Article Figures & Data
Tables
- Table 1.
Baseline characteristics of patients diagnosed with primary NSCLC in Sweden between July 1, 2006 and December 31, 2014 by β-blocker use at cancer diagnosis.
β-Blocker user (N = 5,114) Nonuser (N = 13,315) n Col % n Col % Pa Age at diagnosis, years (mean, SD) 71.9 8.3 67.8 9.8 <0.001b Male 2,756 53.9 6,602 49.6 <0.001 Attained education <0.001 Compulsory 2,433 47.6 5,554 41.7 Secondary 2,010 39.3 5,558 41.7 Post-secondary 671 13.1 2,203 16.5 Marital status at diagnosis <0.001 Unmarried 462 9.0 1,770 13.3 Married/cohabiting 2,582 50.5 6,445 48.4 Divorced/separated 1,087 21.3 3,227 24.2 Widowed 983 19.2 1,873 14.1 TNM stage 0.022 Stage 1 707 13.8 1,644 12.3 Stage 1 or 2c 179 3.5 471 3.5 Stage 2 348 6.8 813 6.1 Stage 3A 429 8.4 1,227 9.2 Stage 3B/C 681 13.3 1,730 13.0 Stage 4 2,440 47.7 6,602 49.6 Recorded incompletelyd 185 3.6 492 3.7 Missinge 145 2.8 336 2.5 Tumor histology 0.035 Adenocarcinoma 3,106 60.7 8,325 62.5 Squamous 1,344 26.3 3,274 24.6 Adenosquamous 65 1.3 156 1.2 Large cell 178 3.5 533 4.0 Other NSCLC 421 8.2 1,027 7.7 Comorbidity score (median, IQR)f 10 (7–14) 6 (3–10) <0.001b Comorbidity diagnosed before lung cancer diagnosis Coronary artery disease 2,041 39.9 1,182 8.9 <0.001 Coronary heart failure 934 18.3 479 3.6 <0.001 Cerebrovascular disease 889 17.4 1,175 8.8 <0.001 Chronic obstructive pulmonary disease 854 16.7 1,753 13.2 <0.001 Asthma 199 3.9 563 4.2 0.303 Diabetes 1,085 21.2 1,297 9.7 <0.001 Other medicationsg (ATC code) Other antihypertensive medicationsh 3,603 70.5 4,012 30.1 <0.001 Nonsteroidal anti-inflammatory drugs (M01A) 1,228 24.0 3,636 27.3 <0.001 Aspirin (B01AC:06,30; N02BA:01,51) 2,719 53.2 2,537 19.1 <0.001 Statin (C10AA) 2,693 52.7 2,564 19.3 <0.001 Note: Patients were considered exposed to β-blocker use if β-blockers collected during 1 year before cancer diagnosis would last until cancer diagnosis date, unexposed otherwise. Tumor staging follows the American Cancer Society classification 6th (until 2010) and 7th (since 2010) editions [stage 1: T1/N0/M0 or T2a/N0/M0; stage 2: T(2b-3)/N0/M0 or T(1-2)/N1/M0; stage 3A: T(1-2)/N2/M0 or T3/N(1-2)/M0 according to the 6th and T(1-3)/N2/M0 or T3/N1/M0 or T4/N(0-1)/M0 according to the 7th editions; stage 3B/C: T(1-4)/N3/M0 or T4/N(0-2)/M0 according to the 6th and T(1-4)/N3/M0 or T4/N2/M0 according to the 7th editions; stage 4: any T, any N, M1]. T stands for the extent (size) of the tumor; N indicates the spread to nearby lymph nodes; M denotes the spread (metastasis) to distant sites. TNM recording in the Cancer Register was introduced in 2004 and has improved over time. Tumor histology was defined using WHO histologic classification of the lung tumors (ICD-O-3 morphologic codes for adenocarcinoma: 8140/3, 8141/3, 8200/3, 8250/3, 8252/3, 8253/3, 8254/3, 8255/3, 8260/3, 8310/3, 8480/3, 8490/3, 8550/3; for squamous cell carcinoma: 8052/3, 8070/3, 8073/3, 8083/3, 8084/3; for adenosquamous carcinoma: 8560/3; for large cell carcinoma: 8012/3; 8013/3, 8014/3, 8082/3, 8123/3; for other or undifferentiated NSCLC: 8022/3, 8031/3, 8032/3, 8033/3, 8046/3, 8972/3,8980/3). Diabetes was defined using ICD codes from the Patient Register and antidiabetic medications (ATC: A10) from the Prescribed Drug Register; other comorbid diagnoses were defined using ICD codes in the Patient Register.
Abbreviations: ATC, Anatomic Therapeutic Chemical classification system; IQR, interquartile range.
↵aP values are from a χ2 test.
↵bTwo-sample t test for age at diagnosis and median test for comorbidity score.
↵cStages 1 versus 2 could not be distinguished whenever T2 a/b subtypes were not specified in the Cancer Register.
↵dEither T, N, or M stage was not specified.
↵eT, N, and M stages were missing or recorded as TxNxMx.
↵fNumber of distinct medication classes (medications with the same initial five characters of ATC classification) within 1 year before cancer diagnosis was used to derive a comorbidity score.
↵gMedications (yes/no variables) are dispensed within 1 year before cancer diagnosis and are not mutually exclusive.
↵hInclude angiotensin-converting enzyme inhibitors (ATC: C09: A, BA, BB), angiotensin receptor blockers (ATC: C09: C, DA, DB), calcium channel blockers (ATC: C08), and thiazide diuretics (ATC: C03A).
- Table 2.
β-Blocker use at lung cancer diagnosis compared with nonuse in relation to lung cancer–specific mortality in 18,429 patients diagnosed with primary NSCLC in Sweden between July 1, 2006 and December 31, 2014.
β-Blocker usea No. of events HRb (95% CI) HRc (95% CI) Any β-blocker 3,695 1.06 (1.02–1.10) 1.01 (0.97–1.06) By adrenoreceptor selectivity β1-Receptor selectived 3,402 1.06 (1.02–1.10) 1.01 (0.96–1.05) Nonselective (β1/β2-blocking)e 239 1.05 (0.93–1.20) 1.08 (0.95–1.23) α1- and β1/β2-Blockingf 70 0.93 (0.74–1.18) 0.88 (0.70–1.12) By solubility Lipophilicg 2,840 1.05 (1.01–1.09) 1.02 (0.97–1.07) Hydrophilich 914 1.06 (0.99–1.14) 1.00 (0.93–1.07) By prescribed daily dose Low dosei 2,002 1.06 (1.01–1.11) 1.01 (0.95–1.06) High dosei 1,661 1.06 (1.00–1.11) 1.01 (0.96–1.07) Note: “No. of events” column shows number of outcome events among β-blocker users. Dose was calculated for 99% of β-blocker users.
Abbreviations: CI, confidence interval; HR, hazard ratio.
↵aExposed if β-blockers collected during 1 year before cancer diagnosis would last until cancer diagnosis date, unexposed otherwise.
↵bUnadjusted for covariates.
↵cAdjusted for age, sex, stage, histology, year of diagnosis, region of residence, attained education, marital status, comorbidity score (number of distinct ATC classes prescribed during 1 year prior to diagnosis), comorbidity (coronary artery disease, heart failure, cerebrovascular disease, chronic obstructive pulmonary disease, asthma, diabetes), other antihypertensive medications, nonsteroidal anti-inflammatory drugs, aspirin, statins.
↵dIncludes metoprolol, atenolol, bisoprolol.
↵eIncludes pindolol, propranolol, sotalol.
↵fIncludes labetalol, carvedilol.
↵gIncludes bisoprolol, carvedilol, labetalol, metoprolol, pindolol, propranolol, metoprolol + felodipine.
↵hIncludes sotalol, atenolol.
↵iCalculated as [tablet strength (mg) multiplied by number of tablets prescribed for daily use] divided with the β-blocker–specific defined daily dose (mg).
- Table 3.
β-Blocker use at lung cancer diagnosis compared with nonuse in relation to lung cancer–specific mortality by tumor stage in patients diagnosed with primary non–small cell lung cancer in Sweden between July 1, 2006 and December 31, 2014.
Early disease Locoregionally advanced Distant metastases (stages I–II) (stage III) (stage IV) N = 4,162 N = 4,067 N = 9,042 β-Blockersa No. of events HRb (95% CI) No. of events HRb (95% CI) No. of events HRb (95% CI) Any β-blocker 432 1.01 (0.89–1.16) 866 0.96 (0.88–1.06) 2,163 1.01 (0.95–1.07) By adrenoreceptor selectivity β1-Receptor selectivec 398 1.03 (0.90–1.18) 788 0.94 (0.85–1.03) 2,005 1.01 (0.95–1.07) Nonselective (β1/β2-blocking)d 26 0.90 (0.61–1.33) 60 1.26 (0.97–1.63) 133 0.99 (0.83–1.18) α1- and β1/β2-blockinge 10 1.06 (0.56–2.00) 17 0.76 (0.47–1.24) 39 0.88 (0.64–1.21) By solubility Lipophilicf 336 0.98 (0.85–1.13) 668 1.00 (0.90–1.10) 1,654 1.02 (0.96–1.09) Hydrophilicg 102 1.04 (0.84–1.29) 214 0.90 (0.78–1.04) 540 0.99 (0.90–1.09) Note: “No. of events” column shows number of outcome events among β-blocker users.
↵aExposed if β-blockers collected during 1 year before cancer diagnosis would last until cancer diagnosis date, unexposed otherwise.
↵bAdjusted for age, sex, stage, histology, year of diagnosis, region of residence, attained education, marital status, comorbidity score (number of distinct ATC classes prescribed during 1 year prior to diagnosis), comorbidity (coronary artery disease, heart failure, cerebrovascular disease, chronic obstructive pulmonary disease, asthma, diabetes), other antihypertensive medications, nonsteroidal anti-inflammatory drugs, aspirin, statins.
↵cIncludes metoprolol, atenolol, bisoprolol.
↵dIncludes pindolol, propranolol, sotalol.
↵eIncludes labetalol, carvedilol.
↵fIncludes bisoprolol, carvedilol, labetalol, metoprolol, pindolol, propranolol, metoprolol + felodipine.
↵gIncludes sotalol, atenolol.
- Table 4.
β-Blocker use compared with nonuse in relation to lung cancer–specific mortality by histology among patients diagnosed with non–small cell lung cancer in Sweden between July 1, 2006 and December 31, 2014.
All patients Early stage (I–II) disease No. of events HRa (95% CI) No. of events HRa (95% CI) In adenocarcinoma 2,210 1.02 (0.97–1.08) 225 0.93 (0.77–1.12) In squamous cell carcinoma 945 1.00 (0.92–1.09) 145 0.93 (0.74–1.15) In large cell carcinoma 139 0.99 (0.78–1.27) 22 2.76 (1.20–6.32) In adenosquamous carcinoma 48 1.58 (0.94–2.65) 8 Not estimated Note: ‘No. of events’ column shows number of outcome events among β-blocker users.
↵aAdjusted for age, sex, stage, year of diagnosis, region of residence, attained education, marital status, comorbidity score (number of distinct ATC classes prescribed during 1 year prior to diagnosis), comorbidity (coronary artery disease, heart failure, cerebrovascular disease, chronic obstructive pulmonary disease, asthma, diabetes), other antihypertensive medications, nonsteroidal anti-inflammatory drugs, aspirin, statins.
- Table 5.
Selected β-blocker use compared with nonuse in relation to lung cancer–specific mortality overall and by stage among patients diagnosed with NSCLC in Sweden between July 1, 2006 and December 31, 2014.
Early disease Locoregionally advanced Distant metastases All patients (stages I–II) (stage III) (stage IV) N = 18,429 N = 4,162 N = 4,067 N = 9,042 β-Blockersa Selectivity ratio Solubility No. of events HRb (95% CI) No. of events HRb (95% CI) No. of events HRb (95% CI) No. of events HRb (95% CI) Nonselectivec β2 vs. β1 Propranolol 8.3 HL 140 1.22 (1.03–1.45) 18 1.01 (0.63–1.61) 32 1.25 (0.88–1.78) 77 1.14 (0.91–1.43) Sotalol 12.0 HD 78 1.00 (0.80–1.25) 6 0.70 (0.31–1.56) 23 1.17 (0.77–1.77) 44 0.95 (0.71–1.28) Carvedilold 4.5 ML 67 0.86 (0.67–1.10) 8 0.91 (0.45–1.86) 17 0.77 (0.47–1.24) 38 0.87 (0.63–1.20) β1-Receptor selective β1 vs. β2 Metoprolol 2.3 HL 2,064 1.00 (0.95–1.06) 233 0.92 (0.79–1.08) 473 0.94 (0.84–1.05) 1,225 1.03 (0.97–1.11) Atenolol 4.7 HD 836 0.99 (0.92–1.07) 96 1.06 (0.86–1.32) 191 0.87 (0.75–1.02) 496 0.99 (0.90–1.09) Bisoprolol 13.5 ML 582 1.05 (0.96–1.14) 78 1.21 (0.94–1.55) 143 1.04 (0.87–1.24) 325 0.98 (0.87–1.10) Note: “No. of events” column shows number of outcome events among β-blocker users.
Abbreviations: HD, hydrophilic; HL, highly lipophilic; ML, moderately lipophilic.
↵aExposed if β-blockers collected during 1 year before diagnosis would last until cancer diagnosis date, unexposed otherwise.
↵bAdjusted for age, sex, stage, histology, year of diagnosis, region of residence, attained education, marital status, comorbidity score (number of distinct ATC classes prescribed during 1 year prior to diagnosis), comorbidity (coronary artery disease, heart failure, cerebrovascular disease, chronic obstructive pulmonary disease, asthma, diabetes), other antihypertensive medications, nonsteroidal anti-inflammatory drugs, aspirin, statins.
↵cBlock β1 and β2 adrenergic receptors.
↵dCarvedilol is a nonselective β-blocker that blocks β1 and β2 adrenergic receptors as well as the α1 adrenergic receptors.
Additional Files
Supplementary Data
- Supplementary Figures 1-2 - Supplementary Figure S1. Study population selection process. Supplementary Figure S2. Kaplan-Meier survival estimates for incident and prevalent β-blocker users and non-users in patients diagnosed with non-small cell lung cancer in Sweden between October 1, 2006 and December 31, 2014.
- Supplementary Tables 1-3 - Supplementary Table S1. β-blockers used at cancer diagnosis by patients diagnosed with primary non-small cell lung cancer in Sweden between July 1, 2006 and December 31, 2014. Supplementary Table S2. β-blocker use compared with non-use in relation to lung cancer mortality by histology among patients diagnosed with non-small cell lung cancer in Sweden between July 1, 2006 and December 31, 2014. Supplementary Table S3. β-blocker use at lung cancer diagnosis compared with non-use in relation to lung cancer mortality in patients diagnosed with non-small cell lung cancer in Sweden between July 1, 2006 and December 31, 2014.
Volume 29, Issue 1
