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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

Drugs volume 64, pages 43–60 (2004)Cite this article

Summary

Background The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome. No study, however, has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease (CHD) in hypertensive patients who are not conventionally deemed dyslipidaemic.

Methods Of 19 342 hypertensive patients (aged 40–79 years with at least three other cardiovascular risk factors) randomised to one of two antihypertensive regimens in the Anglo-Scandinavian Cardiac Outcomes Trial, 10 305 with nonfasting total cholesterol concentrations 6.5 mmol/L or less were randomly assigned additional atorvastatin 10 mg or placebo. These patients formed the lipid-lowering arm of the study. We planned follow-up for an average of 5 years, the primary endpoint being non-fatal myocardial infarction and fatal CHD. Data were analysed by intention to treat.

Findings Treatment was stopped after a median follow-up of 3.3 years. By that time, 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0.64 [95% CI 0.50–0.83], p = 0.0005). This benefit emerged in the first year of follow-up. There was no significant heterogeneity among prespecified subgroups. Fatal and non-fatal stroke (89 atorvastatin vs 121 placebo, 0.73 [0.56–0.96], p = 0.024), total cardiovascular events (389 vs 486, 0.79 [0.69–0.90], p = 0.0005), and total coronary events (178 vs 247, 0.71 [0.59–0.86], p = 0.0005) were also significantly lowered. There were 185 deaths in the atorvastatin group and 212 in the placebo group (0.87 [0.71–1.06], p = 0.16). Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months, and by 1.1 mmol/L after 3 years of follow-up.

Interpretation The reductions in major cardiovascular events with atorvastatin are large, given the short follow-up time. These findings may have implications for future lipid-lowering guidelines.

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References

  1. 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: 1383–89.

    Google Scholar 

  2. The Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–09.

    Article  Google Scholar 

  3. The Long-Term Intervention with Pravastatin Group in Ischaemic Disease (LIPID) Study Group. 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: 1349–57.

    Article  Google Scholar 

  4. Athyros VG, Papageorgiou AA, Mercouris BR. The GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. Curr Med Res Opin 2002; 18: 220–28.

    PubMed  Article  Google Scholar 

  5. Serruys PW, de Feyter P, Macaya C, et al, Intervention Prevention Study (LIPS) Investigators. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomised controlled trial. JAMA 2002; 287: 3215–22.

    PubMed  Article  CAS  Google Scholar 

  6. Shepherd J, Cobbe SM, Ford I, et al, for The West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–07.

    PubMed  Article  CAS  Google Scholar 

  7. Downs JR, Clearfield M, Weis S, et al, for the AFCAPS/ TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998; 279: 1615–22.

    PubMed  Article  CAS  Google Scholar 

  8. 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.

    Article  Google Scholar 

  9. Prosper Study Group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360: 1623–30.

    Article  Google Scholar 

  10. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomised to pravastatin vs usual care. JAMA 2002: 288: 2998–3007.

    Article  Google Scholar 

  11. Woolf N. Pathology of atherosclerosis. In: Betteridge DJ, Illingworth R, Shepherd J, eds. Lipoproteins in health and disease. London: Arnold, 1999.

    Google Scholar 

  12. Stamler J, Wentworth D, Neaton JD, for the MRFIT Research Group. Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? JAMA 1986; 256: 2823–28.

    PubMed  Article  CAS  Google Scholar 

  13. Bloomfield Rubins H, Robins SJ, Collins D, et al, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999; 341: 410–18.

    Article  Google Scholar 

  14. Buchwald H, Varco RL, Matts JP, et al. Report of the program on the surgical control of the hyperlipidemias (POSCH): effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolaemia. N Engl J Med 1990; 323: 946–55.

    PubMed  Article  CAS  Google Scholar 

  15. Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Blood pressure, cholesterol, and stroke in eastern Asia. Lancet 1998; 352: 1801–07.

    Article  Google Scholar 

  16. Crouse III JR, Byington RP, Furberg CD. HMG-CoA reductase inhibitor therapy and stroke risk reduction: an analysis of clinical trials data. Atherosclerosis 1998; 138: 11–24.

    PubMed  Article  CAS  Google Scholar 

  17. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. JAMA 2001; 285: 1711–18.

    PubMed  Article  CAS  Google Scholar 

  18. Martin MJ, Hulley SB, Browner WS, Kuller LH, Wentworth D. Serum cholesterol, blood pressure and mortality: implications from a cohort of 361662 men. Lancet 1986; 2: 933–36.

    PubMed  Article  CAS  Google Scholar 

  19. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000; 18: 207–13.

    Article  Google Scholar 

  20. Kannel WB. Importance of hypertension as a major risk factor in cardiovascular disease. In: Bosch J, Grozsmann RJ, eds. Hypertension: physiopathology and treatment. New York: McGraw Hill, 1999: 888–910.

    Google Scholar 

  21. Stamler R. The primary prevention of hypertension and the population blood pressure problem. In: Marmot M, Elliott P, eds. Coronary heart disease epidemiology. Oxford: Oxford Medical Publications, 1992.

    Google Scholar 

  22. Sever PS, Dahlöf B, Poulter NR, et al. Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. J Hypertens 2001; 6: 1139–47.

    Article  Google Scholar 

  23. Hansson L, Hedner T, Dahlof B. Prospective Randomised Open Blinded Endpoint (PROBE) study: a novel design for intervention trials. Blood Pressure 1992; 1: 113–19.

    PubMed  Article  CAS  Google Scholar 

  24. Anglo-Scandinavian Cardiac Outcomes trial. ASCOT http://www.ascotstudy.co.uk (accessed March 14, 2003).

  25. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001; 103: 357–62.

    PubMed  Article  CAS  Google Scholar 

  26. Bucher HC, Griffith LE, Guyatt GH. Systematic review on the risk and benefit of different cholesterol-lowering interventions. Arterioscler Thromb Vasc Biol 1999; 19: 187–95.

    PubMed  Article  CAS  Google Scholar 

  27. Ramsay LE, Williams B, Johnston GD, et al. Guidelines for management of hypertension: report of the third working party of the British Hypertension Society, 1999. J Hum Hypertens 1999; 13: 569–92.

    PubMed  Article  CAS  Google Scholar 

  28. World Health Organization, International Society of Hypertension Blood Pressure Lowering Treatment Trialists’ Collaboration. Protocol for prospective collaborative overviews of major randomized trials of blood-pressure lowering treatments. J Hypertens 1998; 16: 127–37.

    Google Scholar 

  29. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. JAMA 2001; 285: 2487-97.

    Google Scholar 

  30. Ramsay LE, Haq IQ, Jackson PR, Yeo WW, Pickin DM, Payne JN. Targeting lipid-lowering drug therapy for primary prevention of coronary disease: an updated Sheffield table. Lancet 1996; 348: 387–88.

    PubMed  Article  CAS  Google Scholar 

  31. Wood D, Durrington P, Poulter N, McInnes G, Rees A, Wray R, for the British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, and British Diabetic Association. Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart 1998; 80: S1–29.

    Google Scholar 

  32. Glorioso N, Troffa C, Filigheddu F, et al. Effect of the MHG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia. Hypertension 1999; 34: 1281–86.

    PubMed  Article  CAS  Google Scholar 

  33. EUROASPIRE II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries. Eur Heart J 2001; 22: 554–72.

    Article  Google Scholar 

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Acknowledgments

We thank all trial participants, physicians, nurses, and practices in the participating countries for their important contribution to the study. The study was supported by the principal funding source, Pfizer, New York, NY, USA. Funding was also provided by Servier Research Group, Paris, France, and Leo Laboratories, Copenhagen, Denmark. We thank Yvonne Green and Sandra Johnson for their help in typing and collating the report.

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Authors and Affiliations

  1. Cardiovascular Studies Unit, Department of Clinical Pharmacology, Imperial College London, NHLI, Faculty of Medicine, St Mary’s Campus, London, W2 1PG, UK

    Peter S Sever &  Neil R Poulter

  2. Sahlgrenska University Hospital/Östra, Gothenburg, Sweden

    Björn Dahlöf

  3. City Hospital, Birmingham, UK

    Gareth Beevers

  4. Barts and the London, Queen Mary’s School of Medicine, London, UK

    Mark Caulfield

  5. Radcliffe Infirmary, Oxford, UK

    Rory Collins

  6. Ullevål Sykehus, Oslo, Norway

    Sverre E Kjeldsen

  7. University Hospital, Reykjavik, Iceland

    Arni Kristinsson

  8. University of Glasgow, Glasgow, UK

    Gordon T McInnes

  9. H S Frederiksberg Hospital, Frederiksberg, Denmark

    Jesper Mehlsen

  10. University Central Hospital, Helsinki, Finland

    Markku Nieminen

  11. Beaumont Hospital, Dublin, Ireland

    Eoin O’Brien

  12. Karolinska Hospital, Stockholm, Sweden

    Hans Wedel & Jan Östergren

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  1. Peter S Sever
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Correspondence to Neil R Poulter.

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Sever, P.S., Dahlöf, B., Poulter, N.R. et al. 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. Drugs 64, 43–60 (2004). https://doi.org/10.2165/00003495-200464002-00005

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Keywords

  • Statin
  • Atorvastatin
  • Pravastatin
  • Coronary Heart Disease Event
  • Total Cholesterol Concentration