Β-Blocker–Associated Risks in Patients with Uncomplicated Hypertension Undergoing Noncardiac Surgery

Supplementary Online Content

Jørgensen ME, Hlatky MA, Køber L, et al. β-Blocker–associated risks in patients with uncomplicated hypertension undergoing noncardiac surgery. JAMA Intern Med. Published online October 5, 2015. doi:10.1001/jamainternmed.2015.5346

eTable 1. Variable coding and definitions

eTable 2. Use of beta blocker subtypes in the study population

eTable 3. Distribution of type of surgery stratified by beta blocker use

eTable 4. Distribution of key variables in patients with and without missing values

eFigure 1. Secondary outcomes (individual MACE components) by antihypertensive drug regimen

eFigure 2. Risks of MACE and mortality including patients treated with metoprolol or atenolol only

eFigure 3. Patients with a diagnosis of hypertension and one-drug antihypertensive treatment

eFigure 4. Main results adjusted for type of surgery in 17 categories

eFigure 5. Risks associated with each study drug

eFigure 6. Main results adjusted for alcohol and smoking with imputation for missing values

eFigure 7. Analyses including patients on a 4-drug antihypertensive regimen

eFigure 8. Estimates for other variables from the main model

This supplementary material has been provided by the authors to give readers additional information about their work.

Table of Contents eTable 1 ‐ Variable coding and definitions* ...... 3 eTable 2 – Use of beta blocker subtypes in the study population...... 5

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eTable 3 – Distribution of type of surgery stratified by beta blocker use...... 6 eTable 4 – Distribution of key variables in patients with and without missing values...... 7 eFigure 1 – Secondary outcomes (individual MACE components) by antihypertensive drug regimen...... 8 eFigure 2 – Risks of MACE and mortality including patients treated with metoprolol or atenolol only...... 9 eFigure 3 – Patients with a diagnosis of hypertension and one‐drug antihypertensive treatment...... 10 eFigure 4 – Main results adjusted for type of surgery in 17 categories...... 11 eFigure 5 – Risks associated with each study drug...... 12 eFigure 6 – Main results adjusted for alcohol and smoking with imputation for missing values...... 13 eFigure 7 – Analyses including patients on a 4‐drug antihypertensive regimen...... 14 eFigure 8 – Estimates for other variables from the main model...... 15

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eTable 1 ‐ Variable coding and definitions*

Variable Coding and definitions Pharmacotherapy ATC code Beta blockers C07 RAS inhibitors C09 Calcium antagonists C08 Thiazides C03A Aldosterone antagonists C03D Digoxin C01AA Vitamin‐K anatagonists B01AA Lipid lowering therapy C10A Clopidogrel B01AC04 Glucose lowering agents A10 Loop diuretics C03CA01 RAS inhibitors and calcium antagonist combination C09DX01, C09DB01 therapya RAS inhibitors and thiazides C09DA, C09BA combination therapya Beta blockers and thiazides C07B combination therapya Comorbidity ICD‐10 code Ischemic stroke I63, I64 Acute myocardial infarction I21 Chronic obstructive pulmonary disease J42, J44 Anemia D60‐D69 Cancer C00‐C97 Renal disease N03, N04, N17, N18, N19, R34, I12, I13 Rheumatologic disease M05, M06, M32, M33, M34, M353 Peripheral artery disease I70, I74 Liver disease K70‐K77, B150, B160, B190 Diabetesb E10‐E14 (without E109, E119, E129, E139) Chronic heart failurec I42, I50, I110, J819 Ischemic heart disease I20, I23, I24, I25, Atrial fibrillation I48 Surgery category NCSP code Ear/nose/throat KD Minor orthopedic KNC, KND, KNH Major orthopedic KN (except KNC, KND, KNH) Abdominal (bowel) KJC, KJC, KJF, KJG, KJH Abdominal (non‐bowel) KJ (except KJC, KJF, KJG, KJH) Breast KH Plastic KQ Endocrine KB Eye KC Female reproductive KL Male reproductive KKD, KKE, KKF, KKG Intracranial KAA Neurological KA (Except KAA) Non‐arterial vessels KPH, KPJ Arterial vessels KP (except KPH, KPJ)

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Thoracic/pulmonary KG Urology KK (except KKD, KKE, KKF, KKG) Surgery risk Surgery subtypes Low risk Breast, plastic, endocrine, and eye Elevated risk Ear/nose/throat, major orthopedic, minor orthopedic, abdominal, female reproductive, male reproductive, intracranial, neurological, non‐arterial vessels, thoracic/pulmonary, urology and arterial vessel surgery (exceptions: endoscopic orthopedic procedures and peripheral nerve surgery were low‐risk) *Footnote: aTreatment with a combination drug translated into treatment with two individual antihypertensive drugs. bDiabetes defined as present diagnosis or from use of glucose lowering agents. cChronic heart failure defined as present diagnosis or from use of loop diuretics. ATC code, Anatomical Therapeutic Classification System. ICD‐10 code, International Classification of Disease 10th edition. NCSP code, NOMESCO’s Classification of Surgical Procedures (Danish version).

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eTable 2 – Use of beta blocker subtypes in the study population.

Beta blocker subtypes Patients, n (%) Proportion of beta ‐ main cohort. blocker treated patients, % No beta blocker 40,676 (73.5) NA Atenolol 2,422 (4.4) 16.5 Bisoprolol 707 (1.3) 4.8 Carvedilol 974 (1.8) 6.7 Metoprolol 9,302 (16.8) 63.5 Nebivolol 62 (0.1) 0.4 Pindolol 118 (0.2) 0.8 Propranolol 954(1.7) 6.5 Labetalol 105 (0.2) 0.7 Total 55,320 ( 100) 100

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eTable 3 – Distribution of type of surgery stratified by beta blocker use.

Type of surgery With beta Without beta Type of surgery With beta Without beta n(%) n(%) blockers blockers blockers blockers n=14,644 n=40,676 n=14,644 n=40,676 Ear/nose/throat 193 (1.3) 540 (1.3) Male reproductive 138 (0.9) 503 (1.2) Minor orthopedic 1,471 (10.0) 4,027 (9.9) Intracranial 191 (1.3) 479 (1.2) Major orthopedic 5,069 (34.6) 15,138 (37.2) Neurological 670 (4.6) 1,870 (4.6) Abdominal (bowel) 636 (4.3) 1,635 (4.0) Non‐arterial vessels 577 (3.9) 1,381 (3.4) Breast 293 (2.0) 695 (1.7) Arterial vessels 244 (1.7) 561 (1.4) Plastic 768 (5.2) 1,905 (4.7) Thoracic/pulmonary 146 (1.0) 413 (1.0) Endocrine 143 (1.0) 341 (0.8) Urology 930 (6.4) 2,514 (6.2) Abdominal (non‐ 1,736 (11.9) 5,016 (12.3) Female 1,119 (7.6) 2,741 (6.7) bowel) reproductive Eye 320 (2.2) 917 (2.3)

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eTable 4 – Distribution of key variables in patients with and without missing values.

No missing in alcohol Missing in alcohol No missing in smoking Missing in smoking Age (Mean, years) 65.9 66.1 65.7 66.5 Gender (% female) 41.1 39.6 41.3 39.3 Beta blocker (% treated) 26.4 26.7 26.1 27.5 Urgency (% acute) 20.8 23.8 20.2 24.9 Surgery risk 86.6 82.5 86.9 82.7 (% elevated).

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eFigure 1 – Secondary outcomes (individual MACE components) by antihypertensive drug regimen.

A - 30-day Cardiovascular Death Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 87/20745 Beta blocker + RAS inhibitors 3.50 (2.36-5.20) 39/2789 Beta blocker + calcium antagonists 2.76 (1.72-4.43) 24/1878 Beta blocker + thiazides 2.25 (1.48-3.42) 32/3427 Beta blocker + 2 others 1.23 (0.82-1.85) 37/6550 RAS inhibitors + calcium antagonists 1.29 (0.85-1.97) 33/6055 Three others than beta blockers 0.82 (0.54-1.25) 35/9248 Calcium antagonists + thiazides 1.04 (0.66-1.65) 29/4628

0,1 1 10 Odds ratios (95% CI)

B - 30-day Non-fatal stroke Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 40/20745 Beta blocker + RAS inhibitors 0.52 (0.16-1.68) 3/2789 Beta blocker + calcium antagonists 1.69 (0.75-3.79) 7/1878 Beta blocker + thiazides 0.75 (0.29-1.91) 5/3427 Beta blocker + 2 others 1.32 (0.76-2.32) 19/6550 RAS inhibitors + calcium antagonists 1.19 (0.66-2.16) 15/6055 Three others than beta blockers 0.83 (0.46-1.48) 17/9248 Calcium antagonists + thiazides 1.44 (0.79-2.63) 15/4628

0,1 1 10 Odds ratios (95% CI)

C - 30-day non-fatal AMI Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 34/20745 Beta blocker + RAS inhibitors 0.96 (0.34-2.71) 4/2789 Beta blocker + calcium antagonists 1.24 (0.44-3.52) 4/1878 Beta blocker + thiazides 0.77 (0.27-2.17) 4/3427 Beta blocker + 2 others 1.07 (0.55-2.07) 15/6550 RAS inhibitors + calcium antagonists 0.67 (0.29-1.51) 7/6055 Three others than beta blockers 1.46 (0.86-2.47) 25/9248 Calcium antagonists + thiazides 0.53 (0.21-1.37) 5/4628

0,1 1 10 Odds ratios (95% CI)

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eFigure 2 – Risks of MACE and mortality including patients treated with metoprolol or atenolol only.

Only atenolol

30-day MACE Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 161/20,745 Beta blocker + RAS inhibitors 1.21 (0.44-3.29) 4/431 Beta blocker + calcium antagonists 4.13 (2.25-7.60) 12/354 Beta blocker + thiazides 1.98 (1.03-3.80) 10/672 Beta blocker + 2 others 0.62 (0.25-1.52) 5/965 RAS inhibitors + calcium antagonists 1.14 (0.83-1.57) 55/6,055 Three others than beta blockers 0.98 (0.73-1.30) 77/9,248 Calcium antagonists + thiazides 1.01 (0.72-1.42) 49/4,628

0,1 1 10 Odds ratios (95% CI)

30-day all-cause mortality Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 256/20,745 Beta blocker + RAS inhibitors 2,34 1,25 4,37 11/431 Beta blocker + calcium antagonists 2,60 1,45 4,68 13/354 Beta blocker + thiazides 2,37 1,42 3,95 17/672 Beta blocker + 2 others 1,36 0,81 2,29 16/965 RAS inhibitors + calcium antagonists 1,16 0,90 1,49 93/6,055 Three others than beta blockers 0,82 0,64 1,05 95/9,248 Calcium antagonists + thiazides 1,21 0,94 1,56 94/4,628

0,1 1 10 Odds ratios (95% CI) Only metoprolol

30-day MACE Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 161/20,745 Beta blocker + RAS inhibitors 2.69 (1.85-3.92) 36/1,757 Beta blocker + calcium antagonists 1.73 (1.04-2.88) 18/1,126 Beta blocker + thiazides 1.25 (0.79-1.99) 21/2,104 Beta blocker + 2 others 1.24 (0.88-1.75) 49/4,315 RAS inhibitors + calcium antagonists 1.13 (0.82-1.55) 55/6,055 Three others than beta blockers 0.97 (0.73-1.29) 77/9,248 Calcium antagonists + thiazides 1.01 (0.72-1.41) 49/4,628

0,1 1 10 Odds ratios (95% CI)

30-day all-cause mortality Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 256/20745 Beta blocker + RAS inhibitors 1.92 (1.35-2.73) 40/1757 Beta blocker + calcium antagonists 1.34 (0.84-2.12) 22/1126 Beta blocker + thiazides 1.19 (0.82-1.74) 35/2104 Beta blocker + 2 others 1.20 (0.90-1.60) 66/4315 RAS inhibitors + calcium antagonists 1.15 (0.89-1.48) 93/6055 Three others than beta blockers 0.82 (0.64-1.05) 95/9248 Calcium antagonists + thiazides 1.22 (0.94-1.57) 94/4628

0,1 1 10 Odds ratios (95% CI)

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eFigure 3 – Patients with a diagnosis of hypertension and one‐drug antihypertensive treatment.

Risks of 30-day MACE

A - Main cohort, patients with hypertension diagnosis only. Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 38/6411 Beta blocker + RAS inhibitors 2.46 (1.36-4.47) 17/1057 Beta blocker + calcium antagonists 3.46 (1.90-6.29) 16/682 Beta blocker + thiazides 1.17 (0.54-2.56) 8/1041 Beta blocker + 2 others 1.69 (1.03-2.78) 30/2648 RAS inhibitors + calcium antagonists 1.60 (0.94-2.74) 22/2101 Three others than beta blockers 1.12 (0.67-1.88) 25/3523 Calcium antagonists + thiazides 1.18 (0.62-2.24) 14/1448

0,1 1 10 Odds ratios (95% CI)

B - Hypertension diagnosis and one-drug treatment Odds ratios (95% CI) Events/sample size

Thiazides only 1.19 (0.70-2.01) 23/2,513 Calcium antagonists only 0.72 (0.40-1.29) 18/2,970 Beta blockers only 1.67 (0.95-2.93) 20/1,845 RAS-inhibitors only 1.11 (0.70-1.77) 37/5,436 RAS inhibitors + thiazides 1.00 (ref) 38/6,411 Beta blocker + RAS inhibitors 2.46 (1.36-4.46) 17/1,057 Beta blocker + calcium antagonists 3.48 (1.91-6.33) 16/682 Beta blocker + thiazides 1.15 (0.53-2.50) 8/1,041 Beta blocker + 2 others 1.71 (1.04-2.81) 30/2,648 RAS inhibitors + calcium antagonists 1.60 (0.94-2.73) 22/2,101 Three others than beta blockers 1.13 (0.68-1.88) 25/3,523 Calcium antagonists + thiazides 1.16 (0.61-2.20) 14/1,448

0,1 1 10 Odds ratios (95% CI)

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eFigure 4 – Main results adjusted for type of surgery in 17 categories.

Additional adjustment for type of surgery.

A - 30-day MACE Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 161/20,745 Beta blocker + RAS inhibitors 2.08 (1.48-2.94) 46/2,789 Beta blocker + calcium antagonists 2.10 (1.43-3.10) 35/1,878 Beta blocker + thiazides 1.57 (1.10-2.24) 41/3,427 Beta blocker + 2 others 1.15 (0.85-1.56) 71/6,550 RAS inhibitors + calcium antagonists 1.10 (0.80-1.51) 55/6,055 Three others than beta blockers 0.97 (0.73-1.29) 77/9,248 Calcium antagonists + thiazides 1.04 (0.74-1.47) 49/4,628

0.5 1 23 Odds ratios (95% CI)

B - 30-day all-cause mortality Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 256/20,745 Beta blocker + RAS inhibitors 1.67 (1.23-2.27) 58/2,789 Beta blocker + calcium antagonists 1.71 (1.21-2.41) 44/1,878 Beta blocker + thiazides 1.65 (1.24-2.19) 73/3,427 Beta blocker + 2 others 1.23 (0.97-1.58) 107/6,550 RAS inhibitors + calcium antagonists 1.14 (0.88-1.48) 93/6,055 Three others than beta blockers 0.83 (0.65-1.07) 95/9,248 Calcium antagonists + thiazides 1.27 (0.98-1.65) 94/4,628

0.5 1 23 Odds ratios (95% CI)

Legend: No interaction were found between beta blocker therapy and type of surgery for the risk of MACE, P=0.262.

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eFigure 5 – Risks associated with each study drug.

A - 30-day MACE Odds ratios (95% CI) Events/sample size

RAS-inhibitors 0.83 (0.64-1.08) 396/44,302 Beta blockers 1.29 (1.01-1.65) 193/14,644 Calcium antagonists 0.87 (0.68-1.10) 248/24,154 Thiazides 0.67 (0.52-0.87) 381/43,338

0.5 1 23 Odds ratios (95% CI)

B - 30-day all-cause mortality Odds ratios (95% CI) Events/sample size

RAS-inhibitors 0.73 (0.59-0.90) 586/44,302 Beta blockers 1.20 (0.97-1.48) 282/14,644 Calcium antagonists 0.83 (0.69-1.01) 373/24,154 Thiazides 0.73 (0.59-0.91) 601/43,338

0.5 1 23 Odds ratios (95% CI)

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eFigure 6 – Main results adjusted for alcohol and smoking with imputation for missing values.

A - 30-day MACE Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 161/20,745 Beta blocker + RAS inhibitors 2.01 (1.44-2.81) 46/2,789 Beta blocker + calcium antagonists 1.96 (1.34-2.85) 35/1,878 Beta blocker + thiazides 1.41 (0.99-1.99) 41/3,427 Beta blocker + 2 others 1.21 (0.91-1.61) 71/6,550 RAS inhibitors + calcium antagonists 1.06 (0.78-1.45) 55/6,055 Three others than beta blockers 0.96 (0.73-1.27) 77/9,248 Calcium antagonists + thiazides 1.00 (0.72-1.39) 49/4,628

0.5 1 23 Odds ratios (95% CI)

B - 30-day all-cause mortality Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 256/20,745 Beta blocker + RAS inhibitors 1.62 (1.21-2.18) 58/2,789 Beta blocker + calcium antagonists 1.48 (1.06-2.07) 44/1,878 Beta blocker + thiazides 1.53 (1.16-2.00) 73/3,427 Beta blocker + 2 others 1.22 (0.96-1.54) 107/6,550 RAS inhibitors + calcium antagonists 1.13 (0.89-1.45) 93/6,055 Three others than beta blockers 0.78 (0.61-0.99) 95/9,248 Calcium antagonists + thiazides 1.16 (0.91-1.49) 94/4,628

0.5 1 23 Odds ratios (95% CI)

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eFigure 7 – Analyses including patients on a 4‐drug antihypertensive regimen.

30-day MACE Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 161/20,745 Beta blocker + RAS inhibitors 2.17 (1.55-3.05) 46/2,789 Beta blocker + calcium antagonists 2.17 (1.49-3.17) 35/1,878 Beta blocker + thiazides 1.57 (1.10-2.23) 41/3,427 Beta blocker + 2 others 1.23 (0.91-1.65) 71/6,550 Beta blocker + 3 others 1.79 (1.26-2.56) 43/2,825 RAS inhibitors + calcium antagonists 1.12 (0.82-1.54) 55/6,055 Three others than beta blockers 0.97 (0.73-1.29) 77/9,248 Calcium antagonists + thiazides 1.03 (0.73-1.44) 49/4,628

0.5 1 23 Odds ratios (95% CI) 30-day all-cause mortality Odds ratios (95% CI) Events/sample size

RAS inhibitors + thiazides 1.00 (ref) 256/20,745 Beta blocker + RAS inhibitors 1.81 (1.34-2.44) 58/2,789 Beta blocker + calcium antagonists 1.69 (1.20-2.36) 44/1,878 Beta blocker + thiazides 1.65 (1.25-2.17) 73/3,427 Beta blocker + 2 others 1.32 (1.04-1.67) 107/6,550 Beta blocker + 3 others 1.46 (1.06-2.01) 51/2,825 RAS inhibitors + calcium antagonists 1.16 (0.90-1.49) 93/6,055 Three others than beta blockers 0.82 (0.64-1.05) 95/9,248 Calcium antagonists + thiazides 1.24 (0.96-1.59) 94/4,628

0.5 1 23 Odds ratios (95% CI)

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eFigure 8 – Estimates for other variables from the main model.

30-day MACE Odds ratios (95% CI)

RAS inhibitors + thiazides 1.00. (ref) Beta blocker + RAS inhibitors 2.16 (1.54-3.04) Beta blocker + calcium antagonists 2.17 (1.48-3.17) Beta blocker + thiazides 1.56 (1.10-2.22) Beta blocker + 2 others 1.22 (0.90-1.64) RAS inhibitors + calcium antagonists 1.12 (0.82-1.54) Three others than beta blockers 0.97 (0.73-1.29) Calcium antagonists + thiazides 1.02 (0.73-1.44) Diabetes 1.29 (0.99-1.69) Venous thromboembolisms 2.66 (1.51-4.68) Rheumatologic disease 2.11 (1.26-3.53) Cancer 1.01 (0.93-1.09) Anemia 1.10 (0.70-1.72) Chronic obstructive pulmonary disease 1.84 (1.21-2.80) Acetylsalicylic acid 1.32 (1.09-1.60) Lipid lowering therapy 0.93 (0.75-1.15) Surgery risk - low vs. elevated 0.80 (0.59-1.09) Calendar year 0.92 (0.88-0.97) Body mass index 0.96 (0.94-0.98) Gender - female vs. male 0.69 (0.57-0.83) Age 0.97 (0.73-1.29)

0,1 1 10 Odds ratios (95% CI)

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