Clinical trial NCT01186289: Statin Therapy To Limit Cognitive Dysfunction After Cardiac Surgery
Official title: Statin Therapy To Limit Cognitive Dysfunction After Cardiac Surgery
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: NA
Conditions: Neurocognitive Dysfunction
Keywords: Neurocognitive Dysfunction
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2010-08-23
Enrollment: 0
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The primary aim of our prospective, randomized, double-blind interventional clinical trial is to determine the effectiveness of high dose atorvastatin therapy to reduce post operative cognitive dysfunction (POCD) in patients undergoing cardiac valve surgery. We hypothesize that therapy with high dose atorvastatin will significantly reduce the incidence and/or severity of POCD.


Eligibility criteria: Inclusion Criteria:

* Fifty informed and consenting patients for cardiac valve surgery with CPB , greater than 50 years of age and under the care of one or more of the investigators or consultants will be prospectively enrolled over a one-year period (plus one-year for follow-up).

Exclusion Criteria:

* Patients with a history of the following disease entities will be excluded:

  * symptomatic cerebrovascular disease with substantial residual deficit, alcohol abuse, psychiatric illness, renal failure (creatinine\>2.0),
  * hepatic dysfunction (ALT or AST \> 1.5 x ULN), history of allergy or myopathy with statin therapy, pregnant or breastfeeding women or other comorbidities that in the opinion of the investigator could limit patient participation. Exclusion criteria are designed to limit confounding and enhance differentiation of deficits related to surgery and or treatment.
  * Patients who are unable to read and thus unable to complete the neurocognitive testing will also be excluded.
  * Patients having concomitant carotid endarterectomy or other vascular surgery will also be excluded to provide a more homogeneous sample for comparison.

Primary outcomes:
measure: Neurocognitive Dysfunction
timeFrame: 6 weeks and 1 year post surgery
Secondary outcomes:
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Duke University
name: Mark F Newman, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Small BJ, Gagnon E, Robinson B. Early identification of cognitive deficits: preclinical Alzheimer's disease and mild cognitive impairment. Geriatrics. 2007 Apr;62(4):19-23.
citation: Small N. Living well until you die: quality of care and quality of life in palliative and dementia care. Ann N Y Acad Sci. 2007 Oct;1114:194-203. doi: 10.1196/annals.1396.019. Epub 2007 Oct 12.
citation: Newman S, Stygall J, Hirani S, Shaefi S, Maze M. Postoperative cognitive dysfunction after noncardiac surgery: a systematic review. Anesthesiology. 2007 Mar;106(3):572-90. doi: 10.1097/00000542-200703000-00023.
citation: Newman MF, Mathew JP, Grocott HP, Mackensen GB, Monk T, Welsh-Bohmer KA, Blumenthal JA, Laskowitz DT, Mark DB. Central nervous system injury associated with cardiac surgery. Lancet. 2006 Aug 19;368(9536):694-703. doi: 10.1016/S0140-6736(06)69254-4.
citation: Tuman KJ, McCarthy RJ, Najafi H, Ivankovich AD. Differential effects of advanced age on neurologic and cardiac risks of coronary artery operations. J Thorac Cardiovasc Surg. 1992 Dec;104(6):1510-7.
citation: Weintraub WS, Jones EL, Craver J, Guyton R, Cohen C. Determinants of prolonged length of hospital stay after coronary bypass surgery. Circulation. 1989 Aug;80(2):276-84. doi: 10.1161/01.cir.80.2.276.
citation: Roach GW, Kanchuger M, Mangano CM, Newman M, Nussmeier N, Wolman R, Aggarwal A, Marschall K, Graham SH, Ley C. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med. 1996 Dec 19;335(25):1857-63. doi: 10.1056/NEJM199612193352501.
citation: Barber PA, Hach S, Tippett LJ, Ross L, Merry AF, Milsom P. Cerebral ischemic lesions on diffusion-weighted imaging are associated with neurocognitive decline after cardiac surgery. Stroke. 2008 May;39(5):1427-33. doi: 10.1161/STROKEAHA.107.502989. Epub 2008 Mar 6.
citation: Cimino M, Gelosa P, Gianella A, Nobili E, Tremoli E, Sironi L. Statins: multiple mechanisms of action in the ischemic brain. Neuroscientist. 2007 Jun;13(3):208-13. doi: 10.1177/1073858406297121.
citation: Rikitake Y, Liao JK. Rho GTPases, statins, and nitric oxide. Circ Res. 2005 Dec 9;97(12):1232-5. doi: 10.1161/01.RES.0000196564.18314.23.
citation: Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995 Sep 21;377(6546):239-42. doi: 10.1038/377239a0.
citation: Huang Z, Huang PL, Ma J, Meng W, Ayata C, Fishman MC, Moskowitz MA. Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab. 1996 Sep;16(5):981-7. doi: 10.1097/00004647-199609000-00023.
citation: Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science. 1994 Sep 23;265(5180):1883-5. doi: 10.1126/science.7522345.
citation: Dalkara T, Morikawa E, Panahian N, Moskowitz MA. Blood flow-dependent functional recovery in a rat model of focal cerebral ischemia. Am J Physiol. 1994 Aug;267(2 Pt 2):H678-83. doi: 10.1152/ajpheart.1994.267.2.H678.
citation: Zhang F, Iadecola C. Reduction of focal cerebral ischemic damage by delayed treatment with nitric oxide donors. J Cereb Blood Flow Metab. 1994 Jul;14(4):574-80. doi: 10.1038/jcbfm.1994.71.
citation: Morikawa E, Huang Z, Moskowitz MA. L-arginine decreases infarct size caused by middle cerebral arterial occlusion in SHR. Am J Physiol. 1992 Nov;263(5 Pt 2):H1632-5. doi: 10.1152/ajpheart.1992.263.5.H1632.
citation: Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8880-5. doi: 10.1073/pnas.95.15.8880.
citation: Carloni S, Mazzoni E, Cimino M, De Simoni MG, Perego C, Scopa C, Balduini W. Simvastatin reduces caspase-3 activation and inflammatory markers induced by hypoxia-ischemia in the newborn rat. Neurobiol Dis. 2006 Jan;21(1):119-26. doi: 10.1016/j.nbd.2005.06.014. Epub 2005 Jul 27.
citation: Sironi L, Banfi C, Brioschi M, Gelosa P, Guerrini U, Nobili E, Gianella A, Paoletti R, Tremoli E, Cimino M. Activation of NF-kB and ERK1/2 after permanent focal ischemia is abolished by simvastatin treatment. Neurobiol Dis. 2006 May;22(2):445-51. doi: 10.1016/j.nbd.2005.12.004. Epub 2006 Feb 9.
citation: Weber C, Erl W, Weber KS, Weber PC. HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol. 1997 Nov 1;30(5):1212-7. doi: 10.1016/s0735-1097(97)00324-0.
citation: Elkind MS. Inflammation, atherosclerosis, and stroke. Neurologist. 2006 May;12(3):140-8. doi: 10.1097/01.nrl.0000215789.70804.b0.
citation: Freedman JE, Loscalzo J, Barnard MR, Alpert C, Keaney JF, Michelson AD. Nitric oxide released from activated platelets inhibits platelet recruitment. J Clin Invest. 1997 Jul 15;100(2):350-6. doi: 10.1172/JCI119540.
citation: Laufs U, Gertz K, Huang P, Nickenig G, Bohm M, Dirnagl U, Endres M. Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke. 2000 Oct;31(10):2442-9. doi: 10.1161/01.str.31.10.2442.
citation: Labios M, Martinez M, Gabriel F, Guiral V, Martinez E, Aznar J. Effect of atorvastatin upon platelet activation in hypercholesterolemia, evaluated by flow cytometry. Thromb Res. 2005;115(4):263-70. doi: 10.1016/j.thromres.2004.08.016.
citation: Hwang YS, Tsai WC, Lu YH, Lin CC, Chen YF. Effect of atorvastatin on the expression of CD40 ligand and P-selectin on platelets in patients with hypercholesterolemia. Am J Cardiol. 2004 Aug 1;94(3):364-6. doi: 10.1016/j.amjcard.2004.04.037.
citation: Asahi M, Huang Z, Thomas S, Yoshimura S, Sumii T, Mori T, Qiu J, Amin-Hanjani S, Huang PL, Liao JK, Lo EH, Moskowitz MA. Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia. J Cereb Blood Flow Metab. 2005 Jun;25(6):722-9. doi: 10.1038/sj.jcbfm.9600070.
citation: LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005 Apr 7;352(14):1425-35. doi: 10.1056/NEJMoa050461. Epub 2005 Mar 8.
citation: Waters DD, LaRosa JC, Barter P, Fruchart JC, Gotto AM Jr, Carter R, Breazna A, Kastelein JJ, Grundy SM. Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT (treating to new targets) study. J Am Coll Cardiol. 2006 Nov 7;48(9):1793-9. doi: 10.1016/j.jacc.2006.07.041. Epub 2006 Oct 17.
citation: Muldoon MF, Barger SD, Ryan CM, Flory JD, Lehoczky JP, Matthews KA, Manuck SB. Effects of lovastatin on cognitive function and psychological well-being. Am J Med. 2000 May;108(7):538-46. doi: 10.1016/s0002-9343(00)00353-3.
citation: Harrison RW, Ashton CH. Do cholesterol-lowering agents affect brain activity? A comparison of simvastatin, pravastatin, and placebo in healthy volunteers. Br J Clin Pharmacol. 1994 Mar;37(3):231-6. doi: 10.1111/j.1365-2125.1994.tb04268.x.
citation: Mathew JP, Grocott HP, McCurdy JR, Ti LK, Davis RD, Laskowitz DT, Podgoreanu MV, Swaminathan M, Lynch J, Stafford-Smith M, White WD, Newman MF. Preoperative statin therapy does not reduce cognitive dysfunction after cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2005 Jun;19(3):294-9. doi: 10.1053/j.jvca.2005.03.004.
citation: Parale GP, Baheti NN, Kulkarni PM, Panchal NV. Effects of atorvastatin on higher functions. Eur J Clin Pharmacol. 2006 Apr;62(4):259-65. doi: 10.1007/s00228-005-0073-z. Epub 2006 Feb 18.
citation: LaRosa JC, Grundy SM, Kastelein JJ, Kostis JB, Greten H; Treating to New Targets (TNT) Steering Committee and Investigators. Safety and efficacy of Atorvastatin-induced very low-density lipoprotein cholesterol levels in Patients with coronary heart disease (a post hoc analysis of the treating to new targets [TNT] study). Am J Cardiol. 2007 Sep 1;100(5):747-52. doi: 10.1016/j.amjcard.2007.03.102. Epub 2007 Jun 14.
citation: Schouten O, Boersma E, Hoeks SE, Benner R, van Urk H, van Sambeek MR, Verhagen HJ, Khan NA, Dunkelgrun M, Bax JJ, Poldermans D; Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med. 2009 Sep 3;361(10):980-9. doi: 10.1056/NEJMoa0808207.
citation: Davidson MH, Robinson JG. Safety of aggressive lipid management. J Am Coll Cardiol. 2007 May 1;49(17):1753-62. doi: 10.1016/j.jacc.2007.01.067. Epub 2007 Apr 16.
citation: Mariscalco G, Lorusso R, Klersy C, Ferrarese S, Tozzi M, Vanoli D, Domenico BV, Sala A. Observational study on the beneficial effect of preoperative statins in reducing atrial fibrillation after coronary surgery. Ann Thorac Surg. 2007 Oct;84(4):1158-64. doi: 10.1016/j.athoracsur.2007.05.021.
citation: Coleman CI, Lucek DM, Hammond J, White CM. Preoperative statins and infectious complications following cardiac surgery. Curr Med Res Opin. 2007 Aug;23(8):1783-90. doi: 10.1185/030079907X210570.
citation: Kulik A, Levin R, Ruel M, Mesana TG, Solomon DH, Choudhry NK. Patterns and predictors of statin use after coronary artery bypass graft surgery. J Thorac Cardiovasc Surg. 2007 Oct;134(4):932-8. doi: 10.1016/j.jtcvs.2007.05.039.
citation: Filion KB, Pilote L, Rahme E, Eisenberg MJ. Perioperative use of cardiac medical therapy among patients undergoing coronary artery bypass graft surgery: a systematic review. Am Heart J. 2007 Sep;154(3):407-14. doi: 10.1016/j.ahj.2007.04.036.
citation: Patti G, Pasceri V, Colonna G, Miglionico M, Fischetti D, Sardella G, Montinaro A, Di Sciascio G. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol. 2007 Mar 27;49(12):1272-8. doi: 10.1016/j.jacc.2007.02.025.
citation: Patti G, Chello M, Pasceri V, Colonna D, Nusca A, Miglionico M, D'Ambrosio A, Covino E, Di Sciascio G. Protection from procedural myocardial injury by atorvastatin is associated with lower levels of adhesion molecules after percutaneous coronary intervention: results from the ARMYDA-CAMs (Atorvastatin for Reduction of MYocardial Damage during Angioplasty-Cell Adhesion Molecules) substudy. J Am Coll Cardiol. 2006 Oct 17;48(8):1560-6. doi: 10.1016/j.jacc.2006.06.061. Epub 2006 Sep 26.
citation: Pasceri V, Patti G, Nusca A, Pristipino C, Richichi G, Di Sciascio G; ARMYDA Investigators. Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) study. Circulation. 2004 Aug 10;110(6):674-8. doi: 10.1161/01.CIR.0000137828.06205.87. Epub 2004 Jul 26.
citation: Ruff RM, Parker SB. Gender- and age-specific changes in motor speed and eye-hand coordination in adults: normative values for the Finger Tapping and Grooved Pegboard Tests. Percept Mot Skills. 1993 Jun;76(3 Pt 2):1219-30. doi: 10.2466/pms.1993.76.3c.1219.
citation: Murkin JM, Stump DA, Blumenthal JA, McKhann G. Defining dysfunction: group means versus incidence analysis--a statement of consensus. Ann Thorac Surg. 1997 Sep;64(3):904-5. doi: 10.1016/s0003-4975(97)00743-1. No abstract available.
citation: Murkin JM, Newman SP, Stump DA, Blumenthal JA. Statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery. Ann Thorac Surg. 1995 May;59(5):1289-95. doi: 10.1016/0003-4975(95)00106-u. No abstract available.
citation: Newman MF, Kirchner JL, Phillips-Bute B, Gaver V, Grocott H, Jones RH, Mark DB, Reves JG, Blumenthal JA; Neurological Outcome Research Group and the Cardiothoracic Anesthesiology Research Endeavors Investigators. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med. 2001 Feb 8;344(6):395-402. doi: 10.1056/NEJM200102083440601.
citation: Newman MF, Croughwell ND, Blumenthal JA, White WD, Lewis JB, Smith LR, Frasco P, Towner EA, Schell RM, Hurwitz BJ, et al. Effect of aging on cerebral autoregulation during cardiopulmonary bypass. Association with postoperative cognitive dysfunction. Circulation. 1994 Nov;90(5 Pt 2):II243-9.
citation: Pahan K, Sheikh FG, Namboodiri AM, Singh I. Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages. J Clin Invest. 1997 Dec 1;100(11):2671-9. doi: 10.1172/JCI119812.
citation: Rey A. L'examen clinique en psychologie. Paris: Presses Universitaires de France;1964
citation: Wechsler D. The Wechsler Adult Intelligence Scale-Revised (WAIS-R). San Antonio, Texas: The Psychological Corporation; 1981
citation: Reitan RM. Validity of the trail making test as an indicator of organic brain damage. Percept Mot Skills. 1958;8:271-276.
citation: Benton AL, Hansher K. Multilingual Aphasia Examination. Iowa City: University of Iowa Press; 1978
citation: Hlatky MA, Bacon C, Boothroyd D, Mahanna E, Reves JG, Newman MF, Johnstone I, Winston C, Brooks MM, Rosen AD, Mark DB, Pitt B, Rogers W, Ryan T, Wiens R, Blumenthal JA. Cognitive function 5 years after randomization to coronary angioplasty or coronary artery bypass graft surgery. Circulation. 1997 Nov 4;96(9 Suppl):II-11-4; discussion II-15.
citation: Fillenbaum GG. Multidimensional functional assessment of older adults (The Duke Older Americans Resources and Services Procedures). Hillsdale, N.J.: Erlbaum Associates; 1988
citation: Ware JE, Snow KK, Kosinski M, et al. SF-36 Health Survey: Manual and Interpretation Guide. Lincon, Rhode Island: Qualitymetric, Inc.;2000
citation: Ware JE, Kosinski KK, Keller SD. SF-36 Physical and Mental Health Summary Scales: A User's Manual. Boston: Health Assessment Lab, New England Medical Center; 1994
citation: Axelrad KJ. Locus of Control and Casual Attributions As they Relate to Expectations for Coping With A Heart Attack. Los Angeles, California School of Professional Psychology; 1981.
citation: Radloff LS. The CES-D Scale: A self-report depression scale for research in the general population. Applied Psycological Measures. Vol 1; 1977:385-401.
citation: Spielberger C, Gorsuch R, Lushene R. STAI Manual Palo Alto: Consulting Psychologists Press, Inc; 1970
citation: Blumenthal JA, Burg MM, Barefoot J, Williams RB, Haney T, Zimet G. Social support, type A behavior, and coronary artery disease. Psychosom Med. 1987 Jul-Aug;49(4):331-40. doi: 10.1097/00006842-198707000-00002.
citation: McNair DM, Kahn RJ. Self-assessment of Cognitive Deficits. In: Crook T., Ferris, S.,Bartus, R., ed. Assessment In Geriatric Psychopharmacology. New Canaan, Ct.: Mark Powley Associates, Inc.: 1983.
citation: Rosengarten B, Auch D, Kaps M. Effects of initiation and acute withdrawal of statins on the neurovascular coupling mechanism in healthy, normocholesterolemic humans. Stroke. 2007 Dec;38(12):3193-7. doi: 10.1161/STROKEAHA.107.491423. Epub 2007 Oct 25.
citation: Blanco M, Nombela F, Castellanos M, Rodriguez-Yanez M, Garcia-Gil M, Leira R, Lizasoain I, Serena J, Vivancos J, Moro MA, Davalos A, Castillo J. Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology. 2007 Aug 28;69(9):904-10. doi: 10.1212/01.wnl.0000269789.09277.47.
citation: Cronbach LJ. Essentials of Psychological Testing. New York: Harper and Row; 1970