In addition to these evidence-based recommendations, the guideline development group also identifies points of best clinical practice in the original guideline document.
Levels of evidence (Ia-IV) and grading of recommendations (A-C) are defined at the end of the "Major Recommendations" field.
Women Starting or Continuing Hormone Replacement Therapy (HRT)
C - 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.
C - Universal screening of women for thrombophilic defects prior to or continuing the prescription of HRT is inappropriate.
C - Prior to commencing HRT, a personal history and a family history assessing the presence of venous thromboembolism (VTE) in a first- or second-degree relative should be obtained.
C - HRT should be avoided in women with multiple pre-existing risk factors for VTE.
As VTE may be dependent upon multiple risk factors coming together, it is important to be aware of the presence of pre-existing thrombotic risk factors. In particular, the prescriber should specifically ask whether there is a previous personal history of VTE or a history of VTE in a first- or second-degree relative. If positive, thrombophilia testing (see Table below) may be considered. 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. [Evidence level IV]
Table. Investigations for Potential Thrombophilia
| Thrombophilia screen |
- Activated partial thromboplastin time and prothrombin time
- Antithrombin activity
- Protein C activity
- Total and free protein S antigen
- Modified activated protein C resistance (after predilution in factor V deficient plasma)
- Factor V Leiden (optional if modified APC resistance abnormal)
- Prothrombin 20210A variant
- Lupus anticoagulant and anticardiolipin antibodies (immunoglobulins G and M)
|
| Routine haematology and biochemistry |
- Full blood count including platelet count
- Urea and electrolytes, liver function tests, and urinalysis for protein
|
Women with a Personal or Family History of VTE
C - Testing for thrombophilia should be discussed with and available for women with a personal or family history of VTE.
Testing for thrombophilia (as set out in the table above) may be helpful in women with a personal or family history of VTE. An attempt should be made to assess the severity of any previous event and whether or not it was objectively confirmed. The clinical diagnoses of deep vein thrombosis (DVT) and pulmonary thromboembolism are unreliable, and objective testing is required. However, in the past, objective testing was less available. A history of prolonged anticoagulant therapy would be compatible with a significant previous event.
A - It is recommended that, in women with a previous VTE, with or without an underlying heritable thrombophilia, oral HRT should usually be avoided in view of the relatively high risk of recurrent VTE.
Where the woman has had a previous VTE, with or without an underlying thrombophilia, oral HRT should usually be avoided in view of the relatively high risk of recurrence. However women must be considered as individuals. In each case, the woman's requirement for oestrogen replacement must be defined and the potential benefits for her weighed against the risks. [Evidence level Ib]
If it is considered that HRT is necessary 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. In this situation, prophylactic anticoagulant therapy can be used 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 one-quarter of these bleeds are fatal. Transdermal therapy may be best in such a situation. Specialist advice from a clinician with expertise in thrombosis and thrombophilia should be sought. [Evidence level IV]
B - In women without a personal history of VTE but with an underlying thrombophilic trait that is identified through screening, HRT is not recommended in high-risk situations such as Type 1 antithrombin deficiency or with combinations of defects or additional risk factors for VTE and specialist advice should be sought.
Where there is no personal history of VTE but an underlying thrombophilic trait is identified through screening, because a first- or second-degree relative has a history of previous VTE (e.g., apparently spontaneous VTE, VTE at young age, 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 and specialist advice should be sought. With other thrombophilic defects, there is insufficient evidence at present to indicate that HRT should be completely avoided, although evidence indicates around an 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. [Evidence level III]
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. Consideration should be given to "covering" oestrogen replacement with anticoagulant thromboprophylaxis taking into account the risk of haemorrhage. The risk of anticoagulant-related haemorrhage probably outweighs the risk of HRT-related venous thrombosis in women with a family history of VTE but no personal history of VTE, who have no identifiable thrombophilic defect or who have one of the defects usually associated with a lesser risk of VTE (heterozygosity for factor V Leiden or the prothrombin 20210A polymorphism). As this is a controversial and rapidly developing area, advice should be sought from clinicians with special expertise in thrombophilia. [Evidence level III]
C - In women over 50 years with a history of VTE within the previous year, a full clinical history and examination with appropriate investigations is warranted for underlying disease.
VTE may be precipitated by an underlying malignancy or connective tissue disease, so it is important to consider such a diagnosis in assessing women over 50 years of age with a recent pVTE. [Evidence level IV]
A - It is recommended that, when a woman who is on HRT develops a VTE, HRT should be discontinued.
C - It is recommended that, if a woman requires to continue on HRT after a VTE, long-term anticoagulation should be considered.
Risk of VTE in Users of Selective Oestrogen Receptor Modulators (SERMs)
B - SERMs should be considered to carry the same risk of thrombosis as oestrogen-containing HRT.
Women on HRT Undergoing Surgery
C - HRT should be considered a risk factor for VTE when assessing women preoperatively. However, HRT does not require to be routinely stopped prior to surgery provided that appropriate thromboprophylaxis, such as low-dose or low-molecular-weight heparin, with or without thromboembolic deterrent stockings, is used (Hoibraaten et al., 2000; Ettinger et al., 1999)
Definitions:
Grading of Recommendations
Grade A - Requires at least one randomised controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation (evidence levels Ia, Ib)
Grade B - Requires the availability of well-conducted clinical studies but no randomised clinical trials on the topic of recommendations (evidence levels IIa, IIb, III)
Grade C - Requires evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities. Indicates an absence of directly applicable clinical studies of good quality (evidence level IV)
Levels of Evidence
Ia: Evidence obtained from meta-analysis of randomised controlled trials
Ib: Evidence obtained from at least one randomised controlled trial
IIa: Evidence obtained from at least one well-designed controlled study without randomisation
IIb: Evidence obtained from at least one other type of well-designed quasi-experimental study
III: Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies, and case studies
IV: Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities
