Регрессия атеросклероза при терапии статинами

Атеросклероз с его клиническими проявлениями и осложнениями продолжает лидировать в структуре заболеваемости и смертности развитых и развивающихся стран. Ингибиторы ГМГ-Ко-А редуктазы (статины) являются основными лекарственными препаратами в лечении пациентов с дислипидемиями (ДЛП) и атеросклерозом. Помимо рандомизированных, клинических исследований с “твердыми” конечными точками статины хорошо изучены в “регрессионных” исследованиях. В этих работах проверялась гипотеза, что интенсивное снижение уровня холестерина липопротеидов низкой плотности на 40-50 % от исходных значений может вызвать качественные и количественные изменения в коронарных артериях (КА). Результаты старых регрессионных исследований явились обоснованием для повышения доз статинов в клинической практике и проведения крупных, рандомизированных исследований со статинами. В современных регрессионных исследованиях используются такие методы мониторинга состояния атеросклероза в сосудах, как толщина комплекса интима-медия, ядерно-магнитный резонанс и внутрисосудистый ультразвук. С помощью этих методов было показано как замедление прогрессирования атеросклероза в сонных артериях (METEOR, розувастатин 40 мг/сут.; ENHANCE, эзетимиб 10 мг/ сут. / симвастатин 20 мг/сут.), КА (REVERSAL, аторвастатин 80 мг/сут.) и регрессия (ASTEROID, розувастатин 40 мг/сут.). “Агрессивное” снижение липидов на 40-50 %, полученное в современных регрессионных исследованиях на высоких дозах статинов переносилось хорошо, серьезных побочных эффектов отмечено не было. Результаты и принципы таких исследований могут быть широко использованы в повседневной практике для оптимизации лечения тяжелых больных с ДЛП и атеросклерозом.

1. Pollac OJ. Reduction of blood cholesterol in man. Circulation 1953; 7: 702-6.

2. Endo A. The discovery and development of HMG-CoA reductase inhibitors. J Lipid Res 1992; 33: 1569-82.

3. Jones PH, Davidson MH, Stein EA, et al, STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin accross doses (STELLAR* Trial). Am J Cardiol 2003; 92(2): 152-60.

4. Schuster H. The Galaxy Program: an update on studies investigating efficacy and tolerability of rosuvastatin for reducing cardiovascular risk. Expert Rev Cardiovasc Ther 2007; 5(2): 177-93.

5. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, et al., REVERSAL Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 3; 291(9): 1071-80.

6. Nissen S, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity stain therapy on regression of coronary atherosclerosis. The ASTEROID trial. JAMA 2006; on-line, March 13.

7. Crouse III JR, Raichlen JS, Riley WA. Effect of Rosuvastatin on Progression of Carotid Intima-Media Thickness in Low-Risk Individuals With Subclinical Atherosclerosis The METEOR Trial. JAMA 2007; 297: 1344-53.

8. Kastelein JJP, Akdim F, Stroes E, et al. for the ENHANCE investigators. Simvstatin with or without ezetimibe in familial hypercholesterolaemia. N Engl J Med 2008; 358: 1431-43.

9. Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of aggressive versus conventional lipid-lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomized, double-blind trial. Lancet 2001; 357 (9256): 574-81.

10. Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER 6 HALTS trial 9Arterial biology for the Investigation of the treatment effects of Reducing Cholesterol 6-HDL and LDL treatment Strategies in Atherosclerosis): final results and the inpact of medication adherence, dose and treatment duration. JACC 2010; 55(24): 2721-6.

11. Amtzenius AC, Kromhout D, Barth JD et al. Diet, lipoproteins and the progression of coronary atherosclerosis. The Leiden Intervention Trial. N Engl J Med 1985; 312(13): 805-11.

12. Brown G, Albers JJ, Fisher LD, et al. 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; 323: 1289-98.

13. Blankenhorn DH, Azen SP, Dramsch DM, et al. Coronary Angiographic changes with lovastatin therapy. The Monitored Atherosclerosis Regression Study (MARS). Ann Intern Med 1993; 119 (10); 969-76.

14. Effects of simvastatin on coronary ateroma: The Multicenter Anti-Atheroma Study (MAAS). Lancet 1994; 344: 633-8.

15. Waters D, Higginson L, Gladstone P, et al. Effects of monotherapy with an HMG-Co-A reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography. The Canadian Coronary Atherosclerosis Interventional Trial. Circulation 1994; 89(3): 959-68.

16. Groot E, Jukema JW, Bruschke AV, et al. Effects of lipid-lowering by pravasatin on progression and regression of coronary artery disease in symptomatic men with normal to moderate elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995; 91: 2528-40.

17. Herd JA, Ballantyne CM, Farmer JA, et al. Effects of Fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and coronary atherosclerosis study ([LCAS]). Am J Cardiol 1997; 80: 278-86.

18. Bestehorn H-P, Rensing UFE, Roskamm H, et al. The effect of simvastatin on progression of coronary artery disease. The Multicentre Coronary Interventionn Study (CIS). Eur Heart J 1997; 18(2): 226-34.

19. Pitt B, Mancini GB, Ellis SG, et al. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC-I): reduction in atherosclerosis progression and clinical events. JACC 1995; 26: 1113-20.

20. Waters D. Stabilization of coronary aherosclerosis.Science Press Ltd, 1994. London P.76.

21. Thompson GR. Angiographic trials of lipid-lowering therapy: end of an era? Br Heart J 1995; 74: 343-7.

22. Thompson GR, Holyer J, Waters DD. Percentage change rather than plasma level of LDL — cholesterol determines therapeutic response in coronary heart disease. Curr Opinion Lipidol 1995; 6: 386-8.

23. Thompson GR. What targets should lipid-modulating therapy achieve to optimise the prevention of coronary heart disease? Atherosclerosis 1997; 131: 1-5.

24. Canon C, Steinberg B, Murphy S, et al. Meta-analysis of cardiovascular outcome trials comparing intensive versus moderate statin therapy. JACC 2006; 48(3): 438-45.

25. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol -lowering treatment: prospective meta-analysis of data from 90056 participants in 14 randomized trials of statins. Lancet 2005; 366(9494): 1267-78.

26. Davidson MH, Stein EA, Dujovne CA, et al. The efficacy and six week tolerability of Simvastatin 80 and 160 mg/day. Am J Card 1997; 79: 38-42.

27. Marais AD, Firth JC, Bateman ME, et al. Atorvastatin, an effective lipid — modifying agent in familial hypercholesterolaemia. Arteriosclerosis Thromb Vasc Biol 1997; 17: 1527-31.

28. Wierzbicki AS, Lumb PJ, Chick G, Crook MA. Comparison of therapy with simvastatin 80 mg and atorvastatin 80 mg in patients with familial hypercholesterolaemia. International J Clin Pract 1999; 53(8): 609-11.

29. Stein E, Davidson MH, Dobs AS, et al. Efficacy and safety of simvastatin 80 mg/day in hypercholesterolemic patients. The Expanded Dose Simvastatin U.S. Study Group. Am J Cardiol 1998; 82(3): 311-6.

30. Ose L, Davidson MH, Stein EA, et al. Lipid-altering efficacy and safety of simvastatin 80 mg/day: long-term experience in a large group of patients with hypercholesterolemia. World Wide Expanded Dose Simvastatin Study Group. Clin Cardiol 2000; 23(1): 39-46.

31. Crouse JR 3rd, Frohlich J, Ose L, et al. Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I. Am J Cardiol 1999; 83(10): 1476-7, A7.

32. Illingworth DR. Crouse JR 3rd, Hunninghake DB, et al. A comparison of simvastatin and atorvastatin up to maximal recommended doses in a large multicenter randomized clinical trial. Curr Med Res Opin 2001; 17(1): 43-50.

33. Schwartz GG, Ollson AG, Ezekowitz MD, et al. 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; 285(13): 1711-8.

34. Cannon CP, Braunwald E, McCabe CH, et al. 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; 350: 1495-504.

35. Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus evascularization Treatment Investigators. N Engl J Med 1999; 341(2): 70-6.

36. Olsson AG. Statin therapy and reduction in low-density lipoprotein cholesterol: initial clinical data on the potent new statin rosuvastatin. Am J Cardiol 2001; 87(5 Suppl. 1): 33-6. 3

37. Ollson AG; Pears J, McKellar J, et al. Effect of rosuvastatin on low-density lipoprotein cholesterol in patients with hypercholesterolaemia. Am J Cardiol 2001; 88(5): 504-8.

38. Silva M, Matthews ML, Jarvis C, et al. Meta-analysis of druginduced adverse events associated with intensive-dose statin therapy. Clin Ther 2007; 29(2): 253-60.

39. Underhill HR, Yuan C, Zhao XQ, et al. Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesterolemic patients: a high-resolution magnetic resonance imaging trial. Am Heart J 2008; 155(3): 584- 8. Epub 2008 Jan 18.

40. Nichols SJ, Tuzcu ME, Sipahi I, et al. Statins, High-density lipoprotein cholesterol and regression of coronary atherosclerosis. JAMA 2007; 297: 499-509.

41. Califf R, Lokhnygina Y, Cannon CP, et al. An update on the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) design. Am J Cardiol 2010; in press.