Maturitas 47 (2004) 259–263
`
`Venous and arterial thrombosis: epidemiology
`and risk factors at various ages
`∗
`
`Gordon D.O. Lowe
`
`Department of Medicine, Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, UK
`
`Received 23 June 2003; received in revised form 3 November 2003; accepted 10 December 2003
`
`Abstract
`
`The incidence of both venous and arterial thrombosis increases exponentially with age in both men and women. Possible
`reasons include: increasing immobility, trauma, surgery and acute medical illness; increasing prevalence (and/or cumulative
`effects) of obesity, raised blood pressure, dyslipidaemia and glucose intolerance; increasing prevalence of atherosclerosis; and
`increasing circulating markers of inflammation (C-reactive protein, CRP) and thrombosis. While arterial thrombosis is less
`common in women, the relative risk for classical risk factors associated with myocardial infarction is at least as strong in women
`as in men, in prospective population-based studies using MONICA criteria (e.g. Scottish Heart Health Study, Reykjavik Study).
`Some of these risk factors (e.g. smoking, cholesterol, triglycerides) show decreasing hazard ratios with age. Ongoing studies
`of newer potential risk factors for venous and arterial thrombosis (e.g. homocysteine, haemostatic and inflammatory variables)
`should elucidate their roles in risk prediction, including thrombotic risks of sex hormones which have effects on these variables.
`© 2004 Published by Elsevier Ireland Ltd.
`
`Keywords: Thrombosis; Epidemiology; Risk factors
`
`1. Introduction
`
`Oestrogen and selected (o)estrogen receptor modu-
`lator (SERM) therapies have made major global con-
`tributions to womens’ health and social welfare over
`the past 40 years. Combined oral contraceptive (COC)
`preparations are highly efficient contraceptives, con-
`taining the population explosion and allowing women
`life choices. Hormone replacement therapy (HRT)
`with oestrogens (or with the SERM, raloxifene) al-
`lieviates menopausal symptoms and is effective in
`
`∗
`
`Tel.: +44-141-211-5412; fax: +44-141-211-0414.
`E-mail address: gdl1j@clinmed.gla.ac.uk (G.D.O. Lowe).
`
`prophylaxis of postmenopausal osteoporosis. Another
`SERM, tamoxifen, is effective in secondary prophy-
`laxis of breast carcinoma, and probably also in pri-
`mary prophylaxis. These benefits are partly offset by
`increased risks of venous thromboembolism (VTE),
`stroke, and myocardial infarction; and recent studies
`have shown plausible biological mechanisms through
`which even low doses of oestrogens (or SERMs) may
`promote thrombotic risk.
`To facilitate a balanced assessment of the impact
`of these treatments on the risks of venous and arterial
`thrombosis, one cannot rely only on the case-control
`studies and randomised controlled trials (RCT’s)
`which estimate the relative risks of oestrogen therapy.
`
`0378-5122/$ – see front matter © 2004 Published by Elsevier Ireland Ltd.
`doi:10.1016/j.maturitas.2003.12.009
`
`MYLAN - EXHIBIT 1051
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`260
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`G.D.O. Lowe / Maturitas 47 (2004) 259–263
`
`It is important to estimate the absolute risks of ve-
`nous and arterial thrombotic events at different ages,
`upon which the relative risks should be predicated
`[1]. It is also important to estimate the impact of
`other classical risk factors in individual women, so
`that they can be advised, as far as possible, of their
`baseline individual risks when oestrogen (or SERM)
`therapies are discussed. Finally, it is important to
`consider the impact of newer risk factors (such as
`thrombotic or inflammatory markers), through which
`oestrogen (or SERM) therapies may in part exert their
`prothrombotic effects.
`
`2. Effects of age
`
`The most important risk predictor for both venous
`and arterial thrombosis is age: the increases with age
`in incidence and prevalence of both conditions are
`exponential in both women and men.
`Possible reasons for the increased risk of VTE with
`age include increasing immobility, obesity, trauma,
`surgery and medical illnesses. These potential media-
`tors are interlinked. In a recent study, it was shown that
`increasing habitual physical activity in UK men aged
`60–80 years was associated with decreasing plasma
`levels of thrombotic and inflammatory markers [2].
`Such evidence links two arms of “Virchow’s Triad”:
`stasis and changes in the components of the blood.
`The acute increases in both venous stasis and circu-
`lating levels of thrombotic and inflammatory markers
`which follow acute trauma, surgery or medical illness
`are likely to accentuate the chronic effects of immo-
`bility, obesity and chronic illness; resulting in an in-
`creased risk of VTE with age.
`Possible reasons for the increased risk of arterial
`thrombosis (coronary, stroke or limb) with age in-
`clude: the increasing prevalence of atherosclerosis; the
`increasing prevalence (and/or cumulative effects) of
`
`“classical” risk factors including obesity, raised blood
`pressure, dyslipidaemia and glucose intolerance; and
`increasing circulating markers of inflammation, such
`as C-reactive protein (CRP) [3], and thrombotic and
`rheological variables [4–6].
`The age effect on VTE is important when consid-
`ering the relative risk of oral oestrogen therapies. The
`relative risk of COC and HRT/raloxifene/tamoxifen
`for VTE is about threefold in current users [7]. How-
`ever, Table 1 shows that this relative risk is trans-
`lated into very different absolute risks for women
`at different ages. In a typical COC user (age under
`30) COC use increases the absolute risk of VTE
`from 5 to 15 (second generation) or 30 (third gen-
`eration) per 100,000; which many women might
`perceive as negligible in relation to the benefits of
`COC. Table 1 also shows that the risk of VTE in
`pregnancy (which may be an alternative to use of
`highly-effective COC) is about double that of third
`generation COC’s, and quadruple that of second gen-
`eration COC’s. When a women reaches the median
`age for menopause (about 50 years), her baseline risk
`for VTE has risen to 1 per 10,000; hence for the
`similar relative risk of VTE for oral HRT use as for
`COC use (three-fold) the absolute number of excess
`annual cases will be higher at this age: 1 per 5000
`(although this may be perceived as negligible by
`many women in relation to the symptomatic benefits
`of HRT).
`When a women reaches her sixties, her baseline
`annual risk of venous thromboembolism approaches
`1 per 1000 (Table 1), and continued oral HRT use
`(e.g. prophylaxis of postmenopausal osteoporosis) in-
`creases her annual risk of VTE to about 1 in 300 (e.g. in
`recent randomised controlled trials of oral HRT in pre-
`vention of arterial thrombosis) [8]. At this level, many
`women may look to the several alternative approaches
`to reduce their risks of osteoporosis and of arterial
`thrombosis (e.g. regular exercise, reducing smoking
`
`Table 1
`Venous thromboembolism and age
`
`Age (years)
`
`Annual risk
`
`Oral oestrogen effect
`
`<30
`50 (mean age of starting HRT to prevent perimenopausal symptoms)
`60–70 (average age of developing VTE in general population)
`>80
`
`5/100,000
`1/10,000
`1/1,000
`1/100
`
`COC 15–30/100,000 (pregnancy 50–75/100,000)
`Oral HRT 3/10,000
`Oral HRT (e.g. HERS) 3/1,000
`Not applicable
`
`

`

`G.D.O. Lowe / Maturitas 47 (2004) 259–263
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`261
`
`habit and alternative medications after discussion with
`their primary healthcare team).
`Hence, age is of fundamental importance when as-
`sessing the absolute risk of both arterial and venous
`thrombosis in individual women when considering oe-
`strogen or SERM therapy. While the media tend to
`concentrate on potentially misleading statistics such
`as relative risks, it is important for healthcare profes-
`sionals to concentrate on absolute risks. For example,
`in healthy young women without risk factors for car-
`diovascular disease, COC use has almost negligible
`thrombotic risk.
`
`3. Effects of other risk factors: venous
`thromboembolism
`
`About 50% of episodes of VTE are “idiopathic”,
`occurring without a clear, clinically-identifiable cause
`such as congenital thrombophilias, obesity or intercur-
`rent illnesses including trauma, surgery, acute medical
`illness, immobility (e.g. paralysis), cancer or chronic
`inflammatory diseases [9]. To minimise the risk of
`VTE, evaluation of all women prior to prescription of
`oral oestrogen or SERM therapy should include: past
`or family (first degree relative) history of VTE, obesity
`(body mass index) and chronic diseases. Since oral oe-
`strogen (or SERM) appears to be the causal factor for
`VTE, women at increased risk for VTE should be ad-
`vised to consider less thrombogenic alternatives, such
`as the progestogen-only pill for oral contraception or
`transdermal HRT [9].
`surgery
`Women scheduled for elective major
`should be advised to discontinue oral oestrogen or
`SERM therapy several weeks beforehand [9]. It is
`essential that alternative, effective contraception be
`provided for COC users [9]. Screening for congenital
`thrombophilias prior to COC prescription is neither
`clinically-effective nor cost-effective [10]. Screening
`for congenital thrombophilias prior to oral HRT pre-
`scription may be more clinically- and cost-effective
`[11]: a formal study is currently in progress.
`
`4. Effects of other risk factors: arterial thrombosis
`
`Premenopausal women have lower risks of arte-
`rial thrombosis (coronary, cerebral or limb) compared
`
`to premenopausal men [12]: possible mechanisms in-
`clude higher levels of high-density lipoprotein choles-
`terol [13], and lower levels of haematocrit and blood or
`plasma viscosity [14]. However, the “postmenopausal
`increase” in risk of coronary heart disease (CHD) in
`women may be a myth [15]; and a recent meta-analysis
`of randomised controlled trials of HRT to date sug-
`gests that HRT does not reduce either CHD risk or
`mortality, and increases the risk of stroke [8]. Hence
`observational studies of HRT, CHD, stroke and mor-
`tality may have been irretrievably biased, due to the
`multiple associations of HRT use with risk factors for
`CHD and stroke [8].
`Since oral HRT may increase the risk of CHD
`and stroke, its use is now contraindicated in women
`with previous history of arterial thrombotic events
`[16]. In addition, women should be assessed for
`risk factors for arterial thrombosis (as well as for
`VTE) prior to prescription of oestrogen or SERM
`therapies.
`There is less information on risk factors for arterial
`thrombosis in women compared to men. Prospective
`epidemiological studies have been severely biased
`towards men—perhaps because women have fewer
`“premature” events, which has been the traditional
`focus of prospective studies. To correct this bias,
`prospective studies should include women as well as
`men; should include sufficient numbers, and continue
`follow-up, to allow comparison of women with men;
`and should use internationally—agreed criteria, such
`as those of the WHO—MONICA Study [17]. To date,
`the Scottish Heart Health Study [18] and the Reyk-
`javik Study [19] have provided information that clas-
`sical CHD risk factors (e.g. smoking, blood pressure,
`cholesterol) are at least as strong predictors of CHD
`in women as in men. It would therefore be anticipated
`that the increased risk of CHD and stroke in women
`prescribed oral HRT (or SERMs) might be minimised
`by a formal calculation of such risk [20], followed by
`appropriate advice on reduction in these risk factors
`[20]. Such procedures would follow the experience
`with COC use, in which the increased risk of CHD
`and stroke is minimised by risk factor assessment and
`correction (see Chapter by Farley and Schmidt, this
`volume).
`Some of these classical CHD risk factors (e.g.
`smoking, cholesterol, triglycerides) show decreasing
`hazard ratios with age, in women as well as in men
`
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`

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`[19]. Nevertheless, they continue to confer important
`increases in absolute risk of CHD.
`Moving on from classical CHD and stroke risk fac-
`tors (smoking, blood pressure, cholesterol) to more re-
`cently established risk predictors, it is appropriate to
`examine the potential roles of risk factors which oral
`oestrogens (or SERMs) may increase, such as triglyc-
`erides, C-reactive protein, proinflammatory cytokines
`such as interleukin-6 (IL-6) and tumour necrosis fac-
`tor alpha (TNF-␣), and haemostatic variables such as
`fibrin D-dimer. Triglycerides have a higher impact on
`CHD risk in women than in men [19], which may
`be relevant to the increase in triglycerides induced by
`oral oestrogens. Oral HRT increases CRP levels, pos-
`sibly due to oestrogen stimulation of IL-6 or TNF-␣;
`however, the relative roles of these variables in pre-
`diction of CHD in women require further study [21].
`The effects of oral oestrogens on thrombotic variables
`[22] may be as relevant to risks of CHD and stroke, as
`to risks of VTE: again, further study is required. The
`lesser effects of transdermal HRT on thrombotic and
`inflammatory variables [22] and on risk of VTE [23]
`may also be relevant to risks of CHD and stroke.
`
`5. Conclusion
`
`Recent publications which confirm and extend
`knowledge on the increased relative risks of venous
`and arterial thrombosis in women taking oral oestro-
`gens have focussed interest on the baseline absolute
`risks of thrombotic disorders in women at different
`ages. Formal calculation of these absolute risks in
`individual women facilitates decisions on alternative
`therapies and empowers patient choices.
`
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