Impact of Diabetes on Left Ventricular Remodeling (P3)

This study has been completed.
Sponsor:
Collaborators:
AstraZeneca
Information provided by (Responsible Party):
Dr. Louis J. Dell'Italia, University of Alabama at Birmingham
ClinicalTrials.gov Identifier:
NCT01052272
First received: January 15, 2010
Last updated: November 16, 2012
Last verified: November 2012
  Purpose

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.


Condition Intervention Phase
Diabetes
Drug: Ramipril
Drug: Candesartan cilexetil
Drug: Allopurinol
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:
  • Left Ventricular End Diastolic Volume Indexed to Body Surface Area (LVEDV/BSA) [ Time Frame: 5 visits per Participant over 2 years (about every 6 months) ] [ Designated as safety issue: Yes ]
    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.

  • Left Ventricular End-Diastolic Radius to Wall Thickness (LVED Radius/Wall Thickness) [ Time Frame: 5 visits per Participant over 2 years (about every 6 months) ] [ Designated as safety issue: Yes ]
    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.

  • Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume (LVED Mass/LVEDV) [ Time Frame: 5 visits per Participant over 2 years (about every 6 months) ] [ Designated as safety issue: Yes ]
    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.

  • Left Ventricular Ejection Fraction (LVEF) [ Time Frame: 5 visits per Participant over 2 years (about every 6 months) ] [ Designated as safety issue: Yes ]
    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

  • Left Ventricular End Systolic Volume Indexed to Body Surface Area (LVESV/BSA) [ Time Frame: 5 visits per Participant over 2 years (about every 6 months) ] [ Designated as safety issue: Yes ]
    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.

  • LV End Systolic Maximum Shortening (LVES Max Shortening) [ Time Frame: 5 visits per Participant over 2 years (about every 6 months) ] [ Designated as safety issue: Yes ]
    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.

  • Peak Early Filling Rate Normalized to EDV [ Time Frame: 5 visits per Participant over 2 years (about every 6 months) ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 72
Study Start Date: July 2005
Study Completion Date: November 2010
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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 Name: Altace
Drug: Allopurinol
The starting dose of Allopurinol is 300 mg daily.
Other Name: 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 Name: Atacand
Drug: Allopurinol
The starting dose of Allopurinol is 300 mg daily.
Other Name: Altace

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.

  Eligibility

Ages Eligible for Study:   21 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01052272

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294-2180
Sponsors and Collaborators
University of Alabama at Birmingham
AstraZeneca
Investigators
Principal Investigator: Louis J. Dell'Italia, M.D. University of Alabama at Birmingham
  More Information

Publications:
2. Mukamal KJ, Nesto RW, Cohen MC, Muller JE, Maclure M, Sherwood JB and Mittleman MA. Impact of diabetes on long-term survival after acute myocardial infarction: comparability of risk with prior myocardial infarction. Diabetes Care 24: 1422-1427, 2001.
3. Melchior T, Kober L, Madsen CR, Seibaek M, Jensen GV, Hildebrandt P and Torp-Pedersen C. Accelerating impact of diabetes mellitus on mortality in the years following an acute myocardial infarction. TRACE Study Group. Trandolapril Cardiac Evaluation. Eur Heart J 20: 973-978, 1999.
6. Fiordaliso F, Leri A, Cesselli D, Limana F, Safai B, Nadal-Ginard B, Anversa P and Kajstura J. Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. Diabetes 50: 2363-75, 2001.
8. Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. Angiotensin II-forming pathways in normal and failing human hearts. Circ Res 66:883-890, 1990.
10. Giugliano D, Ceriello A and Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care 19:257-267, 1996.
13. de Jong JW, Schoemaker RG, de Jonge R, Bernocchi P, Keijzer E, Harrison R, Sharma HS and Ceconi C. Enhanced expression and activity of xanthine oxidoreductase in the failing heart. J Mol Cell Cardiol 32:2083-2099, 2000.
15. Desco MC, Asensi M, Marquez R, Martinez-Valls J, Vento M, Pallardo FV, Sastre J and Vina J. Xanthine oxidase is involved in free radical production in type 1 diabetes: protection by allopurinol. Diabetes 51: 1118-24, 2002.
16. Cappola TP, Kass DA, Nelson GS, Berger RD, Rosas GO, Kobeissi ZA, Marban E and Hare JM. Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation 104: 2407-11, 2001.
17. Saavedra WF, Paolocci N, St John ME, Skaf MW, Stewart GC, Xie JS, Harrison RW, Zeichner J, Mudrick D, Marban E, Kass DA and Hare JM. Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart. Circ Res 90: 297-304, 2002.
18. Butler R, Morris AD, Belch JJ, Hill A and Struthers AD. Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension 35:746-51, 2000.
19. American Diabetes Association: Clinical Practice Recommendations. Diabetes Care 26: (Suppl 1) 2003.
20. Diez J, Querejeta R, Lopez B, Gonzalez A, Larman M, Martinez Ubago JL. Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 105:2512-247, 2002.
21. Querejeta R, Varo N, Lopez B, Larman M, Artinano E, Etayo JC, Martinez Ubago JL, Gutierrez-Stampa M, Emparanza JI, Gil MJ, Monreal I, Mindan JP, Diez J. Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease. Circulation 101:1729-35, 2000.
23. Cracowski JL, Tremel F, Marpeau C, et al. Increased formation of F2-isoprostanes in patients with severe heart failure. Heart 84:439-440, 2000.
24. Mallat Z, Philip I, Lebret M, et al. Elevated levels of 8-iso-prostaglandin F2 in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure. Circulation 97:1536-1539, 1998.
27. Rouleau JL, Pitt B, Dhalla NS, Dhalla KS, Swedberg K, Hansen MS, Stanton E, Lapointe N, Packer M. for the Canadian Prospective RandOmized Flosequlanan Longevity Evaluation (PROFILE) Investigators. Prognostic importance of the oxidized product of catecholamines, adrenolutin, in patients with heart failure. Am Heart J 145:926-932, 2003.
30. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 342:145-153, 2000.
34. Solomon SD, Wang D, Finn P, Skali H, Zornoff L, McMurray JJ, Swedberg K, Yusuf S, Granger CB, Michelson EL, Pocock S, Pfeffer MA. Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Circulation 110:2180-2183, 2004.
35. Wachtell K, Palmieri V, Olsen MH et al. Change in Systolic Left Ventricular Performance After 3 Years of Antihypertensive Treatment: The Losartan Intervention for Endpoint (LIFE) Study. Circulation 106:227-232, 2002.
37. Chandra NC, Ziegelstein RC, Rogers WJ, Tiefenbrunn AJ, Gore JM, French WJ and Rubison M. Observations of the treatment of women in the United States with myocardial infarction: a report from the National Registry of Myocardial Infarction-I. Arch Intern Med 158: 981-8, 1998.
38. Taylor HA, Jr., Canto JG, Sanderson B, Rogers WJ and Hilbe J. Management and outcomes for black patients with acute myocardial infarction in the reperfusion era. National Registry of Myocardial Infarction 2 Investigators. Am J Cardiol 82: 1019-23, 1998.
40. Rogers WJ, Canto JG, Lambrew CT, Tiefenbrunn AJ, Kinkaid B, Shoultz DA, Frederick PD and Every N. Temporal trends in the treatment of over 1.5 million patients with myocardial infarction in the US from 1990 through 1999: the National Registry of Myocardial Infarction 1, 2 and 3. J Am Coll Cardiol 36: 2056-63, 2000.
41. Rogers WJ, Canto JG, Barron HV, Boscarino JA, Shoultz DA and Every NR. Treatment and outcome of myocardial infarction in hospitals with and without invasive capability. Investigators in the National Registry of Myocardial Infarction. J Am Coll Cardiol 35: 371-9, 2000.

Responsible Party: Dr. Louis J. Dell'Italia, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT01052272     History of Changes
Other Study ID Numbers: F040105007
Study First Received: January 15, 2010
Results First Received: March 20, 2012
Last Updated: November 16, 2012
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by University of Alabama at Birmingham:
Diabetes
Acute MI
Ang II type-1 receptor blockade (AT1RB)
LV remodeling
ACE inhibitor therapy
XO inhibitor, Allopurinol
Systolic dysfunction
Diastolic dysfunction
LV dimensions
Cardiac MRI

Additional relevant MeSH terms:
Diabetes Mellitus
Ventricular Remodeling
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Pathological Conditions, Anatomical
Allopurinol
Ramipril
Angiotensin-Converting Enzyme Inhibitors
Candesartan cilexetil
Candesartan
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Gout Suppressants
Antirheumatic Agents
Therapeutic Uses
Free Radical Scavengers
Antioxidants
Antimetabolites
Protective Agents
Physiological Effects of Drugs
Protease Inhibitors
Antihypertensive Agents
Cardiovascular Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists

ClinicalTrials.gov processed this record on April 17, 2014