Impact of Diabetes on Left Ventricular Remodeling (P3)

Phase 2/3 Study of Effect of AT1RB Versus ACE Inhibitor in Addition to XO Inhibitor on Progression of LV Remodeling and Dysfunction in Diabetic Patients With Acute MI.

The investigators hypothesize that in patients with diabetes and acute myocardial infarction (MI), Ang II type-1 receptor blockade (AT1RB) attenuates left ventricle (LV) remodeling to a greater extent than angiotensin converting enzyme (ACE) inhibitor therapy and that the addition of xanthine oxidase (XO) inhibitor, Allopurinol, results in further improvement in LV remodeling and function in the follow-up phase after MI.

Study Overview

• Status: Completed
• Conditions: Diabetes
• Intervention / Treatment: Drug: Ramipril; Drug: Candesartan cilexetil; Drug: Allopurinol

Detailed Description

Following myocardial infarction (MI), the incidence of heart failure and mortality rates are approximately two-fold higher in patients with diabetes compared to those without diabetes. This increased risk for heart failure and mortality appears to be refractory to currently available treatments such as angiotensin converting enzyme (ACE) inhibitors, despite the effectiveness of such treatments in reducing overall morbidity and mortality following MI. Hyperglycemia stimulates cardiomyocyte angiotensin II (Ang II) formation, which has been implicated in increased myocyte cell death in diabetes. Furthermore, in humans, chymase is the predominant pathway of Ang II formation and this pathway of Ang II production is not blocked by ACE inhibition. Therefore, in diabetes where Ang II levels may already be elevated due to hyperglycemia the increase in Ang II formation associated with left ventricular (LV) remodeling continued Ang II formation from chymase could be particularly detrimental.

In addition to enhanced Ang II production, hyperglycemia and diabetes also amplify the production of reactive oxygen species (ROS). ROS are associated with increased in LV remodeling and myocyte apoptosis. Furthermore, xanthine oxidase (XO), an important source of ROS in myocytes, is increased in a rat model of myocardial infarction and in diabetes. Thus, increased XO-mediated ROS production following MI may be especially damaging in diabetic patients where ROS production is already elevated. Interestingly, acute treatment with Allopurinol, an inhibitor of XO, improves cardiac function in heart failure and improves endothelial dysfunction in patients with type-2 diabetes.

To test our hypothesis the investigators will investigate the following aims in diabetic patients after acute MI:

Aim 1: Show that the progression of LV remodeling and dysfunction in diabetic patients will be attenuated to greater extent by AT1RB than by ACE inhibitor.

Aim 2: Show that the addition of XO inhibition results in further attenuation of LV remodeling than with AT1RB or ACE inhibitor alone.

Aim 3: Show that baseline and follow-up LV remodeling and dysfunction and inflammatory markers differ in diabetic and non-diabetic patients post-MI.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-2180
      • University of Alabama at Birmingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 21 years old or older

2. MI documented by increase in troponin > 0.78 ng/ml or CKMB ≥ 3% of total CK

   Patients who have Type-2 diabetes defined by any one of the following:

3. Confirmed (i.e., two or more readings) fasting blood glucose >126mg/dl; or
4. Random glucose ≥200mg/dl; or
5. 2 hour glucose ≥200mg/dl following 75g of glucose; or
6. Current treatment with diet or oral agents directed at the control of hyperglycemia either alone or in combination with insulin; or
7. Current treatment with insulin with no prior history of diabetic ketoacidosis.

Exclusion Criteria:

1. Type-1 diabetes.
2. Class III or IV heart failure.
3. Cardiomyopathy (including hypertrophic and amyloidosis).
4. Congenital or pericardial diseases.
5. Intolerance to either ACE inhibitor, AT1-RB or allopurinol.
6. Renal failure with creatinine > 2.5 mg/dl.
7. Renal artery stenosis.
8. Severe comorbidity such as liver disease or malignancy.
9. Pregnancy (negative pregnancy test and effective contraceptive methods are required prior to enrollment of females of childbearing potential (not post-menopausal or surgically sterilized).
10. Chronic steroid use.
11. Unable to understand or cooperate with protocol requirements.
12. Severe claustrophobia.
13. Presence of a pacemaker or non-removable hearing aid.
14. Presence of metal clips in the body.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ramipril; The starting dose of Ramipril will be 2.5 mg once daily and rapidly titrated upward to 5 mg once daily after 5 days if systolic blood pressure is greater than 100 mmHg. After one month the patient will return to clinic for blood pressure check and will be titrated up to 10 mg once daily.	Drug: Ramipril; The starting dose of Ramipril will be 2.5 mg once daily and rapidly titrated upward to 5 mg once daily after 5 days if systolic blood pressure is greater than 100 mmHg. After one month the patient will return to clinic for blood pressure check and will be titrated up to 10 mg once daily.; Other Names: Altace
Active Comparator: Candesartan cilexetil; The starting dose of Candesartan cilexetil will be 4 mg or 8 mg once daily and doubled every 2 weeks, if systolic blood pressure is greater than 100 mmHg, to a maximum dose of 32 mg once daily. After one month the patient will return to clinic for blood pressure check and will be titrated up to 32 mg once daily.	Drug: Candesartan cilexetil; The starting dose of Candesartan cilexetil will be 4 mg or 8 mg once daily and doubled every 2 weeks, if systolic blood pressure is greater than 100 mmHg, to a maximum dose of 32 mg once daily. After one month the patient will return to clinic for blood pressure check and will be titrated up to 32 mg once daily.; Other Names: Atacand
Active Comparator: Ramipril and Allopurinol; The starting dose of Ramipril will be 2.5 mg once daily and rapidly titrated upward to 5 mg once daily after 5 days if systolic blood pressure is greater than 100 mmHg. After one month the patient will return to clinic for blood pressure check and will be titrated up to 10 mg once daily. It is anticipated that the starting dose of each drug will be initiated in hospital and that the second dose will be implemented prior to discharge from the hospital. The starting dose of Allopurinol is 300 mg daily.	Drug: Ramipril; The starting dose of Ramipril will be 2.5 mg once daily and rapidly titrated upward to 5 mg once daily after 5 days if systolic blood pressure is greater than 100 mmHg. After one month the patient will return to clinic for blood pressure check and will be titrated up to 10 mg once daily.; Other Names: Altace; Drug: Allopurinol; The starting dose of Allopurinol is 300 mg daily.; Other Names: Altace
Active Comparator: Candesartan cilexetil and Allopurinol; The starting dose of Candesartan cilexetil will be 4 mg or 8 mg once daily and doubled every 2 weeks, if systolic blood pressure is greater than 100 mmHg, to a maximum dose of 32 mg once daily. After one month the patient will return to clinic for blood pressure check and will be titrated up to 32 mg once daily. The starting dose of Allopurinol is 300 mg daily.	Drug: Candesartan cilexetil; The starting dose of Candesartan cilexetil will be 4 mg or 8 mg once daily and doubled every 2 weeks, if systolic blood pressure is greater than 100 mmHg, to a maximum dose of 32 mg once daily. After one month the patient will return to clinic for blood pressure check and will be titrated up to 32 mg once daily.; Other Names: Atacand; Drug: Allopurinol; The starting dose of Allopurinol is 300 mg daily.; Other Names: Altace

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left Ventricular End Diastolic Volume Indexed to Body Surface Area (LVEDV/BSA)	LVEDV/BSA: As an indicator of heart size, the blood volume of the heart is related to the body size. The relation of heart blood volume to body size is more accurate in determining pathology because larger people require a larger heart blood volume. The values that are too high or too low indicate a diseased myocardium. This is a measure of LV Diastolic Function. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals.	5 visits per Participant over 2 years (about every 6 months)
Left Ventricular End-Diastolic Radius to Wall Thickness (LVED Radius/Wall Thickness)	LVED Radius/Wall thickness As an indicator of heart muscle mass and heart volume chamber diameter, the end-diastolic radius indexed to end diastolic wall thickness determines whether there is an adequate amount of heart muscle to pump the heart blood volume obtained from a two-dimensional analysis. The values that are too high or too low indicate a diseased myocardium. This is a measure of LV Geometry. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes.	5 visits per Participant over 2 years (about every 6 months)
Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume (LVED Mass/LVEDV)	LVED Mass/LVEDV: As an indicator of heart muscle mass and heart blood volume, the mass indexed to end diastolic volume determines whether there is an adequate amount of heart muscle to pump the heart blood volume obtained from a three-dimensional analysis. The values that are too high or too low indicate a diseased myocardium. This is a measure of LV Geometry. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes.	5 visits per Participant over 2 years (about every 6 months)
Left Ventricular Ejection Fraction (LVEF)	LVEF is a calculation of heart pump function determined from the volume after complete filling minus the volume after complete contraction divided by the volume after complete filling. A value of 55% or greater is normal. This is a measure of LV Systolic Function. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes	5 visits per Participant over 2 years (about every 6 months)
Left Ventricular End Systolic Volume Indexed to Body Surface Area (LVESV/BSA)	LVESV/BSA: The end systolic volume is the blood volume of the heart at the end of contraction and is an index of the pump function of the heart. This relation to body size is more accurate in determining pathology because larger people require a larger heart blood volume. The values that are too high or too low indicate a diseased myocardium. This is a measure of LV Systolic Function. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals.	5 visits per Participant over 2 years (about every 6 months)
LV End Systolic Maximum Shortening (LVES Max Shortening)	By identifying three points in three different planes in the heart muscle, the maximum shortening is the average of the difference between the distance between these three points at the end of filling of the heart and the end of contraction divided by the length at the end of filling times 100. The maximum shortening is a three dimensional analysis. The higher values indicate a healthy heart. This is a measure of LV Systolic Function. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes.	5 visits per Participant over 2 years (about every 6 months)
Peak Early Filling Rate Normalized to EDV	The Peak Early Filling Rate Normalized to EDV is calculated from the slope of the volume during the early filling of the heart with respect to time. The higher values indicate a very healthy heart muscle and lower values are indicative of a very stiff muscle. This is a measure of LV Diastolic Function. Since some visits did not occur at the scheduled 6 month intervals, the results have been divided into 3-month visit intervals for reporting purposes.	5 visits per Participant over 2 years (about every 6 months)

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); AstraZeneca
• Investigators: Principal Investigator: Louis J. Dell'Italia, M.D., University of Alabama at Birmingham

Publications and helpful links

General Publications

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• Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S; CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003 Sep 6;362(9386):759-66. doi: 10.1016/s0140-6736(03)14282-1. Erratum In: Lancet. 2009 Nov 21-2009 Nov 27;(9703):1744.
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• Pimentel DR, Amin JK, Xiao L, Miller T, Viereck J, Oliver-Krasinski J, Baliga R, Wang J, Siwik DA, Singh K, Pagano P, Colucci WS, Sawyer DB. Reactive oxygen species mediate amplitude-dependent hypertrophic and apoptotic responses to mechanical stretch in cardiac myocytes. Circ Res. 2001 Aug 31;89(5):453-60. doi: 10.1161/hh1701.096615.
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• Desco MC, Asensi M, Marquez R, Martinez-Valls J, Vento M, Pallardo FV, Sastre J, Vina J. Xanthine oxidase is involved in free radical production in type 1 diabetes: protection by allopurinol. Diabetes. 2002 Apr;51(4):1118-24. doi: 10.2337/diabetes.51.4.1118.
• Cappola TP, Kass DA, Nelson GS, Berger RD, Rosas GO, Kobeissi ZA, Marban E, Hare JM. Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation. 2001 Nov 13;104(20):2407-11. doi: 10.1161/hc4501.098928.
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Study record dates

Study Major Dates

• Study Start: July 1, 2005
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): November 1, 2010

Study Registration Dates

• First Submitted: January 15, 2010
• First Submitted That Met QC Criteria: January 19, 2010
• First Posted (Estimate): January 20, 2010

Study Record Updates

• Last Update Posted (Estimate): December 17, 2012
• Last Update Submitted That Met QC Criteria: November 16, 2012
• Last Verified: November 1, 2012

More Information

Terms related to this study

• Keywords: Diabetes; Cardiac MRI; Diastolic dysfunction; Acute MI; Ang II type-1 receptor blockade (AT1RB); LV remodeling; ACE inhibitor therapy; XO inhibitor, Allopurinol; Systolic dysfunction; LV dimensions
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protease Inhibitors; Protective Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Antioxidants; Free Radical Scavengers; Gout Suppressants; Angiotensin-Converting Enzyme Inhibitors; Allopurinol; Candesartan; Ramipril; Candesartan cilexetil
• Other Study ID Numbers: F040105007