Efficacy and Safety of Combined Lipid-Lowering Therapy with Ezetemibe and Atorvastatin in Patients with Acute Myocardial Infarction

Ya.M. Lutay, O.I. Irkin, A.A. Stepura, D.A. Bely, A.N. Parkhomenko


Statins reduce cholesterol levels, mainly due to the impact on its synthesis in the liver. But the rate and completeness of absorption of cholesterol in the intestine are also affect the lipid spectrum of blood. Ezetimibe is one of the first drugs that block this process. The objective of this work — to examine the safety and efficacy of low-dose combined lipid-lowering therapy compared with aggressive statin therapy in patients with acute myocardial infarction.
A total of 70 patients with acute myocardial infarction admitted to hospital within the first 24 hours (mean 5.2 ± 1.0 h) after symptoms onset. Patients were randomized into two groups: first one — 35 patients receiving low-dose combination of atorvastatin 10 mg and ezetimibe 10 mg (A10/E10), second one — 35 patients treated with atorvastatin 40 mg (A40) on the background of basic therapy.
Combined therapy was similar to atorvastatin monotherapy by lipid-lowering efficacy, but both regimens made it possible to achieve the recommended reduction of low-density lipoprotein cholesterol level less than 2.6 mmol/l only in approximately 75 % of patients, and less than 1.8 mmol/l — only in 1/3 of patients. More significant decrease in serum triglyceride level was noted in patients treated with combined therapy (35 % A10/E10 vs 19.5 % A40, respectively; p < 0.05). A10/E10 combination has anti-inflammatory effect similar to that of A40 and advantages over A40 monotherapy in the effect on the endothelium function. A10/E10 application was associated with a trend to endothelial function improvement already after 7 days of treatment, and after 90 days of treatment increase in brachial artery diameter in this group of patients was significantly higher than in atorvastatin monotherapy (12.19 ± 1.09 A10/E10 vs 9.25 ± 1.16 A40; p < 0.05). Groups did not differ in the incidence of major complications in hospital and early posthospital periods of the disease.


acute myocardial infarction; lipid-lowering therapy; atorvastatin; ezetimibe; endothelial dysfunction


Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S) // Lancet. — 1994. — 344. — 1383-1389.

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. — 360. — 7-22.

Sever P.S., Dahlöf B., Poulter N.R. et al. ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial // Lancet. — 2003. — 361. — 1149-1158.

Ridker P.M., Rifai N., Pfeffer M.A. et al. The cholesterol and recurrent events (CARE) investigators. Long-term effects of pravastatin on plasma concentration of C-reactive protein // Circulation. — 1999. — Vol. 100. — P. 230-235.

Anderson T.J., Meredith I.T., Yeung A.C. et al. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion // New Engl. J. Med. — 1995. — Vol. 332. — P. 488-493.

Dangas G., Smith D.A., Unger A.H. et al. Pravastatin: an antithrombotic effect independent of the cholesterol-lowering effect // Thromb. Haemost. — 2000. — Vol. 83. — P. 688-692.

Dupuis J., Tardif J.C., Cernacek P., Theroux P. Cholesterol reduction improves endothelial function after acute coronary syndromes. The RECIFE (reduction of cholesterol in ischemia and function of the endothelium) trial // Circulation. — 1999. — Vol. 99. — P. 3227-3333.

Ridker P.M., Rifai N., Miles J.S. et al. Lovastatin 20–40 mg/day lowers high sensitivity C-reactive protein levels in AFCAPS/TexCAPS (Abstr.) // Circulation. — 2000. — Vol. 102. (Suppl.). — P. 833.

Lefer A.M., Campbell B., Shin Y.K. et al. Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat hearts // Circulation. — 1999. — Vol. 100. — P. 178-184.

Schwartz G.G., Olsson A.G., Ezekowitz M.D. et al. for the Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischaemic events in acute coronary syndromes. The MIRACL study: a randomized controlled trial // J. Am. Med. Assoc. — 2001. — 285. — 1711-1718.

Cannon C.P., Braunwald E., McCabe C.H. et al. for the 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. Eng. J. Med. — 2004. — 350. — 1495-1504.

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. — 49. — 1272-1278.

Kayikcioglu M., Turkoglu C., Kultursay H. et al. Combined use of pravastatin and thrombolytic agents in acute myocardial infarction. Pravastatin Turkish trial // Circulation. — 1999. — Vol. 100 (Suppl. I). — P. 1-303.

Thompson P.L., Meredith I., Amerena J. et al. Effect of pravastatin compared with placebo initiated within 24 hours of onset of acute myocardial infarction or unstable angina: the Pravastatin in Acute Coronary Treatment (PACT) trial // Am. Heart J. — 2004. — 148. — e2.

Hamm C.W., Bassand J.P., Agewall S. et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation // EHJ. — 2011. — 32. — 2999-3054.

Reiner Z., Catapano A.L., De Backer G. et al. ESC/EAS Guidelines for the management of dyslipidaemias // EHJ. — 2011. — 32. — 1769-1818.

Van de Werf F., Bax J., Betriu A. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation // EHJ. — 2008. — 29. — 2909-2945.

Пархоменко А.Н., Лутай Я.М., Даншан Н. Регистр острого инфаркта миокарда — характеристика пациентов, организация медицинской помощи в первые сутки и внутригоспитальная терапия // Укр. мед. часопис. — 2011. — № 1–2. — С. 20-24.

Foley K.A., Simpson R.J. Jr, Crouse J.R. 3rd et al. Effectiveness of statin titration on low-density lipoprotein cholesterol goal attainment in patients at high risk of atherogenic events // Am. J. Cardiol. — 2003. — 92. — 79-81.

Dembowski E., Davidson M.H. Statin and ezetimibe combination therapy in cardiovascular disease // Curr. Opin. Endocrinol. Diabetes Obes. — 2009. — 16. — 183-8.

Ballantyne C.M., Andrews T.C., Hsia J.A. et al. // Am. J. Cardiol. — 2001. — 88. — 265-269.

Jones P.H., Davidson M.H., Stein E.A. et al. Comparison of the efficacy and safety of rosuvastatin vs. atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial) // Am. J. Cardiol. — 2003. — 92. — 152-60.

Dujovne C.A., Ettinger M.P., McNeer J.F. et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia // Am. J. Cardiol. — 2002. — 90. — 1092-7.

Knopp R.H., Gitter H., Truitt T. et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia // Eur. Heart J. — 2003. — 24. — 729-41.

Altmann S.W., Davis H.R. Jr, Zhu L.J. et al. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption // Science. — 2004. — 303. — 1201-4.

Sudhop T., Lutjohann D., Kodal A. et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans // Circulation. — 2002. — 106. — 1943-8.

Ballantyne C.M., Houri J., Notarbartolo A. et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial // Circulation. — 2003. — 107. — 2409-15.

Genest J. Combination of statin and ezetimibe for the treatment of dyslipidemias and the prevention of coronary artery disease // Can. J. Cardiol. — 2006. — 22. — 863-8.

Fossati P., Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide // Clin. Chem. — 1982. — № 28. — P. 2077-2080.

Allain C.C., Poon L.S., Chan C.S.G. et al. Enzymatic determination of total serum cholesterol // Clin. Chem. — 1974. — № 20. — P. 470-475.

Price C.P., Trull A.K., Berry D. Development and validation of a particle-enhanced turbidimetric immunoassay for C-reactive protein // J. Immunol. Methods. — 1987. — 99. — 205-211.

Otsuji S., Shibata H., Umeda M. Turbodimeric immunoassay of serum C-reactive protein // Clin. Chem. — 1982. — 28. — 2121-4.

Corretti M., Anderson T., Benjamin E. et al. Guidelines for the Ultrasound Assessment of Endothelial-Dependent Flow-Mediated Vasodilatation of the Brahial Artery // J. Am. Coll. Cardiol. — 2002. — Vol. 39. — P. 257-265.

Амосова Е.Н. Cтатины — от эффективности к безопасности: фокус на розувастатин // Серце і судини. — 2008. — № 1. — С. 94-97.

Пархоменко А.Н., Брыль Ж.В., Иркин О.И., Гурьева О.С., Шумаков А.В. Раннее назначение симвастатина у больных с острым инфарктом миокарда: влияние на клиническое течение и размер поражения. Часть 1 // Украинский кардиологический журнал. — 2006. — № 4. — С. 7-13.

Ostad M.A., Eggeling S., Tschentscher P. et al. Flow-mediated dilation in patients with coronary artery disease is enhanced by high dose atorvastatin compared to combined low dose atorvastatin and ezetimibe: results of the CEZAR study // Atherosclerosis. — 2009. — 205. — 227-32.

Лутай М.И., Голикова И.П. Возможности комбинированной гиполипидемической терапии: опыт клинического применения комбинации аторвастатина и эзетимиба // Здоровье Украины. — 2012.

Pearson T.A., Ballantyne C.M., Veltri E. et al. Pooled analyses of effects on C-reactive protein and low density lipoprotein cholesterol in placebo-controlled trials of ezetimibe monotherapy or ezetimibe added to baseline statin therapy // Am. J. Cardiol. — 2009. — 103. — 369-74.

Deanfield J., Donald A., Ferri C. et al. Endothelial function and dysfunction. Part I: methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension // J. Hypertens. — 2005. — 23. — 7-17.

Lerman A., Zeiher A.M. Endothelial function: cardiac events // Circulation. — 2005. — 111. — 363-8.

Lind L., Fors N., Hall J., Marttala K., Stenborg A. A comparison of three different methods to evaluate endothelium-dependent vasodilation in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study // Arterioscler. Thromb. Vasc. Biol. — 2005. — 25. — 2368-75.

Bulut D., Hanefeld C., Bulut-Streich N. et al. Endothelial function in the forearm circulation of patients with the metabolic syndrome-effect of different lipid-lowering regimens // Cardiology. — 2005. — 104. — 176-80.

Olijhoek J.K., Hajer G.R., van der Graaf Y. et al. The effects of low-dose simvastatin and ezetimibe compared to high-dose simvastatin alone on post-fat load endothelial function in patients with metabolic syndrome: a randomized double-blind crossover trial // J. Cardiovasc. Pharmacol. — 2008. — 52. — 145-50.

Gounari P., Tousoulis D., Antoniades C. et al. Rosuvastatin but not ezetimibe improves endothelial function in patients with heart failure, by mechanisms independent of lipid lowering // Int. J. Cardiol. — 2009. — 142. — 87-91.

Landmesser U., Bahlmann F., Mueller M. et al. Simvastatin vs ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans // Circulation. — 2005. — 111. — 2356-63.

Fichtlscherer S., Schmidt-Lucke C., Bojunga S. et al. Differential effects of short-term lipid lowering with ezetimibe and statins on endothelial function in patients with CAD: clinical evidence for 'pleiotropic' functions of statin therapy // Eur. Heart J. — 2006. — 27. — 1182-90.

Курята А.В., Фролова Е.А. Липидный спектр и функция эндотелия сосудов у пациентов с хронической болезнью почек III стадии. Эффективность применения комбинированной терапии эзетимиб/аторвастатин // Укр. мед. часопис. — 2011. — № 11–12. — С. 71-73.

Ye Y., Zhao X., Zhai G., Guo L., Tian Z., Zhang S. Effect of High-Dose Statin Versus Low-Dose Statin Plus Ezetimibe on Endothelial Function: A Meta-analysis of Randomized Trials // J. Cardiovasc. Pharmacol. Ther. — 2012 Jun 18.

Nakamura T., Sato E., Fujiwara N. et al. Ezetimibe decreases serum levels of asymmetric dimethylarginine (ADMA) and ameliorates renal injury in non-diabetic chronic kidney disease patients in a cholesterol-independent manner // Pharmacol. Res. — 2009. — 60. — 525-8.

Kuhlencordt P.J., Padmapriya P., Rutzel S. et al. Ezetimibe potently reduces vascular inflammation and arteriosclerosis in eNOS-deficient ApoE ko mice // Atherosclerosis. — 2009. — 202. — 48-57.

Nakagami H., Osako M.K., Takami Y. et al. Vascular protective effects of ezetimibe in ApoE-deficient mice // Atherosclerosis. — 2009. — 203. — 51-8.

Westerweel P.E., Visseren F.L., Hajer G.R. et al. Endothelial progenitor cell levels in obese men with the metabolic syndrome and the effect of simvastatin monotherapy vs simvastatin/ezetimibe combination therapy // Eur. Heart J. — 2008. — 29. — 2808-17.

Hussein O., Minasian L., Itzkovich Y., Shestatski K., Solomon L., Zidan J. Ezetimibe’s effect on platelet aggregation and LDL tendency to peroxidation in hypercholesterolaemia as monotherapy or in addition to simvastatin // Br. J. Clin. Pharmacol. — 2008. — 65. — 637-65.

Maki-Petaja K.M., Booth A.D., Hall F.C. et al. Ezetimibe and simvastatin reduce inflammation, disease activity, and aortic stiffness and improve endothelial function in rheumatoid arthritis // J. Am. Coll. Cardiol. — 2007. — 50. — 852-8.

Undas A., Machnik A., Potaczek D.P. et al. Ezetimibe combined with simvastatin compared with simvastatin alone results in a greater suppression of oxidative stress and enhanced fibrinolysis in patients after acute coronary events // J. Cardiovasc. Pharmacol. — 2011 Aug. — 58(2). — 167-72.

Lin C.F., Gau C.S., Wu F.L. et al. Impact of ezetimibe coadministered with statins on cardiovascular events following acute coronary syndrome: a 3-year population-based retrospective cohort study in Taiwan // Clin. Ther. — 2011 Sep. — 33(9). — 1120-31. Epub 2011 Aug 27.

Rossebø A.B., Pedersen T.R., Boman K. et al., for the SEAS Investigators Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis // N. Engl. J. Med. — 2008. — 359. — 1343-1356.

SHARP Collaborative Group. Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease // American Heart Journal. — 2010. — 160(5). — 785-794.e10.

Califf R.M., Lokhnygina Y., Cannon C.P. et al. An update on the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) design // American Heart Journal. — 2010. — 159(5). — 705-709.

DOI: https://doi.org/10.22141/2224-0586.3.58.2014.83238


  • There are currently no refbacks.

Copyright (c) 2016 EMERGENCY MEDICINE

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.


© Publishing House Zaslavsky, 1997-2018


 Яндекс.МетрикаSeo анализ сайта Рейтинг@Mail.ru