Drug Safety

, Volume 14, Issue 1, pp 11–24

Benefits and Risks of HMG-CoA Reductase Inhibitors in the Prevention of Coronary Heart Disease

A Reappraisal
  • Terje R. Pedersen
  • Jonathan A. Tobert
Current Opinion

Summary

Although several cholesterol-lowering interventions have reduced coronary heart disease (CHD) events in clinical trials, drug therapy for hypercholesterolaemia has not been as widely used as the US and European guidelines recommend, mainly because until recently there was insufficient clinical trial evidence for improved survival. The Scandinavian Simvastatin Survival Study (4S) is the first trial of lipid-lowering therapy to demonstrate an unequivocal reduction in total mortality. Largely as a result of this study, there is now little disagreement on the necessity to reduce low density lipoprotein (LDL) cholesterol effectively in hypercholesterolaemic patients with CHD. Many physicians believe it is also important to reduce elevated levels of LDL cholesterol in patients without overt coronary disease, but more clinical trial evidence will be required before this is universally accepted. Inhibitors of HMG-CoA reductase are the most effective class of agents for this purpose, and have become widely used.

It is likely that the magnitude of risk reduction produced by lipid-lowering therapy is proportional to the degree of cholesterol lowering achieved, which is an important consideration when selecting an agent and deciding the dosage to use. The results of several multicentre comparative trials have clearly established that the 4 members of the class are not all equipotent on a mg basis in terms of their effects on lowering LDL cholesterol. They have shown that the hypolipidaemic effect of simvastatin 5mg approximately equals that of pravastatin 15mg and lovastatin 15mg and that of fluvastatin 40mg, all given once daily.

The tolerability profiles of HMG-CoA reductase inhibitors are excellent. Five-year data are available for simvastatin and lovastatin, and to date there is no good evidence for important differences in safety or tolerability among the class.

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References

  1. 1.
    Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Summary of the second report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel II). JAMA 1993: 269: 3015–23Google Scholar
  2. 2.
    Pyörälä K, De Backer G, Graham I, et al. Prevention of coronary heart disease in clinical practice. Recommendations of the task force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. Eur Heart J 1994; 15: 1300–31PubMedGoogle Scholar
  3. 3.
    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: 1383–9Google Scholar
  4. 4.
    Kjekshus J, Pedersen TR, for the Scandinavian Simvastatin Survival Study Group. Reducing the risk of coronary events: evidence from 4S. Am J Cardiol 1995; 76: 64C–68CPubMedCrossRefGoogle Scholar
  5. 5.
    Gould AL, Rossouw JE, Santanello NC, et al. Cholesterol reduction yields clinical benefit: a new look at old data. Circulation 1995; 91: 2274–82PubMedCrossRefGoogle Scholar
  6. 6.
    Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ 1994; 308: 367–72PubMedCrossRefGoogle Scholar
  7. 7.
    Thompson SG. Why sources of heterogeneity in meta-analysis should be investigated. BMJ 1994; 309: 13Google Scholar
  8. 8.
    Thompson SG. Controversies in meta-analysis: the case of the trials of serum cholesterol reduction. Stat Methods Med Res 1993; 2: 173–92PubMedCrossRefGoogle Scholar
  9. 9.
    Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia — report of the Program on the Surgical Control of Hyperlipidemias (POSCH). N Engl J Med 1990; 323: 946–55PubMedCrossRefGoogle Scholar
  10. 10.
    Byington RP, Jukema JW, Salonen JT, et al. Reduction in cardiovascular events during pravastatin therapy: pooled analysis of clinical events of the pravastatin atherosclerosis intervention program. Circulation 1995; 92: 2419–25PubMedCrossRefGoogle Scholar
  11. 11.
    ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet 1995; 345: 669–85CrossRefGoogle Scholar
  12. 12.
    Egger M, Davey Smith G. Misleading meta-analysis. Lessons from ‘an effective, safe, simple’ intervention that wasn’t. BMJ 1995; 310: 752–4PubMedCrossRefGoogle Scholar
  13. 13.
    Sacks FM, Pfeffer MA, Moye L, et al. Rationale and design of a secondary prevention trial of lowering normal plasma cholesterol levels after acute myocardial infarction: the Cholesterol and Recurrent Events trial (CARE). Am J Cardiol 1991; 68: 1436–46PubMedCrossRefGoogle Scholar
  14. 14.
    The LIPID Study Management Committee. Lowering cholesterol levels in patients with coronary heart disease. Med J Aust 1995; 162: 455–6Google Scholar
  15. 15.
    MAAS Investigators. Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS). Lancet 1994; 344: 633–8CrossRefGoogle Scholar
  16. 16.
    Brown G, Albers JJ, Fisher LL, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med 1990; 323: 1289–98PubMedCrossRefGoogle Scholar
  17. 17.
    Blankenhorn DH, Azen SP, Kramsch DM, et al. Coronary angiographic changes with lovastatin therapy. The monitored atherosclerosis regression study (MARS). Ann Intern Med 1993; 11(2): 969–76Google Scholar
  18. 18.
    Waters D, Higginson L, Gallstone P, et al. Effects of monotherapy with an HMG-CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography. The Canadian coronary atherosclerosis intervention trial. Circulation 1993; 89(3): 959–68CrossRefGoogle Scholar
  19. 19.
    Jukema JW, Bruschke AVG, van Boven AJ, et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995; 91: 2528–40PubMedCrossRefGoogle Scholar
  20. 20.
    Waters D, Craven T, Lesperance J. Prognostic significance of progression of coronary atherosclerosis. Circulation 1993; 87: 1067–75PubMedCrossRefGoogle Scholar
  21. 21.
    Brown BG, Zhao X-Q, Sacco DE, et al. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation 1993; 87: 1781–91PubMedCrossRefGoogle Scholar
  22. 22.
    Vos J, deFeyter J, Simoons ML, et al. Retardation and arrest of progression or regression of coronary artery disease: a review. Prog Cardiovasc Dis 1993; 35: 435–54PubMedCrossRefGoogle Scholar
  23. 23.
    Davies MJ, Krikler DM, Katz D. Atherosclerosis: inhibition or regression as therapeutic possibilities. Br Heart J 1991; 65: 302–10PubMedCrossRefGoogle Scholar
  24. 24.
    Fuster V, Badimon L, Badimon JJ, et al. The pathogenesis of coronary artery disease and acute coronary syndromes. N Engl J Med 1992; 326: 242–50, 310-8PubMedCrossRefGoogle Scholar
  25. 25.
    Carvalho ACA, Colman RW, Lees RS. Platelet function in hyperlipoproteinemia. N Engl J Med 1974; 290: 434–8PubMedCrossRefGoogle Scholar
  26. 26.
    Notarbartolo A, Davì G, Averna M, et al. Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia. Thromb Vasc Biol 1995; 15: 247–51CrossRefGoogle Scholar
  27. 27.
    Kaczmarek D, Hohlfeld T, Wambach G, et al. The actions of lovastatin on platelet function and platelet eicosanoid receptors in type II hypercholesterolaemia. Eur J Clin Pharmacol 1993; 45: 451–7PubMedCrossRefGoogle Scholar
  28. 28.
    Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81–106CrossRefGoogle Scholar
  29. 29.
    Vita JA, Treasure CB, Nabel EG, et al. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 1990; 81: 491–7PubMedCrossRefGoogle Scholar
  30. 30.
    Seiler C, Hess OM, Buechi M, et al. Influence of serum cholesterol and other coronary risk factors on vasomotion of angiographically normal coronary arteries. Circulation 1993; 88: 2139–48PubMedCrossRefGoogle Scholar
  31. 31.
    Treasure CB, Klein JL, Weintraub WS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995; 332: 481–7PubMedCrossRefGoogle Scholar
  32. 32.
    Anderson TJ, Meredith IT, Yeung AC, et al. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 1995; 332: 488–93PubMedCrossRefGoogle Scholar
  33. 33.
    Leung W-H, Lau C-P, Wong C-K. Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolaemic patients. Lancet 1993; 341: 1496–500PubMedCrossRefGoogle Scholar
  34. 34.
    Furberg CD, Adams Jr HP, Applegate WB, et al. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation 1994; 90: 1679–87PubMedCrossRefGoogle Scholar
  35. 35.
    Scandinavian Simvastatin Survival Study Group. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet 1995; 345: 1274–5Google Scholar
  36. 36.
    Oliver MF. Doubts about preventing coronary heart disease. Multiple interventions in middle aged men may do more harm than good. BMJ 1992; 304: 393–4PubMedCrossRefGoogle Scholar
  37. 37.
    Davey Smith G, Pekkanen J. Should there be a moratorium on the use of cholesterol lowering drugs? BMJ 1992; 304: 431–4PubMedCrossRefGoogle Scholar
  38. 38.
    Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ 1990; 301: 309–14PubMedCrossRefGoogle Scholar
  39. 39.
    Hulley SB, Walsh JMB, Newman TB. Health policy on blood cholesterol: time to change directions. Circulation 1992; 86: 1026–9PubMedCrossRefGoogle Scholar
  40. 40.
    Oliver M, Poole-Wilson P, Shepherd J, et al. Lower patients’ cholesterol now. BMJ 1995; 310: 1280–1PubMedCrossRefGoogle Scholar
  41. 41.
    Wood DA. Cholesterol lowering does have a role in secondary prevention. Br Heart J 1995; 73: 4–5PubMedCrossRefGoogle Scholar
  42. 42.
    Kennedy JW. President’s page: expanding the role of the American College of Cardiology. J Am Coll Cardiol 1995; 26: 289–90PubMedGoogle Scholar
  43. 43.
    Smith SC, Blair SN, Criqui MH, et al. AHA consensus panel statement: preventing heart attack and death in patients with coronary disease. Circulation 1995; 92: 2–4PubMedCrossRefGoogle Scholar
  44. 44.
    Lipid Research Clinics Progam. The Lipid Research Clinics Coronary Primary Prevention Trial results. II: The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984; 251: 365–74CrossRefGoogle Scholar
  45. 45.
    Manninen V, Elo MO, Frick MH, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988; 260: 641–51PubMedCrossRefGoogle Scholar
  46. 46.
    Chen ZM, Peto R, Collins R, et al. Serum cholesterol concentration and coronary heart disease in a population with low cholesterol concentrations. BMJ 1991; 303: 276–82PubMedCrossRefGoogle Scholar
  47. 47.
    Pedersen TR, Kjekshus J, Berg K, et al. Cholesterol lowering and the utilization of healthcare resources: results of the Scandinavian Simvastatin Survival Study (4S). Circulation. In pressGoogle Scholar
  48. 48.
    Steinhagen-Thiessen E, for the Simvastatin Pravastatin European Study Group. Comparative efficacy and tolerability of simvastatin 5 and 10 mg versus pravastatin 10 mg in moderate primary hypercholesterolemia. Cardiology 1994; 85: 244–54PubMedCrossRefGoogle Scholar
  49. 49.
    Douste-Blazy P, Ribeiro VG, Seed M. Comparative study of the efficacy and tolerability of simvastatin and pravastatin in patients with primary hypercholesterolaemia. Drug Invest 1993; 6: 353–61Google Scholar
  50. 50.
    Sweany AE, for the Simvastatin Pravastatin Study Group. A comparison of the efficacy and safety of simvastatin and pravastatin in the treatment of hypercholesterolemia. Am J Cardiol 1993; 71: 1408–14CrossRefGoogle Scholar
  51. 51.
    Lambrecht LJ, Malini PL, and the European Study Group. Efficacy and tolerability of simvastatin 20 mg vs pravastatin 20 mg in patients with primary hypercholesterolaemia. Acta Cardiol 1993; 48: 541–54PubMedGoogle Scholar
  52. 52.
    Farmer JA, Washington L, Jones PH, et al. Comparative effects of simvastatin and lovastatin in patients with hypercholesterolemia. Clin Ther 1992; 14: 708–77PubMedGoogle Scholar
  53. 53.
    McPherson R, Bedard J, Connelly P, et al. Comparison of the short-term efficacy and tolerability of lovastatin and pravastatin in the management of primary hypercholesterolemia. Clin Ther 1992; 14: 276–291PubMedGoogle Scholar
  54. 54.
    Illingworth DR, Erkelens DW, Keller U, et al. Defined daily doses in relation to hypolipidaemic efficacy of lovastatin, pravastatin, and simvastatin. Lancet 1994; 343: 1554–5PubMedCrossRefGoogle Scholar
  55. 55.
    Illingworth DR, Tobert JA. A review of clinical trials comparing HMG-CoA reductase inhibitors. Clin Ther 1994; 16: 366–85PubMedGoogle Scholar
  56. 56.
    Plosker GL, McTavish D. Simvastatin: a reappraisal of its pharmacological properties and therapeutic efficacy. Drugs 1995; 50: 334–63PubMedCrossRefGoogle Scholar
  57. 57.
    Illingworth DR, Stein EA, Knopp RH, et al. A randomized multicenter trial comparing the efficacy of simvastatin and fluvastatin. J Cardiovasc Pharmacol Ther 1996; 1: 23–30PubMedCrossRefGoogle Scholar
  58. 58.
    Ose L, Scott R, and the Simvastatin/Fluvastatin Study Group. Double-blind comparison of the efficacy, safety and tolerability of simvastatin and fluvastatin in patients with primary hypercholesterolaemia. Clin Drug Invest 1995; 10(3): 127–38CrossRefGoogle Scholar
  59. 59.
    Mitchel YB, for the Lovastatin Pravastatin Study Group. A multicenter comparative trial of lovastatin and pravastatin in the treatment of hypercholesterolemia. Am J Cardiol 1993; 71: 810–5CrossRefGoogle Scholar
  60. 60.
    Bradford RH, Shear CL, Chremos AN, et al. Expanded clinical evaluation of lovastatin (EXCEL) study results. Arch Intern Med 1991; 151: 43–9PubMedCrossRefGoogle Scholar
  61. 61.
    Berger ML, Wilson HM, Liss CL. A comparison of the tolerability and efficacy of lovastatin 20mg and fluvastatin 20mg in the treatment of primary hypercholesterolemia. J Cardiovasc Pharmacol Ther. In pressGoogle Scholar
  62. 62.
    Jacotot B, Benghazi R, Pfister P, et al. Comparison of fluvastatin versus pravastatin treatment of primary hypercholesterolemia. Am J Cardiol Preprint: 1PR-3PRGoogle Scholar
  63. 63.
    Tobert JA. Efficacy and long-term adverse effect pattern of lovastatin. Am J Cardiol 1988; 62: 28J–34JPubMedCrossRefGoogle Scholar
  64. 64.
    Tobert JA, Shear CL, Chremos AN, et al. Clinical experience with lovastatin. Am J Cardiol 1990; 65: 23F–26FPubMedCrossRefGoogle Scholar
  65. 65.
    Illingworth DR. HMG-CoA reductase inhibitors. Curr Opin Lipidol 1991; 2: 24–30CrossRefGoogle Scholar
  66. 66.
    Keech A, Collins R, MacMahon S, et al. Three-year follow-up of the Oxford Cholesterol Study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study. Eur Heart J 1994; 15: 255–69PubMedGoogle Scholar
  67. 67.
    ZOCOR (simvastatin) US product circular, June 1995, Merck & Co. Inc., West Point, PA 19486, USAGoogle Scholar
  68. 68.
    Feely J, O’Connor P. Effects of HMG-CoA reductase inhibitors on warfarin binding. Drug Invest 1991; 3: 315–6Google Scholar
  69. 69.
    Rolan PE. Plasma protein binding displacement interactions — why are they still regarded as clinically important? Br J Clin Pharmacol 1994; 37: 125–8PubMedCrossRefGoogle Scholar
  70. 70.
    McGovern ME, Mellies MJ. Long-term experience with pravastatin in clinical research trials. Clin Ther 1993; 15: 57–64PubMedGoogle Scholar
  71. 71.
    Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole [letter]. N Eng J Med 1995 Sep 7; 333: 664–5CrossRefGoogle Scholar
  72. 72.
    Spach DH, Bauwens JE, Clark CD. Rahbdomyolysis associated with lovastatin and erythromycin use. West J Med 1991; 154: 213–6PubMedGoogle Scholar
  73. 73.
    Ballantyne CM, Radoancevic B, Farmer JA, et al. Hyperlipidemia after heart transplantation: report of a 6-year experience, with treatment recommendations. J Am Coll Cardiol 1992; 19: 1315–21PubMedCrossRefGoogle Scholar
  74. 74.
    Barbir M, Rose M, Kushwaha S, et al. Low-dose simvastatin for the treatment of hypercholesterolaemia in recipients of cardiac transplantation. Int J Cardiol 1991; 33: 241–6PubMedCrossRefGoogle Scholar
  75. 75.
    Yoshimura N, Oka T, Okamoto M, et al. The effects of pravastatin on hyperlipidemia in renal transplant patients. Transplantation 1992; 53: 94–9PubMedCrossRefGoogle Scholar
  76. 76.
    Wiklund O, Angelin B, Bergman M, et al. Pravastatin and gemfibrozil alone and in combination for the treatment of hypercholesterolemia. Am J Med 1993; 94: 13–20PubMedCrossRefGoogle Scholar
  77. 77.
    Da Col PG, Fonda M, Fisicaro M, et al. Tolerability and efficacy of combination therapy with simvastatin plus gemfibrozil in type IIb refractory familial combined hyperlipidemia. Curr Ther Res 1993; 53: 473–83CrossRefGoogle Scholar
  78. 78.
    Illingworth DR, Bacon S. The influence of lovastatin plus gemfibrozil on plasma lipids and lipoproteins in patients with heterozygous familial hypercholesterolemia. Circulation 1989; 79: 590–6PubMedCrossRefGoogle Scholar
  79. 79.
    Jacobson TA, Chin MM, Fromell GJ, et al. Fluvastatin with and without niacin for hypercholesterolemia. Am J Cardiol 1994; 73: 339–45CrossRefGoogle Scholar
  80. 80.
    Davignon J, Roederer G, Montigny M, et al. Comparative efficacy and safety of pravastatin, nicotinic acid and the two combined in patients with hypercholesterolemia. Am J Cardiol 1994; 73: 339–45PubMedCrossRefGoogle Scholar
  81. 81.
    Stein EA, Davidson MH, Dujovne CA, et al. Combination low dose simvastatin and niacin in patients with combined hyperlipidaemia and low HDL cholesterol: a prospective study comparing lipid altering efficacy and tolerability. J Cardiovasc Pharmacol Ther. In pressGoogle Scholar
  82. 82.
    Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdomyolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990; 264: 71–5PubMedCrossRefGoogle Scholar
  83. 83.
    Duell PB, Illingworth DR. Combination therapy with HMG-CoA reductase inhibitors and gemfibrozil — practical or perilous? Heart Dis Stroke 1993; 2: 260–2PubMedGoogle Scholar
  84. 84.
    Lovastatin Study Groups I through IV. Lovastatin 5-year safety and efficacy study. Arch Intern Med 1993; 153: 1079–87CrossRefGoogle Scholar
  85. 85.
    The WOSCOPS Study Group. Screening experience and baseline characteristics in the West of Scotland Coronary Prevention Study. Am J Cardiol 1995; 76: 485–91CrossRefGoogle Scholar
  86. 86.
    Eckemas SA, Roos BE, Kvidal P, et al. The effects of simvastatin and pravastatin on objective and subjective measures of nocturnal sleep: a comparison of two structurally different HMG CoA reductase inhibitors in patients with primary moderate hypercholesterolaemia. Br J Clin Pharmacol 1993; 35: 284–9Google Scholar
  87. 87.
    Partinen M, Pihl S, Stranderg TE, et al. Effects on sleep of lovastatin as compared to pravastatin and placebo in patients with hypercholesterolemia. Am J Cardiol 1994; 73: 876–80PubMedCrossRefGoogle Scholar
  88. 88.
    Kostis JB, Rosen RC, Wilson AC. Central-nervous-system effects of HMG-CoA reductase inhibitors — lovastatin and pravastatin on sleep and cognitive performance in patients with hypercholesterolemia. J Clin Pharmacol 1994; 34: 989–96PubMedGoogle Scholar
  89. 89.
    Harrison RWS, Ashton CH. Do cholesterol-lowering agents affect brain activity? A comparison of simvastatin, pravastatin, and placebo in healthy volunteers. Br J Clin Pharmacol 1994; 37: 231–6PubMedCrossRefGoogle Scholar
  90. 90.
    Gengo F, Cwudzinski D, Kinkel P, et al. Effects of treatment with lovastatin and pravastatin on daytime cognitive performance. Clin Cardiol 1995; 18: 209–14PubMedCrossRefGoogle Scholar
  91. 91.
    Pedersen TR, Kjekshus J, Olsson AG, et al. Scandinavian Simvastatin Survival Study (4S) [letter]. Lancet 1994; 344: 1767–8CrossRefGoogle Scholar
  92. 92.
    Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–7PubMedCrossRefGoogle Scholar
  93. 93.
    Pedersen TR. Lowering cholesterol with drugs and diet. N Engl J Med 1995; 333: 1350–1PubMedCrossRefGoogle Scholar
  94. 94.
    Salonen R, Nyyssonen K, Porkkala E, et al. Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 1995; 92: 1758–64PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1996

Authors and Affiliations

  • Terje R. Pedersen
    • 1
  • Jonathan A. Tobert
    • 2
  1. 1.Cardiology Section, Medical DepartmentAker HospitalOsloNorway
  2. 2.Department of Clinical ResearchMerck Research LaboratoriesRahwayUSA

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