Abstract
Many animal studies and studies on intermediate clinical endpoints have shown hormone replacement therapy (HRT) to be associated with both favourable and unfavourable cardiovascular effects. We reviewed the literature regarding HRT and the distinct endpoint of acute myocardial infarction (AMI) in peri- and postmenopausal women.
Searches of the MEDLINE and EMBASE databases were conducted. Fifty papers were identified as eligible for inclusion: eight randomised controlled trials, 18 cohort studies, 23 case-control studies and one case-control and cohort study.
The single large primary prevention randomised controlled trial on HRT and the risk of AMI in generally healthy women (Women’s Health Initiative trial) reported a small yet significantly increased risk of AMI in postmenopausal women receiving combined HRT. This contrasts with a large number of observational studies that suggested a protective effect, although in many of these studies the results were not statistically significant. Inconclusive evidence on the effect of duration of use does not support the notion that a possible protective association is causal. Detection bias and residual confounding are alternative explanations for the associations observed in the randomised controlled trial and observational studies. No studies on groups of women with existing cardiovascular disease or with diabetes mellitus, including the only large secondary prevention trial (Heart and Estrogen/Progestin Replacement Study), reported a significant change in AMI risk between HRT users and non-users.
There is insufficient evidence to suggest that HRT is associated with a change in the risk of AMI in the majority of women. However, certain subgroups of women with specific genetic polymorphisms may be more susceptible to a change in the risk of AMI with HRT use.
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References
The British Medical Association and the Royal Pharmaceutical Society of Great Britain. British National Formulary 42. London: BMA and the Pharmaceutical Society of Great Britain, 2001
Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1997; 350 (9084): 1047–59
Lobo RA. Effects of hormonal replacement on lipids and lipoproteins in postmenopausal women. J Clin Endocrinol Metab 1991; 73(5): 925–30
Walsh BW, Schiff I, Rosner B, et al. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991; 325: 1196–204
Clarkson TB, Anthony MS, Klein KP. Hormone replacement therapy and coronary artery atherosclerosis: the monkey model. Br J Obst Gynaecol 1996; 103Suppl. 13: 53–8
Espeland MA, Marcovina SM, Miller V, et al. Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. Circulation 1998; 97: 979–86
Rosano GM, Caixeta AM, Chierchia S, et al. Short-term antiischemic effect of 17beta-estradiol in postmenopausal women with coronary artery disease. Circulation 1997; 969): 2837–41
Teede HJ, McGrath BP, Smolich JJ, et al. Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis. Arterioscler Thromb Vasc Biol 2000; 20: 1404–9
Ridker PM, Hennekens CH, Rifai N, et al. Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation 1999; 100: 713–6
Cushman M, Legault C, Barret-Connor E, et al. Effect of postmenopausal hormones on inflammation-sensitive proteins: The Postmenopaual Estrogen/Progestin Interventions (PEPI) study. Circulation 1999; 100: 717–22
Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288 (3): 321–33
The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004; 291: 1701–12
Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;] 349(6): 523–34
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 1997; 54(1): 74–9
Shapiro S. Risks of estrogen plus progestin therapy: a sensitivity analysis of findings in the Women’s Health Initiative randomized controlled trial. Climacteric 2003; 6: 302–10
Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991; 151: 75–8
Henderson BE, Ross RK, Paganini-Hill A, et al. Estrogen use and cardiovascular disease. Am J Obstet Gynecol 1986; 154: 1181–6
Henderson BE, Paganini-Hill A, Ross RK. Estrogen replacement therapy and protection from acute myocardial infarction. Am J Obstet Gynecol 1988; 159(2): 312–7
Stampfer MJ, Willett WC, Colditz GA, et al. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med 1985; 313(17): 1044–9
Falkeborn M, Persson I, Adami HO, et al. The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement. Br J Obstet Gynaecol 1992; 99(10): 821–8
Grodstein F, Stampfer MJ, Falkeborn M, et al. Postmenopausal hormone therapy and risk of cardiovascular disease and hip fracture in a cohort of Swedish women. Epidemiology 1999; 10(5): 476–80
Hernandez-Avila M, Walker AM, Jick H. Use of replacement estrogens and the risk of myocardial infarction. Epidemiology 1990; 1(2): 128–33
Løkkegaard E, Pedersen AT, Heitmann BL, et al. Relation between hormone replacement therapy and ischaemic heart disease in women: prospective observational study. BMJ 2003; 326: 426–30
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). Lancet 1998; 352(9145): 1965–9
Petitti DB, Perlman JA, Sidney S. Noncontraceptive estrogens and mortality: long-term follow-up of women in the Walnut Creek Study. Obstet Gynecol 1987; 70(3 Pt 1): 289–93
Lafferty FW, Helmuth DO. Post-menopausal estrogen replacement: the prevention of osteoporosis and systemic effects. Maturitas 1985; 7: 147–59
Lafferty FW, Fiske ME. Postmenopausal estrogen replacement: a long-term cohort study. Am J Med 1994; 97(1): 66–77
Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. The Framingham Study. N Engl J Med 1985; 313(17): 1038–43
Varas-Lorenzo C, Garcia-Rodriguez LA, Perez-Gutthann S, et al. Hormone replacement therapy and incidence of acute myocardial infarction: a population-based nested case-control study. Circulation 2000; 101(22): 2572–8
Heckbert SR, Weiss NS, Koepsell TD, et al. Duration of estrogen replacement therapy in relation to the risk of incident myocardial infarction in postmenopausal women. Arch Intern Med 1997; 157(12): 1330–6
Psaty BM, Heckbert SR, Atkins D, et al. The risk of myocardial infarction associated with the combined use of estrogens and progestins in postmenopausal women. Arch Intern Med 1994; 154(12): 1333–9
Chilvers CE, Knibb RC, Armstrong SJ, et al. Post menopausal hormone replacement therapy and risk of acute myocardial infarction: a case control study of women in the East Midlands, UK. Eur Heart J 2003; 24: 2197–205
Sidney S, Petitti DB, Quesenberry Jr CP. Myocardial infarction and the use of estrogen and estrogen-progestogen in postmenopausal women. Ann Intern Med 1997; 127(7): 501–8
Petitti DB, Sidney S, Quesenberry CP. Hormone replacement therapy and risk of myocardial infarction in women with coronary risk factors. Epidemiology 2000; 11: 603–6
Mann RD, Lis Y, Chukwujindu J, et al. A study of the association between hormone replacement therapy, smoking and the occurrence of myocardial infarction in women. J Clin Epidemiol 1994; 47(3): 307–12
Rosenberg L, Palmer JR, Shapiro S. A case-control study of myocardial infarction in relation to use of estrogen supplements. Am J Epidemiol 1993; 137(1): 54–63
Pfeffer RI, Whipple GH, Kurosaki TT, et al. Coronary risk and estrogen use in postmenopausal women. Am J Epidemiol 1978; 107(6): 479–97
Bain C, Willett W, Hennekens CH, et al. Use of postmenopausal hormones and risk of myocardial infarction. Circulation 1981; 64(1): 42–6
Croft P, Hannaford PC. Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners’ oral contraception study. BMJ 1989; 298: 165–8
Petitti DB, Wingerd J, Pellegrin F, et al. Risk of vascular disease in women: smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA 1979; 242(11): 1150–4
Adam S, Williams V, Vessey MP. Cardiovascular disease and hormone replacement treatment: a pilot case-control study. BMJ Clin Res Ed 1981; 282(6272): 1277–8
Ross RK, Paganini-Hill A, Mack TM, et al. Menopausal oestrogen therapy and protection from death from ischaemic heart disease. Lancet 1981; I(8225): 858–60
Rosenberg L, Armstrong B, Jick H. Myocardial infarction and estrogen therapy in post-menopausal women. N Engl J Med 1976; 294(23): 1256–9
Szklo M, Tonascia J, Gordis L, et al. Estrogen use and myocardial infarction risk: a case-control study. Prev Med 1984; 13(5): 510–6
Jick H, Dinan B, Rothman KJ. Noncontraceptive estrogens and nonfatal myocardial infarction. JAMA 1978; 239(14): 1407–9
Jick H, Dinan B, Herman R, et al. Myocardial infarction and other vascular diseases in young women: role of estrogens and other factors. JAMA 1978; 240(23): 2548–52
La Vecchia C, Franceschi S, Decarli A, et al. Risk factors for myocardial infarction in young women. Am J Epidemiol 1987; 125(5): 832–43
Fioretti F, Tavani A, Gallus S, et al. Menopause and risk of nonfatal acute myocardial infarction: an Italian case-control study and a review of the literature. Hum Reprod 2000; 15(3): 599–603
Rosenberg L, Slone D, Shapiro S, et al. Noncontraceptive estrogens and myocardial infarction in young women. JAMA 1980; 244(4): 339–42
Hulley S, Grady D, Bush TL, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart prevention disease in postmenopausal women. JAMA 1998; 280(7): 605–13
Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy. Heart and Estrogen/Progestin Replacement Study follow-up (HERS II). JAMA 2002; 288(1): 49–57
Shlipak MG, Simon JA, Vittinghoff E, et al. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA 2000; 283(14): 1845–52
Furberg CD, Vittinghoff E, Davidson M, et al. Subgroup interactions in the heart and estrogen/progestin replacement study: lessons learned. Circulation 2002; 105: 917–22
The ESPRIT team. Oestrogen therapy for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet 2002; 360: 2001–8
Herrington DM, Reboussin DM, Brosnihan B, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000; 343(8): 522–9
Clarke SC, Kelleher J, Lloyd-Jones H, et al. A study of hormone replacement therapy in postmenopausal women with ischaemic heart disease: the Papworth HRT Atherosclerosis Study. Br J Obstet Gynaecol 2002; 109: 1056–62
Alexander KP, Newby LK, Hellkamp AS, et al. Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up. J Am Coll Cardiol 2001; 38(1): 1–7
Newton KM, LaCroix AZ, McKnight B, et al. Estrogen replacement therapy and prognosis after first myocardial infarction. Am J Epidemiol 1997; 145(3): 269–77
O’Keefe JH, Kim SC, Hall RR, et al. Estrogen replacement therapy after coronary angioplasty in women. J Am Coll Cardiol 1997; 29: 1–5
Khan MA, Liu MW, Singh D, et al. Long-term (three years) effect of estrogen replacement therapy on major adverse cardiac events in postmenopausal women after intracoronary stenting. Am J Cardiol 2000; 86(3): 330–3
Shlipak MG, Angeja BG, Go AS, et al. Hormone therapy and inhospital survival after myocardial infarction in postmenopausal women. Circulation 2001; 104: 2300–4
Ferrara A, Quesenberry CP, Karter AJ, et al. Current use of unopposed estrogen and estrogen plus progestin and the risk of acute myocardial infarction among women with diabetes. Circulation 2003; 107: 43–8
Kaplan RC, Heckbert SR, Weiss NS, et al. Postmenopausal estrogens and risk of myocardial infarction in diabetic women. Diabetes Care 1998; 21(7): 1117–21
Psaty BM, Smith NL, Lemaitre RN, et al. Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women. JAMA 2001; 285(7): 906–13
Reiner AP, Heckbert SR, Vos HL, et al. Genetic variants of coagulation factor XIII, postmenopausal estrogen therapy and risk of nonfatal myocardial infarction. Blood 2003; 102(1): 25–30
Mikkola TS, Clarkson TB, Notelovitz M. Postmenopausal hormone therapy before and after the women’s health initiative study: what consequences? Ann Med 2004; 36: 1–12
The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995; 273 (3): 199–208
Adams MR, Kaplan JR, Manuck SB, et al. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys: lack of an effect of added progesterone. Arteriosclerosis 1990; 10: 1051–7
Miyagawa K, Rosch J, Stanczyk F, et al. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nat Med 1997; 3(3): 324–7
Barrett-Connor E. Postmenopausal estrogen and prevention bias. Ann Intern Med 1991; 115(6): 455–6
Matthews KA, Kuller LH, Wing R, et al. Prior to use of estrogen replacement therapy, are users healthier than non users? Am J Epidemiol 1996; 143: 971–8
Rodstrom K, Bengtsson C, Lissner L, et al. Pre-existing risk factor profiles in users and non-users of hormone replacement therapy: prospective cohort study in Gothenberg, Sweden. BMJ 1999; 319: 890–3
Bromley SE, de Vries CS, Farmer RDT. Utilisation of hormone replacement therapy in the United Kingdom: a descriptive study using the general practice research database. Br J Obstet Gynaecol 2004; 111: 369–76
Lawrenson RA, Newson RB, Feher MD. Do women with diabetes receive hormone replacement therapy? Practical Diabetes Int 1998; 15(3): 71–2
Petitti DB. Coronary heart disease and estrogen replacement therapy: can compliance bias explain the results of the observational studies? Ann Epidemiol 1994; 4: 115–8
Association of the British Pharmaceutical Industry. Data sheet compendium 1980-81. London: Datapharm Publications Limited, 1980
Sturgeon SR, Schairer C, Brinton LA, et al. Evidence of a healthy estrogen user survivor effect. Epidemiology 1995; 6: 227–31
Wysowski DK, Golden L, Burke L. Use of menopausal estrogens and medroxyprogesterone in the United States, 1982-1992. Obstet Gynecol 1995; 85(1): 6–10
Palacios S. Tibolone: what does tissue specific activity mean? Maturitas 2001; 37: 159–65
Bjarnason NH, Bjarnason K, Haarbo J, et al. Tibolone: influence on markers of cardiovascular disease. J Clin Endocrinol Metab 1997; 82(6): 1752–6
Winkler UH, Altkemper R, Kwee B, et al. Effects of tibolone and continuous combined hormone replacement therapy on parameters in the clotting cascade: a multicenter, double-blind, randomized study. Fertil Steril 2000; 74(1): 10–9
Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 2002; 287(7): 847–57
Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998; 279: 1445–51
Walsh BW, Paul S, Wild RA, et al. The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy post-menopausal women. J Clin Endocrinol Metab 2000; 85: 214–8
Acknowledgements
This study was conducted at the University of Surrey and funded through an unconditional grant from Organon NV, The Netherlands. At the time the study was conducted, all authors were employed by the University of Surrey. The authors have no conflicts of interest that are directly relevant to the content of this study.
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Bromley, S.E., de Vries, C.S., Thomas, D. et al. Hormone Replacement Therapy and Risk of Acute Myocardial Infarction. Drug-Safety 28, 473–493 (2005). https://doi.org/10.2165/00002018-200528060-00002
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DOI: https://doi.org/10.2165/00002018-200528060-00002