|
Virtual Histology Findings and Effects of Varying Doses of Atorvastatin Treatment
|
A Prospective, Double-blinded, Randomised Study to Evaluate the Effects of Different Doses of Statin Treatment on Plaque Volume and Composition in Coronary Disease Determined by Virtual Histology Using Intravascular Ultrasound
|
While statin treatment may induce plaque regression, the effect of statin on plaque composition with varying doses is unknown. This study assessed such effects by volumetric virtual histology intravascular ultrasound (VH-IVUS). In this prospective, randomized, double-blinded pilot study, statin-naïve patients with stable angina requiring percutaneous coronary intervention (PCI) were randomized to receive 6 months of either atorvastatin 10mg or 40 mg daily. VH-IVUS was performed in all non-PCI lesions at baseline and 6 months; all analyses were performed by core laboratory. |
Statin therapy, especially at intensive doses, is beneficial in atherosclerotic coronary disease. Detecting subtle plaque regression after statin therapy is difficult by coronary angiogram; intravascular ultrasound (IVUS) is a far better method. Volumetric IVUS has been used in statin trials to evaluate plaque regression. Intensive statin therapy in the REVERSAL Trial and ASTEROID Trial appeared to achieve better regression outcomes. Stable fibrous plaque is likely to be responsible for stable ischemia, while unstable plaque (large lipid core, calcified nodule and necrotic core), thin-cap fibroatheroma, plaque erosion and plaque rupture may be responsible for acute coronary syndrome (ACS). In vivo tissue characterization of plaque composition is therefore important, yet in this regard grayscale IVUS is insufficient. The development of Virtual Histology (VH) utilizing IVUS generated radiofrequency backscattering signals to virtually separate plaque composition into 4 components corresponding to histopathology has made possible in vivo assessment of plaque composition and stability. We believed plaque regression and VH-IVUS plaque modification with statin therapy could be statin dose dependent, and may affect clinical outcomes. This study was designed to prove our hypothesis, utilizing VH-IVUS. This study is the first prospective, randomised, double-blinded pilot study designed to investigate the varying statin dose effects on plaque regression and VH composition modulation. For ethical reasons, a placebo arm was not designed. Based on available data, clinically realistic doses of atorvastatin 10mg (low dose) and 40mg (moderate dose) were chosen. Only statin-naïve patients without previous history of myocardial infarction (MI) would be selected, aiming to show the "pure" effects of varying doses of statin and to better reveal the subtle differences in the changes. |
Interventional
|
Phase 4
|
Allocation: Randomized Intervention Model: Parallel Assignment Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) Primary Purpose: Treatment
|
- Coronary Disease
- Ultrasonography, Interventional
- Hydroxymethylglutaryl-CoA Reductase Inhibitors
|
Drug: Atorvastatin 10mg versus 40mg.
2 arms comparing atorvastatin 10mg daily for 6 months to atorvastatin 40mg daily for 6 months. The primary endpoint would be the 6 months VH-IVUS findings and clinical outcomes. Other Name: Lipitor 10mg versus 40mg daily for 6 months. |
- Active Comparator: Atorvastatin 10mg low dose
Atorvastatin 10mg daily for 6 months and compared to atorvastatin 40mg daily in the other arm. The primary endpoint of 6 months VH-IVUS findings and clinical outcomes would be monitored and compared. Intervention: Drug: Atorvastatin 10mg versus 40mg. - Active Comparator: Atorvastatin 40mg moderate dose
Atorvastatin 40mg daily for 6 months and compared to atorvastatin 10mg daily in the other arm. The primary endpoint of 6 months VH-IVUS findings and clinical outcomes would be monitored and compared. Intervention: Drug: Atorvastatin 10mg versus 40mg.
|
- Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001 May 16;285(19):2486-97.
- De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, Ebrahim S, Faergeman O, Graham I, Mancia G, Manger Cats V, Orth-Gomér K, Perk J, Pyörälä K, Rodicio JL, Sans S, Sansoy V, Sechtem U, Silber S, Thomsen T, Wood D; Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J. 2003 Sep;24(17):1601-10.
- Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002 Jul 6;360(9326):7-22.
- Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004 Jul 13;110(2):227-39. Review. Erratum in: Circulation. 2004 Aug 10;110(6):763.
- Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001 Apr 4;285(13):1711-8.
- Koren MJ, Hunninghake DB; ALLIANCE Investigators. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study. J Am Coll Cardiol. 2004 Nov 2;44(9):1772-9.
- 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. Epub 2005 Mar 8.
- Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004 Apr 8;350(15):1495-504. Epub 2004 Mar 8. Erratum in: N Engl J Med. 2006 Feb 16;354(7):778.
- Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990 Nov 8;323(19):1289-98.
- Hausmann D, Erbel R, Alibelli-Chemarin MJ, Boksch W, Caracciolo E, Cohn JM, Culp SC, Daniel WG, De Scheerder I, DiMario C, et al. The safety of intracoronary ultrasound. A multicenter survey of 2207 examinations. Circulation. 1995 Feb 1;91(3):623-30.
- Potkin BN, Bartorelli AL, Gessert JM, Neville RF, Almagor Y, Roberts WC, Leon MB. Coronary artery imaging with intravascular high-frequency ultrasound. Circulation. 1990 May;81(5):1575-85.
- Tobis JM, Mallery J, Mahon D, Lehmann K, Zalesky P, Griffith J, Gessert J, Moriuchi M, McRae M, Dwyer ML, et al. Intravascular ultrasound imaging of human coronary arteries in vivo. Analysis of tissue characterizations with comparison to in vitro histological specimens. Circulation. 1991 Mar;83(3):913-26.
- Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, Pinto FJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG. American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2001 Apr;37(5):1478-92. Review.
- Mintz GS, Painter JA, Pichard AD, Kent KM, Satler LF, Popma JJ, Chuang YC, Bucher TA, Sokolowicz LE, Leon MB. Atherosclerosis in angiographically "normal" coronary artery reference segments: an intravascular ultrasound study with clinical correlations. J Am Coll Cardiol. 1995 Jun;25(7):1479-85.
- Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN; REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004 Mar 3;291(9):1071-80.
- Nissen SE. Application of intravascular ultrasound to characterize coronary artery disease and assess the progression or regression of atherosclerosis. Am J Cardiol. 2002 Feb 21;89(4A):24B-31B. Review.
- Takagi T, Yoshida K, Akasaka T, Hozumi T, Morioka S, Yoshikawa J. Intravascular ultrasound analysis of reduction in progression of coronary narrowing by treatment with pravastatin. Am J Cardiol. 1997 Jun 15;79(12):1673-6.
- Schartl M, Bocksch W, Koschyk DH, Voelker W, Karsch KR, Kreuzer J, Hausmann D, Beckmann S, Gross M. Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease. Circulation. 2001 Jul 24;104(4):387-92.
- Jensen LO, Thayssen P, Pedersen KE, Stender S, Haghfelt T. Regression of coronary atherosclerosis by simvastatin: a serial intravascular ultrasound study. Circulation. 2004 Jul 20;110(3):265-70. Epub 2004 Jul 6.
- Okazaki S, Yokoyama T, Miyauchi K, Shimada K, Kurata T, Sato H, Daida H. Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH Study. Circulation. 2004 Aug 31;110(9):1061-8. Epub 2004 Aug 23.
- Kimura BJ, Bhargava V, DeMaria AN. Value and limitations of intravascular ultrasound imaging in characterizing coronary atherosclerotic plaque. Am Heart J. 1995 Aug;130(2):386-96. Review.
- Moore MP, Spencer T, Salter DM, Kearney PP, Shaw TR, Starkey IR, Fitzgerald PJ, Erbel R, Lange A, McDicken NW, Sutherland GR, Fox KA. Characterisation of coronary atherosclerotic morphology by spectral analysis of radiofrequency signal: in vitro intravascular ultrasound study with histological and radiological validation. Heart. 1998 May;79(5):459-67.
- Watson RJ, McLean CC, Moore MP, Spencer T, Salter DM, Anderson T, Fox KA, McDicken WN. Classification of arterial plaque by spectral analysis of in vitro radio frequency intravascular ultrasound data. Ultrasound Med Biol. 2000 Jan;26(1):73-80.
- Nair A, Kuban BD, Tuzcu EM, Schoenhagen P, Nissen SE, Vince DG. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation. 2002 Oct 22;106(17):2200-6.
- Nasu K, Tsuchikane E, Katoh O, Vince DG, Virmani R, Surmely JF, Murata A, Takeda Y, Ito T, Ehara M, Matsubara T, Terashima M, Suzuki T. Accuracy of in vivo coronary plaque morphology assessment: a validation study of in vivo virtual histology compared with in vitro histopathology. J Am Coll Cardiol. 2006 Jun 20;47(12):2405-12. Epub 2006 May 30.
- Rodriguez-Granillo GA, García-García HM, Mc Fadden EP, Valgimigli M, Aoki J, de Feyter P, Serruys PW. In vivo intravascular ultrasound-derived thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis. J Am Coll Cardiol. 2005 Dec 6;46(11):2038-42. Epub 2005 Nov 9.
- Kolodgie FD, Burke AP, Farb A, Gold HK, Yuan J, Narula J, Finn AV, Virmani R. The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes. Curr Opin Cardiol. 2001 Sep;16(5):285-92. Review.
- Virmani R, Burke AP, Kolodgie FD, Farb A. Vulnerable plaque: the pathology of unstable coronary lesions. J Interv Cardiol. 2002 Dec;15(6):439-46. Review.
- Rioufol G, Finet G, Ginon I, André-Fouët X, Rossi R, Vialle E, Desjoyaux E, Convert G, Huret JF, Tabib A. Multiple atherosclerotic plaque rupture in acute coronary syndrome: a three-vessel intravascular ultrasound study. Circulation. 2002 Aug 13;106(7):804-8. Retraction in: Circulation. 2012 Jun 12;125(23):e1019.
- Rioufol G, Gilard M, Finet G, Ginon I, Boschat J, André-Fouët X. Evolution of spontaneous atherosclerotic plaque rupture with medical therapy: long-term follow-up with intravascular ultrasound. Circulation. 2004 Nov 2;110(18):2875-80. Epub 2004 Oct 18.
- Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans. J Lipid Res. 2005 Feb;46(2):179-90. Epub 2004 Nov 16. Review.
|
|
|
|
Completed
|
40
|
Same as current |
June 2010
|
November 2009 (Final data collection date for primary outcome measure)
|
Inclusion Criteria: - Patient aged 18 to 85 (not pregnant) requiring percutaneous intervention to coronary stenosis.
- Statin naive patient.
- No history of myocardial infarction. Angina free for at least 8 weeks.
Exclusion Criteria: - Any history of previous statin treatment and myocardial infarction
- Current acute coronary syndrome or in cardiogenic shock
- Surgical bypass candidate
- Chronic total occlusion and very tortuous calcified arteries precluding safe IVUS examination.
- Patient refused to give written informed consent.
|
Sexes Eligible for Study: | All |
|
18 Years to 85 Years (Adult, Older Adult)
|
No
|
Contact information is only displayed when the study is recruiting subjects |
China
|
|
|
|
NCT01200056
|
UW 07-266 (IRB HKU) HKCTR-517 ( Other Identifier: Clinical Trials Centre, HKU (www.HKClinicalTrials.com) )
|
Yes
|
Not Provided
|
Not Provided
|
Prof. Stephen Lee, The University of Hong Kong
|
Prof. Stephen Lee
|
- Queen Mary Hospital, Hong Kong
- Pfizer
|
Principal Investigator: | Prof. Stephen WL LEE, MD FRCP FACC | Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hospital Authority |
|
The University of Hong Kong
|
February 2013
|
|