The Mini-Sentinel safety study of mirabegron (a treatment for overactive bladder) was replicated using the publicly-available Mini-Sentinel common data model specifications, protocol, and analysis modules using IMS PharMetrics and Truven MarketScan, two databases that do not contribute to Mini-Sentinel. |
Propensity score-matched Cox proportional hazards models indicated no increased risk of acute myocardial infarction or stroke among either new or non-new users of mirabegron compared to oxybutynin in either dataset. |
Findings from the present study are consistent with the results of the US Food and Drug Administration’s Mini-Sentinel report on mirabegron, and the methods described here could be considered for other therapeutic areas, drugs, and outcomes of interest. |
1 Introduction
2 Methods
2.1 Cohort Selection
2.2 Follow-up and Censoring
2.3 Statistical Analysis
3 Results
3.1 IMS PharMetrics Plus Population
3.1.1 New Users
Baseline patient characteristics | Pre-matching mirabegron Mean (SD)a
| Pre-matching oxybutynin Mean (SD)a
| Post-matching mirabegron Mean (SD)a
| Post-matching oxybutynin Mean (SD)a
|
---|---|---|---|---|
New users | (N = 12,429) | (N = 61,548) | NA | NA |
Age (years) at index date | 55.6 (12.3) | 52.9 (13.3) | NA | NA |
Gender (N [%]) | ||||
Male | 3260 (26.2%) | 22,172 (36.0%) | NA | NA |
Female | 9167 (73.8%) | 39,376 (64.0%) | NA | NA |
Charlson–Elixhauser co-morbidity score | 0.4 (1.3) | 0.5 (1.6) | NA | NA |
Inpatient hospitalizations | 0.6 (3.6) | 1.3 (5.8) | NA | NA |
Emergency department visits | 0.2 (0.7) | 0.6 (1.3) | NA | NA |
Non-acute institutional stays | 0.1 (1.3) | 0.2 (2.0) | NA | NA |
Ambulatory visits | 2.5 (4.7) | 3.2 (5.7) | NA | NA |
Other ambulatory events | 10.3 (9.7) | 8.2 (9.4) | NA | NA |
Unique prescriptions | 19.3 (17.8) | 16.1 (16.6) | NA | NA |
Unique generics | 8.0 (5.8) | 7.0 (5.5) | NA | NA |
Non-new users | (N = 9025) | (N = 7899) | (N = 5172) | (N = 5172) |
Age (years) at index date | 57.9 (12.6) | 57.2 (12.4) | 57.9 (12.5) | 57.2 (12.3) |
Gender (N [%]) | ||||
Male | 1996 (22.1%) | 1719 (21.8%) | 1138 (22.0%) | 1134 (21.9%) |
Female | 7029 (77.9%) | 6179 (78.2%) | 4034 (78.0%) | 4038 (78.1%) |
Charlson–Elixhauser co-morbidity score | 0.4 (1.4) | 0.6 (1.7) | 0.4 (1.4) | 0.4 (1.4) |
Inpatient hospitalizations | 0.6 (3.5) | 1.5 (6.7) | 0.8 (4.4) | 0.7 (3.6) |
Emergency department visits | 0.3 (0.8) | 0.4 (1.2) | 0.3 (0.9) | 0.3 (0.8) |
Non-acute institutional stays | 0.1 (1.2) | 0.2 (1.9) | 0.2 (1.3) | 0.2 (1.1) |
Ambulatory visits | 3.0 (5.4) | 3.1 (5.4) | 2.8 (5.3) | 2.8 (4.8) |
Other ambulatory events | 11.8 (11.0) | 9.9 (10.8) | 10.3 (10.1) | 10.2 (10.7) |
Unique prescriptions | 25.8 (19.5) | 24.4 (20.5) | 24.2 (18.7) | 24.2 (19.6) |
Unique generics | 10.2 (5.9) | 9.6 (6.0) | 9.6 (5.6) | 9.6 (6.0) |
3.1.2 Non-new Users
Baseline patient characteristics | Pre-matching mirabegron Mean (SD)a
| Pre-matching oxybutynin Mean (SD)a
| Post-matching mirabegron Mean (SD)a
| Post-matching oxybutynin Mean (SD)a
|
---|---|---|---|---|
New users | (N = 12,379) | (N = 61,411) | NA | NA |
Age at index date | 55.6 (12.3) | 52.9 (13.3) | NA | NA |
Gender (N [%]) | ||||
Male | 3235 (26.1%) | 22,133 (36.0%) | NA | NA |
Female | 9142 (73.9%) | 39,278 (64.0%) | NA | NA |
Charlson–Elixhauser co-morbidity score | 0.4 (1.3) | 0.5 (1.6) | NA | NA |
Inpatient hospitalizations | 0.5 (3.1) | 1.2 (5.6) | NA | NA |
Emergency department visits | 0.2 (0.7) | 0.6 (1.3) | NA | NA |
Non-acute institutional stays | 0.1 (1.2) | 0.2 (1.9) | NA | NA |
Ambulatory visits | 2.4 (4.6) | 3.2 (5.7) | NA | NA |
Other ambulatory events | 10.3 (9.7) | 8.2 (9.3) | NA | NA |
Unique prescriptions | 19.2 (17.7) | 16.1 (16.5) | NA | NA |
Unique generics | 8.0 (5.7) | 7.0 (5.5) | NA | NA |
Non-new users | (N = 8959) | (N = 7872) | (N = 5236) | (N = 5236) |
Age at index date | 57.9 (12.5) | 57.2 (12.4) | 58.0 (12.5) | 57.0 (12.3) |
Gender (N [%]) | ||||
Male | 1967 (22.0%) | 1710 (21.7%) | 1151 (22.0%) | 1159 (22.1%) |
Female | 6992 (78.0%) | 6161 (78.3%) | 4085 (78.0%) | 4077 (77.9%) |
Charlson–Elixhauser co-morbidity score | 0.4 (1.4) | 0.6 (1.7) | 0.4 (1.4) | 0.4 (1.4) |
Inpatient hospitalizations | 0.6 (3.3) | 1.5 (6.6) | 0.7 (4.0) | 0.7 (3.7) |
Emergency department visits | 0.2 (0.7) | 0.4 (1.2) | 0.3 (0.8) | 0.3 (0.8) |
Non-acute institutional stays | 0.1 (1.1) | 0.2 (1.9) | 0.2 (1.3) | 0.1 (1.0) |
Ambulatory visits | 2.9 (5.3) | 3.1 (5.3) | 2.9 (5.7) | 2.8 (4.9) |
Other ambulatory events | 11.8 (11.0) | 9.9 (10.8) | 10.1 (9.8) | 10.3 (10.7) |
Unique prescriptions | 25.7 (19.4) | 24.3 (20.4) | 24.2 (18.2) | 24.3 (19.9) |
Unique generics | 10.1 (5.9) | 9.5 (6.0) | 9.6 (5.6) | 9.6 (5.9) |
3.2 Truven MarketScan Population
3.2.1 New Users
Baseline patient characteristics | Pre-matching mirabegron Mean (SD)a
| Pre-matching oxybutynin Mean (SD)a
| Post-matching mirabegron Mean (SD)a
| Post-matching oxybutynin Mean (SD)a
|
---|---|---|---|---|
New users | (N = 17,182) | (N = 63,962) | (N = 16,452) | (N = 16,452) |
Age at index date | 64.7 (15.2) | 59.7 (16.2) | 64.5 (15.2) | 62.0 (16.1) |
Gender (N [%]) | ||||
Male | 5501 (32.0%) | 23,542 (36.8%) | 5289 (32.1%) | 5208 (31.7%) |
Female | 11,681 (68.0%) | 40,420 (63.2%) | 11,163 (67.9%) | 11,244 (68.3%) |
Charlson–Elixhauser co-morbidity score | 0.6 (1.5) | 0.7 (1.8) | 0.6 (1.5) | 0.6 (1.6) |
Inpatient hospitalizations | 0.4 (2.1) | 0.6 (2.5) | 0.4 (2.1) | 0.4 (1.7) |
Emergency department visits | 0.2 (0.6) | 0.4 (0.9) | 0.2 (0.7) | 0.2 (0.6) |
Non-acute institutional stays | 0.2 (2.3) | 0.3 (3.6) | 0.2 (2.3) | 0.3 (2.1) |
Ambulatory visits | 2.4 (4.3) | 2.9 (5.0) | 2.4 (4.3) | 2.3 (4.0) |
Other ambulatory events | 11.5 (10.0) | 8.6 (9.1) | 11.1 (9.6) | 11.2 (11.4) |
Unique prescriptions | 18.7 (15.5) | 16.3 (15.0) | 18.5 (15.5) | 18.6 (15.7) |
Unique generics | 8.6 (5.5) | 7.4 (5.2) | 8.4 (5.4) | 8.5 (5.6) |
Non-new users | (N = 15,252) | (N = 11,374) | (N = 8123) | (N = 8123) |
Age at index date | 66.3 (14.5) | 65.4 (15.3) | 65.9 (14.8) | 64.9 (14.9) |
Gender (N [%]) | ||||
Male | 4104 (26.9%) | 2727 (24.0%) | 2045 (25.2%) | 2034 (25.0%) |
Female | 11,148 (73.1%) | 8647 (76.0%) | 6078 (74.8%) | 6089 (75.0%) |
Charlson–Elixhauser co-morbidity score | 0.7 (1.6) | 0.8 (2.0) | 0.7 (1.7) | 0.7 (1.7) |
Inpatient hospitalizations | 0.4 (1.9) | 0.9 (3.5) | 0.5 (2.2) | 0.5 (2.1) |
Emergency department visits | 0.3 (0.7) | 0.4 (0.9) | 0.3 (0.8) | 0.3 (0.7) |
Non-acute institutional stays | 0.3 (2.6) | 0.4 (2.9) | 0.3 (2.7) | 0.3 (2.5) |
Ambulatory visits | 2.8 (5.1) | 2.9 (4.9) | 2.7 (5.2) | 2.7 (4.6) |
Other ambulatory events | 12.2 (10.5) | 10.4 (10.2) | 10.7 (9.8) | 10.6 (10.0) |
Unique prescriptions | 24.3 (17.6) | 23.4 (17.9) | 23.5 (17.2) | 23.5 (17.7) |
Unique generics | 10.5 (5.7) | 9.9 (5.6) | 10.0 (5.5) | 10.0 (5.6) |
3.2.2 Non-new Users
Baseline patient characteristics | Pre-matching mirabegron Mean (SD)a
| Pre-matching oxybutynin Mean (SD)a
| Post-matching mirabegron Mean (SD)a
| Post-matching oxybutynin Mean (SD)a
|
---|---|---|---|---|
New users | (N = 17,138) | (N = 63,835) | (N = 15,973) | (N = 15,973) |
Age at index date | 64.6 (15.2) | 59.6 (16.2) | 64.3 (15.3) | 62.8 (15.9) |
Gender (N [%]) | ||||
Male | 5477 (32.0%) | 23,552 (36.9%) | 5065 (31.7%) | 5080 (31.8%) |
Female | 11,661 (68.0%) | 40,283 (63.1%) | 10,908 (68.3%) | 10,893 (68.2%) |
Charlson–Elixhauser co-morbidity score | 0.6 (1.5) | 0.7 (1.8) | 0.6 (1.5) | 0.6 (1.5) |
Inpatient hospitalizations | 0.4 (2.1) | 0.6 (2.5) | 0.4 (2.1) | 0.4 (1.7) |
Emergency department visits | 0.2 (0.7) | 0.4 (0.9) | 0.2 (0.7) | 0.2 (0.6) |
Non-acute institutional stays | 0.2 (2.3) | 0.3 (3.6) | 0.2 (2.3) | 0.2 (2.5) |
Ambulatory visits | 2.4 (4.3) | 2.9 (5.0) | 2.4 (4.4) | 2.4 (4.0) |
Other ambulatory events | 11.4 (10.0) | 8.6 (9.1) | 10.9 (9.6) | 11.0 (11.0) |
Unique prescriptions | 18.7 (15.6) | 16.3 (15.0) | 18.4 (15.5) | 18.6 (15.9) |
Unique generics | 8.6 (5.5) | 7.4 (5.2) | 8.4 (5.4) | 8.4 (5.6) |
Non-new users | (N = 15,173) | (N = 11,314) | (N = 8103) | (N = 8103) |
Age at index date | 66.3 (14.5) | 65.3 (15.3) | 66.2 (14.7) | 64.8 (14.9) |
Gender (N [%]) | ||||
Male | 4083 (26.9%) | 2707 (23.9%) | 2052 (25.3%) | 2052 (25.3%) |
Female | 11,090 (73.1%) | 8607 (76.1%) | 6051 (74.7%) | 6051 (74.7%) |
Charlson–Elixhauser co-morbidity score | 0.7 (1.6) | 0.8 (1.9) | 0.7 (1.7) | 0.6 (1.7) |
Inpatient hospitalizations | 0.4 (1.8) | 0.8 (3.3) | 0.5 (2.1) | 0.5 (2.1) |
Emergency department visits | 0.3 (0.7) | 0.4 (0.9) | 0.3 (0.8) | 0.3 (0.7) |
Non-acute institutional stays | 0.3 (2.6) | 0.4 (2.9) | 0.3 (2.7) | 0.3 (2.2) |
Ambulatory visits | 2.8 (5.1) | 2.9 (4.9) | 2.8 (5.2) | 2.7 (4.8) |
Other ambulatory events | 12.1 (10.4) | 10.3 (10.1) | 10.7 (9.8) | 10.6 (10.0) |
Unique prescriptions | 24.2 (17.5) | 23.3 (17.9) | 23.5 (17.2) | 23.3 (17.6) |
Unique generics | 10.5 (5.7) | 9.9 (5.6) | 10.0 (5.5) | 10.0 (5.6) |
3.3 Outcomes
Mirabegron IR/1000 PYa
| Oxybutynin IR/1000 PYa
| Unadjusted HRb (95% CI) | Adjusted HRb (95% CI) Stratified by PS decile | Adjusted HRb (95% CI) Matching on PS | |
---|---|---|---|---|---|
IMS PharMetrics, new users | |||||
AMI | 4.4 | 6.5 | 0.68 (0.36–1.28) | 0.67 (0.33–1.37) | NA |
Stroke | 6.3 | 9.5 | 0.66 (0.39–1.13) | 0.62 (0.34–1.13) | NA |
IMS PharMetrics, non-new users | |||||
AMI | 5.8 | 2.7 | 0.95 (0.38–2.33) | 1.08 (0.39–3.00) | 2.00 (0.37–10.92) |
Stroke | 5.1 | 6.3 | 0.67 (0.33–1.36) | 0.69 (0.29–1.61) | 0.25 (0.03–2.24) |
Truven MarketScan, new users | |||||
AMI | 3.7 | 6.8 | 0.48 (0.28–0.83) | 0.54 (0.30–0.98) | 0.57 (0.17–1.95) |
Stroke | 5.3 | 8.4 | 0.63 (0.41–0.98) | 0.65 (0.40–1.06) | 0.69 (0.30–1.62) |
Truven MarketScan, non-new users | |||||
AMI | 6.1 | 8.3 | 0.61 (0.36–1.05) | 0.71 (0.38–1.29) | 0.80 (0.32–2.03) |
Stroke | 14.7 | 8.8 | 1.20 (0.78–1.84) | 1.51 (0.93–2.44) | 0.92 (0.40–2.08) |