Venous thromboembolism (VTE) prophylaxis

Recommendations as stated in the source guideline

For patients undergoing major surgery who do not receive pharmacologic prophylaxis, the ASH guideline panel suggests using mechanical prophylaxis over no mechanical prophylaxis (conditional recommendation based on very low certainty in the evidence of effects).

Note

The guideline panel did not consider any adverse events critical for this comparison.

Most of the evidence was from patients undergoing elective hip and knee arthroplasty. Therefore, the guideline panel recognized a need for high-quality studies, especially outside the orthopedic setting. However, they also noted that this may be a lower priority than undertaking studies which evaluate mechanical prophylaxis in combination with pharmacologic prophylaxis.

The guideline panel felt that mechanical prophylaxis was cost effective and that the balance of benefits and harms probably favored mechanical prophylaxis compared with no prophylaxis for patients at moderate or high risk for VTE but not those at low risk for VTE.

ᵃ Mechanical prophylaxis included external pneumatic compression, compression stockings, and sequential compression devices.

This evidence table is related to the following section/s:

• Diagnosis Approach

Recommendations as stated in the source guideline

For patients undergoing major surgery, the ASH guideline panel suggests using either pharmacologic prophylaxis or mechanical prophylaxis (conditional recommendation based on low certainty in the evidence of effects).

Note

The guideline panel notes that the balance of effects may favor mechanical prophylaxis over pharmacologic prophylaxis in patients who are considered to be at high risk of bleeding.

The guideline panel also notes that mechanical prophylaxis may not be feasible in some settings due to the nature of the surgical procedure (e.g., some lower extremity surgeries).

The evidence underpinning the recommendation in this table is mostly based on elective hip and knee arthroplasty. The guideline panel therefore notes the value of undertaking high-quality studies comparing pharmacologic and mechanical prophylaxis outside of an orthopedic and hospital setting.

ᵃ Mechanical prophylaxis included external pneumatic compression, compression stockings, and sequential compression devices. Pharmacologic prophylaxis included low-dose heparin, dalteparin, unfractionated heparin (UFH), and low molecular weight heparin (LMWH).

This evidence table is related to the following section/s:

• Diagnosis Approach

Recommendations as stated in the source guideline

For patients undergoing major neurosurgical procedures, the ASH guideline panel suggests against using pharmacological prophylaxis (conditional recommendation based on very low certainty in the evidence of effects).

Note

The guideline panel noted that patients who undergo major neurological procedures should receive mechanical prophylaxis. However, they suggested that pharmacological prophylaxis may be used in patients with a higher risk of VTE, for example, those with prolonged immobility following surgery. Patients who undergo major neurosurgical procedures which have a lower risk of major bleeding and patients with ongoing mobility restrictions following a reduction in bleeding risk after surgery could also be considered for pharmacological prophylaxis.

ᵃ Pharmacological prophylaxis included low-dose heparin, dalteparin, unfractionated heparin (UFH), low-molecular-weight heparin (LMWH).

ᵇ No further information reported in the guideline.

ᶜ The panel stated that the potential small benefit of reducing VTE events with pharmacological prophylaxis was outweighed by the potential moderate increase of major bleeding (absolute risk 10 more per 1000, 95% CI from 5 fewer to 43 more, with pharmacological prophylaxis compared with no pharmacological prophylaxis). Similar results were found in the nonrandomised studies.

This evidence table is related to the following section/s:

• Diagnosis Approach

Note

The Cochrane Clinical Answer (CCA) notes that moderate-quality evidence shows that fondaparinux reduces total VTE and total DVT compared with LMWH, but also increases the risk of major bleeding.The Cochrane review, which underpins this CCA, performed a subgroup analysis dividing studies into orthopedic, abdominal surgery, bariatric surgery, and ICU patients subgroups. No differences were found between subgroups.

ᵃ Reasons for anticoagulant therapy were: surgical procedure (orthopedic [9 trials], bariatric [1 trial], abdominal [1 trial]); immobilization (1 trial); or intensive care patients with hypercoagulability secondary to traumatic infection (1 trial).

ᵇ Primary outcome as stated in the Cochrane Review which this CCA is based upon.

This evidence table is related to the following section/s:

• Treatment algorithm
• Management Approach

Recommendations as stated in the source guideline

For patients undergoing total hip arthroplasty or total knee arthroplasty, the ASH guideline panel suggest using DOACs over LMWH (conditional recommendation based on moderate certainty in the evidence of effects).

Note

The guideline panel noted that the differences between the benefits and harms of DOACs and LMWH, even where statistically significant, were minor in magnitude. However, the use of DOACs may be more cost-effective than LMWH. Also, DOACs are favored as an out-of-hospital prophylaxis compared with LMWH, following total hip or knee arthroplasty, since the latter requires parenteral administration.

The guideline panel also assessed the effectiveness of one DOAC versus another DOAC and recommended that “For patients undergoing surgery, the ASH guideline panel suggests using any of the DOACs approved for use (conditional recommendation based on low certainty in the evidence of effects).” Due to a lack of head-to-head studies comparing different DOACs or different classes of DOACs, this recommendation is based upon indirect evidence comparing DOACs with LMWH.

ᵃ The guideline estimated proximal and distal DVTs using the pooled estimate from 30 studies reporting symptomatic DVTs.

This evidence table is related to the following section/s:

• Management Approach

Note

The Cochrane review which this Cochrane Clinical Answer (CCA) is based on notes that the evidence for graduated compression stockings reducing the risk of venous thromboembolism is mostly in hospitalized patients who had undergone general or orthopedic surgery, and that there is insufficient evidence assessing their effectiveness in medical patients.

ᵃ Includes those undergoing general surgery, orthopedic surgery, neurosurgery, cardiac surgery, gynecological surgery, or who have experienced a myocardial infarction.

ᵇ Results reported narratively; seven RCTs reported on adverse events but none of the studies reported if the events took place in the intervention or comparison groups.

This evidence table is related to the following section/s:

• Management Approach

Recommendations as stated in the source guideline

In acutely ill medical patients, the ASH guideline panel suggests using UFH, LMWH, or fondaparinux rather than no parenteral anticoagulant (conditional recommendation, low certainty in the evidence of effects). Among these anticoagulants, the panel suggests using LMWH (low certainty in the evidence of effects) or fondaparinux (very low certainty in the evidence of effects) rather than UFH (conditional recommendation).

Note

The guideline panel noted that there were limitations with the evidence, including the levels of imprecision and the indirect evidence for fondaparinux. However, overall they felt the beneficial effects and cost effectiveness of LMWH or fondaparinux favored their use compared with UFH for VTE prophylaxis in acutely ill medical patients.

ᵃ None of the included studies reported any events of gastrointestinal bleeding in either arm.

ᵇ Due to a lack of head-to-head studies comparing fondaparinux with LMWH or UFH, this evidence was based on indirect comparison of “fondaparinux v no prophylaxis” and ‘“heparin v no prophylaxis” in acutely ill medical patients.

This evidence table is related to the following section/s:

• Management Approach

Recommendations as stated in the source guideline

In critically ill medical patients, the ASH guideline panel suggests using LMWH over UFH (conditional recommendation, moderate certainty in the evidence of effects).

Note

The guideline panel noted that the beneficial effects of LMWH outweighed the harms when compared with UFH in critically ill patients. The panel also noted that due to uncertainty around the exact magnitude of effect, and also since critically ill patients who have renal failure and hepatic failure may require alternative treatment, a conditional recommendation was appropriate.

ᵃ The guideline noted that the incidence of HIT was probably lower in people who received LMWH compared with people who received UFH (3/1000 patients with LMWH v 6/1000 with UFH).

This evidence table is related to the following section/s:

• Treatment algorithm
• Management Approach

Recommendations as stated in the source guideline

For patients undergoing major surgery who receive pharmacologic prophylaxis, the ASH guideline panel suggest using combined prophylaxis with mechanical and pharmacological methods over prophylaxis with pharmacological agents alone (conditional recommendation based on very low certainty in the evidence of effects).

For patients undergoing major surgery, the ASH guideline panel suggest using either combined prophylaxis with mechanical and pharmacological prophylaxis or mechanical prophylaxis alone, depending on the risk of VTE and bleeding based on the individual patient and the type of surgical procedure (conditional recommendation based on low certainty in the evidence of effects).

Note

The guideline panel noted that baseline risk of VTE and bleeding (based on individual patient factors and type of surgery) are important considerations, and that there is a stronger indication for combined prophylaxis in people at high risk of VTE.

For combined prophylaxis versus pharmacological prophylaxis alone, the guideline panel noted that most of the evidence for this question came from an orthopedic (joint arthroplasty) setting and that further research in other settings would add more certainty to the recommendation. They also felt that the balance of benefits and harms probably favored pharmacological prophylaxis combined with mechanical prophylaxis over pharmacological prophylaxis alone. They noted moderate costs associated with combined prophylaxis and that cost-effectiveness probably favors this approach.

ᵃ Pharmacological prophylaxis included low-dose heparin, unfractionated heparin (UFH), and low molecular weight heparin (LMWH). Mechanical prophylaxis included graduated compression stockings, intermittent pneumatic compression devices, and sequential compression devices.

ᵇ The guideline noted that none of the patients in the combination group or in the pharmacological prophylaxis group alone required reoperation. This was based on 121 patients in two studies that were at high risk of bias due to lack of blinding and a lack of reporting about the method of randomization or allocation concealment.

This evidence table is related to the following section/s:

• Management Approach

Recommendations as stated in the source guideline

The guideline committee states that pharmacologic VTE prophylaxis should be added for a minimum of 7 days for people undergoing abdominal surgery whose risk of VTE outweighs their risk of bleeding, taking into account individual patient factors and according to clinical judgement. Choose either:

• LMWH or

• fondaparinux.

Note

• A total of thirty-nine comparisons (67 randomized controlled trials) were included in the guideline review, evaluating the use of pharmacologic (unfractionated heparin, LMWH, vitamin K antagonist, and fondaparinux) and mechanical (AES, IPCD, foot pump, FID, and electrical stimulation) interventions for VTE prophylaxis. Included in this table is the evidence they found for combination prophylaxis with LMWH or fondaparinux plus mechanical prophylaxis versus mechanical prophylaxis alone.

• A separate network meta-analysis (NMA) conducted by the guideline showed that combination prophylaxis strategies (pharmacologic and mechanical interventions) are more clinically beneficial in terms of reducing DVT hence the recommendation to “add” LMWH (or fondaparinux) to mechanical prophylaxis.

ᵃ Zero events in both arms.

ᵇ The guideline reported a possible clinical benefit of the combined treatment. However, there was serious or very serious imprecision around the estimates.

ᶜ The guideline reported a possible clinical harm of the fondaparinux plus IPCD combination in terms of all-cause mortality. However, there was very serious imprecision around the estimate.

This evidence table is related to the following section/s:

• Management Approach

Recommendations as stated in the source guideline

The ASH guideline panel suggest using either LMWH or UFH in patients undergoing cardiac or major vascular surgical procedures (conditional recommendation based on very low certainty of the evidence about effects).

Note

The guideline panel noted that heparin-induced thrombocytopenia (HIT) was a recognized complication in a cardiac and vascular surgery setting and that since the risk of HIT in other settings was higher with UFH compared with LMWH, the guideline panel agreed that, despite a lack of RCT evidence, an anticoagulant with a lower risk of HIT (e.g., LMWH over UFH) should be considered. The panel also recommended that should either LMWH or UFH be given to patients, platelet counts should be periodically monitored.

ᵃ None of the patients in the LMWH group or in the UFH group (1 study, N=233) developed a symptomatic pulmonary embolism.

ᵇ None of the included studies reported this outcome.

This evidence table is related to the following section/s:

• Treatment algorithm
• Management Approach

Recommendations as stated in the source guideline

• The guideline committee states that mechanical VTE prophylaxis on admission should be considered for people who are undergoing cardiac surgery who are at increased risk of VTE. Choose either:

  • anti-embolism stockings OR

  • intermittent pneumatic compression.

  Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility.

• The guideline committee also state that adding pharmacologic VTE prophylaxis for a minimum of 7 days should be considered for people who are undergoing cardiac surgery and are not having other anticoagulation therapy. Choose either:

  • LMWH as first-line treatment OR

  • If LMWH is contraindicated, use fondaparinux sodium.

Note

• The guideline committee concluded that the small amount of evidence found for fondaparinux use in a cardiac population suggests a benefit for reducing DVT. However, fondaparinux use in this population is off-label in the UK since it does not have a UK marketing authorization for this indication at the time of consultation (October 2017 recommendation).

• The guideline committee therefore recommended LMWH in the first instance and fondaparinux only when LMWH is contraindicated. Due to the high baseline risk of VTE in this population, it was considered that the additional cost of combined prophylaxis would be off-set by savings from averted VTE events.

• No relevant clinical studies were identified for thoracic surgery, but the guideline committee recommend the same treatment option as for people undergoing cardiac surgery.

ᵃ The guideline identified one small study comparing fondaparinux plus anti-embolism stockings (AES) and/or intermittent pneumatic compression (IPC) device versus AES or IPC alone. No studies were found assessing LMWH.

This evidence table is related to the following section/s:

• Treatment algorithm
• Management Approach

Recommendations as stated in the source guideline

• Consider mechanical VTE prophylaxis for people undergoing cranial surgery.

• If using mechanical VTE prophylaxis for people undergoing cranial surgery, start on admission. Choose either:

  • AES or

  • IPC.

Continue for 30 days or until the person is mobile or discharged, whichever is sooner.

Note

The guideline identified one small study that assessed IPC devices (thigh-length, from the night prior to the operation until at least 72 hours after the operation) plus AES (thigh length, from pre-operation for 10 days or until ambulant) compared with AES alone from admission until discharge (hospital stay duration not reported) in people with intracranial tumor undergoing neurosurgery.

ᵃ Zero events in both arms

This evidence table is related to the following section/s:

• Treatment algorithm
• Management Approach

Recommendations as stated in the source guideline

• If using mechanical VTE prophylaxis for people undergoing cranial surgery, start it on admission. Choose either:

  • anti-embolism stockings OR

  • intermittent pneumatic compression.

  Continue for 30 days or until the person is mobile or discharged, whichever is sooner.

• Consider adding preoperative pharmacologic venous thromboembolism (VTE) prophylaxis with LMWH. Give the last dose no less than 24 hours before surgery for people undergoing cranial surgery whose risk of VTE outweighs their risk of bleeding.

• Consider adding pharmacologic VTE prophylaxis with LMWH, starting 24-48 hours after surgery for people undergoing cranial surgery whose risk of VTE outweighs their risk of bleeding. Continue for a minimum of 7 days.

• Do not offer pharmacologic VTE prophylaxis to people with ruptured cranial vascular malformations (for example, brain aneurysms) or people with intracranial hemorrhage (spontaneous or traumatic) until the lesion has been secured or the condition has stabilized.

Note

• The guideline only identified one small study which assessed high-dose, standard duration LMWH plus IPCD compared with IPCD alone in people with intracranial tumur undergoing neurosurgery.

• The guideline also presents very low-quality evidence which suggests in people undergoing neurosurgery there is no difference between LMWH plus IPCD versus unfractionated heparin (UFH) plus IPCD for all-cause mortality, DVT, and major bleeding, all at 30 days follow up.

• The guideline made general recommendations for VTE prophylaxis for cranial surgery but discusses that clinicians must make decisions taking into account the risks of VTE and major bleeding of the surgery (based on the indication and procedure) and on individual patient factors.

ᵃ The guideline committee felt there was a possible clinical benefit of LMWH plus IPCD compared with IPCD alone in terms of all-cause mortality and DVT (symptomatic and asymptomatic).

ᵇ Zero events in both arms.

ᶜ The guideline committee felt there was a possible clinical harm of LMWH in terms of major bleeding.

This evidence table is related to the following section/s:

• Management Approach

Recommendations as stated in the source guideline

For the subset of patients undergoing major neurosurgical procedures for whom pharmacological prophylaxis is used, the ASH guideline panel suggest using LMWH over UFH (conditional recommendation based on very low certainty in the evidence of effects).

Note

The guideline panel noted that both interventions should be used with caution in patients at high risk of bleeding.

The panel also noted that the differences between the benefits and harms of LMWH and UFH were small, and that considering the very low quality of the evidence underpinning the results on balance they favored LMWH over UFH.

ᵃ The guideline noted that none of the patients in the LMWH group or in the UFH group required reoperation. However, this was based on a single study that was at unclear risk of bias due to lack of concealment and lack of blinding, and imprecision was rated “very serious”.

This evidence table is related to the following section/s:

• Management Approach

Recommendations as stated in the source guideline

For patients undergoing hip fracture repair, the ASH guideline panel suggest using pharmacological prophylaxis over no pharmacological prophylaxis (conditional recommendation based on very low certainty in the evidence of effects).

Note

In a subgroup analysis of patients treated with aspirin the guideline found no subgroup effect.

The guideline panel recognized a need for high-quality studies evaluating the effectiveness of prophylaxis with anticoagulants or aspirin compared with no pharmacological prophylaxis. However, they also noted that this may be a lower priority than undertaking studies which evaluate different antithrombotic regimens for the prevention of VTE following hip fracture repair.

ᵃ Pharmacological prophylaxis included low-dose heparin, unfractionated heparin (UFH), low molecular weight heparin (LMWH), and aspirin.

ᵇ No further information reported in the guideline.

This evidence table is related to the following section/s:

• Treatment algorithm
• Management Approach

Recommendations as stated in the source guideline

For patients undergoing hip fracture repair, the ASH guideline panel suggest using either LMWH or UFH (conditional recommendation based on very low certainty in the evidence of effects).

Note

The guideline panel noted that the differences between the benefits and harms of LMWH and UFH did not favor either intervention following hip fracture repair and that either could be recommended, keeping in mind the very low quality of the evidence. LMWH may be more cost-effective than UFH. However, this is based on a single study.

The panel also recognized a need for large randomized controlled trials (RCTs) focusing on clinically important outcomes which will better define the benefits and harms of LMWH compared with UFH following hip fracture repair.

ᵃ None of the included studies reported this outcome.

This evidence table is related to the following section/s:

• Treatment algorithm
• Management Approach

Recommendations as stated in the source guideline

• Offer mechanical VTE prophylaxis with intermittent pneumatic compression on admission to people with serious or major trauma. Continue until the person no longer has significantly reduced mobility relative to their normal or anticipated mobility.

• Consider pharmacologic VTE prophylaxis for people with serious or major trauma as soon as possible after the risk assessment when the risk of VTE outweighs the risk of bleeding. Continue for a minimum of 7 days.

Note

• The guideline committee noted that for the major trauma population, the risk of bleeding is high, and therefore mechanical prophylaxis may be preferable.

• The committee concluded that pharmacologic prophylaxis should be considered for major trauma patients, but felt (due to insufficient evidence) the particular prophylaxis preparation used would need to be based on clinical judgement on consideration of the individual patient factors. With regards to whether pharmacologic prophylaxis should be given in addition to or as an alternative to mechanical prophylaxis, the committee agreed that it would depend on a clinical judgement taking into account the individual patient.

ᵃ The guideline committee noted that very low-quality evidence suggests that LMWH (standard dose) plus IPCD (below knee) provides a clinical benefit of LMWH for DVT, and a clinical harm for LMWH for fatal PE when compared with IPCD (below knee) alone. However, there was uncertainty around effect estimates.

ᵇ Zero events in both arms

This evidence table is related to the following section/s:

• Treatment algorithm