166 US PACE (1994/ /12) No of patient episoes = 195,954 * No of patient episoes = 74,488 * No of patient episoes = 61,136 No of patient episoes = 60,330 * No of patient episoes = 32,737 No of patient episoes = 27,593 * No of patient episoes = 41 * No of patient episoes = 0 * No of patient episoes = 23,271 * No of patients = 0 Database (Stuy Perio) US PAAD (1995/ /12) No of patient episoes = 116,121 * No of patient episoes = 51,230 * No of patient episoes = 31,467 No of patient episoes = 33,424 * No of patient episoes = 17,419 No of patient episoes = 16,005 * No of patient episoes = 1,309 * No of patient episoes = 0 * No of patient episoes = 11,870 * No of patients = 158 Italy RER (2003/7-2013/12) No of patient episoes = 179,864 * No of patient episoes = 3,892 * No of patient episoes = 152,210 No of patient episoes = 23,762 * No of patient episoes = 12,512 No of patient episoes = 11,250 * No of patient episoes = 0 * No of patient episoes = 0 * No of patient episoes = 8,168 * No of patients = 28 Taiwan NHI (2007/ /12) No of patient episoes = 187,487 * No of patient episoes = 5,716 * No of patient episoes = 97,300 No of patient episoes = 84,471 * No of patient episoes = 54,487 No of patient episoes = 29,984 * No of patient episoes = 0 * No of patient episoes = 18 * No of patient episoes = 23,579 * No of patients = 84 Patients inclue No of patients = 6,679 No of patients = 4,281 No of patients = 2,668 No of patients = 3,054 No of patients = 6,303 * Carioselective BBs = 6,383 * Non-DHP CCBs =296 * Carioselective BBs = 3,372 * Non-DHP CCBs =909 * Carioselective BBs = 2,108 * Non-DHP CCBs =560 * Carioselective BBs = 2,489 * Non-DHP CCBs = 565 * Carioselective BBs = 4,054 * Non-DHP CCBs = 2,249 Abbreviations: ACS, acute coronary synromes; BBs, β-blockers; COPD, chronic obstructive pulmonary isease; DHP CCBs, ihyropyriine calcium channel blockers; NHI, national health insurance; PAAD, Pharmacy Assistance for the Age an Disable; PACE, Pharmacy Assistance Contract for the Elerly; RER, Emilia-Romagna Region. 11

12 Table S5a. Baseline Demographics, Resource Utilization, Comorbiities, an Meication Use Between Carioselective BB or Non-DHP CCB Initiators in US Optum Database Before Matching Carioselective BBs Total Stuy Cohort (n=6,679) Non-DHP CCBs (n=296) After Matching 1: 1 Ranom-Sample Matche Cohort c (n=554) Non-DHP CCBs (n=6,383) (n=277) Age, mean (SD) 60.9 (10.6) 63.2 (11.1) (11.5) 62.9 (11.1) STD Carioselective BBs Male, % Length of stay of ACS hospitalization, 6.5 (6.0) 8.22 (7.0) (12.8) 8.1 (6.9) 0.03 ay, mean (SD) COPD uration, ay, mean (SD) 427.3(593.6) 483.7(582.4) (503.3) 463.1(571.9) 0.03 Year of the inex ate, % Enrollment uration, ay, mean (SD) 985.6(717.6) 881.8(618.0) (625.0) 873.8(606.5) (n=277) STD Resource utilization No of hospitalization ue to any 1.2 (0.5) 1.4 (0.8) (0.7) 1.3 (0.7) episoes, mean (SD) No of outpatient visits ue to any 3.9 (3.9) 5.3 (4.8) (4.5) 5.0 (4.6) 0.08 episoes, mean (SD) No of outpatient visits ue to CV 2.3 (4.2) 3.5 (4.8) (6.3) 3.4 (4.8) 0.06 episoes a, mean (SD) No of outpatient visits ue to 1.3 (2.9) 3.8 (5.8) (5.1) 3.2 (4.9) pulmonary-relate episoes b, mean (SD) No. of rugs, mean (SD) 10.0 (5.3) 12.9 (6.9) (6.4) 12.5 (6.7) 0.04 Comorbiities, % Before the ACS amission ate MI PTCA Stent CABG Hemorrhagic stroke Ischemic stroke TIA Between the ACS amission ate an the inex ate MI PTCA Stent

13 CABG Hemorrhagic stroke NA Ischemic stroke TIA Before the inex ate Hypertension Angina IHD Cariac ysrhythmia Atrial fibrillation CHF Cerebrovascular isease PVD Disorers of lipi metabolism Diabetes mellitus Thyroi isease Asthma Pneumonia, influenza, an acute bronchitis Chronic liver isease Gastritis or peptic ulcer isease Chronic kiney isease Rheumatoi arthritis /Osteoarthritis Osteoporosis Any cancer (except lung cancer) Lung cancer Dementia 2.1 < Seizure Psychiatric isorer Meication use, % Before the ACS amission ate ACEIs / ARBs / renin inhibitors Non-carioselective BBs DHP CCBs Diuretics Other anti-hypertensive agents Nitrates Anti-arrhythmic agents Digoxin Antiplatelet agents Anticoagulants Fibrates / statins < Between the ACS amission ate an the inex ate ACEIs / ARBs / renin inhibitors Non-carioselective BBs DHP CCBs Diuretics Other anti-hypertensive agents Nitrates Anti-arrhythmic agents Digoxin Antiplatelet agents Anticoagulants

14 Fibrates / statins Before the inex ate Anti-iabetic agents Thyroi-therapy rugs Short-acting bronchoilators Long-acting bronchoilators ICS Oral corticosterois Oral bronchoilators Antibiotics Histamine 2 antagonists / PPIs COX-2 selective NSAIDs COX-2 nonselective NSAIDs Anti-epileptics < Anti-psychiatric rugs Estrogen Abbreviations: ACEIs, angiotensin converting enzyme inhibitors; ACS, acute coronary synromes; ARBs, angiotensin Ⅱ receptor blockers; BBs, β-blockers; CABG, Coronary Artery Bypass Graft Surgery; CHF, Congestive heart failure; COPD, chronic obstructive pulmonary isease; Cox, cyclooxygenase; CV, cariovascular; DHP CCBs, ihyropyriine calcium channel blockers; ICS, inhale corticosterois; IHD, Ischemia heart isease; MI, myocarial infarction; NA, not applicable; NSAIDs, non-steroial anti-inflammatory rugs; PPIs, proton pump inhibitors; PTCA, percutaneous transluminal coronary angioplasty; Peripheral vascular isease, PVD; SD, stanar eviation; STD, stanarize ifferences; TIA, Transient ischemic attack. a CV episoes inclue: MI, coronary revascularization (PTCA, stent, CABG), hemorrhagic stroke, ischemic stroke, TIA, hypertension, angina, IHD, cariac ysrhythmia, atrial fibrillation, CHF, cerebrovascular isease, an PVD. b Pulmonary-relate episoes inclue COPD, asthma, pneumonia, influenza, an acute bronchitis. c 1 ranomly sample carioselective BBs user : 1 non-dhp CCBs user in each matche subset. No of events<11 14

15 Table S5b. Baseline Demographics, Resource Utilization, Comorbiities, an Meication Use Between Carioselective BB or Non-DHP CCB Initiators in US PACE Database Before Matching Total Stuy Cohort (n=4,281) Cario-selective BBs Non-DHP CCBs After Matching 1: 1 Ranom-Sample Matche Cohort c (n=1,408) (n=3,372) (n=909) (n=704) (n=704) Age, mean (SD) 79.5 (7.1) 78.4 (6.8) (6.9) (6.9) 0.03 Male, % < Length of stay of ACS hospitalization, 9.1 (6.2) 9.9 (7.4) (6.8) 9.6 (7.3) 0.01 ay, mean (SD) COPD uration, ay, mean (SD) (952.7) 797.5(782.0) (856.4) 822.9(821.2) <0.01 Year of the inex ate, % STD Cario-selective BBs Non-DHP CCBs Enrollment uration, ay, mean (SD) (974.1) 921.8(702.8) (758.0) 976.1(736.7) 0.03 STD Resource utilization No of hospitalization ue to any 1.5 (0.9) 1.6 (1.0) (0.9) 1.5 (0.9) 0.04 episoes, mean (SD) No of outpatient visits ue to any 4.5 (3.9) 4.7 (3.9) (4.0) 4.6 (3.8) 0.04 episoes, mean (SD) No of outpatient visits ue to CV 3.7 (3.9) 3.3 (3.6) (3.8) 3.5 (3.6) 0.05 episoes a, mean (SD) No of outpatient visits ue to 1.0 (1.9) 2.3 (3.0) (2.6) 1.8 (2.5) 0.02 pulmonary-relate episoes b, mean (SD) No. of rugs, mean (SD) 10.7 (4.8) 11.6 (5.3) (5.2) 11.1 (5.0) 0.07 Comorbiities, % Before the ACS amission ate MI PTCA Stent CABG Hemorrhagic stroke Ischemic stroke TIA Between the ACS amission ate an the inex ate MI PTCA

16 Stent CABG Hemorrhagic stroke Ischemic stroke TIA Before the inex ate Hypertension Angina IHD Cariac ysrhythmia Atrial fibrillation CHF <0.01 Cerebrovascular isease PVD Disorers of lipi metabolism Diabetes mellitus Thyroi isease Asthma Pneumonia, influenza, an acute bronchitis Chronic liver isease Gastritis or peptic ulcer isease Chronic kiney isease <0.01 Rheumatoi arthritis /Osteoarthritis Osteoporosis Any cancer (except lung cancer) Lung cancer Dementia Seizure Psychiatric isorer Meication use, % Before the ACS amission ate ACEIs / ARBs / renin inhibitors Non-carioselective BBs DHP CCBs Diuretics Other anti-hypertensive agents Nitrates Anti-arrhythmic agents Digoxin Antiplatelet agents Anticoagulants Fibrates / statins Between the ACS amission ate an the inex ate ACEIs / ARBs / renin inhibitors Non-carioselective BBs DHP CCBs Diuretics Other anti-hypertensive agents Nitrates Anti-arrhythmic agents Digoxin Antiplatelet agents

17 Anticoagulants Fibrates / statins <0.01 Before the inex ate Anti-iabetic agents Thyroi-therapy rugs Short-acting bronchoilators Long-acting bronchoilators ICS Oral corticosterois Oral bronchoilators Antibiotics Histamine 2 antagonists / PPIs COX-2 selective NSAIDs COX-2 nonselective NSAIDs Anti-epileptics Anti-psychiatric rugs Estrogen Abbreviations: ACEIs, angiotensin converting enzyme inhibitors; ACS, acute coronary synromes; ARBs, angiotensin Ⅱ receptor blockers; BBs, β-blockers; CABG, Coronary Artery Bypass Graft Surgery; CHF, Congestive heart failure; COPD, chronic obstructive pulmonary isease; Cox, cyclooxygenase; CV, cariovascular; DHP CCBs, ihyropyriine calcium channel blockers; ICS, inhale corticosterois; IHD, Ischemia heart isease; MI, myocarial infarction; NSAIDs, non-steroial anti-inflammatory rugs; PACE, Pharmacy Assistance Contract for the Elerly; PPIs, proton pump inhibitors; PTCA, percutaneous transluminal coronary angioplasty; Peripheral vascular isease, PVD; SD, stanar eviation; STD, stanarize ifferences; TIA, Transient ischemic attack. a CV episoes inclue: MI, coronary revascularization (PTCA, stent, CABG), hemorrhagic stroke, ischemic stroke, TIA, hypertension, angina, IHD, cariac ysrhythmia, atrial fibrillation, CHF, cerebrovascular isease, an PVD. b Pulmonary-relate episoes inclue COPD, asthma, pneumonia, influenza, an acute bronchitis. c 1 ranomly sample carioselective BBs user : 1 non-dhp CCBs user in each matche subset. No of events<11 17

18 Table S5c. Baseline Demographics, Resource Utilization, Comorbiities, an Meication Use Between Carioselective BB or Non-DHP CCB Initiators in US PAAD Database Before Matching Total Stuy Cohort (n=2,668) Cario-selective BBs Non-DHP CCBs After Matching 1: 1 Ranom-Sample Matche Cohort c (n=850) (n=2,108) (n=560) (n=425) (n=425) Age, mean (SD) 79.5 (7.2) 78.4 (7.1) (6.7) 78.8 (7.0) <0.01 Male, % Length of stay of ACS hospitalization, 9.9 (7.3) 10.3 (8.2) (7.2) 9.9 (8.2) 0.02 ay, mean (SD) COPD uration, ay, mean (SD) (101.0) 917.0(919.3) (913.6) 974.8(960.4) Between the ACS amission ate an the inex ate MI PTCA Stent STD Cario-selective BBs Non-DHP Year of the inex ate, % Enrollment uration, ay, mean (SD) (980.7) (829.0) (842.5) (869.1) 0.06 Resource utilization No of hospitalization ue to any 1.4 (0.8) 1.7 (1.1) (1.0) 1.6 (1.0) 0.04 episoes, mean (SD) No of outpatient visits ue to any 5.2 (4.4) 5.4 (4.4) (4.5) 5.1 (4.0) 0.06 episoes, mean (SD) No of outpatient visits ue to CV 3.8 (3.9) 3.8 (4.2) < (4.1) 3.7 (4.0) 0.07 episoes a, mean (SD) No of outpatient visits ue to 1.1 (2.0) 2.3 (2.7) (2.9) 1.9 (2.3) 0.02 pulmonary-relate episoes b, mean (SD) No. of rugs, mean (SD) 11.8 (5.4) 13.2 (5.7) (5.8) 12.4 (5.3) 0.08 Comorbiities, % Before the ACS amission ate MI PTCA Stent CABG Hemorrhagic stroke Ischemic stroke TIA CCBs STD

19 CABG Hemorrhagic stroke Ischemic stroke TIA Before the inex ate Hypertension Angina IHD Cariac ysrhythmia Atrial fibrillation CHF Cerebrovascular isease PVD Disorers of lipi metabolism Diabetes mellitus Thyroi isease Asthma Pneumonia, influenza, an acute bronchitis Chronic liver isease Gastritis or peptic ulcer isease Chronic kiney isease Rheumatoi arthritis /Osteoarthritis Osteoporosis Any cancer (except lung cancer) Lung cancer Dementia Seizure Psychiatric isorer Meication use, % Before the ACS amission ate ACEIs / ARBs / renin inhibitors Non-carioselective BBs DHP CCBs Diuretics Other anti-hypertensive agents Nitrates Anti-arrhythmic agents Digoxin Antiplatelet agents Anticoagulants < Fibrates / statins Between the ACS amission ate an the inex ate ACEIs / ARBs / renin inhibitors Non-carioselective BBs DHP CCBs Diuretics Other anti-hypertensive agents Nitrates <0.01 Anti-arrhythmic agents Digoxin Antiplatelet agents Anticoagulants

20 Fibrates / statins Before the inex ate Anti-iabetic agents Thyroi-therapy rugs Short-acting bronchoilators Long-acting bronchoilators ICS Oral corticosterois Oral bronchoilators Antibiotics Histamine 2 antagonists / PPIs COX-2 selective NSAIDs COX-2 nonselective NSAIDs Anti-epileptics Anti-psychiatric rugs Estrogen Abbreviations: ACEIs, angiotensin converting enzyme inhibitors; ACS, acute coronary synromes; ARBs, angiotensin Ⅱ receptor blockers; BBs, β-blockers; CABG, Coronary Artery Bypass Graft Surgery; CHF, Congestive heart failure; COPD, chronic obstructive pulmonary isease; Cox, cyclooxygenase; CV, cariovascular; DHP CCBs, ihyropyriine calcium channel blockers; ICS, inhale corticosterois; IHD, Ischemia heart isease; MI, myocarial infarction; NSAIDs, non-steroial anti-inflammatory rugs; PAAD, Pharmacy Assistance for the Age an Disable; PPIs, proton pump inhibitors; PTCA, percutaneous transluminal coronary angioplasty; Peripheral vascular isease, PVD; SD, stanar eviation; STD, stanarize ifferences; TIA, Transient ischemic attack. a CV episoes inclue: MI, coronary revascularization (PTCA, stent, CABG), hemorrhagic stroke, ischemic stroke, TIA, hypertension, angina, IHD, cariac ysrhythmia, atrial fibrillation, CHF, cerebrovascular isease, an PVD. b Pulmonary-relate episoes inclue COPD, asthma, pneumonia, influenza, an acute bronchitis. c 1 ranomly sample carioselective BBs user : 1 non-dhp CCBs user in each matche subset. No of events<11 20

21 Table S5. Baseline Demographics, Resource Utilization, Comorbiities, an Meication Use Between Carioselective BB or Non-DHP CCB Initiators in Italy RER Database Before Matching Total Stuy Cohort (n=3,054) Cario-selective BBs Non-DHP CCBs After Matching 1: 1 Ranom-Sample Matche Cohort c (n=896) Cario-selective Non-DHP STD (n=2,489) (n=565) (n=448) (n=448) Age, mean (SD) 76.6 (10.1) 76.8 (8.7) (10.0) 77.0 (9.0) Male, % Length of stay of ACS hospitalization, 11.4 (10.7) 11.5 (7.6) < (10.0) 11.6 (8.0) ay, mean (SD) COPD uration, ay, mean (SD) (906.4) (731.3) (756.8) (786.0) Year of the inex ate, % Enrollment uration, ay, mean (SD) (1039.2) (963.0) (1011.6) (986.4) 0.01 STD BBs CCBs Resource utilization No of hospitalization ue to any 1.9 (1.2) 1.8 (1.1) (1.1) 1.8 (1.1) episoes, mean (SD) No of outpatient visits ue to any episoes, mean (SD) NA NA NA NA NA NA No of outpatient visits ue to CV episoes a, mean (SD) NA NA NA NA NA NA No of outpatient visits ue to pulmonary-relate episoes b, mean NA NA NA NA NA NA (SD) No. of rugs, mean (SD) 11.8 (4.7) 12.3 (4.7) (5.2) 12.1 (4.7) <0.01 Comorbiities, % Before the ACS amission ate MI PTCA Stent CABG Hemorrhagic stroke Ischemic stroke TIA Between the ACS amission ate an the inex ate MI PTCA <0.01 Stent

22 CABG Hemorrhagic stroke 0.02 Ischemic stroke TIA Before the inex ate Hypertension Angina IHD < Cariac ysrhythmia Atrial fibrillation CHF Cerebrovascular isease PVD Disorers of lipi metabolism Diabetes mellitus Thyroi isease Asthma Pneumonia, influenza, an acute bronchitis Chronic liver isease Gastritis or peptic ulcer isease Chronic kiney isease Rheumatoi arthritis /Osteoarthritis Osteoporosis Any cancer (except lung cancer) Lung cancer Dementia Seizure Psychiatric isorer Meication use, % Before the ACS amission ate ACEIs / ARBs / renin inhibitors Non-carioselective BBs DHP CCBs Diuretics Other anti-hypertensive agents Nitrates Anti-arrhythmic agents Digoxin Antiplatelet agents <0.01 Anticoagulants Fibrates / statins Between the ACS amission ate an the inex ate ACEIs / ARBs / renin inhibitors Non-carioselective BBs DHP CCBs Diuretics <0.01 Other anti-hypertensive agents Nitrates <0.01 Anti-arrhythmic agents Digoxin Antiplatelet agents <0.01 Anticoagulants

23 Fibrates / statins <0.01 Before the inex ate Anti-iabetic agents Thyroi-therapy rugs Short-acting bronchoilators Long-acting bronchoilators ICS Oral corticosterois Oral bronchoilators <0.01 Antibiotics Histamine 2 antagonists / PPIs COX-2 selective NSAIDs COX-2 nonselective NSAIDs Anti-epileptics Anti-psychiatric rugs Estrogen Abbreviations: ACEIs, angiotensin converting enzyme inhibitors; ACS, acute coronary synromes; ARBs, angiotensin Ⅱ receptor blockers; BBs, β-blockers; CABG, Coronary Artery Bypass Graft Surgery; CHF, Congestive heart failure; COPD, chronic obstructive pulmonary isease; Cox, cyclooxygenase; CV, cariovascular; DHP CCBs, ihyropyriine calcium channel blockers; ICS, inhale corticosterois; IHD, Ischemia heart isease; MI, myocarial infarction; NA, not applicable; NSAIDs, non-steroial anti-inflammatory rugs; PPIs, proton pump inhibitors; PTCA, percutaneous transluminal coronary angioplasty; Peripheral vascular isease, PVD; SD, stanar eviation; RER, Emilia-Romagna Region; STD, stanarize ifferences; TIA, Transient ischemic attack. a CV episoes inclue: MI, coronary revascularization (PTCA, stent, CABG), hemorrhagic stroke, ischemic stroke, TIA, hypertension, angina, IHD, cariac ysrhythmia, atrial fibrillation, CHF, cerebrovascular isease, an PVD. b Pulmonary-relate episoes inclue COPD, asthma, pneumonia, influenza, an acute bronchitis. c 1 ranomly sample carioselective BBs user : 1 non-dhp CCBs user in each matche subset. No of events<11 23

24 Table S5e. Baseline Demographics, Resource Utilization, Comorbiities, an Meication Use Between Carioselective BB or Non-DHP CCB Initiators in Taiwan NHI Database Before Matching After Matching Total Stuy Cohort (n=6,303) Cario-selective BBs Non-DHP CCBs 1: 1 Ranom-Sample Matche Cohort c (n=3,468) (n=4,054) (n=2,249) (n=1,734) (n=1,734) Age, mean (SD) 69.4 (12.6) 71.5 (12.7) (12.2) 70.9 (12.8) 0.03 Male, % Length of stay of ACS hospitalization, 9.1 (11.0) 10.8 (17.8) (14.4) 10.5 (17.5) ay, mean (SD) COPD uration, ay, mean (SD) (1176.6) (1164.7) (1144.9) (1181.4) 0.04 Year of the inex ate, % < Before the inex ate Hypertension Angina IHD Cariac ysrhythmia <0.01 Atrial fibrillation STD Cario-selective BBs Non-DHP Enrollment uration, ay, mean (SD) (528.2) (528.4) ,031.0 (524.6) 1,028.6 (531.7) <0.01 Resource utilization No of hospitalization ue to any 1.5 (0.9) 1.7 (1.1) (1.0) 1.6 (1.0) <0.01 episoes, mean (SD) No of outpatient visits ue to any 19.6 (12.5) 21.9 (13.9) (13.2) 21.2 (13.7) 0.01 episoes, mean (SD) No of outpatient visits ue to CV 6.5 (5.0) 6.5 (5.6) < (5.1) 6.7 (5.7) <0.01 episoes a, mean (SD) No of outpatient visits ue to 1.3 (3.0) 2.7 (4.2) (3.9) 2.0 (3.5) pulmonary-relate episoes b, mean (SD) No. of rugs, mean (SD) 27.5 (12.5) 30.0 (13.5) (13.4) 29.0 (13.0) 0.02 Comorbiities, % Before the ACS amission ate MI Coronary revascularization Hemorrhagic stroke < Ischemic stroke < TIA <0.01 Between the ACS amission ate an the inex ate MI Coronary revascularization Hemorrhagic stroke Ischemic stroke TIA CCBs STD

25 CHF Cerebrovascular isease PVD Disorers of lipi metabolism Diabetes mellitus Thyroi isease Asthma <0.01 Pneumonia, influenza, an acute <0.01 bronchitis Chronic liver isease Gastritis or peptic ulcer isease Chronic kiney isease <0.01 Rheumatoi arthritis /Osteoarthritis Osteoporosis Any cancer (except lung cancer) < Lung cancer Dementia Seizure <0.01 Psychiatric isorer <0.01 Meication use, % Before the ACS amission ate ACEIs / ARBs / renin inhibitors <0.01 Non-carioselective BBs DHP CCBs Diuretics Other anti-hypertensive agents Nitrates <0.01 Anti-arrhythmic agents <0.01 Digoxin <0.01 Antiplatelet agents Anticoagulants <0.01 Fibrates / statins <0.01 Between the ACS amission ate an the inex ate ACEIs / ARBs / renin inhibitors Non-carioselective BBs DHP CCBs Diuretics Other anti-hypertensive agents Nitrates Anti-arrhythmic agents Digoxin Antiplatelet agents <0.01 Anticoagulants Fibrates / statins <0.01 Before the inex ate Anti-iabetic agents Thyroi-therapy rugs Short-acting bronchoilators Long-acting bronchoilators ICS Oral corticosterois Oral bronchoilators Antibiotics

26 Histamine 2 antagonists / PPIs COX-2 selective NSAIDs COX-2 nonselective NSAIDs < <0.01 Anti-epileptics <0.01 Anti-psychiatric rugs Estrogen Abbreviations: ACEIs, angiotensin converting enzyme inhibitors; ACS, acute coronary synromes; ARBs, angiotensin Ⅱ receptor blockers; BBs, β-blockers; CABG, Coronary Artery Bypass Graft Surgery; CHF, Congestive heart failure; COPD, chronic obstructive pulmonary isease; Cox, cyclooxygenase; CV, cariovascular; DHP CCBs, ihyropyriine calcium channel blockers; ICS, inhale corticosterois; IHD, Ischemia heart isease; MI, myocarial infarction; NHI, national health insurance; NSAIDs, non-steroial anti-inflammatory rugs; PPIs, proton pump inhibitors; PTCA, percutaneous transluminal coronary angioplasty; Peripheral vascular isease, PVD; SD, stanar eviation; STD, stanarize ifferences; TIA, Transient ischemic attack. a CV episoes inclue: MI, coronary revascularization (PTCA, stent, CABG), hemorrhagic stroke, ischemic stroke, TIA, hypertension, angina, IHD, cariac ysrhythmia, atrial fibrillation, CHF, cerebrovascular isease, an PVD. b Pulmonary-relate episoes inclue COPD, asthma, pneumonia, influenza, an acute bronchitis. c 1 ranomly sample carioselective BBs user : 1 non-dhp CCBs user in each matche subset. 26

27 Table S6. Distribution of Propensity Scores for Iniviual Databases Carioselective BBs Non-DHP CCBs Database Min 25 percentile Meian 75 Percentile Max Min 25 percentile Meian 75 Percentile Max US Optum US PACE US PAAD Italy RER Taiwan NHI Abbreviations: BBs, β-blockers; DHP CCBs, ihyropyriine calcium channel blockers; NHI, National Health Insurance; PAAD, Pharmacy Assistance for the Age an Disable; PACE, Pharmacy Assistance Contract for the Elerly; RER, Emilia-Romagna Region. 27

28 Table S7. Follow-up an Iniviual Outcome Event Rates for Carioselective BB or Non-DHP CCB Initiators Database Carioselective BBs (n=18,406) No of patients No of events Follow-up person years Crue incience (per 1000 personyears) Acute MI a Non-DHP CCBs (n=4,579) No of patients No of events Follow-up person years b b Crue incience (per 1000 personyears) US Optum 6, , ( ) ( ) US PACE 3, , ( ) , ( ) US PAAD 2, , ( ) , ( ) Italy RER 2, , ( ) , ( ) Taiwan NHI 4, , ( ) 2, , ( ) Summary estimate 33.3 ( ) 28.4 ( ) Unstable angina a US Optum 6, , ( ) 296 b b 0.00 US PACE 3, , ( ) , ( ) US PAAD 2, , ( ) , ( ) Italy RER 2, , ( ) , ( ) Taiwan NHI 4, , ( ) 2, , ( ) Summary estimate 9.0 ( ) 17.5 ( ) CHF a US Optum 6, , ( ) ( ) US PACE 3, , ( ) , ( ) US PAAD 2, , ( ) , ( ) Italy RER 2, , ( ) , ( ) Taiwan NHI 4, , ( ) 2, , ( ) Summary estimate 52.1 ( ) 59.9 ( ) Abbreviations: BBs, β-blockers; CHF, congestive heart failure; CV, cariovascular; DHP CCBs, ihyropyriine calcium channel blockers; MI, myocarial infarction; NHI, National Health Insurance; PAAD, Pharmacy Assistance for the Age an Disable; PACE, Pharmacy Assistance Contract for the Elerly; RER, Emilia-Romagna Region. a base on the analysis that consiere first exposure carrie forwar. b No of events<11 28