Please select the eligibility criteria that correspond to the clinical trial below.
Title: Replication of the LEADER 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 liraglutide in the U.S. started on January 20, 2010. For Marketscan and Medicare: January 20, 2010-Dec 31, 2016 (end of data availability).

For Optum: January 20, 2010-Sep 30, 2017 (end of data availability).

Inclusion Criteria:

* Men or women with type 2 diabetes
* Either of the following:

  * Prior cardiovascular disease cohort: Age ≥ 50 years at screening, AND at least one of the following:

    * Prior MI
    * Prior stroke or TIA
    * Prior coronary, carotid or peripheral arterial revascularization
  * \>50% stenosis of coronary, carotid, or lower extremity arteries coded by Peripheral vascular disease
  * Chronic heart failure NYHA class II-III
  * CKD stage 3-6 as Chronic renal failure:
* No Prior cardiovascular disease group: Age ≥ 60 years at screening, AND at least one of the following:

  * Microalbuminuria or proteinuria
  * Hypertension and left ventricular hypertrophy by ECG or imaging
  * Ankle-brachial index \<0.9

Exclusion Criteria:

* Type 1 diabetes
* Use of a GLP-1 receptor agonist (exenatide, liraglutide or other) or pramlintide or any (dipeptidyl peptidase 4 (DPP-4) inhibitor within the 3 months prior to screening
* Use of long-term insulin in 90 days prior
* Diabetic ketoacidosis in 3 months prior to index date as Acute decompensation of glycaemic control requiring immediate intensification of treatment to prevent acute complications of diabetes (e.g., diabetic ketoacidosis) in the previous 3 months
* Inpatient (hospitalization) code for MI, stroke, revascularization, PTCA, CABG IN PRIOR 14 DAYS as An acute coronary or cerebrovascular event in the previous 14 days
* inpatient Heart failure (CHF) as Chronic heart failure NYHA class IV
* ESRD codes as Current continuous renal replacement therapy
* Liver disease as "End stage liver disease, defined as the presence of acute or chronic liver disease and recent history of one or more of the following: ascites, encephalopathy, variceal bleeding, bilirubin ≥ 2.0 mg/dL, albumin level ≤ 3.5 g/dL, prothrombin time ≥ 4 seconds prolonged, international normalised ratio (INR) ≥1.7 or prior liver transplant"
* Organ transplant codes as A prior solid organ transplant or awaiting solid organ transplant
* History of malignant neoplasm in previous 5 years 140.xx-208.xx (except 173.xx, non-melanoma skin cancer)
* Family or personal history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma (FMTC)
* Personal history of non-familial medullary thyroid carcinoma
* Drug abuse or dependence as Known use of non prescribed narcotics or illicit drugs
* Encounter for contraceptive management, Oral contraceptives, and pregnancy as "Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods (adequate contraceptive measures as required by local law or practice)"
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 empagliflozin in the U.S. started on August 1, 2014.

* For Marketscan and Medicare: Aug 1, 2014-Dec 31, 2017 (end of data availability).
* For Optum: Aug 1, 2014-Mar 31, 2019 (end of data availability).

Inclusion Criteria:

All of the following criteria needed to be met:

* Subjects with T2DM on a diet and exercise regimen who are drug-naïve (no anti-diabetes therapy for ≥12 weeks prior to randomization) or treated with any anti-diabetes therapy (except pioglitazone in Japan)

  * Drug-naive patients were required to have HbA1c ≥7.0% (≥53 mmol/mol) and ≤9.0% (≤75 mmol/mol) at screening
  * Pre-treated patients were required to have HbA1c ≥7.0% (≥53 mmol/mol) and ≤10.0 (≤86 mmol/mol) at screening

    * Background anti-diabetes therapy had to be unchanged for ≥12 weeks prior to randomization
    * If background anti-diabetes therapy included insulin, insulin dose had to be unchanged by \>10% from the dose at randomization in the previous 12 weeks
* Age ≥18 years (≥20 years in Japan and ≤65 years in India)
* Body mass index ≤45 kg/m2 at screening
* High risk of a cardiovascular event defined as ≥1 of the following:

  * Confirmed history of myocardial infarction (\>2 months prior to informed consent)
  * Evidence of multivessel coronary artery disease (CAD), in ≥2 major coronary arteries or in the left main coronary artery, irrespective of revascularization status, i.e. one of the following:

    * Presence of a significant stenosis (imaging evidence of ≥50% narrowing of the luminal diameter measured during a coronary angiography or a multi-sliced computed tomography \[CT\] angiography)
    * Revascularization (percutaneous transluminal coronary angioplasty \[PTCA\] with or without stent, or coronary artery bypass grafting \[CAGB\]) ≥2 months prior to consent
    * Combination of revascularization in one major coronary artery ≥2 months prior to consent (PCTA with or without stent, or CABG), and the presence of significant stenosis in another major coronary artery (imaging evidence of ≥50% narrowing of the luminal diameter measured during a coronary angiography or a multi-sliced CT angiography)
  * Evidence of a single vessel CAD with the presence of significant stenosis i.e. imaging evidence of ≥50% narrowing of the luminal diameter of one major coronary artery in patients not subsequently successfully revascularized (measured during a coronary angiography or a multi-sliced CT angiography) and one or both of the following:

    -- A positive non-invasive stress test, confirmed by one of the following:
    * Positive exercise tolerance test in subjects without a complete left bundle branch block, Wolff-Parkinson-White syndrome, or paced ventricular rhythm
    * Positive stress echocardiography showing regional systolic wall motion abnormalities
    * Positive scintigraphic test showing stress-induced ischemia, i.e. development of transient perfusion defects during myocardial perfusion imaging
  * Patient discharged from hospital with a documented diagnosis of unstable angina within 12 months of consent
  * Last episode of unstable angina \>2 months prior informed consent with confirmed evidence of single- or multi-vessel CAD as defined above
  * History of ischemic or haemorrhagic stroke (\>2 months prior to informed consent)
  * Presence of peripheral artery disease (symptomatic or asymptomatic ) documented by one of the following:

    * Previous limb angioplasty, stenting, or bypass surgery
    * Previous limb or foot amputation due to circulatory insufficiency; or angiographic evidence of significant (\>50%) peripheral artery stenosis in at least one limb
    * Evidence from a non-invasive measurement of significant (\>50% or as reported as hemodynamically significant) peripheral artery stenosis in at least one limb
    * Ankle brachial index of \<0.9 in at least one limb
  * Signed and dated written informed consent prior to screening in accordance with Good Clinical Practice and local legislation

Exclusion Criteria:

* Uncontrolled hyperglycemia with glucose \>240 mg/dL (\>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day)
* Indication of liver disease, defined by serum levels of alanine amininotransferase, aspartate aminotransferase, or alkaline phosphatase above 3 x upper limit of normal (ULN) during screening or run-in phase
* Planned cardiac surgery or angioplasty within 3 months
* Estimated glomerular filtration rate \<30 ml/min/1.73m2 (according to the Modification of Diet in Renal Disease equation) at screening or during run-in phase
* Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption
* Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells e.g. malaria, babesiosis, hemolytic anemia)
* Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years
* Contraindications to background therapy according to the local label
* Treatment with anti-obesity drugs 3 months prior to informed consent or any other treatment at time of screening leading to unstable body weight (e.g. surgery, aggressive diet regimen, etc.)
* Treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent
* Any uncontrolled endocrine disorder except T2DM
* Pre-menopausal women (last menstruation ≤1 year prior to informed consent) who were nursing, pregnant, or of child-bearing potential and were not practicing an acceptable method of birth control, or did not plan to continue using this method throughout the study, or did not agree to submit to periodic pregnancy testing during the trial

  - Acceptable methods of birth control include tubal ligation, transdermal patch, intrauterine devices/systems, oral, implantable or injectable contraceptives, sexual abstinence, double barrier method, vasectomy of partner
* Alcohol or drug abuse within 3 months of informed consent that would interfere with trial participation or any ongoing condition leading to decreased compliance with study procedures or study drug intake
* Intake of an investigational drug in another trial within 30 days prior to intake of study medication in this trial or participating in another trial involving an investigational drug and/or follow-up
* Any clinical condition that would jeopardize patient safety while participating in this clinical trial (in Canada, this included current genito-urinal infection or genito-urinal infection within 2 weeks prior to informed consent)
* Acute coronary syndrome, stroke, or transient ischemic attack within 2 months prior to informed consent

Answer: C