Vaskuloprotekcinės statinų savybės M.dr. Jolanta Marcinkevičienė

Vaskuloprotekcinės statinų savybės M.dr. Jolanta Marcinkevičienė
Previously, atherosclerosis was thought to result from passive lipid deposition in the vascular wall. However, accumulating evidence has shown that the atherosclerotic disease process is much more complex and that the vascular endothelium plays an integral role in the initiation and progression of cardiovascular disease (CVD)1,2 The endothelium is responsible for maintenance of vascular tone; monocyte adhesion and penetration; platelet adherence; smooth muscle cell migration and proliferation; and inflammation, oxidation, and alterations in the permeability, deposition, and clearance of lipoproteins. The endothelium also regulates thrombogenesis2-4 Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase), otherwise known as statins, have emerged as agents with potentially multiple functions. Not only do they lower cholesterol levels but they may also have beneficial effects on other aspects of the disease process. In this slide kit we will review evidence regarding these vasculoprotective effects of statins1,2 References: 1. Schönbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation. 2004;109(suppl II):II-18–II Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(suppl III):III-27–III Pepine CJ. The effects of angiotensin-converting enzyme inhibition on endothelial dysfunction: potential role in myocardial ischemia. Am J Cardiol. 1998;82(suppl 10A):23S-27S. 4. Omoigui N, Dzau VJ. Differential effects of antihypertensive agents in experimental and human atherosclerosis. J Vasc Med Biol. 1991;3:

Kalcio kanalų blokatoriai
Kai kurie vaistai, naudojami kardiovaskulinių ligų, ypač hipertenzijos ir dislipidemijų gydymui turi papildomą, vaskuloprotekcinį (pleotropinį) poveikį: AKF inhibitoriai Statinai Kalcio kanalų blokatoriai

Wassmann S, Nickenig G. Endothelium. 2003;10:23-33.
Statinų poveikis - ne tik cholesterolį mažinantis, bet ir antiaterosklerotinis Poveikis į endotelį Priešuždegiminis efektas Antioksidacinis efektas Plokštelės progresavimo (augimo) mažinimas Plokštelės stabilizavimas + Cholesterolio mažinimas In addition to reducing LDL-C concentrations, atorvastatin may delay the development of atherosclerosis via endothelial, anti-inflammatory, or antioxidant effects, or by reducing plaque progression or promoting plaque stabilization Wassmann S, Nickenig G. Endothelium. 2003;10:23-33.

Statinų poveikis Kardiovaskulinių įvykių Dienos Savaitės Metai
Slopina trombocitų adheziją ir agregaciją Mažina lipidų koncentraciją kraujyje Gerina endotelio funkciją Didina ath plokštelės stabilumą ! Mažina kraujo krešumo veiksnių koncentraciją Slopina uždegimą,maži-na oksidacinį stresą Kardiovaskulinių įvykių Dienos Savaitės Metai LaRosa J. C. AHJ 144; 6:25-26

Aterosklerozė: lėtai progresuojanti liga
Monocitai LDL-C Adhezijos molekulės Makrofagai Putotos ląstelės Oksiduotas MTL-Ch Plokštelės plyšimas Lygiųjų raumenų ląstelės CRB Endothelial dysfunction may be the earliest stage of coronary atherosclerosis1 Reference: 1. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340: Endotelio disfunkcija Uždegimas Oksidacija Nestabili plokštelė ir trombas Libby P. Circulation. 2001;104: ; Ross R. N Engl J Med. 1999;340:

Putotosios ląstelės Riebaliniai ruoželiai Vidinis įplyšimas Fibrozinė plokštelė Atsidalinimas /plyšimas Ateroma Aterosklerozė prasideda nuo endotelio pažeidimo ir progresuoja daug metų Endotelio disfunkcija Pirmame dešimtmetyje Antrame dešimtmetyje Pradedant ketvirtu dešimtmečiu Lygieji raumenys ir kalogenas Trombozė Hematoma Augimas dėl lipidų akumuliacijos Lygieji raumenys ir kalogeai

Statinų veikimo mechanizmas (HMG-CoA redutazės slopinimas→cholesterolio sintezės↓)
Acetyl-CoA + Acetoacetyl-CoA HMG-CoA Mevalonate Isopentanyl PP Geranyl PP Farnesyl PP Statinai block Lėtas, vėlyvas poveikis Ankstyvas/greitas poveikis (vaskuloprotekcija) MTL-chol sumažėjimas Geranyl geranyl PP Prenylation By blocking the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, statins inhibit distinct cellular pathways and thereby affect downstream events1 Statins block the conversion of acetoacetyl-CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis. In addition, they inhibit the pathway leading to the generation of farnesyl pyrophosphate (PP) and geranylgeranyl PP, 2 pyrophosphates that are critical for the induction of a variety of signal transduction pathways1 Activation of signaling molecules such as Rho promotes a cascade of events leading to endothelial dysfunction, inflammation, adhesion, migration, proliferation, apoptosis, matrix degradation, and coagulation.1,2 These non-lipid-lowering effects may explain the early vasculoprotective benefits of statins, whereas changes in cholesterol biosynthesis may bring about long-term CV benefits3 References: 1. Schönbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation. 2004;109(suppl II):II-18–II Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001;21: Ray KK, Cannon CP. Intensive statin therapy in acute coronary syndromes: clinical benefits and vascular biology. Curr Opin Lipidol. 2004;15: Rho Squalene Cholesterol Poveikis į ląstelių membraną PP=pyrophosphate. Adapted from Ray KK, Cannon CP. Curr Opin Lipidol. 2004;15:

Vaskuloprotekcinis statinų poveikis
Trombogeniškumas Endotelio funkcija Trombocitų aktyvumą NO Endoteliną Koagulacija Endotelio pirmines ląsteles Plokštelės stabilumas Kolageno Imuninis pažeidimas MMPs Makrofagus Plokštelės didėjimas Uždegimą Preclinical and clinical data suggest that statins may have a wide range of vasculoprotective effects: Normalize vasomotion by upregulating levels of nitric oxide (NO), the most potent endogenous vasodilator, and inhibiting the synthesis of endothelin, a potent vasoconstrictor1,2 Modulate immunoreactions and decrease immune injury by arresting the functional differentiation of monocytes into macrophages and promoting apoptosis; decrease inflammatory markers2-4 Decrease the production of free radicals (via a downregulation of angiotensin AT1 receptor expression) that may enhance the proliferation of vascular smooth muscle cells and induce apoptosis5 Retard plaque progression by inhibiting the oxidation of LDL, VLDL, and HDL and by suppressing the uptake of oxidized LDL by macrophages1 Promote plaque stability by decreasing the production of matrix metalloproteinases (MMPs) and increasing collagen content, thus strengthening the fibrous cap and making it less likely to rupture2,6 Decrease platelet activation and increase fibrinolytic activity in endothelial cells2 References: 1. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(suppl III):III-27–III Wassmann S, Nickenig G. Interrelationship of free oxygen radicals and endothelial dysfunction—modulation by statins. Endothelium. 2003;10: Vamvakopoulos JE, Green C. HMG-CoA reductase inhibition aborts functional differentiation and triggers apoptosis in cultured primary human monocytes: a potential mechanism of statin-mediated vasculoprotection. BMC Cardiovasc Disorders. 2003;3. Available at: 4. Hognestad A, Aukrust P, Wergeland R, et al. Effects of conventional and aggressive statin treatment on markers of endothelial function and inflammation. Clin Cardiol. 2004;27: Wassmann S, Laufs U, Bäumer AT, et al. Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol. 2001;59: Xu Z, Zhao S, Zhou H, et al. Atorvastatin lowers plasma matrix metalloproteinase-9 in patients with acute coronary syndrome. Clin Chem. 2004;50: Proliferaciją MTL-C DTL-C Trigliceridus (TG) Imunomoduliaciją Antioksidacinis poveikis AT1 receptor Laisvuosius radikalus NO=nitric oxide; MMPs=matrix metalloproteinases. Wassmann S, Nickenig G. Endothelium. 2003;10:23-33.

Aterosklerozės progresavimas prasideda nuo endotelio disfunkcijos

Endotelio disfunkcija - pirmasis aterosklerotinio proceso etapas
Normalus endotelis Pažeistas endotelis MTL-Ch Hipertenzija Diabetas Rūkymas Disfunkcija The endothelium is the major regulator of vascular homeostasis. This illustration compares the physical and functional characteristics of normal endothelium with an abnormal or dysfunctional endothelium1 Risk factors, such as high LDL-C, hypertension, diabetes, and smoking may disrupt vascular homeostasis and can cause endothelial dysfunction that is characterized by the impairment of arterial compliance and is mediated by the variety of factors discussed in the previous slide1,2 References: 1. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(suppl III):III-27–III Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340: Krjg.tonusas Reguliuoja trombocitų/ leukocitų adheziją Slopina LRL migraciją/ proliferaciją Barjeras lipidams ir kt. plazmos komponentams Vazokonstrikcija  trombocitų/ leukocitų adhezija LRLmigracija ir augimas  Lipidų kaupimasis LRL-lygiųjų raumenų ląstelės. Omoigui N, Dzau VJ. J Vasc Med Biol.1991;3: ; Ross R. N Engl J Med. 1999;340: ; Kathir K, Adams MR. Semin Vasc Med. 2003;3: ; Davignon J, Ganz P. Circulation. 2004;109(suppl III):III-27–III-32.

Endotelio funkcija palaiko kraujagyslių homeostazę
Vazodilatacija Priešuždegiminis Antioksidacija LRL augimo slopinimas Anti-trombogeninis Vazokonstrikcija Uždegimas Pro-oksidacija LRL proliferacija Trombozė In healthy vascular tissue, the endothelium maintains a balance between vasodilation and vasoconstriction, inhibition and stimulation of smooth muscle cell (SMC) proliferation and migration, and thrombogenic and fibrinolytic activity1 Reference: 1. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(suppl III):III-27–III-32. Kathir K, Adams MR. Semin Vasc Med. 2003;3: ; Omoigui N, Dzau VJ. J Vasc Med Biol.1991;3:

Endotelio disfunkcija: endotelio funkcijos sutrikimas
Vazodilatacija Priešuždegiminis Antioksidacija LRL augimo slopinimas Anti-trombogeninis Vazokonstrikcija Uždegimas Pro-oksidacija LRL proliferacija Trombozė When endothelial dysfunction occurs vascular homeostasis is disrupted and the balance of cellular activities favors initiation and progression of atherosclerosis1 Reference: 1. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(suppl III):III-27–III-32. Kathir K, Adams MR. Semin Vasc Med. 2003;3: ; Omoigui N, Dzau VJ. J Vasc Med Biol.1991;3:

Endotelio disfunkcija apibūdinama kaip relaksuojančių ir konstrikcinių faktorių pusiausvyros sutrikimas pastarųjų naudai, dėl ko vystosi generalizuotas ar lokalus vazospazmas, trombozė, aterosklerozė, restenozė

Endotelio disfunkcija yra susijusi su kardiovaskuliniais įvykiais
200 16 † 14% 14 150 12 10 100 Kardiovaskuliniai įvykiai Vid per 28 mėn. 8 Vainikinės kraujotakos kitimas (ACh) (%) 50 6 * 4 2 0% 0% In patients with coronary endothelial dysfunction, intracoronary injection of the endothelium-dependent vasodilator acetylcholine (ACh) produces vasoconstriction1 Suwaidi and colleagues separated 157 patients with mildly diseased coronary arteries into 3 groups (normal, mild, and severe endothelial dysfunction) based on the reactivity of their left anterior coronary artery to a bolus injection of ACh. Arterial diameter and coronary blood flow (CBF) were measured after each injection1 The number of cardiac events experienced by each patient was recorded during the follow-up period (mean = 28 months; range months)1 The results showed that the CBF response to ACh decreased as a function of the severity of the endothelial dysfunction. Even patients with mild endothelial dysfunction showed substantial vasoconstriction compared with normal controls1 Only patients with severe endothelial dysfunction experienced CV events during follow-up1 Reference: 1. Al Suwaidi J, Hamasaki S, Higano ST, et al. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000;101: 50 Normal endo fxn Mild endo dysfxn Severe endo dysfxn Normal endo fxn Mild endo dysfxn Severe endo dysfxn *P<.0001 vs normal endothelial function and severe endothelial dysfunction; †P<.05 vs normal endothelial function and severe endothelial dysfunction. ACh=acetylcholine; endo=endothelial; fxn=function; dysfxn=dysfunction. . Al Suwaidi J et al. Circulation. 2000;101:

Aterosklerotinio kraujagyslių pažeidimo modelis
Rizikos fakt Oksidacinis stresas Endotelio disfunkcija NO Lokalūs mediatoriai Audinių ACE-Ang II PAI-1 VCAM ICAM cytokinai Endotelis Augimo faktoriai Proteolizė LDL-C AH Širdies nepakankamumas Rūkymas Diabetas Vazokonstrikcija Krjg.pažeidimas ir remodeliacija Plokštelės ruptūra Uždegimas Trombozė Klinikiniai sindromai Well-recognised cardiovascular risk factors (hypertension, dyslipidaemia, diabetes, smoking, etc) are associated with changes in the vessel wall that lead to cardiovascular disease. One of the earliest changes associated with these risk factors is an increase in oxidative stress in the vessel wall. This causes endothelial cells to decrease production of some compounds and increase production of others.1 Production of nitric oxide (NO), a powerful vasodilator, is decreased. Production of vasoconstrictors, notably endothelin and angiotensin II (Ang II), is increased. Greater production of local mediators (eg. vascular cell adhesion molecule [VCAM], and plasminogen activator inhibitor 1 [PAI-1]) promotes inflammation, disrupts fibrinolysis, increases vascular remodeling and plaque rupture. The vascular endothelium secretes numerous other substances that modulate blood vessel tone and participate in the development and progression of atherosclerosis. Thus, the presence of cardiovascular risk factors begins a progression that sets the stage for clinical events. Reference 1. Gibbons GH, Dzau VJ. N Engl J Med 1994;330;1431–1438. NO Nitric oxide Gibbons GH, Dzau VJ. N Engl J Med 1994;330;

Aterogenezė – tai arterijos sienos struktūrų sąveikos su
kraujo plazmos ingredientais ir kraujo ląstelėmis pasekmė 2. Monocitų sukibimas ir penetracija MTL-C 1. Endotelio disfunkcija E-selection 7. Monocitų chemotaktinis baltymas (MCP-I) O2 OH 6. Lygiųjų raumenų ląstelių proliferacija ir migracija 3. Laisvieji radikalai oksiduoja MTL-C Ox-LDL 5. Uždegiminės medžiagos 4. Monocitai-makrofagai fagocituoja MTL-C ir virsta putotomis ląstelėmis

Endotelio sąlygota vazodilatacija žasto arterijoje (FMD)
Gydymas atorvastatinu gerina endotelio funkciją moterims pomenopauzėje su hipercholesterolemija Endotelio sąlygota vazodilatacija žasto arterijoje (FMD) † † † FMD (%) ‡ ‡ ‡ * Patients with hypercholesterolemia typically have endothelial dysfunction1 This study compared the effects of 2 lipid-lowering treatment regimens, atorvastatin 10 mg and the American Heart Association step 1 diet, on endothelial reactivity in 30 postmenopausal women with hypercholesterolemia and no concomitant CV risk factors. The percent change in brachial artery flow- mediated vasodilation (FMV) was measured at baseline and after 1, 2, 4, and 8 weeks of drug or diet therapy1 FMV was significantly increased in the atorvastatin group vs the diet group as early as 2 weeks after the initiation of treatment. Patients taking atorvastatin continued to show improvement during the 8-week study period, whereas those on diet therapy did not1 Reference: 1. Marchesi S, Lupattelli G, Siepi D, et al. Short-term atorvastatin treatment improves endothelial function in hypercholesterolemic women. J Cardiovasc Pharmacol. 2000;36: *P<.05; †P<.05 vs baseline; ‡P<.001 vs atorvastatin. Vidutinis moterų amžius – 56,8m. Marchesi S et al. J Cardiovasc Pharmacol. 2000;36:

Statinai ženkliai gerina endotelio funkciją ir mažina uždegimą sergantiems IŠL
Atorvastatino grupė (80 mg) Simvastatino grupė (20 mg) 60 50 * * * † * 40 † Levels 30 NS 20 * 10 Statins have also been shown to improve measures of inflammation and endothelial function1 This study compared the effects of intensive (atorvastatin 80 mg) vs conventional (simvastatin 20 mg) lipid-lowering therapy on cholesterol levels, inflammatory markers, and endothelial function in 97 patients with CAD after 6 months of treatment1 Both intensive and conventional treatment regimens significantly improved LDL-C, NO, CRP, and fibrinogen levels compared with baseline levels. However, much larger changes were observed in each of these parameters following intensive treatment with atorvastatin, particularly in the case of the inflammatory marker, CRP1 Reference: 1. Hognestad A, Aukrust P, Wergeland R, et al. Effects of conventional and aggressive statin treatment on markers of endothelial function and inflammation. Clin Cardiol. 2004;27: Ox-LDL NO CRP Fibrinogen (U/L) (umol/mL (ug/dL) (mg/dL) Baseline 6 months Pacientai, sirgę MI (N=97) amžiaus vidurkis 61.2±9.7m. *P<.01 vs baseline; †P<.05 vs baseline. Ox-LDL=oksiduotas MTL; NO=azoto oksidas; CRP=C-reaktyvus baltymas Hognestad A et al. Clin Cardiol. 2004;27:

Aterosklerozė – uždegiminė liga

Uždegimas skatina aterosklerozės vystymąsi
Kraujagyslės spindis Monocitai MTL-Ch Endotelis Adhezijos molekulės (VCAM-1, ICAM-1) MTL-Ch Uždegiminiai mediatoriai (CRP, CD40/CD40L, TNF-α, IL-1, IL-6) Ox-MTL-Ch Adhesion of monocytes to the endothelium is an early event in atherosclerosis. The activation of inflammatory cytokines induces the expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and E-selectin, which are required for the attachment of monocytes to the vascular wall1 Disease progression is also promoted by oxidation of LDL-C that stimulates the production of inflammatory gene products in vascular endothelial cells, leading to increased expression of cellular adhesion molecules2 In addition, oxidized LDL-C triggers the production of monocyte chemoattractants, which play an important role in the transformation of monocytes to macrophage foam cells. Foam cells result when activated macrophages express scavenger receptors and internalize oxidized LDL-C. Migration of smooth muscle cells from the intima into the media leads to formation of a fibrous atheroma3 Inflammatory mediators such as CRP, CD40/CD40 ligand (CD40L), tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and IL-6 also promote the atherosclerotic process by inhibiting collagen synthesis and stimulating secretion of collagenases, making the fibrous cap vulnerable and susceptible to rupture1,2,4 References: 1. Cockerill GW, Rye K-A, Gamble JR, et al. High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules. Arterioscler Thromb Vasc Biol. 1995;15: Libby P, Ridker PM, Maseri A, et al. Inflammation and atherosclerosis. Circulation. 2002;105: Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001;104: André P, Nannizzi-Alaimo L, Prasad SK, Phillips DR. Platelet-derived CD40L: the switch-hitting player of cardiovascular disease. Circulation. 2002;106: Intima Putotoji ląstelė Makrofagas CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule; ICAM=intercellular adhesion molecule. Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15: ; Andre P et al. Circulation. 2002;106: ; Libby P. Circulation. 2001;104: ; Libby P et al. Circulation. 2002;105: ; Ross R. N Engl J Med. 1999; :

Uždegiminių ir lipidinių faktorių įtaka kardiovaskulinių įvykių rizikai
Interleukin-6 B. cholesterolis MT cholesterolis ICAM-1 Serumo amyloidas A Apolipoproteinas B B.cholesterolis:DT cholesterolis A direct comparison of lipid and nonlipid risk factors for coronary disease suggests that factors other than lipid levels may help predict future risk of cardiovascular events. Hs-CRP and hs-CRP plus total cholesterol:HDL-C ratio were the strongest predictors of risk. A multivariate analysis showed that only hs-CRP levels and total:HDL-C ratio had independent predictive value after accounting for confounding factors. These data suggest that hs-CRP, in addition to lipid levels, may facilitate the identification and treatment of high-risk patients. Moreover, these data suggest future avenues for the treatment of cardiovascular disease. Ridker, PM. Circulation. 2001;103: dj-CRB dj-CRB + bendras cholesterolis :DT cholesterolis 1.0 2.0 4.0 6.0 Reliatyvi rizika Ridker, PM. Circulation. 2001;103:

CRB – kardiovaskulinės ligos prediktorius
9 8.7 8 7 7.2 6.0 6 Reliatyvi IŠL rizika 6.0 5 5.1 4.2 4 5.0 4.2 3.5 3 4.2 3.0 3.5 2 2.9 2.5 2.2 2.9 2.5 1 2.1 High-sensitivity C-reactive protein (hsCRP) is considered to be an independent predictor of heart attack and stroke in apparently healthy men and women1 This figure illustrates the relationship between quintiles of hsCRP and the TC:HDL-C ratio in healthy, middle-aged patients. The relative risk of CHD increases with increasing levels of cholesterol and CRP1 In this survey, the median CRP level was 0.16 mg/dL and the CRP ranges for quintiles 1 to 5 were: 0.01 to mg/dL, to 0.11 mg/dL, 0.12 to 0.19 mg/dL, 0.20 to 0.38 mg/dL, and >0.38 mg/dL, respectively1 The quintile ranges for TC:HDL-C recommended in clinical practice are: <3.5, 3.5 to 4.3, 4.4 to 5.0, 5.1 to 6.1, and >6.1 for men and <3.1, 3.1 to 3.6, 3.7 to 4.3, 4.4 to 5.2, and >5.2 for women1 Importantly, patients in the lowest cholesterol quintile but the highest quintile of CRP have an elevated risk of CHD1 Use of this quintile-based analysis may facilitate the identification of patients with low to moderate cholesterol levels who may be at increased risk of vascular disease1 Reference: 1. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation. 2001;103: 1.7 2.0 1.7 1.4 1.4 1.2 5 5 4 4 1.0 3 3 dj-CRB kvintilės BCh:DTL-C kvintilės 2 2 1 1 Ridker PM. Circulation. 2001;103: ; Libby P et al. Circulation. 2002;105:

dj-CRB ir kardiovaskulinė rizika
dj-CRB koncentracija Santykinė rizika < 1 mg/L Maža 1.0 – 3.0 mg/L Vidutinė > 3.0 mg/L Didelė AHA/CDC Statement. Circulation 2003; 107:499–511

DALI: Atorvastatinas (priklausomai nuo dozės) ženkliai mažina CRB kiekį pacientams sergantiems 2 tipo CD N=197pts. 30sav. Placebo Atorvastatinas 10 mg Atorvastatinas 80 mg 6.6 ↓ 54% MTL 40%TG -14.6 Atorvastatin has been shown to reduce CRP levels in patients with type 2 diabetes in a dose-dependent fashion1 197 patients with type 2 diabetes and dyslipidemia and no evidence of CAD were randomized to receive either 10-mg or 80-mg atorvastatin or placebo for 30 weeks1 Atorvastatin achieved significant dose-dependent reductions in lipid levels: -41% (LDL-C) and -30% (TC) with atorvastatin 10 mg, and -54% (LDL-C) and -40% (TC) with atorvastatin 80 mg (P<.001)1 The high dose of atorvastatin significantly decreased CRP levels compared with placebo and low-dose atorvastatin1 Reference: 1. van de Ree MA, Huisman MV, Princen HMG, et al. Strong decrease of high sensitivity C-reactive protein with high-dose atorvastatin in patients with type 2 diabetes mellitus. Atherosclerosis. 2003;166: -46.7 * *P<.001. DALI=diabetes atorvastatin lipid intervention study. IQR=interquartile range van de Ree MA et al. Atherosclerosis. 2003;166:

MIRACL: Gydymas atorvastatinu ženkliai sumažina CRB
11.5 11.0 -34%* 2.9 In the MIRACL study, patients with ACS were randomized to receive atorvastatin 80 mg or placebo within 24 to 96 hours of hospital admission. Since CRP is an acute phase reactant, there was the expected dramatic reduction in levels in both groups1 Compared with placebo, 16 weeks of therapy with atorvastatin had a highly significant effect on CRP—levels decreased 83% with atorvastatin and 74% with placebo. Overall, CRP levels were 34% lower in patients treated with atorvastatin than those treated with placebo1 Reference: 1. Kinlay S, Schwartz GG, Olsson AG, et al. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation. 2003;108: 1.9 *P<.0001. Kinlay S et al. Circulation. 2003;108:

ASAP: ilgalaikis gydymas atorvastatinu ženkliai sumažina CRB
Baseline 1 metai 2 metai -50 -40 -30 -20 -10 Taip pat nustatyta, kad: nėra koreliacijos tarp CRB ir MTL-Ch mažėjimo Akivaizdus ryšys tarp CRB sumažėjimo ir IMS suplonėjimo (r =.13; P=.03) Pacientams, kuriems ryškiausiai mažėjo CRB, labiausiai mažėjo ir IMS 14.0 19.7 Pokytis (%) P<.001 P<.022 In ASAP, atorvastatin 80 mg reduced CRP significantly more than simvastatin 40 mg. At 1 year, the median percent change in CRP was 44.9% with atorvastatin and 14.0% with simvastatin (P<.001). By 2 years, the median percent change was 40.1% with atorvastatin and 19.7% with simvastatin (P<.022)1 There was no correlation between reductions in CRP and LDL-C. However, decreases in CRP were significantly correlated with reductions in IMT (r =.13; P=.03)1 Patients in the highest CRP tertile experienced the greatest mean reduction in IMT1 Reference: 1. van Wissen S, Trip MD, Smilde TJ, et al. Differential hs-CRP reduction in patients with familial hypercholesterolemia treated with aggressive or conventional statin therapy. Atherosclerosis. 2002;165: 40.1 44.9 Atorvastatin 80 mg Simvastatin 40 mg van Wissen S et al. Atherosclerosis. 2002;165:

Nėra ryšio tarp pasiekto MTL-chol ir CRB lygio gydant statinais
30 80 130 180 .1 1 10 100 Pasiektas MTL-chol (mg/dL) Pasiektas CRB (mg/L) r = 0.18 Variance = 3 percent KW: CRP, statin, LDL Ridker et al NEJM 2005;352:20-28. PROVE IT – TIMI 22

REVERSAL: CRB ir MTL-Ch mažėjimas gydant statinais
N = 654 IŠL pts. Gydymas 18 mėn MTL-Ch CRB -5.2 -25.2 -36.4 * In REVERSAL, investigators also compared the CRP-lowering and lipid-lowering effects of atorvastatin 80 mg with pravastatin 40 mg in 654 patients with obstructive CAD. After 18 months of therapy, atorvastatin therapy was associated with significantly greater reductions in both LDL-C and CRP levels compared with pravastatin1 Reference: 1. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291: -46.3 * *P<.001. Nissen SE et al. JAMA. 2004;291:

REVERSAL: ateromos tūrio vertinimas intrakraujagysliniu ultragarsu (IVUS)
Total atheroma volume (TAV) was calculated from measurements taken using videotapes obtained from IVUS pullbacks that were analyzed in a core laboratory in a blinded fashion. Every 60th image was analyzed, generating a series of images that were exactly 1.0 mm apart1 The primary end point—percent change in TAV— was calculated as the difference between external elastic membrane (EEM) and lumen areas across all segments suitable for evaluation, divided by TAV at baseline1 Reference: 1. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291: Nissen SE et al. JAMA. 2004;291:

Ateromos tūrio pokytis (mm3)
REVERSAL: aterosklerozės regresija gydant statinais pirmiausiai stebima tiems kuriems sumažėjo ir MTL-chol ir CRB kartu +8mm3 Progresavi mas Ateromos tūrio pokytis (mm3) +2mm3 KW: CRP, statin, LDL, REVERSAL - 1mm3 Regresija - 2mm3 MTL CRB MTL CRB MTL CRB MTL CRB Nissen et al NEJM 2005; 352:29-38

Ateromos tūrio polkytis (%)
REVERSAL: CRB mažėjimas turi tiesioginį ryšį su ateromos tūrio mažėjimu 3.5 2.5 1.5 Ateromos tūrio polkytis (%) 0.5 0.0 0.5 1.5 The REVERSAL investigators examined the effect of change in LDL-C and change in CRP on atherosclerotic disease progression in 502 patients with CAD treated with either atorvastatin 80 mg or pravastatin 40 mg1 The change in LDL-C was positively correlated with change in atheroma volume. In addition, there was also a significant positive correlation between change in CRP and change in both percent atheroma volume and total atheroma volume1 Analysis of the entire patient population showed a weak but significant correlation between reduction in CRP and change in LDL-C; however, there was no correlation within treatment groups1 Reference: 1. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005;352:29-38. 3.5 14 12 10 8 6 4 2 2 4 6 CRB pokytis (mg/L) Nissen SE et al. N Engl J Med. 2005;352:29-38.

PROVE IT: CRB greičiau mažėja vartojant atorvastatiną sergantiems ūmiais koronariniais sindromais
100 P=.6 Vidurinis CRB lygis (mg/L) 10 P<.001 P<.001 P<.001 In the PROVE IT trial, patients who had been hospitalized with ACS were treated with either atorvastatin 80 mg or pravastatin 40 mg immediately after their condition had stabilized. Patients treated with atorvastatin experienced reductions in recurrent clinical events as early as 30 days after the start of therapy1 At randomization, patients in both treatment groups had similar median levels of CRP. However, these data show that, after 30 days of treatment, atorvastatin 80 mg lowered levels of CRP significantly more than pravastatin 40 mg (1.7 mg/L vs 2.4 mg/L; P<.001). This effect continued at 4 months (1.3 mg/L vs 2.0 mg/L; P<.001) and persisted until study completion, when patients treated with atorvastatin achieved CRP levels that were 38% lower than those in the pravastatin group (1.3 mg/L vs 2.1 mg/L; P<.001)2,3 As expected, atorvastatin 80 mg also caused bigger reductions in LDL-C at all time points compared with pravastatin 40 mg. At the end of the study the rate of the occurrence of the composite primary end point was 16% lower in patients treated with atorvastatin1 The authors stated that this early benefit with atorvastatin is similar to what was seen in the MIRACL trial, but is about 1 to 2 years earlier than what is usually observed for patients with chronic atherosclerosis. They speculated further that patients with ACS may have additional vulnerable plaques and therefore may derive particular benefit from early and intensive statin therapy that stabilizes these lesions1 References: 1. Cannon CP, Braunwald E, McCabe CH, et al. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350: Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352: Ridker PM, Morrow D, Cannon CP, et al. Interrelationships of LDL cholesterol and hsCRP in the PROVE-IT clinical trial comparing intensive versus moderate lipid-lowering strategies among patients with acute coronary syndromes [abstract 2342]. Circulation. 2004;110(suppl III):III-499. 38% 1 Randomizacija 30 dienų 4 mėn. Studijos pabaiga Atorvastatin 80 mg Pravastatin 40 mg Ridker PM et al. N Engl J Med. 2005;352:20-28.

PROVE IT: CRB ir MTL-Ch lygis susijęs su ūmių koronarinių įvykių pasikartojimu
0.10 MTL-C >70 mg/dL, CRB >2 mg/L 0.08 MTL-C 70 mg/dL, CRB <2 mg/L MTL-C <70 mg/dL, CRB >2 mg/L 0.06 Pasikartojęs miokardo infarktas Ar satigi koronarinė mirtis (%) MTL-C <70 mg/dL, CRB <2 mg/L 0.04 MTL-C <70 mg/dL, CRB <1 mg/L 0.02 Although statin therapy is proven to lower levels of CRP, there is a lack of evidence showing that greater reductions in CRP provide CV benefits. The PROVE IT investigators examined the effects of atorvastatin 80 mg and pravastatin 40 mg and the impact of reductions in LDL-C and CRP on the risk of recurrent CV events in patients with ACS1 Patients were divided into groups with LDL-C levels above and below 70 mg/dL, the approximate median LDL-C level attained by the patient population. Analyses were performed to measure the risk of recurrent events in patients with LDL-C levels above and below this value. Similarly, patients were divided into groups according to the approximate median CRP value of 2 mg/L, and the relationship between the CRP level attained and rate of recurrent events was determined1 Although LDL-C and CRP were both reduced by statin therapy, there was only a slight correlation between the levels achieved. Despite this, however, there was a linear relationship between the reduction in CRP and recurrence of MI and coronary death1 The figure above shows that, in patients with LDL-C levels 70 mg/dL, those with a CRP value <2 mg/L were less likely to experience a recurrent MI or die from coronary causes than patients with CRP 2 mg/dL. Correspondingly, patients with LDL-C <70 mg/dL and CRP <2 mg/L were at lower risk of experiencing a recurrent event compared with those with low LDL-C but CRP 2 mg/L. In general, patients with CRP levels <2 mg/L had better clinical outcomes than those with higher levels, regardless of LDL-C1 Reference: 1. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20-28. 0.00 0.0 0.0 0.0 0.5 0.5 0.5 1.0 1.0 1.0 1.5 1.5 1.5 2.0 2.0 2.0 2.5 2.5 2.5 Stebėjimo metai Adapted from Ridker PM et al. N Engl J Med. 2005;352:20-28; Ridker PM et al. Presented at AHA Scientific Sessions; 2004.

Simva (40-80 mg) vs placebo + simva 20 mg
Atorvastatinas labiau sumažina CRB pacientams su ūmiais koronariniais sindromais A to Z MIRACL PROVE IT Gydymas Simva (40-80 mg) vs placebo + simva 20 mg Atorva 80 mg vs placebo Atorva 80 mg vs prava 40 mg Randomizuota pacientų 4497 3086 4162 MTL-C skirtumas (mg/dL) Ankstyvas* Vėlyvas 62 15 63 NA 33 28 CRB skirtumas (%) 17 34 38 Įvykių sumažėjimas (%) Ankstyvas Vėlyvas‡ 0* 11 16* 18† 16 A to Z, MIRACL, and PROVE IT all studied patients with ACS. In both A to Z and MIRACL, patients experienced similar early reductions in LDL-C (62 mg/dL vs 63 mg/dL). However, despite the significant LDL-C reduction with simvastatin 40 mg in A to Z, there was no reduction in clinical events during the first 4 months of the trial. In comparison, atorvastatin 80 mg achieved significant relative risk reductions of 16% and 18% in MIRACL and PROVE IT, respectively. These data suggest that the benefits of statin therapy cannot be entirely explained by reductions in LDL-C1 The table shows that in MIRACL and PROVE IT atorvastatin 80 mg achieved greater reductions in levels of CRP than were achieved with simvastatin 40 to 80 mg in A to Z. This greater reduction in CRP with atorvastatin may have contributed to the early reduction in clinical events seen in MIRACL and PROVE IT1 Reference: 1. Nissen SE. High-dose statins in acute coronary syndromes: not just lipid levels. JAMA. 2004;292: *Measured 120 days after randomization. †Measured 90 days after randomization. ‡Measured at trial completion—24 months in A to Z and PROVE IT. Nissen SE. JAMA. 2004;292: ; de Lemos et al. JAMA. 2004;292: ; Cannon CP et al. N Engl J Med. 2004;350:

Padidėjęs uždegiminio mediatoriaus (tirpaus ligando CD40) kiekis susijęs su didesne kardiovaskuline rizika sergantiems ŪKS Quartile 1 Quartile 2 Quartile 3 Quartile 4 * 3.5 3 * † 2.5 † * † 2 Hazard ratio (HR) 1.5 1 0.5 CD40 ligand (CD40L) is an inflammatory mediator that is expressed by several cell types including endothelial cells, SMCs, monocytes, macrophages, and platelets. When activated, it is released into the plasma as its soluble form (sCD40L), where it plays a role in atherosclerotic disease progression. Levels of CD40L are elevated in patients with ACS and peripheral arterial disease. Furthermore, in apparently healthy women, high plasma levels of CD40L are a risk predictor for future CVD1 In a nested case-control study, 390 patients with ACS were followed for up to 10 months. The prespecified study end points were death, MI, or congestive heart failure (CHF)2 After adjustment for other risk factors, elevated plasma levels of sCD40L were found to be an independent predictor of increased risk of death, recurrent MI, and the composite end point of death/MI/CHF. As shown in the chart above, when patients were divided into quartiles according to the sCD40L levels, those with concentrations above the median were at the greatest risk of having another cardiovascular event2 These data suggest that elevated levels of sCD40L precede recurrent MI and support the hypothesis that CD40L may play an integral role in the pathophysiology of ACS2 References: 1. André P, Nannizzi-Alaimo L, Prasad SK, Phillips DR. Platelet-derived CD40L: the switch-hitting player of cardiovascular disease. Circulation. 2002;106: Varo N, de Lemos JA, Libby P, et al. Soluble CD40L: risk prediction after acute coronary syndromes. Circulation. 2003;108: Mirtis MI D/MI LŠN D/MI/LŠN N- 390 , stebėjimas – 10 mėn. *P<.01 versus first quartile; †P<.05 versus first quartile. Varo N et al. Circulation. 2003;108;

MIRACL: atorvastatino poveikis pakartotiniems kardiovaskuliniams įvykiams (vertinant sCD40L)
Atorvastatinas 16 sav. gydymas Placebo Pakartotiniai įvykiai pacientams su >90th centile sCD40L 30 30 25 25 20 - 48% 20 Kardialinių įvykių dažnis (%) 15 Kardialinių įvykių dažnis (%) 15 10 10 5 In the MIRACL trial, sCD40L levels were measured in ACS patients at baseline and after 16 weeks of treatment with either atorvastatin 80 mg or placebo. Patients with sCD40L levels in the >90th centile experienced a higher incidence of cardiac events compared with patients with lower levels (OR 1.86; 95% CI, )1 Despite the lack of a significant reduction in sCD40L, atorvastatin reduced the risk associated with high sCD40L levels by 48% (OR 1.09; 95% CI, ). This observation may be explained by the authors’ suggestion that atorvastatin may inhibit downstream effects of high sCD40L that promote inflammation or thrombogenesis1 These data suggest that inhibition of anti-inflammatory and antithrombotic pathways may contribute to the vasculoprotective effects of atorvastatin1 Reference: 1. Kinlay S, Schwartz GG, Olsson AG, et al. Effect of atorvastatin in risk of recurrent cardiovascular events after an acute coronary syndrome associated with high soluble CD40 ligand in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study. Circulation. 2004;110: 5 90th sCD40L >90th centile 90th sCD40L >90th centile Visi pacientai (n-3086) Placebo Atorvastatin 80 mg Kinlay S et al. Circulation. 2004;110:

Oksidacija aterosklerotinio proceso progresavime

Aktyvūs deguonies radikalai (ROS) skatina aterosklerozės progresavimą
Monocitai atpalaiduoja MPO, O2, and NO esant uždegimui ROS pažeidžia baltymus, susidaro azoto junginiai (nitrotyrosine) Monocitas O2 Superoxide Maža plokštelė MPO generuoja ROS MPO Nitric oxide ROS Endotelis Myeloperoxidase (MPO) is an iron-containing protein that is secreted by monocytes and activated macrophages. MPO uses hydrogen peroxide to generate a variety of reactive oxygen and nitrogen species that may promote endothelial dysfunction, atherosclerosis, and acute coronary events1 Markers of MPO have been shown to be present at all stages of atherosclerosis,1 and accumulating evidence suggests that MPO plays an early role in the relationship between oxidation and CVD.2 Levels of MPO are elevated in the plasma of patients with CVD and in the culprit lesions of sudden- death patients. In addition, statin therapy causes reductions in levels of oxidative markers of protein damage by MPO2 MPO generates ROS that can lead to the generation of reactive nitrogen species and other ROS that may cause lipid oxidation. Oxidized lipids are proatherogenic and are engulfed by activated macrophages to form foam cells, the earliest component of atherosclerotic plaque2,3 References: 1. Heinecke JW. Oxidative stress: new approaches to diagnosis and prognosis in atherosclerosis. Am J Cardiol. 2003;91(suppl):12A-16A. 2. Brennan M-L, Hazen SL. Emerging role of myeloperoxidase and oxidant stress markers in cardiovascular risk assessment. Curr Opin Lipidol. 2003;14: Libby P. Atherosclerosis: the new view. Sci Am. 2002;286:46-55. Putlioji ląstelė Lipidų oksidatacija paverčia MTL aterogeniniais oxMTL LDL Makrofagai fagocituoja oxMTL ir virsta putotomis ląstelėmis-ankstyvas ath plokštelės komponentas MPO=myeloperoxidase; O2 =superoxide; NO=nitric oxide Adapted from Shishehbor MH, Hazen SL. Cleve Clin J Med. 2004;71:

MTL-Ch oksidacija skatina aterosklerotinio pažeidimo vystymąsi
Grynas MTL-Ch Oksidacinis stresas Modifikuotas (oksiduotas) MTL-Ch Aterogeniniai poveikiai Putotų ląstelių formavimasis Monocitų mobilumo ↑ Monocitų adhezijos prie endotelio ↑ Laisvųjų-radikalų produkcija For many years it has been known that elevated LDL-C is a risk factor for CVD. However, it appears that for LDL-C to be atherogenic it must first be modified.1 Oxidative modification of LDL facilitates its uptake by scavenger receptors on the cell surface of macrophages present in the vascular endothelium. Oxidized LDL has other proatherogenic properties including promoting monocyte mobility and adhesion to the endothelium, smooth muscle cell proliferation, vasodilation, and free-radical production2,3 References: 1. Heinecke JW. Oxidative stress: new approaches to diagnosis and prognosis in atherosclerosis. Am J Cardiol. 2003;91(suppl):12A-16A. 2. Meagher EA, FitzGerald GA. Indices of lipid peroxidation in vivo: strengths and limitations. Free Rad Biol Med. 2000;28: Chisolm GM, Steinberg D. The oxidative modification hypothesis of atherogenesis: an overview. Free Rad Biol Med. 2000;28: Meagher EA, FitzGerald GA. Free Rad Biol Med. 2000;28: ; Chisolm GM, Steinberg D. Free Rad Biol Med. 2000;28: ; Heinecke JW. Am J Cardiol. 2003;91(suppl):12A-16A.

Atorvastatinas yra vienintelis statinas HMG CoA reduktazės inhibitorius su aktyviais metabolitais
Atorvastatino pirminė molekulė CH3 CH3 O CH O OH - 70% atorvastatino aktyvumo yra sąlygota jo aktyviųjų metabolitų .. NHC N F Aktyvus ortho-hydroxy-atorvastatino metabolitas Apsaugo MTL-Ch nuo oksidacijos H H H3C O O CH3 Atorvastatin is a synthetic lipid-lowering agent that is administered as the calcium salt of the active hydroxy acid (parent molecule).1 After administration, atorvastatin is rapidly absorbed and metabolized to the active hydroxylated metabolites, and peak plasma concentrations occur in 1 to 2 hours. Approximately 70% of atorvastatin’s activity is attributed to the active metabolites The o-hydroxy group, which is unique to the active atorvastatin metabolite, has been shown to protect LDL-C from oxidation1 Reference: 1. Walter MF, Jacob RF, Weng Y, Mason RP. Active hydroxy metabolite of atorvastatin increases resistance of human low-density lipoproteins to oxidative modification [abstract 882-4]. J Am Coll Cardiol. 2004;43(5 pt A):529A. OH O . . O N N H *Unique to ortho-hydroxy metabolite. Data on file (RP Mason). Pfizer Inc., New York, NY. F

Atorvastatinas ženkliai mažina MTL-Ch oksidacijos greitį
Grynas MTL-Ch Oksidacinis stresas Modifikuotas MTL-Ch Grynas MTL-Ch Negydoma + Atorvastatino metabolitai Aterogeniniai efektai Putotųjų ląstelių formavimasis Monocitų mobilumo ↑ Chemoatrakcija Monocitų adhezijos prie endotelio ↑ Laisvųjų-radikalų produkcija Native LDL is not atherogenic.1 However, oxidative modification enhances lipid binding to the vascular endothelium and accumulation within the vessel wall. In the intima, oxLDL is engulfed by macrophages to form foam cells, a major component of atheroslcerotic plaque. In addition, modified LDL promotes inflammatory pathways that attract monocytes to the affected area2 Fluvastatin and simvastatin have demonstrated antioxidant effects at suprapharmacologic doses. However, the active o-hydroxy atorvastatin metabolite protects LDL from oxidation at pharmacologic concentrations in a dose-dependent manner. By protecting LDL from oxidative modification, the active atorvastatin metabolite may preserve the native form of the molecule and so maintain its normal activity3-5 References: 1. Heinecke JW. Oxidative stress: new approaches to diagnosis and prognosis in atherosclerosis. Am J Cardiol. 2003;91(suppl):12A-16A. 2. Rosenson RS. Statins in atherosclerosis: lipid-lowering agents with antioxidant capabilities. Atherosclerosis. 2004;173: Mason RP, Walter MF, Jacob RF. Effects of HMG-CoA reductase inhibitors on endothelial function: role of microdomains and oxidative stress. Circulation. 2004;190(suppl II):II-34–II Yamamoto A, Hoshi K, Ichihara K. Fluvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, scavenges free radicals and inhibits lipid peroxidation in rat liver microsomes. Eur J Pharmacol. 1998;361: Girona J, La Ville AE, Solà R, et al. Simvastatin decreases aldehyde production derived from lipoprotein oxidation. Am J Cardiol. 1999;83: Normalus aktyvumas Heinecke JW. Am J Cardiol. 2003;91(suppl):12A-16A; Meagher EA, FitzGerald GA. Free Rad Biol Med. 2000;28: ; Chisolm GM, Steinberg D. Free Rad Biol Med. 2000;28: ; Mason RP et al. Circulation. 2004;190(suppl II):II-34–II-41.

Įvairių statinų poveikis į oksidacinį stresą membranose
60 * 54 50 40 Oksiduotų lipidų (LOOH) formavimiosi slopinimas (%) 30 20 * * 10 12 11 A recent in vitro study compared the abilities of atorvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin to protect LDL from oxidation. The o-hydroxy atorvastatin metabolite dramatically inhibited the formation of modified LDL in a dose-dependent manner (54% inhibition; P<.01). The atorvastatin parent molecule brought about a significant 12% reduction in lipid oxidation (P<.01). Lovastatin inhibited lipid oxidation by 11% (P<.01). Pravastatin, rosuvastatin, and simvastatin did not protect LDL from oxidative modification1 Small X-ray diffraction analyses and molecular modeling calculations showed that the hydroxy portion of the active atorvastatin metabolite forms a close interaction with susceptible acyl groups in the lipid moiety, independently of HMG-CoA reductase inhibition. This unique interaction enables the atorvastatin metabolite to increase LDL resistance to oxidative modification. Unlike the parent compound and other statins, the o-hydroxy group of the metabolite can quench free-radical reactions1 Reference: 1. Walter MF, Jacob RF, Weng Y, Mason RP. Active hydroxy metabolite of atorvastatin increases resistance of human low-density lipoproteins to oxidative modification [abstract 882-4]. J Am Coll Cardiol. 2004;43(5 pt A):529A. Atorvastatino metabolitas Atorvastatinas pirminis Lovastatinas -10 Gydymas(500 nM) Pravastatinas, rozuvastatinas, ir simvastatinas neapsaugo MTL-Ch nuo oksidacinio streso *P<.01 vs control. LOOH=lipid hydroperoxide. Walter MF et al. J Am Coll Cardiol. 2004;43(5 pt A):529A.

Atorvastatinas slopina įvairius oksidacijos būdus
Dityrosine Chlorotyrosine Nitrotyrosine Orthotyrosine -32 -30 -25 -11 -5 -10 Oksidacijos žymenų sumažėjimas (%) -15 -20 -25 ‡ This study by Shishehbor et al provides evidence of the antioxidant effect of atorvastatin in a clinical setting1 In order to identify distinct oxidative pathways that are inhibited by statin therapy, hypercholesterolemic patients without clinical evidence of CAD were treated with atorvastatin 10 mg for 12 weeks. Plasma levels of dityrosine, chlorotyrosine, nitrotyrosine, and orthotyrosine—markers of the activity of specific oxidative pathways—were measured at baseline and after 12 weeks of treatment. Lipid levels and CRP were measured in parallel1 Dityrosine, chlorotyrosine, nitrotyrosine, and orthotyrosine are MPO and NO-derived oxidants that are elevated in atheroma taken from atherosclerotic human aorta. The oxidative pathways that lead to formation of these oxidants have been shown to promote lipid peroxidation, NO consumption, endothelial dysfunction, and the activation of MMP and other protease cascades that result in the formation of vulnerable plaque. Atorvastatin produced significant reductions in levels of dityrosine, chlorotyrosine, and nitrotyrosine (-32%, -30%, -25%, respectively). The 11% decrease in orthotyrosine did not reach statistical significance. Reductions in oxidative markers were independent of reductions in lipids and CRP1 These data indicate that treatment with atorvastatin brings about the inhibition of distinct oxidative pathways known to promote atherosclerosis1 Reference: 1. Shishehbor MH, Brennan M-L, Aviles RJ, et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation. 2003;108: -30 † * -35 *P<.001; †P<.01; ‡P<.02. Hypercholesteroleminiai pts (N=35) be IŠL gydyti atorvastatinu (10 mg) 12 sav. CRB ir lipidų mažėjimas buvo nepriklausomas nuo antioksidacinio poveikio Shishehbor MH et al. Circulation. 2003;108;

Procentinis pokytis bendrojo oxPL/apoB Reliatyvus pokytis (%)
MIRACL: atorvastatinas gali mobolizuoti oksiduotus fosfolipidus (oxPL) iš kraujagyslės sienelės Procentinis pokytis bendrojo oxPL/apoB Reliatyvus pokytis oxPL/apoB -0.2 * 9.5 * 8.8 Pokytis (%) Reliatyvus pokytis (%) -0.7 Oxidized phospholipids (oxPL) are present in atherosclerotic plaque and are bound to lipoprotein(a) [Lp(a)] in the circulation. The MIRACL investigators examined the effect of atorvastatin 80 mg on plasma levels of oxLDL in patients with ACS. After 16 weeks of treatment, a 29.7% reduction in total apoB-oxPL was achieved with atorvastatin compared with a reduction of 0.2% with placebo. In addition, atorvastatin significantly reduced absolute and relative levels of apoB-100 and total apoB-IC1 However, when normalized to apoB, there were significant increases in oxPL/apoB and Lp(a) with atorvastatin compared with placebo (P<.0001). These observations led the authors to suggest that atorvastatin may augment oxPL efflux from the vessel wall and increase binding to apoB—primarily in the form of Lp(a)—and thus enhance clearance from the circulation. Lp(a) levels may have increased in response to improved oxPL mobilization, to facilitate its transport and clearance from the circulation1 Atorvastatin may lower levels of oxPL by reducing levels of the substrate for oxidation (LDL) and also through the anti-inflammatory and antioxidant effects of its active metabolite. Significant reductions in levels of vasoactive and pro-inflammatory oxPL may have contributed to the 16% reduction in recurrent ischemic events at 16 weeks in ACS patients treated with atorvastatin 80 mg in MIRACL1,2 References: 1. Tsimikas S, Witztum JL, Miller ER, et al. High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial. Circulation. 2004;110: Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. JAMA. 2001;285: -29.7 * -3.9 Atorvastatinas Placebo oxPL/apoB Lp(a) Atorvastatinas 80 mg Placebo *P<.0001 vs placebo. Lp(a)=lipoprotein(a). Tsimikas S et al. Circulation. 2004;110;

Lygiųjų raumenų ląstelės
Aterosklerozės kulminacija: plokštelės nestabilumas, plyšimas, trombozė Monocitai LDL-C Adhezijos molekulės Makrofagai Putotos ląstelės Oksiduotas MTL-Ch Plokštelės plyšimas Lygiųjų raumenų ląstelės CRB Endothelial dysfunction may be the earliest stage of coronary atherosclerosis1 Reference: 1. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340: Endotelio disfunkcija Uždegimas Oksidacija Nestabili plokštelė ir trombas Libby P. Circulation. 2001;104: ; Ross R. N Engl J Med. 1999;340:

Aterosklerotinės plokštelės stabilumas
Nestabili plokštelė Stabili plokštelė Lipidinė šerdis Fibrotinė kepurėlė Fibrotinė kepurėlė Nedaug uždegiminių ląstelių Uždegiminės Ląstelės (TF) Atherogenic plaque consists of a lipid core separated from the vascular lumen by a fibrous cap. The lipid core is composed of lipid-filled macrophages—foam cells—and other inflammatory cells. Foam cells produce tissue factor (TF), a powerful coagulant that triggers thrombosis when it comes into contact with blood1 Unstable plaque has a thin vulnerable cap that is prone to rupture, bringing the blood into contact with thrombogenic TF, which may result in thrombus and an acute vascular event1 Stable plaque, however, tends to have fewer inflammatory cells and a thick fibrous cap that protects the lipid core from making contact with blood1 Reference: 1. Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91: Lipidinė šerdis TF- audinių faktorius - stiprus koaguliantas, kuris inicijuoja trombozę, po kontakto su krauju Toschi V et al. Circulation. 1997;95: ; Libby P. Circulation. 1995;91:

GAIN: Ženklus plokštelės echogeniškumo padidėjimas gydant atorvastatinu
50 42.2 40 N= 131 30 Vidutinis pokytis po 12 mėn. gydymo (%) 20 * 10.1 11.8 10 2.5 -0.3 -2.1 -10 Plokštelės tūris Hyperechogeniška stabili (fibrotinė plokštelė) Hypoechogeniška, nestabili (lipidinė plokštelė) In this study, 131 patients were randomized to atorvastatin or usual care that consisted of treatment with a variety of other lipid-lowering drugs. The initial atorvastatin dose was 20 to 40 mg and was titrated to 80 mg if the LDL-C goal of <100 mg/dL was not achieved1 Plaque echogenicity was determined by intracoronary ultrasound (ICUS). Hyperechogenicity is thought to indicate the presence of dense fibrous tissue; whereas hypoechogenicity may identify a greater proportion of loose fibrous, lipid, or necrotic tissue. Therefore, increased hyperechogenicity would imply improved plaque stability and hypoechogenicity would imply plaque vulnerability1 In the atorvastatin group, LDL-C was reduced to a mean level of 86 mg/dL. Patients receiving usual care achieved a mean LDL-C level of 140 mg/dL1 There was less plaque progression, as measured by intravascular ultrasound (IVUS), with atorvastatin compared with usual care, 2.5% vs 11.8%, respectively1 Plaque hyperechogenicity was increased considerably more with atorvastatin compared with usual care. The mean percent change was 42.2% for atorvastatin and 10.1% for usual care (P=.021)1 The authors suggested that the increase in hyperechogenicity with atorvastatin could indicate changes in composition that result in greater stability and a lower probability of rupture. This hypothesis was supported by the lower cardiac event rates in patients treated with atorvastatin1 Reference: 1. Schartl M, Bocksch W, Koschyk DH, et al. 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;104: Patients (N=131) aged 18 to 75 years who were recommended for intracoronary revascularization and who had previously undergone successful intracoronary intervention were randomized to atorvastatin 20 to 40 mg initial dose with titration to 80 mg to attain LDL-C <100 mg/dL if necessary; or usual care. Follow-up was 12 months. Aim: to measure change in plaque echogenicity and atherosclerosis progression with intensive lipid lowering with atorvastatin. Atorvastatinas mg Įprastas gyd. *P=.021. GAIN=German atorvastatin intravascular ultrasound study. Schartl M et al. Circulation. 2001;104:

MMP-9 kiekio plazmoje pokytis Atorvastatino koncentracija (mol/L)
Atorvastatinas priklausomai nuo dozės ženkliai sumažina matrix metaloproteinazių (MMP-9) kiekį MMP-9 kiekio plazmoje pokytis N=40 Cirkuliuojančių MMP-9 kiekio ↓ 200 100 0.1 1 10 * * * PBMC supernatant MMP-9 (mg/L) † † Matrix metalloproteinases (MMPs) are extracellular enzymes that have the ability to degrade the collagen matrix of the fibrous cap of atherosclerotic plaque, increasing the likelihood of rupture. In atherosclerotic plaque, macrophages are the primary source of matrix-degrading MMP, of which MMP-9 is the most prevalent1 This in vitro study examined the effect of atorvastatin on levels of MMP in patients with ACS. Following their first ACS episode, 40 patients were randomly assigned to conventional therapy plus atorvastatin 10 mg or conventional therapy alone. Conventional therapy consisted of treatment with aspirin, beta-blocker, angiotensin-converting enzyme inhibitor, low-molecular-weight heparin, and urokinase. Plasma levels of MMP-9 were measured at baseline and after 4 weeks of treatment1 Concurrent treatment with conventional therapy and atorvastatin achieved significant reductions in LDL-C levels. With conventional therapy alone, lipid levels were not significantly altered1 Plasma levels of MMP-9 were lowered significantly in both treatment groups. However, with atorvastatin, the reduction was significantly greater than with conventional therapy (P<.05). Atorvastatin reduced MMP-9 levels in a dose-dependent manner1 These results led the authors to speculate that some of the clinical benefits in patients with ACS may be attributed to atorvastatin-related reductions in levels of MMP-91 Reference: 1. Xu Z, Zhao S, Zhou H, et al. Atorvastatin lowers plasma matrix metalloproteinase-9 in patients with acute coronary syndrome. Clin Chem. 2004;50: Atorvastatino koncentracija (mol/L) MMPs - enzimai (iš makrofagų), ardantys kolageno matriksą plokštelės fibrotinėje kepurėlėje - ↑ plyšimo rizika *P<.05; †P< PBMC=peripheral blood mononuclear cells. Xu Z et al. Clin Chem. 2004;50:

ATROCAP: atorvastatinas keičia plokštelės trombogeniškumo ir uždegiminį profilį
Plokštelių su uždegiminiaias požymiais pokytis N=59 Plokštelių su makrofagais pokytis Ploklštelės (%) 25 50 75 100 Placebo Atorvastatinas 20 mg Plokštelės(%) 25 50 75 100 Placebo Atorvastatinas 20 mg The Atorvastatin and ThRombogenicity Of the Carotid Atherosclerotic Plaque (ATROCAP) investigators examined the effect of atorvastatin 10 mg on plaque stability and thrombogenicity in the carotid arteries of patients with bilateral carotid stenosis who were eligible for a 2-step carotid endoarterectomy (CEA)1 Eligible patients underwent their first CEA, and all specimens were sent to a central laboratory for evaluation. The day after the first procedure, 59 patients were randomized to atorvastatin 20 mg or placebo. The second procedure was performed after 4 to 5 months of treatment. The specimens acquired were used to evaluate plaque ulceration, thrombosis, inflammation, and intraplaque thrombogenic factors (TF and TF pathway inhibitor [TFPI])1 In patients treated with atorvastatin, plaque specimens taken during the second CEA had a lower percentage of inflammatory cells and a lower macrophage content. These data suggest that atorvastatin reduces the inflammatory profile of atherosclerotic plaque, which may result in vasculoprotective effects1 Reference: 1. Cortellaro M, Cofrancesco E, Arbustini E, et al. Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study. Thromb Haemost. 2002;88:41-47. 1st CEA 2nd CEA po 4-5 mėn CEA – karotidinė endarterektomija Adapted from Cortellaro M et al. Thromb Haemost. 2002;88:41-47.

ATROCAP: atorvastatinas mažina plokštelės trombogeniškumą
Audinių faktoriaus aktyvumas * † ‡ -140 -90 -40 10 60 110 TF Ag TF aktyvumas Audinių faktoriaus aktyvumas (pg/mg) Plaque removed from atorvastatin-treated patients during the second CEA had significantly lower TF Ag and TF activity compared with plaque from patients given placebo1 Since TF is known to stimulate thrombosis following plaque rupture, a reduction in levels would be expected to reduce thrombogenesis2 References: 1. Cortellaro M, Cofrancesco E, Arbustini E, et al. Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study. Thromb Haemost. 2002;88: Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91: Atorvastatinas 20 mg Placebo *P=.049 (vs placebo).†P=.029 (1st vs 2nd CEA). ‡P=.085 (1st vs 2nd CEA). Cortellaro M et al. Thromb Haemost. 2002;88:41-47.

Pravastatinas40mg geriau
PROVE IT: atorvastatinas mažina ūmios revaskuliarizacijos poreikį pacientams po ūmių koronarinių sindromų OR & 95% CI Aukštas MTL-C 125 mg/dL Ūmi revask. Aukštas MTL-C 125 mg/dL Atidėta revask. Žemas MTL-C <125 mg/dL Ūmi revask. Žemas MTL-C <125 mg/dL Atidėta revask. Atorvastatin 80 mg significantly reduced the need for urgent revascularizations compared with pravastatin 40 mg. Elective revascularizations were not significantly reduced1 In patients in the high LDL-C group (125 mg/dL), the need for both urgent and elective revascularizations was reduced significantly more with atorvastatin than with pravastatin1 In the low LDL-C group, atorvastatin caused a small reduction in urgent revascularizations and no change in the need for elective revascularizations compared with pravastatin1 These data suggest that, by reducing LDL-C levels and inhibiting inflammatory and proliferative pathways, atorvastatin may slow plaque growth and stabilize vulnerable, rupture-prone plaque in patients with ACS1 Reference: 1. Sabatine MS, Morrow DA, McCabe CH, et al. Does intensive statin therapy reduce both urgent and elective coronary revascularization? Results from PROVE-IT TIMI 22 [abstract 3220]. Circulation. 2004;110(suppl III):III-696. 0.25 0.50 1.00 2.00 Atorvastatinas 80mg geriau Pravastatinas40mg geriau Atorvastatinas gali stabilizuoti linkusias progresuoti plokšteles pacientams po ūmių koronarinių sindromų Adapted from Sabatine MS et al. Circulation. 2004;110(suppl III):III-696.

Vaskuloprotekcinis (nuo cholesterolio nepriklausantis) statinų poveikis
Figure 1. Cholesterol-independent effects of statins. Plus sign enhanced/activated; minus sign inhibited; AT1 angiotensin 1; ET-1 endothelin 1; hs-CRP high-sensitivity C-reactive protein; MMPs matrix metalloproteinases; NO nitric oxide; PAI-1 plasminogen activator inhibitor-1; ROS reactive oxygen species; SMC smooth muscle cell; TF tissue factor; t-PA tissue-type plasminogen activator; TXA2 thromboxane A2. (Adapted with permission from Arterioscler Thromb Vasc Biol.)4

Atorvastatinas, šalia lipidus mažinančio poveikio, pasižymi vaskuloprotektinėmis savybėmis :
Gerina endotelio funkciją Mažina CRB ir kitus uždegiminius markerius Didina plokštelės stabilumą mažindamas jos tūrį ir oksidacinį stresą. Nepriklausomas nuo lipidų kiekio palankus vazoprotekcinis statinų poveikis ilgalaikio gydymo pasėkoje gali sąlygoti kardiovaskulinių komplikacijų mažėjimą.

...Todėl statinus (atorvastatiną) skiriame ne tik lipidams mažinti,
Bet ir... apsaugoti kraujagysles nuo atrosklerozės ir jos komplikacijų progresavimo (ypač po ūmių, nestabilių būklių)

Dėkoju už dėmesį

Ačiū už dėmesį !

PROVE IT: Effect of Intensive vs Less Intensive Statin Therapy on Urgent and Elective Coronary Revascularization The PROVE IT investigators hypothesized that intensive statin therapy would reduce the need for urgent coronary revascularization more than the need for elective revascularization Patients were given atorvastatin 80 mg or pravastatin 40 mg for an average of 2 years In this analysis, patients were divided by baseline LDL values into 2 groups and the rates of urgent and elective coronary revascularization were compared High LDL 125 mg/dL Low LDL <125 mg/dL Since the propensity of a plaque to rupture is related to lipid content, among other factors, the PROVE IT investigators hypothesized that intensive lipid lowering with atorvastatin would reduce the need for urgent revascularization more than the need for elective procedures1 The investigators examined the effects of atorvastatin 80 mg, pravastatin 40 mg, and the impact of baseline lipid levels on the rates of urgent and elective revascularization in 4162 patients with ACS1 Reference: 1. Sabatine MS, Morrow DA, McCabe CH, et al. Does intensive statin therapy reduce both urgent and elective coronary revascularization? Results from PROVE-IT TIMI 22 [abstract 3220]. Circulation. 2004;110(suppl III):III-696. Sabatine MS et al. Circulation. 2004;110(suppl III):III-696.

Summary Atorvastatin has been shown to reduce CV events in patients with: Hypertension and mildly elevated LDL-C (ASCOT-LLA) Diabetes (CARDS) ACS (MIRACL, PROVE IT) Stable CHD (ALLIANCE) Atherosclerotic plaque progression can be halted with intensive atorvastatin therapy (REVERSAL) Compared with other statins, treatment with atorvastatin achieves greater CV benefits (ASAP, REVERSAL, PROVE IT) Significant clinical benefits with atorvastatin were evident as early as 30 days (PROVE IT) Atorvastatin provides significant lipid reductions across the dose range LDL-C 39% to 60%; TG 19% to 37% Accumulating evidence suggests that atorvastatin may have vasculoprotective effects beyond lipid lowering, including: Improving endothelial function Reducing CRP and other markers of inflammation Increasing plaque stability by reducing plaque volume and oxidative stress Enhanced cholesterol-independent benefits with intensive statin therapy may contribute to greater reductions in CV outcomes The results of landmark statin trials have shown that atorvastatin reduces CV events in a wide range of patients, including those with: Hypertension and mildly elevated LDL-C (ASCOT-LLA)1 Diabetes (CARDS)2 ACS (MIRACL, PROVE IT)3,4 Stable CHD (ALLIANCE)5 REVERSAL demonstrated that atherosclerotic plaque progression can be halted with intensive atorvastatin therapy6 Compared with other statins, atorvastatin achieves greater CV benefits (ASAP, REVERSAL, PROVE IT)4,6,7 Significant clinical benefits with atorvastatin were evident as early as 30 days (PROVE IT)8 Accumulating evidence suggests that atorvastatin may have vasculoprotective effects beyond lipid lowering, including: Improving endothelial function9 Reducing CRP,10 and Increasing plaque stability by reducing oxidative stress and plaque volume11 These enhanced cholesterol-independent effects may contribute to improved CV outcomes12 References: 1. Sever PS, Dahlof B, Poulter NR, et al. 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: Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364: Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. The MIRACL study: a randomized controlled trial. JAMA. 2001;285: Cannon CP, Braunwald E, McCabe CH, et al. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350: Koren MJ, Hunninghake DB. 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;44: Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291: 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, randomised, double-blind trial. Lancet. 2001;357: Cannon CP, Ray KK, McCabe CH, et al. Two windows of cardioprotection: the early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes. Results from the PROVE IT-TIMI 22 trial [abstract 2341]. Circulation. 2004;110(suppl III):III Marchesi S, Lupattelli G, Siepi D, et al. Short-term atorvastatin treatment improves endothelial function in hypercholesterolemic women. J Cardiovasc Pharmacol. 2000;36: Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352: Walter MF, Jacob RF, Weng Y, Mason RP. Active hydroxy metabolite of atorvastatin increases resistance of human low-density lipoproteins to oxidative modification [abstract 882-4]. J Am Coll Cardiol. 2004;43(5 pt A):529A. 12. Gupta S. Does aggressive statin therapy offer improved cholesterol-independent benefits compared to conventional statin therapy? Int J Cardiol. 2004;96: Sever PS et al. Lancet. 2003;361: ; Colhoun HM et al. Lancet. 2004;364: ; Schwartz GG et al. JAMA. 2001;285: ; Cannon CP et al. N Engl J Med. 2004;350: ; Koren MJ, Hunninghake DB. J Am Coll Cardiol. 2004;44: ; Nissen SE et al JAMA. 2004;291: ; Smilde TJ et al. Lancet. 2001;357: ; Cannon CP et al. Circulation. 2004;110(suppl III);III-499; Marchesi S et al J Cardiovasc Pharmacol. 2000;36: ; Ridker PM et al. N Engl J Med. 2005;532:20-28; Walter MF et al. J Am Coll Cardiol. 2004; (5 pt A):529A; Gupta S. Int J Cardiol. 2004;96:

Summary (cont’d) Pooled data from 44 completed trials were used to assess the safety of atorvastatin 10 to 80 mg In more than 9000 patients, atorvastatin demonstrated safety across the 10- to 80-mg dose range Incidence of treatment-associated adverse events did not rise with increased doses of atorvastatin (10-80 mg) Overall incidence of treatment-associated adverse events was similar for atorvastatin, placebo, and other statins The most frequent treatment-associated adverse event for any statin was related to the digestive system Occurrence of serious adverse events was infrequent and rarely resulted in withdrawal Myopathy*—considered an important adverse effect of statins—occurred in approximately 0.1% of patients Pooled data from 44 atorvastatin trials completed by November 1, 2001 were used to analyze the safety of atorvastatin. The analysis included data from 16,495 patients with dyslipidemia. Of these patients, 9416 received atorvastatin, 1789 were given placebo, and 5290 received other statins—simvastatin, pravastatin, lovastatin, or fluvastatin1 Atorvastatin demonstrated safety across the 10- to 80-mg dose range. With increasing doses of atorvastatin (10-80 mg) there was no increase in the overall incidence of treatment-associated adverse events1 The overall incidence of treatment-associated events was similar for atorvastatin, placebo, and other statins1 For any statin, the most common treatment-associated adverse event was related to the digestive system1 Occurrence of serious adverse events was infrequent and rarely resulted in withdrawal1 Myopathy, considered an important adverse effect of statins, occurred in approximately 0.1% of patients1 Reference: 1. Newman CB, Palmer G, Silbershatz H, et al. Safety of atorvastatin derived from analysis of 44 completed trials in 9416 patients. Am J Cardiol. 2003;92: *Myopathy defined as creatine phosphokinase (CPK) >10 times the upper limit of normal (ULN). Newman CB et al. Am J Cardiol. 2003;92:

Primary prevention trials
CV Benefits of Intensive LDL-C Lowering With Atorvastatin Have Been Shown in Primary Prevention Trials Primary prevention trials 10 y=.0599x  R2=.9305 P=.0019 9 CARDS-P 8 7 WOSCOPS-P 6 WOSCOPS-PR 5 CHD events (%) AFCAPS-P CARDS-AT 4 AFCAPS-LO 3 ASCOT-P 2 ASCOT-AT Observational studies revealed an association between LDL-C and risk of CHD. This relationship was evident even at LDL-C levels below those generally seen in modern populations1 More than 100,000 people have received statins in CHD prevention trials, and the results of these studies have shown that for both primary and secondary prevention, there is a correlation between on-treatment LDL-C and CHD risk1 The authors suggested that for primary prevention, the LDL-C level at which the CHD rate is predicted to approach 0 is 57 mg/dL1 Of the major primary prevention trials, the greatest reductions in LDL-C and CHD events occurred with atorvastatin 10 mg in ASCOT. In this trial, atorvastatin 10 mg reduced the risk of the nonfatal MI and fatal CHD by 36% in hypertensive patients at moderate risk for CVD2 References: 1. O’Keefe JH, Cordain L, Harris WH, et al. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004;43: Sever PS, Dahlof B, Poulter NR, et al. 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: 1 -1 55 75 95 115 135 155 175 195 LDL-C (mg/dL) Atorvastatin Pravastatin Placebo Lovastatin AT=atorvastatin; LO=lovastatin; P=placebo; PR=pravastatin. Adapted from O’Keefe JH et al. J Am Coll Cardiol. 2004;43: ; Colhoun HM et al. Lancet. 2004;364:

Secondary prevention trials
CV Benefits of Intensive LDL-C Lowering With Atorvastatin Have Been Shown in Secondary Prevention Trials Secondary prevention trials 30 y=0.1629x  R2=0.9029 P<.0001 4S-P ALLIANCE-UC 25 20 ALLIANCE-AT HPS-P LIPID-P 4S-S CHD events (%) 15 HPS-S CARE-P LIPID-PR 10 PROVE IT-AT CARE-PR PROVE IT-PR 5 CHD event rates in secondary prevention trials were also directly proportional to on-treatment LDL-C levels. The authors speculated that the secondary event rate will approach 0 at LDL-C levels of 30 mg/dL (0.78 mmol/L)1 Among the secondary prevention trials used in this analysis, the greatest reductions in LDL-C and CHD events were with atorvastatin 80 mg in PROVE IT1,2 References: 1. O’Keefe JH, Cordain L, Harris WH, et al. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004;43: Cannon CP, Brauwald E, McCabe BS, et al. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350: 30 50 70 90 110 130 150 170 190 210 LDL-C (mg/dL) Atorvastatin Pravastatin Simvastatin Usual care Placebo AT=atorvastatin; P=placebo; PR=pravastatin; S=simvastatin; UC=usual care. Adapted from O’Keefe JH et al. J Am Coll Cardiol. 2004;43: ; Koren MJ et al. J Am Coll Cardiol ;44:

Simva (40-80 mg) vs placebo + simva 20 mg
Despite Similar Reductions in LDL-C, Significant Clinical Benefits Seen Only With Atorvastatin A to Z MIRACL PROVE IT Treatment Simva (40-80 mg) vs placebo + simva 20 mg Atorva 80 mg vs placebo Atorva 80 mg vs prava 40 mg No. of patients randomized 4497 3086 4162 LDL-C differential (mg/dL) Early* Late 62 15 63 NA 33 28 Event reduction (%) Early Late‡ 0* 11 16* 18† 16 This chart shows the magnitude of the LDL-C reduction and percent decrease in major cardiac events experienced by patients treated with simvastatin, atorvastatin, or pravastatin in the A to Z, MIRACL, and PROVE IT trials1 When comparing the early effects of statin treatment (4 months/16 weeks), patients in A to Z and MIRACL experienced similar reductions in LDL-C. However, in the MIRACL trial, treatment with atorvastatin caused a significant 16% reduction in the occurrence of early CV events, whereas no early benefit was seen with simvastatin in A to Z1 The results from these trials suggest that although lowering LDL-C is important, other factors may play a role in the vasculoprotective effects of atorvastatin1 Reference: 1. Nissen SE. High-dose statins in acute coronary syndromes: not just lipid levels. JAMA. 2004;292: *Measured 120 days after randomization. †Measured 90 days after randomization. ‡Measured at trial completion—24 months for A to Z and PROVE IT. LDL-C=low-density lipoprotein cholesterol. NA=data not available. Adapted from Nissen SE. JAMA. 2004;292:

REVERSAL: Intensive Lipid Lowering With Atorvastatin Halted Plaque Progression After 18 Months
20 15 10 Pravastatin (40 mg) 5 Change in atheroma volume (mm3) Atorvastatin (80 mg) -5 -10 -15 As one would expect, results from the REVERSAL trial demonstrated an inverse relationship between reduction in LDL-C and change in atheroma volume. Pravastatin and atorvastatin produced parallel regression lines. However, for any degree of reduction in LDL-C, the progression rate was lower with atorvastatin than with pravastatin. The investigators suggested that this added benefit with atorvastatin was equivalent to an additional 20% reduction in LDL-C. Data such as these suggest that, although LDL-C plays a central role in the progression of atherosclerosis, improved outcomes with atorvastatin are not due to intensive LDL-C lowering alone1 Reference: 1. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291: For any degree reduction in LDL-C, the progression rate was lower with atorvastatin than with pravastatin Change in LDL-C (%) Nissen SE et al. JAMA. 2004;291:

Aterosklerozė prasideda anksti ir lėtai progresuoja daug metų
Foam cells Fatty streak Intermediate lesion Atheroma Fibrous plaque Complicated lesion/rupture Atherosclerosis begins early in life and progresses silently for many years. During the first 3 decades of life, plaque growth occurs primarily through the accumulation of lipids in the vascular wall. Oxidized LDL-C becomes incorporated into macrophages, resulting in the formation of plaque-forming foam cells. Fatty streaks appear due to the local accumulation of serum lipoproteins in the vessel wall1 As plaque continues to grow, intermediate lesions and atheromas appear. This is due to continued lipid accumulation, the migration and proliferation of smooth muscle cells, and the deposition of an extracellular connective tissue matrix, which together form a fibrous cap over the lipid-laden core2 Rupture of the plaque exposes the highly thrombogenic core and may result in thrombus formation and the occlusion of blood flow2 References: 1. Pepine CJ. The effects of angiotensin-converting enzyme inhibition on endothelial dysfunction: potential role in myocardial ischemia. Am J Cardiol. 1998;82(suppl 10A):23S-27S. 2. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340: Endothelial dysfunction From first decade From third decade From fourth decade Growth mainly by lipid accumulation Smooth muscle and collagen Thrombosis hematoma Pepine CJ. Am J Cardiol. 1998;82(suppl 10A):23S-27S.

Aterogenezė – tai arterijos sienos struktūrų sąveikos su kraujo plazmos ingredientais ir kraujo ląstelėmis pasekmė Krjg.spindis MTL-chol MTL-chol Arterijos sienelė J Hypertens 1999; 17 (12 Part 2):

Vaskuloprotekcinės statinų savybės M.dr. Jolanta Marcinkevičienė

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Vaskuloprotekcinės statinų savybės M.dr. Jolanta Marcinkevičienė

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