A study of cancer occurrence in users of mirabegron and antimuscarinic treatments for overactive bladder

Figures & data

Figure 1. Matched cohort creation for all data sources. ^aPatients eligible for matching are those with prescription of mirabegron or antimuscarinic medications that met all study inclusion criteria (i.e. not excluded due to the listed exclusion criteria). ^bMatched patients are those that met all study inclusion/exclusion criteria and were PS-matched at a 1:4 ratio. ^cOnly 1:1 matching was performed in Denmark. For all other data sources, 1:1 up to 1:4 matching was performed. ^dAfter case adjudication, 2 patients with adjudicated cancer dates before the index date (mirabegron cohort) were removed, together with their 4 matches, from the final analytic file. Abbreviations. CPRD, Clinical Practice Research Datalink; OAB, overactive bladder.

Table 1. Baseline characteristics of mirabegron and antimuscarinic initiators in propensity score matched cohorts, all study populations.

	Danish National Register		Swedish National Register		CPRD-linked, UK		CPRD-unlinked, UK		Optum Research Database, USA		Humana Research Database, USA		All Data Sources
	Mirabegron	AMs	Mirabegron	AMs	Mirabegron	AMs	Mirabegron	AMs	Mirabegron	AMs	Mirabegron	AMs	Total Mirabegron^e	Total AMs^e
N	21,815	21,815	32,283	62,838	2502	7479	3491	10,627	9625	28,981	10,921	38,145	80,637	169,885
Age ≥65 years, n (%)	14,205 (65.1)	14,205 (65.1)	21,109 (65.4)	39,348 (62.6)	1402 (56.0)	4139 (55.3)	1910 (54.7)	5897 (55.5)	7696 (80.0)	22,687 (78.3)	8254 (75.6)	28,742 (75.3)	54,576 (67.7)	115,018 (67.7)
Female sex, n (%)	12,335 (56.5)	12,335 (56.5)	20,361 (63.1)	37,851 (60.2)	1745 (69.7)	5224 (69.8)	2493 (71.4)	7556 (71.1)	6984 (72.6)	21,267 (73.4)	8005 (73.3)	28,180 (73.9)	51,923 (64.4)	112,413 (66.2)
Any antimuscarinic medication in prior 12 months, n
Darifenacin	107 (0.5)	107 (0.5)	211 (0.7)	393 (0.6)	13 (0.5)	17 (0.2)	14 (0.4)	24 (0.2)	37 (0.4)	112 (0.4)	34 (0.3)	108 (0.3)	416	761
Fesoterodine	582 (2.7)	526 (2.4)	669 (2.1)	626 (1.0)	124 (5.0)	179 (2.4)	186 (5.3)	287 (2.7)	147 (1.5)	326 (1.1)	91 (0.8)	202 (0.5)	1799	2146
Oxybutynin	37 (0.2)	28 (0.1)	152 (0.5)	196 (0.3)	272 (10.9)	741 (9.9)	334 (9.6)	977 (9.2)	513 (5.3)	866 (3.0)	588 (5.4)	1253 (3.3)	1896	4061
Solifenacin	1145 (5.2)	1073 (4.9)	1229 (3.8)	1146 (1.8)	621 (24.8)	1236 (16.5)	902 (25.8)	1688 (15.9)	382 (4.0)	965 (3.3)	347 (3.2)	1067 (2.8)	4626	6175
Tolterodine	746 (3.4)	763 (3.5)	959 (3.0)	1067 (1.7)	200 (8.0)	437 (5.8)	250 (7.2)	582 (5.5)	37 (0.4)	113 (0.4)	236 (2.2)	786 (2.1)	2428	3748
Trospium	503 (2.3)	481 (2.2)	N/A (N/A)	N/A (N/A)	107 (4.3)	176 (2.4)	137 (3.9)	247 (2.3)	40 (0.4)	117 (0.4)	37 (0.3)	93 (0.2)	824	1114
Comorbidities, n
Hormone-replacement therapy^a	9064 (41.5)	9064 (41.5)	15,480 (48.0)	26,015 (41.4)	1002 (40.0)	2837 (37.9)	1399 (40.1)	4068 (38.3)	1049 (10.9)	2783 (9.6)	1378 (12.6)	4640 (12.2)	29,372	49,407
Inflammatory bowel disease^b	468 (2.1)	446 (2.0)	556 (1.7)	1029 (1.6)	54 (2.2)	129 (1.7)	52 (1.5)	170 (1.6)	669 (7.0)	1961 (6.8)	1065 (9.8)	3605 (9.5)	2864	7340
Hypertension^c	10,106 (46.3)	10,079 (46.2)	16,492 (51.1)	32,291 (51.4)	1175 (47.0)	3478 (46.5)	1642 (47.0)	5037 (47.4)	8325 (86.5)	25,004 (86.3)	8961 (82.1)	31,172 (81.7)	46,701	107,061
Polycystic ovary syndrome	n < 5 (<0.1)	n < 5 (<0.1)	13 (<0.1)	26 (<0.1)	NR (N/A)	12 (0.2)	NR (N/A)	NR (N/A)	12 (0.1)	43 (0.1)	11 (0.1)	44 (0.1)	36	125
Endometrial polyps or other benign growths of the uterine lining	74 (0.3)	73 (0.3)	201 (0.6)	317 (0.5)	NR (N/A)	21 (0.4)	NR (N/A)	9 (0.1)	73 (0.8)	221 (0.8)	74 (0.7)	253 (0.7)	422	894
Diabetes^c	2849 (13.1)	2805 (12.9)	4029 (12.5)	7923 (12.6)	378 (15.1)	1045 (14.0)	502 (14.4)	1595 (15.0)	3837 (39.9)	11,604 (40.0)	4209 (38.5)	14,715 (38.6)	15,804	39,687
History of bilateral mastectomy	n < 5 (<0.1)	n < 5 (<0.1)	N/A (N/A)	N/A (N/A)	0 (0.0)	NR (N/A)	0 (0.0)	NR (N/A)	1 (<0.1)		2 (<0.1)	6 (<0.1)	3	6
Any immunomodulator medications (past 12 months)^a	831 (3.8)	851 (3.9)	4056 (12.6)	7768 (12.4)	29 (1.2)	56 (0.7)	29 (0.8)	78 (0.7)	1760 (18.3)	5323 (18.4)	65 (0.6)	187 (0.5)	6770	14,263
Obesity^d	739 (3.4)	732 (3.4)	472 (1.5)	947 (1.5)	764 (30.5)	2214 (29.6)	1148 (32.9)	3539 (33.3)	2284 (23.7)	7027 (24.2)	2985 (27.3)	10,223 (26.8)	8392	24,682

^aPast 12 months; ^bUlcerative colitis and Crohn’s disease; ^cMedications or diagnosis; ^dDiagnosis codes, procedures, medications; ^eTable cells with n < 5 or NR were not included in calculations for Total mirabegron and Total AMs.

Abbreviations. AMs, antimuscarinics; CPRD, Clinical Practice Research Datalink; N/A, not applicable; NR, not reported (number masked due to data source restrictions).

Table 2. Meta-analysis results for hazard ratios of sex-specific composite cancer endpoints, propensity-score matched cohorts, all ages, all study populations by time since treatment initiation.

	N	No. of cases	PY	IR/1000 PY	95% CI^a	HR	95% CI^a	I^2 (%)
Overall
Women^b
Mirabegron^c	65,066	1219	120,826	10.09	9.53–10.67	1.05	0.98–1.14	12.96
Antimuscarinics	112,372	1531	175,746	8.71	8.28–9.16
Men^b
Mirabegron^c	34,923	1351	64,305	21.01	19.91–22.15	1.06	0.98–1.14	0.00
Antimuscarinics	57,428	1734	91,295	18.99	18.12–19.90
First year of treatment initiation
Women^b
Mirabegron^c	65,066	566	54,504	10.39	9.56–11.27	1.03	0.92–1.15	31.93
Antimuscarinics	112,372	793	87,202	9.09	8.48–9.74
Men^b
Mirabegron^c	34,923	748	29,284	25.54	23.76–27.42	1.02	0.93–1.13	21.03
Antimuscarinics	57,428	1033	44,984	22.96	21.60–24.40
Excluding first year of treatment initiation
Women^b
Mirabegron^c	43,818	653	66,286	9.85	9.12–10.63	1.06	0.95–1.19	29.22
Antimuscarinics	64,345	738	88,519	8.34	7.75–8.96
Men^b
Mirabegron^c	23,710	603	34,996	17.23	15.90–18.65	1.08	0.97–1.21	9.34
Antimuscarinics	34,220	701	46,291	15.14	14.05–16.30

^aCIs for IRs were calculated using Byar’s formula. HRs and CIs for the HRs were from fixed-effects models and were calculated using the Comprehensive Meta Analysis (CMA) V3 software.

^bPatients censored on the index date were excluded from IR calculations and pooled analyses (women: 33 mirabegron, 41 antimuscarinics; men: 24 mirabegron, 43 antimuscarinics)  .

^cIncludes matched mirabegron initiators and antimuscarinic initiators who switched to mirabegron; therefore total mirabegron (i.e. N = 99,989 [65,066 + 34,923 for women and men], after excluding patients censored on the index date) is greater than total mirabegron observed in Table 1 (i.e. N = 80,637).

Abbreviations. CI, confidence interval; HR, hazard ratio; IR, incidence rate; PY, person-years.

Figure 2. Summary of incidence rates for bladder cancer in women and men and prostate cancer in men, propensity-score matched cohorts, stratified by time since treatment initiation, all data sources. Abbreviation. IR, incidence rate.

Table 3. Hazard ratios of sex-specific composite cancer endpoints, a comparison within tertiles of mirabegron cumulative dose.

Tertiles of mirabegron cumulative dose	No. of cases	PY	IR/1000 PY	95% CI^a	HR	95% CI^a	I^2 (%)
Women
Low	451	45,401	9.93	9.05–10.88
Medium	415	38,959	10.65	9.66–11.72	1.11	0.97–1.27	0.00
High	271	26,771	10.12	8.97–11.38	1.13	0.97–1.32	65.47
Men
Low	606	25,001	24.24	22.37–26.23
Medium	423	20,823	20.32	18.45–22.32	0.86	0.76–0.98	0.00
High	231	13,801	16.74	14.68–19.00	0.74	0.63–0.86	0.00

^aCIs for IRs were calculated using Byar’s formula. HRs and CIs for the HRs were from fixed-effects models and were calculated using the Comprehensive Meta Analysis (CMA) V3 software.

Abbreviations. CI, confidence interval; HR, hazard ratio; IR, incidence rate; PY, person-years.

Data availability statement

This observational study is based on individual patient data. Therefore, we are not able to make this data fully available to the public.