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National Clinical Guideline Centre – Acute and Chronic Conditions (UK). Venous Thromboembolism: Reducing the Risk of Venous Thromboembolism (Deep Vein Thrombosis and Pulmonary Embolism) in Patients Admitted to Hospital. London: Royal College of Physicians (UK); 2010. (NICE Clinical Guidelines, No. 92.)

23General medical patients

23.1. Introduction

Although VTE is most often associated with surgery, 70–80% of hospital-acquired fatal pulmonary embolisms (PEs) occur in medical patients192. Apart from being an older cohort, 40% of medical patients have more than one risk factor for VTE, including previous VTE, cancer, stroke, heart failure, chronic obstructive airways disease, sepsis and bed rest. The baseline risk of VTE is estimated to be around 15% for those who are acutely unwell in medical beds217, with risks rising to about 50–60% having been reported after severe stroke335.

The risk of bleeding is different from surgical patients as medical patients by definition do not have the same open wounds however they are at similar risks of gastrointestinal haemorrhage. The use of thromboprophylaxis in medical patients provides an opportunity to greatly reduce the morbidity due to VTE, however the uptake of thromboprophylaxis in medical patients is poor and some studies report that the majority of patients are left unprotected107,123.

23.2. Evidence of methods of prophylaxis

Eleven (11) randomised controlled trials which reported at least one of the three main outcomes (DVT, PE and major bleeding) were identified45,121,141,191,256,257,350,387,390,395,579.

Another two studies did not report DVT, PE or major bleeding but reported all cause mortality and other outcomes212,418.

All included RCTs were either individually critically appraised to be of a high quality (level 1+ or level 1++) or came from systematic reviews of RCTs which had been critically appraised to be of a high quality (level 1+ or level 1++).

23.2.1. Summary of comparisons identified for any main outcomes

Figure 23-44. Number of studies which compared various types of prophylaxis methods.

Figure 23-44Number of studies which compared various types of prophylaxis methods

Numbers in boxes indicate the number of RCTs for each comparison. Boxes shaded grey indicates areas where no studies were identified.

GCS – anti-embolism/graduated compression stockings; IPCD/FID – intermittent pneumatic compression devices or foot impulse devices; LMWH – low molecular weight heparin; UFH – unfractionated heparin; Asp (HD) – high dose aspirin (>300mg), Asp (LD) - low dose aspirin (≤ 300mg); mech – mechanical prophylaxis (i.e. anti-embolism/graduated compression stockings, intermittent pneumatic compression devices or foot impulse devices); pharm – pharmacological prophylaxis

23.2.3. Additional information

23.2.3.2. Composite venous thromboembolism outcomes

Composite venous thromboembolism was reported as the primary outcome in five studies 45,121,350,395,579. The results obtained using composite VTE outcomes were consistent with the PE and DVT data reported separately and did not change the conclusions of the study.

23.2.3.3. Other outcomes

No studies reported chronic thromboembolic pulmonary hypertension or post thrombotic syndrome. One study reported on the incidence of heparin induced thrombocytopenia45 but found no significant difference between the group receiving LMWH and the group receiving UFH (1/233 and 0/216 respectively).

23.3. Network meta-analysis results

23.3.1. Introduction

A network meta-analysis was completed for DVT, symptomatic pulmonary embolism and major bleeding. Details on the network meta-analysis methods can be found in section 3.10.

23.3.2. Results

DVT results

There were 7 studies included in the network meta-analysis for DVT 45,121,141,191,256,387,579 (see Figure 23-45, Figure 23-46, Table 23-117).

Figure 23-45. Network diagram for DVT.

Figure 23-45

Network diagram for DVT. Numbers indicate the number of studies which contributed results for each comparison

Figure 23-46. DVT – network meta-analysis results of interventions compared to no prophylaxis.

Figure 23-46

DVT – network meta-analysis results of interventions compared to no prophylaxis.

Table 23-117. DVT – network meta-analysis results.

Table 23-117

DVT – network meta-analysis results.

Symptomatic PE results

There were 8 studies included in the network meta-analysis for symptomatic PE 45,121,257,350,387,390,394,579 (see Figure 23-47, Figure 23-48, Table 23-118).

Figure 23-47. Network diagram for symptomatic pulmonary embolism.

Figure 23-47

Network diagram for symptomatic pulmonary embolism. Numbers indicate the number of studies which contributed results for each comparison

Figure 23-48. Symptomatic pulmonary embolism – network meta-analysis results of interventions compared to no prophylaxis.

Figure 23-48

Symptomatic pulmonary embolism – network meta-analysis results of interventions compared to no prophylaxis.

Table 23-118. Symptomatic pulmonary embolism – network meta-analysis results.

Table 23-118

Symptomatic pulmonary embolism – network meta-analysis results.

Major bleeding results

A network meta-analysis for major bleeding was conducted using studies across hip fracture surgery, hip replacement surgery, knee replacement surgery, general medical patients and general surgical patients.

One hundred and twenty eight (128) studies were included in the analysis of which:

Seven of these studies included three comparison arms153,299,380,504,533,633,655 (see Figure 23-49, Figure 23-50, Table 23-119).

Figure 23-49. Network diagram for major bleeding.

Figure 23-49

Network diagram for major bleeding. Numbers indicate the number of studies which contributed results for each comparison

Figure 23-50. Major bleeding – network meta-analysis results of interventions compared to no prophylaxis (pooled across all population subgroups).

Figure 23-50

Major bleeding – network meta-analysis results of interventions compared to no prophylaxis (pooled across all population subgroups).

Table 23-119. Major bleeding – network meta-analysis results (pooled across all population subgroups).

Table 23-119

Major bleeding – network meta-analysis results (pooled across all population subgroups).

All cause mortality

Twelve studies were included in the analysis of all cause mortality45,121,141,191,212,256,257,387,390,394,418,579 (see Figure 23-51, Figure 23-52, Table 23-120).

Figure 23-51. Network diagram for all cause mortality.

Figure 23-51

Network diagram for all cause mortality. Numbers indicate the number of studies which contributed results for each comparison

Figure 23-52. All cause mortality – network meta-analysis results of interventions compared to no prophylaxis.

Figure 23-52

All cause mortality – network meta-analysis results of interventions compared to no prophylaxis.

Table 23-120. All cause mortality– network meta-analysis results.

Table 23-120

All cause mortality– network meta-analysis results.

23.4. Cost-effectiveness evidence

23.4.1. Introduction

General assumptions and methods for model are described in chapter 4.

Data used for the cost-effectiveness analysis which were specific to medical patients can be found in Table 23-121 and Table 23-122.

Table 23-121. Baseline risk and other population specific parameters used in the economic model for general medical patients.

Table 23-121

Baseline risk and other population specific parameters used in the economic model for general medical patients.

Table 23-122. Weights used for events in the base case analysis.

Table 23-122

Weights used for events in the base case analysis.

23.4.2. Results: standard duration prophylaxis

23.4.2.2. Deterministic sensitivity analysis

Table 23-124. Deterministic sensitivity analysis results

Table 23-125. Deterministic results, by baseline risk of pulmonary embolism and major bleeding

We considered in a threshold sensitivity analysis what would happen if patients discharged early received their prophylaxis at home. We found that even if every patient required district nurse visits to deliver their prophylaxis, LMWH was still cost-effective.

23.4.3. Conclusion of cost-effectiveness analysis

The cost effective analysis for general medical patients indicates that LMWH is the most effective and most cost effective strategy followed by unfractionated heparin. Fondaparinux was less effective than no prophylaxis in the base case, due to the increase in major bleeding.

LMWH remained the most cost effective in all of the deterministic sensitivity analyses completed.

23.5. Patient views

There is a lack of patient views evidence from medically ill patients about thromboprophylaxis. Therefore, patient views of thromboprophylaxis in this group could only be inferred from other populations. A recent qualitative study conducted in the United Kingdom among cancer patients receiving palliative care showed acceptability of thromboprophylaxis. This study found that patients were aware of the purpose of subcutaneous LMWH thromboprophylaxis. They balanced the potential benefit of venous thromboembolism reduction against potential side effects (bruising was quoted) and found it acceptable 492.

For patient views about specific prophylaxis agents, see section 6.6 Patient views.

23.6. Summary of evidence

Table 23-126Summary of evidence from network meta-analysis results for DVT, symptomatic pulmonary embolism and major bleeding outcomes

Intervention(s)Comparison(s)Intervention favoured
DVTPEMB
Prophylaxis vs no prophylaxis
UFHNo prophylaxisNot sigNot sigNot sig
LMWHNo prophylaxisLMWHNot sigNot sig
FondaparinuxNo prophylaxisNot sigNot sigNot sig
Cost-effectiveness
In the base case cost effectiveness analysis using probabilistic analysis, LMWH is the most cost-effective strategy, followed by unfractionated heparin.
LMWH remained the most cost effective in all of the deterministic sensitivity analyses.

The prophylaxis strategy which is significantly more effective in reducing DVT or PE; or resulting in significantly less major bleeding is stated in bold.

Not sig - not statistically significant difference; no events – nobody in the study had the outcome. MB = Major bleeding

23.7. Recommendations and link to evidence

RecommendationOffer pharmacological VTE prophylaxis to general medical patients assessed to be at increased risk of VTE. Choose any one of: Start pharmacological prophylaxis as soon as possible after risk assessment has been completed. Continue until the patient is no longer at increased risk of VTE.
*At the time of publication (January 2010) some types of LMWH do not have UK marketing authorisation for VTE prophylaxis in medical patients. Prescribers should consult the summary of product characteristics for the individual LMWH. Informed consent for of label use should be obtained and documented.
Recommendation –from section 5.9Regard medical patients as being at increased risk of VTE if they:
  • have had or are expected to have significantly reduced mobility for 3 days or more, or
  • are expected to have ongoing reduced mobility relative to their normal state and have one or more of the risk factors shown in Box 1.
Box 1 – Risk Factors for VTE For women who are pregnant for have given birth within the previous 6 weeks please refer to recommendations in Chapter 30 (Pregnancy and up to 6 weeks post partum)
Relative values of different outcomesThe outcomes included in the economic model were thromboembolic events (asymptomatic and symptomatic DVT, symptomatic pulmonary embolism and fatal pulmonary embolism), bleeding events (major bleeding, fatal bleeding and stroke) and other long term events occurring as a result of VTE (chronic thromboembolic pulmonary hypertension and post thrombotic syndrome). Each of these events had a cost and loss of quality adjusted life year associated with it, the details of which are provided in the methods of cost effectiveness chapter (chapter 4).
Trade off between clinical benefit and harmsThe benefit of reducing the risk of venous thromboembolism and long term events occurring as a result of thromboembolism were considered against the risk of major bleeding in the economic model.
Our decision model indicated that the QALYs lost due to major bleeding were outweighed by the QALYs gained from drug prophylaxis.
Economic considerationsAn original cost-effectiveness analysis was conducted for medical patients. The cost effectiveness analysis for general medical patients indicates that LMWH is the most effective and most cost effective strategy followed by unfractionated heparin.
Lower risk patients are often not included in trials. It was felt by the Guideline Development Group that for those medical patients who are soon mobile and do not have predisposing risk factors, the risk of VTE was too low for prophylaxis to be cost-effective.
Quality of evidenceAll included RCTs were either individually critically appraised to be of a high quality (level 1+ or level 1++) or came from systematic reviews of RCTs which had been critically appraised to be of a high quality (level 1+ or level 1++).
Only LMWH was demonstrated to be statistically significant in reducing the risk of DVT compared to no prophylaxis among general medical patients. The efficacy of UFH and fondaparinux were not statistically significant. It is unclear whether the sample sizes were powered to demonstrate a difference. However, there was a trend that these prophylactic methods reduce the risk of DVT and PE compared to no prophylaxis. Their efficacy could be also be inferred from studies conducted in surgical patients.
Directness of evidence obtained was a concern due to the strict inclusion criteria used in many of the clinical trials. There are only a small number of trials identified in medical patients and generally the inclusion criteria was narrow, including only patients with acute medical illness with a hospital stay of at least 3 days and often with severely limited mobility. Many studies excluded patients with an increased risk of bleeding.
Other considerationsAlternative thromboprophylaxis options were listed so that individual patient factors could be taken into account when selecting an appropriate prophylaxis agent. For example, some patients may have concerns about using a product of animal origin. If this is a concern, a synthetic product such as fondaparinux may be appropriate.
Although UFH is seldom used, it will be a useful alternative for patients with renal failure.
There is a lack of information about patient views on the acceptability or preference of thromboprophylaxis agents in this population. It is also unclear how thromboprophylaxis strategies impact on patient’s quality of life. A qualitative study which had been conducted in UK among palliative care patients showed that patients found LMWH acceptable and a component of care.
Despite the recognition of specific risk factors it is impossible to predict exactly within a group at risk, which individual will have a VTE. Therefore in the view of the Guideline Development Group, the standard approach should be to administer thromboprophylaxis to all those at increased risk.
RecommendationConsider offering mechanical VTE prophylaxis to medical patients in whom pharmacological prophylaxis is contraindicated. Choose any one of:
Relative values of different outcomesThe Guideline Development Group considered that it was a priority to reduce the risk of death from PE and to prevent long term morbidity from DVT such as post thrombotic syndrome. The main consideration for this recommendation is ensuring some measure of thromboprophylaxis is provided for patients at increased risk of VTE but who are also at an increased of bleeding.
Trade off between clinical benefit and harmsFor mechanical methods (IPCD, FID and anti-embolism stockings) it is unclear whether the benefits outweigh the risks in general medical patients because RCT evidence in this group is lacking.
For anti-embolism stockings, there is even greater uncertainty about the benefit vs risk trade off than IPCDs and FIDs. Although shown to be effective in surgical patients (Chapter 9), it was shown to be ineffective in stroke patients and associated with cutaneous adverse reactions (Chapter 24). Although evidence from stroke patients cannot be directly applied to medical patients, neither can it be ignored.
The benefits are more likely to outweigh the harms in patients that aren’t receiving other forms of prophylaxis.
Economic considerationsMechanical methods of prophylaxis were not considered in the economic model because there were no suitable trials in medical patients. Such methods are highly cost-effective for general surgery patients when compared with no prophylaxis and are not associated with increased bleeding (Chapter 9). However anti-embolism stockings have been shown to be ineffective and harmful in stroke patients (Chapter 24). We think it possible that they would be cost-effective in medical patients who are at elevated risk of VTE (in the absence of drug prophylaxis).
Quality of evidenceNo studies which investigated anti-embolism stockings, intermittent pneumatic compression devices or foot impulse devices in general medical patients were found.
Randomised controlled trials in surgical populations showed that these methods are effective at reducing venous thromboembolism without an associated increase in bleeding.
The following are the evidence available in non-surgical patients:
Foot impulse devices and intermittent pneumatic pump devices:
  • Stroke patients: a very small RCT with total of 26 patient, and two RCTs in patients who also used GCS all showed no significant difference.
Anti-embolism stockings:
  • Acute coronary syndrome: One RCT (n=160) showed no significant difference in DVT risk reduction.
  • Stroke: Two RCTs were found and both showed no significant difference in effectiveness. One of these, a large multi-centred RCT with 2518 participants, showed increased risks of cutaneous adverse events.
Other considerationsBecause there was uncertainty about the trade off between risk and benefits in these methods, the GDG deliberated at great length whether a recommendation should be made about mechanical prophylaxis in medical patients.
However, the GDG considered that the absence of any recommendations for medical patients at increased risk of VTE but contraindicated to pharmacological prophylaxis may result in variations of practice and may result in some high risk patients going without thromboprophylaxis. Therefore, a decision was made to make a cautious recommendation that clinicians should consider one of the three forms of mechanical prophylaxis (including anti-embolism stockings) in medical patients contraindicated to pharmacological prophylaxis. The decision was not unanimous but it was the majority decision of the GDG.
The GDG were unanimous that this is an area where research is needed.

23.7.1. Other recommendations of relevance

The specific recommendations for general medical admissions in this chapter should be read in conjunction with other relevant recommendations presented elsewhere in the guideline. These are:

23.8. Recommendations for research

23.8.1. Pharmacological and mechanical prophylaxis in a broader population of medical patients

The Guideline Development Group recommended the following research question:

  • What is the clinical and cost effectiveness of pharmacological prophylaxis, mechanical prophylaxis and combined pharmacological and mechanical prophylaxis for reducing the risk of VTE in medical patients?

Why this is important

Only a small number of trials with medical patients were identified and generally the inclusion criteria were narrow, for example, patients with an acute medical illness, with a hospital stay of more than 5 days, and often with severely limited mobility. Further research into less severely ill patient groups would be beneficial.

The evidence concerning mechanical prophylaxis in medical patients is sparse. There have been a few small trials of patients with coronary syndrome but the only large, randomised controlled trial was of patients with stroke. This trial showed that routine care plus thigh-length anti-embolism stockings did not confer significantly more protection against VTE than routine care alone and was associated with significantly more harm. All of these trials included large proportions of patients who were taking aspirin, which may have influenced the results.

New trial(s) should investigate the benefits of reducing the risk of VTE balanced against the risk of bleeding. The trial(s) should compare pharmacological prophylaxis alone, mechanical prophylaxis alone, and combined mechanical and pharmacological prophylaxis. The benefit of extended-duration prophylaxis in medical patient groups may also be investigated.

Recommended design: RCT

Further details are provided in Appendix F

23.9. Summary of recommendations

Box Icon

Box 1

Risk factors for VTE. Active cancer or cancer treatment Age over 60 years

Footnotes

1

Only the results for interventions included in the network meta-analysis for DVT were shown included in Figure 23-50 and Table 23-119.

2

At the time of publication (January 2010) some types of LMWH do not have UK marketing authorisation for VTE prophylaxis in medical patients. Prescribers should consult the summary of product characteristics for the individual LMWH. Informed consent for off label use should be obtained and documented.

Copyright © 2010, National Clinical Guideline Centre - Acute and Chronic Conditions.

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Cover of Venous Thromboembolism
Venous Thromboembolism: Reducing the Risk of Venous Thromboembolism (Deep Vein Thrombosis and Pulmonary Embolism) in Patients Admitted to Hospital.
NICE Clinical Guidelines, No. 92.
National Clinical Guideline Centre – Acute and Chronic Conditions (UK).

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