Venous%20thromboembolism%20-%20management Treatment
Principles of Therapy
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
Pharmacotherapy
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
- Monotherapy with LMWH may be used in patients with active cancer or established renal failure, and considered in patients with liver disease and coagulopathy
- 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
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
- 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