Beta-blocker use and urothelial bladder cancer survival: a Swedish register-based cohort study

Figures & data

Table 1. Baseline characteristics of patients diagnosed with primary urothelial bladder cancer in Sweden in 2006 to 2014 by β-blocker use at cancer diagnosis.

	Nonselective β–blocker (N = 345)		Selective β–blocker (N = 4,104)		No β–blocker (N = 12,220)		p^a
	N	Col %	N	Col %	N	Col %
Age at diagnosis, years (mean, SD)	74.6	9.6	75.0	9.1	70.7	11.3	<0.001^b
Male	267	77.4	3216	78.4	9140	74.8	<0.001
Attained education							<0.001
Compulsory	151	43.8	1994	48.6	4944	40.5
Secondary	123	35.7	1507	36.7	4698	38.4
Post-secondary	71	20.6	603	14.7	2578	21.1
Marital status at diagnosis							<0.001
Unmarried	29	8.4	356	8.7	1390	11.4
Married/cohabiting	191	55.4	2309	56.3	6926	56.7
Divorced/separated	51	14.8	656	16.0	2024	16.6
Widowed	74	21.4	783	19.1	1880	15.4
Grade							0.174
Grade 1	98	28.4	1014	24.7	3159	25.9
Grade 2	89	25.8	1095	26.7	3352	27.4
Grade 3	108	31.3	1489	36.3	4219	34.5
Unspecified	50	14.5	506	12.3	1490	12.2
Disease stage^d							0.210
NMIBC (Tis/Ta/T1, N0/X, M0/X)	257	74.5	2977	72.5	8890	72.7
MIBC (T2-4a, N0, M0)	23	6.7	311	7.6	1052	8.6
At least MIBC (T2-4a, N0MX, NXM0)	44	12.8	589	14.4	606	5.0
Advanced (T4b/N+/M1)	18	5.2	195	4.8	1572	12.9
Unspecified (TX, NX, MX)	3	0.9	32	0.8	100	0.8
Medication-based comorbidity score (median, IQR)^e	7	5–10	7	5–9	3	1–6	<0.001^c
Charlson comorbidity index							<0.001
0	133	38.6	1284	31.3	7436	60.9
1	101	29.3	1212	29.5	2721	22.3
2	48	13.9	764	18.6	1148	9.4
>2	63	18.3	844	20.6	915	7.5
Other antihypertensive medications within 90 days before diagnosis^f
ACEi	89	25.8	1361	33.2	1508	12.3	<0.001
ARB	72	20.9	784	19.1	1073	8.8	<0.001
CCB	83	24.1	1129	27.5	1412	11.6	<0.001
Thiazide diuretics	20	5.8	287	7.0	435	3.6	<0.001

Notes: Patients were considered exposed to β-blocker use at cancer diagnosis if they collected at least one prescription during the 90-day period before cancer diagnosis, and unexposed otherwise. Patients using both selective and nonselective β-blockers (n = 14) are in the nonselective subgroup. Grade1 includes Papilloma (SNOMED 3: 81201) and PUNLMP (SNOMED 3: 81301). 

Abbreviations: IQR: interquartile range; MIBC: muscle invasive bladder cancer; NMIBC: non-muscle invasive bladder cancer; PUNLMP: papillary neoplasm of low malignant potential; SD: standard deviation.

^ap Values are from a χ² test.

^bRobust one-way ANOVA.

^c Median test.

^dEvaluations of N and M stages have not been performed for most patients with Ta and Tis tumors and many patients with T1 tumors, as well as for many older patients with T2–T4 tumors. Where possible, morphological codes have also been used to identify T stage (Tis: 81202; Ta: 81302; PUNLMP: 81301; muscle invasive: 81203, 81303).

^eNumber of distinct medication classes (medications with the same initial five characters of ATC classification) within 90 days before cancer diagnosis were used to derive a medication-based comorbidity score.

^fMedications (yes/no variables) are dispensed within 90 days before cancer diagnosis and are not mutually exclusive.

Table 2. Cox proportional hazards regression analyses for the association between β-blocker use and bladder cancer-specific mortality in patients diagnosed with primary urothelial bladder cancer (N = 16,669) in Sweden in 2006 to 2014.

β-blockers^a	No. of events	HR^b (95% CI)	p	HR^c (95% CI)	p	HR^d (95% CI)	p
Any β-blocker	894	0.99 [0.91,1.07]	0.743	0.88 [0.81,0.96]	0.004	0.88 [0.81,0.96]	0.005
Nonselective^e	56	0.77 [0.59,1.00]	0.052	0.66 [0.50,0.86]	0.002	0.66 [0.50,0.86]	0.002
β1-receptor selective^f	838	1.01 [0.93,1.09]	0.880	0.90 [0.83,0.99]	0.024	0.91 [0.83,0.99]	0.026
Lipophilic^g	702	1.00 [0.92,1.09]	0.956	0.91 [0.83,1.00]	0.039	0.91 [0.83,1.00]	0.043
Hydrophilic^h	192	0.95 [0.82,1.10]	0.500	0.81 [0.70,0.95]	0.007	0.82 [0.70,0.95]	0.008

Abbreviations: CI: confidence interval; HR: hazard ratio.

^aExposed if collected at least one prescription during the 90-day period before bladder cancer diagnosis, unexposed otherwise. Patients using both selective and nonselective β-blockers (n = 14) are in the nonselective subgroup, and patients using both lipophilic and hydrophilic β-blockers (n = 18) are in the lipophilic subgroup.

^bβ-blocker use compared with nonuse, adjusting for age at diagnosis.

^cβ-blocker use compared with nonuse, adjusting for age at diagnosis, sex, disease stage, tumor grade, diagnosis year, healthcare/residence region, attained education, marital status, medication-based comorbidity score, Charlson comorbidity index.

^dFurther adjusted for transurethral resection of a bladder tumor (TURBT), radical cystectomy and lymphadenectomy modeled as time-varying covariates.

^eIncludes: pindolol, propranolol, timolol, sotalol, labetalol, carvedilol.

^fIncludes: metoprolol, atenolol, bisoprolol, metoprolol + felodipine.

^gIncludes: bisoprolol, carvedilol, labetalol, metoprolol, pindolol, propranolol, timolol, metoprolol + felodipine.

^hIncludes: sotalol, atenolol.

Figure 1. Bladder cancer-specific survival for nonusers and β-blocker users standardized to the observed covariate distribution in the sample at diagnosis (age, sex, year, grade, stage, marital status, education, health care region, medication-based comorbidity score, Charlson comorbidity index).

Table 3. β-blocker use at bladder cancer diagnosis compared with nonuse in relation to bladder cancer-specific mortality by tumor stage in patients diagnosed with primary urothelial bladder cancer (N = 16,669) in Sweden in 2006–2014.

		Nonselective β-blockers			β1-receptor selective β-blockers
Disease stage	Total N	No. of events^a	HR^b (95% CI)	p	No. of events^a	HR^b (95% CI)	p
NMIBC (Tis/Ta/T1, N0/X, M0/X)	12,124	25	1.06 [0.71,1.60]	0.762	274	0.94 [0.80,1.09]	0.396
Low/intermediate risk (TaG1-2)	6,734	9	1.12 [0.56,2.24]	0.751	68	1.00 [0.73,1.36]	0.991
High risk (TaG3/Tis/T1)	4,812	15	1.04 [0.62,1.75]	0.884	199	0.94 [0.78,1.12]	0.476
MIBC (T2-4a, N0, M0)	1,386	9	0.66 [0.34,1.30]	0.234	141	0.90 [0.73,1.11]	0.339
At least MIBC (T2-4a, N0MX, NXM0)	2,205	13	0.68 [0.39,1.19]	0.173	274	0.86 [0.74,1.00]	0.053
Advanced (T4b/ N+/ M1)	819	9	0.35 [0.18,0.68]	0.002	148	0.97 [0.78,1.20]	0.757

Abbreviations: CI: confidence interval; HR: hazard ratio; MIBC: muscle invasive bladder cancer; NMIBC: non-muscle invasive bladder cancer; advanced: locally advanced/metastatic.

^aNumber of events among β-blocker users.

^bCox regression models were adjusted for age at diagnosis, sex, disease stage, tumor grade, diagnosis year, healthcare/residence region, attained education, marital status, medication-based comorbidity score, and Charlson comorbidity index modeled as time-invariant covariates as well as transurethral resection of a bladder tumor (TURBT), radical cystectomy and lymphadenectomy modeled as time-varying covariates.

Table 4. β-blocker use at bladder cancer diagnosis compared with nonuse in relation to all-cause mortality by tumor stage in patients diagnosed with primary urothelial bladder cancer (N = 16,669) in Sweden in 2006–2014.

		Nonselective β-blockers			β1-receptor selective β-blockers
Disease stage	Total N	No. of events^a	HR^b (95% CI)	p	No. of events^a	HR^b (95% CI)	p
NMIBC (Tis/Ta/T1, N0/X, M0/X)	12,124	111	1.14 [0.94,1.39]	0.185	1,016	0.90 [0.83,0.98]	0.013
Low/intermediate risk (TaG1-2)	6,734	56	1.11 [0.84,1.46]	0.472	460	0.90 [0.80,1.02]	0.089
High risk (TaG3/Tis/T1)	4,812	48	1.21 [0.90,1.63]	0.198	510	0.91 [0.81,1.01]	0.089
MIBC (T2-4a, N0, M0)	1,386	16	0.85 [0.51,1.42]	0.532	200	0.90 [0.76,1.08]	0.255
At least MIBC (T2-4a, N0MX, NXM0)	2,205	31	0.93 [0.64,1.34]	0.701	433	0.84 [0.75,0.96]	0.007
Advanced (T4b/ N+/ M1)	819	14	0.45 [0.26,0.78]	0.004	179	0.94 [0.77,1.15]	0.567

Abbreviations: CI: confidence interval; HR: hazard ratio; MIBC: muscle invasive bladder cancer; NMIBC: non-muscle invasive bladder cancer, advanced: locally advanced/metastatic.

^aNumber of events among β-blocker users.

^bCox regression models were adjusted for age at diagnosis, sex, disease stage, tumor grade, diagnosis year, healthcare/residence region, attained education, marital status, medication-based comorbidity score, and Charlson comorbidity index modeled as time-invariant covariates as well as transurethral resection of a bladder tumor (TURBT), radical cystectomy and lymphadenectomy modeled as time-varying covariates.

Data availability statement

The data come from national population and health registers, and are not publicly available due to ethical restrictions.