The ezetimibe controversy - Can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together?

Expert Opinion on Pharmacotherapy

Volumn 13, Issue 10, 2012, Pages 1469-1480

  Doggrell, Sheila A ^a  

^a QUEENSLAND UNIVERSITY OF TECHNOLOGY   (Australia)

Author keywords

Cardiovascular disease; Clinical outcomes; Ezetimibe; LDL cholesterol; Simvastatin

Indexed keywords

ATORVASTATIN; EZETIMIBE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LOW DENSITY LIPOPROTEIN CHOLESTEROL; NICOTINIC ACID; PLACEBO; ROSUVASTATIN; SIMVASTATIN;

AORTA STENOSIS; ATHEROSCLEROSIS; CLINICAL PRACTICE; CLINICAL TRIAL (TOPIC); CORONARY ARTERY DISEASE; DRUG ACTIVITY; DRUG EFFICACY; DRUG MEGADOSE; HEART FAILURE; HIGH RISK POPULATION; HUMAN; HYPERCHOLESTEROLEMIA; KIDNEY DISEASE; LOW DRUG DOSE; MONOTHERAPY; MORBIDITY; MORTALITY; REVIEW; TREATMENT OUTCOME; VASCULAR SURGERY;

ANTICHOLESTEREMIC AGENTS; AZETIDINES; CHOLESTEROL, LDL; CLINICAL TRIALS AS TOPIC; DRUG THERAPY, COMBINATION; HUMANS; HYPERCHOLESTEROLEMIA; SIMVASTATIN;

EID: 84863085365     PISSN: 14656566     EISSN: 17447666     Source Type: Journal    
DOI: 10.1517/14656566.2012.696098     Document Type: Review

References (75)

1. Lipid Research Clinics Program. the lipid research clinics coronary primary prevention trial results. reduction in incidence of coronary heart disease. JAMA 1984;251:351-64.Available from: http://www.nhlbi.nih.gov/ guidelines/cholesterol/atp3full.pdf
2. Spector R, Snappinn SM. Statins for secondary prevention of cardiovascular disease: The right dose. Pharmacology 2011;87:63-9
3. Mikhailidis DP, Lawson RW, McCormick AL, et al. Comparative efficacy of the addition of ezetimibe to statin vs statin titration in patients with hypercholesterolaemia: Systematic review and meta-analysis. Curr Med Res Opin 2011;27:1191-200
4. Lioudaki E, Ganotakis ES, Mikhailidis DP, et al. Ezetimibe: More than a low density lipoprotein cholesterol lowering drug? An update after 4 years. Curr Vasc Pharmacol 2011;9:62-86
5. Buckwald H, Varco RL, Boen JR, et al. Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: Five-year partial follow-up report from the POSCH. Program on the Surgical Control of the Hyperlipidemias. Arch Intern Med 1998; 158:1253-61
6. the Lipid Research Clinics Coronary Primary Prevention Trial results. 1. Reduction in incidence of coronary heart disease. JAMA 1984; 251:351-64
7. Bays HE, Neff D, Tomassini JE, Tershakovec AM. Ezetimibe: Cholesterol lowering and beyond. Expert Rev Cardiovasc Ther 2008;6:447-70
8. Hamilton-Craig I, Kostner K, Colquhoun D, Woodhouse S. Combination therapy of statin and ezetimibe for the treatment of familial hypercholesterolemia. Vasc Health Risk Manag 2010; 6:1023-37
9. the Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9
10. Pedersen TR, Olsson AG, Faegeman O, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin survival study (4S). Circulation 1998;97:1453-60
11. Pedersen TR, Wilhelmsen L, Faergeman O, et al. Follow-up study of patients randomized in the Scandinavian simvastatin survival study (4S) of cholesterol lowering. Am J Cardiol 2000;86:257-62
12. Pedersen TR, Kjekshus J, Pyorala K, et al. Effects of simvastatin of ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol 1998;81:333-5
13. Haffner SM, Alexander CM, Cook TJ, et al. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose: Subgroup analyses in the Scandinavian Simvastatin survival study. Arch Intern Med 1999;159:2661-7
14. Chonchol M, Cook T, Kjekshus J, et al. Simvastatin for secondary prevention of all-cause mortality and major coronary events in patients with mild chronic renal insufficiency. Am J Kidney Dis 2007;49:373-82
15. Huskey J, Lindenfeld J, Cook T, et al. Effect of simvastatin on kidney function loss in patients with coronary artery disease - Findings from the Scandinavian Simvastatin Survival Study (4S). Atherosclerosis 2009;205:202-6
16. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002;360:7-22
17. Collins R, Armitage J, Parish S, et al. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757-67
18. Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: A randomized placebo-controlled trial. Lancet 2003;361:2005-16
19. Heart Protection Study Collaborative Group. Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions. J Vasc Surg 2007;45:645-54
20. Aronow WS, Nayak D, Woodworth S, Ahn C. Effect of simvastatin versus placebo on treadmill exercise time until the onset of intermittent claudication in older patients with peripheral arterial disease at 6 months and at one year after treatment. Am J Cardiol 2003;92:711-12
21. 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
22. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH) collaborative group. Intensive lowering of cholesterol with 80 mg versus 20 mg simvastatin daily in 12064 survivors of myocardial infarction: A double-blind randomized trial. Lancet 2010;376:1658-69
23. Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 1700 participants in 26 randomised trials. Lancet 2010;376:1670-81
24. Zhou Z, Rahme E, Pilate L. Are statins created equal? evidence from randomized trials with pravastatin, simvastatin, and atorvastatin for cardiovascular disease prevention. Am Heart J 2006;151:273-81
25. 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;357:577-81
26. Pedersen TR, Faergeman O, Kastelein JJP, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction - the IDEAL study: A randomized controlled trial. JAMA 2005;294:2437-45
27. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78
28. Delahoy PJ, Magliano DJ, Webb K, et al. the relationship between reduction in low-density lipoprotein cholesterol by statins and reduction in risk of cardiovascular outcomes: An updated meta-analysis. Clin Ther 2009;31:236-44
29. the Multicentre Anti-Atheroma Study Investigators. Effect of simvastatin on coronary atheroma: The Multicentre Anti-Atheroma Study (MAAS). Lancet 1994;344:633-8
30. Bestehorn HP, Rensing UF, Roskamm H, et al. the effect of simvastatin on progression of coronary artery disease. the multicenter coronary intervention study (CIS). Eur Heart J 1997;18:226-34
31. Corti R, Fayad ZA, Fuster V, et al. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions - a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001;104:249-52
32. Corti R, Fuster V, Fayad ZA, et al. Lipid lowering by simvastatin induces regress of human atherosclerotic lesions - two years' follow-up by high-resolution noninvasive magnetic resonance imaging. Circulation 2002;106:2884-7
33. Notting PR, de Groot E, Zwinderman AH, et al. Regression of carotid and femoral artery intima-media thickness in familial hypercholesterolemia: Treatment with simvastatin. Arch Intern Med 2003;163:1837-41
34. Bays HE, Moore PB, Drehobi MA, et al. Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. Clin Ther 2001;23:1209-30
35. Dujovne CA, Ettinger MP, McNeer JF, et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol 2001;90:1092-7
36. Knopp RH, Gitter H, Truitt T, et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J 2003;24:729-41
37. Pandor A, Ara RM, Tumur I, et al. Ezetimibe monotherapy for cholesterol lowering in 2,722 people: Systematic review and meta-analysis of randomized controlled trials. J Intern Med 2009;265:568-80
38. 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
39. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009;361:2113-22
40. Villines TC, Stanek EJ, Devine PJ, et al. the ARBITER 6 HALTS Trial (arterial biology for the investigation of the treatment of reducing cholesterol 6-HDL and LDL treatment strategies in atherosclerosis): Final results and the impact of medication adherence, dose, and treatment duration. J Am Coll Cardiol 2010;55:2721-6
41. Davidson MH, McGarry T, Bettis R, et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002;40:2125-34
42. Leiter LA, Betteridge DJ, Famier M, et al. Lipid-altering efficacy and safety profile of combination therapy with ezetimibe/statin vs statin monotherapy in patients with and without diabetes: An analysis of pooled data from 27 clinical trials. Diabetes Obes Metab 2011;13:615-28
43. Bays HE, Ose L, Fraser N, et al. A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. Clin Ther 2004;26:1758-73
44. Pearson T, Ballantyne C, Sisk C, et al. Comparison of effects of ezetimibe/simvastatin versus simvastatin versus atorvastatin in reducing C-reactive protein and low-density lipoprotein cholesterol levels. Am J Cardiol 2007;99:1706-13
45. Catapano AL, Davidson MH, Ballantyne CM, et al. Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients. Curr Med Res Opin 2006;22:2041-53
46. Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43
47. Paraskevas KI, Veith FJ, Mikhailidis DP. Editorial - Carotid intima-media thickness and ezetimibe: The end of a misunderstanding. Curr Vasc Pharmacol 2011;9:381-4
48. Avellone G, Di Garbo V, Guarnotta R, et al. Efficacy and safety of long-term ezetimibe/simvastatin treatment in patients with familial hypercholesterolemia. Int Angiol 2010;29:514-24
49. Meaney A, Ceballos G, Asburn J, et al. the VYtorin on carotid intima-media thickness and overall arterial rigidity (VYCTOR) study. J Clin Pharmacol 2009;49:838-47
50. Howard BV, Roman MJ, Devereux RB, et al. Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: The SANDS ramdomized trial. JAMA 2008;299:1678-89
51. Fleg JL, Mete M, Howard BV, et al. Effect of statins alone versus statins plus ezetimibe on carotid atherosclerosis in type 2 diabetes: The SANDS (Stop Atherosclerosis in Native Diabetic Study) trial. J Am Coll Cardiol 2008;52:2198-205
52. West AM, Anderson JD, Meyer CH, et al. the effect of ezetimibe on peripheral arterial atherosclerosis depends upon statin use at baseline. Atherosclerosis 2011;218:155-62
53. Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-56
54. Gerdts E, Rossebø AB, Pedersen TR, et al. Impact of baseline severity of aortic valve stenosis on effect of intensive lipid lowering therapy (from the SEAS study). Am J Cardiol 2010;106:1634-9
55. Baigent C, Landray MJ, Reith C, et al. the effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): A randomised, placebo-controlled trial. Lancet 2011;377:2181-92
56. Lin CF, Gau CS, Wu FL, et al. Impact of ezetimibe coadministered with statins on cardiovascular events following acute coronary syndrome: A 3-year populationbased retrospective cohort study in Taiwan. Clin Ther 2011;33:1120-31
57. Brown BG, Taylor AJ. Does ENHANCE diminish confidence in lowering LDL or in Ezetimibe? N Engl J Med 2008;358:1504-7
58. Mikhailidis DP, Elisaf M, Rizzo M, et al. European panel on low density lipoprotein (LDL) subclasses: A statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses. Curr Vasc Pharmacol 2011;9:533-71
59. Rizzo M, Rini GB, Spinas GA, Berneis K. the effects of ezetimibe on LDL-cholesterol: quantitative or qualitative changes? Atherosclerosis 2009;204:330-3
60. Berneis K, Rizzo M, Berthold HK, Spinas GA, Krone W, Gouni-Berthold I. Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: A randomized trial. Eur Heart J 2010;31:1633-9
61. Cannon CP, Giugliano RP, Blazing MA, et al. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: vytorin Efficacy International Trial): Comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J 2008;156:862-32
62. Examining outcomes in subjects with acute coronary syndrome: Vytorin (ezetimibe/simvastatin) vs stimvastatin (study P04103AM3. Available from: http://clinicaltrials.gov/ct2/show/NCT00202878?term=ezetimibe +simvastatin&rank=5 IMPROVE-IT [Last accessed 4 May 2012]
63. Holme I, Boman K, Btudi P, et al. Observed and predicted reduction of ischemic cardiovascular events in the simvastatin and ezetimibe in aortic stenosis trial. Am J Cardiol 2010;105:1802-8
64. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:238-48
65. Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395-407
66. Holdaas H, Holme I, Schmeider RE, et al. Rosuvastatin in diabetic hemodialysis patients. J Am Soc Nephrol 2011;22:1335-41
67. Bardini G, Giorda CB, Pontiroli AE, et al. Ezetimibe + simvastatin versus doubling the dose of simvastatin in high cardiovascular risk diabetics: A multicenter, randomized trial (the LEAD study). Cardiovasc Diabetol 2010;9:20
68. Katz PM, Mendelsohn AA, Goodman SG, et al. Use of treatment optimization algorithm involving statin-ezetimibe combination aids in achievement of guideline-based lowdensity lipoprotein targets in patients with dyslipidemia at high vascular risk guideline-based undertaking to improve Dyslipidemia management in Canada (GUIDANC). Can J Cardiol 2011;27:138-45
69. Farnier M, Averna M, Missault L, et al. Lipid-altering efficacy of ezetimibe/simvastatin 10/20 mg compared with rosuvastatin 10 mg in high-risk hypercholestrolaemic patients inadequately controlled with prior statin monotherapy - the IN-Cross study. Int J Clin Pract 2009;63:547-59
70. McCormack T, Harvey P, Gaunt R, et al. Incremental cholesterol reduction with ezetimibe/simvastatin, atorvastatin and rosuvastatin in UK General Practice (IN-PRACTICE): Randomized controlled trial of achievement of Joint British Societies (JBS-2) cholesterol targets. Int J Clin Pract 2010;64:1052-61
71. Foody JM, Brown WV, Zieve F, et al. Safety and efficacy of ezetimibe/simvastatin combination versus atorvastatin alone in adults 65 years of age with hypercholesterolemia and with or at moderately high/high risk for coronary heart disease (the VYTELD study). Am J Cardiol 2010;106:1255-63
72. Heart Protection Study Collaborative Group. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20536 high-risk individuals: A randomised controlled trial. Lancet 2011;378:2013-20
73. Rossebø AB, Pedersen TR, Allen C, et al. Design and baseline characteristics of the simvastatin and ezetimibe in aortic stenosis (SEAS) study. Am J Cardiol 2007;99:970-3
74. Peto R, Emberson J, Landray M, et al. Analyses of cancer data from three ezetimibe trials. N Engl J Med 2008;359:1357-66
75. SHARP Collaborative Group. Study of heart and renal protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease. Am Heart J 2010;160:785-94