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Table 2 Main characteristics of studies included in the meta-analysis

From: Cardiovascular risk associated with the use of glitazones, metformin and sufonylureas: meta-analysis of published observational studies

Reference, source population, study period Study design, population size, age Diabetes type 2 population definition Study endpoints (number of cases) Case validation Exposure assessment Exposure recency Exposure group(s) vs. reference group (n)
A: Comparison(s) contributing to meta-analysis
B: Other comparison(s)
Studies included in both meta-analysis endpoints, AMI and stroke
Bilik, 2010 [26]
TRIAD study group USA
2000–2003
Cohort
N = 2,382
Age ≥ 18 years (patients taking only insulin and aged younger than 30 years were excluded)
First prescription for glitazones. Patients filling prescriptions for more than one TZD were excluded Non-fatal AMI (ICD-9: 410) (N = 39)
Non-fatal stroke (ICD-9: 431, 433, 434) (N = 32)
None Prevalent and new users
Dispensed prescriptions
Current, continuous use until 90 days after the supply date of their most recently filled prescription duration A: Rosiglitazone (n = 773) vs. pioglitazone (n = 711)
Graham, 2010 [30]
Medicare, USA
2006–2009
Cohort
227,571
Age ≥ 65 years
First prescriptions for glitazones Hospitalisation for fatal and non-fatal AMI/ACS/SCHD
(ICD-9: 410)
(N = 1,746)
Hospitalisation for fatal and non-fatal acute stroke, ischaemic or haemorrhagic
(ICD-9: 430, 431, 433.x1, 434.x1, and 436)
(N = 1,052)
External
PPV for AMI: 89 % – 97 %
PPV for stroke: 92 % – 100 %
New users
Dispensed prescriptions
Current continuous use, including a gap of no more than 7 days A: Rosiglitazone (n = 67,593) vs. pioglitazone (n = 159,978)
Winkelmayer, 2008 [41]
Medicare, New Jersey, USA
1999–2005
Cohort
28,361
Age > 65 years
First prescription for a glitazone, regardless of previous treatment with other diabetic drug(s) Ever and first ever
Fatal and non-fatal AMI (ICD-9: not reported )
(n = 737)
Hospitalisation for a non-fatal stroke: ischaemic or haemorrhagic
(ICD-9: 433,434,436)
(N = 1,869)
External
PPV for AMI: 94 %
PPV for stroke: 96 %
New users
Dispensed prescriptions
Current, continuous use until 60 days after the end of supply date of their most recently filled prescription duration or until switching to other TZD A: Rosiglitazone (n = 14,101) vs. pioglitazone (n = 14,260)
Studies included only in the meta-analysis of AMI
Horsdal, 2011 [31]
Danish National Registries
1996–2004
Nested case–control
N = 101,313
>30 years
Subjects were classified as having T1DM and excluded if they were aged younger than 30 years at the time of their first related prescription or diagnosis and had never received a prescription for an oral glucose–lowering drug. Subjects with T2DM were those with codes for diabetes mellitus who had not received pharmacotherapy, had received prescriptions for oral glucose–lowering drugs, or were aged older than 30 years when they had their first diagnostic code or prescription. Hospitalisation for AMI (codes not reported)
(N = 10,616)
External Prevalent and new users
Dispensed prescriptions
At least one prescription of study drug within 90 days before hospitalisation A: Sulfonylurea monotherapy (n = 26,778) vs. metformin monotherapy (n = 5,927)
B: Sulfonylurea monotherapy (n = 26,778) vs. any combination (n = 12,425); metformin monotherapy (n = 5,927) vs. individual sulfonylurea monotherapy (n = 26,778)
Loebstein, 2011 [35]
Maccabi Healthcare Services, Israel
2000–2007
Cohort
N = 15,436
Age, mean (SD): 59.1 (11.4) years
Subjects in the Maccabi diabetes registry with prescriptions for rosiglitazone or metformin for at least 6 months Hospitalisation for AMI
(ICD-9 and Y codes 410XX, Y139XX and Y225XX)
(N = 645)
None Prevalent and new users
Dispensed prescriptions
Current, continuous use within study period with gaps not longer than 3 months A: Rosiglitazone monotherapy (n = 745) or in combination with metformin (n = 2,753) vs. metformin monotherapy (n = 11,938)
(Formulary restriction allowed to use rosiglitazone only if inadequate control from SU, metformin, or both)
Brownstein, 2010 [27]
Partners Healthcare System: Research Patient Data Registry, USA
2000–2006
Cohort
N = 26,375
Age ≥ 18 years
ICD-9: 250.XX or hemoglobin A1C of at least 6.0 % and at least one record of prescription of an oral diabetes medication as an outpatient or dispensing as an inpatient Hospitalisation for AMI (ICD-9: 410)
(N = 1,343)
External
PPV: 92 % –94 %
Prevalent and new users
Prescriptions issued and dispensed
Current, continuous use within study period with gaps not longer than 6 months A: Rosiglitazone monotherapy (n = 1,879) vs. pioglitazone monotherapy (n = 806) or metformin monotherapy (n = 12,490) or sulfonylurea monotherapy (n = 11,200)
Wertz, 2010 [40]
HealthCore Integrated Research Database, USA
2001–2005
Cohort
N = 36,628
Age ≥ 18 years
First prescription for glitazones Hospitalisation for AMI (ED visits included) (ICD-9 410.xx)
(n = 217)
None New users
Dispensed prescriptions
Current use if refill occurred < 1.5 times the days’ supply of the preceding claim for TZD A: Rosiglitazone (n = 14,469) vs. pioglitazone (n = 14,469)
Dormuth, 2009 [28]
British Columbia Health databases, Canada
1997–2007
Nested case–control
N = 11,147
Age, mean (SD): 70 (12) years
Subjects with a pharmacy dispensing for metformin, without a dispensing of metformin, other antidiabetic medication, or insulin in the previous 365 days Hospitalisations for fatal and non-fatal AMI (ICD-9: 410)
(N = 2,244)
None New users
Dispensed prescriptions
Current use within 90 days of the index date A: Rosiglitazone (n = 462) vs. pioglitazone (n = 235)
Rosiglitazone (n = 462) vs. metformin (n = 10,685)
Rosiglitazone (n = 462) vs. sulfonylurea (n = 1,612)
Pioglitazone (n = 235) vs. metformin (n = 10,912)
Sulfonylurea (n = 1,612) vs. metformin (n = 9,535)
Hsiao, 2009 [32]
Taiwan Health Insurance Database
2001–2005
Cohort
N = 473,483
Age, not reported
Subjects with their first ambulatory visit with ICD-9-CM code 250.xx who were prescribed oral blood glucose–lowering agents at least three times. Subjects were excluded if they had T1DM (ICD-9-CM codes 250.x1) or if they had been prescribed only insulin during the study period. Fatal and non-fatal hospitalisation for AMI (ICD-9: 410.xx and 411.xx)
(N = 15,917)
None New users
Dispensed prescriptions
Current, continuous use during study period A: Pioglitazone monotherapy (n = 495) or rosiglitazone monotherapy (n = 2,093) vs. metformin-based therapy (n = 46,444) and vs. SU-based therapy (n = 97,651)
B: Pioglitazone + SU + metformin (n = 9,510) vs. Rosiglitazone + SU + metformin (n = 39,962)
Pioglitazone + metformin (n = 774) vs. rosiglitazone + metformin (n = 2,408)
Pioglitazone + SU (n = 1,231) vs. rosiglitazone + SU (n = 5,141)
Juurlink, 2009 [33]
Ontario diabetes database, Canada
2002–2008
Cohort
N = 39,736
Age ≥ 66 years
First prescription for a glitazone Hospitalisation for AMI (ICD-10: I20, I21, I22)
(N = 698)
External
PPV ≈ 90 %
New users prescription
Dispensed prescriptions
Current use if refill occurred < 1.5 times the days’ supply of the preceding TZD claim A: Rosiglitazone (n = 22,785) vs. pioglitazone (n = 16,951)
Tzoulaki, 2009 [38]
GPRD, United Kingdom
1990–2005
Cohort
N = 91,521
Age 35–90 years
One episode of care associated with a clinical or referral event for diabetes and prescriptions for oral blood glucose–lowering treatment First ever diagnosis of AMI according to Read codes (N = 3,588) External
Confirmed 90 % of AMI diagnoses
Prevalent and new users
Prescriptions issued
Current, continuous intervals of use within the study period A: First-generation SU monotherapy (n = 6,053) or second-generation SU monotherapy (n = 58,095) or rosiglitazone monotherapy (n = 8,442) and combination therapy (n = 9,640) or pioglitazone including monotherapy and combination therapy (n = 3,816) vs. metformin (n = 68,181)
B: Glibenclamide or gliclazide or glimepiride or glipizide or gliquidone vs. metformin (n = 68,181)
Ziyadeh, 2009 [42]
i3, USA
2000–2007
Cohort
N = 95,002
Age ≥ 18 years
Initiators of glitazones Hospitalisations for fatal and non-fatal AMI (ICD-9: 410.xx)
(N = 460)
External New users
Dispensed prescriptions
Current, use at index date A: Rosiglitazone monotherapy (n = 47,501) vs. pioglitazone monotherapy (n = 47,501)
Koro, 2008 [34]
Integrated HealthCore Information Services, USA
1999–2006
Nested case–control
N = 891,901
Age ≥ 30 years
Subjects with a diagnosis of type 2 diabetes and at least one prescription claim for an antidiabetic agent during their follow-up time available in the database First-ever hospitalisation for AMI (ICD-9: 410.xx)
(N = 9,870)
None Prevalent and new users
Dispensed prescriptions
Current use, a prescription in the last 3 months prior to index date A: Rosiglitazone (n = 3,839) vs. pioglitazone (n = 3,343)
Walker, 2008 [39]
Pharmetrics integrated outcomes database
USA
2000–2007
Cohort
≈543,000
Age ≥ 18 years
Subjects were users of rosiglitazone, pioglitazone, metformin, or a sulfonylurea Hospitalisation for fatal and non-fatal AMI (no codes reported)
(N = 502)
None New users
Dispensed prescriptions
Current, use at index date A: Rosiglitazone monotherapy (n = 12,440) vs. pioglitazone monotherapy (n = 16,302); rosiglitazone monotherapy (n = 12,440) or pioglitazone monotherapy (16,302) vs. metformin (n = 131,075); rosiglitazone monotherapy (n = 12,440) vs. sulfonylurea monotherapy (n = 48,376)
Gerrits, 2007 [29]
Ingenix Research Database, USA
2003–2006
Cohort
N = 29,911
Age ≥ 45 years
Subjects with ICD-9 code of 250.xx and a dispensing of pioglitazone or rosiglitazone Hospitalisation for AMI (ICD-9: 410.xx)
(N = 375)
External;
PPV ≥ 95 %
New users
Dispensed prescriptions
Exposure to pioglitazone and rosiglitazone was treated as a unidirectional time-varying covariate; that is, once a patient met the exposure definition, the patient was considered exposed from that point forward, even if the index drug was discontinued A: Rosiglitazone (n = 15,104) vs. pioglitazone (n = 14,807)
McAfee, 2007 [36]
Ingenix Research Database, USA
2000–2004
Cohort
N = 33,363
Age ≥ 18 years
Initiators of rosiglitazone, metformin, or a sulfonylurea Hospitalisation for AMI (ICD-9: 410.xx)
(N = 226)
External New users
Dispensed prescriptions
Current use during study period. Dispensing of a different study drug or insulin for the monotherapy group (at which time the subject became eligible for a different study cohort); cessation of study drug use alone was not sufficient to end follow-up A: Rosiglitazone monotherapy (n = 8,977) vs. metformin monotherapy (n = 8,977) or sulfonylureas monotherapy (n = 8,977)
B:
Rosiglitazone + metformin (n = 1,362) or rosiglitazone + sulfonylurea (n = 1,362) vs. metformin + sulfonylurea (n = 1,362)
Rosiglitazone (n = 12,874) vs. non-rosiglitzazone drug (n = 20,489)
Sauer, 2006 [37]
Philadelphia Metropolitan area, USA
1998–2002
Case–control (field study)
Controls were community controls selected using random digit dialing
N = 764
Age 40–75 years
Subjects with T2DM treated with antidiabetic drugs or diet only First-ever AMI (identified using medical records)
(N = 113)
AMI validated by Minnesota Heart Survey criteria Prevalent and new users
Interviews
Current, use in the 7 days before index date A: Sulfonylurea monotherapy (n = 158) vs. metformin monotherapy (n = 125)
B: Sulfonylureas (n = 158) or metformin (125) vs. thiazolidinedione (n = 26)
Sulfonylureas (n = 158) vs. thiazolidinediones + sulfonylureas (n = 27)
Sulfonylureas (n = 158) vs. metformin + sulfonylureas (n = 102)
Metformin (n = 125) vs. thiazolidinediones + metformin (n = 21)
  1. ACS acute coronary syndrome, AMI acute myocardial infarction, ED emergency department, GPRD General Practice Research Database (now the Clinical Practice Research Datalink [CPRD]), hemoglobin A1C glycated hemoglobin, ICD-9 international classification of diseases, 9th revision, ICD-9-CM, International Classification of Diseases, 9th Revision, Clinical Modification; ICD-10, International Statistical Classification of Diseases and Related Health Problems, 10th Revision; PPV, positive predictive value; SCHD, serious coronary heart disease; SD, standard deviation; SU, sulphonylurea(s); T1DM, type 1 diabetes mellitus; T2DM type 2 diabetes mellitus, TZD thiazolidinedione(s), USA United States of America
  2. Note: When it is not indicated that the endpoint is the first ever identified, the study included patients with and without prior history of the study endpoint