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Research Articles

Beta-Blocker Use and Lung Cancer Mortality in a Nationwide Cohort Study of Patients with Primary Non–Small Cell Lung Cancer

Ruzan Udumyan, Scott Montgomery, Fang Fang, Unnur Valdimarsdottir, Hronn Hardardottir, Anders Ekbom, Karin E. Smedby and Katja Fall
Ruzan Udumyan
1Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden.
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  • For correspondence: Ruzan.Udumyan@oru.se
Scott Montgomery
1Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden.
2Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
3Department of Epidemiology and Public Health, University College London, London, United Kingdom.
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Fang Fang
4Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
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Unnur Valdimarsdottir
4Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
5Center of Public Health Sciences, University of Iceland, Reykjavik, Iceland.
6Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
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Hronn Hardardottir
5Center of Public Health Sciences, University of Iceland, Reykjavik, Iceland.
7Department of Respiratory Medicine, Landspitali University Hospital, Reykjavik, Iceland.
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Anders Ekbom
2Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
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Karin E. Smedby
2Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
8Hematology Clinic, Karolinska University Hospital, Stockholm, Sweden.
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Katja Fall
1Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden.
4Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
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DOI: 10.1158/1055-9965.EPI-19-0710 Published January 2020
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  • 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)
    nCol %nCol %Pa
    Age at diagnosis, years (mean, SD)71.98.367.89.8<0.001b
    Male2,75653.96,60249.6<0.001
    Attained education<0.001
     Compulsory2,43347.65,55441.7
     Secondary2,01039.35,55841.7
     Post-secondary67113.12,20316.5
    Marital status at diagnosis<0.001
     Unmarried4629.01,77013.3
     Married/cohabiting2,58250.56,44548.4
     Divorced/separated1,08721.33,22724.2
     Widowed98319.21,87314.1
    TNM stage0.022
     Stage 170713.81,64412.3
     Stage 1 or 2c1793.54713.5
     Stage 23486.88136.1
     Stage 3A4298.41,2279.2
     Stage 3B/C68113.31,73013.0
     Stage 42,44047.76,60249.6
     Recorded incompletelyd1853.64923.7
     Missinge1452.83362.5
    Tumor histology0.035
     Adenocarcinoma3,10660.78,32562.5
     Squamous1,34426.33,27424.6
     Adenosquamous651.31561.2
     Large cell1783.55334.0
     Other NSCLC4218.21,0277.7
    Comorbidity score (median, IQR)f10(7–14)6(3–10)<0.001b
    Comorbidity diagnosed before lung cancer diagnosis
     Coronary artery disease2,04139.91,1828.9<0.001
     Coronary heart failure93418.34793.6<0.001
     Cerebrovascular disease88917.41,1758.8<0.001
     Chronic obstructive pulmonary disease85416.71,75313.2<0.001
     Asthma1993.95634.20.303
     Diabetes1,08521.21,2979.7<0.001
    Other medicationsg (ATC code)
     Other antihypertensive medicationsh3,60370.54,01230.1<0.001
     Nonsteroidal anti-inflammatory drugs (M01A)1,22824.03,63627.3<0.001
     Aspirin (B01AC:06,30; N02BA:01,51)2,71953.22,53719.1<0.001
     Statin (C10AA)2,69352.72,56419.3<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 useaNo. of eventsHRb (95% CI)HRc (95% CI)
    Any β-blocker3,6951.06 (1.02–1.10)1.01 (0.97–1.06)
    By adrenoreceptor selectivity
     β1-Receptor selectived3,4021.06 (1.02–1.10)1.01 (0.96–1.05)
     Nonselective (β1/β2-blocking)e2391.05 (0.93–1.20)1.08 (0.95–1.23)
     α1- and β1/β2-Blockingf700.93 (0.74–1.18)0.88 (0.70–1.12)
    By solubility
     Lipophilicg2,8401.05 (1.01–1.09)1.02 (0.97–1.07)
     Hydrophilich9141.06 (0.99–1.14)1.00 (0.93–1.07)
    By prescribed daily dose
     Low dosei2,0021.06 (1.01–1.11)1.01 (0.95–1.06)
     High dosei1,6611.06 (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 diseaseLocoregionally advancedDistant metastases
    (stages I–II)(stage III)(stage IV)
    N = 4,162N = 4,067N = 9,042
    β-BlockersaNo. of eventsHRb (95% CI)No. of eventsHRb (95% CI)No. of eventsHRb (95% CI)
    Any β-blocker4321.01 (0.89–1.16)8660.96 (0.88–1.06)2,1631.01 (0.95–1.07)
    By adrenoreceptor selectivity
     β1-Receptor selectivec3981.03 (0.90–1.18)7880.94 (0.85–1.03)2,0051.01 (0.95–1.07)
     Nonselective (β1/β2-blocking)d260.90 (0.61–1.33)601.26 (0.97–1.63)1330.99 (0.83–1.18)
     α1- and β1/β2-blockinge101.06 (0.56–2.00)170.76 (0.47–1.24)390.88 (0.64–1.21)
    By solubility
     Lipophilicf3360.98 (0.85–1.13)6681.00 (0.90–1.10)1,6541.02 (0.96–1.09)
     Hydrophilicg1021.04 (0.84–1.29)2140.90 (0.78–1.04)5400.99 (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 patientsEarly stage (I–II) disease
    No. of eventsHRa (95% CI)No. of eventsHRa (95% CI)
    In adenocarcinoma2,2101.02 (0.97–1.08)2250.93 (0.77–1.12)
    In squamous cell carcinoma9451.00 (0.92–1.09)1450.93 (0.74–1.15)
    In large cell carcinoma1390.99 (0.78–1.27)222.76 (1.20–6.32)
    In adenosquamous carcinoma481.58 (0.94–2.65)8Not 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 diseaseLocoregionally advancedDistant metastases
    All patients(stages I–II)(stage III)(stage IV)
    N = 18,429N = 4,162N = 4,067N = 9,042
    β-BlockersaSelectivity ratioSolubilityNo. of eventsHRb (95% CI)No. of eventsHRb (95% CI)No. of eventsHRb (95% CI)No. of eventsHRb (95% CI)
    Nonselectivecβ2 vs. β1
     Propranolol8.3HL1401.22 (1.03–1.45)181.01 (0.63–1.61)321.25 (0.88–1.78)771.14 (0.91–1.43)
     Sotalol12.0HD781.00 (0.80–1.25)60.70 (0.31–1.56)231.17 (0.77–1.77)440.95 (0.71–1.28)
     Carvedilold4.5ML670.86 (0.67–1.10)80.91 (0.45–1.86)170.77 (0.47–1.24)380.87 (0.63–1.20)
    β1-Receptor selectiveβ1 vs. β2
     Metoprolol2.3HL2,0641.00 (0.95–1.06)2330.92 (0.79–1.08)4730.94 (0.84–1.05)1,2251.03 (0.97–1.11)
     Atenolol4.7HD8360.99 (0.92–1.07)961.06 (0.86–1.32)1910.87 (0.75–1.02)4960.99 (0.90–1.09)
     Bisoprolol13.5ML5821.05 (0.96–1.14)781.21 (0.94–1.55)1431.04 (0.87–1.24)3250.98 (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

  • Tables
  • 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.
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Cancer Epidemiology Biomarkers & Prevention: 29 (1)
January 2020
Volume 29, Issue 1
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Beta-Blocker Use and Lung Cancer Mortality in a Nationwide Cohort Study of Patients with Primary Non–Small Cell Lung Cancer
Ruzan Udumyan, Scott Montgomery, Fang Fang, Unnur Valdimarsdottir, Hronn Hardardottir, Anders Ekbom, Karin E. Smedby and Katja Fall
Cancer Epidemiol Biomarkers Prev January 1 2020 (29) (1) 119-126; DOI: 10.1158/1055-9965.EPI-19-0710

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Beta-Blocker Use and Lung Cancer Mortality in a Nationwide Cohort Study of Patients with Primary Non–Small Cell Lung Cancer
Ruzan Udumyan, Scott Montgomery, Fang Fang, Unnur Valdimarsdottir, Hronn Hardardottir, Anders Ekbom, Karin E. Smedby and Katja Fall
Cancer Epidemiol Biomarkers Prev January 1 2020 (29) (1) 119-126; DOI: 10.1158/1055-9965.EPI-19-0710
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