Skip to main content
SpringerLink
Log in

Low-Dose Pravastatin and Age-Related Differences in Risk Factors for Cardiovascular Disease in Hypercholesterolaemic Japanese

Analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA Study)

  • Original Research Article
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

Background: Limited data are available regarding the relationship between age and the effect of HMG-CoA reductase inhibitor (statin) treatment.

Objective: The aim of the present analysis was to evaluate the relationships between age, baseline patient characteristics, and pravastatin treatment with respect to the development of cardiovascular disease (CVD) in the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, a large-scale clinical study conducted in Japanese patients with mild or moderate hyperlipidaemia to evaluate the primary preventive effect of pravastatin against coronary heart disease.

Methods: To compare the prevalence of CVD risk factors, the incidence of CVD in relation to each risk factor, and final values and changes in lipid parameters, the 7832 patients were classified into six age groups: <45, 45–9, 50–54, 55–59, 60–64 and ≤65 years. The relationship between pravastatin (10–20mg/day) treatment efficacy and aging and the incidence of events in relation to the age groups were compared using the multivariable Cox proportional hazards model.

Results: The prevalences of diabetes mellitus and hypertension were higher in older men than in younger men, while the prevalences of smoking and obesity were higher in younger men. However, a similar difference in risk factors was not seen in women. High-density lipoprotein cholesterol was higher in women than in men across all age groups. Triglycerides were higher in younger men than in older men and all groups of women. The mean follow-up levels of total cholesterol and low-density lipoprotein cholesterol were lower in older patients than in younger patients. Pravastatin (10–20mg/day) reduced the risk of CVD by about 30–40% across all age groups, and there was no difference between men and women. Of particular note in this analysis, CVD risk was markedly reduced in older women compared with younger women (53% vs 30% in women aged ≥65 vs ≥45 years).

Conclusion: A similar satisfactory risk reduction for CVD was achieved with low-dose pravastatin in all men and in older women in particular, despite differences in the prevalence of risk factors.

Trial registration: ClinicalTrials.gov Identifier: NCT00211705.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Fig. 2
Fig. 3
Fig. 4
Table II

Similar content being viewed by others

References

  1. Health and Welfare Statistics Association. Statistical abstracts on health and welfare in Japan 2006. Tokyo: Health and Welfare Statistics Association, 2007

    Google Scholar 

  2. Berger K, Schulte H, Stögbauer F, et al. Incidence and risk factors for stroke in an occupational cohort: the PROCAM study. Prospective Cardiovascular Muenster study. Stroke 1998 Aug; 29(8): 1562–6

    Article  PubMed  CAS  Google Scholar 

  3. Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol 1992 Dec 14; 70(19): 3H–9H

    Article  PubMed  CAS  Google Scholar 

  4. Castelli WP, Garrison RJ, Dawber TR, et al. The filter cigarette and coronary heart disease: the Framingham study. Lancet 1981 Jul 18; 2(8238): 109–13

    Article  PubMed  CAS  Google Scholar 

  5. Kannel WB, Dawber TR, McGee DL. Perspectives on systolic hypertension: the Framingham study. Circulation 1980 Jun; 61(6): 1179–82

    Article  PubMed  CAS  Google Scholar 

  6. Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the Framingham study. Circulation 1979 Jan; 59(1): 8–13

    Article  PubMed  CAS  Google Scholar 

  7. Kannel WB, Wilson PW, Nam BH, et al. Risk stratification of obesity as a coronary risk factor. Am J Cardiol 2002 Oct 1; 90(7): 697–701

    Article  PubMed  Google Scholar 

  8. Kubo M, Kiyohara Y, Kato I, et al. Trends in the incidence, mortality, and survival rate of cardiovascular disease in a Japanese community: the Hisayama study. Stroke 2003 Oct; 34(10): 2349–54

    Article  PubMed  Google Scholar 

  9. Nakamura Y, Yamamoto T, Okamura T, et al. Combined cardiovascular risk factors and outcome: NIPPON DATA80, 1980–1994. Circ J 2006 Aug; 70(8): 960–4

    Article  PubMed  Google Scholar 

  10. Wakugami K, Iseki K, Kimura Y, et al. Relationship between serum cholesterol and the risk of acute myocardial infarction in a screened cohort in Okinawa, Japan. Jpn Circ J 1998 Jan; 62(1): 7–14

    Article  PubMed  CAS  Google Scholar 

  11. Wilson PW, Garrison RJ, Castelli WP, et al. Prevalence of coronary heart disease in the Framingham Offspring study: role of lipoprotein cholesterols. Am J Cardiol 1980 Oct; 46(4): 649–54

    Article  PubMed  CAS  Google Scholar 

  12. King RB. Quality of life after stroke. Stroke 1996 Sep; 27(9): 1467–72

    Article  PubMed  CAS  Google Scholar 

  13. Westin L, Carlsson R, Israelsson B, et al. Quality of life in patients with ischaemic heart disease: a prospective controlled study. J Intern Med 1997 Sep; 242(3): 239–47

    Article  PubMed  CAS  Google Scholar 

  14. Hackett ML, Yapa C, Parag V, et al. Frequency of depression after stroke: a systematic review of observational studies. Stroke 2005 Jun; 36(6): 1330–40

    Article  PubMed  Google Scholar 

  15. Spertus JA, McDonell M, Woodman CL, et al. Association between depression and worse disease-specific functional status in outpatients with coronary artery disease. Am Heart J 2000 Jul; 140(1): 105–10

    Article  PubMed  CAS  Google Scholar 

  16. Barba R, Martinez-Espinosa S, Rodriguez-Garcia E, et al. Poststroke dementia: clinical features and risk factors. Stroke 2000 Jul; 31(7): 1494–501

    Article  PubMed  CAS  Google Scholar 

  17. Hellénius ML, de Faire U, Berglund B, et al. Diet and exercise are equally effective in reducing risk for cardiovascular disease: results of a randomized controlled study in men with slightly to moderately raised cardiovascular risk factors. Atherosclerosis 1993 Oct; 103(1): 81–91

    Article  PubMed  Google Scholar 

  18. Stampfer MJ, Hu FB, Manson JE, et al. Primary prevention of coronary heart disease in women through diet and life style. N Engl J Med 2000 Jul 6; 343(1): 16–22

    Article  PubMed  CAS  Google Scholar 

  19. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002 Dec 18; 288(23): 2998–3007

    Article  Google Scholar 

  20. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004 Aug 21–27; 364(9435): 685–96

    Article  PubMed  CAS  Google Scholar 

  21. 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 Mar 6; 363(9411): 757–67

    Article  PubMed  Google Scholar 

  22. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/Tex-CAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998 May 27; 279(20): 1615–22

    Article  PubMed  CAS  Google Scholar 

  23. Long-Term Intervention with Pravastatin 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 Nov 5; 339(19): 1349–57

    Article  Google Scholar 

  24. Sacks FM, Pfeffer MA, Moye LA, 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 Oct 3; 335(14): 1001–9

    Article  PubMed  CAS  Google Scholar 

  25. 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 Nov 19; 344(8934): 1383–9

    Google Scholar 

  26. Sever PS, Dahlof B, Poulter NR, 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. Lancet 2003 Apr 5; 361(9364): 1149–58

    Article  PubMed  CAS  Google Scholar 

  27. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002 Nov 23; 360(9346): 1623–30

    Article  PubMed  CAS  Google Scholar 

  28. Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study Group. Design and baseline characteristics of a study of primary prevention of coronary events with pravastatin among Japanese with mildly elevated cholesterol levels. Circ J 2004 Sep; 68(9): 860–7

    Article  Google Scholar 

  29. Nakamura H, Arakawa K, Itakura H, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA study): a prospective randomised controlled trial. Lancet 2006 Sep 30; 368(9542): 1155–63

    Article  PubMed  CAS  Google Scholar 

  30. Hansson L, Hedner T, Dahlof B. Prospective randomized open blinded end-point (PROBE) study: a novel design for intervention trials. Prospective Randomized Open Blinded End-Point. Blood Press 1992 Aug; 1(2): 113–9

    Article  PubMed  CAS  Google Scholar 

  31. National Cholesterol Education Program: second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1993; 89(3): 1333–445

    Google Scholar 

  32. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972 Jun; 18(6): 499–502

    PubMed  CAS  Google Scholar 

  33. Tanaka Y, Matsuyama Y, Ohashi Y. Estimation of treatment effect adjusting for treatment changes using the intensity score method: application to a large primary prevention study for coronary events (MEGA study). Stat Med 2008 May 10; 27(10): 1718–33

    Article  PubMed  Google Scholar 

  34. Ishikawa T, Mizuno K, Nakaya N, et al., for the MEGA Study Group. The relationship between the effect of pravastatin and risk factors for coronary heart disease in Japanese patients with hypercholesterolemia. Circ J 2008 Oct; 72: 1576–82

    Article  PubMed  CAS  Google Scholar 

  35. Uchiyama S, Nakaya N, Mizuno K, et al., for the MEGA Study Group. Risk factors for stroke and lipid-lowering effect of pravastatin on the risk of stroke in Japanese patients with hypercholesterolemia: analysis of data from the MEGA study, a large randomized controlled trial. J Neurol Sci 2009 Sep 15; 284: 72–6

    Article  PubMed  CAS  Google Scholar 

  36. Qiu H, Depre C, Vatner SF, et al. Sex differences in myocardial infarction and rupture. J Mol Cell Cardiol 2007 Nov; 43(5): 532–4

    Article  PubMed  CAS  Google Scholar 

  37. Hunt D, Young P, Simes J, et al. Benefits of pravastatin on cardiovascular events and mortality in older patients with coronary heart disease are equal to or exceed those seen in younger patients: results from the LIPID trial. Ann Intern Med 2001 May 15; 134(10): 931–40

    PubMed  CAS  Google Scholar 

  38. LIPID Study Group (Long-term Intervention with Pravastatin in Ischaemic Disease). Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholesterol concentrations: the LIPID trial follow-up. Lancet 2002 Apr 20; 359(9315): 1379–87

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank all the study participants, physicians, co-medical staff and co-workers. We thank Ray Hill of inScience Communications, a Wolters Kluwer business, who provided copy editing and journal styling prior to submission. This assistance was funded by Daiichi Sankyo.

The following authors have received speakers bureau, expert witness, research grant and/or consultant fees as follows: N. Nakaya: Novartis, Daiichi Sankyo, Kowa, ASKA; K. Mizuno: Nippon Boehringer Ingelheim, Shionogi, Daiichi Sankyo, Kyowa Hakko Kirin, Mochida, Eisai, Pfizer, Novartis, Mitsubishi Tanabe, Astellas, Sanofi-Aventis, Teijin, Banyu, Dainippon Sumitomo; Y. Ohashi: Shionogi, Daiichi Sankyo, Banyu, Kowa, AstraZeneca, Merck Sharp & Dohme; T. Teramoto: Daiichi Sankyo, Banyu, Kissei, Astellas, Shionogi, Schering-Plough, Kowa, Mitsubishi-Tanabe, Pfizer, Bayer, GlaxoSmithKline, Merck Sharp & Dohme; S. Yokoyama: Daiichi Sankyo, AstraZeneca, ASKA, Novartis, Astellas, Kowa, Pfizer, Kissei, Mitsubishi; and H. Nakamura: Daiichi Sankyo, Banyu, Merck Sharp & Dohme, Pfizer. The other authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Nakaya Clinic, 4-7-8 Higashinakano Nakano-ku, Tokyo, 164-0003, Japan

    Noriaki Nakaya MD, PhD

  2. Department of Internal Medicine, Nippon Medical School, Tokyo, Japan

    Kyoichi Mizuno

  3. Department of Biostatistics/Epidemiology and Preventive Health Sciences, University of Tokyo, Tokyo, Japan

    Yasuo Ohashi

  4. Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan

    Tamio Teramoto

  5. Nagoya City University Graduate School of Medical Science, Nagoya, Japan

    Shinji Yokoyama

  6. Hirahara Internal Clinic, Niigata, Japan

    Katsumi Hirahara

  7. Asahiyama Internal Clinic, Hokkaido, Japan

    Masahiro Mizutani

  8. Mitsukoshi Health and Welfare Foundation, Tokyo, Japan

    Haruo Nakamura

Authors
  1. Noriaki Nakaya MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyoichi Mizuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasuo Ohashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tamio Teramoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shinji Yokoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Katsumi Hirahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Masahiro Mizutani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Haruo Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Noriaki Nakaya MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nakaya, N., Mizuno, K., Ohashi, Y. et al. Low-Dose Pravastatin and Age-Related Differences in Risk Factors for Cardiovascular Disease in Hypercholesterolaemic Japanese. Drugs Aging 28, 681–692 (2011). https://doi.org/10.2165/11595620-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11595620-000000000-00000

Keywords

Search

Navigation