Key Clinical Trials

Key Clinical Trials

Most of the largest trials to assess therapeutic approaches to atherosclerosis have involved statins55. Details of the key studies are summarised in the table.

The first of the large clinical trials, 4S famously enrolled 4,444 patients and proved the efficacy of simvastatin as secondary prevention against a mortality endpoint and other CHD events. The ASTEROID trial has attracted much recent publicity as the first to find that intensive rosuvastatin therapy results in highly significant regression in coronary atherosclerosis assessed by IVUS. The conclusions may have important implications for the usage and indication for statins and summarised as follows:

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References:
  1. Ray, K.K., Cannon, C.P., Braunwald, E. Recent trials of Lipid Lowering International Journal of Clinical practice 2007 61 (1) 1145-1159 http://www.ncbi.nlm.nih.gov/pubmed/17577297
  2. De Lemos J.A., Blazing M.A., Wiviott S.D. 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 http://www.ncbi.nlm.nih.gov/pubmed/15337732
  3. Bays H.E. Dujovne C.A.; McGovern M.E.; White T.E.; Kashyap M.L.; Hutcheson A.G.; Crouse J.R. Comparison of Once-Daily, niacin Extended-Release/lovastatin with standard doses of atorvastatin and simvastatin (the advicor versus other Cholesterol-Modulating agents trial evaluation [ADVOCATE]) The American Journal of Cardiology 2003; 91 (6) , 667-672 http://www.ncbi.nlm.nih.gov/pubmed/12633795
  4. Knopp R.H., D´Emden M, Smilde J.G. et al. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN). Diabetes Care. 2006; 29:1478-85. http://www.ncbi.nlm.nih.gov/pubmed/16801565
  5. Nissen S.E., Nicholls S.J., Sipahi, I. et al Regression of Coronary Atherosclerosis: The Effect of Very High-Intensity Statin Therapy on ASTEROID Trial JAMA. 2006;295(13):1556-1565 http://www.ncbi.nlm.nih.gov/pubmed/16533939
  6. Colhoun H.M., Betteridge D.J., Durrington P.N. et al Primary preparation of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS) multicentre randomized placebo-controlled trial Lancet 2004 364:685-96 http://www.ncbi.nlm.nih.gov/pubmed/15325833
  7. Sacks F.M., Pfeffer M.A., Moye L.A., 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(14):1001-9 http://www.ncbi.nlm.nih.gov/pubmed/8801446
  8. Kjekshus J, Apetrei E, Barrios V et al Rosuvastatin in older patients with systolic heart failure. N. Eng. J. Med 2007;357(22):2248-61 http://www.ncbi.nlm.nih.gov/pubmed/17984166
  9. Keech A, Simes R.J., Barter P et al Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes (the FIELD study); randomized controlled trial Lancet 2005 366 1849-61 http://www.ncbi.nlm.nih.gov/pubmed/16310551
  10. Liem A, van Boven A.J., Eidhagen A.P. et al Fluvastatin in acute myocardial infarction: effects of early and late ischemic events: the FLORIDA trial Circulation 2000 102:2672 http://www.ncbi.nlm.nih.gov/pubmed/11138604
  11. Yusuf S, Sleight P, Pogue J et al Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342(3):145-53 http://www.ncbi.nlm.nih.gov/pubmed/10639539
  12. Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 20,536 high risk individuals: a randomized placebo-controlled trial Lancet 2002: 360 7-22 http://www.ncbi.nlm.nih.gov/pubmed/12114036
  13. Pederson TR, Faergeman O, Kastelein JJ 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 http://www.ncbi.nlm.nih.gov/pubmed/16287954
  14. Ridker P.M., Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial. Circulation 2003;108(19):2292-7. http://www.ncbi.nlm.nih.gov/pubmed/14609996
  15. Nakamura, H., Arakawa, K., Itakura, H et al Primary prevention of Cardivascular disease with pravastatin in Japan (MEGA study). A prospective randomized controlled trial Lancet 2006 368:1155-63 http://www.ncbi.nlm.nih.gov/pubmed/17011942
  16. Crouse, J.R., Raichlen, J.S., Riley, W.A et al Effect of Rosuvastatin on progression of Carotid Intima-Media thickness in low-risk individuals with subclinical atherosclerosis JAMA 2007 297 (12) 1344-1353 http://www.ncbi.nlm.nih.gov/pubmed/17384434
  17. Schwartz G.G. Olsson A.G. Ezekowitz M.D. et al Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromess, the MIRACL study: a randomized controlled trial JAMA 2001; 285:1711-1718 http://www.ncbi.nlm.nih.gov/pubmed/11277825
  18. Dormandy J.A., Charbonnel B., Eckland D.J. et al Secondary prevention of macrovascular events in patients with type II diabetes in the PROACTIVE study Prospective piogitazone clinical trial in macrovascular events a randomized controlled trial Lancet 2005 366 1279-89 http://www.ncbi.nlm.nih.gov/pubmed/16214598
  19. Scririca B.M., Morrow D.A. Cannon C.P. et al Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study. J. Am Coll Cardiol. 2006;47(11):2326-31. http://www.ncbi.nlm.nih.gov/pubmed/16750703
  20. Nissen S.E., Tuzcu E.M., 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; 1071-80 http://www.ncbi.nlm.nih.gov/pubmed/14996776
  21. [no authors listed] Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study Lancet 1994; 344 1383-1389 http://www.ncbi.nlm.nih.gov/pubmed/7968073
  22. Amarenco, P, Bogousslavsky J, Callahan A III et al The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:459-559. http://www.ncbi.nlm.nih.gov/pubmed/16899775
  23. LaRosa J.C., Grundy S.M., Waters D.D. et al Intensive lipid lowering with atorvastatin in patients with stable coronary disease N Engl J Med 2005 352:1425-35 http://www.ncbi.nlm.nih.gov/pubmed/15755765
  24. Avecado, M, Sprecher D.L. Stains in acute coronary syndromes: start them in the hospital Cleveland Clinic Journal of Medicine 69 (1) 25-33 2002 http://www.ccjm.org/pdffiles/Acevedo102.pdf
  25. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol and regression of atherosclerosis. JAMA 2007; 297:499-508 http://www.ncbi.nlm.nih.gov/pubmed/17284700
  26. Go A.S. Lee W.Y, Yang J.et al. (2006) Statin therapy and risks for death and hospitalization in chronic heart failure. JAMA 296: 2105-2111 http://www.ncbi.nlm.nih.gov/pubmed/17077375
  27. Lipinski M.J., Abbate, A, Fuster V.,Vetrovek G.W. Drug Insight: Statins for Nonischemic Heart Failure - Evidence and Potential Mechanisms with HF and in turn their effects on LV function and other outcome measures remains unknown. Nat Clin Pract Cardiovasc Med. 2007;4(4):196-205. http://www.ncbi.nlm.nih.gov/pubmed/17380165
  28. Cleland J.G. et al. (2006) Clinical trials update from the American College of Cardiology: Darbepoetin alfa, ASTEROID, UNIVERSE, paediatric carvedilol, UNLOAD and ICELAND. Eur J Heart Fail 8: 326-329 http://www.ncbi.nlm.nih.gov/pubmed/16698503
  29. American Diabetes Association. Standards of medical care for patients with diabetes mellitus (position statement). Diabetes Care. 2006; 29:S4-42.
  31. Fung M.A. & Frohlich J.J. Common problems in the management of hypertriglyceremia CMAJ, 2002; 167 (11) 1261-6 http://www.ncbi.nlm.nih.gov/pubmed/12451083

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