CONTENTS

• Approach to personalized DVT prophylaxis in ICU
• Indications for DVT prophylaxis
• Contraindications to DVT prophylaxis
• Agents
  • LMWH
  • Fondaparinux
  • UFH
  • Apixiban
  • Aspirin
  • Low-dose heparin infusion
• Nonpharmacological DVT prophylaxis

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general approach to personalized DVT prophylaxis in critical illness

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Important factors to consider include:

[#1/5] Weight

• >100 kg and/or BMI >30 increases DVT risk & reduces heparin concentrations.

[#2/5] GFR

• GFR <60 ml/min: patients may require less enoxaparin & bleeding risk is mildly elevated.
• GFR >100 ml/min: increasing likelihood of augmented renal clearance, with high enoxaparin requirements. (36942874)
  • (Further discussion of augmented renal clearance: 📖)

[#3/5] Systemic inflammation

• Systemic inflammation causes heparin resistance.  This may be suggested by clinical features such as:
  • Sepsis.
  • Thrombocythemia.
  • Elevated fibrinogen.

[#4/5] IMPROVE-BLEED score

• Risk factors for bleeding:
  • Age:
    • 40-84 = 1.5 points.
    • ≧85 = 3.5 points.
  • Male gender = 1 point.
  • GFR:
    • 30-59 = 1 point.
    • <30 = 2.5 points.
  • Active malignancy in <6 months = 2 points.
  • Rheumatic disease = 2 points.
  • Central venous catheter = 2 points.
  • ☑️ ICU/CCU = 2.5 points.
  • Hepatic failure (INR>1.5) = 2.5 points.
  • Platelet count <50 = 4 points.
  • Bleeding in 3 months before admission = 4 points.
  • Active gastroduodenal ulcer = 4.5 points.
• Interpretation:
  • Score <7 = Low risk (major bleeding risk ~0.4-1.5%). (27307054)
  • Score ≧7 = High risk (major bleeding risk ~4-5.4%). (26867833)

[#5/5] Concurrent antiplatelet agents?

• A lower heparin dose may be adequate.
• (Discussion of aspirin below ⚡️)

(Another essential reminder: Dosing frequency versus dose size)

• Bleeding risk relates to the peak anti-Xa level, whereas efficacy relates to the trough anti-Xa level.
• Giving smaller doses more frequently may improve efficacy and safety compared to a single daily dose (e.g., 30 mg q12 is probably safer and more effective than 60 mg q24).

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indications for DVT prophylaxis

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critically ill patients

• Critically ill patients are at increased risk of DVT due to numerous factors (immobility, systemic inflammation, vascular injury for invasive devices, etc.). Consequently, DVT prophylaxis is generally indicated for any critically ill patient (in the absence of contraindications).

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hospitalized medical patients (not ICU patients)

The risk of DVT is lower among hospitalized medical patients as compared to critically ill patients. Consequently, some patients may not require DVT prophylaxis. The risks and benefits may be assessed using risk assessment tools:

Padua score for VTE risk among hospitalized medicine patients (excluding ICU)

• Risk factors for VTE:
  • Active malignancy (3 points).
  • Prior VTE (excluding superficial vein thrombosis; 3 points).
  • Reduced mobility (3 points).
  • Known thrombophilic condition (3 points).
  • Recent (<1 month) surgery or trauma (2 points).
  • Age ≧70 (1 point).
  • Heart and/or respiratory failure (1 point).
  • Acute MI and/or ischemic stroke (1 point).
  • Acute infection and/or rheumatological disorder (1 point).
  • BMI ≧30 (1 point).
• Interpretation:
  • Score <4 is low risk.
  • Score ≧4 is high risk.

IMPROVE-BLEED risk score for major bleeding among medical patients (including ICU)

• Risk factors for bleeding:
  • Age:
    • 40-84 = 1.5 points.
    • ≧85 = 3.5 points.
  • Male gender = 1 point.
  • GFR:
    • 30-59 = 1 point.
    • <30 = 2.5 points.
  • Active malignancy in <6 months = 2 points.
  • Rheumatic disease = 2 points.
  • Central venous catheter = 2 points.
  • ICU/CCU = 2.5 points.
  • Hepatic failure (INR>1.5) = 2.5 points.
  • Platelet count <50 = 4 points.
  • Bleeding in 3 months before admission = 4 points.
  • Active gastroduodenal ulcer = 4.5 points.
• Interpretation:
  • Score <7 = Low risk (major bleeding risk 0.4-1.5%). (27307054)
  • Score ≧7 = High risk (major bleeding risk 4-5.4%). (26867833)

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contraindications for DVT prophylaxis

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[1/3] hemorrhage

• Active bleeding
• Intracranial hemorrhage (although most guidelines do allow DVT prophylaxis after >48 hours of stability).
  • DVT prophylaxis following intracranial hemorrhage is discussed here: 📖

[2/3] substantial coagulopathy

• ⚠️ Consider the totality of bleeding risk factors & coagulopathies (including medications such as aspirin).
• Thrombocytopenia:
  • <50,000 platlets is often quoted as a contraindication to DVT prophylaxis. The IMPROVE investigators found that a platelet count <50,000 increased the risk of in-hospital bleeding with an odds ratio of 3.37. (20453069)
  • However, patients with isolated consumptive coagulopathy (i.e., DIC) are at increased risk of thrombosis. Consequently, <~30,000 platelets might be a more appropriate cutoff to contraindicate DVT prophylaxis without any other risk factors for bleeding in that context. (22929300) Further discussion of DVT prophylaxis for patients with DIC is here: 📖
• Cirrhosis:
  • Most patients with elevated INR still need DVT prophylaxis (the elevated INR doesn't indicate that they are “auto-anticoagulated”).
  • Full discussion of DVT prophylaxis in cirrhosis is here: 📖

[3/3] planned procedure

• DVT prophylaxis is generally not a significant issue for most procedures (when in doubt, discuss with the service performing the procedure).
• DVT prophylaxis should be held before lumbar puncture (discussed further: 📖).

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DVT prophylaxis with LMWH (low molecular weight heparin)

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dosing enoxaparin

dosing for medical patients who aren't critically ill (“conventional dosing”)

• GFR >30 ml/min:
  • Weight <45 kg (♀) or <57 kg (♂): 0.75 mg/kg actual body weight QD; check anti-Xa levels.
  • Intermediate weight: 40 mg enoxaparin QD.
  • Weight >120 kg: consider 0.25 mg/kg enoxaparin SQ q12 hours. (Rondina 2010; Canadian guidelines)
• GFR 20-30 ml/min:
  • Weight <45 kg (♀) or <57 kg (♂): avoid enoxaparin. Just use unfractionated heparin 5000 IU q12 hr.
  • Intermediate/elevated weight: 30 mg enoxaparin QD with monitoring of levels.

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dosing for trauma patients & selected critically ill medical patients (“trauma dosing”)

introduction to trauma dosing

• Trauma patients are at a relatively elevated risk of DVT, so standard dosing of DVT prophylaxis is inadequate. Consequently, the American College of Surgeons (ACS) developed guidelines for DVT prophylaxis in trauma patients. (34797813) These have been adopted as standard care. As illustrated below, trauma dosing for enoxaparin makes a lot of sense:
  • Twice-daily dosing avoids sub-therapeutic trough levels (trough levels are likely the primary determinant of efficacy).
  • Unusual weight is a primary predictor of inappropriate dosing. Correcting the dose for weight increases the likelihood of obtaining target drug levels.
• Medical ICU patients are also at elevated risk of DVT, as compared to most hospitalized medical patients. Standard dosing of DVT prophylaxis (e.g., 40 mg/day enoxaparin) is often inadequate for critically ill patients – especially patients with obesity, augmented renal clearance 📖, and/or substantial systemic inflammation causing heparin resistance. 🌊
• Unfortunately, high-quality data regarding the optimal dosing of DVT prophylaxis in medical ICU patients is lacking. In the absence of such data, it may be reasonable to utilize protocols designed for trauma patients for the management of medical ICU patients felt to be at high risk for DVT. The advantage of using a trauma protocol is that it is a well-defined protocol that has been clinically validated in critically ill patients at risk of bleeding. To further support the validity of generalizing this protocol beyond trauma patients, the enoxaparin dose of 0.5 mg/kg BID has been suggested by studies involving both trauma and non-trauma patients. (5990203, 30954541, 28228055, 29649055, 32915054, 34340862) 

initial enoxaparin dosing

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monitoring peak Xa level for prophylactic enoxaparin

• Indications for Xa monitoring include:
  • GFR 20-30 ml/min.
  • Pregnancy.
  • Morbid obesity.
  • Underweight (<45 kg (♀) or <57 kg (♂))
  • Trauma dosing (except for 50-89 kg patients on 30 mg Q12, who may not require monitoring).
• Measure peak anti-Xa levels 3-5 hours after the 3rd or 4th dose.
• Target a peak level of 0.2-0.4 IU/ml for patients on BID prophylactic SQ enoxaparin:
  • <0.2 IU/ml: increase by 10 mg per dose.
  • 0.41-0.5 IU/ml: decrease by 10 mg per dose.
  • >0.5 IU/ml: consider a greater reduction in dose.
• Target a peak level of ~0.2-0.5 IU/ml for patients on QD prophylactic enoxaparin. (29649055)

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contraindications to enoxaparin

• GFR <20 ml/min.
• HIT.

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indications/use of enoxaparin

• Enoxaparin is generally used as a default agent for DVT prophylaxis if the GFR is >20 ml/min. Advantages of LMWH heparin over unfractionated heparin include the following:
  • [1] Fewer injections (more humane for patients)
  • [2] Substantially reduced risk of HIT.
  • [3] More predictable pharmacokinetics with increased efficacy. (23782973)

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DVT prophylaxis with fondaparinux

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dose of fondaparinux

• 2.5 mg SQ QD.

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contraindications to fondaparinux

• GFR <30 ml/min.

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indications/use of fondaparinux

• [1] It may be useful if there is concern/history regarding HIT.
• [2] NSTEMI patients with no plan for cardiac catheterization.  2.5 mg fondaparinux provides both DVT prophylaxis and also treatment of NSTEMI based on the OASIS-5 trial (where fondaparinux 2.5 mg SQ was superior to a therapeutic dose of enoxaparin).
  • Further discussion of fondaparinux therapy in NSTEMI is here: 📖

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DVT prophylaxis with UFH (unfractionated heparin)

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dose

• Low body weight: 5000 IU q12 hrs.
• Usual dose: 5000 IU sq q8hr.
• Morbid obesity:
  • Consider scaling up the dose in proportion to the patient's weight
  • A commonly used dose is 7500 IU q8hr.
• Renal failure: no adjustment (the kidneys don't clear unfractionated heparin).

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contraindications

• [1] HIT.
• [2] No contraindication to use enoxaparin (as a rule, enoxaparin is favored over unfractionated heparin).

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indications/use

• Unfractionated heparin is the standard agent for DVT prophylaxis in renal failure (GFR <20 ml/min).

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DVT prophylaxis with apixiban

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dose

• Dose:  2.5 mg PO BID has been studied in RCTs.

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contraindications

• Renal dysfunction (GFR < 30 ml/min).
• Thrombocytopenia.
• Anticoagulants (other than 81 mg aspirin).
• There is a possibility that the patient may require a procedure in the near term.

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indications/use

evidence base

• A meta-analysis included three RCTs involving apixaban for DVT prophylaxis (ADOPT in medical patients and ADVANCE1 and ADVANCE2 in elective knee replacement patients). The ADOPT and ADVANCE2 trials compared apixaban 2.5 mg BID versus enoxaparin 40 mg daily, whereas ADVANCE1 compared apixaban 2.5 mg BID versus enoxaparin 30 mg BID. There were no differences in bleeding rates or venous thromboembolism (with trends that showed benefit favoring apixaban). (30082040)
• The ADOPT trial is the largest RCT involving medical patients. 4495 patients were randomized to receive apixaban 2.5 mg BID for 30 days or enoxaparin subcutaneously for 6-14 days.  The efficacy was equivalent (2.7% rate of thrombosis in the apixaban group versus 3.1% in the enoxaparin group). By day 30, there was an increased risk of major bleeding in patients treated with apixaban (0.47% vs. 0.19%, p=0.04). The actual data shows that the two agents are essentially equivalent – with the differences being caused by different durations of therapy (enoxaparin was utilized for a shorter duration of time; see figure below). (22077144) The finding that extending thromboprophylaxis with any agent will increase bleeding rates is consistent with the EXCLAIM trial, which compared shorter versus longer durations of therapy with enoxaparin (revealing that a longer duration increased the rate of bleeding events). (20621900)

current role of apixaban for DVT prophylaxis

• Apixaban is not generally a preferred agent for DVT prophylaxis. Especially in critically ill patients, accumulation may be highly problematic (if patients develop bleeding or require an emergent procedure).
• Apixaban could be a valid option if the following conditions are met:
  • [1] The patient refuses SQ injections.
  • [2] Moderate to high risk for venous thromboembolic disease.
  • [2] The patient is sufficiently stable to receive apixaban (e.g., stable renal function, no anticipated procedural needs).
• Heparin resistance is another situation in which apixaban could be a rational choice. If the patient previously required massive heparin doses to achieve therapeutic anticoagulation, it's doubtful that standard prophylactic doses of UFH or LMWH would be effective. (Heparin resistance is discussed further here: 📖)

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aspirin & DVT prophylaxis

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evidentiary support

• In 2000, the PEP trial involving 13,356 orthopedic surgery patients randomized patients to placebo versus aspirin 160 mg/day.  Aspirin reduced the risk of PE (by 43%) and the risk of symptomatic DVT (by 29%). (10776741)
• In 2016, the POISE-2 trial, involving 10,010 non-cardiac surgery patients, randomized patients to placebo versus aspirin (200 mg loading dose, then 100 mg daily). The hazard ratio for venous thromboembolic disease among patients treated with aspirin was not statistically significant (HR 0.89, 95% CI 0.61-1.28). The low degree of benefit may have reflected that two-thirds of patients also received anticoagulation.
• In 2022, the CRYSTAL trial, involving 9,711 patients status post hip or knee replacement, randomized patients to aspirin (100 mg/day) versus enoxaparin (40 mg/day). The rate of venous thromboembolic disease was higher among patients treated with enoxaparin (3.45% vs 1.82%, p=0.007).
• In 2023, the METRIC trial, involving 12,211 patients with extremity trauma, randomized patients to aspirin (81 mg/day) versus enoxaparin (30 mg BID). DVT occurred in 2.51% of patients in the aspirin group compared to 1.71% in the enoxaparin group (the difference wasn't statistically significant).

synthesis and clinical significance

• Aspirin moderately reduces the risk of venous thromboembolism (although it's probably less effective than LMWH). This reduction in VTE risk comes at the cost of a slight increase in the risk of bleeding.
• Aspirin has been studied primarily among surgical patients.
• Aspirin should not be initiated solely for DVT prophylaxis in medical patients.
• If a medical patient is on aspirin for another indication, the aspirin probably doesn't provide adequate DVT prophylaxis. However, concomitant aspirin might be a reason to consider more conservative dosing of heparin products.

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low-dose heparin infusion for DVT prophylaxis

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There is no high-quality evidence supporting this intervention, but it could be considered rarely in niche situations.

indications might include

• Patient refusing SQ injections who isn't a candidate for apixaban and has high VTE risk.
• Patient on high-dose vasopressors who clearly isn't perfusing their skin (and unlikely to absorb SQ medications).

nuts and bolts

• This is fairly simple to do (unlike with SQ heparin, there is no need to distinguish between peak and trough anti-Xa levels).
• Start an infusion of unfractionated heparin at 6 units/kg/hour without a bolus (this is one-third the typical dosing for a therapeutic heparin infusion).
• Check an anti-Xa level:
  • 8 hours after any adjustment to the heparin rate (including 8 hours after starting the infusion).
  • Daily in the AM.
• Adjust the infusion to target anit-Xa levels of 0.15-0.20. (15186625)

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nonpharmacological DVT prophylaxis

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mobilization 

• Mobilization is usually hugely beneficial for any patient.
• The main benefit is the prevention of reconditioning, but mobility might also reduce DVT risk.

intermittent pneumatic compression devices 

• These are safe and effective.
• It's doubtful that intermittent pneumatic compression adds significant benefit beyond chemical DVT prophylaxis. (PREVENT trial 30779530) Consequently, intermittent pneumatic compression devices should be utilized in patients with contraindications to chemical DVT prophylaxis. (ASH guidelines 30482763)
• ⚠️ Intermittent pneumatic compression devices only work if they are actually attached to the patient.

avoid prolonged femoral access

• A major problem with femoral lines is the risk of DVT.  Lines at other sites (particularly the IJ position) may cause DVT, but upper extremity DVTs are less likely to be life-threatening because the clot volume is smaller.
• Femoral venous access is excellent for an emergency.  However, once the dust settles, it is probably desirable to remove the femoral access (with placement of an upper extremity catheter if central access is still needed).

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questions & discussion

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