Venous%20thromboembolism%20-%20management Treatment

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

Phases of Anticoagulation in DVT

• Initial treatment phase up to 10 days with the aim of rapidly initiating anticoagulation to prevent progression of DVT and PE
• Principal treatment phase during the 1st 3 months to maintain therapeutic levels of anticoagulation to prevent DVT progression and PE, and reduce risk of early recurrent VTE
  • Anticoagulation for 3 months is recommended in patients with provoked proximal DVT with a major transient risk factor
• Extended treatment phase after 3 months of primary treatment to reduce long-term risk of recurrent VTE
  • Recommended for patients with 2nd or subsequent unprovoked DVT
  • Indefinite anticoagulation is recommended in patients with high risk of recurrence unless patient is with high risk of bleeding
    • Includes patients with active cancer, persistent major risk factor (eg rheumatic disorder, severe thrombophilia)
  • Extended anticoagulation is recommended in patients with medium risk of recurrence
    • Includes patients with recurrent VTE, unprovoked event, minor, soft and transient risk factor (eg travel), obesity, HF, chronic obstructive pulmonary disease (COPD), male gender 

General Therapy Principles Regarding Heparin

• 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 be started after consultation with surgeon and at 12-24 hours after major surgery
  • Treatment could be delayed even longer if there is any evidence of bleeding from the surgical site
• Similar initial and long-term treatment is recommended for asymptomatic DVT
• Protamine sulfate may be used for reversal of anticoagulation 

General Therapy Principles Regarding Anticoagulant Therapy

• For patients with DVT or PE, primary treatment 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 unprovoked, provoked by active cancer or antiphospholipid antibody syndrome or by a chronic risk factor: 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

Thrombus Removal

• Early thrombus removal strategies may be considered in patients with symptomatic iliofemoral DVT

Thrombolysis in Massive/Sub-massive PE

• 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 followed by 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 
• Catheter-directed thrombolytic therapy may also be considered in patients with massive iliofemoral DVT (weigh risk vs benefit) with symptoms of <14 days, limb-threatening DVT (phlegmasia cerulea dolens), good functional status, low risk of bleeding and ≥1-year life expectancy

Massive PE

• 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 (RV) thrombus or patent foramen ovale documented by echocardiography
  • Massive hemodynamically significant PE without systemic hypotension or profound hypoxemia

Sub-massive PE

• The use of thrombolytics in patients with sub-massive PE (hemodynamically stable patients with echocardiographic and/or biomarker evidence of 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
• Thrombolysis may be reasonably considered in select younger patients with sub-massive PE at low bleeding risk or for those with high decompensation risk because of concomitant cardiopulmonary disease 

Deep Vein Thrombosis and Non-massive Pulmonary Embolism

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
• Use for initial management of patients with phlegmasia cerulea dolens delivered in combination with aggressive leg elevation and fluid resuscitation
• Patients with confirmed PE and hemodynamic instability may be given continuous UFH infusion with thrombolytic therapy
• 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 
• May be a treatment option for VTE in patients with brain tumor
• Use for initial management of patients with phlegmasia cerulea dolens delivered in combination with aggressive leg elevation and fluid resuscitation
• 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 or established renal failure, and considered in patients with liver disease and coagulopathy
    • May also be given concurrently with a VKA for patients with active cancer or antiphospholipid syndrome
  • 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, bleeding risk is low and routine monitoring is not required
• Studies suggest that NOACs have a safety advantage over conventional therapy for VTE treatment in Asian patients
• May be given to patients with renal impairment or active cancer 
  • May be a treatment option for VTE in patients with brain tumor
• 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)
• For reversal of anticoagulation, Idarucizumab may be used for patients taking Dabigatran while Andexanet alfa may be used for patients taking Apixaban or Rivaroxaban 
  • Ciraparantag is an investigational agent that can bind and inhibit factor Xa inhibitors, UFH, LMWH, and Fondaparinux 

Apixaban

• Prior Heparin treatment is not necessary, though short courses of Heparin should be given when there is treatment delay 
• Considered as an alternative agent to LMWH for patients with cancer-associated thrombosis without high risk for GI or genitourinary bleeding

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) 

Rivaroxaban

• Initial treatment for both PE and DVT without additional anticoagulation
• A direct factor Xa 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) in 2 consecutive readings
  • 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, LMWH or dose-reduced Enoxaparin may be considered in patients with severe renal impairment, established renal failure or increased risk of bleeding
• Patients with antiphospholipid antibody syndrome are recommended to undergo indefinite VKA treatment 

Massive or Sub-massive Pulmonary Embolism

Thrombolytic Agents

Alteplase (Recombinant Tissue Plasminogen Activator [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

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
  • Counteract increased venous pressure and improve venous flow leading to reduction of edema and optimal calf muscle function
• 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
  • Use may be limited to 6-12 months in patients with proximal DVT and with limited signs and symptoms
• Should be used with caution in patients with post-thrombotic syndrome
• Contraindicated in patients with peripheral artery disease
• Some studies show the ineffectiveness of GECS for prophylaxis and they also cause lower extremity skin damage; thus, routine use of compression stockings is not recommended in patients with DVT, with or without an increased risk of post-thrombotic syndrome