In addition to these evidence-based recommendations, the guideline development group also identifies points of best clinical practice in the original guideline document.
Classification of evidence levels (1++ to 4) and grades of recommendations (A-D) are defined at the end of the "Major Recommendations" field.
How Should Venous Thromboembolism (VTE) Risk Be Approached When Hormone Replacement Therapy (HRT) Is Being Considered?
A - Women starting or continuing HRT should be counselled with regard to the perceived benefits and possible risks for their individual situations, including consideration of alternative therapies.
Do HRT Type and Duration Influence VTE Risk?
The Influence of Estrogen Type
D - The risk of VTE may be less with esterified estrogens compared with conjugated equine estrogen.
The Effect of Combination HRT
C - There may be a greater risk of VTE with combination therapy and definitive information on individual estrogen types is still lacking. However, the results to date suggest that therapy with estrogen alone is associated with a significant VTE risk.
VTE Relationship to Estrogen Dose
D - There is some evidence that the effect of estrogen therapy may be dose related.
Duration of Therapy
B - The risk of VTE is highest in the 1st year of HRT use, with no evidence of continuing risk on stopping HRT.
What Is the Role of Screening for Heritable Thrombophilia When Assessing the VTE Risk Associated with HRT?
C - Universal screening of women for thrombophilic defects before prescribing or before continuing the prescription of HRT is inappropriate.
There is limited information on the natural history of thrombophilias, the mechanism of estrogen-associated thrombosis and how these two factors interact. The absolute risk of VTE with HRT is, however, low. The cost-effectiveness of screening women for thrombophilia has been examined in a number of at-risk clinical circumstances and screening selected women before prescribing oral HRT may be the most cost-effective method. However, on the available evidence, universal screening of women for thrombophilic defects before prescribing or before continuing the prescription of HRT is inappropriate and should be discouraged.
D - In women without a personal history of VTE but with a high-risk thrombophilic trait (such as deficiency of antithrombin, protein C or protein S) that has been identified through screening because of a symptomatic family member, oral HRT should be avoided and specialist advice sought.
Where there is no personal history of VTE but an underlying thrombophilic trait is identified through screening carried out because a first-degree relative has a history of previous VTE (e.g., apparently spontaneous VTE, or VTE at a young age, or VTE events in two or more family members), HRT should be avoided in high-risk situations such as type 1 antithrombin deficiency or combinations of defects. Specialist advice should be sought. With other thrombophilic defects, there is insufficient evidence at present to indicate that HRT should be completely avoided, although, as noted above, evidence indicates around an overall eight-fold increase in risk of VTE. An assessment of other risk factors for VTE should be made. In the presence of multiple risk factors for VTE, HRT should be avoided. If HRT is to be used, a clear discussion of the potential excess risk should occur with the woman and transdermal therapy may be best. As this remains a controversial and rapidly developing area, advice should be sought from clinicians with special expertise in thrombophilia. [Evidence Level 4]
How Should HRT be Managed in Those with a Previous VTE?
C - A personal history of thrombosis is a contraindication to oral HRT.
D - If it is considered that quality of life is so severely affected that the benefits of HRT outweigh the risks, a transdermal preparation should be used.
If it is considered that HRT is desirable for a particular woman, the risk of recurrence should be discussed carefully with her and she must be advised to report promptly if any symptoms compatible with VTE arise. Where HRT is to be used in those with prior VTE, prophylactic anticoagulant therapy may be considered while the woman is taking HRT. However, if anticoagulant thromboprophylaxis has to be used, the risk of haemorrhage must be considered in the risk–benefit analysis. On standard anticoagulant thromboprophylaxis, major haemorrhage occurs at a rate of around 1% per year of treatment and 25% of these bleeds are fatal.
As discussed above, transdermal therapy may be best in such a situation. Specialist advice from a clinician with expertise in thrombosis and thrombophilia should be sought.
Testing for thrombophilia in selected women (e.g., those with previous severe unprovoked or recurrent VTE) may be helpful in assessing the overall thrombotic risk in women with a personal history of VTE, but the result will not alter the advice that oral HRT should be avoided. In general, testing for thrombophilia in unselected women who have experienced a first episode of VTE is not routinely recommended, as there is insufficient evidence that testing reduces the risk of recurrence or that the results should influence the duration of anticoagulant therapy. Testing when a severe defect (such as deficiency of antithrombin, protein C or protein S) is suspected may be helpful in assessing the overall thrombotic risk. If thrombophilia testing is suggested, the limitations of testing should be discussed.
How Should HRT Be Managed in Those Who Develop VTE While Receiving HRT?
C - It is recommended that, when a woman who is on HRT develops a VTE, HRT should be discontinued.
What Other Risk Factors Should Be Considered When Assessing the Risk of VTE Associated with HRT?
C - Before commencing HRT, any personal or family history of VTE should be assessed.
C - A history of VTE in a first-degree relative (i.e., parent, sibling or offspring) is a relative contraindication to HRT.
D - Where there is a family history in a first-degree relative, alternatives to oral HRT should be suggested. If HRT is considered desirable, transdermal preparations are associated with a significantly lower risk of venous thrombosis.
As VTE is usually dependent on multiple risk factors coming together, it is important to be aware of the presence of pre-existing thrombotic risk factors. The prescriber should specifically ask whether there is a previous personal history of VTE or a history of VTE in a first-degree relative. The presence of multiple pre-existing risk factors for VTE may suggest that HRT, itself a risk factor, might be best avoided. In particular, women with a previous VTE are at high risk of recurrence. However, it is important to review the overall situation for each individual. Given the polygenic nature of VTE, even where a familial thrombophilia has been identified, the risk of VTE may also be increased in those members of the family who do not carry that thrombophilia. Consequently, a negative thrombophilia result does not necessarily exclude an increased risk. Therefore, thrombophilia testing may not be informative in predicting risk without consideration of individual risk factors and the nature of the family history. Where a heritable thrombophilia has been detected in an affected family member, testing for heritable thrombophilia will not provide a definitive estimate of risk in most cases and is not routinely recommended. However, where a high-risk heritable thrombophilia has been identified in a symptomatic family member (e.g., deficiency of antithrombin, protein C or protein S), testing for thrombophilia may assist in the counselling of overall thrombotic risk. [Evidence Level 2+]
D - HRT should be avoided in women with multiple pre-existing risk factors for VTE.
Multiple defects or combinations of acquired and/or inherited risk factors are likely to be important in VTE risk. Such additional risk factors include patient factors, as detailed below. Consequently, the increase in relative risk associated with HRT has to be viewed in the context of that associated with other risk factors and the potential for interaction between risk factors should not be underestimated.
Additional risk factors for venous thromboembolism
- Increasing age
- Obesity (body mass index >30)
- Previous VTE
- Post-thrombotic syndrome
- Varicose veins with phlebitis
- First-degree family history of VTE
- Immobility for more than 3 days
- Surgical procedures (anaesthesia and surgical time >60 minutes)
- Other disorders, e.g., malignancy, myeloproliferative disorders, cardiac disease, paralysis of lower limbs, systemic infection, inflammatory bowel disease, nephritic syndrome, sickle cell disease
Grades of Recommendations
A - At least one meta-analysis, systematic review or randomised controlled trial rated as 1++, and directly applicable to the target population; or
A systematic review of randomised controlled trials or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population and demonstrating overall consistency of results
B - A body of evidence including studies rated as 2++ directly applicable to the target population, and demonstrating overall consistency of results; or
Extrapolated evidence from studies rated as 1++ or 1+
C - A body of evidence including studies rated as 2+ directly applicable to the target population and demonstrating overall consistency of results; or
Extrapolated evidence from studies rated as 2++
D - Evidence level 3 or 4; or
Extrapolated evidence from studies rated as 2+
Good Practice Point - Recommended best practice based on the clinical experience of the guideline development group
Classification of Evidence Levels
1++ High-quality meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a very low risk of bias
1+ Well-conducted meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a low risk of bias
1– Meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a high risk of bias
2++ High-quality systematic reviews of case–control or cohort studies or high-quality case–control or cohort studies with a very low risk of confounding, bias or chance and a high probability that the relationship is causal
2+ Well-conducted case–control or cohort studies with a low risk of confounding, bias or chance and a moderate probability that the relationship is causal
2– Case–control or cohort studies with a high risk of confounding, bias or chance and a significant risk that the relationship is not causal
3 Non-analytical studies, e.g., case reports, case series
4 Expert opinion