Please select the eligibility criteria that correspond to the clinical trial below.
Title: Large-Scale Randomized Clinical Trial Assessing Intensive Blood Pressure Control for Reduction of Major Cardiovascular Events in Patients With Diabetes Mellitus (OPTIMAL-DIABETES)
Brief Summary: High blood pressure (BP) is a major public health concern, especially in low and middle income countries. High BP is a highly prevalent condition, and it is usually associated with diabetes mellitus. Both high BP and diabetes are risk factors for major cardiovascular events including cardiovascular death, acute myocardial infarction, stroke, unstable angina and heart failure. In addition, high BP is also related to cognitive decline. The OPTIMAL-DIABETES trial consists of a two-arm, multicenter, randomized clinical trial designed to test whether a lower systolic blood pressure (SBP) target will reduce the occurrence of major cardiovascular events in diabetic patients compared to the standard SBP target.


Options:
A: Inclusion Criteria:

* Age 45 years or older
* Male and female patients are eligible. Female patients must be post-menopausal for one year, surgically sterile, or using effective contraceptive methods such as a double barrier method with spermicide, an intra-uterine device, or hormonal contraceptives. Post-menopausal women on a stable dose of hormone replacement therapy (HRT) for at least three (3) months prior to the screening visit are eligible for the study.
* Uncontrolled systolic hypertension on a maximum of two (2) antihypertensive medications at the time of screening.
* Echocardiographic ejection fraction ≥50% and evidence of diastolic dysfunction.
* Provide written informed consent to participate in the study prior to any screening or study procedures
* Have the ability to communicate well and comply with all study requirements

Exclusion Criteria:

* Severe hypertension defined as a MSSBP \>200 mmHg and/or MSDBP \>120 mmHg.
* History of a secondary cause of hypertension including but not limited to: coarctation of the aorta, hyperaldosteronism, unilateral or bilateral renal artery stenosis, Cushing's disease, pheochromocytoma, polycystic kidney disease, etc.
* Ejection fraction \<50 %
* History of stroke, transient ischemic attack, myocardial infarction, coronary artery bypass graft surgery, or unstable angina pectoris within 6 months of screening
* Presence of clinically significant ventricular or supraventricular arrhythmias (e.g. atrial fibrillation/flutter)
* History of congestive heart failure
* History of diabetes mellitus
* History of renal impairment with serum creatinine \>2.0 mg/dL at screening, history of dialysis, or history of nephritic syndrome
* Antihypertensive therapy with three (3) or more medications at the time of screening
* Active and/or treated malignancy of any organ system within twelve (12) months of enrollment, with the exception of localized basal cell carcinoma of the skin
* Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (\>5 mIU/ml)
* Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels \>40 mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy OR are using one or more of the following acceptable methods of contraception: barrier method with spermicidal agent, an intrauterine device, hormonal contraceptives, or total abstinence at the discretion of the investigator in cases where the age, career, lifestyle, or sexual orientation of the patient ensures compliance. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Reliable contraception should be maintained throughout the study
* Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of any drug including, but not limited to, any of the following: history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, bowel resection, gastric bypass, gastric stapling, or gastric banding, currently active, or active inflammatory bowel syndrome within 12 months prior to Visit 1, currently active gastritis, ulcers, or gastrointestinal/rectal bleeding, or urinary tract obstruction regarded as clinically meaningful by the investigator
* Pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury within 12 months prior to Visit 1
* Any serum AST or ALT elevation two (2) times the upper limit of normal

Other protocol-defined inclusion/exclusion criteria may apply
B: Inclusion Criteria:

* Systolic Blood Pressure (SBP) between 130 and 180 mm Hg:

  * 130 to 150 mm Hg (if on 0-4 medications)
  * 130 to 160 mm Hg (if on 0-3 medications)
  * 130 to 170 mm Hg (if on 0-2 medications)
  * 130 to 180 mm Hg (if on 0-1 medications)
* Type 2 diabetes
* To be considered as having a high cardiovascular risk, including AT LEAST ONE of the following factors:

  1. Established cardiovascular disease (CVD), including:

     * Coronary artery disease: previous myocardial infarction, previous acute coronary syndrome, previous percutaneous coronary intervention, previous coronary artery bypass graft surgery, or at least 50% stenosis in a main coronary artery associated with typical angina pectoris; or
     * Cerebrovascular disease: previous stroke (except those events caused by intracranial aneurysm or arteriovenous malformation) or previous transient ischemic attack (TIA), stable for at least 2 weeks preceding inclusion in the study; or
     * Carotid artery disease: previous carotid endarterectomy, previous percutaneous intervention with carotid stent implantation, or stenosis of at least 50% in a carotid shown by the Doppler ultrasonography, CT angiography or MR angiography; or
     * Peripheral artery disease: prior surgical or percutaneous revascularization of a peripheral artery, limb amputation due to vascular cause, abdominal aortic aneurysm ≥ 5 cm (with or without prior surgical or percutaneous repair), or stenosis of at least 50% in a peripheral artery associated to intermittent claudication.
  2. Subclinical CVD, including:

     * Coronary calcium score ≥ 300 Agatston units; or
     * Ankle-brachial index ≤ 0.90 in the last two years; or
     * Left ventricular hypertrophy on the electrocardiogram, echocardiogram or other cardiac imaging exam in the last two years.
  3. Chronic kidney disease (CKD):

     ▪ Definition of CKD: glomerular filtration rate (GFR) between 20 and 59 ml/min/1.73m2 calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).
  4. Additional cardiovascular risk factors, including:

     * Active smoking: Defined as regular use of cigarettes or other tobacco products, such as cigars and pipe, in the last six months;
     * Dyslipidemia: Defined as LDL cholesterol \> 70 mg/dL or non-HDL cholesterol \> 100 mg/dL in patients with previous CVD; or LDL cholesterol \> 100 mg/dL or non-HDL cholesterol \> 130 mg/dL in patients without previous CVD; or Triglycerides \> 200 mg/dL or HDL \< 40 mg/dL regardless of treatment; or use of statins or other lipid lowering medication; or
     * Age ≥ 75 years

Exclusion Criteria:

* Refusal to provide written informed consent
* Body mass index \> 45 kg/m2
* Known secondary cause of hypertension
* Severe renal dysfunction with GFR \< 20 mL/min/1.73m2 calculated by the CKD-EPI equation
* Angina at rest Class IV Canadian Cardiovascular Society (CCS)
* Acute coronary syndrome in the last six months
* Symptomatic heart failure Class IV New York Heart Association (NYHA) or ejection fraction \< 35% on Doppler echocardiography in the last six months
* Factors that at the research team´s judgment may limit adherence to the intervention and study protocol, including, but not limited to, the following examples:

  * Recent history of alcohol and illicit drug abuse
  * Psychiatric comorbidities (severe depression, schizophrenia, psychosis, etc.)
  * History of poor medication adherence and attendance to consultations
  * Any plans to move the city of residence in the next four years
  * Any plans to leave the city of residence for more than three months in the next few years
  * Living in the same residence of another patient previously included in this study
* Patients currently enrolled in another study for CVD prevention, including those evaluating pharmacological and non-pharmacological interventions
* Pregnancy or breastfeeding
C: Inclusion Criteria:

* coronary artery diseases which require coronary angiography or percutaneous coronary intervention
* primary hypertension (systolic blood pressure 140-180mmHg within one month)

Exclusion Criteria:

* severe hypertension
* secondary hypertension
* treated with more than three antihypertensive drugs
* left main trunk trunk coronary artery disease
* moderate heart failure
* severe valvular disease
* liver dysfunction renal dysfunction (Cr\>=2.0mg/dl) Pregnant or nursing women severe arrhythmia
D: Inclusion Criteria:

1. Male or female aged ≥ 19 years and \< 80 years
2. Diagnosis of mild-moderate AS or mild-moderate AR
3. Applicable to 2.0\~3.9 m/s of aortic jet velocity for mild-moderate AS or to 0.2\~0.6 cm of Vena contracta for mild-moderate AR
4. Diagnosis of hypertension (SBP \> 130 mmHg if being treated or SBP \> 140 mmHg if being untreated)
5. For females of childbearing potential; negative pregnancy test results during the screening period and prior to administration of the investigational product, and agreement on use of medically allowable contraceptive measures (condom, oral contraceptive pills, injectable or implantable contraceptives, intrauterine devices, birth control patches, etc.) during the study period
6. Voluntary written consent to taking part in the clinical study and willingness to comply with requirements of the study

Exclusion Criteria:

1. History of a cardiac valve replacement surgery (replacement surgery of mitral valve, aortic valve or tricuspid valve)
2. Accompanied by severe mitral regurgitation
3. Admitted to needing a surgery by the current treatment guidelines
4. Accompanied by symptoms such as angina pectoris, exertional dyspnea, syncope, etc.
5. \< 50% of left ventricular ejection fraction
6. History of hypersensitivity reaction to active ingredients of the investigational product (Amlodipine, Losartan and Chlorthalidone), dihydropyridine derivatives, thiazide drugs and other sulfonamide derivatives or their compositions
7. Pregnant or breastfeeding
8. Symptomatic orthostatic hypotension
9. Severe liver failure or renal failure (\< 30 mL/min of creatinine clearance)
10. Hereditary angioedema or history of angioedema at treatment with ACE inhibitors or angiotensin II receptor blockers
11. Primary hyperaldosteronism
12. Genetic problems such as galactose intolerance, Lapp Lapp lactase deficiency or glucose-galactose malabsorption
13. Anuria
14. Refractory hypokalemia
15. Hyponatremia or hypercalcemia
16. Symptomatic hyperuricemia (history of gout or uric acid lithiasis)
17. Untreated Addison's disease
18. Appropriately uncontrolled diabetes
19. Congenital or incurable hypertension
20. Diagnosis of severe cerebrovascular disorders (stroke, cerebral infarction, cerebral hemorrhage, etc.) within six months prior to the date of ICF obtainment
21. Wasting disease, autoimmune disease or connective tissue disease
22. Diagnosis of malignant tumor within five years prior to the date of ICF obtainment
23. Administration of another investigational product within four weeks prior to the date of ICF obtainment
24. For a patient who is taking anticoagulants and thrombolytic agents; considered difficult to keep a stable dosage/regimen by the investigator.
25. Considered unsuitable to be a subject by the investigator

Answer: B