Clinical trial NCT01052272: Impact of Diabetes on Left Ventricular Remodeling
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Diabetes
Keywords: 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
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: AstraZeneca
First posted: 2010-01-20
Enrollment: 72
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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.

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 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.

Primary outcomes:
measure: Left Ventricular End Diastolic Volume Indexed to Body Surface Area (LVEDV/BSA)
timeFrame: 5 visits per Participant over 2 years (about every 6 months)
measure: Left Ventricular End-Diastolic Radius to Wall Thickness (LVED Radius/Wall Thickness)
timeFrame: 5 visits per Participant over 2 years (about every 6 months)
measure: Left Ventricular End-diastolic Mass Indexed to Left Ventricular End-diastolic Volume (LVED Mass/LVEDV)
timeFrame: 5 visits per Participant over 2 years (about every 6 months)
measure: Left Ventricular Ejection Fraction (LVEF)
timeFrame: 5 visits per Participant over 2 years (about every 6 months)
measure: Left Ventricular End Systolic Volume Indexed to Body Surface Area (LVESV/BSA)
timeFrame: 5 visits per Participant over 2 years (about every 6 months)
measure: LV End Systolic Maximum Shortening (LVES Max Shortening)
timeFrame: 5 visits per Participant over 2 years (about every 6 months)
measure: Peak Early Filling Rate Normalized to EDV
timeFrame: 5 visits per Participant over 2 years (about every 6 months)
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
Study officials:
affiliation: University of Alabama at Birmingham
name: Louis J. Dell'Italia, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Solomon SD, St John Sutton M, Lamas GA, Plappert T, Rouleau JL, Skali H, Moye L, Braunwald E, Pfeffer MA; Survival And Ventricular Enlargement (SAVE) Investigators. Ventricular remodeling does not accompany the development of heart failure in diabetic patients after myocardial infarction. Circulation. 2002 Sep 3;106(10):1251-5. doi: 10.1161/01.cir.0000032313.82552.e3.
citation: Mukamal KJ, Nesto RW, Cohen MC, Muller JE, Maclure M, Sherwood JB, Mittleman MA. Impact of diabetes on long-term survival after acute myocardial infarction: comparability of risk with prior myocardial infarction. Diabetes Care. 2001 Aug;24(8):1422-7. doi: 10.2337/diacare.24.8.1422.
citation: Melchior T, Kober L, Madsen CR, Seibaek M, Jensen GV, Hildebrandt P, 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. 1999 Jul;20(13):973-8. doi: 10.1053/euhj.1999.1530.
citation: Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet. 1993 Oct 2;342(8875):821-8.
citation: Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992 Sep 3;327(10):669-77. doi: 10.1056/NEJM199209033271001.
citation: Fiordaliso F, Leri A, Cesselli D, Limana F, Safai B, Nadal-Ginard B, Anversa P, Kajstura J. Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. Diabetes. 2001 Oct;50(10):2363-75. doi: 10.2337/diabetes.50.10.2363.
citation: Fiordaliso F, Li B, Latini R, Sonnenblick EH, Anversa P, Leri A, Kajstura J. Myocyte death in streptozotocin-induced diabetes in rats in angiotensin II- dependent. Lab Invest. 2000 Apr;80(4):513-27. doi: 10.1038/labinvest.3780057.
citation: Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. Angiotensin II-forming pathways in normal and failing human hearts. Circ Res. 1990 Apr;66(4):883-90. doi: 10.1161/01.res.66.4.883.
citation: Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001 Dec 13;414(6865):813-20. doi: 10.1038/414813a.
citation: Giugliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care. 1996 Mar;19(3):257-67. doi: 10.2337/diacare.19.3.257.
citation: Sorescu D, Griendling KK. Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Fail. 2002 May-Jun;8(3):132-40. doi: 10.1111/j.1527-5299.2002.00717.x.
citation: 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.
citation: de Jong JW, Schoemaker RG, de Jonge R, Bernocchi P, Keijzer E, Harrison R, Sharma HS, Ceconi C. Enhanced expression and activity of xanthine oxidoreductase in the failing heart. J Mol Cell Cardiol. 2000 Nov;32(11):2083-9. doi: 10.1006/jmcc.2000.1240.
citation: Matsumoto S, Koshiishi I, Inoguchi T, Nawata H, Utsumi H. Confirmation of superoxide generation via xanthine oxidase in streptozotocin-induced diabetic mice. Free Radic Res. 2003 Jul;37(7):767-72. doi: 10.1080/1071576031000107344.
citation: 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.
citation: 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.
citation: Saavedra WF, Paolocci N, St John ME, Skaf MW, Stewart GC, Xie JS, Harrison RW, Zeichner J, Mudrick D, Marban E, Kass DA, Hare JM. Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart. Circ Res. 2002 Feb 22;90(3):297-304. doi: 10.1161/hh0302.104531.
citation: Butler R, Morris AD, Belch JJ, Hill A, Struthers AD. Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension. 2000 Mar;35(3):746-51. doi: 10.1161/01.hyp.35.3.746.
citation: American Diabetes Association: clinical practice recommendations 1995. Diabetes Care. 1995 Jan;18 Suppl 1:1-96. No abstract available.
citation: 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. 2002 May 28;105(21):2512-7. doi: 10.1161/01.cir.0000017264.66561.3d.
citation: 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. 2000 Apr 11;101(14):1729-35. doi: 10.1161/01.cir.101.14.1729.
citation: Lopez B, Querejeta R, Varo N, Gonzalez A, Larman M, Martinez Ubago JL, Diez J. Usefulness of serum carboxy-terminal propeptide of procollagen type I in assessment of the cardioreparative ability of antihypertensive treatment in hypertensive patients. Circulation. 2001 Jul 17;104(3):286-91. doi: 10.1161/01.cir.104.3.286.
citation: Cracowski JL, Tremel F, Marpeau C, Baguet JP, Stanke-Labesque F, Mallion JM, Bessard G. Increased formation of F(2)-isoprostanes in patients with severe heart failure. Heart. 2000 Oct;84(4):439-40. doi: 10.1136/heart.84.4.439. No abstract available.
citation: Mallat Z, Philip I, Lebret M, Chatel D, Maclouf J, Tedgui A. Elevated levels of 8-iso-prostaglandin F2alpha 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. 1998 Apr 28;97(16):1536-9. doi: 10.1161/01.cir.97.16.1536.
citation: Nonaka-Sarukawa M, Yamamoto K, Aoki H, Takano H, Katsuki T, Ikeda U, Shimada K. Increased urinary 15-F2t-isoprostane concentrations in patients with non-ischaemic congestive heart failure: a marker of oxidative stress. Heart. 2003 Aug;89(8):871-4. doi: 10.1136/heart.89.8.871.
citation: Mak S, Newton GE. The oxidative stress hypothesis of congestive heart failure: radical thoughts. Chest. 2001 Dec;120(6):2035-46. doi: 10.1378/chest.120.6.2035.
citation: Rouleau JL, Pitt B, Dhalla NS, Dhalla KS, Swedberg K, Hansen MS, Stanton E, Lapointe N, Packer M; Canadian Prospective RandOmized FlosequInan Longevity Evaluation Investigators. Prognostic importance of the oxidized product of catecholamines, adrenolutin, in patients with severe heart failure. Am Heart J. 2003 May;145(5):926-32. doi: 10.1016/s0002-8703(02)94782-4.
citation: Lopez Farre A, Casado S. Heart failure, redox alterations, and endothelial dysfunction. Hypertension. 2001 Dec 1;38(6):1400-5. doi: 10.1161/hy1201.099612.
citation: Heart Outcomes Prevention Evaluation Study Investigators; Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000 Jan 20;342(3):145-53. doi: 10.1056/NEJM200001203420301.
citation: 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.
citation: Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003 Sep 6;362(9386):772-6. doi: 10.1016/S0140-6736(03)14284-5.
citation: Young JB, Dunlap ME, Pfeffer MA, Probstfield JL, Cohen-Solal A, Dietz R, Granger CB, Hradec J, Kuch J, McKelvie RS, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Held P, Solomon SD, Yusuf S, Swedberg K; Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) Investigators and Committees. Mortality and morbidity reduction with Candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials. Circulation. 2004 Oct 26;110(17):2618-26. doi: 10.1161/01.CIR.0000146819.43235.A9. Epub 2004 Oct 18.
citation: 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. 2004 Oct 12;110(15):2180-3. doi: 10.1161/01.CIR.0000144474.65922.AA. Epub 2004 Oct 4.
citation: Wachtell K, Palmieri V, Olsen MH, Gerdts E, Papademetriou V, Nieminen MS, Smith G, Dahlof B, Aurigemma GP, Devereux RB. Change in systolic left ventricular performance after 3 years of antihypertensive treatment: the Losartan Intervention for Endpoint (LIFE) Study. Circulation. 2002 Jul 9;106(2):227-32. doi: 10.1161/01.cir.0000021601.49664.2a.
citation: Rogers WJ, Bowlby LJ, Chandra NC, French WJ, Gore JM, Lambrew CT, Rubison RM, Tiefenbrunn AJ, Weaver WD. Treatment of myocardial infarction in the United States (1990 to 1993). Observations from the National Registry of Myocardial Infarction. Circulation. 1994 Oct;90(4):2103-14. doi: 10.1161/01.cir.90.4.2103.
citation: Chandra NC, Ziegelstein RC, Rogers WJ, Tiefenbrunn AJ, Gore JM, French WJ, 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. 1998 May 11;158(9):981-8. doi: 10.1001/archinte.158.9.981.
citation: Taylor HA Jr, Canto JG, Sanderson B, Rogers WJ, 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. 1998 Nov 1;82(9):1019-23. doi: 10.1016/s0002-9149(98)00547-5.
citation: Rogers WJ, Canto JG, Lambrew CT, Tiefenbrunn AJ, Kinkaid B, Shoultz DA, Frederick PD, 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. 2000 Dec;36(7):2056-63. doi: 10.1016/s0735-1097(00)00996-7.
citation: Rogers WJ, Canto JG, Barron HV, Boscarino JA, Shoultz DA, 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. 2000 Feb;35(2):371-9. doi: 10.1016/s0735-1097(99)00505-7.