Allopurinol in Diabetes Mellitus and Multivessel Coronary Artery Disease

Sponsor

Tel-Aviv Sourasky Medical Center (Other)

Overall Status

Unknown status

CT.gov ID

NCT03700645

Collaborator

(none)

100

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Atherosclerosis is a progressive disease of the arterial wall, arising from the combination of endothelial dysfunction and inflammation. This link is exacerbated in diabetic patients.

Uric acid is known to generate oxidative stress and it's elevated levels has been shown to be associated with cardiac hypertrophy, inflammation, myocardial fibrosis and diastolic dysfunction. Allopurinol inhibits xanthine oxidase, an enzyme that regulates uric acid production. In observational studies it has been shown to reduce ischemia, inflammation and improve coronary flow. The aim of this study is to see whether treatment with Allopurinol in patients diagnosed with multivessel disease and undergoing treatment with either percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) , will reduce markers of inflammation and improve quality of life and major adverse cardiovascular effects (MACE).

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus Ischemic Heart Disease Multi Vessel Coronary Artery Disease	Drug: Allopurinol	Phase 4

Detailed Description

This is a pilot study, PROBE design (prospective randomized open label blinded endpoints study), that will include 100 patients.

Patients will be recruited during their hospitalization in the cardiology department of Ichilov- Tel-Aviv Sourasky Medical Center.

It will include patients with known or newly diagnosed diabetes mellitus, hospitalized with diagnosis of acute coronary syndrome and multi-vessel coronary artery disease (CAD) that will be demonstrated by cardiac catheterization that the patients will undergo during their hospitalization in concordance with their diagnosis and practice guidelines.

The decision about intervention with either PCI or CABG will be accepted by a heart team after the initial demonstration of multi-vessel disease.

Study recruitment will take place either in the first 24 hours after PCI or before CABG.

All patients will sign an informed consent and randomized before any intervention is done.

After enrollment, patients will undergo the following baseline procedure (no later than 24 hours from PCI):

Physical examination and medical interview
Quality of life questionnaires (Seattle angina , EQ-5D)
Echocardiogram
Blood tests- see below for description
Endothelial function using the EndoPat®

Blood sampling will be done via IV cannula that will be placed in an antecubital vein. Blood sample analyses will be performed using reagents, calibrators and control materials in the local labs of each participating site. A 40 ml blood sample will be obtained for the following blood tests

Full chemistry including: lipid levels, thyroid function, liver enzymes function, Troponin, BNP, HbA1c, uric acid, creatinine and glucose levels.
Blood count
Inflammatory biomarker (hs-CRP, fibrinogen, IL-6, IL-1B, IL-18, MMP, IL-10, IL-35, TNFa, AchE , PAI-1, MPO, cholinergic status.)
Endothelial function markers: Endothelin-1, I-CAM, V-CAM, superoxide dismutase ADMA, and oxidized LDL
Oxidative Stress- superoxide dismutase ADMA, and oxidized LDL, Plasma protein carbonyls.
Urine samples- microalbuminuria, albumin/creatinine. Uric acid.

Endothelial function will be assessed using EndoPAT 2000 device (Itamar Medical Inc., Caesarea, Israel) that is a device that measures endothelial function using a sensor placed on the fingers. This device has been validated and used previously to assess peripheral arterial tone in other populations. EndoPAT bio-sensors are placed on the index fingers of both arms. EndoPAT quantifies the endothelium-mediated changes in vascular tone, elicited by a 5-minute occlusion of the brachial artery (using a standard blood pressure cuff). When the cuff is released, the surge of blood flow causes an endothelium-dependent Flow Mediated Dilatation (FMD). The dilatation, manifested as reactive hyperemia, is captured by EndoPAT as an increase in the PAT Signal amplitude. A post-occlusion to pre-occlusion ratio is calculated by the EndoPAT software, providing the EndoPAT index. In addition, the EndoPAT system will measure heart rate variability.

After randomization and assessment as described above, the patients will receive treatment according to the study arm they were assigned to which will include either standard medical therapy alone, or standard medical therapy and allopurinol.

Allopurinol will be given initially at 100 mg once daily dose, with dose escalation by 100 mg every 2 weeks till final dose of 300 mg daily will be reached.

After discharge, patients will be assessed several times:

One month after in cardiology clinic. Assessment will include all the tests as in the pre study exam (see above). also, patients will be monitored for the possible side effects of allopurinol treatment.
Three months- in cardiology clinic. Assessment will include all the tests as in the pre study exam (see above).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Allopurinol in the Treatment of Patients With Diabetes Mellitus and Multivessel Coronary Artery Disease Treated by Either PCI or CABG: Pilot Study

Anticipated Study Start Date :

Dec 1, 2018

Anticipated Primary Completion Date :

Dec 31, 2019

Anticipated Study Completion Date :

Jan 31, 2020

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: PCI and standard medical treatment Patients diagnosed with multi vessel disease that after Heart team discussion underwent intervention by PCI and receive standard medical treatment according to practice guidelines.
Active Comparator: PCI, standard treatment and Allopurinol Patients diagnosed with multi vessel disease that after Heart team discussion underwent intervention by PCI and in addition to standard medical treatment, receive treatment with allopurinol.	Drug: Allopurinol Allopurinol Other Names: Alloril
No Intervention: CABG and standard medical treatment Patients diagnosed with multi vessel disease that after Heart team discussion underwent intervention by CABG and receive standard medical treatment according to practice guidelines.
Active Comparator: CABG standard treatment and Allopurinol Patients diagnosed with multi vessel disease that after Heart team discussion underwent intervention by CABG and in addition to standard medical treatment, receive treatment with allopurinol.	Drug: Allopurinol Allopurinol Other Names: Alloril

Outcome Measures

Primary Outcome Measures

hs-CRP [3 months.]
Change in inflammatory biomarkers

Secondary Outcome Measures

hs-CRP [one month]
Change in inflammatory biomarkers
Endothelial function markers [3 month]
Endothelin-1, I-CAM, V-CAM, superoxide dismutase ADMA, and oxidized LDL, Change of RH-PAT
Heart rate variability [3 month]
Heart rate variability
functional status and quality of life: the Seattle angina questionnaire [3 month]
Quality of life evaluation- evaluates functional limitation in different activities due to chest pain and angina
Uric acid levels [one month and 3 month]
Uric acid levels
functional status, quality of life: EuroQol EQ-5D questionnaire [3 month]
evaluation of degree of limitation in different daily activities
Reduction of peri-procedural myocardial infarction [72 hours]
Reduction of peri-procedural myocardial infarction
MACE [3 month]
major adverse cardiac events
Diastolic function [3 month]
Diastolic function per echocardiogram- E/A
Diastolic function [3 month]
Diastolic function per echocardiogram-E/E' med
Diastolic function [3 month]
Diastolic function per echocardiogram- E/E' lat
Diastolic function [3 month]
Diastolic function per echocardiogram- DT time

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Acute Coronary Syndrome with positive troponin
Patients with known or newly diagnosed diabetes mellitus with HbA1c above 7% and below 10%
Patients above the age of 40
Stable Hemodynamic state (At least 12 hours from presentation with acute coronary syndrome)
Uric Acid > 6mg/dl or 355 micromol/l (males) and >5mg/dl or 297 Micromol/l (females)

Exclusion Criteria:

HbA1c below 7% or above 10%
Severe valvular insufficiency/Stenosis
Major surgery within 30 days
Any medical condition that would impair participation (e.g. progressive neurological disorders, mental illness)
Known intolerance/ current use of allopurinol/colchicine
Chronic inflammatory diseases: e.g. Lupus, rheumatoid arthritis, etc.
Current treatment with steroids, NSAID, chemotherapy or biologic medications
Extra-cardiac illness that is expected to limit survival to less than 2 years.
Past Cancer within the past 5 years (excluding BCC and SCC).