Shackleton Department of Anaesthetics, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK
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Abstract |
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Br J Anaesth 2001; 86: 70916
Keywords: hormones, hormone replacement therapy; complications, venous thromboembolism
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Introduction |
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What types of HRT are used? |
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The oestrogen and progesterone used for HRT are structurally different chemicals than those used in the oral contraceptive pill, and are of lower potency. The doses of oestrogen (as 17ß-oestradiol) in transdermal patches and of conjugated equine oestrogen in oral preparations of HRT are approximately one-sixth as potent as the ethinyl oestradiol used in oral contraceptives. The doses used in HRT are designed to restore oestradiol levels to the lower end of the normal pre-menopausal range.55 This contrasts with the oral contraceptive pill which is designed to suppress the natural ovulatory cycle.
Studies differ in their conclusions about the relative importance of the different HRT regimens in current use.11 44 Some studies investigating the effects of HRT do not differentiate between the different preparations available. Further work is needed to address this issue. Finally, there is still relatively little work on the newer drugs such as tibolone, which is a synthetic compound with oestrogenic, progestogenic, and androgenic properties.
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Indications for HRT |
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Considerable interest has been generated by the more long-term potential benefits of HRT therapy, which include a possible reduction in morbidity and mortality from cardiovascular disease (both coronary heart disease and stroke), reduction in morbidity and mortality associated with osteoporosis, and reduction in the cutaneous ageing process. However, there are also potential hazards of HRT therapy. Reported adverse effects include increased risk of malignant disease (specifically breast cancer) and increased risk of venous thromboembolism.
These issues are relevant for the anaesthetist, and an understanding of them will help rationalize the perioperative management of post-menopausal women who present for anaesthesia and surgery.
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HRT and venous thromboembolism |
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Mechanism of increased risk of venous thromboembolism
It is recognized that there are both congenital and acquired risk factors for thromboembolic disease, and that these are both exogenous and endogenous. The Thromboembolic Risk Factors Consensus Group (THRIFT) has published a widely accepted list of both groups of risk factors.49 HRT affects haematological variables relating to coagulation and fibrinolysis;36 these are summarized in Table 1.
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Inherited thrombophilic defects can be broadly classified as antithrombin deficiencies, or abnormalities of the protein C-protein S system.
The prevalence of inherited thrombophilias varies between 1 in 500 for protein C deficiency, to up to 1 in 14 for Factor V Leiden mutation. Current research suggests that in many cases inherited thrombophilia is not a single but a multi-gene defect. There may well be further, as yet undetectable genetic variants associated with increased risk of venous thromboembolism occurring in relatives of women with proven defects.
The prevalence of thrombophilic abnormalities in an asymptomatic population has been estimated at 6.2%, but this rises to 60.2% in patients presenting with venous thromboembolism who have a personal or family history of venous thromboembolism.57 It has, therefore, been suggested that patients with a personal or family history of venous thromboembolism should be routinely screened for inherited thrombophilic defects.54 The financial implications of such a policy would be considerable. In an attempt to determine the potential benefits of routine screening, a recent study has investigated the interactions between HRT use and risk of venous thromboembolism in women with and without pro-thrombotic states.33 The key findings of the study are shown in Table 2.
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Acquired thrombophilias
Acquired thrombophilias are, by definition, associated with increased risk of thrombosis. The most common cause of acquired thrombophilia is antiphospholipid syndrome, which may occur in isolation, or in association with systemic lupus erythematosus (SLE). There have been small observational studies suggesting that HRT can be safely used in patients with inactive, stable, or moderate disease; a large prospective double-blind placebo-controlled study (Safety of Estrogens in Lupus ErythematosusNational Assessment) is also in progress which should enable definitive evidence-based recommendations to be made.5 Both antiphospholipid syndrome and oestrogen therapy are quoted risk factors in the THRIFT guidelines, and it would, therefore, seem sensible to use thromboprophylaxis in all women presenting for surgery who have SLE irrespective of whether they are receiving HRT.
Mode of administration of HRT
A recent study suggests that the risk of venous thromboembolism may be related to the mode of administration of HRT. The findings demonstrated increased prothrombin activation peptide and decreased antithrombin activity in women receiving oral oestrogens, but not in those receiving transdermal preparations.44 This difference between transdermal and oral oestrogen preparations has been confirmed in a recent review,50 but contradicted in another study23 which demonstrated significant changes in thrombophilia profile associated with the administration of transdermal oestradiol, and concluded that these changes paralleled those observed with oral HRT.
The exercise habits and fat distribution of women may be as important as HRT use in determining risk of venous thromboembolism. Plasma fibrinogen levels are reduced in physically active women regardless of HRT use.12 However, a study that controlled for the effects of age, smoking, body mass index and the use of diuretics demonstrated decreased fibrinogen levels and decreased plasma viscosity values in women receiving both unopposed oestrogens and combination therapy.16
The possible effect of HRT on arterial thrombosis has not been reported in humans, but in a recent study in monkeys there was no increased risk of occlusive thrombus following a standardized stenosis/injury procedure to the carotid artery.4 This finding may be relevant when considering the relevance of thrombotic risk following surgery.
Current recommendations for women receiving HRT and undergoing surgery
Unfortunately, there is no evidence base for any of the current recommendations concerning pre- and perioperative management of women using HRT (Table 3). In practice, many women admitted for intermediate or major surgery (especially those presenting for gynaecological surgery) will have additional risk factors that mandate the use of thromboprophylaxis.
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Issues of relevance to the anaesthetist |
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Is the magnitude of increased risk quantifiable?
There is now consistent data suggesting a 3- to 4-fold increase in relative risk of venous thromboembolism in all women during the first year of taking HRT. The absolute risk of venous thromboembolism for any individual woman will be influenced by other additional risk factors. The only published evidence currently available suggests a substantial (but variable according to particular abnormality) further increase in risk of venous thromboembolism for women with underlying prothrombotic states.33 There is still no published evidence that enables the anaesthetist to accurately advise a woman taking HRT about the magnitude of the increase in risk of perioperative venous thromboembolism, particularly after the first year of therapy.
Does the risk versus benefit balance favour stopping HRT pre-operatively?
The decision to stop medication pre-operatively implies that the risks of continuing a drug outweigh the risks of stopping it. This debate has been extensively rehearsed in the case of the oral contraceptive pill, where it is clear that the potential risks of stopping the Pill pre-operatively include unwanted pregnancy, the effects of surgery and anaesthesia on that pregnancy, the risks of therapeutic abortion, and the risks of pregnancy itself. The risks of stopping HRT are considerably less dramatic, but equally the risks of continuing it are undefined. This applies particularly to women whose proposed surgical procedure would place them in a high-risk category for venous thromboembolism independent of HRT use. Recent guidelines from the Royal College of Obstetricians and Gynaecologists state that there is no evidence to support a policy of routinely stopping HRT before surgery, and that patients with oestrogen implants should be advised that they must not discontinue their cyclical progestogen.21
Should perioperative mechanical and/or pharmaceutical thromboprophylaxis be used?
Clinical guidelines suggest the use of graduated compression stockings for patients at low risk of venous thromboembolism. For patients at moderate or high risk of venous thromboembolism, RCTs strongly recommend the use of prophylactic heparin perioperatively.33 A recent review of the prevention and treatment of venous thromboembolism consistently recommends the use of low molecular weight heparin prophylaxis for elective hip or knee replacement surgery, and for hip fractures, but does not mention HRT as an additional risk factor.26
There is good evidence that administration of either low molecular weight heparin or suitable doses of oral anticoagulants pre-discharge reduces the relative risk of DVT following hip surgery by about 50%.7 Many women receiving HRT and undergoing surgery will, therefore, receive prophylactic heparin regardless of HRT use.
The decision to use prophylactic heparin in women receiving HRT who would otherwise be in a low risk group cannot at present be made on the basis of RCT evidence, but remains a clinical judgement.
The question of need for ongoing prophylaxis against venous thromboembolism has not been extensively debated in the literature either, despite an awareness of the frequency of late symptomless DVT after total hip replacement. The recent publication of the results of the Pulmonary Embolism Prevention trial, and an accompanying editorial, suggest the need for further research into the role of low dose aspirin for post-hospital discharge thromboprophylaxis.43 47 It would seem sensible for such research to also consider the use of low dose aspirin for women receiving HRT.
Use of any perioperative pharmacological thromboprophylaxis carries a risk of increased surgical bleeding and subsequent morbidity. Interpretation of published data and clinical decision-making must include consideration of these risks.10
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HRT and cardiovascular disease |
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Effects of HRT on lipoproteins
Lipoprotein profile appears to be an important determinant in development of cardiovascular disease. In women, high-density lipoprotein cholesterol (HDL-C) has been shown to have a strong inverse relationship to heart disease risk2 and observational studies suggest that increasing HDL-C is accompanied by a reduction in heart disease risk. (It is, however, important to note that there have been no specifically directed RCTs to confirm this.) Oestrogen has been consistently demonstrated to increase HDL-C in post-menopausal women, and is therefore considered to be one of the most important mechanisms by which HRT confers cardioprotection. A recent major multi-centre prospective randomized trial concluded that both unopposed oestrogen and various oestrogenprogesterone combination therapies improved lipoprotein profiles and lowered plasma fibrinogen levels.59
Several studies demonstrate that HRT reduces low density lipoprotein cholesterol (LDL-C), but the significance of this in relation to cardiovascular risk is unknown. Similarly, effects of HRT on plasma triglyceride levels are inconsistent between studies, and their relevance is not clear.
Effects of HRT on arterial physiology
Progressive arterial endothelial damage occurs with increasing age, and this predisposes to atherosclerosis. Studies on the carotid artery have investigated the effects of HRT. The media layer of the carotid artery wall contains high levels of collagen types I and III. A thick, healthy media is necessary for maintenance of a healthy intimal layer of the vessel wall. In post-menopausal women, the media layer becomes thin (as a result of collagen depletion), allowing the intimal layer to thicken, which predisposes to formation of atheromatous plaques. Use of HRT encourages thickening of the media and delays progress of atheromatous change.1
von Willebrand factor, soluble thrombomodulin, and tissue plasminogen activator are all significantly reduced after 6 weeks of HRT. These are markers of endothelial function, and therefore provide further evidence to support the beneficial effects on the cardiovascular system of HRT.31
A further study of carotid wall thickness in diabetic and non-diabetic HRT users confirmed the potentially beneficial effect of HRT in both groups.14
Another indirect measure of atherosclerosis is systemic arterial complianceatherosclerotic arteries will be stiffer, and cause a decrease in systemic compliance. HRT (oestrogen or oestrogenprogesterone) has been shown to significantly increase total systemic arterial compliance in both smokers and non-smokers.35
The study of carotid and radial artery tonometry in women taking HRT compared with non-treatment control groups has demonstrated a reversal of age-related arterial stiffening in HRT users.24
Using another indirect measure of arterial compliance (flow-mediated dilatation in response to reactive hyperaemia), HRT (oestrogen alone or a combined preparation) appears to be protective. Dilatation was decreased compared with pre-menopausal women, but to a significantly lesser extent than in post-menopausal women not using HRT.34 These findings have been confirmed in a study investigating peripheral vascular flow velocity in post-menopausal women using HRT (oral oestrogen, oestrogen patch, or combined oestrogenprogesterone) compared with a no treatment control group. Peripheral vascular flow velocities were increased in all HRT groups.30
These studies support suggestions that HRT has a beneficial effect on blood pressure. Although such an effect has not been consistently demonstrated, this may be a reflection of study design. A recent study has demonstrated significant decreases in both systolic and diastolic ambulatory blood pressures compared with a control group after 1 year of HRT. However, these changes were not revealed by office blood pressure measurement.53
Proudler, who examined the effect of combined oestrogenprogestogen HRT on angiotensin-converting-enzyme (ACE) activity, has proposed a further mechanism for the cardioprotective effects of HRT. Serum ACE activity was significantly reduced in treated women compared with untreated controls.42
HRT and cardiac function
Several studies have suggested that HRT has a directly beneficial effect on cardiac performance. In one prospective study of combined HRT for 6 months, echocardiographic measurement of left ventricular ejection fraction was significantly increased in the HRT group compared with control, and there was significant improvement in diastolic function.48 A similar study investigated the effect of HRT on left ventricular diastolic function in both normotensive and hypertensive women before and during treatment, and found significant improvement in several parameters (assessed by echocardiography) of diastolic function in both groups of women after 12 months of HRT.3
HRT and cerebrovascular accident
Most studies report a reduction in death rate from stroke in HRT users. However, the data are less consistent than those relating to death from coronary heart disease, and at least one large retrospective study has failed to demonstrate any influence of HRT (either unopposed oestrogens or combination therapy) on the risk of non-fatal haemorrhagic or thromboembolic stroke.40
What is the relevance of these findings for the anaesthetist?
Until there is more direct RCT evidence it is unlikely that women will be prescribed HRT for the sole purpose of secondary prevention of coronary heart disease.56 HRT has effects on cardiovascular physiology that are of uncertain clinical significance. The anaesthetist should be aware of this area of ongoing research; if the potentially cardioprotective effects of HRT are confirmed this would be an important factor in determining the balance of risks and benefits of continuing perioperative use of HRT.
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HRT and osteoporosis |
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A recent epidemiological study of more than 11 000 women found that those using HRT were more likely to have a high level of education, take more physical exercise, and have a higher intake of dietary fibre. The study concludes that caution is required in interpreting observational studies of HRT effects, since selection bias may operate.41
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HRT and malignant disease |
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Conclusions |
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Although there is clear evidence from RCTs that use of HRT is associated with a small increase in relative risk of venous thromboembolism, there is no such evidence to demonstrate any increased risk of peri-operative venous thromboembolism in HRT users. Current advice (based on limited evidence and expert opinion rather than on the results of RCTs) is that HRT use should be regarded as one of the risk factors for venous thromboembolism to be considered when assessing patients pre-operatively. There is no evidence to support stopping HRT pre-operatively. Use of mechanical or pharmacological methods of thromboprophylaxis is recommended for women taking HRT; the choice of thromboprophylaxis will depend upon the number of risk factors for venous thromboembolism.
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