Please select the eligibility criteria that correspond to the clinical trial below.
Title: Replication of the SAVOR-TIMI Diabetes Trial in Healthcare Claims
Brief Summary: Investigators are building an empirical evidence base for real world data through large-scale replication of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies.


Options:
A: Please see: https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV for full code and algorithm definitions.

Market availability of prasugrel in the U.S. started on 2009-07-10.

* For Marketscan: 2009-07-10 to 2017-12-31 (end of data availability).
* For Optum: 2009-07-10 to 2019-03-31 (end of data availability).

Inclusion Criteria:

* 1. Acute coronary syndrome based on the disease diagnostic criteria with planned PCI (ACS definition; one of the following):

  * 1a. Moderate to high risk Unstable angina: A history of chest discomfort or ischemic symptoms of 10 min or longer at rest, 72 h or less before randomization, with persistent or transient ST-segment deviation 1 mm or higher in one or more electrocardiogram (ECG) leads without elevation of creatine kinase-MB (CK-MB) or troponin T or I but with a TIMI risk score 321 or greater
  * 1b. II. Moderate to high-risk NSTEMI. A history of chest discomfort or ischemic symptoms of 10 min or longer at rest, 72 h or less before randomization with no evidence of persistent ST-segment elevation. Subjects must also have CK-MB or troponin T or I greater than the upper limit of normal (ULN) and a TIMI risk score 3 or greater. If CK-MB or troponin is not available, total CK 2 times or greater ULN is acceptable
  * 1c. III. STEMI. A history of chest discomfort or ischemic symptoms of greater than 20 minutes duration at rest, within 14 days or less randomization with one of the following ECG features:

    1. ST-segment elevation 1 mm or higher in 2 or more contiguous ECG leads
    2. New or presumably new left bundle branch block
    3. ST-segment depression 1 mm or greater in 2 anterior precordial leads (V1 through V4) with clinical history and evidence suggestive of true posterior infarction"
* 2. Legal age (and \>18 y) and competent mental condition to provide written informed consent
* 3. For women of childbearing potential only, test negative for pregnancy between ACS presentation and enrollment (based on a urine or serum pregnancy test) and agree to use a reliable method of birth control during the study

Exclusion Criteria:

* Cardiovascular exclusion criteria

  * 1. Cardiogenic shock at the time of randomization
  * 2. Refractory ventricular arrhythmias
  * 3. New York Heart Association class IV congestive heart failure
* Bleeding risk exclusion criteria

  * 4. Fibrin-specific fibrinolytic therapy less than 24 h before randomization
  * 5. Non-fibrin-specific fibrinolytic therapy less than 48 h before randomization
  * 6. Active internal bleeding or history of bleeding diathesis
  * 7. Clinical findings, in the judgment of the investigator, associated with an increased risk of bleeding
  * 8. Any of the following:

    1. History of hemorrhagic stroke
    2. Intracranial neoplasm, arteriovenous malformation, or aneurysm
    3. Ischemic stroke within 3 months prior to screening
  * 9. International normalized ratio known to be greater than 1.5 at the time of screening
  * 10. Platelet count of less than 100000/mm3 at the time of screening
  * 11. Anemia (hemoglobin b10 g/dL) at the time of screening
* Prior/concomitant therapy exclusion criteria

  * 12. One or more doses of a thienopyridine 5 d or less before PCI
  * 13. Oral anticoagulation or other antiplatelet therapy that cannot be safely discontinued for the duration of the study
  * 14. Daily treatment with nonsteroidal antiinflammatory drugs (NSAIDs) or cyclooxygenase-2 inhibitors (COX-2 inhibitors)
* General exclusion criteria

  * 15. Investigative site personnel directly affiliated with the study or immediate family
  * 16. Employed by Eli Lilly and Company; Ube Industries Limited, Daiichi Sankyo Co.; The TIMI Study Group; Quintiles
  * 17. Treatment within the last 30 d with an investigational drug or are presently enrolled in another drug or device study
  * 18. Previously completed or withdrawn from this study or any other study investigating prasugrel
  * 19. Women who are known to be pregnant, have given birth within the past 90 d, or are breast-feeding
  * 20. Concomitant medical illness that in the opinion of the investigator is associated with reduced survival
  * 21. Known severe hepatic dysfunction
  * 22. Any condition associated with poor treatment compliance including alcoholism, mental illness, or drug dependence
  * 23. Intolerance of or allergy to aspirin, tilopidine, or clopidogrel
  * 24. May be unable to cooperate with protocol requirements and follow-up procedures
B: Inclusion Criteria:

* Patients with Type 2 diabetes who were new users of Linagliptin or new users of Glimepiride and:

  - Had no more than 3 anti-diabetic drugs including index drug
* AND at elevated risk of cardiovascular (CV) events according to specific criteria:

  * Previous vascular disease
  * Evidence of vascular-related end-organ damage
  * Age ⩾ 70 years
  * ⩾ 2 CV risk factors:

    * Treated hypertension
    * Smoking
    * Using any lipid lowering treatment
* Age ≥ 40 and ≤ 85 years at treatment initiation

Exclusion Criteria:

* Patients with Type 1 Diabetes Mellitus
* Previous exposure to dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, thiazolidinediones (TZDs), insulin or sodium glucose co-transporter-2 (SGLT-2s).
* Exclude anti-diabetic background therapy if initiated in 2 months prior
* Morbid obesity or treatment with anti-obesity drugs 3 months prior to treatment initiation
* Severe hyperglycemia
* Active liver disease or impaired hepatic function
* Any previous bariatric surgery
* Coronary artery re-vascularisation ≤ 6 weeks prior to treatment initiation
* Prior hospitalization for congestive heart failure
* Acute or chronic metabolic acidosis
* Hereditary galactose intolerance
* Alcohol or drug abuse within the 3 months prior to treatment initiation
* Use of oral corticosteroids
* Pregnant women
* Patients with cancer
* Acute coronary syndrome ≤ 6 weeks prior to treatment initiation
* Stroke or Transient ischemic attack ≤ 3 months prior to treatment initiation
C: Please see: https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV for full code and algorithm definitions.

Eligible cohort entry dates Market availability of linagliptin in the U.S. started on May 2, 2011. For Marketscan and Medicare: May 2, 2011-Dec 31, 2016 (end of data availability).

For Optum: May 2, 2011-Sep 30, 2017 (end of data availability).

Inclusion Criteria:

1. Documented diagnosis of T2DM before visit 1 (screening).
2. Male or female patients who are drug-naïve or pre-treated with any antidiabetic background therapy, excluding treatment with GLP-1 receptor agonists, DPP-4 inhibitors or SGLT-2 inhibitors if ≥ 7 consecutive days.
3. Stable antidiabetic background medication (unchanged daily dose) for at least 8 weeks prior to randomization. If insulin is part of the background therapy, the average daily insulin dose should not have been changed by more than 10% within the 8 weeks prior to randomization compared with the daily insulin dose at randomization.
4. HbA1c of ≥ 6.5% and ≤ 10.0% at visit 1 (screening).
5. Age ≥ 18 years at visit 1 (screening). For Japan only: Age ≥ 20 years at Visit 1.
6. Body Mass Index (BMI) 45 kg/m2 at visit 1 (screening).
7. Signed and dated written informed consent by date of visit 1 (screening) in accordance with GCP and local legislation prior to any study related procedure.
8. High risk of CV events (I and/or II):

Albuminuria (UACR ≥ 30 mg/g creatinine or ≥ 30 µg/min \[microgram albumin per minute\] or ≥ 30 mg/24 h \[milligram albumin per 24 hours\] in two out of three unrelated spot urine or timed samples in the last 24 months prior to randomization)\*

AND previous macrovascular disease, defined as either one or more:

Confirmed history of MI (\> 2 months prior to Visit 1)

Advanced coronary artery disease, defined by any one of the following:

* ≥ 50% narrowing of the luminal diameter in 2 or more major coronary arteries by coronary angiography, MRI angiography or CT angiography; Definition of major coronary arteries: LAD (Left Anterior Descending). CX (Circumflex) or RCA (right coronary artery)
* Left main stem coronary artery with ≥ 50% narrowing of the luminal diameter by coronary angiography, MRI angiography or CT angiography;
* Prior percutaneous or surgical revascularization of 2 major coronary arteries at least 2 months prior to Visit 1 (screening);
* The combination of prior percutaneous or surgical revascularization of 1 major coronary artery at least 2 months prior to visit 1 (screening), and ≥ 50% narrowing of the luminal diameter by coronary angiography, MRI angiography or CT angiography of at least 1 additional major coronary artery.

  10) High-risk single-vessel coronary artery disease, defined as the presence of 50% narrowing of the luminal diameter of one major coronary artery by coronary angiography, MRI angiography or CT angiography in patients not revascularised:

AND at least one of the following:

* A positive non invasive stress test, confirmed by either:
* a positive ECG exercise tolerance test in patients without left bundle branch block, Wolff-Parkinson-White syndrome, left ventricular hypertrophy with repolarization abnormality, or paced ventricular rhythm, atrial fibrillation in case of abnormal ST-T segments;
* a positive stress echocardiogram showing induced regional systolic wall motion abnormalities;
* a positive nuclear myocardial perfusion imaging stress test showing stress- induced reversible perfusion abnormality;
* a positive cardiac stress perfusion MRI showing a stress induced perfusion defect;
* Patient discharged from hospital with a documented diagnosis of unstable angina pectoris between 2 and 12 months prior to visit 1 (screening).

  10) History of ischemic or haemorrhagic stroke (\>3 months prior to visit 1) 11) Presence of carotid artery disease (symptomatic or not) documented by either:
* imaging techniques with at least one lesion estimated to be ≥50% narrowing of the luminal diameter;
* prior percutaneous or surgical carotid revascularization. 12) Presence of peripheral artery disease documented by either:
* previous limb angioplasty, stenting or bypass surgery;
* previous limb or foot amputation due to macrocirculatory insufficiency;
* angiographic evidence of peripheral artery stenosis 50% narrowing of the luminal diameter in at least one limb (definition of peripheral artery: common iliac artery, internal iliac artery, external iliac artery, femoral artery, popliteal artery).

  13) Evidence of impaired renal function with predefined UACR, with or without CV co- morbidities, defined as follows (and/or criteria):
  * Impaired renal function (as defined by MDRD formula) with an eGFR: 15- \<45 mL/min/1.73 m2 at visit 1 (screening) with any UACR.
  * Impaired renal function (as defined by MDRD formula) with an eGFR ≥ 45-75 mL/min/1.73 m2 at visit 1 (screening) with an UACR \> 200 mg/g creatinine or \> 200 µg/min (microgram albumin per minute) or \> 200 mg/24 h \[milligram albumin per 24 hours\] demonstrated in two out of three unrelated spot urine or timed samples in the last 24 months prior to randomization.

Exclusion Criteria:

1. Type 1 diabetes mellitus.
2. Treatment (≥ 7 consecutive days) with GLP-1 receptor agonists, other DPP-4 inhibitors or SGLT-2 inhibitors prior to informed consent. Note: This also includes clinical trials where these antidiabetic drugs have been provided to the patient.
3. Active liver disease or impaired hepatic function, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase (AP) ≥3 x upper limit of normal (ULN) as determined at Visit 1.
4. eGFR \<15 ml/min/1.73 m2 (severe renal impairment or ESRD, MDRD formula), as determined during screening at Visit 1 and/or the need for maintenance dialysis.
5. Any previous (or planned within next 12 months) bariatric surgery (open or laparoscopic) or intervention (gastric sleeve).
6. Pre-planned coronary artery re-vascularisation (PCI, CABG) or any previous PCI and/or CABG ≤ 2 months prior informed consent"
7. Known hypersensitivity or allergy to the investigational products or its excipients.
8. Any previous or current alcohol or drug abuse that would interfere with trial participation in the opinion of the investigator.
9. Participation in another trial with an investigational drug ongoing or within 2 months prior to visit 1 (screening)\*.
10. Pre-menopausal women (last menstruation 1 year prior to informed consent) who:

    * are nursing or pregnant,
    * or are of child-bearing potential and are not practicing an acceptable method of birth control (acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence (if allowed by local authorities), double barrier method and vasectomised partner) or do not plan to continue using acceptable method of birth control throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial.
11. Patients considered unreliable by the investigator concerning the requirements for follow- up during the study and/or compliance with study drug administration, have a life expectancy less than 5 years for non-CV causes, or have cancer other than non-melanoma skin cancer within last 3 years, or has any other condition than mentioned which in the opinion of the investigator, would not allow safe participation in the study."
12. Acute coronary syndrome (ACS), diagnosed ≤ 2 months prior to visit 1 (screening).
13. Stroke or TIA ≤ 3 months prior to visit 1 (screening).
D: Please see: https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV for full code and algorithm definitions.

Eligible cohort entry dates:

Market availability of saxagliptin in the U.S. started on July 31, 2009 For Marketscan and Medicare: July 31, 2009-Dec 31, 2016 (end of data availability).

For Optum: July 31, 2009-Sep 30, 2017 (end of data availability).

Inclusion Criteria:

* Diagnosed with T2DM based on the current American Diabetes Association guidelines Age ≥40 years Glycated hemoglobin level of ≥6.5% (based on the last measured and documented laboratory measurement in the previous 6 months)

High risk for a CV event defined as having either established CV disease and/or multiple risk factors:

* History of established cardiovascular disease

  * Ischemic heart disease, and/or
  * Peripheral vascular disease (eg, intermittent claudication), and/or
  * Ischemic stroke
* Multiple risk factors for vascular disease - At least 55 years of age (men) or 60 years of age (women), AND at least one of the following additional risk factors

  * Dyslipidemia (based on the last measured and documented laboratory measurement in the previous 6 months and defined as at least 1 of the following):

    * High level of low-density lipoprotein cholesterol (LDL-C), defined as N130 mg/dL (N 3.36 mmol/L) regardless of lipid-lowering therapy
    * Low level of high-density lipoprotein cholesterol (HDL-C), defined as b40 mg/dL (b1.04 mmol/L) for men or b50 mg/dL (b1.30 mmol/L) for women
  * Hypertension, as confirmed at the enrolment visit

    * BP N140/N90 mm Hg, or
    * BP N130/N80 mm Hg on BP-lowering agent
  * Currently smoking, as confirmed at the enrolment visit Women of childbearing potential must take precautions to avoid pregnancy throughout the study and for 4 weeks after intake of the last dose. Men participating in the study should also take precautions not to father a childwhile participating in the study and for 4 weeks after intake of the last dose.

Provision of informed consent before any study specific procedures

Exclusion Criteria:

Current or previous (within 6 months) treatment with an incretin-based therapy such as DPP-4 inhibitors and/or GLP-1 mimetics Acute vascular (cardiac or stroke) event \<2 months before randomization Initiation of chronic dialysis and/or renal transplant and/or a serum creatinine \>6.0 mg/dL Pregnant or breastfeeding History of human immunodeficiency virus Patients being treated for severe autoimmune diseases such as lupus Any patient currently receiving long-term (\>30 consecutive days) treatment with an oral steroid Patients with

* Body mass index \>50 kg/m2
* Last measured HbA1c ≥12%
* Sustained BP \>180/100 mm Hg
* LDL-C \>250 mg/dL (\>6.48 mmol/L) (based on the last measured and documented laboratory measurement in the previous 6 months) regardless of lipid-lowering therapy
* Triglycerides \>1,000 mg/dL (N11.3 mmol/L) (based on the last measured and documented laboratory measurement in the previous 6months)
* HDL-C b25 mg/dL (\<0.64 mmol/L) (based on the last measured and documented laboratory measurement in the previous 6 months)
* Known liver function tests \>3 times upper limit of normal (ULN) (based on the last measured and documented laboratory measurement in the previous 6 months) Involvement in the planning and/or conduct of the study (applies to both AstraZeneca and Bristol-- Myers Squibb or representative staff and/or staff at the study site) Previous randomization in the present study Participation in another clinical study with an investigational product and/or intervention within 30 days before visit 1 Individuals at risk for poor protocol or medication compliance

Answer: D