Abstract
Purpose
The purpose of this study was to evaluate how total cholesterol (TC) concentration in subjects treated with statins predicts myocardial infarction (MI) risk in the absence of low density lipoprotein cholesterol (LDL-C) measurement in clinical trials and in the setting of usual care.
Methods
A systematic review of published English language randomised clinical trials comparing statins with placebo that reported TC changes in subjects with or without prior MI between 1993 and 2008 was carried out using Medline, the Cochrane Library, Web of Science and the ISI Web of Knowledge. In addition, a cohort study of MI patients who had at least two TC measurements in Tayside, Scotland, between 1989 and 2002 was performed. The main outcome was TC concentration changes and risk of subsequent MI.
Results
In the meta-analyses of secondary and primary prevention trials statins decreased TC by 1.54 mmol/L and 1.37 mmol/L versus placebo. Statin-associated TC reduction translated into a risk reduction of 18% per mmol (RR 0.82; 95%CI 0.72–0.93) for secondary prevention and 24% per mmol (RR 0.76; 95%CI 0.62–0.93) for primary prevention. In the cohort study, statin use reduced TC by 0.98 mmol/L compared with non statin-use. Statin use was associated with a 28% reduction (adjusted HR 0.72; 95%CI 0.51–0.98) for recurrent MI.
Conclusions
Total cholesterol measurements can be used with confidence in the absence of LDL measurements to make decisions about statin drug introduction or titration. Randomised trials of statin therapy had good external validity and cholesterol changes and outcomes in trials were comparable to those observed in the setting of usual care.
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References
Collins R, Armitage J, Parish S, Sleight P, Peto R, Heart Protection Study Collaborative Group (2002) MCR/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals. Lancet 360:7–22
Sacks FM, Moye LA, Davis BR, Cole TG, Rouleau JL, Nash DT, Pfeffer MA, Braunwald E (1998) Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the cholesterol and recurrent events trial. Circulation 97(15):1446–1452
Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group (2002) Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholesterol concentrations. Lancet 359:1379–1387
Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J (2003) ASCOT investigators. 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). Lancet 361:1149–1158
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E (1996) The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators (CARE). N Engl J Med 335(14):1001–1009
Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG (2002) Pravastatin in elderly individuals at risk of vascular disease (PROSPER). Lancet 360:1623–1630
Serruys PW, de Feyter P, Macaya C, Kokott N, Puel J, Vrolix M, Branzi A, Bertolami MC, Jackson G, Strauss B, Meier B, Lescol Intervention Prevention Study, Lescol Intervention Prevention Study (LIPS) Investigators (2002) Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial. JAMA 287:3215–3222
The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group (1998) 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 339:1349–1357
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ, West of Scotland Coronary Prevention Study Group (1995) Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 333:1301–1307
Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R, Cholesterol Treatment Trialists’ (CTT) Collaborators (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 366(9493):1267–1278
Vrecer M, Turk S, Drinovec J, Mrhar A (2003) Use of statins in primary and secondary prevention of coronary heart disease and ischemic stroke. Meta-analysis of randomized trials. Int J Clin Pharmacol Ther 41(12):567–577
Murphy MJ, Wei L, Waston AD, Macdonald TM (2008) ‘Real-life’ reduction in cholesterol with statins, 1993 to 2002. Br J Clin Pharmacol 65(4):587–592
Blettner M, Sauerbrei W, Schlehofer B, Scheuchenpflug T, Friedenreich C (1999) Traditional reviews, meta-analyses and pooled analyses in epidemiology. Int J Epidemiol 28:1–9
Wei L, Parkinson J, Macdonald TM (2005) The Tayside Medicines Monitoring Unit (MEMO). In: Strom BL (ed) Pharmacoepidemiology, 4th edn. Wiley, Chichester, pp 323–336
Tamura A, Mikuriya Y, Nasu M (1997) Effect of pravastatin (10 mg/day) on progression of coronary atherosclerosis in patients with serum total cholesterol levels from 160 to 220 mg/dl and angiographically documented coronary artery disease. Coronary Artery Regression Study (CARS) Group. Am J Cardiol 79(7):893–896
The Pravastatin Multinational Study Group for Cardiac Risk Patients (1993) Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. Am J Cardiol 72(14):1031–1037
Pitt B, Mancini GB, Ellis SG, Rosman HS, Park JS, McGovern ME (1995) Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. PLAC I investigation. J Am Coll Cardiol 26(5):1133–1139
Crouse JR III, Byington RP, Bond MG, Espeland MA, Craven TE, Sprinkle JW, McGovern ME, Furberg CD (1995) Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II). Am J Cardiol 75(7):455–459
Jukema JW, Bruschke AV, van Boven AJ, Reiber JH, Bal ET, Zwinderman AH, Jansen H, Boerma GJ, van Rappard FM, Lie KI (1995) 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 91(10):2528–2540
Scandinavian Simvastatin Survival Study Group (1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Atheroscler Suppl 5(3):81–87
MAAS Investigators (1994) Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS). Lancet 344(8923):633–638
Teo KK, Burton JR, Buller CE, Plante S, Catellier D, Tymchak W, Dzavik V, Taylor D, Yokoyama S, Montague TJ (2000) Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: the Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation 102(15):1748–1754
Blankenhorn DH, Azen SP, Kramsch DM, Mack WJ, Cashin-Hemphill L, Hodis HN, DeBoer LW, Mahrer PR, Masteller MJ, Vailas LI, Alaupovic P, Hirsch LJ; MARS Research Group (1993) Coronary angiographic changes with lovastatin therapy. The Monitored Atherosclerosis Regression Study (MARS). Ann Intern Med 119(10):969–976
Waters D, Lespérance J, Gladstone P, Boccuzzi SJ, Cook T, Hudgin R, Krip G, Higginson L (1996) Effects of cigarette smoking on the angiographic evolution of coronary atherosclerosis. A Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) Substudy. CCAIT Study Group. Circulation 94(4):614–621
Herd JA, Ballantyne CM, Farmer JA, Ferguson JJ III, Jones PH, West MS, Gould KL, Gotto AM Jr (1997) Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol 80:278–286
Riegger G, Abletshauser C, Ludwig M, Schwandt P, Widimsky J, Weidinger G, Welzel D (1999) The effect of fluvastatin on cardiac events in patients with symptomatic coronary artery disease during one year of treatment. Atherosclerosis 144(1):263–270
Furberg CD, Adams HP Jr, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley WA (1994) Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) research group. Circulation 90(4):1679–1687
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr (1998) 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 279(20):1615–1622
Salonen R, Nyyssönen K, Porkkala E, Rummukainen J, Belder R, Park JS, Salonen JT, Kuopio Atherosclerosis Prevention Study (KAPS) (1995) A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 92(7):1758–1764
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ (2004) Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. Atheroscler Suppl 5(3):91–97
Bestehorn HP, Rensing UF, Roskamm H, Betz P, Benesch L, Schemeitat K, Blümchen G, Claus J, Mathes P, Kappenberger L, Wieland H, Neiss A (1997) The effect of simvastatin on progression of coronary artery disease. The Multicenter Coronary Intervention Study (CIS). Eur Heart J 18(2):226–234
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH, CARDS investigators (2004) Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 364(9435):685–696
Dean BB, Borenstein JE, Henning JM, Knight K, Merz CN (2004) Can change in high-density lipoprotein cholesterol levels reduce cardiovascular risk? Am Heart J 147(6):966–976
Wei L, Ebrahim S, Bartlett C, Davey PD, Sullivan FM, MacDonald TM (2005) Statin use in the secondary prevention of coronary heart disease in primary care: cohort study and comparison of inclusion and outcome with patients in randomized trials. BMJ 330:821
Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R (2004) Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 292(21):2585–90
Acknowledgements
LW holds a Special Training Fellowship in Health Services and a Health of the Public Research Award from the Medical Research Council, UK.
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Sheng, X., Wei, L., Murphy, M.J. et al. Statins and total (not LDL) cholesterol concentration and outcome of myocardial infarction: results from a meta-analysis and an observational study. Eur J Clin Pharmacol 65, 1071–1080 (2009). https://doi.org/10.1007/s00228-009-0720-x
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DOI: https://doi.org/10.1007/s00228-009-0720-x