Wang (2023)

Multiple conditions including cardiovascular outcomes, diabetes, antiplatelet agents, anticoagulants, hypertension, osteoporosis, kidney disease, heart failure, asthma, COPD, and prostate cancer

All areas • Claims Data • US

View Paper Protocol

Study Metrics

Covariates 100

PICO Comparisons 32

Quality Indicators

Transparency High

DAG Usage No

QBA Performed No

Study Information

First Author:	Wang
Publication Year:	2023
DOI:	https://doi.org/10.1001/jama.2023.4221
Preprint:	No preprint

Institution & Funding

Institutions:	Brigham and Women's Hospital, Harvard Medical School, McGill University, Vanderbilt University, Stanford University, Duke University, US Food and Drug Administration, Optum, Aetion Inc, AbbVie Inc, Moderna
Funding:	Declared: Public
Funding Institutions:	This DUPLICATE Initiative was funded by contracts from the U.S. Food and Drug Administration (HHSF223201710186C and HHSF223201810146C) to the Brigham and Women's Hospital (PI Dr. Schneeweiss and Wang). Drs. Wang and Schneeweiss were further supported by funding from the National Institutes of Health RO1HL141505, R01AG053302, and R01AR080194. The content is solely the responsibility of the authors and does not necessarily represent the official views of the U.S. Food and Drug Administration.

Study Context

Disease:	Multiple conditions including cardiovascular outcomes, diabetes, antiplatelet agents, anticoagulants, hypertension, osteoporosis, kidney disease, heart failure, asthma, COPD, and prostate cancer
Disease Category:	All areas
Data Type:	Claims Database
Number of Data Sources:	3

Geography:	US
Number of Emulations:	32

Analytical Methods

Matching Method:	PS matching
Analysis Method:	Cox PH

Quality Methods

Directed Acyclic Graph (DAG) Not Used

Quantitative Bias Analysis (QBA) Not Performed

Target Trial Information

Target Trial Name:	LEADER
Registration Number:	NCT01179048
Target Trial DOI:	https://doi.org/10.1007/s13300-018-0524-z

TTE vs RCT Comparisons

Detailed comparison between Target Trial Emulation results and corresponding Randomized Controlled Trial outcomes.

All cause death, non-fatal myocardial infarction, stroke

ISAR-REACT 5

HR Efficacy

Population

Intervention

Prasugrel

Comparison

Ticagrelor

Outcome

All cause death, non-fatal myocardial infarction, stroke

RCT Result

1.36

95% CI: [1.09, 1.70]

TTE Result

Not available

Asthma exacerbation

P04334

HR Efficacy

Population

Intervention

Mometasone furoate / formoterol

Comparison

Formoterol

Outcome

Asthma exacerbation

RCT Result

0.54

95% CI: [0.44, 0.72]

TTE Result

0.78

95% CI: [0.62, 0.97]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Asthma related death, intubation, hospitalization

D5896

HR Efficacy

Population

Intervention

Budesonide + formoterol

Comparison

Budenoside

Outcome

Asthma related death, intubation, hospitalization

RCT Result

1.07

95% CI: [0.70, 1.65]

TTE Result

1.38

95% CI: [0.90, 2.13]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

CARMELINA

HR Efficacy

Population

Intervention

Linagliptin

Comparison

Sulfonylureas

Outcome

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

RCT Result

1.02

95% CI: [0.89, 1.17]

TTE Result

0.90

95% CI: [0.84, 0.96]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Different Direction
Different conclusions

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

SAVOR-TIMI

HR Efficacy

Population

Intervention

Saxagliptin

Comparison

Sulfonylureas

Outcome

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

RCT Result

1.00

95% CI: [0.89, 1.12]

TTE Result

0.81

95% CI: [0.76, 0.86]

Concordance Assessment

Confidence Interval Overlap: No
CIs do not overlap

Direction Agreement: Different Direction
Different conclusions

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

TRITON-TIMI

HR Efficacy

Population

Intervention

Prasugrel

Comparison

Clopidogrel

Outcome

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

RCT Result

0.81

95% CI: [0.73, 0.90]

TTE Result

0.88

95% CI: [0.79, 0.97]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

PLATO

HR Efficacy

Population

Intervention

Ticagrelor

Comparison

Clopidogrel

Outcome

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

RCT Result

0.84

95% CI: [0.77, 0.92]

TTE Result

0.92

95% CI: [0.83, 1.02]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

LEADER

HR Efficacy

Population

Intervention

Liraglutide

Comparison

Dipeptidyl peptidase 4 inhibitors (DPP4i)

Outcome

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

RCT Result

0.87

95% CI: [0.78, 0.97]

TTE Result

0.82

95% CI: [0.76, 0.87]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

EMPA-REG

HR Efficacy

Population

Intervention

Empagliflozin

Comparison

Dipeptidyl peptidase 4 inhibitors (DPP4i)

Outcome

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

RCT Result

0.86

95% CI: [0.74, 0.99]

TTE Result

0.83

95% CI: [0.73, 0.95]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

CANVAS

HR Efficacy

Population

Intervention

Canagliflozin

Comparison

Dipeptidyl peptidase 4 inhibitors (DPP4i)

Outcome

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

RCT Result

0.86

95% CI: [0.75, 0.97]

TTE Result

0.77

95% CI: [0.70, 0.85]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

CAROLINA

HR Efficacy

Population

Intervention

Linagliptin

Comparison

Glimepiride

Outcome

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

RCT Result

0.95

95% CI: [0.84, 1.14]

TTE Result

0.91

95% CI: [0.79, 1.05]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

PRONOUNCE

HR Efficacy

Population

Intervention

Degarelix

Comparison

Leuprolide

Outcome

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE)

RCT Result

1.28

95% CI: [0.59, 2.79]

TTE Result

1.35

95% CI: [0.94, 1.93]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE) + angina

TECOS

HR Efficacy

Population

Intervention

Sitagliptin

Comparison

Sulfonylureas

Outcome

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE) + angina

RCT Result

0.98

95% CI: [0.88, 1.09]

TTE Result

0.89

95% CI: [0.86, 0.91]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE) + Hospitalization for heart failure

ONTARGET

HR Efficacy

Population

Intervention

Telmisartan

Comparison

Ramipril

Outcome

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE) + Hospitalization for heart failure

RCT Result

1.01

95% CI: [0.94, 1.09]

TTE Result

0.83

95% CI: [0.77, 0.90]

Concordance Assessment

Confidence Interval Overlap: No
CIs do not overlap

Direction Agreement: Different Direction
Different conclusions

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE) + Hospitalization for heart failure

TRANSCEND

HR Efficacy

Population

Intervention

Telmisartan+Loop/CCB/TZ

Comparison

Loop/CCB/TZ

Outcome

Composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death (3p MACE) + Hospitalization for heart failure

RCT Result

0.92

95% CI: [0.81, 1.05]

TTE Result

0.88

95% CI: [0.83, 0.96]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

COPD exacerbation

INSPIRE

HR Efficacy

Population

Intervention

Advair

Comparison

Tiotropium

Outcome

COPD exacerbation

RCT Result

0.97

95% CI: [0.84, 1.12]

TTE Result

0.93

95% CI: [0.90, 0.96]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Deep vein thrombosis, pulmonary embolism, death

RECORD1

HR Efficacy

Population

Intervention

Rivaroxaban

Comparison

Enoxaparin

Outcome

Deep vein thrombosis, pulmonary embolism, death

RCT Result

0.25

95% CI: [0.14, 0.47]

TTE Result

0.17

95% CI: [0.10, 0.29]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

End stage renal disease / death

DAPA-CKD

HR Efficacy

Population

Intervention

Dapagliflozin

Comparison

Sitagliptin

Outcome

End stage renal disease / death

RCT Result

0.61

95% CI: [0.51, 0.72]

TTE Result

0.80

95% CI: [0.52, 1.26]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Hemoglobin A1c

LEAD-2

MD Efficacy

Population

Intervention

Liraglutide + metformin

Comparison

Glimepiride + metformin

Outcome

Hemoglobin A1c

RCT Result

Not available

TTE Result

0.05

95% CI: [-0.11, 0.22]

Hip Fracture

HORIZON-PFT

HR Efficacy

Population

Intervention

Zoledronic Acid

Comparison

Raloxifene

Outcome

Hip Fracture

RCT Result

0.59

95% CI: [0.42, 0.83]

TTE Result

0.72

95% CI: [0.55, 0.94]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Hospitalization for heart failure + cardiovascular death

DECLARE-TIMI58

HR Efficacy

Population

Intervention

Dapagliflozin

Comparison

Dipeptidyl peptidase 4 inhibitors (DPP4i)

Outcome

Hospitalization for heart failure + cardiovascular death

RCT Result

0.83

95% CI: [0.73, 0.95]

TTE Result

0.69

95% CI: [0.59, 0.81]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Hospitalization for heart failure / mortality

PARADIGM-HF

HR Efficacy

Population

Intervention

Sacubitril/Valsartan

Comparison

Angiotensin-converting enzyme inhibitor

Outcome

Hospitalization for heart failure / mortality

RCT Result

0.80

95% CI: [0.73, 0.87]

TTE Result

1.02

95% CI: [0.91, 1.14]

Concordance Assessment

Confidence Interval Overlap: No
CIs do not overlap

Direction Agreement: Different Direction
Different conclusions

Moderate or severe COPD exacerbation

IMPACT

HR Efficacy

Population

Intervention

Fluticasone, umeclidinium, vilanterol

Comparison

Fluticasone, vilanterol

Outcome

Moderate or severe COPD exacerbation

RCT Result

0.85

95% CI: [0.80, 0.90]

TTE Result

1.13

95% CI: [1.04, 1.23]

Concordance Assessment

Confidence Interval Overlap: No
CIs do not overlap

Direction Agreement: Different Direction
Different conclusions

Moderate or severe COPD exacerbation

POET-COPD

HR Efficacy

Population

Intervention

Tiotropium

Comparison

Salmeterol

Outcome

Moderate or severe COPD exacerbation

RCT Result

0.83

95% CI: [0.77, 0.90]

TTE Result

1.02

95% CI: [0.93, 1.12]

Concordance Assessment

Confidence Interval Overlap: No
CIs do not overlap

Direction Agreement: Different Direction
Different conclusions

Stroke/Systemic Embolism

RE-LY

HR Efficacy

Population

Intervention

Dabigatran

Comparison

Warfarin

Outcome

Stroke/Systemic Embolism

RCT Result

0.66

95% CI: [0.53, 0.82]

TTE Result

0.73

95% CI: [0.60, 0.90]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Stroke/Systemic Embolism

ROCKET AF

HR Efficacy

Population

Intervention

Rivaroxaban

Comparison

Warfarin

Outcome

Stroke/Systemic Embolism

RCT Result

0.79

95% CI: [0.66, 0.96]

TTE Result

0.70

95% CI: [0.62, 0.80]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Stroke/Systemic Embolism

ARISTOTLE

HR Efficacy

Population

Intervention

Apixaban

Comparison

Warfarin

Outcome

Stroke/Systemic Embolism

RCT Result

0.79

95% CI: [0.66, 0.95]

TTE Result

0.68

95% CI: [0.61, 0.76]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Venous thromboembolism

EINSTEIN PE

HR Efficacy

Population

Intervention

Rivaroxaban

Comparison

Warfarin

Outcome

Venous thromboembolism

RCT Result

1.12

95% CI: [0.75, 1.68]

TTE Result

0.67

95% CI: [0.55, 0.80]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Different Direction
Different conclusions

Venous thromboembolism

EINSTEIN DVT

HR Efficacy

Population

Intervention

Rivaroxaban

Comparison

Warfarin

Outcome

Venous thromboembolism

RCT Result

0.68

95% CI: [0.44, 1.04]

TTE Result

0.75

95% CI: [0.62, 0.90]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Venous thromboembolism / Venous thromboembolism Related Death

AMPLIFY

HR Efficacy

Population

Intervention

Apixaban

Comparison

Warfarin

Outcome

Venous thromboembolism / Venous thromboembolism Related Death

RCT Result

0.84

95% CI: [0.60, 1.18]

TTE Result

0.81

95% CI: [0.54, 1.23]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Venous thromboembolism / Venous thromboembolism Related Death

RE-COVER II

HR Efficacy

Population

Intervention

Dabigatran

Comparison

Warfarin

Outcome

Venous thromboembolism / Venous thromboembolism Related Death

RCT Result

1.08

95% CI: [0.64, 1.80]

TTE Result

1.15

95% CI: [0.74, 1.78]

Concordance Assessment

Confidence Interval Overlap: Yes
CIs overlap, suggesting concordance

Direction Agreement: Same Direction
Both point to similar conclusion

Vertebral fracture

VERO

HR Efficacy

Population

Intervention

Teriparatide

Comparison

Risedronate

Outcome

Vertebral fracture

RCT Result

0.44

95% CI: [0.29, 0.68]

TTE Result

Not available

Transparency Indicators

Protocol Registration Available

Data Sharing Not Available

Code Sharing Not Available

Overall Transparency Score:

High Transparency - This study meets good transparency standards.

Conflicts & Funding

Conflicts of Interest:	Declared: Financial
COI Institutions:	Aetion Inc, UCB Pharma, Boehringer Ingelheim, Alosa Health, Blue Cross Blue Shield, Amarin, Kowa, Novartis, Pfizer, AstraZeneca, Atara, Bristol Myers Squibb, Panalgo, Merck, Seqirus
Funding Source:	Declared: Public
Funding Institutions:	This DUPLICATE Initiative was funded by contracts from the U.S. Food and Drug Administration (HHSF223201710186C and HHSF223201810146C) to the Brigham and Women's Hospital (PI Dr. Schneeweiss and Wang). Drs. Wang and Schneeweiss were further supported by funding from the National Institutes of Health RO1HL141505, R01AG053302, and R01AR080194. The content is solely the responsibility of the authors and does not necessarily represent the official views of the U.S. Food and Drug Administration.

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