Venous Thromboembolism - Management Management

Evaluation

Clinical Evaluation

A reasonable clinical suspicion (ie patient with VTE risk factors and prior history of DVT) is required to avoid missing the diagnosis of pulmonary embolism. Evaluating the likelihood of pulmonary embolism in an individual patient according to the clinical presentation is of utmost importance in the interpretation of diagnostic test results and the selection of an appropriate diagnostic strategy. A rapid diagnosis should be done with a CTPA or perfusion scan. A bedside transthoracic echocardiogram may be done in patients who are hemodynamically unstable to differentiate suspected high-risk pulmonary embolism from other acute life-threatening conditions. Patients should also be evaluated for risk factors for VTE. 

It is recommended to perform initial risk stratification in hemodynamically unstable patients with suspected or confirmed pulmonary embolism to identify those with a high risk of early mortality. Acute pulmonary embolism severity may be stratified using validated scores from combined clinical, laboratory, and imaging prognostic factors in patients who are hemodynamically stable. The Pulmonary Embolism Severity Index (PESI) identifies the patient's overall mortality risk using pulmonary embolism severity and comorbidity. It may be used to evaluate if the patient is appropriate for outpatient therapy. A score of ≥1 indicates a 30-day mortality risk of 10.9% in the simplified version of PESI (sPESI) and should be considered for initial inpatient therapy.  
 
Absolute Contraindications to Thrombolysis

The following are absolute contraindications to thrombolysis: 

• Hemorrhagic stroke or stroke of unknown origin at any time (including intracerebral hemorrhage)
• Major trauma, surgery, or head injury in the past 3 months
• Ischemic stroke within the past 6 months
• Central nervous system (CNS) damage or tumors, intracranial vascular lesions
• Severe coagulation disorders
• Active major bleeding
• Known increased risk for bleeding (severe bleeding diathesis)
• Suspected aortic dissection

Relative Contraindications to Thrombolysis 

The following are relative contraindications to thrombolysis:

• Transient ischemic attack within the past 6 months
• Puncture of a non-compressible vessel
• Uncontrolled severe hypertension (systolic blood pressure of >180 mmHg, diastolic blood pressure [DBP] of >100 mmHg)
• Neurosurgery or ophthalmologic surgery within the last 1 month
• Ischemic stroke within the last 2 months
• Gastrointestinal bleeding within the last 10 days
• Active peptic ulcer disease
• Recent traumatic cardiopulmonary resuscitation (CPR)
• Pregnancy or within 1 week postpartum 
• Infective endocarditis
• Oral anticoagulant therapy
• Advanced liver disease

Prompt Management of Clinical Instability

Hemodynamically unstable patients with pulmonary embolism may present with an SBP <90 mmHg for 15 minutes (requiring vasopressors) or over shock and with increased risk for right heart failure and death.

O₂ Supplementation  

O₂ supplementation may be necessary in patients with hypoxemia. Hypoxemia can usually be reversed with nasal O₂ so mechanical ventilation is rarely necessary.  

Mechanical Ventilation  

Mechanical ventilation may be needed temporarily in patients who appear toxic and hypoxic. Care should be taken to limit its hemodynamic adverse effects. Positive intrathoracic pressures induced by mechanical ventilation may reduce venous return and worsen RV failure. Low tidal volumes of approximately 6 mL/kg body weight are recommended.  

Hemodynamic Support  

Fluid Loading  

Fluids may be administered initially and cautiously, but other vasoactive therapies should promptly follow. The usefulness of fluid challenge is controversial and should not exceed 500 mL over 15 to 30 minutes. It may be harmful when systemic hypotension is present.  

Adrenergic Agonists  

Adrenergic agonists should be considered for patients with low cardiac index and normal blood pressure or with impending hypotension. In high-risk pulmonary embolism patients, Dobutamine and/or Norepinephrine should be considered.  

Please see Adrenergic Agonists under Pharmacological Therapy: Prompt Management of Clinical Instability for further information.  

Nitric Oxide Inhalation  

Nitric oxide inhalation may be indicated in patients with pulmonary hypertension and a patent foramen ovale. It may improve the hemodynamic status and gas exchange in patients with pulmonary embolism.

Principles of Therapy

All patients with acute VTE should undergo a bleeding risk assessment before starting anticoagulation therapy. The decision to start empirical anticoagulation while awaiting diagnostic confirmation should be guided by the level of clinical suspicion for VTE, the anticipated timing of tests results, and the patient’s risk of bleeding.

Phases of Anticoagulation in DVT  

The initial treatment phase is up to 10 days with the aim of rapidly initiating anticoagulation after a diagnosis of VTE to prevent the progression of DVT and pulmonary embolism. Delay in DVT treatment may result in loss of the patient’s limb, circulatory collapse, shock or death. 

The principal treatment phase is during the first 3 months to maintain therapeutic levels of anticoagulation to prevent DVT progression and pulmonary embolism and reduce the risk of early recurrent VTE. Anticoagulation for 3 months is recommended in patients with provoked proximal DVT with a major transient risk factor. Interruptions in anticoagulation should be minimized during the first 3 months due to the high risk of recurrent thrombosis. 

The extended treatment phase is after 3 months of primary treatment is given to reduce the long-term risk of recurrent VTE. It is recommended for patients with second or subsequent unprovoked DVT. Extended anticoagulation is recommended in patients with a medium risk of recurrence which includes patients with recurrent VTE, unprovoked event, minor, soft transient risk factors (eg travel), obesity, HF, COPD, and male gender. Indefinite anticoagulation is recommended in patients with a high risk of recurrence unless the patient is with a high risk of bleeding, including patients with active cancer or persistent major risk factors (eg rheumatic disorder, severe thrombophilia). 

General Therapy Principles Regarding Anticoagulant Therapy

Immediate therapeutic anticoagulation should be given in the first 24 hours as the recurrence rate for venous thromboembolism is higher if anticoagulation is non-therapeutic. Factors affecting choice of anticoagulant include hemodynamic stability, comorbidities, prior history of renal impairment and HIT, bleeding risk, anticipated need for discontinuation, patient preference and cost.

For patients with DVT or pulmonary embolism, the primary treatment of 3 months duration is recommended: 

• Proximal DVT or pulmonary embolism provoked by major surgery or trauma that is transient: Treatment is stopped after 3 months
• Proximal DVT or pulmonary embolism which is unprovoked or associated with a non-surgical transient risk factor: Treat for 3-6 months 
• Proximal DVT or pulmonary embolism 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

General Therapy Principles Regarding Heparin

Anticoagulation should be administered without delay in patients with intermediate or high clinical probability of pulmonary embolism during diagnostic workup and in low probability patients once pulmonary embolism is confirmed.  

If pulmonary embolism occurs postoperatively, Heparin therapy should be started after consultation with the 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 the reversal of anticoagulation. 

Criteria for Appropriate Setting for DVT Management

• Outpatient: Stable hemodynamic and clinical status, low bleeding risk, absence of severe renal function impairment, adequate home support for anticoagulation therapy, and monitoring for DVT and bleeding complications
• Inpatient: Massive DVT, high risk of bleeding on anticoagulation and comorbid conditions (eg concurrent pulmonary embolism)

Criteria for Outpatient Pulmonary Embolism Management

• No O₂ or narcotic requirement
• No respiratory distress
• No recent history of or risk factors for bleeding
• No serious comorbid conditions
• No concurrent DVT
• No needle aversion if low-molecular-weight Heparin (LMWH) is chosen
• Normal pulse, BP, and mental status
• Ready access to non-vitamin K antagonist oral anticoagulants (NOACs)
• Low risk of death on PESI or sPESI
• Have good home support and reliable hospital access

Thrombus Removal  

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

Thrombolysis in Massive or Sub-Massive Pulmonary Embolism  

High-risk pulmonary embolism 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 pulmonary embolism 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 versus benefit) or spontaneous proximal upper extremity thrombosis with symptoms of <14 days, limb-threatening DVT (phlegmasia cerulea dolens), good functional status, low risk of bleeding, and ≥1-year life expectancy. 

Massive Pulmonary Embolism  

The use of thrombolytic therapy in pulmonary embolism should be individualized. Patients with hemodynamically unstable pulmonary embolism who are at low risk of bleeding are the most appropriate candidates.  

Thrombolytic therapy may also be considered in patients with compromised oxygenation or worsening right HF; pre-resuscitation cardiopulmonary arrest; free-floating RV thrombus or patent foramen ovale documented by echocardiography; and massive hemodynamically significant pulmonary embolism without systemic hypotension or profound hypoxemia.  

Sub-massive Pulmonary Embolism  

The use of thrombolytics in patients with sub-massive pulmonary embolism (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 pulmonary embolism at low bleeding risk or for those with high decompensation risk because of concomitant cardiopulmonary disease.  

Please see Thrombolytic Agents under Pharmacological Therapy: Thrombolysis in Massive or Sub-massive Pulmonary Embolism for further information.

Pharmacological therapy

Oral Anticoagulants in the Management of DVT and Non-massive Pulmonary Embolism

NOACs  

Example drugs: Apixaban, Dabigatran, Edoxaban, Rivaroxaban  

NOACs are also known as direct oral anticoagulants (DOACs). They are the recommended anticoagulant agents for patients with leg DVT or pulmonary embolism during the first 3 months of therapy. They are preferred over vitamin K antagonists in eligible pulmonary embolism patients for the acute-phase treatment of low- or intermediate-risk pulmonary embolism. 

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. They may be given to patients with renal impairment or active cancer. They may also 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). Standard doses of Apixaban and Rivaroxaban may be considered in obese patients for VTE prophylaxis and treatment. For the 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  

When Apixaban is given, prior Heparin treatment is not necessary, though short courses of Heparin should be given when there is a treatment delay. Apixaban is considered an alternative agent to LMWH for patients with cancer-associated thrombosis without high risk for gastrointestinal or genitourinary bleeding. It is preferred for patients with coronary artery disease, dyspepsia, or history of gastrointestinal bleeding. It may be used in patients with end-stage renal disease without dose adjustment.  

Dabigatran etexilate  

Dabigatran etexilate is approved for the management of DVT and pulmonary embolism in patients who have been treated with parenteral anticoagulant for 5-10 days, and to reduce the risk of recurrent DVT and pulmonary embolism in patients who have been previously treated.  

Edoxaban  

Edoxaban may be used for the treatment of DVT and pulmonary embolism in patients who have been treated with parenteral anticoagulant for 5-10 days. It is preferred for patients with coronary artery disease. It is considered an alternative agent to LMWH for pulmonary embolism patients with cancer (except gastrointestinal cancer).  

Rivaroxaban  

Rivaroxaban is a direct factor Xa inhibitor that is non-inferior to Warfarin in the management of acute VTE. It is an initial treatment for both pulmonary embolism and DVT without additional anticoagulation. It is preferred for patients with coronary artery disease. It is considered an alternative agent to LMWH for pulmonary embolism patients with cancer (except gastrointestinal cancer).  

Warfarin  

Warfarin is a vitamin K antagonist and is used to reduce the risk of VTE recurrence and complications. It should only be started once VTE has been reliably confirmed. It is started 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 (eg Heparin) for at least 5 days until therapeutic INR is stable and >2.0 (range: 2.0-3.0) in 2 consecutive readings.  

A high-loading dose (>10 mg) of Warfarin is not recommended as it has no clinical use, and it predisposes patients to hemorrhage at the start of therapy. Overdose may be reversed with vitamin K administration, 4-factor prothrombin complex concentrate, or fresh frozen plasma.

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. A vitamin K antagonist is preferred for patients with coronary artery disease or history of gastrointestinal bleeding. Warfarin may be used as an alternative in patients where there are concerns about the limited availability of reversal agents. Patients with antiphospholipid antibody syndrome are recommended to undergo indefinite vitamin K antagonist treatment.

Parenteral Anticoagulants in the Management of DVT and Non-massive Pulmonary Embolism

LMWH and Unfractionated Heparin (UFH)

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

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 reducing mortality and the risk of major bleeding during initial therapy.  

LMWH is preferred over UFH in patients with acute non-massive pulmonary embolism and it is also preferred over vitamin K antagonists. LMWH or Fondaparinux is recommended over UFH for the acute-phase treatment of low- or intermediate-risk pulmonary embolism.  

It may be a treatment option for VTE in patients with brain tumors. It is also used for the initial management of patients with phlegmasia cerulea dolens delivered in combination with aggressive leg elevation and fluid resuscitation. Weight-based LMWH dose is recommended for obese patients with acute VTE.  

Patients with symptomatic pulmonary embolism 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 and effective and 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, and in pregnancy. It may also be given concurrently with a vitamin K antagonist for patients with active cancer or antiphospholipid syndrome. Outpatient management of DVT should be extended to include stable patients with stable pulmonary embolism who have been carefully screened for risk factors for hemorrhage. Laboratory monitoring is not required except for a regular platelet count before treatment initiation and on the fifth day, then every 2-3 days if LMWH treatment is continued. 

UFH  

Intravenous UFH treatment in pulmonary embolism is well-established. UFH should be considered as a first-dose bolus; for massive or sub-massive pulmonary embolism; without delay in suspected high-risk pulmonary embolism patients with hemodynamic instability; and when rapid reversal of effect may be required.  

It may also be given to patients with obesity or poor absorption (eg anasarca, massive edema), high bleeding risks, receiving thrombolysis, or undergoing invasive procedures. It is used for the initial management of patients with phlegmasia cerulea dolens delivered in combination with aggressive leg elevation and fluid resuscitation. Patients with confirmed pulmonary embolism and hemodynamic instability may be given continuous UFH infusion with thrombolytic therapy. UFH is preferred over LMWH in patients with severe renal failure.  

Intravenous UFH has been proven effective in the therapy of pulmonary embolism and DVT. Studies have shown a reduced mortality rate when UFH has been used to treat VTE disease. The recurrence of VTE is unusual when UFH is infused at a rate that prolongs the aPTT >1.5-2.5 times the control value and when adequate levels are reached within 24 hours. 

Intravenous UFH typically requires hospitalization with close laboratory monitoring and dose adjustment. The most common complication is HIT.  
 
Fondaparinux  

Fondaparinux, a selective inhibitor of activated factor X (Xa), is also a preferred initial treatment for DVT and pulmonary embolism. It may be used as an alternative to Heparin in patients with HIT. Heparin assay (anti-factor Xa) has been used to monitor the effects of Fondaparinux. Warfarin is initiated usually within 72 hours of therapy. A platelet count should be obtained prior to the start of therapy.  

Duration of Therapy  

Treatment with LMWH, UFH 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 to 3.0) for 2 consecutive days.   

Prompt Management of Clinical Instability  

Adrenergic Agonists  

Dobutamine  

Dobutamine is considered a first-line agent to treat right-sided HF and cardiogenic shock. It affects vasodilatation of both systemic and pulmonary vascular beds and increases myocardial contractility while decreasing right-sided filling pressures.  

Dopamine  

Dopamine has also been used for hemodynamic support in pulmonary embolism patients. Its use may be limited by the development of tachycardia.  

Epinephrine  

Epinephrine may be effective when shock complicates acute pulmonary embolism. Its vasoconstrictor effect is similar to Norepinephrine. Its inotropic effect is more due to potent β₁ stimulation rather than the β₂ effect, accounting for improved pulmonary vascular resistance.  

Norepinephrine  

Norepinephrine may be appropriate in acute massive pulmonary embolism when there is profound hypertension (eg cardiogenic shock). Norepinephrine stimulates both α-adrenergic (inducing vasoconstriction) and β₁-adrenergic receptors (augmenting cardiac contractility) resulting in improved systemic blood pressure, cardiac output, pulmonary vascular resistance, and RV pressure. A combination with other vasoactive agents (eg Dobutamine) needs further evaluation.  

Thrombolysis in Massive or Sub-Massive Pulmonary Embolism  

Thrombolytic Agents  

Alteplase (Recombinant Tissue Plasminogen Activator [rt-PA])  

Alteplase has comparable thrombolytic capacity to Streptokinase and Urokinase but can be administered for a shorter duration (2 hours). It is the preferred thrombolytic agent because of its shorter administration time.  

Streptokinase or Urokinase  

Streptokinase and Urokinase have similar thrombolytic effects in pulmonary embolism and have been shown to resolve pulmonary embolism comparatively at 24 hours and 3x that as seen with Heparin alone. 12 hours of Urokinase has equivalent thrombolytic efficacy to 24 hours of Streptokinase.

Venous Thromboembolism - Management_Management 2

Nonpharmacological

Patient Education  

Educate patients and their families about DVT or pulmonary embolism, especially its signs and symptoms, risk of recurrence of disease, risk of long-term disability, and the possibility of genetic predisposition. Explain the treatment options to patients and discuss the benefits, risks, and side effects of anticoagulation therapy. Discuss lifestyle issues with patients and advise patients to drink plenty of fluids. The lay public may not be familiar with pulmonary embolism and discussing it may assuage their emotional burden.  

Bed Rest and Leg Elevation  

The affected extremity should be elevated above the level of the heart until edema and tenderness subside.  

Early Ambulation  

Early ambulation is preferred over bed rest when feasible in patients with acute DVT.  

Exercise  

Encourage patients confined to a chair or bed to perform regular leg exercises.  

Graduated Elastic Compression Stockings (GECS)  

Graduated elastic compression stockings provide continuous stimulation of blood flow and prevent dilation of the venous system in the legs. It counteracts increased venous pressure and improves venous flow leading to the reduction of edema and optimal calf muscle function.  

Graduated elastic compression stockings combined with early ambulation do not increase the chances of developing pulmonary embolism and provide faster resolution of pain and swelling. It is recommended to start at 1 month of diagnosis of proximal DVT until a minimum of 2 years to prevent postthrombotic syndrome. Graduated compression, knee-high, custom-fitted stockings with at least 30 to 40 mmHg on the affected leg may be used. Use may be limited to 6-12 months in patients with proximal DVT and with limited signs and symptoms.  

Venous Thromboembolism - Management_Management

Surgery

Invasive Procedures

In patients with cardiac arrest or refractory circulatory collapse, extracorporeal membrane oxygenation (ECMO) may be considered in combination with a catheter-directed treatment or surgical embolectomy.  

Catheter Extraction  

Catheter extraction involves the suction extraction of pulmonary embolism under fluoroscopy with ECG monitoring. This approach should be reserved for highly compromised patients who cannot receive thrombolytic therapy or whose status is so critical that it does not allow time to infuse thrombolytic therapy.  

Pulmonary Embolectomy 

Pulmonary embolectomy is performed in emergency situations when more conservative measures have failed. It should be reserved for the following patients:

• Massive pulmonary embolism (preferably angiographically documented) 
• Hemodynamic instability despite Heparin and resuscitation
• High-risk pulmonary embolism or hemodynamically deteriorating patients with failure of thrombolytic therapy or contraindication to its use

Thrombectomy  

Percutaneous Venous Thrombectomy  

Patients with acute DVT should not be treated with percutaneous thrombectomy alone.  

Surgical Venous Thrombectomy  

Surgical venous thrombectomy reduces acute symptoms and postthrombotic morbidity in patients with acute iliofemoral DVT. These patients have extensive venous thrombosis and have contraindications for anticoagulation and thrombolytic therapy.  

Vena Caval Interruption  

Inferior Vena Caval (IVC) Filters  

Inferior vena caval filters should be considered in DVT or pulmonary embolism patients with failure, contraindication or complication of anticoagulant therapy and in patients with large, free-floating iliocaval thrombus, with a proximal DVT that developed during surveillance or with a pulmonary embolism that developed during anticoagulation therapy. Contraindications to anticoagulation are reassessed and once mitigated, initiation of anticoagulation is attempted. If successful, anticoagulation is administered for at least 3 months and evaluation for removal of IVC filter is done (usually 4 weeks after initiation of anticoagulation). Consider removing the inferior vena caval filter if anticoagulation has been established and is no longer contraindicated.  

Inferior vena caval may also be considered in patients who suffer from recurrent VTE despite adequate anticoagulant therapy and patients with chronic recurrent embolism with pulmonary hypertension. It may be indicated after surgical embolectomy or pulmonary thromboendarterectomy.

It is preferable in patients with proximal DVT with active hemorrhage, platelet count <50,000 x 10⁹/L, or previous intracerebral hemorrhage. It should not be used routinely in patients with DVT who are also being treated with anticoagulants.