Drugs

, Volume 66, Issue 13, pp 1727–1740

Cardiovascular Health and Aromatase Inhibitors

Review Article

Abstract

Cardiovascular disease is the most frequent cause of death in North American women, and so death resulting from cardiovascular disease, rather than from malignancy, is not uncommon in breast cancer patients. This may be a consequence of the shared risk factors for developing breast cancer and cardiovascular disease, as well as the difficulty of managing cancer patients at higher risk for developing cardiovascular disease. Recently, much attention has focused on understanding the cardiovascular risk factors associated with breast cancer therapies. Tamoxifen has a lowering effect on serum lipids and is reported to decrease the risk of myocardial infarction but to increase the risk of thromboembolic events. Current data indicate that aromatase inhibitors (AIs) are not associated with an increased risk of thromboembolic or cerebrovascular events. Reports of a greater incidence of hypercholesterolaemia when AIs are compared head-to-head with tamoxifen may be a result of the intrinsic lipid-lowering effects of tamoxifen therapy and may be confounded by differences in data collection among trials. The incidence of cardiovascular events associated with AIs in large trials has been reported to be higher in trials comparing AIs with tamoxifen; comparisons within the MA.17 trial, which evaluated an AI versus placebo, did not show increases in hypercholesterolaemia or in cardiovascular events with the AI.

When treating breast cancer patients, oncologists should consider the same positive lifestyle changes that are proposed to lower the risk of cardiovascular disease in patients who do not have breast cancer. Moreover, physicians should assess cardiovascular risk, and monitor and treat patients already diagnosed with or at risk for coronary heart disease, according to established guidelines.

References

  1. 1.
    American Heart Association. Heart disease and stroke statistics: 2005 update. Dallas (TX): American Heart Association, 2005Google Scholar
  2. 2.
    Sourander L, Rajala T, Raiha I, et al. Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERT) [published erratum appears in Lancet 1999; 353: 330]. Lancet 1998; 352: 1965–9PubMedCrossRefGoogle Scholar
  3. 3.
    Nilsson G, Holmberg L, Garmo H, et al. Increased incidence of stroke in women with breast cancer. Eur J Cancer 2005; 41: 423–9PubMedCrossRefGoogle Scholar
  4. 4.
    Early Breast Cancer Trialists’ Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000; 355: 1757–70CrossRefGoogle Scholar
  5. 5.
    Fetting JH, Gray R, Fairclough DL, et al. Sixteen-week multidrug regimen versus cyclophosphamide, doxorubicin, and fluorouracil as adjuvant therapy for node-positive, receptor-negative breast cancer: an Intergroup study. J Clin Oncol 1998; 16: 2382–91PubMedGoogle Scholar
  6. 6.
    De Maio E, Gravina A, Pacilio C, et al. Compliance and toxicity of adjuvant CMF in elderly breast cancer patients: a single-center experience. BMC Cancer 2005; 5: 30PubMedCrossRefGoogle Scholar
  7. 7.
    Bonneterre J, Roche H, Kerbrat P, et al. Long-term cardiac follow-up in relapse-free patients after six courses of fluorouracil, epirubicin, and cyclophosphamide, with either 50 or 100mg of epirubicin, as adjuvant therapy for node-positive breast cancer: French adjuvant study group. J Clin Oncol 2004; 22: 3070–9PubMedCrossRefGoogle Scholar
  8. 8.
    Venturini M, Bighin C, Monfardini S, et al. Multicenter phase II study of trastuzumab in combination with epirubicin and docetaxel as first-line treatment for HER2-overexpressing metastatic breast cancer. Breast Cancer Res Treat 2006; 95: 45–53PubMedCrossRefGoogle Scholar
  9. 9.
    Youssef G, Links M. The prevention and management of cardiovascular complications of chemotherapy in patients with cancer. Am J Cardiovasc Drugs 2005; 5: 233–43PubMedCrossRefGoogle Scholar
  10. 10.
    Herceptin [package insert]. South San Francisco (CA): Genentech Inc., 2005Google Scholar
  11. 11.
    Braithwaite RS, Chlebowski RT, Lau J, et al. Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med 2003; 18: 937–47PubMedCrossRefGoogle Scholar
  12. 12.
    Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365: 1687–717CrossRefGoogle Scholar
  13. 13.
    Nordenskjold B, Rosell J, Rutqvist LE, et al. Coronary heart disease mortality after 5 years of adjuvant tamoxifen therapy: results from a randomized trial. J Natl Cancer Inst 2005; 97: 1609–10PubMedCrossRefGoogle Scholar
  14. 14.
    Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 2005; 23: 619–29PubMedCrossRefGoogle Scholar
  15. 15.
    Thürlimann B, on behalf of the BIG 1-98 Collaborative Group. BIG 1-98: a prospective randomized double-blind double-dummy phase III study to evaluate letrozole as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer [abstract]. Breast 2005; 14 Suppl. 1: S3CrossRefGoogle Scholar
  16. 16.
    Howell A, Cuzick J, Baum M, et al. ATAC Trialists’ Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005; 365: 60–2Google Scholar
  17. 17.
    Coombes RC, Hall E, Gibson LJ, et al. Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer [published erratum appears in N Engl J Med 2004; 351: 2461]. N Engl J Med 2004; 350:1081–92PubMedCrossRefGoogle Scholar
  18. 18.
    Cuzick J, Howell A. Optimal timing of the use of an aromatase inhibitor in the adjuvant treatment of postmenopausal hormone receptor-positive breast cancer [abstract no. 658]. J Clin Oncol 2005; 25 (16 Suppl.): 43SGoogle Scholar
  19. 19.
    Markopoulos C, Chrissochou M, Michailidou A, et al. Effect of exemestane on the lipidemic profile if post-menopausal operable breast cancer patients following 5–7 years of adjuvant tamoxifen: preliminary results of the ATENA substudy. Anti-cancer Drugs 2005; 16: 879–83PubMedCrossRefGoogle Scholar
  20. 20.
    Goss PE, Ingle JN, Martino S, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA. 17. J Natl Cancer Inst 2005; 97: 1262–71CrossRefGoogle Scholar
  21. 21.
    Boccardo F, Rubagotti A, Puntoni M, et al. Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: preliminary results of the Italian Tamoxifen Anastrozole Trial. J Clin Oncol 2005; 23: 5138–47PubMedCrossRefGoogle Scholar
  22. 22.
    Thurlimann B, Keshaviah A, Coates AS, et al. Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005; 353: 2747–57Google Scholar
  23. 23.
    Mouridsen HT, Robert NJ. The role of aromatase inhibitors as adjuvant therapy for early breast cancer in postmenopausal women. Eur J Cancer 2005; 41: 1678–89PubMedCrossRefGoogle Scholar
  24. 24.
    Jakesz R, Jonat W, Gnant M, et al., on behalf of the ABCSG, the GABG. Switching of postmenopausal women with endocrine responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 2005; 366: 455–62PubMedCrossRefGoogle Scholar
  25. 25.
    Kännel WB, Hjortland MC, McNamara PM, et al. Menopause and risk of cardiovascular disease: the Framingham Study. Ann Intern Med 1976; 85: 447–52PubMedGoogle Scholar
  26. 26.
    Heart and Stroke Foundation of Canada. The changing face of heart disease and stroke in Canada 2000. Ottawa, Canada, 1999 [online]. Available from URL: http://www.phacaspc.gc.ca/ccdpc-cpcmc/cvd-mcv/publications/hdsc_2000_e.html [Accessed 2006 Apr 24]
  27. 27.
    British Heart Foundation. Peterson S, Peto V, Rayner M, et al. European cardiovascular disease statistics 2005 [online]. Available from URL: http://www.heartstats.org [Accessed 2005 Sep 13]
  28. 28.
    American Heart Association/American Stroke Association. Primary prevention of ischcmic stroke. Stroke 2006; 37: 1583–633Google Scholar
  29. 29.
    Rosano GM, Vitale C, Silvestri A, et al. Hormone replacement therapy and cardioprotection: the end of the tale? Ann N Y Acad sci 2003; 997: 351–7PubMedCrossRefGoogle Scholar
  30. 30.
    Breast Cancer Risk Reduction. Practice guidelines in oncology [online]. National Comprehensive Cancer Network. Version 1. 2005. Available from URL: http://www.nccn.org/professionals/physician_gls/PDF/breast_risk.pdf. [Accessed 2005 Sep 17]
  31. 31.
    The Susan G. Komen Breast Cancer Foundation. Facts for life: beast cancer risk factors [online]. Available from URL: http://www.komen.org/stellent/groups/harvard_group/@dallas/documents/-komen_site_documents/rfapfactors.pdf [Accessed 2006 Sep 1]
  32. 32.
    Louwman WJ, Janssen-Heijnen ML, Houterman S, et al. Less extensive treatment and inferior prognosis for breast cancer patient with comorbidity: a population-based study. Eur J Cancer 2005; 41: 779–85PubMedCrossRefGoogle Scholar
  33. 33.
    Franklin SS, Gustin W, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation 1997; 96: 308–15Google Scholar
  34. 34.
    Neaton JD, Wentworth D. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med 1992; 152: 56–64Google Scholar
  35. 35.
    Coebergh JW, Janssen-Heijnen ML, Post PN, et al. Serious comorbidity among unselected cancer patients newly diagnosed in the southeastern part of The Netherlands in 1993–1996. J Clin Epidemiol 1999; 52: 1131–6PubMedCrossRefGoogle Scholar
  36. 36.
    Davies GM, Cook JR, Erbey J, et al. Projected coronary heart disease risk benefit with ezetimibe. Atherosclerosis 2005; 179: 375–8PubMedCrossRefGoogle Scholar
  37. 37.
    Grundy SM, Cleeman JI, Merz CN, et al. Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Arterioscler Thromb Vasc Biol 2004; 24: el49–161CrossRefGoogle Scholar
  38. 38.
    Sniderman AD, Furberg CD, Keech A, et al. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet 2003; 361: 777–80PubMedCrossRefGoogle Scholar
  39. 39.
    Baessler A, Fischer M, Huf V, et al. Failure to achieve recommended LDL cholesterol levels by suboptimal statin therapy relates to elevated cardiac event rates. Int J Cardiol 2005; 101: 293–8PubMedCrossRefGoogle Scholar
  40. 40.
    Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337: 1641–7PubMedCrossRefGoogle Scholar
  41. 41.
    Mannucci PM, Bettega D, Chantarangkul V, et al. Effect of tamoxifen on measurements of hemostasis in healthy women. Arch Intern Med 1996; 156: 1806–10PubMedCrossRefGoogle Scholar
  42. 42.
    Herrington DM, Klein KP. Effects of SERMs on important indicators of cardiovascular health: lipoproteins, hemostatic factors, and endothelial function. Womens Health Issues 2001; 11: 95–102PubMedCrossRefGoogle Scholar
  43. 43.
    Mikhailidis DP, Ganotakis ES, Georgoulias VA, et al. Tamoxifen-induced hypertriglyceridemia: seven case reports and suggestions for remedial action. Oncol Rep 1997; 4: 625–8PubMedGoogle Scholar
  44. 44.
    Kusama M, Kaise H, Nakayama S, et al. Crossover trial for lipid abnormality in postmenopausal breast cancer patients during selective estrogen receptor modulators (SERMs) administration. Breast Cancer Res Treat 2004; 88: 9–16PubMedCrossRefGoogle Scholar
  45. 45.
    Novoa FJ, Boronat M, Carrillo A, et al. Effects of tamoxifen on lipid profile and coagulation parameters in male patients with pubertal gynecomastia. Horm Res 2002; 57: 187–91PubMedCrossRefGoogle Scholar
  46. 46.
    Stein O, Stein Y. Lipid transfer proteins (LTP) and atherosclerosis. Atherosclerosis 2005; 178: 217–30PubMedCrossRefGoogle Scholar
  47. 47.
    Vehmanen L, Saarto T, Blomqvist C, et al. Tamoxifen treatment reverses the adverse effects of chemotherapy-induced ovarian failure on serum lipids. Br J Cancer 2004; 91: 476–81PubMedCrossRefGoogle Scholar
  48. 48.
    Wiseman H, Paganga G, Rice-Evans C, et al. Protective actions of tamoxifen and 4-hydroxytamoxifen against oxidative damage to human low-density lipoproteins: a mechanism accounting for the cardioprotective action of tamoxifen? Biochem J 1993; 292: 635–8PubMedGoogle Scholar
  49. 49.
    Wiseman H. Tamoxifen as an antioxidant and cardioprotectant. Biochem Soc Symp 1995; 61: 209–19PubMedGoogle Scholar
  50. 50.
    Liberopoulos E, Pavlidis N, Elisaf M. The effect of tamoxifen therapy on serum apolipoprotein A-I level is modified by the apolipoprotein E phenotype. Clin Biochem 2001; 34: 161PubMedCrossRefGoogle Scholar
  51. 51.
    Liberopoulos E, Karabina S-A, Tselepis A, et al. Are the effects of tamoxifen on the serum lipid profile modified by apolipoprotein E phenotypes? Oncology 2002; 62: 115–20PubMedCrossRefGoogle Scholar
  52. 52.
    Pradhan A, Manson JE, Rossouw JE, et al. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the women’s health initiative observational study. JAMA 2002; 288: 980–7PubMedCrossRefGoogle Scholar
  53. 53.
    Abramson B, Derzko C, Lalonde A, et al. Hormone replacement therapy and cardiovascular disease. J Obstet Gynaecol Can 2002; 116: 577–82Google Scholar
  54. 54.
    Nachtigall LE, Nachtigall RH, Nachtigall RD, et al. Estrogen replacement therapy II: a prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol 1979; 54: 74–9PubMedCrossRefGoogle Scholar
  55. 55.
    Mosca L, Barrett-Connor E, Wenger NK, et al. Design and methods of the Raloxifene Use for The Heart (RUTH) study. Am J Cardiol 2001; 88: 392–5PubMedCrossRefGoogle Scholar
  56. 56.
    Lilly announces preliminary coronary and breast cancer results from Raloxifene Use for The Heart (RUTH) study [press release]. 2006 Apr 12; Indianapolis, IN. Available from URL: http://www.prnewswire.com/cgi-bin/stories.pl?.ACCT=104&STORY=/www/story/04-12-2006/0004338728&EDATE [Accessed 2006 Apr 26]
  57. 57.
    Land SR, Wickerham DL, Costantino JP, et al. Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention; The NSABP study of tamoxifen and raloxifene (STAR) P-2 Trial. JAMA 2006; 295: 2742–51PubMedCrossRefGoogle Scholar
  58. 58.
    Wickerham DL, Costantino JP, Vogel V, et al. The study of tamoxifen and raloxifene (STAR): initial findings from the NSABP P-2 breast cancer prevention study [abstract no. LBA5]. J Clin Oncol 2006; 24 (18 Suppl.): 930sGoogle Scholar
  59. 59.
    Hozumi Y, Hakamata Y, Sasanuma H, et al. Effects of anastrozole on lipid metabolism compared with tamoxifen in rats. Breast Cancer Res Treat 2002; 76: 131–6PubMedCrossRefGoogle Scholar
  60. 60.
    Goss PE, Qi S, Hu H, et al. The effects of atamestane, toremifene, and atamestane plus toremifene compared to letrozole on bone, serum lipids and uterus [abstract no. 600]. J Clin Oncol 2005; 23 (16 Suppl.): 28SGoogle Scholar
  61. 61.
    Goss PE, Qi S, Cheung AM, et al. Effects of the steroidal aromatase inhibitor exemestane and nonsteroidal aromatase inhibitor letrozole on bone and lipid metabolism in ovariectomized rats. Clin Cancer Res 2004; 10: 5717–23PubMedCrossRefGoogle Scholar
  62. 62.
    Elisaf MS, Bairaktari ET, Nicolaides C, et al. Effect of letrozole on the lipid profile in postmenopausal women with breast cancer. Eur J Cancer 2001; 37: 1510–3PubMedCrossRefGoogle Scholar
  63. 63.
    Engen T, Krane J, Johannessen DC, et al. Plasma changes in breast cancer patients during endocrine therapy: lipid measurements and nuclear magnetic resonance (NMR) spectroscopy. Breast Cancer Res Treat 1995; 36: 287–97CrossRefGoogle Scholar
  64. 64.
    Atalay G, Dirix L, Biganzoli L, et al. The effect of exemestane on serum lipid profile in postmenopausal women with metastatic breast cancer: a companion study to EORTC Trial 10951, “randomised phase II study in first line hormonal treatment for metastatic breast cancer with exemestane or tamoxifen in postmenopausal patients. ” Ann Oncol 2004; 15: 211–7PubMedCrossRefGoogle Scholar
  65. 65.
    Sawada S, Sato K. Effect of anastrozole and tamoxifen on serum lipid levels in Japanese postmenopausal women with early breast cancer [abstract no. 143]. 26th Annual San Antonio Breast Cancer Symposium; 2003 Dec 3–6; San Antonio (TX) [online]. Available from URL: http://www.abstracts2view.com/bcs03 [Accessed 2005 Aug 24]
  66. 66.
    Sawada S, Sato K, Kusuhara M, et al. Effect of anastrozole and tamoxifen on lipid metabolism in Japanese postmenopausal women with early breast cancer. Acta Oncol 2005; 44: 134–41PubMedCrossRefGoogle Scholar
  67. 67.
    Wojtaki J, Lesniewski-Kmak K, Kruszewski J. Anastrozole therapy does not compromise lipid metabolism in breast cancer patients treated with tamoxifen [abstract no.262]. 25th Annual San Antonio Breast Cancer Symposium; 2002Dec 11–14; San Antonio (TX) [online]. Available from URL: http://www.abstracts2view.com/bcsO2 [Accessed 2005 Sep 25]
  68. 68.
    Harper-Wynne C, Ross G, Sacks N, et al. Effects of the aromatase inhibitor letrozole on normal breast epithelial cell proliferation and metabolic indices in postmenopausal women: a pilot study for breast cancer prevention. Cancer Epidemiol Biomarkers Prev 2002; 11: 614–21PubMedGoogle Scholar
  69. 69.
    McCloskey E, Eastell R, Lakner G, et al. Initial results from the LEAP study: the first direct comparison of safety parameters between aromatase inhibitors in healthy postmenopausal women [abstract no. 2052]. 28th San Antonio Breast Cancer Symposium; 2005 Dec 8–11; San Antonio (TX) [online]. Available from URL: http://www.abstracts2view.com/sabcs05/sessionindex.php [Accessed 2006 Apr 24]
  70. 70.
    Heshmati HM, Khosla S, Robins SP, et al. Role of low levels of endogenous estrogen in regulation of bone resorption in late postmenopausal women. J Bone Miner Res 2002; 17: 172–8PubMedCrossRefGoogle Scholar
  71. 71.
    Lonning PE, Geisler J, Krag LE, et al. Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol 2005; 23: 4847–9CrossRefGoogle Scholar
  72. 72.
    Jakesz R, Samonigg H, Greil R, et al., on behalf of the ABCSG. Extended adjuvant treatment with anastrozole: results from the Austrian Breast and Colorectal Cancer Study Group Trial 6a (ABCSG-6a) [abstract no. 527]. J Clin Oncol 2005; 23 (16 Suppl.): 20SGoogle Scholar
  73. 73.
    Wasan KM, Goss PE, Pritchard PH, et al. The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol 2005; 16: 707–15PubMedCrossRefGoogle Scholar
  74. 74.
    Banerjee S, Smith IE, Folkerd L, et al. Comparative effects of anastrozole, tamoxifen alone and in combination on plasma lipids and bone-derived resorption during neoadjuvant therapy in the impact trial. Ann Oncol 2005; 16: 1632–8PubMedCrossRefGoogle Scholar
  75. 75.
    Anastrozole [package insert]. Wilmington (DE): AstraZeneca Pharmaceuticals LP, 2005Google Scholar
  76. 76.
    Food and Drug Administration. Food and Drug Administration medical review report on anastrozole from the ATAC trial results [online]. Available from URL: http://www.fda.gov/cder/foi/nda/2002/20-541s010_Arimidex.htm [Accessed 2005 Nov 9]
  77. 77.
    Markopoulos C, Polychronis A, Zobolis V, et al. The effect of exemestane on the lipidemic profile of postmenopausal early breast cancer patients: preliminary results of the TEAM Greek sub-study. Breast Cancer Res Treat 2005; 93: 61–6PubMedCrossRefGoogle Scholar
  78. 78.
    Chlebowski RT, Anderson GL, Geller M, et al. Coronary heart disease and stroke with aromatase inhibitor, tamoxifen, and menopausal hormone therapy use. Clin Breast Cancer 2006; 6 Suppl. 2: S58–64PubMedCrossRefGoogle Scholar
  79. 79.
    Baum M, on behalf of the ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359: 2131–9PubMedCrossRefGoogle Scholar
  80. 80.
    Rutqvist LE, Mattsson A. Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. J Natl Cancer Inst 1993; 185: 1398–406Google Scholar
  81. 81.
    McDonald CC, Alexander FE, Whyte BW, et al. Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial. The Scottish Cancer Trials Breast Group. BMJ 1995; 311: 977–80Google Scholar
  82. 82.
    Costantino JP, Kuller LH, Ives DG, et al. Coronary heart disease mortality and adjuvant tamoxifen therapy. J Natl Cancer Inst 1997; 89: 776–82PubMedCrossRefGoogle Scholar
  83. 83.
    Stamatelopoulos KS, Lekakis JP, Poulakaki NA, et al. Tamoxifen improves endothelial function and reduces carotid intima-media thickness in postmenopausal women. Am Heart J 2004; 147: 1093–9PubMedCrossRefGoogle Scholar
  84. 84.
    Bradbury BD, Lash TL, Kaye JA, et al. Tamoxifen-treated breast carcinoma patients and the risk of acute myocardial infarction and newly-diagnosed angina. Cancer 2005; 103: 1114–21PubMedCrossRefGoogle Scholar
  85. 85.
    Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90: 1371–88PubMedCrossRefGoogle Scholar
  86. 86.
    Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 2001; 93: 684–90PubMedCrossRefGoogle Scholar
  87. 87.
    Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349: 1793–802PubMedCrossRefGoogle Scholar
  88. 88.
    Coombes RC, Hall E, Snowdon CF, et al. The Intergroup Exemestane Study: a randomized trial in postmenopausal patients with early breast cancer who remain disease-free after two to three years of tamoxifen-updated survival analysis [abstract no. 3]. Breast Cancer Res Treat 2004; 88: SIGoogle Scholar
  89. 89.
    Medicines and Healthcare Products Regulatory Agency (MHRA). Publication assessment report: Femara 2.5 mg tablet [online]. Available from URL: http://www.mhra.gov.uk/home/groups/lnitl/documents/websiteresources/con2023055.pdf (2005) [Accessed 2006 Apr 24]
  90. 90.
    Anderson FA, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT Study. Arch Intern Med 1991; 151: 933–8PubMedCrossRefGoogle Scholar
  91. 91.
    Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158: 585–93PubMedCrossRefGoogle Scholar
  92. 92.
    Nordström M, Lindblad B, Bergqvist D, et al. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med 1992; 232: 155–60PubMedCrossRefGoogle Scholar
  93. 93.
    Oger E. Incidence of venous thromboembolism: a community-based study in Western France. Thromb Haemos 2001; 83: 657–60Google Scholar
  94. 94.
    Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. WHI Investigators. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a randomized trial. JAMA 2003; 289: 2673–84Google Scholar
  95. 95.
    Howell A, Cuzick J. Vascular effects of aromatase inhibitors: data from clinical trials. J Steroid Biochem Mol Biol 2005; 95: 143–9PubMedCrossRefGoogle Scholar
  96. 96.
    Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 1989; 320: 479–84PubMedCrossRefGoogle Scholar
  97. 97.
    Goss PE, Strasser-Weippl K. Prevention strategies with aromatase inhibitors. Clin Cancer Res 2004; 10: 372–9SCrossRefGoogle Scholar
  98. 98.
    Bundred NJ. The effects of aromatase inhibitors on lipids and thrombosis. Br J Cancer 2005 Aug; 93 Suppl. 1: S23–7PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.Toronto-Sunnybrook Regional Cancer Centre, Sunnybrook Health Sciences Centre, and the University of TorontoTorontoCanada
  2. 2.Saint Michael’s Hospital and the University of TorontoTorontoCanada
  3. 3.Division of Clinical Trials and EpidemiologyToronto-Sunnybrook Regional Cancer CenterTorontoCanada

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