It has repeatedly been shown that statins decrease morbidity and mortality in patients with atherosclerosis, thus supporting their use for the primary and secondary prevention of ischemic heart disease. Different pathological pathways that are triggered in the setting of acute coronary syndrome (ACS), such as endothelial dysfunction, activation of inflammatory and coagulation cascades, and thrombus formation, are known to be inhibited by statins, thereby justifying the use of these agents in patients with ACS. Several recent prospective controlled clinical trials have demonstrated the safety and, in some cases, the efficacy of statins when administered early after ACS. An increasing number of publications have reported, however, that statins may confer a beneficial effect not only in early secondary prevention, but also in the direct treatment of ACS (ie, when statins are administered as first-line treatment in clinically unstable patients). This therapeutic option is supported by the following: numerous experimental studies demonstrating a protective effect of statins under conditions of acute ischemia; analysis of different registries and trials, which has demonstrated a more favourable prognosis for statin-treated patients at the time of acute myocardial ischemia; and small clinical trials reporting a lower periprocedural infarction rate during coronary intervention or lower levels of several prognostic biomarkers, in addition to a lower incidence of cardiovascular events associated with statin therapy. Nevertheless, confirmation of this hypothesis in large prospective controlled clinical trials will be necessary before the implementation of statins as first-line therapy in unstable patients with ACS, irrespective of blood cholesterol levels.

Cardiovascular Center Department of Cardiology Na Homolce Hospital Prague Czech Republic

Zobrazit více v PubMed

Zhou Q, Liao JK. Pleiotropic effects of statins – basic research and clinical perspectives. Circ J. 2010;74:818–26. PubMed PMC

Blum A, Shamburek R. The pleiotropic effects of statins on endothelial function, vascular inflammation, immunomodulation and thrombogenesis. Atherosclerosis. 2009;203:325–30. PubMed

Lardizabal JA, Deedwania PC. The anti-ischemic and anti-anginal properties of statins. Curr Atheroscler Rep. 2011;13:43–50. PubMed PMC

Aikawa M, Libby P. The vulnerable atherosclerotic plaque: Pathogenesis and therapeutic approach. Cardiovasc Pathol. 2004;13:125–38. PubMed

Davies MJ. Acute coronary thrombosis – the role of plaque disruption and its initiation and prevention. Eur Heart J. 1995;(16 Suppl):L:3–7. PubMed

Davies MJ. Detecting vulnerable coronary plaques. Lancet. 1996;347:1422–3. PubMed

Ambrose JA, Hjemdahl-Monsen CE, Borrico S, Gorlin R, Fuster V. Angiographic demonstration of a common link between unstable angina pectoris and non-Q-wave acute myocardial infarction. Am J Cardiol. 1988;61:244–7. PubMed

Pasterkamp G, Schoneveld AH, Hijnen DJ, et al. Atherosclerotic arterial remodeling and the localization of macrophages and matrix metalloproteases 1, 2 and 9 in the human coronary artery. Atherosclerosis. 2000;150:245–53. PubMed

Dickson BC, Gotlieb AI. Towards understanding acute destabilization of vulnerable atherosclerotic plaques. Cardiovasc Pathol. 2003;12:237–48. PubMed

Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657–71. PubMed

Rabbani R, Topol EJ. Strategies to achieve coronary arterial plaque stabilization. Cardiovasc Res. 1999;41:402–17. PubMed

Bank AJ, Versluis A, Dodge SM, Douglas WH. Atherosclerotic plaque rupture: A fatigue process? Med Hypotheses. 2000;55:480–4. PubMed

Shah PK, Falk E, Badimon JJ, et al. Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation. 1995;92:1565–9. PubMed

Loree HM, Kamm RD, Stringfellow RG, Lee RT. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res. 1992;71:850–8. PubMed

Heinecke JW. Oxidized amino acids: Culprits in human atherosclerosis and indicators of oxidative stress. Free Radic Biol Med. 2002;32:1090–101. PubMed

Sugiyama S, Okada Y, Sukhova GK, Virmani R, Heinecke JW, Libby P. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am J Pathol. 2001;158:879–91. PubMed PMC

Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest. 1996;98:2572–9. PubMed PMC

Libby P. Atherosclerosis: The new view. Sci Am. 2002;286:46–55. PubMed

Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A. 1989;86:2839–43. PubMed PMC

Lupu F, Bergonzelli GE, Heim DA, et al. Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler Thromb. 1993;13:1090–100. PubMed

Colley KJ, Wolfert RL, Cobble ME. Lipoprotein associated phospholipase A(2): Role in atherosclerosis and utility as a biomarker for cardiovascular risk. EPMA J. 20112:27–38. PubMed PMC

Epps KC, Wilensky RL. Lp-PLA – a novel risk factor for high-risk coronary and carotid artery disease. J Intern Med. 2011;269:94–106. PubMed

Zalewski A, Macphee C. Role of lipoprotein-associated phospholipase A2 in atherosclerosis: Biology, epidemiology, and possible therapeutic target. Arterioscler Thromb Vasc Biol. 2005;25:923–31. PubMed

Kolodgie FD, Burke AP, Skorija KS, et al. Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26:2523–9. PubMed

Mallat Z, Lambeau G, Tedgui A. Lipoprotein-associated and secreted phospholipases A in cardiovascular disease: Roles as biological effectors and biomarkers. Circulation. 2010;122:2183–200. PubMed

Ryu SK, Mallat Z, Benessiano J, et al. Phospholipase A2 enzymes, high-dose atorvastatin, and prediction of ischemic events after acute coronary syndromes. Circulation. 2012;125:757–66. PubMed

Nicholls SJ, Cavender MA, Kastelein JJ, et al. Inhibition of secretory phospholipase A(2) in patients with acute coronary syndromes: Rationale and design of the Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks (VISTA-16) trial. Cardiovasc Drugs Ther. 2012;26:71–5. PubMed

Cybulsky MI, Iiyama K, Li H, et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest. 2001;107:1255–62. PubMed PMC

Gu L, Okada Y, Clinton SK, et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 1998;2:275–81. PubMed

Plutzky J. Inflammatory pathways in atherosclerosis and acute coronary syndromes. Am J Cardiol. 2001;88:10K–5K. PubMed

Kadar A, Glasz T. Development of atherosclerosis and plaque biology. Cardiovasc Surg. 2001;9:109–21. PubMed

Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski T, Luscher TF. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation. 1998;97:2494–8. PubMed

Braganza DM, Bennett MR. New insights into atherosclerotic plaque rupture. Postgrad Med J. 2001;77:94–8. PubMed PMC

Libby P. Changing concepts of atherogenesis. J Intern Med. 2000;247:349–58. PubMed

Pinderski LJ, Fischbein MP, Subbanagounder G, et al. Overexpression of interleukin-10 by activated T lymphocytes inhibits atherosclerosis in LDL receptor-deficient mice by altering lymphocyte and macrophage phenotypes. Circ Res. 2002;90:1064–71. PubMed

Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study) Am J Cardiol. 1998;81:582–7. PubMed

Insull W, Kafonek S, Goldner D, Zieve F. Comparison of efficacy and safety of atorvastatin (10mg) with simvastatin (10mg) at six weeks. ASSET Investigators. Am J Cardiol. 2001;87:554–9. PubMed

Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: The pravastatin inflammation/CRP evaluation (PRINCE): A randomized trial and cohort study. JAMA. 2001;286:64–70. PubMed

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;108:1560–6. PubMed

Ridker PM, Rifai N, Lowenthal SP. Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia. Circulation. 2001;103:1191–3. PubMed

Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S. Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels. Circulation. 2001;103:1933–5. PubMed

Riesen WF, Engler H, Risch M, Korte W, Noseda G. Short-term effects of atorvastatin on C-reactive protein. Eur Heart J. 2002;23:794–9. PubMed

van de Ree MA, Huisman MV, Princen HM, Meinders AE, Kluft C. Strong decrease of high sensitivity C-reactive protein with high-dose atorvastatin in patients with type 2 diabetes mellitus. Atherosclerosis. 2003;166:129–35. PubMed

Koh KK, Schenke WH, Waclawiw MA, Csako G, Cannon RO., III Statin attenuates increase in C-reactive protein during estrogen replacement therapy in postmenopausal women. Circulation. 2002;105:1531–3. PubMed

Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Taylor AJ. Effect of atorvastatin and pravastatin on serum C-reactive protein. Am Heart J. 2003;145:e8. PubMed

Ansell BJ, Watson KE, Weiss RE, Fonarow GC. hsCRP and HDL effects of statins trial (CHEST): Rapid effect of statin therapy on C-reactive protein and high-density lipoprotein levels: A clinical investigation. Heart Dis. 2003;5:2–7. PubMed

Kleemann R, Verschuren L, de Rooij BJ, et al. Evidence for anti-inflammatory activity of statins and PPARalpha activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro. Blood. 2004;103:4188–94. PubMed

Romano M, Diomede L, Sironi M, et al. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest. 2000;80:1095–100. PubMed

Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res. 2001;89:763–71. PubMed

Koh KK, Son JW, Ahn JY, et al. Non-lipid effects of statin on hypercholesterolemic patients established to have coronary artery disease who remained hypercholesterolemic while eating a step-II diet. Coron Artery Dis. 2001;12:305–11. PubMed

Rezaie-Majd A, Maca T, Bucek RA, et al. Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2002;22:1194–9. PubMed

Brull DJ, Sanders J, Rumley A, Lowe GD, Humphries SE, Montgomery HE. Statin therapy and the acute inflammatory response after coronary artery bypass grafting. Am J Cardiol. 2001;88:431–3. PubMed

Ikeda U, Shimada K. Statins and monocytes. Lancet. 1999;353:2070. PubMed

Ferro D, Parrotto S, Basili S, Alessandri C, Violi F. Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia. J Am Coll Cardiol. 2000;36:427–31. PubMed

Bustos C, Hernandez-Presa MA, Ortego M, et al. HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis. J Am Coll Cardiol. 1998;32:2057–64. PubMed

Ikeda U, Shimpo M, Ohki R, et al. Fluvastatin inhibits matrix metalloproteinase-1 expression in human vascular endothelial cells. Hypertension. 2000;36:325–9. PubMed

Aikawa M, Rabkin E, Sugiyama S, et al. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation. 2001;103:276–83. PubMed

Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation. 2001;103:926–33. PubMed

Seljeflot I, Tonstad S, Hjermann I, Arnesen H. Reduced expression of endothelial cell markers after 1 year treatment with simvastatin and atorvastatin in patients with coronary heart disease. Atherosclerosis. 2002;162:179–85. PubMed

Sardo MA, Castaldo M, Cinquegrani M, et al. Effects of atorvastatin treatment on sICAM-1 and plasma nitric oxide levels in hypercholesterolemic subjects. Clin Appl Thromb Hemost. 2002;8:257–63. PubMed

Niwa S, Totsuka T, Hayashi S. Inhibitory effect of fluvastatin, an HMG-CoA reductase inhibitor, on the expression of adhesion molecules on human monocyte cell line. Int J Immunopharmacol. 1996;18:669–75. PubMed

O’Donoghue M, Morrow DA, Sabatine MS, et al. Lipoprotein-associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndromes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) trial. Circulation. 2006;113:1745–52. PubMed

Tsiara S, Elisaf M, Mikhailidis DP. Early vascular benefits of statin therapy. Curr Med Res Opin. 2003;19:540–56. PubMed

Suzumura K, Yasuhara M, Narita H. Superoxide anion scavenging properties of fluvastatin and its metabolites. Chem Pharm Bull (Tokyo) 1999;47:1477–80. PubMed

Suzumura K, Yasuhara M, Tanaka K, Odawara A, Narita H, Suzuki T. An in vitro study of the hydroxyl radical scavenging property of fluvastatin, and HMG-CoA reductase inhibitor. Chem Pharm Bull (Tokyo) 1999;47:1010–2. PubMed

Suzumura K, Yasuhara M, Tanaka K, Suzuki T. Protective effect of fluvastatin sodium (XU-62-320), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on oxidative modification of human low-density lipoprotein in vitro. Biochem Pharmacol. 1999;57:697–703. PubMed

Hussein O, Schlezinger S, Rosenblat M, Keidar S, Aviram M. Reduced susceptibility of low density lipoprotein (LDL) to lipid peroxidation after fluvastatin therapy is associated with the hypocholesterolemic effect of the drug and its binding to the LDL. Atherosclerosis. 1997;128:11–8. PubMed

Kalinowski L, Dobrucki IT, Malinski T. Cerivastatin potentiates nitric oxide release and enos expression through inhibition of isoprenoids synthesis. J Physiol Pharmacol. 2002;53:585–95. PubMed

Kalinowski L, Dobrucki LW, Brovkovych V, Malinski T. Increased nitric oxide bioavailability in endothelial cells contributes to the pleiotropic effect of cerivastatin. Circulation. 2002;105:933–8. 26; PubMed

Fuhrman B, Koren L, Volkova N, Keidar S, Hayek T, Aviram M. Atorvastatin therapy in hypercholesterolemic patients suppresses cellular uptake of oxidized-LDL by differentiating monocytes. Atherosclerosis. 2002;164:179–85. PubMed

Endres M, Laufs U. Effects of statins on endothelium and signaling mechanisms. Stroke. 2004;35(11 Suppl 1):2708–11. PubMed

Vaughan CJ, Murphy MB, Buckley BM. Statins do more than just lower cholesterol. Lancet. 1996;348:1079–82. PubMed

Jeremy JY, Rowe D, Emsley AM, Newby AC. Nitric oxide and the proliferation of vascular smooth muscle cells. Cardiovasc Res. 1999;43:580–94. PubMed

De Caterina R, Libby P, Peng HB, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995;96:60–8. PubMed PMC

Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998;97:1129–35. PubMed

Morikawa S, Takabe W, Mataki C, et al. The effect of statins on mRNA levels of genes related to inflammation, coagulation, and vascular constriction in HUVEC. Human umbilical vein endothelial cells. J Atheroscler Thromb. 2002;9:178–83. PubMed

Laufs U, Gertz K, Dirnagl U, Bohm M, Nickenig G, Endres M. Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice. Brain Res. 2002;942:23–30. PubMed

Laufs U, Endres M, Custodis F, et al. Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription. Circulation. 2000;102:3104–10. PubMed

Laufs U, Liao JK. Targeting Rho in cardiovascular disease. Circ Res. 2000;87:526–8. PubMed

Jacobson JR. Statins in endothelial signaling and activation. Antioxid Redox Signal. 2009;11:811–21. PubMed PMC

Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M. Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol. 2000;20:61–9. PubMed

Jagroop IA, Mikhailidis DP. Effect of endothelin-1 on human platelet shape change: Reversal of activation by naftidrofuryl. Platelets. 2000;11:272–7. PubMed

Barton M, Lattmann T, d’Uscio LV, Luscher TF, Shaw S. Inverse regulation of endothelin-1 and nitric oxide metabolites in tissue with aging: Implications for the age-dependent increase of cardiorenal disease. J Cardiovasc Pharmacol. 2000;36(5 Suppl 1):S153–6. PubMed

Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998;101:2711–9. PubMed PMC

Dupuis J, Tardif JC, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (ReductIon of Cholesterol in Ischemia and Function of the Endothelium) trial. Circulation. 1999;99:3227–33. PubMed

de Jongh S, Lilien MR, op’t Roodt J, Stroes ES, Bakker HD, Kastelein JJ. Early statin therapy restores endothelial function in children with familial hypercholesterolemia. J Am Coll Cardiol. 2002;40:2117–21. PubMed

Marchesi S, Lupattelli G, Siepi D, et al. Short-term atorvastatin treatment improves endothelial function in hypercholesterolemic women. J Cardiovasc Pharmacol. 2000;36:617–21. PubMed

Tsunekawa T, Hayashi T, Kano H, et al. Cerivastatin, a hydroxymethylglutaryl coenzyme a reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days. Circulation. 2001;104:376–9. PubMed

Omori H, Nagashima H, Tsurumi Y, et al. Direct in vivo evidence of a vascular statin: A single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects. Br J Clin Pharmacol. 2002;54:395–9. PubMed PMC

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

Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol. 1997;17:265–72. PubMed

Ferro D, Basili S, Alessandri C, Cara D, Violi F. Inhibition of tissue-factor-mediated thrombin generation by simvastatin. Atherosclerosis. 2000;149:111–6. PubMed

Nagata K, Ishibashi T, Sakamoto T, et al. Rho/Rho-kinase is involved in the synthesis of tissue factor in human monocytes. Atherosclerosis. 2002;163:39–47. PubMed

Eto M, Kozai T, Cosentino F, Joch H, Luscher TF. Statin prevents tissue factor expression in human endothelial cells: Role of Rho/Rho-kinase and Akt pathways. Circulation. 2002;105:1756–9. PubMed

Camera M, Toschi V, Comparato C, et al. Cholesterol-induced thrombogenicity of the vessel wall: Inhibitory effect of fluvastatin. Thromb Haemost. 2002;87:748–55. PubMed

Baetta R, Camera M, Comparato C, Altana C, Ezekowitz MD, Tremoli E. Fluvastatin reduces tissue factor expression and macrophage accumulation in carotid lesions of cholesterol-fed rabbits in the absence of lipid lowering. Arterioscler Thromb Vasc Biol. 2002;22:692–8. PubMed

Ferro D, Basili S, Alessandri C, Mantovani B, Cordova C, Violi F. Simvastatin reduces monocyte-tissue-factor expression type IIa hypercholesterolaemia. Lancet. 1997;350:1222. PubMed

Holschermann H, Hilgendorff A, Kemkes-Matthes B, et al. Simvastatin attenuates vascular hypercoagulability in cardiac transplant recipients. Transplantation. 2000;69:1830–6. PubMed

Cortellaro M, Cofrancesco E, Arbustini E, et al. Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: The ATROCAP study. Thromb Haemost. 2002;88:41–7. PubMed

Hansen JB, Huseby KR, Huseby NE, Sandset PM, Hanssen TA, Nordoy A. Effect of cholesterol lowering on intravascular pools of TFPI and its anticoagulant potential in type II hyperlipoproteinemia. Arterioscler Thromb Vasc Biol. 1995;15:879–85. PubMed

Lorena M, Perolini S, Casazza F, Milani M, Cimminiello C. Fluvastatin and tissue factor pathway inhibitor in type IIA and IIB hyperlipidemia and in acute myocardial infarction. Thromb Res. 1997;87:397–403. PubMed

Nordoy A, Bonaa KH, Sandset PM, Hansen JB, Nilsen H. Effect of omega-3 fatty acids and simvastatin on hemostatic risk factors and postprandial hyperlipemia in patients with combined hyperlipemia. Arterioscler Thromb Vasc Biol. 2000;20:259–65. PubMed

Morishita E, Asakura H, Saito M, et al. Elevated plasma levels of free-form of TFPI antigen in hypercholesterolemic patients. Atherosclerosis. 2001;154:203–12. PubMed

Krysiak R, Okopien B, Herman Z. Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolysis processes. Drugs. 2003;63:1821–54. PubMed

Szczeklik A, Musial J, Undas A, et al. Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia. J Am Coll Cardiol. 1999;33:1286–93. PubMed

Musial J, Undas A, Undas R, Brozek J, Szczeklik A. Treatment with simvastatin and low-dose aspirin depresses thrombin generation in patients with coronary heart disease and borderline-high cholesterol levels. Thromb Haemost. 2001;85:221–5. PubMed

Aoki I, Aoki N, Kawano K, et al. Platelet-dependent thrombin generation in patients with hyperlipidemia. J Am Coll Cardiol. 1997;30:91–6. PubMed

Alessandri C, Basili S, Maurelli M, et al. Relationship between prothrombin activation fragment F1 + 2 and serum cholesterol. Haemostasis. 1996;26:214–9. PubMed

Puccetti L, Bruni F, Di Renzo M, et al. Hypercoagulable state in hypercholesterolemic subjects assessed by platelet-dependent thrombin generation: In vitro effect of cerivastatin. Eur Rev Med Pharmacol Sci. 1999;3:197–204. PubMed

Puccetti L, Bruni F, Bova G, et al. Effect of diet and treatment with statins on platelet-dependent thrombin generation in hypercholesterolemic subjects. Nutr Metab Cardiovasc Dis. 2001;11:378–87. PubMed

Meade TW, Mellows S, Brozovic M, et al. Haemostatic function and ischaemic heart disease: Principal results of the Northwick Park Heart Study. Lancet. 1986;2:533–7. PubMed

Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311:501–5. PubMed

Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA. 1987;258:1183–6. PubMed

Davidson M, McKenney J, Stein E, et al. Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia. Atorvastatin Study Group I. Am J Cardiol. 1997;79:1475–81. PubMed

Seeger H, Wallwiener D, Mueck AO. Lipid-independent effects of an estrogen-statin combination: Inhibition of expression of adhesion molecules and plasminogen activator inhibitor-I in human endothelial cell cultures. Climacteric. 2001;4:209–14. PubMed

Warkentin TE. Hemostasis and atherosclerosis. Can J Cardiol. 1995;11(Suppl C):29C–34C. PubMed

Essig M, Nguyen G, Prie D, Escoubet B, Sraer JD, Friedlander G. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins. Circ Res. 1998;83:683–90. PubMed

Mussoni L, Banfi C, Sironi L, Arpaia M, Tremoli E. Fluvastatin inhibits basal and stimulated plasminogen activator inhibitor 1, but induces tissue type plasminogen activator in cultured human endothelial cells. Thromb Haemost. 2000;84:59–64. PubMed

Haslinger B, Goedde MF, Toet KH, Kooistra T. Simvastatin increases fibrinolytic activity in human peritoneal mesothelial cells independent of cholesterol lowering. Kidney Int. 2002;62:1611–9. PubMed

Lopez S, Peiretti F, Bonardo B, Juhan-Vague I, Nalbone G. Effect of atorvastatin and fluvastatin on the expression of plasminogen activator inhibitor type-1 in cultured human endothelial cells. Atherosclerosis. 2000;152:359–66. PubMed

Bourcier T, Libby P. HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells. Arterioscler Thromb Vasc Biol. 2000;20:556–62. PubMed

Ishibashi T, Nagata K, Ohkawara H, et al. Inhibition of Rho/Rho-kinase signaling downregulates plasminogen activator inhibitor-1 synthesis in cultured human monocytes. Biochim Biophys Acta. 2002;1590:123–30. PubMed

Wiesbauer F, Kaun C, Zorn G, Maurer G, Huber K, Wojta J. HMG CoA reductase inhibitors affect the fibrinolytic system of human vascular cells in vitro: A comparative study using different statins. Br J Pharmacol. 2002;135:284–92. PubMed PMC

Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S) Lancet. 1994;344:1383–9. PubMed

Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001–9. PubMed

Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349–57. PubMed

Stenestrand U, Wallentin L. Early statin treatment following acute myocardial infarction and 1-year survival. JAMA. 2001;285:430–6. PubMed

Aronow HD, Topol EJ, Roe MT, et al. Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: An observational study. Lancet. 2001;357:1063–8. PubMed

Cannon CP, McCabe CH, Bentley J, Braunwald E. Early statin therapy is associated with markedly lower mortality in patients with acute coronary syndromes: Observations from OPUS-TIMI 16. J Am Coll Cardiol. 2001;37(Suppl A):334A. (Absts 831-2). PubMed

Newby LK, Kristinsson A, Bhapkar MV, et al. Early statin initiation and outcomes in patients with acute coronary syndromes. JAMA. 2002;287:3087–95. PubMed

Heeschen C, Hamm CW, Laufs U, Snapinn S, Bohm M, White HD. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002;105:1446–52. PubMed

Schiele R, Gitt AK, Heer T. Early statin use in acute myocardial is associated with a reduced hospital mortality: Results of the Mitra-2. Circulation [Abstract] 2000;102(Suppl 2):II-435. (Abst 2117).

Briguori C, Colombo A, Airoldi F, et al. Statin administration before percutaneous coronary intervention: Impact on periprocedural myocardial infarction. Eur Heart J. 2004;25:1822–8. PubMed

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;285:1711–8. PubMed

Thompson PL, Meredith I, Amerena J, Campbell TJ, Sloman JG, Harris PJ. 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. PubMed

LaBlanche JM, Jukema JW, Charbonneau F, et al., editors. PRINCESS: Prevention of ischemic events by early treatment of cerivastatin after acute myocardial infarction. ESC Congress; Munich. August 28 to Septenmber 1, 2004.

Serruys PW, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;287:3215–22. PubMed

Liem AH, van Boven AJ, Veeger NJ, Withagen AJ, Robles de Medina RM, Tijssen JG, et al. Effect of fluvastatin on ischaemia following acute myocardial infarction: a randomized trial. Eur Heart J. 2002;23:1931–7. PubMed

Kayikcioglu M, Turkoglu C, Kultursay H, Evrengul H, Can L. The short term results of combined use of pravastatin with thrombolytic therapy in acute myocardial infarction. Circulation. 1999;100(Suppl 1):I–303. (Abst 1586).

Arntz HR, Agrawal R, Wunderlich W, et al. Beneficial effects of pravastatin (+/−colestyramine/niacin) initiated immediately after a coronary event (the randomized Lipid-Coronary Artery Disease [L-CAD] Study) Am J Cardiol. 2000;86:1293–8. PubMed

de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: Phase Z of the A to Z trial. JAMA. 2004;292:1307–16. PubMed

Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–504. PubMed

Briel M, Vale N, Schwartz GG, et al. Updated evidence on early statin therapy for acute coronary syndromes: Meta-analysis of 18 randomized trials involving over 14,000 patients. Int J Cardiol. 2012;158:93–100. PubMed

Briel M, Schwartz GG, Thompson PL, et al. Effects of early treatment with statins on short-term clinical outcomes in acute coronary syndromes: A meta-analysis of randomized controlled trials. JAMA. 2006;295:2046–56. PubMed

Hulten E, Jackson JL, Douglas K, George S, Villines TC. The effect of early, intensive statin therapy on acute coronary syndrome: A meta-analysis of randomized controlled trials. Arch Intern Med. 2006;166:1814–21. PubMed

Vale N, Nordmann AJ, Schwartz GG, et al. Statins for acute coronary syndrome. Cochrane Database Syst Rev. 2011;(6):CD006870. PubMed

Shiu JR, Pearson GJ, Charrois TL, Gyenes G, Koshman SL. Frequency of intensive statin therapy in patients with acute coronary syndrome admitted to a tertiary care center. Am J Cardiol. 2012;109:1–5. PubMed

Ostadal P, Alan D, Vejvoda J. Statins in the first-line therapy of acute coronary syndrome – similar to aspirin? Exp Clin Cardiol. 2005;10:9–16. PubMed PMC

Lefer AM, Campbell B, Shin YK, Scalia R, Hayward R, Lefer DJ. Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat hearts. Circulation. 1999;100:178–84. PubMed

Ueda Y, Kitakaze M, Komamura K, et al. Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction. J Am Coll Cardiol. 1999;34:2120–5. PubMed

Lefer DJ, Scalia R, Jones SP, et al. HMG-CoA reductase inhibition protects the diabetic myocardium from ischemia-reperfusion injury. Faseb J. 2001;15:1454–6. PubMed

Di Napoli P, Antonio Taccardi A, et al. Simvastatin reduces reperfusion injury by modulating nitric oxide synthase expression: An ex vivo study in isolated working rat hearts. Cardiovasc Res. 2001;51:283–93. PubMed

Bauersachs J, Galuppo P, Fraccarollo D, Christ M, Ertl G. Improvement of left ventricular remodeling and function by hydroxymethylglutaryl coenzyme a reductase inhibition with cerivastatin in rats with heart failure after myocardial infarction. Circulation. 2001;104:982–5. PubMed

Hayashidani S, Tsutsui H, Shiomi T, et al. Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation. 2002;105:868–73. PubMed

Bell RM, Yellon DM. Atorvastatin, administered at the onset of reperfusion, and independent of lipid lowering, protects the myocardium by up-regulating a pro-survival pathway. J Am Coll Cardiol. 2003;41:508–15. PubMed

Wolfrum S, Dendorfer A, Schutt M, et al. Simvastatin acutely reduces myocardial reperfusion injury in vivo by activating the phosphatidylinositide 3-kinase/Akt pathway. J Cardiovasc Pharmacol. 2004;44:348–55. PubMed

Zheng X, Hu SJ. Effects of simvastatin on cardiohemodynamic responses to ischemia-reperfusion in isolated rat hearts. Heart Vessels. 2006;21:116–23. PubMed

Szarszoi O, Maly J, Ostadal P, et al. Effect of acute and chronic simvastatin treatment on post-ischemic contractile dysfunction in isolated rat heart. Physiol Res. 2008;57:793–6. PubMed

Ostadal P, Alan D, Hajek P, et al. The effect of early treatment by cerivastatin on the serum level of C-reactive protein, interleukin-6, and interleukin-8 in the patients with unstable angina and non-Q-wave myocardial infarction. Mol Cell Biochem. 2003;246:45–50. PubMed

Luo Y, Jiang D, Wen D, Yang J, Li L. Changes in serum interleukin-6 and high-sensitivity C-reactive protein levels in patients with acute coronary syndrome and their response to simvastatin. Heart Vessels. 2004;19:257–62. PubMed

Macin SM, Perna ER, Farias EF, et al. Atorvastatin has an important acute anti-inflammatory effect in patients with acute coronary syndrome: Results of a randomized, double-blind, placebo-controlled study. Am Heart J. 2005;149:451–7. PubMed

Pitt B, Loscalzo J, Ycas J, Raichlen JS. Lipid levels after acute coronary syndromes. J Am Coll Cardiol. 2008;51:1440–5. PubMed

Ostadal P, Alan D, Vejvoda J, et al. Immediate effect of fluvastatin on lipid levels in acute coronary syndrome. Mol Cell Biochem. 2007;306:19–23. PubMed

Vondrakova D, Ostadal P, Kruger A. Immediate effect of intensive atorvastatin therapy on lipid parameters in patients with acute coronary syndrome. Lipids Health Dis. 2010;9:71. PubMed PMC

Michelena HI, Osorio LA, Citkowitz E. Cholesterol levels after 3 days of high-dose simvastatin in patients at moderate to high risk for coronary events. Int J Cardiol. 2005;101:111–4. PubMed

Ostadal P, Alan D, Vejvoda J, et al. Fluvastatin in the first-line therapy of acute coronary syndrome: Results of the multicenter, randomized, double-blind, placebo-controlled trial (the FACS-trial) Trials. 2010;11:61. PubMed PMC

Kim JS, Kim J, Choi D, et al. Efficacy of high-dose atorvastatin loading before primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: The STATIN STEMI trial. JACC Cardiovasc Interv. 2010;3:332–9. PubMed