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VENOUS THROMBOEMBOLISM - MANAGEMENT
Deep vein thrombosis is a frequent manifestation of venous thromboembolism in which there is a blood clot blocking a deep vein.
Clinical findings are important to the diagnosis of deep vein thrombosis but are poor predictors of the presence or severity of thrombosis.
Pulmonary embolism is the blockage of the blood vessels in the lungs usually due to blood clots from the veins, especially veins in the legs and pelvis.
Dyspnea, pleuritic chest pain, syncope and tachypnea occur in most cases of pulmonary embolism.
Massive pulmonary embolism has the prime symptom of dyspnea and systemic arterial hypotension, that requires pressor support, is the predominant sign.

Principles of Therapy

Deep Vein Thrombosis (DVT) and Non-massive Pulmonary Embolism (PE)

Parenteral Anticoagulant Therapy

  • Anticoagulation should be administered without delay in patients with intermediate or high clinical probability of PE during diagnostic workup and in low probability patients once PE is confirmed
  • If PE occurs postoperatively, Heparin therapy should not be started until 12-24 hours after major surgery and after consultation with surgeon
    • Treatment could be delayed even longer if there is any evidence of bleeding from the surgical site
  • Same initial and long-term treatment is recommended for asymptomatic DVT

Oral Anticoagulant Therapy

  • For patients with DVT or PE, long-term management of 3 months duration is recommended
    • Proximal DVT or PE provoked by major surgery or trauma that is transient: Treatment is stopped after 3 months
    • Proximal DVT or PE which is unprovoked or associated with a non-surgical transient risk factor: Treat for 3-6 months 
    • Proximal DVT or PE which is recurrent and provoked by active cancer or antiphospholipid antibody syndrome: Treat with extended anticoagulation 
    • Distal DVT provoked by a transient risk factor: Treat for 6 weeks   
    • Distal DVT which is unprovoked or with persisting risk factors: Treatment is stopped after 3 months

Thrombolysis in Massive/Sub-massive Pulmonary Embolism

  • High-risk PE patients are recommended to receive systemic thrombolytic therapy 
  • Patients with hemodynamic deterioration on anticoagulation therapy are recommended to undergo rescue thrombolytic treatment
  • Studies have shown a more rapid improvement in radiographic and hemodynamic abnormalities in acute massive PE patients who received thrombolytic agents and anticoagulant agents over conventional anticoagulant agents alone
    • There were no clinically relevant outcomes for death rate or for the resolution of symptoms
  • Treatment started within 48 hours of symptom onset provides the most benefit, though thrombolysis can still be used in those who are symptomatic for 6-14 days 
  • May also be considered in younger patients with massive iliofemoral thrombosis (weigh risk versus benefit)

Massive Pulmonary Embolism

  • The use of thrombolytic therapy in PE should be individualized
    • Patients with hemodynamically unstable PE who are at low risk of bleeding are the most appropriate candidates
  • Thrombolytic therapy may also be considered in patients with the following:
    • Compromised oxygenation
    • Free-floating right ventricular thrombus or patent foramen ovale documented by echocardiography
    • Massive hemodynamically significant PE without systemic hypotension or profound hypoxemia

Sub-massive Pulmonary Embolism

  • The use of thrombolytics in patients with sub-massive PE [hemodynamically stable patients with echocardiographic evidence of right ventricular (RV) dysfunction] is controversial
    •  Further studies are needed to show a clinically relevant improvement in the benefit-risk ratio of thrombolytic treatment over traditional anticoagulant therapy in these patients

Pharmacotherapy

Deep Vein Thrombosis (DVT) and Non-massive Pulmonary Embolism (PE)

Parenteral Anticoagulant Therapy

  • Both subcutaneous (SC) LMWH and intravenous (IV) UFH short-course treatments are recommended for objectively confirmed non-massive PE
    • Either LMWH or UFH is appropriate for the initial treatment of PE
    • It is not recommended to give UFH or LMWH monotherapy in patients with severe renal impairment (CrCl <30 mL/min) 

Unfractionated Heparin (UFH)

  • IV UFH treatment in PE is well-established
  • UFH should be considered:
    • As a 1st-dose bolus
    • For massive/sub-massive PE
    • Without delay in suspected high-risk PE patients with hemodynamic instability
    • When rapid reversal of effect may be required
  • May also be given to patients with high bleeding risks, receiving thrombolysis, or undergoing invasive procedures
  • UFH is preferred over LMWH in patients with severe renal failure
  • Effects: IV UFH has been proven effective in the therapy of PE and DVT 
    • Studies have shown a reduced mortality rate when UFH has been used to treat VTE disease
    • Recurrence of VTE is unusual when UFH is infused at a rate that prolongs the activated partial thromboplastin time (aPTT) >1.5 times the control value and when adequate levels are reached within 24 hours
  • IV UFH typically requires hospitalization with close lab monitoring and dose adjustment
  • Most common complication is Heparin-induced thrombocytopenia

Low-Molecular-Weight Heparin (LMWH)

  • LMWH should be used whenever possible for the initial inpatient treatment of DVT rather than UFH
    • LMWH is superior to UFH for the initial treatment of DVT in terms of reducing mortality and the risk for major bleeding during the initial therapy
  • LMWH is now preferred over UFH in patients with acute non-massive PE 
    • Also preferred over vitamin K antagonists (VKA)
  • LMWH or Fondaparinux is recommended over UFH for the acute-phase treatment of low- or intermediate-risk PE 
  • A number of studies have shown that LMWH has equal efficacy to UFH in patients with non-massive PE
  • Patients with symptomatic PE should initially be treated in the hospital because of decreased cardiorespiratory reserve, complications and for monitoring of international normalized ratio (INR) to guide Warfarin therapy
  • The use of LMWH is safe, effective, may shorten hospital stay and improve the quality of life for patients
    • Monotherapy with LMWH may be used in patients with active cancer and considered in patients with liver disease and coagulopathy
    • Outpatient management of DVT should be extended to include stable patients with stable PE who have been carefully screened for risk factors for hemorrhage
  • Lab monitoring is not required except for a regular platelet count before treatment initiation and on the 5th day, then every 2-3 days if LMWH treatment is continued

Fondaparinux

  • Also a preferred initial treatment for DVT and PE
  • Heparin assay (anti-factor Xa) has been used to monitor effects of Fondaparinux
  • Warfarin is initiated usually within 72 hours of therapy
  • Obtain a platelet count prior to the start of therapy

Duration of Therapy

  • Treatment with UFH, LMWH, or Fondaparinux should be continued for at least 5-7 days after the initiation of Warfarin and until therapeutic INR is stable and ≥2.0 (range: 2.0-3.0) for 2 consecutive days

Oral Anticoagulant Therapy

Non-Vitamin K Antagonist Oral Anticoagulants (NOACs)

  • Eg Apixaban, Dabigatran, Edoxaban, Rivaroxaban
  • Also known as direct oral anticoagulants (DOACs) 
  • Recommended anticoagulant agents for patients with leg DVT or PE during the 1st 3 months of therapy
    • Preferred over VKA in eligible PE patients for the acute phase treatment of low- or intermediate risk PE
  • Drug interactions are few and routine monitoring is not required
  • Studies suggest that NOACs have a safety advantage over conventional therapy for VTE treatment in Asian patients
  • Apixaban and Rivaroxaban are given according to the single-drug approach (monotherapy) while Dabigatran and Edoxaban should be given after initial treatment with Heparin (dual therapy)

Apixaban

  • Prior Heparin treatment is not necessary, though short courses of Heparin should be given when there is treatment delay 

Dabigatran etexilate

  • Approved for the management of DVT and PE in patients who have been treated with parenteral anticoagulant for 5-10 days, and to reduce risk of recurrent DVT and PE in patients who have been previously treated

Edoxaban

  • May be used for treatment of DVT and PE in patients who have been treated with parenteral anticoagulant for 5-10 days
  • Considered as an alternative agent to LMWH for PE patients with cancer (except GI cancer) 
  • Should only be used in patients with high creatinine clearance (>95 mL/minute)

Rivaroxaban

  • Initial treatment for both PE and DVT without additional anticoagulation
  • A direct factor X inhibitor that is non-inferior to Warfarin in the management of acute VTE 
  • Considered as an alternative agent to LMWH for PE patients with cancer (except GI cancer)

Warfarin

  • Warfarin is a VKA and is used to reduce the risk of VTE recurrence and complications
  • Should only be started once VTE has been reliably confirmed
    • Start on day 1 of Heparin therapy
  • Bolus dose is not effective, therefore it requires at least 5 days to achieve its full effects
    • Thus, it is recommended that Warfarin therapy overlap with parenteral anticoagulation at least 4-5 days until therapeutic INR is stable and >2.0 (range: 2.0-3.0)
    • Warfarin high loading dose (>10 mg) is not recommended as it has no clinical use and it predisposes patients to hemorrhage at start of therapy
    • Overdose may be reversed easily with vitamin K administration 
  • Warfarin overlapping with UFH or dose-reduced Enoxaparin may be considered in patients with severe renal impairment 
  • Patients with antiphospholipid antibody syndrome are recommended to undergo indefinite VKA treatment 

Massive or Sub-massive Pulmonary Embolism

Thrombolytic Agents

Alteplase (rt-PA)

  • Has comparable thrombolytic capacity to Streptokinase and Urokinase but can be administered for a shorter duration (2 hours)
  • Preferred thrombolytic agent because of its shorter administration time

Streptokinase or Urokinase

  • These 2 agents have similar thrombolytic effects in PE and have been shown to resolve PE comparatively at 24 hours and 3x that as seen with Heparin alone
  • 12 hours of Urokinase have equivalent thrombolytic efficacy to 24 hours of Streptokinase

Non-Pharmacological Therapy

Bed Rest and Leg Elevation

  • Affected extremity should be elevated above the level of the heart until edema and tenderness subside

Early Ambulation

  • Preferred over bed rest when feasible in patients with acute DVT

Exercise

  • Encourage patients confined to a chair or bed to perform regular leg exercise

Graduated Elastic Compression Stockings (GECS)

  • Provide continuous stimulation of blood flow and prevent dilation of venous system in the legs
  • GECS combined with early ambulation does not increase PE and provides faster resolution of pain and swelling
  • Recommended to start at 1 month of diagnosis of proximal DVT until a minimum of 2 years to prevent post-thrombotic syndrome
    • Use graduated compression knee-high custom-fitted stockings with at least 30-40 mmHg on the affected leg
  • Should be used with caution in patients with postthrombotic syndrome
  • Contraindicated in patients with peripheral artery disease
  • Although some studies show the ineffectiveness of GECS for prophylaxis and they also cause lower extremity skin damage 

 

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