REVIEW URRENT C OPINION
Women, the menopause, hormone replacement therapy and coronary heart disease Thomas F. Whayne Jr a and Debabrata Mukherjee b
Purpose of review Cardiovascular disease considerations are associated with the menopause. Despite a misconception that women have a minimal risk for coronary heart disease (CHD), it is the major cause of female deaths. This review highlights issues of hormone replacement therapy (HRT) and CHD in women. Recent findings A woman under age 60 who suffers a myocardial infarction (MI) has a 2-year post-MI mortality of 28.9%; it is 19.6% in men. CHD and MI in women are subtle. In addition, female mortality from CHD increases after the menopause. The increased inflammatory risk factor status of women plays a role in development of atherosclerosis, before and after the menopause. Until after the menopause, women overall have a lower CHD mortality rate. Menopause is associated with unique symptoms, especially vasomotor ones; preexisting cardiovascular disease further exacerbates problems associated with the menopause. Use of HRT after the menopause is a major issue. Early menopause at age 39 years or younger and late menopause at age 56 years or older increase cardiovascular risk. HRT should not be prescribed for cardiovascular risk prevention, but when less than 10 years from menopause at a normal age, women can be reassured that cardiovascular risk from HRT is very low. Summary Prescription of HRT should never be made only for cardiovascular risk reduction. However, when symptomrelated and other indications are present, HRT is appropriate and well tolerated in the early years after menopause with onset at a normal age. Keywords cardiovascular risk, coronary heart disease, oestrogens, hormone replacement, inflammation, menopause, thrombosis
INTRODUCTION Specific differences between women and men include: women develop a first myocardial infarction (MI) at an older age, coronary heart disease (CHD) events occur more after the menopause, and, overall, women are less likely than men to die of CHD [1]. Nevertheless, the major medical problem women face is CHD and other cardiovascular disease; breast cancer is much less of a lethal problem. The lay press has hit on the idea that women have more CHD than men, possibly because of the reality that if a relatively young woman has a CHD event, their mortality is higher [1]. Women with cardiovascular disease tend to have more hypertension and diabetes mellitus at the presentation of acute coronary syndrome (ACS); on the contrary, men at presentation of ACS are more likely to be tobacco smokers [2]. Young women under the age of 40 years with ACS are at the greatest risk of www.co-cardiology.com
cardiovascular death compared with men of the same age; this disadvantage then decreases as women age [2]. A problem in evaluating CHD in women is their underrepresentation in clinical trials [3]. Enrolment in randomized trials has improved but is still low compared with the overall female disease incidence [4]. Despite improved evidencebased treatments in recent years, there is a gap in the use of such treatments in both older and younger a Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, Kentucky and bDivision of Cardiovascular Medicine, Texas Tech University HSC, and Paul Foster School of Medicine, El Paso, Texas, USA
Correspondence to Thomas F. Whayne, Jr, MD, PhD, 326 Wethington Building, 900 South Limestone Street, Lexington, KY 40536-0200, USA. Tel: +1 859 218 5332; fax: +1 859 323 6475; e-mail: [email protected] Curr Opin Cardiol 2015, 30:432–438 DOI:10.1097/HCO.0000000000000157 Volume 30 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Women, menopause, hormone therapy, and coronary heart disease Whayne et al.
KEY POINTS Coronary heart disease is the major cause of death in women before, during and after the menopause. Hormone replacement therapy is not indicated if given solely for any possible cardiovascular risk benefit. The use of hormone replacement therapy in the early years after a normal menopause is associated with neutral or low cardiovascular risk.
women [5]. The purpose of this review is to clarify some of these issues and possible explanations, mechanisms and differences. Consideration of the anatomical, hormonal, inflammatory and metabolic status of women appears to offer possible clarification of female cardiovascular risk. Treatment of cardiovascular disease in women involves specific problems, especially revascularization of coronary arteries, which, when stenosed, appear to offer unique challenges and differences.
CORONARY HEART DISEASE DIFFERENCES IN WOMEN In spite of previous thinking that women have a minimal CHD risk and the failure of some clinicians to pay proper attention to early CHD symptoms, the reality is that a young woman has increased risk from CHD if an acute event occurs. In a study of 6826 patients who were MI survivors from 1975 to 1995, Vaccarino et al. [6] found that the overall 2-year mortality rate was 28.9% in women compared with 19.6% in men, and for each decrease in age by decade, the 2-year female mortality increased by 15.4% [95% confidence interval (95% CI), 4.3–27.6] compared with men. Younger women, defined as under age 60 years, were found to have an increased risk for death after MI compared with age-matched male counterparts [6]. In 2009, Shaw et al. [7] commented on the evolving knowledge of CHD in women and discussed how women have a lower incidence of anatomical CHD but when CHD is present, cardiovascular risk is higher than in men, and women have more symptoms, evidence of ischemia and unfavourable outcomes. The paradox may be from an increased coronary reactivity in women, including microvascular dysfunction [7]. Also, there appears to be a lower incidence of obstructive CHD in women, but, if present, CHD in a woman is associated with a higher incidence of unfavourable outcomes after acute MI [8]. Ischaemic heart disease may be a more appropriate term for CHD in women due to the spectrum of
obstructive CHD, coronary microvascular dysfunction and endothelial dysfunction [8]. In addition, the size of coronary arteries in women is relevant, as these arteries are smaller [9] and may be a factor in decreased benefit from invasive management. Due to smaller body surface area, smaller left ventricular mass and smaller coronary artery size, Kang et al. [10] noted that reduced myocardial territory size may account for a higher fractional flow reserve (FFR) for a specific coronary artery stenosis than in men. This is relevant to surgical benefit in women, in whom Desai et al. [11] provided data that small coronary target vessel size has an adverse effect on coronary artery bypass graft (CABG) patency, modified favourably to increase graft patency in the presence of more severe proximal stenoses with also a significantly increased benefit of a radial artery CABG conduit. Unique symptoms of CHD in women must be considered. This was discussed by Albarran et al. [12] after evaluating 12 female patients postacute MI. They concluded that distribution and presentation of symptoms of female patients failed to follow the pattern associated with a traditional acute MI presentation. Presentation may be with nonspecific symptoms around the chest, making recognition difficult for both patients and health team personnel [12]. In an extensive review, Bozkurt [13] considered statistics involving women in the United States and emphasized that far more women die of cardiovascular disease than cancer; there are nearly 250 000 cardiovascular deaths in women each year, and, despite the lower prevalence of cardiovascular disease in women, the absolute cardiovascular disease death rate in women is higher than in men due to a longer female life span. The fact that cardiovascular disease mortality in women remains high, as compared with improvement in survival trends in men, may be related to multiple factors such as in the ACS, wherein the following occur: women delay calling for professional help, which results in a sicker patient at the time of diagnosis; they present with more atypical symptoms; there is decreased recognition of a problem by caregivers, including a bias against the presence of CHD in women; and women are less likely to receive optimal cardiovascular risk control or referral for cardiac catheterization and coronary interventional procedures, with an eight-fold higher referral rate in men [13]. This serves to emphasize the importance of a commitment to explain and account for any chest pain at any age and never dismiss it as irrelevant until evaluated. Thus far, women are managed less frequently than men with percutaneous coronary intervention (PCI) and the use of evidence-based cardiovascular disease management is less frequent [14 ]. &
0268-4705 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-cardiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
433
Lipids and emerging risk factors
CHARACTERISTIC PROBLEMS OF THE MENOPAUSE The menopause is associated with some bothersome symptoms, most characteristic of which are those related to vasomotor abnormalities, mood swings and quality-of-life symptoms [15]. Increased haemostasis risk is associated with oestrogen use, with also an increased risk with early or late menopause. In a report of 426 women with a first episode of venous thromboembolism (VTE), including 294 events not associated with a procedure, Canonico et al. [16 ] found that women with early menopause (age 55 years) had a significant increase in risk for VTE (hazard ratio 1.8, 95% CI 1.2–2.7 and hazard ratio 1.5, 95% CI 1.0–2.4, respectively). Stress associated with the menopause may be a relevant cardiovascular risk factor, with an apparent relationship with increased C-reactive protein (CRP) and inflammation, not seen in men [17]. Problems that women have with the menopause are significantly worsened by associated cardiovascular diseases such as diabetes mellitus. Postmenopausal women with diabetes mellitus have an increased cardiometabolic risk, with a special emphasis on inflammation [18]. The same applies to hypertension, in that after the menopause loss of oestrogen protection may contribute to the occurrence of a female population more susceptible to hypertension as a part of their increased cardiovascular risk [19]. &
ISSUES OF HORMONE REPLACEMENT THERAPY IN WOMEN There are multiple options for HRT. Oestrogen-only administration should be considered only when no uterus is present [20]. A summary of the options for HRT can be made as follows [21]. Oestrogen administration can involve the following routes: oral, transdermal, vaginal and injection. Progestins can be given orally or transdermally (the transdermal form involves an oestrogen-progestin patch). Progestin-only use is for women with vasomotor symptoms in whom oestrogen is contraindicated. There is also a vaginal progesterone gel used every second day to promote stable endometrial activity of progesterone, although there is only a minimal systemic effect. Raloxifene is an oral selective oestrogen receptor modulator intended for asymptomatic postmenopausal women to prevent and treat osteoporosis. Tibolone is in tablet form and is a derivative of norethynodrel consisting of some oestrogenic, progestogenic and androgenic activity. It has appeal as treatment for menopausal symptoms with a single medication [21]. 434
www.co-cardiology.com
Relief of menopausal symptoms appears to be the major reason for HRT. Because of extensive usage, it appears indicated to define bioidentical hormones, which are also frequently administered, as molecular compounds essentially identical in structure to human hormones [22]. Appropriate usage of HRT involves assessment of balance between benefits and risks [23]. Both an older age and an increased time since menopause predict increased HRT risk. Women initiating HRT within 10 years of menopause and under age 60 were reported to have reduced CHD risk compared with initiation of HRT more distant from the menopause [24]. In general, the smallest effective dose of HRT should be used as briefly as possible with evaluation each year to assess the benefits of HRT continuation [20]. Other mitigating factors in favour of HRT include low-risk plasma lipids, absence of metabolic syndrome, absence of factor V Leiden genotype [25], no history of VTE or pulmonary embolus, and no history of breast cancer, where HRT use can be complex [26]. Key components in favour of HRT include increased severity of menopausal symptoms, individual patient preferences, presence of any HRT contraindications, patient age, time from menopause [23] and route of administration. In a comparison of data from a community pharmacy in postmenopausal women where essentially 100% received progesterone, Ruiz and Daniels [15] found that topical oestrogens did not relieve postmenopausal symptoms as much as sublingual administration of oestrogens. Ultimately, discontinuation of HRT is important and Newton et al. [27] found that, in a study of 2328 postmenopausal women, advice by their physician as well as symptom resolution, especially improvement in mood swings and depression and improved sense of well being as well as quality of life [28], led to successful HRT cessation. Enhanced tendency for haemostasis and increased risk of thrombosis appear to be hallmarks of oestrogen use. A review of the effects of oestrogen on haemostasis reported that there was an imbalance in haemostasis with oral oestrogens, including a decrease in inhibitors of coagulation and an increase in activation of coagulation with a resultant enhancement of production of thrombin [29]. Use of transdermal oestrogen was not associated with increased haemostasis or coagulation. Oestrogen also increases risk for ischaemic strokes [28]. The issue of any increased cancer risk with HRT must be considered. Oestrogen in HRT is in a high enough concentration to cause endometrial proliferation, hyperplasia and increased endometrial cancer risk. A review found that after 10–15 years of oestrogen use there was a 10-fold increase in risk for endometrial cancer, but fortunately the resultant Volume 30 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Women, menopause, hormone therapy, and coronary heart disease Whayne et al.
cancers were usually low grade, low stage, and carried a good prognosis, and association of a progestin with the HRT for at least 10 days per month eliminated the endometrial cancer risk [30]. A moderate increase in breast cancer risk (relative risk of 1.3–1.5) was also found, with a greater risk in subgroups associated with family history, benign proliferative disease or late occurrence of natural menopause, with no decreased risk associated with the use of a progestin [30]. However, there did not appear to be any definite contraindication to oestrogen use from this standpoint, although a relative risk as small as 1.2 could increase the risk of breast cancer from 1 in 250 to 1 in 200. The role played by female hormones in CHD has been associated with much confusion and has major implications. Despite the accepted cardiovascular benefits of exercise, studies of amenorrheic female athletes suggest an increased risk for early cardiovascular disease [31], whereas reports from observational studies have suggested that HRT decreases cardiovascular mortality in postmenopausal women [32]. However, the large randomized trial with placebo control, Heart and Estrogen/progestin Replacement Study (HERS), found that women with known cardiovascular disease had increased cardiovascular disease events during the first year of HRT use despite reported favourable benefit from randomized trials of HRT on total cholesterol (C), lipoproteins [increased high-density lipoproteins (HDLs) and decreased low-density lipoproteins (LDLs)], vasodilatation and reduced inflammation [32]. In studies of any inflammatory effect of oestrogen, it has been shown that oestrogen at physiological levels, at pregnancy levels and with HRT inhibits secretion of pro-inflammatory cytokines, stimulates synthesis and secretion of anti-inflammatory cytokines and also decreases cell responses to lipopolysaccharide-induced inflammation [33]. However, such a beneficial effect on high cardiovascular risk markers is not universal. A study of 76 early postmenopausal women found continuous oral HRT and sequential transdermal HRT had no significant effect on decreasing serum monocyte chemoattractant protein-1 or homocysteine levels [34]. The oestrogen vasodilatation effect also carries over to the lung, wherein oestrogen has been shown to cause pulmonary arterial vasodilatation and attenuate vasoconstriction, such as from hypoxia [35]. In the Women’s Health Initiative (WHI), Hsia et al. [36] found that various trials have shown HRT with conjugated equine oestrogens (CEEs) combined with medroxyprogesterone acetate does not protect postmenopausal women from CHD, and questions have been raised about some increased risk. These authors also found that CEE alone offered
no significant protection from MI or CHD death in women who were healthy, postmenopausal and followed for 7 years, although there was a suggestion of decreased CHD risk in women aged 50–59 years at onset of use. In a cross-sectional study of HRT effects performed by Prelevic et al. [37], occurrence of different effects on some markers of cardiovascular risk was noted. These authors found significantly increased high-sensitivity CRP (hsCRP) levels in women receiving CEE and tibolone compared with women on no HRT. They also found that glycated haemoglobin was significantly decreased with transdermal oestrogens and tibolone vs. no HRT. Tibolone resulted in a significantly increased SBP compared with women on no HRT. These variable effects on cardiovascular risk factors from different forms of HRT may have clinical importance [37]. The issue of HRT replacement in the postmenopausal female remains unresolved, but it appears well validated to state that HRT should not be prescribed for cardiovascular disease risk prevention, but, when symptom-related and other indications are present in a female patient with fairly recent menopause, that patient can be reassured that cardiovascular risk from HRT is quite low.
INFLAMMATION Inflammation appears to be a major mechanism for development of CHD. Triggers of low-grade inflammation and augmented autoimmune reactions include thyroid-stimulating hormone (TSH), platelet-activating factor acetylhydrolase, acylationstimulating protein, lipoprotein (a), asymmetric dimethylarginine and creatinine [38]. In an assessment of biomarkers of CHD risk in postmenopausal women, Spoletini et al. [39] found a consistent association with CRP (usually specified as hsCRP), interleukin-6 and lipoprotein(a). However, they commented on lack of proof for a specific link between such biomarkers and the occurrence of CHD, and the need for such studies. In a review of various inflammatory markers (additional markers not already mentioned include metallic metalloproteinase-9, monocyte chemotactic protein-1, lipoprotein-associated phospholipase A2 and tumour/tissue necrosis factor alpha) and their occurrence with coronary artery calcification (CAC), Hamirani et al. [40] found a weak association with CAC, mainly in women and by univariate analysis, the association of which was lost after obesity and BMI corrections. Nevertheless, such an observation is consistent with association of increased inflammation and CHD in women. It was stated by Krintus et al. [41] that the complex multifactorial cause of CHD goes beyond inflammatory risk factors to include factors such as electrocardiogram results, lipid profile, renal
0268-4705 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-cardiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
435
Lipids and emerging risk factors
function, and imaging and clinical parameters. Favourable modification of inflammatory risk factors is of major interest, and Soares and de Sousa [42] reviewed 15 selected articles with women as the protagonists and found that 12 of 15 articles showed decreased inflammatory biomarkers in association with exercise. Inflammatory risk status was the major factor in the Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. JUPITER’s findings centred on patients with hsCRP at least 2 mg/l and LDL-C less than 130 mg/dl with no perceived cardiovascular risk indication for a statin; these patients had a higher probability of being female [43], consistently with a greater association of inflammation with CHD in women. In these JUPITER patients, including women, rosuvastatin use resulted in a significant decrease in the occurrence of major cardiovascular events [44]. Observations contributing further to the importance of inflammation in women involve inflammatory bowel disease, which, in a review by Singh et al. [45], was shown to have a modest association with an increase in cardiovascular morbidity risk from stroke and CHD, especially in women.
LIPIDS, LIPOPROTEINS AND THE MENOPAUSE Statins and other lipid-lowering medications play a major role in CHD revascularization regarding plaque stability and even regression. Although there has been some controversy regarding statin benefit in women, there is ample evidence to support their use along with the lowering of LDL-C in the woman at a high cardiovascular risk. In the Scandinavian Simvastatin Survival Study (4S), the reduction of C by simvastatin resulted in similar decreases in relative risk as for men regarding the occurrence of major CHD events [46]. In the Air Force/Texas Coronary Atherosclerosis Prevention (AFCAPS/TexCAPS) study, lovastatin decreased risk for a first major CHD event in both men and women with average total C levels, average LDL-C levels and below-average HDL-C levels [47]. In an analysis of multiple trials of statins, Wenger [48] reported on the decrease in elevated LDL-C by statins in women with elevated CHD risk and found decreased incidence of revascularization procedures, CHD death and nonfatal MI. She found no alteration in total mortality in women, probably because there were too few women in the trials assessed. She commented on the apparent underutilization of statins in women as a chance to improve their cardiovascular outcomes [48]. In JUPITER, rosuvastatin decreased cardiovascular events in women similarly to what resulted in men [49]. A meta-analysis by Bukkapatnam et al. [50] showed that treatment with 436
www.co-cardiology.com
statins along with diet and exercise in women with a moderate elevation in plasma lipids and no prior clinical cardiovascular disease resulted in a significant benefit for the prevention of CHD events. The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial also found that women as well as men were benefited by intensive statin administration after ACS [51]. A 2015 meta-analysis of 27 trials of statin therapy, published in The Lancet by the Cholesterol Treatment Trialists’ (CTT) Collaboration, found that the decrease in major cardiovascular events, as compared with the same reduction in LDL-C, was the same for men and women, regardless of vascular risk or outcome [52 ]. &&
THROMBOSIS AND THE MENOPAUSE Risk of thrombosis and arterial disease has been looked at in several trials, with some studies suggesting that delayed menopause and longer exposure to endogenous oestrogens protect against cardiovascular diseases [53–55]. A large metaanalysis, however, suggested that there was no convincing relationship between postmenopausal status and cardiovascular disease [56]. In the HERS, Grady et al. [57] reported that being 52 years or older at the last menstrual period was independently associated with a higher risk of thromboembolism. Similar findings were reported by Simon et al. [58] in a case–control study of idiopathic thromboembolism and demonstrated that, independently of BMI, women with late menopause had a higher thrombotic risk than did women with menopause at a normal age. One recent study, however, showed a U-shaped association between age at menopause and the risk of nonprocedure-related thromboembolism among postmenopausal women who had never had a history of thrombosis [16 ]. After adjustment for potential confounders, women who experienced menopause at 39 years or younger or at 56 years or older had increased thrombotic risk as compared with women with age at menopause between 40 and 49 years [16 ]. Mechanistically, oestrogens have many different effects on the coagulation system, which include increases in the levels of procoagulant factors VII, X, XII and XIII and reductions in the anticoagulant factors protein S and antithrombin, leading to a prothrombotic state [59]. &
&
SPECIFIC RECOMMENDATIONS REGARDING CORONARY HEART DISEASE RISK AND HORMONE REPLACEMENT THERAPY Several randomized clinical trials of HRT in women with and without CHD have found no benefit of Volume 30 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Women, menopause, hormone therapy, and coronary heart disease Whayne et al.
HRT in decreasing cardiovascular events [60]. In fact, the WHI study and the HERS reported an association between HRT and increased cardiovascular events [61,62]. A meta-analysis of all randomized trials of HRT to estimate cardiovascular event rates reported that HRT use is not associated with reduced death, MI, or revascularization rate, and HRT is not an effective agent for cardiovascular disease prevention [60]. The United States Preventive Services Task Force (USPSTF) recommends that administration of a combination consisting of oestrogens and progesterone for management of postmenopausal women should not be advised, and this was also stated in the Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women [63]. The administration of HRT has been noted as Class D, as the USPSTF has found sufficient evidence proving that HRT has not been effective, and that potential complications exceed possible benefits [63]. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines state that there is no basis for adding or continuing oestrogens in postmenopausal women with clinically evident CHD or cerebrovascular disease in an effort to prevent or retard progression of their underlying disease [64]. At this time, HRT should not be administered for either primary or secondary prevention of cardiovascular disease. If HRT is indicated for control of other symptoms or for other indications, its use should be decided for each woman based on symptoms, health status, personal beliefs, expectations and individual risk–benefit analysis.
CONCLUSION CHD is the major cause of female mortality, both before and after the menopause, with a marked increase in risk from CHD when the young woman under age 60 years suffers an MI. Presentation of CHD and MI in women is more subtle and occult. Early menopause (age 39 years) and late menopause (age 56 years) exacerbate cardiovascular and thrombotic risk. The use of HRT after menopause is a major issue and it remains unresolved. Nevertheless, it can be specifically stated that HRT solely for cardiovascular risk prevention is contraindicated. However, the female patient less than 10 years from menopause and at a normal age for menopause can be reassured that any cardiovascular risk from HRT is quite low. Therefore, when symptom-related and other noncardiovascular indications are present, HRT appears appropriate, well tolerated and beneficial following the menopause.
Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Whayne T. Women and cardiovascular disease – prevention of heart disease. Int J Angiol 2006; 14:218–224. 2. Claassen M, Sybrandy KC, Appelman YE, Asselbergs FW. Gender gap in acute coronary heart disease: myth or reality? World J Cardiol 2012; 4:36– 47. 3. Tsang W, Alter DA, Wijeysundera HC, et al. The impact of cardiovascular disease prevalence on women’s enrollment in landmark randomized cardiovascular trials: a systematic review. J Gen Intern Med 2012; 27:93–98. 4. Melloni C, Berger JS, Wang TY, et al. Representation of women in randomized clinical trials of cardiovascular disease prevention. Circ Cardiovasc Qual Outcomes 2010; 3:135–142. 5. Nguyen HL, Goldberg RJ, Gore JM, et al. Age and sex differences, and changing trends, in the use of evidence-based therapies in acute coronary syndromes: perspectives from a multinational registry. Coron Artery Dis 2010; 21:336–344. 6. Vaccarino V, Krumholz HM, Yarzebski J, et al. Sex differences in 2-year mortality after hospital discharge for myocardial infarction. Ann Intern Med 2001; 134:173–181. 7. Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol 2009; 54:1561–1575. 8. Vavas E, Hong SN, Henry S, et al. Imaging tests, provocative tests, including exercise testing in women with suspected coronary artery disease. Curr Cardiovasc Risk Rep 2012; 6:469–478. 9. Niemela M, Kervinen K, Romppanen H, Vikman S. Coronary artery disease in women [in Finnish]. Duodecim 2009; 125:739–746. 10. Kang SJ, Ahn JM, Han S, et al. Sex differences in the visual-functional mismatch between coronary angiography or intravascular ultrasound versus fractional flow reserve. JACC Cardiovasc Interv 2013; 6:562–568. 11. Desai ND, Naylor CD, Kiss A, et al. Impact of patient and target-vessel characteristics on arterial and venous bypass graft patency: insight from a randomized trial. Circulation 2007; 115:684–691. 12. Albarran JW, Clarke BA, Crawford J. ‘It was not chest pain really, I can’t explain it!’ An exploratory study on the nature of symptoms experienced by women during their myocardial infarction. J Clin Nurs 2007; 16:1292–1301. 13. Bozkurt B. Where do we currently stand with advice on hormone replacement therapy for women? Methodist Debakey Cardiovasc J 2010; 6:21–25. 14. Ostadal B, Ostadal P. Sex-based differences in cardiac ischaemic injury & and protection: therapeutic implications. Br J Pharmacol 2014; 171:541– 554. Ostadal and Ostadal [14&] emphasize ischaemic CHD as a major issue in women. 15. Ruiz AD, Daniels KR. The effectiveness of sublingual and topical compounded bioidentical hormone replacement therapy in postmenopausal women: an observational cohort study. Int J Pharm Compd 2014; 18:70–77. 16. Canonico M, Plu-Bureau G, O’Sullivan MJ, et al. Age at menopause, repro& ductive history, and venous thromboembolism risk among postmenopausal women: the Women’s Health Initiative Hormone Therapy clinical trials. Menopause 2014; 21:214–220. & Canonico et al. [16 ] discuss the issue of age at the time of the menopause. 17. Barbosa-Leiker C, Roper V, McPherson S, et al. Cross-sectional and longitudinal relationships between perceived stress and C-reactive protein in men and women. Stress Health 2014; 30:158–165. 18. Mascarenhas-Melo F, Marado D, Palavra F, et al. Diabetes abrogates sex differences and aggravates cardiometabolic risk in postmenopausal women. Cardiovasc Diabetol 2013; 12:61. 19. Masszi G. Hypertension and menopause [in Hungarian]. Orv Hetil 2002; 143:2821–2828. 20. Dull P. Hormone replacement therapy. Prim Care 2006; 33:953–963. 21. Rowe TC. Hormone replacement therapy: what is available now, and what is on the horizon. BC Med J 2001; 43:521–526. 22. Whelan AM, Jurgens TM, Trinacty M. Defining bioidentical hormones for menopause-related symptoms. Pharm Pract (Granada) 2011; 9:16–22.
0268-4705 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-cardiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
437
Lipids and emerging risk factors 23. Manson JE. Current recommendations: what is the clinician to do? Fertil Steril 2014; 101:916–921. 24. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007; 297:1465–1477. 25. Bassuk SS, Manson JE. Menopausal hormone therapy and cardiovascular disease risk: utility of biomarkers and clinical factors for risk stratification. Clin Chem 2014; 60:68–77. 26. Carpenter JS, Byrne MM, Studts JL. Factors related to menopausal symptom management decisions. Maturitas 2011; 70:10–15. 27. Newton KM, Reed SD, Nekhyludov L, et al. Factors associated with successful discontinuation of hormone therapy. J Womens Health (Larchmt) 2014; 23:382–388. 28. Manson JE. The role of personalized medicine in identifying appropriate candidates for menopausal estrogen therapy. Metabolism 2013; 62 (Suppl 1): S15– S19. 29. Canonico M. Hormone therapy and hemostasis among postmenopausal women: a review. Menopause 2014; 21:753–762. 30. Hulka BS. Links between hormone replacement therapy and neoplasia. Fertil Steril 1994; 62:168S–175S. 31. O’Donnell E, De Souza MJ. The cardiovascular effects of chronic hypoestrogenism in amenorrhoeic athletes: a critical review. Sports Med 2004; 34:601–627. 32. Joswig M, Hach-Wunderle V, von Holst T, Nawroth PP. Postmenopausal hormone replacement therapy and the vascular wall: epidemiology and clinical studies. Vasa 2000; 29:243–251. 33. Villablanca AC, Jayachandran M, Banka C. Atherosclerosis and sex hormones: current concepts. Clin Sci (Lond) 2010; 119:493–513. 34. Tasci T, Sukur YE, Ozmen B, et al. Effects of transdermal and oral hormone replacement therapies on monocyte chemoattractant protein-1 levels: a randomized clinical trial. Eur J Obstet Gynecol Reprod Biol 2014; 176:50–54. 35. Lahm T, Crisostomo PR, Markel TA, et al. The effects of estrogen on pulmonary artery vasoreactivity and hypoxic pulmonary vasoconstriction: potential new clinical implications for an old hormone. Crit Care Med 2008; 36:2174–2183. 36. Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med 2006; 166:357–365. 37. Prelevic GM, Kwong P, Byrne DJ, et al. A cross-sectional study of the effects of hormone replacement therapy on the cardiovascular disease risk profile in healthy postmenopausal women. Fertil Steril 2002; 77:945–951. 38. Onat A, Can G. Enhanced proinflammatory state and autoimmune activation: a breakthrough to understanding chronic diseases. Curr Pharm Des 2014; 20:575–584. 39. Spoletini I, Vitale C, Rosano GM. Biomarkers for predicting postmenopausal coronary heart disease. Biomark Med 2011; 5:485–495. 40. Hamirani YS, Pandey S, Rivera JJ, et al. Markers of inflammation and coronary artery calcification: a systematic review. Atherosclerosis 2008; 201:1–7. 41. Krintus M, Kozinski M, Kubica J, Sypniewska G. Critical appraisal of inflammatory markers in cardiovascular risk stratification. Crit Rev Clin Lab Sci 2014; 51:263–279. 42. Soares FH, de Sousa MB. Different types of physical activity on inflammatory biomarkers in women with or without metabolic disorders: a systematic review. Women Health 2013; 53:298–316. 43. Spatz ES, Canavan ME, Desai MM. From here to JUPITER: identifying new patients for statin therapy using data from the 1999–2004 National Health and Nutrition Examination Survey. Circ Cardiovasc Qual Outcomes 2009; 2:41–48. 44. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359:2195–2207. 45. Singh S, Singh H, Loftus EV Jr, Pardi DS. Risk of cerebrovascular accidents and ischemic heart disease in patients with inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2014; 12:382–393.
438
www.co-cardiology.com
46. Miettinen TA, Pyorala K, Olsson AG, et al. Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study (4S). Circulation 1997; 96:4211–4218. 47. 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/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279:1615–1622. 48. Wenger N. Coronary heart disease in women: a ‘new’ problem. Hosp Pract 1992; 27:59–74. 49. Mora S, Glynn RJ, Hsia J, et al. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010; 121:1069–1077. 50. Bukkapatnam RN, Gabler NB, Lewis WR. Statins for primary prevention of cardiovascular mortality in women: a systematic review and meta-analysis. Prev Cardiol 2010; 13:84–90. 51. Truong QA, Murphy SA, McCabe CH, et al. Benefit of intensive statin therapy in women: results from PROVE IT-TIMI 22. Circ Cardiovasc Qual Outcomes 2011; 4:328–336. 52. Mosca L. Sex, statins, and statistics. Lancet [serial on the Internet] 2015. && http://www.ncbi.nlm.nih.gov/pubmed/25595662. [Accessed 13 January 2015] && The 2015 meta-analysis by Mosca [52 ], even though specifically on statins and not HRT, is of major importance in further clarifying the use of statins in the female patient and in adding an emphasis to cardiovascular risk management in women. 53. van der Schouw YT, van der Graaf Y, Steyerberg EW, et al. Age at menopause as a risk factor for cardiovascular mortality. Lancet 1996; 347:714–718. 54. Hu FB, Grodstein F, Hennekens CH, et al. Age at natural menopause and risk of cardiovascular disease. Arch Intern Med 1999; 159:1061–1066. 55. Wellons M, Ouyang P, Schreiner PJ, et al. Early menopause predicts future coronary heart disease and stroke: the Multi-Ethnic Study of Atherosclerosis. Menopause 2012; 19:1081–1087. 56. Atsma F, Bartelink ML, Grobbee DE, van der Schouw YT. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause 2006; 13:265–279. 57. Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/ progestin Replacement Study. Ann Intern Med 2000; 132:689–696. 58. Simon T, Beau Yon de Jonage-Canonico M, Oger E, et al. Indicators of lifetime endogenous estrogen exposure and risk of venous thromboembolism. J Thromb Haemost 2006; 4:71–76. 59. Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol 2002; 22:201–210. 60. Cho L, Mukherjee D. Hormone replacement therapy and secondary cardiovascular prevention: a meta-analysis of randomized trials. Cardiology 2005; 104:143–147. 61. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321–333. 62. Speroff L. The heart and estrogen/progestin replacement study (HERS). Maturitas 1998; 31:9–14. 63. US Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the U.S. Preventive Services Task Force. Ann Intern Med 2005; 142:855– 860. 64. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina – summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 2003; 107:149–158.
Volume 30 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Women, the menopause, hormone replacement therapy and coronary heart disease Thomas F. Whayne Jr a and Debabrata Mukherjee b
Purpose of review Cardiovascular disease considerations are associated with the menopause. Despite a misconception that women have a minimal risk for coronary heart disease (CHD), it is the major cause of female deaths. This review highlights issues of hormone replacement therapy (HRT) and CHD in women. Recent findings A woman under age 60 who suffers a myocardial infarction (MI) has a 2-year post-MI mortality of 28.9%; it is 19.6% in men. CHD and MI in women are subtle. In addition, female mortality from CHD increases after the menopause. The increased inflammatory risk factor status of women plays a role in development of atherosclerosis, before and after the menopause. Until after the menopause, women overall have a lower CHD mortality rate. Menopause is associated with unique symptoms, especially vasomotor ones; preexisting cardiovascular disease further exacerbates problems associated with the menopause. Use of HRT after the menopause is a major issue. Early menopause at age 39 years or younger and late menopause at age 56 years or older increase cardiovascular risk. HRT should not be prescribed for cardiovascular risk prevention, but when less than 10 years from menopause at a normal age, women can be reassured that cardiovascular risk from HRT is very low. Summary Prescription of HRT should never be made only for cardiovascular risk reduction. However, when symptomrelated and other indications are present, HRT is appropriate and well tolerated in the early years after menopause with onset at a normal age. Keywords cardiovascular risk, coronary heart disease, oestrogens, hormone replacement, inflammation, menopause, thrombosis
INTRODUCTION Specific differences between women and men include: women develop a first myocardial infarction (MI) at an older age, coronary heart disease (CHD) events occur more after the menopause, and, overall, women are less likely than men to die of CHD [1]. Nevertheless, the major medical problem women face is CHD and other cardiovascular disease; breast cancer is much less of a lethal problem. The lay press has hit on the idea that women have more CHD than men, possibly because of the reality that if a relatively young woman has a CHD event, their mortality is higher [1]. Women with cardiovascular disease tend to have more hypertension and diabetes mellitus at the presentation of acute coronary syndrome (ACS); on the contrary, men at presentation of ACS are more likely to be tobacco smokers [2]. Young women under the age of 40 years with ACS are at the greatest risk of www.co-cardiology.com
cardiovascular death compared with men of the same age; this disadvantage then decreases as women age [2]. A problem in evaluating CHD in women is their underrepresentation in clinical trials [3]. Enrolment in randomized trials has improved but is still low compared with the overall female disease incidence [4]. Despite improved evidencebased treatments in recent years, there is a gap in the use of such treatments in both older and younger a Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, Kentucky and bDivision of Cardiovascular Medicine, Texas Tech University HSC, and Paul Foster School of Medicine, El Paso, Texas, USA
Correspondence to Thomas F. Whayne, Jr, MD, PhD, 326 Wethington Building, 900 South Limestone Street, Lexington, KY 40536-0200, USA. Tel: +1 859 218 5332; fax: +1 859 323 6475; e-mail: [email protected] Curr Opin Cardiol 2015, 30:432–438 DOI:10.1097/HCO.0000000000000157 Volume 30 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Women, menopause, hormone therapy, and coronary heart disease Whayne et al.
KEY POINTS Coronary heart disease is the major cause of death in women before, during and after the menopause. Hormone replacement therapy is not indicated if given solely for any possible cardiovascular risk benefit. The use of hormone replacement therapy in the early years after a normal menopause is associated with neutral or low cardiovascular risk.
women [5]. The purpose of this review is to clarify some of these issues and possible explanations, mechanisms and differences. Consideration of the anatomical, hormonal, inflammatory and metabolic status of women appears to offer possible clarification of female cardiovascular risk. Treatment of cardiovascular disease in women involves specific problems, especially revascularization of coronary arteries, which, when stenosed, appear to offer unique challenges and differences.
CORONARY HEART DISEASE DIFFERENCES IN WOMEN In spite of previous thinking that women have a minimal CHD risk and the failure of some clinicians to pay proper attention to early CHD symptoms, the reality is that a young woman has increased risk from CHD if an acute event occurs. In a study of 6826 patients who were MI survivors from 1975 to 1995, Vaccarino et al. [6] found that the overall 2-year mortality rate was 28.9% in women compared with 19.6% in men, and for each decrease in age by decade, the 2-year female mortality increased by 15.4% [95% confidence interval (95% CI), 4.3–27.6] compared with men. Younger women, defined as under age 60 years, were found to have an increased risk for death after MI compared with age-matched male counterparts [6]. In 2009, Shaw et al. [7] commented on the evolving knowledge of CHD in women and discussed how women have a lower incidence of anatomical CHD but when CHD is present, cardiovascular risk is higher than in men, and women have more symptoms, evidence of ischemia and unfavourable outcomes. The paradox may be from an increased coronary reactivity in women, including microvascular dysfunction [7]. Also, there appears to be a lower incidence of obstructive CHD in women, but, if present, CHD in a woman is associated with a higher incidence of unfavourable outcomes after acute MI [8]. Ischaemic heart disease may be a more appropriate term for CHD in women due to the spectrum of
obstructive CHD, coronary microvascular dysfunction and endothelial dysfunction [8]. In addition, the size of coronary arteries in women is relevant, as these arteries are smaller [9] and may be a factor in decreased benefit from invasive management. Due to smaller body surface area, smaller left ventricular mass and smaller coronary artery size, Kang et al. [10] noted that reduced myocardial territory size may account for a higher fractional flow reserve (FFR) for a specific coronary artery stenosis than in men. This is relevant to surgical benefit in women, in whom Desai et al. [11] provided data that small coronary target vessel size has an adverse effect on coronary artery bypass graft (CABG) patency, modified favourably to increase graft patency in the presence of more severe proximal stenoses with also a significantly increased benefit of a radial artery CABG conduit. Unique symptoms of CHD in women must be considered. This was discussed by Albarran et al. [12] after evaluating 12 female patients postacute MI. They concluded that distribution and presentation of symptoms of female patients failed to follow the pattern associated with a traditional acute MI presentation. Presentation may be with nonspecific symptoms around the chest, making recognition difficult for both patients and health team personnel [12]. In an extensive review, Bozkurt [13] considered statistics involving women in the United States and emphasized that far more women die of cardiovascular disease than cancer; there are nearly 250 000 cardiovascular deaths in women each year, and, despite the lower prevalence of cardiovascular disease in women, the absolute cardiovascular disease death rate in women is higher than in men due to a longer female life span. The fact that cardiovascular disease mortality in women remains high, as compared with improvement in survival trends in men, may be related to multiple factors such as in the ACS, wherein the following occur: women delay calling for professional help, which results in a sicker patient at the time of diagnosis; they present with more atypical symptoms; there is decreased recognition of a problem by caregivers, including a bias against the presence of CHD in women; and women are less likely to receive optimal cardiovascular risk control or referral for cardiac catheterization and coronary interventional procedures, with an eight-fold higher referral rate in men [13]. This serves to emphasize the importance of a commitment to explain and account for any chest pain at any age and never dismiss it as irrelevant until evaluated. Thus far, women are managed less frequently than men with percutaneous coronary intervention (PCI) and the use of evidence-based cardiovascular disease management is less frequent [14 ]. &
0268-4705 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-cardiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
433
Lipids and emerging risk factors
CHARACTERISTIC PROBLEMS OF THE MENOPAUSE The menopause is associated with some bothersome symptoms, most characteristic of which are those related to vasomotor abnormalities, mood swings and quality-of-life symptoms [15]. Increased haemostasis risk is associated with oestrogen use, with also an increased risk with early or late menopause. In a report of 426 women with a first episode of venous thromboembolism (VTE), including 294 events not associated with a procedure, Canonico et al. [16 ] found that women with early menopause (age 55 years) had a significant increase in risk for VTE (hazard ratio 1.8, 95% CI 1.2–2.7 and hazard ratio 1.5, 95% CI 1.0–2.4, respectively). Stress associated with the menopause may be a relevant cardiovascular risk factor, with an apparent relationship with increased C-reactive protein (CRP) and inflammation, not seen in men [17]. Problems that women have with the menopause are significantly worsened by associated cardiovascular diseases such as diabetes mellitus. Postmenopausal women with diabetes mellitus have an increased cardiometabolic risk, with a special emphasis on inflammation [18]. The same applies to hypertension, in that after the menopause loss of oestrogen protection may contribute to the occurrence of a female population more susceptible to hypertension as a part of their increased cardiovascular risk [19]. &
ISSUES OF HORMONE REPLACEMENT THERAPY IN WOMEN There are multiple options for HRT. Oestrogen-only administration should be considered only when no uterus is present [20]. A summary of the options for HRT can be made as follows [21]. Oestrogen administration can involve the following routes: oral, transdermal, vaginal and injection. Progestins can be given orally or transdermally (the transdermal form involves an oestrogen-progestin patch). Progestin-only use is for women with vasomotor symptoms in whom oestrogen is contraindicated. There is also a vaginal progesterone gel used every second day to promote stable endometrial activity of progesterone, although there is only a minimal systemic effect. Raloxifene is an oral selective oestrogen receptor modulator intended for asymptomatic postmenopausal women to prevent and treat osteoporosis. Tibolone is in tablet form and is a derivative of norethynodrel consisting of some oestrogenic, progestogenic and androgenic activity. It has appeal as treatment for menopausal symptoms with a single medication [21]. 434
www.co-cardiology.com
Relief of menopausal symptoms appears to be the major reason for HRT. Because of extensive usage, it appears indicated to define bioidentical hormones, which are also frequently administered, as molecular compounds essentially identical in structure to human hormones [22]. Appropriate usage of HRT involves assessment of balance between benefits and risks [23]. Both an older age and an increased time since menopause predict increased HRT risk. Women initiating HRT within 10 years of menopause and under age 60 were reported to have reduced CHD risk compared with initiation of HRT more distant from the menopause [24]. In general, the smallest effective dose of HRT should be used as briefly as possible with evaluation each year to assess the benefits of HRT continuation [20]. Other mitigating factors in favour of HRT include low-risk plasma lipids, absence of metabolic syndrome, absence of factor V Leiden genotype [25], no history of VTE or pulmonary embolus, and no history of breast cancer, where HRT use can be complex [26]. Key components in favour of HRT include increased severity of menopausal symptoms, individual patient preferences, presence of any HRT contraindications, patient age, time from menopause [23] and route of administration. In a comparison of data from a community pharmacy in postmenopausal women where essentially 100% received progesterone, Ruiz and Daniels [15] found that topical oestrogens did not relieve postmenopausal symptoms as much as sublingual administration of oestrogens. Ultimately, discontinuation of HRT is important and Newton et al. [27] found that, in a study of 2328 postmenopausal women, advice by their physician as well as symptom resolution, especially improvement in mood swings and depression and improved sense of well being as well as quality of life [28], led to successful HRT cessation. Enhanced tendency for haemostasis and increased risk of thrombosis appear to be hallmarks of oestrogen use. A review of the effects of oestrogen on haemostasis reported that there was an imbalance in haemostasis with oral oestrogens, including a decrease in inhibitors of coagulation and an increase in activation of coagulation with a resultant enhancement of production of thrombin [29]. Use of transdermal oestrogen was not associated with increased haemostasis or coagulation. Oestrogen also increases risk for ischaemic strokes [28]. The issue of any increased cancer risk with HRT must be considered. Oestrogen in HRT is in a high enough concentration to cause endometrial proliferation, hyperplasia and increased endometrial cancer risk. A review found that after 10–15 years of oestrogen use there was a 10-fold increase in risk for endometrial cancer, but fortunately the resultant Volume 30 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Women, menopause, hormone therapy, and coronary heart disease Whayne et al.
cancers were usually low grade, low stage, and carried a good prognosis, and association of a progestin with the HRT for at least 10 days per month eliminated the endometrial cancer risk [30]. A moderate increase in breast cancer risk (relative risk of 1.3–1.5) was also found, with a greater risk in subgroups associated with family history, benign proliferative disease or late occurrence of natural menopause, with no decreased risk associated with the use of a progestin [30]. However, there did not appear to be any definite contraindication to oestrogen use from this standpoint, although a relative risk as small as 1.2 could increase the risk of breast cancer from 1 in 250 to 1 in 200. The role played by female hormones in CHD has been associated with much confusion and has major implications. Despite the accepted cardiovascular benefits of exercise, studies of amenorrheic female athletes suggest an increased risk for early cardiovascular disease [31], whereas reports from observational studies have suggested that HRT decreases cardiovascular mortality in postmenopausal women [32]. However, the large randomized trial with placebo control, Heart and Estrogen/progestin Replacement Study (HERS), found that women with known cardiovascular disease had increased cardiovascular disease events during the first year of HRT use despite reported favourable benefit from randomized trials of HRT on total cholesterol (C), lipoproteins [increased high-density lipoproteins (HDLs) and decreased low-density lipoproteins (LDLs)], vasodilatation and reduced inflammation [32]. In studies of any inflammatory effect of oestrogen, it has been shown that oestrogen at physiological levels, at pregnancy levels and with HRT inhibits secretion of pro-inflammatory cytokines, stimulates synthesis and secretion of anti-inflammatory cytokines and also decreases cell responses to lipopolysaccharide-induced inflammation [33]. However, such a beneficial effect on high cardiovascular risk markers is not universal. A study of 76 early postmenopausal women found continuous oral HRT and sequential transdermal HRT had no significant effect on decreasing serum monocyte chemoattractant protein-1 or homocysteine levels [34]. The oestrogen vasodilatation effect also carries over to the lung, wherein oestrogen has been shown to cause pulmonary arterial vasodilatation and attenuate vasoconstriction, such as from hypoxia [35]. In the Women’s Health Initiative (WHI), Hsia et al. [36] found that various trials have shown HRT with conjugated equine oestrogens (CEEs) combined with medroxyprogesterone acetate does not protect postmenopausal women from CHD, and questions have been raised about some increased risk. These authors also found that CEE alone offered
no significant protection from MI or CHD death in women who were healthy, postmenopausal and followed for 7 years, although there was a suggestion of decreased CHD risk in women aged 50–59 years at onset of use. In a cross-sectional study of HRT effects performed by Prelevic et al. [37], occurrence of different effects on some markers of cardiovascular risk was noted. These authors found significantly increased high-sensitivity CRP (hsCRP) levels in women receiving CEE and tibolone compared with women on no HRT. They also found that glycated haemoglobin was significantly decreased with transdermal oestrogens and tibolone vs. no HRT. Tibolone resulted in a significantly increased SBP compared with women on no HRT. These variable effects on cardiovascular risk factors from different forms of HRT may have clinical importance [37]. The issue of HRT replacement in the postmenopausal female remains unresolved, but it appears well validated to state that HRT should not be prescribed for cardiovascular disease risk prevention, but, when symptom-related and other indications are present in a female patient with fairly recent menopause, that patient can be reassured that cardiovascular risk from HRT is quite low.
INFLAMMATION Inflammation appears to be a major mechanism for development of CHD. Triggers of low-grade inflammation and augmented autoimmune reactions include thyroid-stimulating hormone (TSH), platelet-activating factor acetylhydrolase, acylationstimulating protein, lipoprotein (a), asymmetric dimethylarginine and creatinine [38]. In an assessment of biomarkers of CHD risk in postmenopausal women, Spoletini et al. [39] found a consistent association with CRP (usually specified as hsCRP), interleukin-6 and lipoprotein(a). However, they commented on lack of proof for a specific link between such biomarkers and the occurrence of CHD, and the need for such studies. In a review of various inflammatory markers (additional markers not already mentioned include metallic metalloproteinase-9, monocyte chemotactic protein-1, lipoprotein-associated phospholipase A2 and tumour/tissue necrosis factor alpha) and their occurrence with coronary artery calcification (CAC), Hamirani et al. [40] found a weak association with CAC, mainly in women and by univariate analysis, the association of which was lost after obesity and BMI corrections. Nevertheless, such an observation is consistent with association of increased inflammation and CHD in women. It was stated by Krintus et al. [41] that the complex multifactorial cause of CHD goes beyond inflammatory risk factors to include factors such as electrocardiogram results, lipid profile, renal
0268-4705 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-cardiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
435
Lipids and emerging risk factors
function, and imaging and clinical parameters. Favourable modification of inflammatory risk factors is of major interest, and Soares and de Sousa [42] reviewed 15 selected articles with women as the protagonists and found that 12 of 15 articles showed decreased inflammatory biomarkers in association with exercise. Inflammatory risk status was the major factor in the Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. JUPITER’s findings centred on patients with hsCRP at least 2 mg/l and LDL-C less than 130 mg/dl with no perceived cardiovascular risk indication for a statin; these patients had a higher probability of being female [43], consistently with a greater association of inflammation with CHD in women. In these JUPITER patients, including women, rosuvastatin use resulted in a significant decrease in the occurrence of major cardiovascular events [44]. Observations contributing further to the importance of inflammation in women involve inflammatory bowel disease, which, in a review by Singh et al. [45], was shown to have a modest association with an increase in cardiovascular morbidity risk from stroke and CHD, especially in women.
LIPIDS, LIPOPROTEINS AND THE MENOPAUSE Statins and other lipid-lowering medications play a major role in CHD revascularization regarding plaque stability and even regression. Although there has been some controversy regarding statin benefit in women, there is ample evidence to support their use along with the lowering of LDL-C in the woman at a high cardiovascular risk. In the Scandinavian Simvastatin Survival Study (4S), the reduction of C by simvastatin resulted in similar decreases in relative risk as for men regarding the occurrence of major CHD events [46]. In the Air Force/Texas Coronary Atherosclerosis Prevention (AFCAPS/TexCAPS) study, lovastatin decreased risk for a first major CHD event in both men and women with average total C levels, average LDL-C levels and below-average HDL-C levels [47]. In an analysis of multiple trials of statins, Wenger [48] reported on the decrease in elevated LDL-C by statins in women with elevated CHD risk and found decreased incidence of revascularization procedures, CHD death and nonfatal MI. She found no alteration in total mortality in women, probably because there were too few women in the trials assessed. She commented on the apparent underutilization of statins in women as a chance to improve their cardiovascular outcomes [48]. In JUPITER, rosuvastatin decreased cardiovascular events in women similarly to what resulted in men [49]. A meta-analysis by Bukkapatnam et al. [50] showed that treatment with 436
www.co-cardiology.com
statins along with diet and exercise in women with a moderate elevation in plasma lipids and no prior clinical cardiovascular disease resulted in a significant benefit for the prevention of CHD events. The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial also found that women as well as men were benefited by intensive statin administration after ACS [51]. A 2015 meta-analysis of 27 trials of statin therapy, published in The Lancet by the Cholesterol Treatment Trialists’ (CTT) Collaboration, found that the decrease in major cardiovascular events, as compared with the same reduction in LDL-C, was the same for men and women, regardless of vascular risk or outcome [52 ]. &&
THROMBOSIS AND THE MENOPAUSE Risk of thrombosis and arterial disease has been looked at in several trials, with some studies suggesting that delayed menopause and longer exposure to endogenous oestrogens protect against cardiovascular diseases [53–55]. A large metaanalysis, however, suggested that there was no convincing relationship between postmenopausal status and cardiovascular disease [56]. In the HERS, Grady et al. [57] reported that being 52 years or older at the last menstrual period was independently associated with a higher risk of thromboembolism. Similar findings were reported by Simon et al. [58] in a case–control study of idiopathic thromboembolism and demonstrated that, independently of BMI, women with late menopause had a higher thrombotic risk than did women with menopause at a normal age. One recent study, however, showed a U-shaped association between age at menopause and the risk of nonprocedure-related thromboembolism among postmenopausal women who had never had a history of thrombosis [16 ]. After adjustment for potential confounders, women who experienced menopause at 39 years or younger or at 56 years or older had increased thrombotic risk as compared with women with age at menopause between 40 and 49 years [16 ]. Mechanistically, oestrogens have many different effects on the coagulation system, which include increases in the levels of procoagulant factors VII, X, XII and XIII and reductions in the anticoagulant factors protein S and antithrombin, leading to a prothrombotic state [59]. &
&
SPECIFIC RECOMMENDATIONS REGARDING CORONARY HEART DISEASE RISK AND HORMONE REPLACEMENT THERAPY Several randomized clinical trials of HRT in women with and without CHD have found no benefit of Volume 30 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Women, menopause, hormone therapy, and coronary heart disease Whayne et al.
HRT in decreasing cardiovascular events [60]. In fact, the WHI study and the HERS reported an association between HRT and increased cardiovascular events [61,62]. A meta-analysis of all randomized trials of HRT to estimate cardiovascular event rates reported that HRT use is not associated with reduced death, MI, or revascularization rate, and HRT is not an effective agent for cardiovascular disease prevention [60]. The United States Preventive Services Task Force (USPSTF) recommends that administration of a combination consisting of oestrogens and progesterone for management of postmenopausal women should not be advised, and this was also stated in the Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women [63]. The administration of HRT has been noted as Class D, as the USPSTF has found sufficient evidence proving that HRT has not been effective, and that potential complications exceed possible benefits [63]. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines state that there is no basis for adding or continuing oestrogens in postmenopausal women with clinically evident CHD or cerebrovascular disease in an effort to prevent or retard progression of their underlying disease [64]. At this time, HRT should not be administered for either primary or secondary prevention of cardiovascular disease. If HRT is indicated for control of other symptoms or for other indications, its use should be decided for each woman based on symptoms, health status, personal beliefs, expectations and individual risk–benefit analysis.
CONCLUSION CHD is the major cause of female mortality, both before and after the menopause, with a marked increase in risk from CHD when the young woman under age 60 years suffers an MI. Presentation of CHD and MI in women is more subtle and occult. Early menopause (age 39 years) and late menopause (age 56 years) exacerbate cardiovascular and thrombotic risk. The use of HRT after menopause is a major issue and it remains unresolved. Nevertheless, it can be specifically stated that HRT solely for cardiovascular risk prevention is contraindicated. However, the female patient less than 10 years from menopause and at a normal age for menopause can be reassured that any cardiovascular risk from HRT is quite low. Therefore, when symptom-related and other noncardiovascular indications are present, HRT appears appropriate, well tolerated and beneficial following the menopause.
Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Whayne T. Women and cardiovascular disease – prevention of heart disease. Int J Angiol 2006; 14:218–224. 2. Claassen M, Sybrandy KC, Appelman YE, Asselbergs FW. Gender gap in acute coronary heart disease: myth or reality? World J Cardiol 2012; 4:36– 47. 3. Tsang W, Alter DA, Wijeysundera HC, et al. The impact of cardiovascular disease prevalence on women’s enrollment in landmark randomized cardiovascular trials: a systematic review. J Gen Intern Med 2012; 27:93–98. 4. Melloni C, Berger JS, Wang TY, et al. Representation of women in randomized clinical trials of cardiovascular disease prevention. Circ Cardiovasc Qual Outcomes 2010; 3:135–142. 5. Nguyen HL, Goldberg RJ, Gore JM, et al. Age and sex differences, and changing trends, in the use of evidence-based therapies in acute coronary syndromes: perspectives from a multinational registry. Coron Artery Dis 2010; 21:336–344. 6. Vaccarino V, Krumholz HM, Yarzebski J, et al. Sex differences in 2-year mortality after hospital discharge for myocardial infarction. Ann Intern Med 2001; 134:173–181. 7. Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol 2009; 54:1561–1575. 8. Vavas E, Hong SN, Henry S, et al. Imaging tests, provocative tests, including exercise testing in women with suspected coronary artery disease. Curr Cardiovasc Risk Rep 2012; 6:469–478. 9. Niemela M, Kervinen K, Romppanen H, Vikman S. Coronary artery disease in women [in Finnish]. Duodecim 2009; 125:739–746. 10. Kang SJ, Ahn JM, Han S, et al. Sex differences in the visual-functional mismatch between coronary angiography or intravascular ultrasound versus fractional flow reserve. JACC Cardiovasc Interv 2013; 6:562–568. 11. Desai ND, Naylor CD, Kiss A, et al. Impact of patient and target-vessel characteristics on arterial and venous bypass graft patency: insight from a randomized trial. Circulation 2007; 115:684–691. 12. Albarran JW, Clarke BA, Crawford J. ‘It was not chest pain really, I can’t explain it!’ An exploratory study on the nature of symptoms experienced by women during their myocardial infarction. J Clin Nurs 2007; 16:1292–1301. 13. Bozkurt B. Where do we currently stand with advice on hormone replacement therapy for women? Methodist Debakey Cardiovasc J 2010; 6:21–25. 14. Ostadal B, Ostadal P. Sex-based differences in cardiac ischaemic injury & and protection: therapeutic implications. Br J Pharmacol 2014; 171:541– 554. Ostadal and Ostadal [14&] emphasize ischaemic CHD as a major issue in women. 15. Ruiz AD, Daniels KR. The effectiveness of sublingual and topical compounded bioidentical hormone replacement therapy in postmenopausal women: an observational cohort study. Int J Pharm Compd 2014; 18:70–77. 16. Canonico M, Plu-Bureau G, O’Sullivan MJ, et al. Age at menopause, repro& ductive history, and venous thromboembolism risk among postmenopausal women: the Women’s Health Initiative Hormone Therapy clinical trials. Menopause 2014; 21:214–220. & Canonico et al. [16 ] discuss the issue of age at the time of the menopause. 17. Barbosa-Leiker C, Roper V, McPherson S, et al. Cross-sectional and longitudinal relationships between perceived stress and C-reactive protein in men and women. Stress Health 2014; 30:158–165. 18. Mascarenhas-Melo F, Marado D, Palavra F, et al. Diabetes abrogates sex differences and aggravates cardiometabolic risk in postmenopausal women. Cardiovasc Diabetol 2013; 12:61. 19. Masszi G. Hypertension and menopause [in Hungarian]. Orv Hetil 2002; 143:2821–2828. 20. Dull P. Hormone replacement therapy. Prim Care 2006; 33:953–963. 21. Rowe TC. Hormone replacement therapy: what is available now, and what is on the horizon. BC Med J 2001; 43:521–526. 22. Whelan AM, Jurgens TM, Trinacty M. Defining bioidentical hormones for menopause-related symptoms. Pharm Pract (Granada) 2011; 9:16–22.
0268-4705 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-cardiology.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
437
Lipids and emerging risk factors 23. Manson JE. Current recommendations: what is the clinician to do? Fertil Steril 2014; 101:916–921. 24. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007; 297:1465–1477. 25. Bassuk SS, Manson JE. Menopausal hormone therapy and cardiovascular disease risk: utility of biomarkers and clinical factors for risk stratification. Clin Chem 2014; 60:68–77. 26. Carpenter JS, Byrne MM, Studts JL. Factors related to menopausal symptom management decisions. Maturitas 2011; 70:10–15. 27. Newton KM, Reed SD, Nekhyludov L, et al. Factors associated with successful discontinuation of hormone therapy. J Womens Health (Larchmt) 2014; 23:382–388. 28. Manson JE. The role of personalized medicine in identifying appropriate candidates for menopausal estrogen therapy. Metabolism 2013; 62 (Suppl 1): S15– S19. 29. Canonico M. Hormone therapy and hemostasis among postmenopausal women: a review. Menopause 2014; 21:753–762. 30. Hulka BS. Links between hormone replacement therapy and neoplasia. Fertil Steril 1994; 62:168S–175S. 31. O’Donnell E, De Souza MJ. The cardiovascular effects of chronic hypoestrogenism in amenorrhoeic athletes: a critical review. Sports Med 2004; 34:601–627. 32. Joswig M, Hach-Wunderle V, von Holst T, Nawroth PP. Postmenopausal hormone replacement therapy and the vascular wall: epidemiology and clinical studies. Vasa 2000; 29:243–251. 33. Villablanca AC, Jayachandran M, Banka C. Atherosclerosis and sex hormones: current concepts. Clin Sci (Lond) 2010; 119:493–513. 34. Tasci T, Sukur YE, Ozmen B, et al. Effects of transdermal and oral hormone replacement therapies on monocyte chemoattractant protein-1 levels: a randomized clinical trial. Eur J Obstet Gynecol Reprod Biol 2014; 176:50–54. 35. Lahm T, Crisostomo PR, Markel TA, et al. The effects of estrogen on pulmonary artery vasoreactivity and hypoxic pulmonary vasoconstriction: potential new clinical implications for an old hormone. Crit Care Med 2008; 36:2174–2183. 36. Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch Intern Med 2006; 166:357–365. 37. Prelevic GM, Kwong P, Byrne DJ, et al. A cross-sectional study of the effects of hormone replacement therapy on the cardiovascular disease risk profile in healthy postmenopausal women. Fertil Steril 2002; 77:945–951. 38. Onat A, Can G. Enhanced proinflammatory state and autoimmune activation: a breakthrough to understanding chronic diseases. Curr Pharm Des 2014; 20:575–584. 39. Spoletini I, Vitale C, Rosano GM. Biomarkers for predicting postmenopausal coronary heart disease. Biomark Med 2011; 5:485–495. 40. Hamirani YS, Pandey S, Rivera JJ, et al. Markers of inflammation and coronary artery calcification: a systematic review. Atherosclerosis 2008; 201:1–7. 41. Krintus M, Kozinski M, Kubica J, Sypniewska G. Critical appraisal of inflammatory markers in cardiovascular risk stratification. Crit Rev Clin Lab Sci 2014; 51:263–279. 42. Soares FH, de Sousa MB. Different types of physical activity on inflammatory biomarkers in women with or without metabolic disorders: a systematic review. Women Health 2013; 53:298–316. 43. Spatz ES, Canavan ME, Desai MM. From here to JUPITER: identifying new patients for statin therapy using data from the 1999–2004 National Health and Nutrition Examination Survey. Circ Cardiovasc Qual Outcomes 2009; 2:41–48. 44. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359:2195–2207. 45. Singh S, Singh H, Loftus EV Jr, Pardi DS. Risk of cerebrovascular accidents and ischemic heart disease in patients with inflammatory bowel disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2014; 12:382–393.
438
www.co-cardiology.com
46. Miettinen TA, Pyorala K, Olsson AG, et al. Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study (4S). Circulation 1997; 96:4211–4218. 47. 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/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279:1615–1622. 48. Wenger N. Coronary heart disease in women: a ‘new’ problem. Hosp Pract 1992; 27:59–74. 49. Mora S, Glynn RJ, Hsia J, et al. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010; 121:1069–1077. 50. Bukkapatnam RN, Gabler NB, Lewis WR. Statins for primary prevention of cardiovascular mortality in women: a systematic review and meta-analysis. Prev Cardiol 2010; 13:84–90. 51. Truong QA, Murphy SA, McCabe CH, et al. Benefit of intensive statin therapy in women: results from PROVE IT-TIMI 22. Circ Cardiovasc Qual Outcomes 2011; 4:328–336. 52. Mosca L. Sex, statins, and statistics. Lancet [serial on the Internet] 2015. && http://www.ncbi.nlm.nih.gov/pubmed/25595662. [Accessed 13 January 2015] && The 2015 meta-analysis by Mosca [52 ], even though specifically on statins and not HRT, is of major importance in further clarifying the use of statins in the female patient and in adding an emphasis to cardiovascular risk management in women. 53. van der Schouw YT, van der Graaf Y, Steyerberg EW, et al. Age at menopause as a risk factor for cardiovascular mortality. Lancet 1996; 347:714–718. 54. Hu FB, Grodstein F, Hennekens CH, et al. Age at natural menopause and risk of cardiovascular disease. Arch Intern Med 1999; 159:1061–1066. 55. Wellons M, Ouyang P, Schreiner PJ, et al. Early menopause predicts future coronary heart disease and stroke: the Multi-Ethnic Study of Atherosclerosis. Menopause 2012; 19:1081–1087. 56. Atsma F, Bartelink ML, Grobbee DE, van der Schouw YT. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause 2006; 13:265–279. 57. Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/ progestin Replacement Study. Ann Intern Med 2000; 132:689–696. 58. Simon T, Beau Yon de Jonage-Canonico M, Oger E, et al. Indicators of lifetime endogenous estrogen exposure and risk of venous thromboembolism. J Thromb Haemost 2006; 4:71–76. 59. Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol 2002; 22:201–210. 60. Cho L, Mukherjee D. Hormone replacement therapy and secondary cardiovascular prevention: a meta-analysis of randomized trials. Cardiology 2005; 104:143–147. 61. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321–333. 62. Speroff L. The heart and estrogen/progestin replacement study (HERS). Maturitas 1998; 31:9–14. 63. US Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the U.S. Preventive Services Task Force. Ann Intern Med 2005; 142:855– 860. 64. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina – summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 2003; 107:149–158.
Volume 30 Number 4 July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
