NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
National Guideline Centre (UK). Venous thromboembolism in over 16s: Reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. London: National Institute for Health and Care Excellence (NICE); 2018 Mar. (NICE Guideline, No. 89.)
December 2019: In recommendation 1.3.5 the British Standards for anti-embolism hosiery were updated because BS 6612 and BS 7672 have been withdrawn. August 2019: Recommendation 1.12.11 (1.5.30 in this document) was amended to clarify when anti-embolism stockings can be used for VTE prophylaxis for people with spinal injury.
Venous thromboembolism in over 16s: Reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism.
Show details16.1. Introduction
Many medical patients have more than one risk factor for VTE. Apart from being an older cohort, other risk factors reported include previous VTE, cancer, stroke, heart failure, chronic obstructive airways disease, sepsis and bed rest. At the time the previous guideline (CG92) was written the uptake of thromboprophylaxis in medical patients was poor. Following the publication of CG92 with the details of the National VTE Risk Assessment Tool, it is now estimated that 73% of medical patients receive VTE prophylaxis (NHS Safety Thermometer Data – March 2016 to March 2017, published April 12, 2017; accessed 15 August 2017).
16.2. Review question: What is the effectiveness of different pharmacological and mechanical prophylaxis strategies (alone or in combination) for acutely ill medical patients admitted to hospital?
For full details see review protocol in appendix C.
Table 86
PICO characteristics of review question.
16.3. Clinical evidence
Twenty studies describing seventeen trials were included in the review. Nine studies 35 43 71 94 98 100 101 108169 were previously included in the previous guideline (CG92) and eleven studies 36 60 66 81 82 87 117 160 184 172 173 were added in the update. These are summarised in Table 87 below. Evidence from these studies is summarised in the clinical evidence summary tables below. See also the study selection flow chart in appendix E, forest plots in appendix L, study evidence tables in appendix H, GRADE tables in appendix K and excluded studies list in appendix N.
One Cochrane review 6 was identified which looked at heparin for the prevention of venous thromboembolism in acutely ill medical patients, however the review protocol differed slightly and the Cochrane could therefore not be included in full.
Summary of included studies
Table 87
Summary of studies included in the review.
Table 88
Clinical evidence summary: LMWH (standard dose; standard duration) versus no prophylaxis.
Table 89
Clinical evidence summary: LMWH (high dose; standard duration) versus no prophylaxis.
Table 90
Clinical evidence summary: LMWH (low dose; standard duration) versus no prophylaxis.
Table 91
Clinical evidence summary: LMWH (high dose; standard duration) versus LMWH (standard dose; standard duration).
Table 92
Clinical evidence summary: LMWH (standard dose; standard duration) versus LMWH (low dose; standard duration).
Table 93
Clinical evidence summary: LMWH (standard dose; extended duration) versus LMWH (standard dose; standard duration).
Table 94
Clinical evidence summary: LMWH (standard dose; standard duration) + AES versus AES.
Table 95
Clinical evidence summary: LMWH (standard dose; standard duration) versus UFH.
Table 96
Clinical evidence summary: LMWH (standard dose; standard duration) versus apixaban.
Table 97
Clinical evidence summary: Rivaroxaban versus LMWH (standard dose; standard duration).
Table 98
Clinical evidence summary: Fondaparinux versus no prophylaxis.
16.4. Economic evidence
Published literature
An original model was developed in CG92 for this question and is included here.124 Additionally, two health economic studies were identified with the relevant comparison and have been included in this review. 115,199 These are summarised in the health economic evidence profiles below (Table 99, Table 100 and Table 101) and the health economic evidence tables in appendix J.
See also the health economic study selection flow chart in appendix F.
Table 99
Health economic evidence profile: LMWH (standard dose, standard duration), UFH (standard duration), Fondaparinux (standard duration) vs no prophylaxis.
Table 100
Health economic evidence profile: LMWH (standard dose, standard duration) vs no prophylaxis.
Table 101
Health economic evidence profile: LMWH (standard dose, standard duration) vs UFH (standard duration).
16.5. Evidence statements
Clinical
LMWH at a standard dose for a standard duration was compared with no prophylaxis, the outcomes all-cause mortality, DVT (symptomatic and asymptomatic), PE, major bleeding, fatal PE, heparin-induced thrombocytopenia and clinically relevant non-major bleeding were reported across four studies. There was clinical benefit of LMWH in terms of all-cause mortality and DVT (symptomatic and asymptomatic), although the mortality outcome was also consistent with no difference. There was possible clinical benefit in terms of PE, fatal PE and heparin-induced thrombocytopenia, although there was considerable uncertainty around these results. There was possible clinical harm in terms of major bleeding and clinically relevant non-major bleeding, however there was also considerable uncertainty around these results. The quality of the evidence ranged from very low to low due to risk of bias, indirectness and imprecision.
LMWH at a high dose for a standard duration was compared with no prophylaxis, the outcomes all-cause mortality, DVT (symptomatic and asymptomatic) and fatal PE were reported in one study. There was possible clinical benefit of LMWH in terms of DVT (symptomatic and asymptomatic) and fatal PE and no clinical difference in terms of all-cause mortality, however the considerable uncertainty around these results meant that they could in fact be consistent with harm, no difference and benefit. The quality of the evidence ranged from very low to low due to risk of bias and imprecision.
LMWH at a low dose for a standard duration was compared with no prophylaxis, the outcomes all-cause mortality, DVT (symptomatic and asymptomatic), PE, major bleeding and fatal PE were reported in one study. There was possible clinical benefit of LMWH in terms of PE and major bleeding, although the confidence intervals around these estimates were very imprecise. There was possible clinical harm in terms of all-cause mortality and no clinical difference in terms of DVT (symptomatic and asymptomatic) and fatal PE, although again there was considerable uncertainty around these results. The quality of the evidence was very low due to risk of bias, indirectness and imprecision.
LMWH at a high dose for a standard duration was compared with LMWH at a standard dose at a standard duration, the outcomes all-cause mortality, major bleeding and heparin-induced thrombocytopenia were reported in one study. There was possible clinical benefit of LMWH in terms of all-cause mortality and no clinical difference in terms of major bleeding and heparin-induced thrombocytopenia. However there was considerable uncertainty around all these results. The quality of the evidence was low due to imprecision.
LMWH at a standard dose for a standard duration was compared with LMWH at a low dose at a standard duration, the outcomes all-cause mortality, DVT (symptomatic and asymptomatic), PE, major bleeding and fatal PE were reported in one study. Low quality evidence showed clinical benefit of LMWH at a standard dose for DVT (symptomatic and asymptomatic). Very low quality evidence suggested possible clinical benefit of LMWH at a standard dose in terms of all-cause mortality and PE. There was possible clinical harm of LMWH at a standard dose in terms of major bleeding and fatal PE. However for these four outcomes there was considerable uncertainty around the results. The quality of the evidence ranged from very low to low due to risk of bias, indirectness and imprecision.
LMWH at a standard dose for an extended duration was compared with LMWH at a standard dose for a standard duration, the outcomes all-cause mortality, PE and fatal PE were reported in one study. There was possible clinical benefit of LMWH for an extended duration in terms of PE and fatal PE, but these results were also consistent with both no difference and possible harm when considering their uncertainty. There was no clinical difference in terms of all-cause mortality. The quality of the evidence ranged from very low to low due to risk of bias and imprecision.
LMWH at a standard dose for a standard duration in combination with AES was compared with AES alone, the outcomes all-cause mortality, major bleeding and clinically relevant non-major bleeding were reported in one study. There was a suggested clinical benefit of LMWH in combination with AES in terms of all-cause mortality, however this finding was also consistent with no difference. There was possible clinical harm of LMWH in combination with AES in terms of major bleeding and clinically relevant non-major bleeding, however there was very serious imprecision around both of these results. The quality of the evidence ranged from low to high due to imprecision. The outcome with high quality evidence was all-cause mortality.
LMWH at a standard dose for a standard duration was compared with UFH, the outcomes all-cause mortality, DVT (symptomatic and asymptomatic), PE, major bleeding, fatal PE and heparin-induced thrombocytopenia were reported across five studies. There was possible clinical benefit of LMWH in terms of all-cause mortality, DVT (symptomatic and asymptomatic), major bleeding, heparin-induced thrombocytopenia. However the uncertainty around these results was also consistent with no difference and in some cases clinical harm (all cause mortality and HIT). There was no clinical difference in terms of PE and fatal PE, however there was also uncertainty around these results. The quality of the evidence was very low due to risk of bias, indirectness, imprecision and inconsistency.
LMWH at a standard dose for a standard duration was compared with apixaban, the outcomes all-cause mortality, PE and major bleeding were reported in one study. There was possible clinical benefit of LMWH in terms of major bleeding, however the imprecision around this result may also have been consistent with no difference. There was no clinical difference in terms of all-cause mortality and PE, but the imprecision around these results showed consistency with both possible benefit and harm. The quality of the evidence ranged from very low to low due to risk of bias and imprecision.
Rivaroxaban was compared with LMWH at a standard dose for a standard duration, the outcomes all-cause mortality, DVT (symptomatic and asymptomatic), PE and major bleeding were reported in one study. There was possible clinical benefit of rivaroxaban in terms of PE, however the uncertainty around this result was also consistent with no difference or harm. High quality evidence showed clinical harm of rivaroxaban in terms of major bleeding, Moderate quality evidence suggested possible clinical harm in terms of all-cause mortality, although this finding was also consistent with no difference. There was no clinical difference in terms of DVT (symptomatic and asymptomatic). The quality of the evidence ranged from very low to high due to risk of bias, indirectness and imprecision. The outcome with high quality evidence was major bleeding.
Fondaparinux was compared with no prophylaxis, the outcomes all-cause mortality, DVT (symptomatic and asymptomatic), PE, major bleeding and fatal PE were reported in one study. There was possible clinical benefit of fondaparinux in terms of all-cause mortality, DVT (symptomatic and asymptomatic), PE and fatal PE, however the uncertainty around these results were also consistent with no difference and in the case of the PE outcomes, also clinical harm. There was no clinical difference in terms of major bleeding, although this finding was also very uncertain. The quality of the evidence ranged from very low to low due to risk of bias and imprecision.
Economic
- One cost-utility analysis found that for VTE prophylaxis in general medical patients admitted to hospital the following interventions were cost-effective (having positive incremental net monetary benefit [INMB) compared to no prophylaxis: low molecular weight heparin (standard dose, standard duration) (INMB: 328), unfractionated heparin (standard duration)(INMB: £118). The same analysis found that for VTE prophylaxis in general medical patients admitted to hospital fondaparinux sodium (standard duration) was not cost-effective compared to no prophylaxis (INMB: −£61). This analysis was assessed as directly applicable with potentially serious limitations.
- One cost-consequences analysis found that in general medical patients admitted to hospital:This analysis was assessed as partially applicable with potentially serious limitations.
- One cost-consequences analysis found that for VTE prophylaxis:
- In internal medicine patients admitted to hospital, low molecular weight heparin (standard dose, standard duration) was more costly (£4 more) and had 0.003 fewer DVT events per patient and 0.013 fewer untoward events (PE, major bleeding and death) per patient compared to unfractionated heparin (standard duration).
- In the cancer patients sub group, low molecular weight heparin (standard dose, standard duration) was more costly (£2 more per patient) and had 0.006 fewer DVT events per patient and 0.007 fewer untoward events (PE, major bleeding and death) per patient compared to unfractionated heparin (standard duration).
This analysis was assessed as partially applicable with potentially serious limitations.
16.6. Recommendations and link to evidence
| Recommendations |
|
| Research recommendation | None |
| Relative values of different outcomes |
The committee considered all-cause mortality (up to 90 days from hospital discharge), deep vein thrombosis (symptomatic and asymptomatic) (up to 7–90 days from hospital discharge), pulmonary embolism (up to 7–90 days from hospital discharge), fatal PE (7–90 days from hospital discharge), and major bleeding (up to 45 days from hospital discharge) as critical outcomes. The committee considered clinically relevant non-major bleeding (up to 45 days from hospital discharge), health-related quality of life (up to 90 days from hospital discharge), heparin-induced thrombocytopenia (duration of study), and technical complications of mechanical interventions (duration of study) as important outcomes. Please see section 4.4.3 in the methods chapter for further detail on prioritisation of the critical outcomes. |
| Quality of the clinical evidence |
Nineteen randomised controlled studies were included in this review. Nine of these studies were included in the previous guideline (CG92). Ten new studies were added to the review. Data from subgroup analyses following two of the included studies was included in the clinical evidence tables for information and was not analysed. One of the studies included had subgroup analyses evaluating people with cancer and health failure within the study population as well as the influence of age. The other study evaluated people with ischaemic stroke within the study population. Eleven comparisons were included in this review, evaluating the use of pharmacological (LMWH, UFH, apixaban, rivaroxaban and fondaparinux) and mechanical (AES) interventions for VTE prophylaxis. A majority of the studies evaluated the use of LMWH versus other pharmacological interventions. The committee noted that a number of studies failed to clearly define their outcomes or methods of ascertaining VTE events. This was particularly notable for the major bleeding outcome where many failed to clearly define this. The committee chose to include these papers and downgrade the evidence for indirectness of outcome. The committee noted that overall the quality of evidence was low due to an increased risk of bias across many studies and imprecision around the effect estimates. |
| Trade-off between clinical benefits and harms |
Overall, the committee considered that the clinically beneficial effects of LMWH and fondaparinux were prominent enough to adopt the recommendation from CG92. The committee commented that the LMWHs that are more commonly used in practice in the acutely ill medical population are enoxaparin, dalteparin and tinzaparin. The committee also noted that a majority of the studies evaluated patients who are at higher risk of VTE, including older adults and people who are immobilised. The committee noted that DOACs offered equal benefit in reduction of VTE compared to LMWH, however they also led to an increased risk of major bleeding. The committee also noted that DOACs are not currently licenced for use in acutely ill medical patients. NICE policy states that off-label use may be recommended if the clinical need cannot be met by a licensed product and there is sufficient evidence and/or experience of using the medicine to demonstrate its safety and efficacy to support this. As clinical need can be met by a licensed product (i.e. LMWH), DOACs were not recommended. The committee wished to highlight that there was no evidence for the effectiveness of mechanical prophylaxis in this population. Therefore given the size of this population and possible resource impact of recommending AES or IPCD which have no proven benefit, the committee decided not to make a recommendation about mechanical prophylaxis. For those contraindicated for pharmacological prophylaxis, the committee decided that the clinician must use clinical judgement to weigh the risk of VTE with the risk of bleeding, and for those with a high risk of bleeding or for those who may be contraindicated for pharmacological prophylaxis for other reasons, they did not feel they could recommend mechanical prophylaxis on the basis of no evidence. |
| Trade-off between net clinical effects and costs |
Three economic studies were included for this review. One was the model from CG92 which compared LMWH (standard dose, standard duration), UFH (standard duration), fondaparinux (standard duration) to no prophylaxis. The second compared LMWH (standard dose, standard duration) to no prophylaxis and the third compared LMWH (standard dose, standard duration) to UFH (standard duration). The CG92 model was assessed as directly applicable while the other two studies were assessed as partially applicable. All three studies were assessed to have potentially serious limitations. The committee noted that there was potential for the DOACs to offer an advantage in this population given their effectiveness in relation to DVT and PE compared to LMWH (standard dose, standard duration), and their oral route of administration and lower acquisition cost; however; it was noted that they also had a much higher risk of bleeding, so it is not clear whether they would be cost-effective in this population. The committee noted that without a clear evidence of benefit, these DOACs would not be recommended for off-label use in this population. The committee discussed the evidence and noted the lack of good quality evidence to support the use of mechanical prophylaxis in this population despite its potential benefit from reducing the use of pharmacological prophylaxis, with its associated risk of bleeding, in this largely elderly and immobile population. The committee determined that the new evidence is in line with current practice (that largely followed the CG92 recommendation), to offer pharmacological prophylaxis for people assessed to be at higher risk of VTE and low risk of bleeding. Hence, the committee decided to adopt the CG92 recommendation. The committee discussed whether both LMWH and fondaparinux should be offered as options, given that fondaparinux was not cost-effective according to CG92 model, and decided that fondaparinux can be recommended only as an option if LMWH was contraindicated. |
| Other considerations |
The committee commented on the broad terminology used in the previous guideline for this population – general medical patients. It is difficult to define this population as definitions can vary across hospital settings. The committee considered a more helpful term would be acutely ill medical patients (for example acute medical admissions), but appreciated the fact that no matter what terminology is used this population is very mixed, presenting patients with different risks of developing VTE. The committee discussed that there is a high prescription rate of pharmacological VTE prophylaxis within this population and thus discussed the crucial need for an appropriate risk tool that will effectively reduce the number of patients being given VTE prophylaxis when they are not highly at risk of VTE. The committee agreed it necessary to highlight the particular need for VTE risk assessment in this population to ensure that VTE prophylaxis is not over-prescribed. The committee discussed the use of VTE prophylaxis in people with renal impairment (eGFR <30 ml/min). Based on the pharmacokinetics, manufacturer’s licensing and known clinical practice, the committee determined that LMWH or unfractionated heparin would be the most appropriate options for prophylaxis in this population, rather than fondaparinux or oral anticoagulants because the risk of bleeding may be increased in the renal impairment population. Because of this, dose reduction of LMWH or UFH may be required. Unfractionated heparin may occasionally be preferred to LMWH as it has a shorter half life and it can be reversed with protamine. Additionally it does not usually require dose adjustment in patients with significant renal impairment. It may be preferred in patients where reversal may be required, for example if bleeding may occur or there may be a need for acute surgery. The two recommendations for people with renal impairment will be cross-referred to from each of the different population chapters within the guideline. |
Footnotes
- qqq
At the time of publication (March 2018), LMWH did not have a UK marketing authorisation for use in young people under 18 for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.
- rrr
At the time of publication (March 2018), LMWH did not have a UK marketing authorisation for use in young people under 18 for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.
- sss
At the time of publication (March 2018), fondaparinux sodium did not have a UK marketing authorisation for use in young people under 18 for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.
- ttt
At the time of publication (March 2018), LMWH did not have a UK marketing authorisation for use in young people under 18 for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.
- uuu
At the time of publication (March 2018), LMWH did not have a UK marketing authorisation for use in young people under 18 for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Prescribing guidance: prescribing unlicensed medicines for further information.
- Acutely ill medical patients admitted to hospital - Venous thromboembolism in ov...Acutely ill medical patients admitted to hospital - Venous thromboembolism in over 16s
Your browsing activity is empty.
Activity recording is turned off.
See more...