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