Optimal Blood Pressure for the prevenTIon of Major vAscuLar Events in Patients With DIABETES Mellitus (OPTIMAL-DIABETES)

Study Overview
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Brief Summary
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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.

Official Title
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Large-Scale Randomized Clinical Trial Assessing Intensive Blood Pressure Control for Reduction of Major Cardiovascular Events in Patients With Diabetes Mellitus (OPTIMAL-DIABETES)

Conditions
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Diabetes Mellitus, High Blood Pressure, Cardiovascular Diseases, Cognitive Impairment

Intervention / Treatment
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* Drug: Intensive Control of Systolic Blood Pressure (SBP)
* Drug: Standard control of Systolic Blood Pressure (SBP)


Participation Criteria
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Eligibility Criteria
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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: 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. 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. 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). 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

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intensive Control of Systolic Blood Pressure (SBP)<br>Participants randomized into the Intensive Blood Pressure arm will have a goal of SBP <120 mm Hg. | Drug: Intensive Control of Systolic Blood Pressure (SBP)<br>* Participants in the Intensive arm have a goal of SBP <120 mm Hg. The use of angiotensin converting enzyme (ACE) inhibitors/angiotension receptor blockers (ARB), thiazide-type diuretics, and calcium channel blockers (CCB) will be encouraged, preferably fixed-dose combinations of indapamide + perindopril arginine, perindopril arginine + amlodipine or indapamide + perindopril arginine + amlodipine<br>* Other names: Intensive BP control targeting SBP <120 mm Hg;|
| Active Comparator: Standard Control of Systolic Blood Pressure (SBP)<br>Participants randomized into the Standard arm will have a goal of SBP <140 mm Hg. | Drug: Standard control of Systolic Blood Pressure (SBP)<br>* The same medications used in the Intensive BP arm will be used for the Standard BP arm.<br>* Other names: Standard control of SBP targeting SBP < 140 mm Hg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, hospitalization for unstable angina or hospitalization for heart failure | Time to first event of cardiovascular death, non-fatal myocardial infarction (MI), non-fatal stroke, hospitalization for unstable angina or hospitalization for heart failure | From randomization; for approximately a median of 3.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to cardiovascular death, non-fatal myocardial infarction (MI) or non-fatal stroke | Time to first event of cardiovascular death, non-fatal myocardial infarction (MI) or non-fatal stroke | From randomization; for approximately a median of 3.5 years | 
| Time to total death, non-fatal myocardial infarction (MI), non-fatal stroke, hospitalization for unstable angina or hospitalization for heart failure | Time to first event of total death, non-fatal myocardial infarction (MI), non-fatal stroke, hospitalization for unstable angina or hospitalization for heart failure | From randomization; for approximately a median of 3.5 years | 
| Time to Death | Time to all cause death | From randomization; for approximately a median of 3.5 years | 
| Time to Cardiovascular Death | Time to death from cardiovascular causes | From randomization; for approximately a median of 3.5 years | 
| Time to Renal Death | Time to death from renal causes | From randomization; for approximately a median of 3.5 years | 
| Time to Myocardial Infarction (MI) | Time to myocardial infarction (MI) | From randomization; for approximately a median of 3.5 years | 
| Time to Stroke | Time to stroke | From randomization; for approximately a median of 3.5 years | 
| Time to Ischemic Stroke | Time to ischemic stroke | From randomization; for approximately a median of 3.5 years | 
| Time to Hemorrhagic Stroke | Time to hemorrhagic stroke | From randomization; for approximately a median of 3.5 years | 
| Time to Undetermined type of Stroke | Time to Undetermined type of Stroke | From randomization; for approximately a median of 3.5 years | 
| Time to Transient Ischemic Attack (TIA) | Time to transient ischemic attack (TIA) | From randomization; for approximately a median of 3.5 years | 
| Time to Hospitalization for Unstable Angina | Time to Hospitalization for unstable angina | From randomization; for approximately a median of 3.5 years | 
| Time to Hospitalization for Heart Failure | Time to hospitalization for heart failure | From randomization; for approximately a median of 3.5 years | 
| Time to Renal Outcome | Time to Renal Outcome, defined as a 50% reduction in the glomerular filtration rate (GRF) associated with a final GFR of < 60 mL/min/1.73m2 in patients without chronic kidney disease (GFR 60-90 mL/min/1.73m2) at baseline. In those patients with chronic kidney disease (<60 mL/min/1.73m2) at baseline, the renal outcome will be defined as a 50% reduction in GFR or progression of renal disease to stage IV, requiring dialysis or kidney transplantation. | From randomization; for approximately a median of 3.5 years | 
| Time to Mild Cognitive Impairment | Time to Mild Cognitive Impairment | From randomization; for approximately a median of 3.5 years | 
| Time to Mild Cognitive Impairment or All-Cause Probable Dementia | Time to mild cognitive impairment or all-cause probable dementia | From randomization; for approximately a median of 3.5 years | 
| Time to All-Cause Probable Dementia | Time to all-cause probable dementia | From randomization; for approximately a median of 3.5 years |