Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors, Reality or Dream in Managing Patients with Cardiovascular Disease

Author(s): Mohammad Alkhalil*.

Journal Name: Current Drug Metabolism

Volume 20 , Issue 1 , 2019

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Graphical Abstract:


Background: Statins have been a major keystone in the management of patients with atherosclerotic cardiovascular disease. The benefits of inhibiting HMG CoA reductase, via statins, were translated into reduction in LDL-c with proportionate decrease in cardiovascular events in response to the magnitude of LDL-c reduction. Despite major advances in pharmacological treatments, including the use of high-dose statins, there are urgent need to further reduce future cardiovascular risk. This is in particularly important since 1 out of 5 high-risk atherosclerotic patients who achieve low LDL-c return with a second cardiovascular event within five years. Although this residual risk post-statin is largely heterogeneous, lowering LDL-c beyond ‘normal’ or guidelines-recommended level using novel therapies has resulted in further reduction in cardiovascular events.

Objective: The current review will discuss the use of PCSK9 inhibitors in patients with atherosclerotic disease. PCSK9 inhibitors are a new class of lipid-lowering drugs that are either fully human monoclonal antibodies (evolocumab and alirocumab) or humanised monoclonal antibodies (bococizumab) that effectively reduce LDL-c to unprecedented level. By blocking circulating PCSK9, these drugs would preserve LDL receptors and prevent them from cellular degradation. This process promotes recycling of LDL receptors back to hepatocytes surface, leading into further reduction of LDL-c. Combining PCSK9 inhibitors with statin have led into lower LDL-c, reduction in plaque volume and more importantly reduction in future cardiovascular events.

Conclusion: These drugs are very promising, nonetheless, the unselective approach of applying these monoclonal antibodies may not prove to be cost-effective and potentially exposing some patients to unnecessary side effects.

Keywords: Lipid-lowering drugs, PCSK9 inhibitors, statins, risk stratification, vascular imaging, plaque burden, plaque composition.

Townsend, N.; Wilson, L.; Bhatnagar, P.; Wickramasinghe, K.; Rayner, M.; Nichols, M. Cardiovascular disease in Europe: Epidemiological update 2016. Eur. Heart J., 2016, 37(42), 3232-3245.
Bhatnagar, P.; Wickramasinghe, K.; Williams, J.; Rayner, M.; Townsend, N. The epidemiology of cardiovascular disease in the UK 2014. Heart, 2015, 101(15), 1182-1189.
Smolina, K.; Wright, F.L.; Rayner, M.; Goldacre, M.J. Determinants of the decline in mortality from acute myocardial infarction in England between 2002 and 2010: Linked national database study. BMJ, 2012, 344, d8059.
Unal, B.; Critchley, J.A.; Capewell, S. Explaining the decline in coronary heart disease mortality in England and Wales between 1981 and 2000. Circulation, 2004, 109(9), 1101-1107.
Yusuf, S.; Hawken, S.; Ounpuu, S. Dans, T.; Avezum, A.; Lanas, F.; McQueen, M.; Budaj, A.; Pais, P.; Varigos, J.; Lisheng, L.; Investigators, I.S. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet, 2004, 364(9438), 937-952.
Constantinou, J.; Jayia, P.; Hamilton, G. Best evidence for medical therapy for carotid artery stenosis. J. Vasc. Surg., 2013, 58(4), 1129-1139.
Baigent, C.; Keech, A.; Kearney, P.M.; Blackwell, L.; Buck, G.; Pollicino, C.; Kirby, A.; Sourjina, T.; Peto, R.; Collins, R.; Simes, R. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet, 2005, 366(9493), 1267-1278.
Baigent, C.; Blackwell, L.; Emberson, J.; Holland, L.E.; Reith, C.; Bhala, N.; Peto, R.; Barnes, E.H.; Keech, A.; Simes, J.; Collins, R. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet, 2010, 376(9753), 1670-1681.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet, 1994, 344(8934), 1383-1389.
Cannon, C.P.; Braunwald, E.; McCabe, C.H.; Rader, D.J.; Rouleau, J.L.; Belder, R.; Joyal, S.V.; Hill, K.A.; Pfeffer, M.A.; Skene, A.M. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med., 2004, 350(15), 1495-1504.
Ridker, P.M.; Danielson, E.; Fonseca, F.A.; Genest, J.; Gotto, A.M., Jr; Kastelein, J.J.; Koenig, W.; Libby, P.; Lorenzatti, A.J.; MacFadyen, J.G.; Nordestgaard, B.G.; Shepherd, J.; Willerson, J.T.; Glynn, R.J.; Group, J.S. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med., 2008, 359(21), 2195-2207.
LaRosa, J.C.; Grundy, S.M.; Waters, D.D.; Shear, C.; Barter, P.; Fruchart, J.C.; Gotto, A.M.; Greten, H.; Kastelein, J.J.; Shepherd, J.; Wenger, N.K. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N. Engl. J. Med., 2005, 352(14), 1425-1435.
Jarcho, J.A.; Keaney, J.F. Jr proof that lower is better-LDL cholesterol and IMPROVE-IT. N. Engl. J. Med., 2015, 372(25), 2448-2450.
Boden, W.E.; Probstfield, J.L.; Anderson, T.; Chaitman, B.R.; Desvignes-Nickens, P.; Koprowicz, K.; McBride, R.; Teo, K.W.W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med., 2011, 365, 2255-2267.
Barter, P.J.; Caulfield, M.; Eriksson, M.; Grundy, S.M.; Kastelein, J.J.; Komajda, M. Lopez- Sendon J; Mosca L; Tardif JC; Waters DD; Shear CL; Revkin JH; Buhr KA; Fisher MR; Tall AR; B; B; Investigators. I. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med., 2007, 357, 2109-2122.
Landray, M.J.; Haynes, R.; Hopewell, J.C.; Parish, S.; Aung, T.; Tomson, J.; Wallendszus, K.; Craig, M.; Jiang, L.; Collins, R.; Armitage, J. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med., 2014, 371(3), 203-212.
Cannon, C.P.; Blazing, M.A.; Giugliano, R.P.; McCagg, A.; White, J.A.; Theroux, P.; Darius, H.; Lewis, B.S.; Ophuis, T.O.; Jukema, J.W.; De Ferrari, G.M.; Ruzyllo, W.; De Lucca, P. Im, K.; Bohula, E.A.; Reist, C.; Wiviott, S.D.; Tershakovec, A.M.; Musliner, T.A.; Braunwald, E.; Califf, R.M. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N. Engl. J. Med., 2015, 372(25), 2387-2397.
Sabatine, M.S.; Giugliano, R.P.; Keech, A.C.; Honarpour, N.; Wiviott, S.D.; Murphy, S.A.; Kuder, J.F.; Wang, H.; Liu, T.; Wasserman, S.M.; Sever, P.S.; Pedersen, T.R.; Committee, F.S. Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N. Engl. J. Med., 2017, 376, 1713-1722.
Lambert, G.; Sjouke, B.; Choque, B.; Kastelein, J.J.; Hovingh, G.K. The PCSK9 decade. J. Lipid Res., 2012, 53(12), 2515-2524.
Chaudhary, R.; Garg, J.; Shah, N.; Sumner, A. PCSK9 inhibitors: A new era of lipid lowering therapy. World J. Cardiol., 2017, 9(2), 76-91.
Norata, G.D.; Tibolla, G.; Catapano, A.L. PCSK9 inhibition for the treatment of hypercholesterolemia: promises and emerging challenges. Vascul. Pharmacol., 2014, 62(2), 103-111.
Awan, Z.; Seidah, N.G.; MacFadyen, J.G.; Benjannet, S.; Chasman, D.I.; Ridker, P.M.; Genest, J. Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. Clin. Chem., 2012, 58(1), 183-189.
Welder, G.; Zineh, I.; Pacanowski, M.A.; Troutt, J.S.; Cao, G.; Konrad, R.J. High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J. Lipid Res., 2010, 51(9), 2714-2721.
Careskey, H.E.; Davis, R.A.; Alborn, W.E.; Troutt, J.S.; Cao, G.; Konrad, R.J. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J. Lipid Res., 2008, 49(2), 394-398.
Davignon, J.; Dubuc, G. Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels. Trans. Am. Clin. Climatol. Assoc., 2009, 120, 163-173.
Nilsson, L.M.; Abrahamsson, A.; Sahlin, S.; Gustafsson, U.; Angelin, B.; Parini, P.; Einarsson, C. Bile acids and lipoprotein metabolism: effects of cholestyramine and chenodeoxycholic acid on human hepatic mRNA expression. Biochem Biophys Res Commun, 2007, 357, 707-711.
Rashid, S;.; Curtis, DE;.; Garuti , R;.; Anderson, NN;.; Bashmakov, Y;Ho YK;.; Hammer, RE;.; Moon, YA;.; Horton, JD.;. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc. Natl. Acad. Sci. USA, 2005, 102, 5374-5379.
Berge, K.E.; Ose, L.; Leren, T.P. Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler. Thromb. Vasc. Biol., 2006, 26(5), 1094-1100.
Essalmani, R.; Susan-Resiga, D.; Chamberland, A.; Abifadel, M.; Creemers, J.W.; Boileau, C.; Seidah, N.G.; Prat, A. In vivo evidence that furin from hepatocytes inactivates PCSK9. J. Biol. Chem., 2011, 286(6), 4257-4263.
Kotowski, I.K.; Pertsemlidis, A.; Luke, A.; Cooper, R.S.; Vega, G.L.; Cohen, J.C.; Hobbs, H.H. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am. J. Hum. Genet., 2006, 78(3), 410-422.
Seidah, N.G.; Benjannet, S.; Wickham, L.; Marcinkiewicz, J.; Jasmin, S.B.; Stifani, S.; Basak, A.; Prat, A.; Chretien, M. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Natl. Acad. Sci. USA, 2003, 100(3), 928-933.
Abifadel, M.; Varret, M.; Rabès, J.P.; Allard, D.; Ouguerram, K.; Devillers, M.; Cruaud, C.; Benjannet, S.; Wickham, L.; Erlich, D.; Derré, A.; Villéger, L.; Farnier, M.; Beucler, I.; Bruckert, E.; Chambaz, J.; Chanu, B.; Lecerf, J.M.; Luc, G.; Moulin, P.; Weissenbach, J.; Prat, A.; Krempf, M.; Junien, C.; Seidah, N.G.; Boileau, C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet., 2003, 34(2), 154-156.
Abboud, S.; Karhunen, P.J.; Lütjohann, D.; Goebeler, S.; Luoto, T.; Friedrichs, S.; Lehtimaki, T.; Pandolfo, M.; Laaksonen, R. Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is a risk factor of large-vessel atherosclerosis stroke. PLoS One, 2007, 2(10), e1043.
Naoumova, R.P.; Tosi, I.; Patel, D.; Neuwirth, C.; Horswell, S.D.; Marais, A.D.; van Heyningen, C.; Soutar, A.K. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler. Thromb. Vasc. Biol., 2005, 25(12), 2654-2660.
Bottomley, M.J.; Cirillo, A.; Orsatti, L.; Ruggeri, L.; Fisher, T.S.; Santoro, J.C.; Cummings, R.T.; Cubbon, R.M.; Lo Surdo, P.; Calzetta, A.; Noto, A.; Baysarowich, J.; Mattu, M.; Talamo, F.; De Francesco, R.; Sparrow, C.P.; Sitlani, A.; Carfí, A. Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants. J. Biol. Chem., 2009, 284(2), 1313-1323.
Cohen, J.; Pertsemlidis, A.; Kotowski, I.K.; Graham, R.; Garcia, C.K.; Hobbs, H.H. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet., 2005, 37(2), 161-165.
Cohen, J.C.; Boerwinkle, E.; Mosley, T.H., Jr; Hobbs, H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease N Engl J Med., 2006, 354, 1264-1272.
Shan, L;.; Pang, L;.; Zhang, R;; Murgolo, NJ;.; Lan, H;.; Hedrick, JA. PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide. Biochem. Biophys. Res. Commun., 2008, 375, 69-73.
Mitchell, T.; Chao, G.; Sitkoff, D.; Lo, F.; Monshizadegan, H.; Meyers, D.; Low, S.; Russo, K.; DiBella, R.; Denhez, F.; Gao, M.; Myers, J.; Duke, G.; Witmer, M.; Miao, B.; Ho, S.P.; Khan, J.; Parker, R.A. Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering. J. Pharmacol. Exp. Ther., 2014, 350(2), 412-424.
Graham, M.J.; Lemonidis, K.M.; Whipple, C.P.; Subramaniam, A.; Monia, B.P.; Crooke, S.T.; Crooke, R.M. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J. Lipid Res., 2007, 48(4), 763-767.
Frank-Kamenetsky, M.; Grefhorst, A.; Anderson, N.N.; Racie, T.S.; Bramlage, B.; Akinc, A.; Butler, D.; Charisse, K.; Dorkin, R.; Fan, Y.; Gamba-Vitalo, C.; Hadwiger, P.; Jayaraman, M.; John, M.; Jayaprakash, K.N.; Maier, M.; Nechev, L.; Rajeev, K.G.; Read, T.; Röhl, I.; Soutschek, J.; Tan, P.; Wong, J.; Wang, G.; Zimmermann, T.; de Fougerolles, A.; Vornlocher, H.P.; Langer, R.; Anderson, D.G.; Manoharan, M.; Koteliansky, V.; Horton, J.D.; Fitzgerald, K. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc. Natl. Acad. Sci. USA, 2008, 105(33), 11915-11920.
Bergeron, N.; Phan, B.A.; Ding, Y.; Fong, A.; Krauss, R.M. Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk. Circulation, 2015, 132(17), 1648-1666.
Ray, K.K.; Landmesser, U.; Leiter, L.A.; Kallend, D.; Dufour, R.; Karakas, M.; Hall, T.; Troquay, R.P.; Turner, T.; Visseren, F.L.; Wijngaard, P.; Wright, R.S.; Kastelein, J.J. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N. Engl. J. Med., 2017, 376(15), 1430-1440.
Giugliano, R.P.; Sabatine, M.S. Are PCSK9 Inhibitors the Next Breakthrough in the Cardiovascular Field? J. Am. Coll. Cardiol., 2015, 65(24), 2638-2651.
Alkhalil, M.; Chai, J.T.; Choudhury, R.P. Plaque imaging to refine indications for emerging lipid-lowering drugs. Eur. Heart J. Cardiovasc. Pharmacother., 2017, 3(1), 58-67.
Dias, C.S.; Shaywitz, A.J.; Wasserman, S.M.; Smith, B.P.; Gao, B.; Stolman, D.S.; Crispino, C.P.; Smirnakis, K.V.; Emery, M.G.; Colbert, A.; Gibbs, J.P.; Retter, M.W.; Cooke, B.P.; Uy, S.T.; Matson, M.; Stein, E.A. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J. Am. Coll. Cardiol., 2012, 60(19), 1888-1898.
Stein, E.A.; Honarpour, N.; Wasserman, S.M.; Xu, F.; Scott, R.; Raal, F.J. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation, 2013, 128(19), 2113-2120.
Raal, F.J.; Honarpour, N.; Blom, D.J.; Hovingh, G.K.; Xu, F.; Scott, R.; Wasserman, S.M.; Stein, E.A.; Investigators, T. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet, 2015, 385(9965), 341-350.
Raal, F.J.; Stein, E.A.; Dufour, R.; Turner, T.; Civeira, F.; Burgess, L.; Langslet, G.; Scott, R.; Olsson, A.G.; Sullivan, D.; Hovingh, G.K.; Cariou, B.; Gouni-Berthold, I.; Somaratne, R.; Bridges, I.; Scott, R.; Wasserman, S.M.; Gaudet, D.; Investigators, R. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet, 2015, 385(9965), 331-340.
Robinson, J.G.; Nedergaard, B.S.; Rogers, W.J.; Fialkow, J.; Neutel, J.M.; Ramstad, D.; Somaratne, R.; Legg, J.C.; Nelson, P.; Scott, R.; Wasserman, S.M.; Weiss, R.; Investigators, L. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA, 2014, 311(18), 1870-1882.
Giugliano, R.P.; Desai, N.R.; Kohli, P.; Rogers, W.J.; Somaratne, R.; Huang, F.; Liu, T.; Mohanavelu, S.; Hoffman, E.B.; McDonald, S.T.; Abrahamsen, T.E.; Wasserman, S.M.; Scott, R.; Sabatine, M.S. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet, 2012, 380(9858), 2007-2017.
Sullivan, D.; Olsson, A.G.; Scott, R.; Kim, J.B.; Xue, A.; Gebski, V.; Wasserman, S.M.; Stein, E.A. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA, 2012, 308(23), 2497-2506.
Koren, M.J.; Scott, R.; Kim, J.B.; Knusel, B.; Liu, T.; Lei, L.; Bolognese, M.; Wasserman, S.M. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet, 2012, 380(9858), 1995-2006.
Nissen, S.E.; Stroes, E.; Dent-Acosta, R.E.; Rosenson, R.S.; Lehman, S.J.; Sattar, N.; Preiss, D.; Bruckert, E.; Ceška, R.; Lepor, N.; Ballantyne, C.M.; Gouni-Berthold, I.; Elliott, M.; Brennan, D.M.; Wasserman, S.M.; Somaratne, R.; Scott, R.; Stein, E.A.; Investigators, G. Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA, 2016, 315(15), 1580-1590.
Stein, E.A.; Mellis, S.; Yancopoulos, G.D.; Stahl, N.; Logan, D.; Smith, W.B.; Lisbon, E.; Gutierrez, M.; Webb, C.; Wu, R.; Du, Y.; Kranz, T.; Gasparino, E.; Swergold, G.D. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med., 2012, 366(12), 1108-1118.
Stein, E.A.; Gipe, D.; Bergeron, J.; Gaudet, D.; Weiss, R.; Dufour, R.; Wu, R.; Pordy, R. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet, 2012, 380(9836), 29-36.
Roth, E.M.; McKenney, J.M.; Hanotin, C.; Asset, G.; Stein, E.A. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N. Engl. J. Med., 2012, 367(20), 1891-1900.
Stroes, E.; Guyton, J.R.; Lepor, N.; Civeira, F.; Gaudet, D.; Watts, G.F.; Baccara-Dinet, M.T.; Lecorps, G.; Manvelian, G.; Farnier, M.; Investigators, O.C.I. Efficacy and safety of alirocumab 150 mg every 4 weeks in patients with hypercholesterolemia not on statin therapy: The odyssey choice II study. J. Am. Heart Assoc., 2016, 5(9), e003421.
Moriarty, P.M.; Thompson, P.D.; Cannon, C.P.; Guyton, J.R.; Bergeron, J.; Zieve, F.J.; Bruckert, E.; Jacobson, T.A.; Kopecky, S.L.; Baccara-Dinet, M.T.; Du, Y.; Pordy, R.; Gipe, D.A.; Investigators, O.A. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J. Clin. Lipidol., 2015, 9(6), 758-769.
Ballantyne, C.M.; Neutel, J.; Cropp, A.; Duggan, W.; Wang, E.Q.; Plowchalk, D.; Sweeney, K.; Kaila, N.; Vincent, J.; Bays, H. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am. J. Cardiol., 2015, 115(9), 1212-1221.
Erqou, S.; Kaptoge, S.; Perry, P.L.; Di Angelantonio, E.; Thompson, A.; White, I.R.; Marcovina, S.M.; Collins, R.; Thompson, S.G.; Danesh, J.; Danesh, J. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA, 2009, 302(4), 412-423.
van Capelleveen, J.C.; van der Valk, F.M.; Stroes, E.S. Current therapies for lowering lipoprotein (a). J. Lipid Res., 2016, 57(9), 1612-1618.
Gaudet, D.; Kereiakes, D.J.; McKenney, J.M.; Roth, E.M.; Hanotin, C.; Gipe, D.; Du, Y.; Ferrand, A.C.; Ginsberg, H.N.; Stein, E.A. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am. J. Cardiol., 2014, 114(5), 711-715.
Raal, F.J.; Giugliano, R.P.; Sabatine, M.S.; Koren, M.J.; Langslet, G.; Bays, H.; Blom, D.; Eriksson, M.; Dent, R.; Wasserman, S.M.; Huang, F.; Xue, A.; Albizem, M.; Scott, R.; Stein, E.A. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J. Am. Coll. Cardiol., 2014, 63(13), 1278-1288.
Sabatine, M.S.; Giugliano, R.P.; Wiviott, S.D.; Raal, F.J.; Blom, D.J.; Robinson, J.; Ballantyne, C.M.; Somaratne, R.; Legg, J.; Wasserman, S.M.; Scott, R.; Koren, M.J.; Stein, E.A. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med., 2015, 372(16), 1500-1509.
Robinson, J.G.; Farnier, M.; Krempf, M.; Bergeron, J.; Luc, G.; Averna, M.; Stroes, E.S.; Langslet, G.; Raal, F.J.; El Shahawy, M.; Koren, M.J.; Lepor, N.E.; Lorenzato, C.; Pordy, R.; Chaudhari, U.; Kastelein, J.J.; Investigators, O.L.T. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med., 2015, 372(16), 1489-1499.
Lipinski, M.J.; Benedetto, U.; Escarcega, R.O.; Biondi-Zoccai, G.; Lhermusier, T.; Baker, N.C.; Torguson, R.; Brewer, H.B., Jr; Waksman, R. The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: A network meta-analysis. Eur. Heart J., 2016, 37(6), 536-545.
Giugliano, R.P.; Pedersen, T.R.; Park, J.G.; De Ferrari, G.M.; Gaciong, Z.A.; Ceska, R.; Toth, K.; Gouni-Berthold, I.; Lopez-Miranda, J.; Schiele, F.; Mach, F.; Ott, B.R.; Kanevsky, E.; Pineda, A.L.; Somaratne, R.; Wasserman, S.M.; Keech, A.C.; Sever, P.S.; Sabatine, M.S.; Investigators, F. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet, 2017, 390(10106), 1962-1971.
Catapano, A.L.; Graham, I.; De Backer, G.; Wiklund, O.; Chapman, M.J.; Drexel, H.; Hoes, A.W.; Jennings, C.S.; Landmesser, U.; Pedersen, T.R.; Reiner, Ž.; Riccardi, G.; Taskinen, M.R.; Tokgozoglu, L.; Verschuren, W.M.M.; Vlachopoulos, C.; Wood, D.A.; Zamorano, J.L.; Cooney, M.T.; Group, E.S.C.S.D. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur. Heart J., 2016, 37(39), 2999-3058.
Gragnano, F.; Calabrò, P. Role of dual lipid-lowering therapy in coronary atherosclerosis regression: Evidence from recent studies. Atherosclerosis, 2018, 269, 219-228.
Giugliano, R.P.; Keech, A.; Murphy, S.A.; Huber, K.; Tokgozoglu, S.L.; Lewis, B.S.; Ferreira, J.; Pineda, A.L.; Somaratne, R.; Sever, P.S.; Pedersen, T.R.; Sabatine, M.S. Clinical efficacy and safety of evolocumab in high-risk patients receiving a statin: Secondary analysis of patients with low LDL cholesterol levels and in those already receiving a maximal-potency statin in a randomized clinical trial. JAMA Cardiol., 2017, 2(12), 1385-1391.
Ridker, P.M.; Revkin, J.; Amarenco, P.; Brunell, R.; Curto, M.; Civeira, F.; Flather, M.; Glynn, R.J.; Gregoire, J.; Jukema, J.W.; Karpov, Y.; Kastelein, J.J.P.; Koenig, W.; Lorenzatti, A.; Manga, P.; Masiukiewicz, U.; Miller, M.; Mosterd, A.; Murin, J.; Nicolau, J.C.; Nissen, S.; Ponikowski, P.; Santos, R.D.; Schwartz, P.F.; Soran, H.; White, H.; Wright, R.S.; Vrablik, M.; Yunis, C.; Shear, C.L.; Tardif, J.C.; Investigators, S.C.O. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N. Engl. J. Med., 2017, 376(16), 1527-1539.
Landmesser, U.; Chapman, M.J.; Stock, J.K.; Amarenco, P.; Belch, J.J.F.; Boren, J.; Farnier, M.; Ference, B.A.; Gielen, S.; Graham, I.; Grobbee, D.E.; Hovingh, G.K.; Luscher, T.F.; Piepoli, M.F.; Ray, K.K.; Stroes, E.S.; Wiklund, O.; Windecker, S.; Zamorano, J.L.; Pinto, F.; Tokgozoglu, L.; Bax, J.J.; Catapano, A.L. 2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia. Eur. Heart J., 2018, 39(14), 1131-1143.
Schwartz, G.G.; Bessac, L.; Berdan, L.G.; Bhatt, D.L.; Bittner, V.; Diaz, R.; Goodman, S.G.; Hanotin, C.; Harrington, R.A.; Jukema, J.W.; Mahaffey, K.W.; Moryusef, A.; Pordy, R.; Roe, M.T.; Rorick, T.; Sasiela, W.J.; Shirodaria, C.; Szarek, M.; Tamby, J.F.; Tricoci, P.; White, H.; Zeiher, A.; Steg, P.G. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am. Heart J., 2014, 168(5), 682-689.
Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) American College of Cardiology Congress; Orlando, FL, USA; Mar 10-12, 2018,,
Navarese, E.P.; Robinson, J.G.; Kowalewski, M.; Kolodziejczak, M.; Andreotti, F.; Bliden, K.; Tantry, U.; Kubica, J.; Raggi, P.; Gurbel, P.A. Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality After LDL-C Lowering: A Systematic Review and Meta-analysis. JAMA, 2018, 319(15), 1566-1579.
Lloyd-Jones, D.M.; Morris, P.B.; Ballantyne, C.M.; Birtcher, K.K.; Daly, D.D., Jr; DePalma, S.M.; Minissian, M.B.; Orringer, C.E.; Smith, S.C., Jr 2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J. Am. Coll. Cardiol., 2017, 70(14), 1785-1822.
Cannon, C.P.; Steinberg, B.A.; Murphy, S.A.; Mega, J.L.; Braunwald, E. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J. Am. Coll. Cardiol., 2006, 48(3), 438-445.
Alkhalil, M.; Choudhury, R.P. Evolocumab Added to Statins to Reduce Progression of Coronary Atherosclerosis. JAMA, 2017, 317(16), 1690-1691.
Sacks, F.M.; Pfeffer, M.A.; Moye, L.A.; Rouleau, J.L.; Rutherford, J.D.; Cole, T.G.; Brown, L.; Warnica, J.W.; Arnold, J.M.; Wun, C.C.; Davis, B.R.; Braunwald, E. 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(14), 1001-1009.
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet, 2002, 360(9326), 7-22.
Shepherd, J.; Cobbe, S.M.; Ford, I.; Isles, C.G.; Lorimer, A.R.; MacFarlane, P.W.; McKillop, J.H.; Packard, C.J. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N. Engl. J. Med., 1995, 333(20), 1301-1307.
Collins, R.; Reith, C.; Emberson, J.; Armitage, J.; Baigent, C.; Blackwell, L.; Blumenthal, R.; Danesh, J.; Smith, G.D.; DeMets, D.; Evans, S.; Law, M.; MacMahon, S.; Martin, S.; Neal, B.; Poulter, N.; Preiss, D.; Ridker, P.; Roberts, I.; Rodgers, A.; Sandercock, P.; Schulz, K.; Sever, P.; Simes, J.; Smeeth, L.; Wald, N.; Yusuf, S.; Peto, R. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet, 2016, 388(10059), 2532-2561.
Steinberg, D.; Grundy, S.M.; Mok, H.Y.; Turner, J.D.; Weinstein, D.B.; Brown, W.V.; Albers, J.J. Metabolic studies in an unusual case of asymptomatic familial hypobetalipoproteinemia with hypolphalipoproteinemia and fasting chylomicronemia. J. Clin. Invest., 1979, 64(1), 292-301.
Steinberg, D.; Glass, C.K.; Witztum, J.L. Evidence mandating earlier and more aggressive treatment of hypercholesterolemia. Circulation, 2008, 118(6), 672-677.
Hooper, A.J.; Marais, A.D.; Tanyanyiwa, D.M.; Burnett, J.R. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis, 2007, 193(2), 445-448.
Koren, M.J.; Sabatine, M.S.; Giugliano, R.P.; Langslet, G.; Wiviott, S.D.; Kassahun, H.; Ruzza, A.; Ma, Y.; Somaratne, R.; Raal, F.J. Long-term low-density lipoprotein cholesterol-lowering efficacy, persistence, and safety of evolocumab in treatment of hypercholesterolemia: results up to 4 years from the open-label OSLER-1 extension study. JAMA Cardiol., 2017, 2(6), 598-607.
Robinson, J.G.; Rosenson, R.S.; Farnier, M.; Chaudhari, U.; Sasiela, W.J.; Merlet, L.; Miller, K.; Kastelein, J.J. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: Pooled data from randomized trials. J. Am. Coll. Cardiol., 2017, 69(5), 471-482.
Ference, B.A.; Robinson, J.G.; Brook, R.D.; Catapano, A.L.; Chapman, M.J.; Neff, D.R.; Voros, S.; Giugliano, R.P.; Davey Smith, G.; Fazio, S.; Sabatine, M.S. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N. Engl. J. Med., 2016, 375(22), 2144-2153.
Sabatine, M.S.; Leiter, L.A.; Wiviott, S.D.; Giugliano, R.P.; Deedwania, P.; De Ferrari, G.M.; Murphy, S.A.; Kuder, J.F.; Gouni-Berthold, I.; Lewis, B.S.; Handelsman, Y.; Pineda, A.L.; Honarpour, N.; Keech, A.C.; Sever, P.S.; Pedersen, T.R. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol., 2017, 5(12), 941-950.
Khan, A.R.; Bavishi, C.; Riaz, H.; Farid, T.A.; Khan, S.; Atlas, M.; Hirsch, G.; Ikram, S.; Bolli, R. Increased risk of adverse neurocognitive outcomes with proprotein convertase subtilisin-kexin type 9 inhibitors. Circ. Cardiovasc. Qual. Outcomes, 2017, 10(1), 10.
Giugliano, R.P.; Mach, F.; Zavitz, K.; Kurtz, C. Im, K.; Kanevsky, E.; Schneider, J.; Wang, H.; Keech, A.; Pedersen, T.R.; Sabatine, M.S.; Sever, P.S.; Robinson, J.G.; Honarpour, N.; Wasserman, S.M.; Ott, B.R.; Investigators, E. Cognitive function in a randomized trial of evolocumab. N. Engl. J. Med., 2017, 377(7), 633-643.
Kazi, D.S.; Moran, A.E.; Coxson, P.G.; Penko, J.; Ollendorf, D.A.; Pearson, S.D.; Tice, J.A.; Guzman, D.; Bibbins-Domingo, K. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA, 2016, 316(7), 743-753.
Hlatky, M.A.; Kazi, D.S. PCSK9 inhibitors: Economics and policy. J. Am. Coll. Cardiol., 2017, 70(21), 2677-2687.
Kazi, D.S.; Penko, J.; Coxson, P.G.; Moran, A.E.; Ollendorf, D.A.; Tice, J.A.; Bibbins-Domingo, K. Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial. JAMA, 2017, 318(8), 748-750.
Alirocumab for Treatment of High Cholesterol. Effectiveness and Value., 2018. Alirocumab-Preliminary- New-Evidence-Update_03102018.pdf
Eisen, A.; Cannon, C.P.; Blazing, M.A.; Bohula, E.A.; Park, J.G.; Murphy, S.A.; White, J.A.; Giugliano, R.P.; Braunwald, E. The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial. Eur. Heart J., 2016, 37(48), 3576-3584.
Bonaca, M.P.; Nault, P.; Giugliano, R.P.; Keech, A.C.; Pineda, A.L.; Kanevsky, E.; Kuder, J.; Murphy, S.A.; Jukema, J.W.; Lewis, B.S.; Tokgozoglu, L.; Somaratne, R.; Sever, P.S.; Pedersen, T.R.; Sabatine, M.S. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: Insights from the FOURIER trial (further cardiovascular outcomes research With PCSK9 inhibition in subjects with elevated risk). Circulation, 2018, 137(4), 338-350.
Tsujita, K.; Sugiyama, S.; Sumida, H.; Shimomura, H.; Yamashita, T.; Yamanaga, K.; Komura, N.; Sakamoto, K.; Oka, H.; Nakao, K.; Nakamura, S.; Ishihara, M.; Matsui, K.; Sakaino, N.; Nakamura, N.; Yamamoto, N.; Koide, S.; Matsumura, T.; Fujimoto, K.; Tsunoda, R.; Morikami, Y.; Matsuyama, K.; Oshima, S.; Kaikita, K.; Hokimoto, S.; Ogawa, H. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: The multicenter randomized controlled PRECISE-IVUS trial. J. Am. Coll. Cardiol., 2015, 66(5), 495-507.
Nicholls, S.J.; Ballantyne, C.M.; Barter, P.J.; Chapman, M.J.; Erbel, R.M.; Libby, P.; Raichlen, J.S.; Uno, K.; Borgman, M.; Wolski, K.; Nissen, S.E. Effect of two intensive statin regimens on progression of coronary disease. N. Engl. J. Med., 2011, 365(22), 2078-2087.
Nicholls, S.J.; Puri, R.; Anderson, T.; Ballantyne, C.M.; Cho, L.; Kastelein, J.J.; Koenig, W.; Somaratne, R.; Kassahun, H.; Yang, J.; Wasserman, S.M.; Scott, R.; Ungi, I.; Podolec, J.; Ophuis, A.O.; Cornel, J.H.; Borgman, M.; Brennan, D.M.; Nissen, S.E. Effect of evolocumab on progression of coronary disease in statin-treated patients: The GLAGOV randomized clinical trial. JAMA, 2016, 316(22), 2373-2384.
Libby, P.; Aikawa, M. Mechanisms of plaque stabilization with statins. Am. J. Cardiol., 2003, 91(4A), 4B-8B.
Crisby, M.; Nordin-Fredriksson, G.; Shah, P.K.; 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(7), 926-933.
Kini, A.S.; Baber, U.; Kovacic, J.C.; Limaye, A.; Ali, Z.A.; Sweeny, J.; Maehara, A.; Mehran, R.; Dangas, G.; Mintz, G.S.; Fuster, V.; Narula, J.; Sharma, S.K.; Moreno, P.R. Changes in plaque lipid content after short-term intensive versus standard statin therapy: the YELLOW trial (reduction in yellow plaque by aggressive lipid-lowering therapy). J. Am. Coll. Cardiol., 2013, 62(1), 21-29.
Zhao, X.Q.; Dong, L.; Hatsukami, T.; Phan, B.A.; Chu, B.; Moore, A.; Lane, T.; Neradilek, M.B.; Polissar, N.; Monick, D.; Lee, C.; Underhill, H.; Yuan, C. MR imaging of carotid plaque composition during lipid-lowering therapy a prospective assessment of effect and time course. JACC Cardiovasc. Imaging, 2011, 4(9), 977-986.
Alkhalil, M.; Biasiolli, L.; Chai, J.T.; Galassi, F.; Li, L.; Darby, C.; Halliday, A.; Hands, L.; Magee, T.; Perkins, J.; Sideso, E.; Jezzard, P.; Robson, M.D.; Handa, A.; Choudhury, R.P. Quantification of carotid plaque lipid content with magnetic resonance T2 mapping in patients undergoing carotid endarterectomy. PLoS One, 2017, 12(7), e0181668.
Chai, J.T.; Biasiolli, L.; Li, L.; Alkhalil, M.; Galassi, F.; Darby, C.; Halliday, A.W.; Hands, L.; Magee, T.; Perkins, J.; Sideso, E.; Handa, A.; Jezzard, P.; Robson, M.D.; Choudhury, R.P. Quantification of lipid-rich core in carotid atherosclerosis using magnetic resonance T2 mapping: Relation to clinical presentation. JACC Cardiovasc. Imaging, 2017, 10(7), 747-756.
Alkhalil, M.; Edmond, E.; Edgar, L.; Digby, J.E.; Omar, O.; Robson, M.D.; Choudhury, R.P. The relationship of perivascular adipose tissue and atherosclerosis in the aorta and carotid arteries, determined by magnetic resonance imaging. Diab. Vasc. Dis. Res., 2017.
Ridker, P.M.; Everett, B.M.; Thuren, T.; MacFadyen, J.G.; Chang, W.H.; Ballantyne, C.; Fonseca, F.; Nicolau, J.; Koenig, W.; Anker, S.D.; Kastelein, J.J.P.; Cornel, J.H.; Pais, P.; Pella, D.; Genest, J.; Cifkova, R.; Lorenzatti, A.; Forster, T.; Kobalava, Z.; Vida-Simiti, L.; Flather, M.; Shimokawa, H.; Ogawa, H.; Dellborg, M.; Rossi, P.R.F.; Troquay, R.P.T.; Libby, P.; Glynn, R.J.; Group, C.T. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med., 2017, 377(12), 1119-1131.
Results of the low-dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction: Do stopped trials contribute to overall knowledge? GISSI Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico). Ital. Heart J., 2000, 1(12), 810-820.
Officers, A. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT-LLT). JAMA, 2002, 288(23), 2998-3007.
Holdaas, H.; Fellström, B.; Jardine, A.G.; Holme, I.; Nyberg, G.; Fauchald, P.; Grönhagen-Riska, C.; Madsen, S.; Neumayer, H.H.; Cole, E.; Maes, B.; Ambühl, P.; Olsson, A.G.; Hartmann, A.; Solbu, D.O.; Pedersen, T.R. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet, 2003, 361(9374), 2024-2031.
Serruys, P.W.; de Feyter, P.; Macaya, C.; Kokott, N.; Puel, J.; Vrolix, M.; Branzi, A.; Bertolami, M.C.; Jackson, G.; Strauss, B.; Meier, B. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA, 2002, 287(24), 3215-3222.
Downs, J.R.; Clearfield, M.; Weis, S.; Whitney, E.; Shapiro, D.R.; Beere, P.A.; Langendorfer, A.; Stein, E.A.; Kruyer, W.; Gotto, A.M., Jr Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA, 1998, 279(20), 1615-1622.
Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N. Engl. J. Med., 1998, 339(19), 1349-1357.
Shepherd, J.; Blauw, G.J.; Murphy, M.B.; Bollen, E.L.E.M.; Buckley, B.M.; Cobbe, S.M.; Ford, I.; Gaw, A.; Hyland, M.; Jukema, J.W.; Kamper, A.M.; Macfarlane, P.W.; Meinders, A.E.; Norrie, J.; Packard, C.J.; Perry, I.J.; Stott, D.J.; Sweeney, B.J.; Twomey, C.; Westendorp, R.G.J. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial. Lancet, 2002, 360(9346), 1623-1630.
Sever, P.S.; Dahlöf, B.; Poulter, N.R.; Wedel, H.; Beevers, G.; Caulfield, M.; Collins, R.; Kjeldsen, S.E.; Kristinsson, A.; McInnes, G.T.; Mehlsen, J.; Nieminen, M.; O’Brien, E.; Ostergren, J. 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(9364), 1149-1158.
The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N. Engl. J. Med., 1997, 336(3), 153-162.
Colhoun, H.M.; Betteridge, D.J.; Durrington, P.N.; Hitman, G.A.; Neil, H.A.; Livingstone, S.J.; Thomason, M.J.; Mackness, M.I.; Charlton-Menys, V.; Fuller, J.H. 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(9435), 685-696.

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Year: 2019
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DOI: 10.2174/1389200219666180816141827
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