Anticoagulation Decreases Risk of Deep Venous Thrombosis Recurrence and the Decreases the Mortality Rate (Lancet, 1960) [MEDLINE]
In Patients Admitted for Acute Pulmonary Embolism Through the Emergency Department, Early Anticoagulation was Associated with Decreased Mortality Rate (Chest, 2010) [MEDLINE]: n = 400 emergency department patients with acute pulmonary embolism (treated with unfractionated heparin from 2002-2005)
Overall, the In-Hospital Mortality Rate was 3.0% and 30-Day Mortality Rate was 7.7% in the Study
Patients Who Received Heparin in the Emergency Department Had Decreased In-Hospital Mortality Rate (1.4% vs 6.7%; P = 0.009) and Decreased 30-Day Mortality Rate (4.4% vs 15.3%; P < 0.001), as Compared to Patients Who Received Heparin After Admission
Patients Who Achieved a Therapeutic PTT within 24 hrs Had Decreased In-Hospital Mortality Rate (1.5% vs 5.6%; P = 0.093) and Decreased 30-Day Mortality Rate (5.6% vs 14.8%; P = .037), as Compared to Patients Who Achieved a Therapeutic PTT After 24 hrs
In Multiple Logistic Regression Models, Receiving Heparin in the Emergency Department Remained Predictive of Decreased Mortality Rate, and Intensive Care Unit Admission Remained Predictive of Increased Mortality Rate
Large Prospective Cohort Study of the Effects of Anticoagulation on Major Cardiovascular Events in Patients with Venous Thromboembolism (Chest, 2022) [MEDLINE]: n = 3,790
Treatment of Venous Thromboembolism for >3 Months was Associated with a Decreased Risk of Major Cardiovascular Events (Non-Fatal Acute Coronary Syndrome, Non-Fatal Stroke, and All-Cause Mortality)
Treatment of Venous Thromboembolism with Direct Oral Anticoagulant (DOAC) vs Coumadin was Associated with Decreased Risk of Major Cardiovascular Events
Prevention of Late Complications of Venous Thromboembolism
Prevention of Recurrent Deep Venous Thrombosis (DVT)
Anticoagulation Decreased Risk of DVT Recurrence and Mortality Rate (Lancet, 1960) [MEDLINE]
Anticoagulation Decreased the Risk of Recurrent Venous Thromboembolism to 3.4% and Risk of Fatal Venous Thromboembolism to 0.4% (Ann Intern Med, 2010) [MEDLINE]
Systematic Review and Meta-Analysis of Anticoagulation Regimens for Venous Thromboembolism (JAMA, 2014) [MEDLINE]: n = 45 trials (44,989 patients)
No Statistically Significant Differences (in Terms of Safety/Efficacy) Between Anticoagulation Regimens (Low Molecular Weight Heparin/Coumadin, Unfractionated Heparin/Coumadin, Fondaparinux/Coumadin, Low Molecular Weight Heparin with Dabigatran/Edoxaban, Apixaban, Rivaroxaban, or Low Molecular Weight Heparin Alone)
Combination of Unfractionated Heparin/Coumadin Appeared to Have the Highest Risk of Venous Thromboembolism Recurrence (Hazard Ratio 1.42)
Apixaban/Rivaroxaban Regimens were Associated with the Lowest Risk of Hemorrhage
Clinical Features Which May Influence the Choice of Specific Initial/Long-Term Anticoagulants (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) (Chest, 2016) [MEDLINE] (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) (Chest, 2021) [MEDLINE]
Direct Oral Anticoagulants and Low Molecular Weight Heparins are Contraindicated with Severe Renal Insufficiency
Dosing of Direct Oral Anticoagulants are Variable, Dependent on the Agent
Systematic Review/Meta-Analysis Comparing Rates of Hemorrhage of Novel Oral Anticoagulants vs Coumadin When Used in the Setting of Renal Insufficiency (Chest, 2016) [MEDLINE]
CrCl 50-80 mL/min: direct oral anticoagulants had a significantly decreased risk of major bleeding, as compared to coumadin
CrCl <50 mL/min: direct oral anticoagulants had a non-significantly decreased risk of major bleeding, as compared to coumadin
Apixaban Had the Lowest Rate of Major Bleeding in this Subgroup
There is a More Extensive Clinical Experience with Unfractionated Heparin Use in Patients Treated with Thrombolytic Therapy
Cost/Coverage Issues
Preferred Agents
Variable
Clinical Data
Cost-Effectiveness of Rivaroxaban Compared to Enoxaparin/Coumadin in Treatment of Venous Thrombembolism (J Med Econ, 2014) [MEDLINE]
Rivaroxaban Cost $2,448 Per-Patient Less and was Associated with 0.0058 More QALY’s, as Compared with Enoxaparin + Coumadin
Cost-Effectiveness of Novel Oral Anticoagulants, Compared to Coumadin, in Non-Valvular Atrial Fibrillation and Venous Thromboembolism (J Med Econ, 2015) [MEDLINE]
Medical Costs are Reduced When Direct Oral Anticoagulants are Used Instead of Coumadin for the Treatment of Non-Valvular Atrial Fibrillation/Venous Thromboembolism, with Apixaban Being Associated with the Greatest Reduction in Medical Costs
UK Study of Cost-Effectiveness of Rivaroxaban Compared to Enoxaparin/Coumadin in Treatment of Venous Thrombembolism (Thromb J, 2015) [MEDLINE]
Rivaroxaban was a Cost-Effective Choice for Acute Treatment of Venous Thromboembolism and Secondary Prevention of Venous Thromboembolism, as Compared with Low Molecular Weight Heparin/Coumadin Treatment, Regardless of the Treatment Duration
Requirements for Initial Parenteral Anticoagulation with Specific Long-Term Anticoagulants
Parenteral Anticoagulation is Indicated Prior to Coumadin (see Coumadin)
Conversion from Parenteral Anticoagulation to Coumadin
Coumadin Should Be Started Concurrently with Parenteral Anticoagulation, Rather Than Waiting (Grade 2C Recommendation) (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]: start coumadin 5 mg qday (with a lower dose used in elderly or those with a high risk of bleeding, malnutrition, debility, congestive heart failure, or liver disease)
Coumadin Should Be Overlapped with Parenteral Anticoagulation for at Least 4-5 Days
Parenteral Anticoagulation Can Be Discontinued When INR Remains >2 for at Least 2 Consecutive Days
Parenteral Anticoagulation is Indicated Prior to Dabigatran (Pradaxa) (see Dabigatran)
Conversion from Unfractionated Heparin Drip/Argatroban Drip to Dabigatran: start dabigatran as soon as heparin drip is stopped
Conversion from Low Molecular Weight Heparin (Enoxaparin, Dalteparin, Tinzaparin) or Fondaparinux to Dabigatran: start dabigatran approximately 2 hrs prior to next scheduled dose of subcutaneous anticoagulant
Parenteral Anticoagulation is Indicated Prior to Edoxaban (Savaysa, Lixiana) (see Edoxaban)
Conversion from Unfractionated Heparin/Argatroban Drip to Edoxaban (Savaysa, Lixiana): discontinue heparin/argatroban drip and initiate edoxaban 4 hrs later
Conversion from Low Molecular Weight Heparin (Enoxaparin, Dalteparin, Tinzaparin) to Edoxaban: discontinue low molecular weight heparin and initiate edoxaban at the time of the next scheduled administration of low molecular weight heparin
Parenteral Anticoagulation is Not Indicated Prior to Apixaban (Eliquis)/Rivaroxaban (Xarelto) (see Apixaban and Rivaroxaban): monotherapy with these agents is considered safe and effective when administered as monotherapy (without heparin pre-treatment) to outpatients
EINSTEIN Trial Demonstrated that in Acute Symptomatic Deep Venous Thrombosis, Rivaroxaban “Monotherapy” was Non-Inferior to Enoxaparin (SQ) Followed by Coumadin (NEJM, 2010) [MEDLINE]
AMPLIFY Trial Demonstrated that in Acute Symptomatic Venous Thromboembolism, Apixaban “Monotherapy” was Non-Inferior to Enoxaparin (SQ) Followed by Coumadin and was Associated with Significantly Lower Risk of Bleeding (NEJM, 2013) [MEDLINE]
Parenteral Anticoagulant Dosing in Morbid Obesity (see Obesity)
Dosing Weight = Ideal Body Weight + 0.3 (Actual Body Weight – Ideal Body Weight)
Dosing weight = Ideal Body Weight + 0.4 (Actual Body Weight – Ideal Body Weight)
Long-Term Treatment of Venous Thromboembolism (Deep Venous Thrombosis of Acute Pulmonary Embolism) without Cancer
Agents
First-Line Agents (Oral Anticoagulants)
General Comments
Risk of Bleeding with DOAC’s (and Particularly Intracranial Bleeding) is Less with DOAC’s than with Coumadin Therapy (Chest, 2021) [MEDLINE]
On the Basis of Patients with Atrial Fibrillation, Gastrointestinal Bleeding May Be Higher with Dabigatran, Edoxaban, and Rivaroxaban than with Coumadin Therapy, Although This Has Not Been Seen in Patients with Venous Thromboembolism (Chest, 2021) [MEDLINE]
However, on the Basis of Indirect Comparisons and Studies Reporting on DOAC’s for the Treatment of Cancer-Associated Thrombosis, the Risk of Bleeding May Be Lower with Apixaban than with Other DOAC’s (Chest, 2021) [MEDLINE]
Specific Reversal Agents for DOAC’s Have Been Approved (Yet Even Before the Availability of These, the Risk that a Major Bleed Will Be Fatal Appears to Be No Higher for DOAC’s than for Coumadin Therapy) (Chest, 2021) [MEDLINE]
Direct Comparison Between DOAC’s is Very Limited, But Suggests that Apixaban May Carry a Lower Risk of Bleeding than Other DOAC’s (Chest, 2021) [MEDLINE]
Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
For Patients with Venous Thromboembolism, Use of Direct Oral Anticoagulants (DOAC’s) is Recommended Over Coumadin (Conditional Recommendation, Moderate Certainty in the Evidence)
This Recommendation May Not Apply to Patients with the Following
For Patients with Venous Thromboembolism, There is No Recommendation of One DOAC Over Another (Conditional Recommendation, Very Low Certainty in the Evidence)
Factors Which May Influence the Selection of a Specific DOAC
Cancer
Concomitant Medications (Need for a Concomitant Drug Metabolized Through the CYP3A4 Enzyme or P-Glycoprotein)
Once vs Twice Daily Dosing
Out-of-Pocket Cost
Renal Function
Requirement for Lead-In Parenteral Anticoagulation
For Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism with Stable Cardiovascular Disease Who Initiate Anticoagulation and were Previously Taking Aspirin for Cardiovascular Risk Modification, Suspending Aspirin is Recommended Over Continuing it for the Duration of Anticoagulation Therapy (Conditional Recommendation, Very Low Certainty in the Evidence)
A Critical Review of the Indication for Aspirin Therapy is Needed at the Time Anticoagulant Therapy is Initiated, Considering the Increased Risk of Bleeding vs the Potential Benefit in Terms of Cardiovascular Prevention
This Recommendation Does Not Apply to Patients with a Recent Acute Coronary Event or Coronary Intervention
In Patients with Venous Thromboembolism (Lower Extremity Deep Venous Thrombosis or Acute Pulmonary Embolism), Apixaban/Dabigatran/Edoxaban/Rivaroxaban are Recommended Over Coumadin as the Treatment-Phase (First 3 Months) Anticoagulant Therapy (Strong Recommendation, Moderate-Certainty Evidence)
Long-Term Treatment of Venous Thromboembolism with Cancer
Agents
First-Line Agents (Oral Xa Inhibitors)
General Comments
Risk of Bleeding with DOAC’s (and Particularly Intracranial Bleeding) is Less with DOAC’s than with Coumadin Therapy (Chest, 2021) [MEDLINE]
On the Basis of Patients with Atrial Fibrillation, Gastrointestinal Bleeding May Be Higher with Dabigatran, Edoxaban, and Rivaroxaban than with Coumadin Therapy, Although This Has Not Been Seen in Patients with Venous Thromboembolism (Chest, 2021) [MEDLINE]
However, on the Basis of Indirect Comparisons and Studies Reporting on DOAC’s for the Treatment of Cancer-Associated Thrombosis, the Risk of Bleeding May Be Lower with Apixaban than with Other DOAC’s (Chest, 2021) [MEDLINE]
Specific Reversal Agents for DOAC’s Have Been Approved (Yet Even Before the Availability of These, the Risk that a Major Bleed Will Be Fatal Appears to Be No Higher for DOAC’s than for Coumadin Therapy) (Chest, 2021) [MEDLINE]
In Patients with Venous Thromboembolism and Cancer (Cancer-Associated Thrombosis, There is a Higher Risk for Recurrence as Well as a Higher Risk for Major Bleeding than in Patients with Venous Thromboembolism without Cancer (Chest, 2021) [MEDLINE]
Systematic Review and Meta-Analysis of Treatment of Venous Thromboembolism in Patients with Cancer (Lancet Oncol, 2008) [MEDLINE]
Long-Term Full-Dose Low Molecular Weight Heparin is More Effective than Coumadin in the Secondary Prophylaxis of Venous Thromboembolism in Patients with Cancer of Any Stage, Performance Status, or Prognosis
Optimum Treatment Duration is Unclear, But Because the Prothrombotic Tendency Will Persist in Patients with Advanced Cancer, Indefinite Treatment is Generally Recommended
Unblinded, Comparative Effectiveness, Noninferiority Randomized CANVAS Trial of Direct Oral Anticoagulants vs Low Molecular Weight Heparin in Patients with Diagnosis of New Venous Thromboembolism and Cancer (JAMA, 2023) [MEDLINE]: n = 638 (from 67 oncology practices in the US)
Rates of Recurrent Venous Thromboembolism were 6.1% in the Direct Oral Anticoagulant Group and 8.8% in the Low Molecular Weight Heparin Group (Difference -2.7%; 1-sided 95% CI: -100% to 0.7%) Consistent with the Prespecified Noninferiority Criterion
Of the 6 Prespecified Secondary Outcomes, None were Statistically Significant
Major Bleeding Occurred in 5.2% of Participants in the Direct Oral Anticoagulant Group and 5.6% in the Low Molecular Weight Heparin Group (Difference -0.4%; 1-sided 95% CI: -100% to 2.5%) and Did Not Meet the Noninferiority Criterion
Severe Adverse Events Occurred in 33.8% of Participants in the Direct Oral Anticoagulant Group and 35.1% in the Low Molecular Weight Heparin Group
The Most Common Serious Adverse Events were Anemia and Death
Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
For Patients with Venous Thromboembolism, Use of Direct Oral Anticoagulants (DOAC’s) is Recommended Over Coumadin (Conditional Recommendation, Moderate Certainty in the Evidence)
This Recommendation May Not Apply to Patients with the Following
For Patients with Venous Thromboembolism, There is No Recommendation of One DOAC Over Another (Conditional Recommendation, Very Low Certainty in the Evidence)
Factors Which May Influence the Selection of a Specific DOAC
Cancer
Concomitant Medications (Need for a Concomitant Drug Metabolized Through the CYP3A4 Enzyme or P-Glycoprotein)
Once vs Twice Daily Dosing
Out-of-Pocket Cost
Renal Function
Requirement for Lead-In Parenteral Anticoagulation
In Patients with Venous Thromboembolism (Lower Extremity Deep Venous Thrombosis or Acute Pulmonary Embolism) in the Setting of Cancer (Cancer-Associated Thrombosis), Oral Xa Inhibitors (Apixaban, Edoxaban, Rivaroxaban) are Recommended Over Low Molecular Weight Heparin for the Initiation and Treatment Phases of Anticoagulant Therapy (Strong Recommendation, Moderate-Certainty Evidence)
Edoxaban and Rivaroxaban Appear to Be Associated with a Higher Risk of Gastrointestinal Major Bleeding than Low Molecular Weight Heparins in Patients with Cancer-Associated Thrombosis and a Luminal Gastrointestinal Malignancy, While Apixaban Does Not
Consequently, Apixaban or Low Molecular Weight Heparins May Be the Preferred Options in Patients with Luminal Gastrointestinal Malignancies
Specific Duration of Anticoagulation
General Comments
Subgroups of Patients with Venous Thromboembolism (Chest, 2021) [MEDLINE]
Venous Thromboembolism Provoked by Surgery (a Major Transient Risk Factor): 3% recurrence rate at 5 yrs
Venous Thromboembolism Provoked by a Nonsurgical Transient Risk Factor (Estrogen Therapy, Pregnancy, Leg Injury, Flight of >8 hrs): 15% recurrence rate at 5 yrs
Unprovoked (Idiopathic) Venous Thromboembolism (Not Meeting Criteria for Provocation by a Transient Risk Factor or by Cancer): 30% recurrence rate at 5 yrs
Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
For Primary Treatment of Patients with Venous Thromboembolism (Whether Provoked by a Transient Risk Factor or by a Chronic Risk Factor or Unprovoked, Use of a Shorter Course of Anticoagulation for Primary Treatment (3-6 mos) is Recommended Over a Longer Course of Anticoagulation for Primary Treatment (6-12 mos) (Conditional Recommendations, Moderate Certainty in the Evidence
These Recommendations are Intended to Address the Duration of Primary Anticoagulant Treatment for All Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism, Defined as the Minimal Length of Time for Treatment of the Initial Venous Thromboembolism
Most Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by Temporary Risk Factors Will Discontinue Anticoagulant Therapy After Completion of the Primary Treatment
In Contrast, Many Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by Chronic Risk Factors, as Well as Patients with Unprovoked Deep Venous Thrombosis and/or Acute Pulmonary Embolism, May Continue Anticoagulant Therapy Indefinitely for Secondary Prevention After Completion of the Primary Treatment
However, if Patient and Clinician Decides to Stop Anticoagulation, Use of a Longer Course of Primary Anticoagulant Therapy (6-12 mos) is Not Recommended
For Selected Patients with a Chronic Risk Factor for Which Some Improvement is Expected Over Time (Due to Improved Mobility with Rehabilitation, etc), a Longer Course of Anticoagulation for the Primary Treatment Phase (6-12 mos) Could Be Justified
For Patients with Unprovoked Deep Venous Thrombosis and/or Acute Pulmonary Embolism, Routine Use of Prognostic Scores, D-Dimer Testing, or Ultrasound to Detect Residual Vein Thrombosis are Not Recommended to Guide the Duration of Anticoagulation (Conditional Recommendations, Very Low Certainty in the Evidence)
Indefinite Anticoagulation is Probably Appropriate for the Majority of Patients with Unprovoked Venous Thromboembolism
However, in Certain Circumstances, Such as When Patients are Undecided or the Balance Between Risks and Benefits is Uncertain, Clinicians and Patients May Use Prognostic Scores, D-Dimer Testing, or Ultrasound Assessment for Residual Thrombosis from an Initial Deep Venous Thrombosis to Aid in Reaching a Final Decision
After Completion of Primary Treatment of Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by a Chronic Risk Factor, Indefinite Antithrombotic Therapy is Recommended Over Stopping Anticoagulation (Conditional Recommendation, Moderate Certainty in the Evidence)
Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by a Transient Risk Factor Typically Do Not Require Antithrombotic Therapy after Completion of Primary Treatment
This Recommendation Refers to Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by a Chronic Persistent Risk Factor
However, This Recommendation Does Not Apply to Patients Who Have a High Risk for Bleeding Complications
After Completion of Primary Treatment for Patients with Unprovoked Deep Venous Thrombosis and/or Acute Pulmonary Embolism, Indefinite Antithrombotic Therapy is Recommended Over Stopping Anticoagulation (Conditional Recommendation, Moderate Certainty in the Evidence)
This Recommendation Does Not Apply to Patients Who Have a High Risk for Bleeding Complications
For Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Who Have Completed Primary Treatment and Will Continue to Receive Secondary Prevention, the Use of Anticoagulation is Recommended Over Aspirin (Conditional Recommendation, Moderate Certainty in the Evidence)
For Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Who Have Completed Primary Treatment and Will Continue Coumadin as Secondary Prevention, the Use of International Normalized Ratio (INR) Range of 2-3 is Recommended Over a Lower INR Range (1.5-1.9) (Strong Recommendation, Moderate Certainty in the Evidence)
For Patients with Deep Venous Thrombosis and/or Acute Pulmonary Embolism Who Have Completed Primary Treatment and Will Continue with a DOAC for Secondary Prevention, Use of Either a Standard-Dose DOAC or a Lower-Dose DOAC is Recommended (Conditional Recommendation, Moderate Certainty in the Evidence)
Lower-Dose DOAC Regimens Which May Be Considered for Patients Who Have Completed Primary Treatment and Will Continue with a DOAC Include the Following
In Patients with Acute Venous Thromboembolism Who Do Not Have a Contraindication, a 3 Month Treatment Phase of Anticoagulation is Recommended (Strong Recommendation, Moderate-Certainty Evidence)
Upon Completion of the 3 Month Treatment Phase of Therapy, All Patients Should Be Assessed for Extended-Phase Therapy
In Patients with Venous Thromboembolism Diagnosed in the Setting of a Major Transient Risk Factor, Extended-Phase Anticoagulation is Not Recommended (Strong Recommendation, Moderate-Certainty Evidence)
Confinement to Bed in Hospital (Only “Bathroom Privileges”) for ≥3 Days with an Acute Illness
Surgery with General Anesthesia for >30 min
In Patients with Venous Thromboembolism Diagnosed in the Setting of a Minor Transient Risk Factor, Extended-Phase Anticoagulation is Not Recommended (Weak Recommendation, Moderate-Certainty Evidence)
Minor Transient Risk Factors
Admission to Hospital for <3 Days with an Acute Illness
Confinement to Bed Out of Hospital for ≥3 Days with an Acute Illness
Leg Injury Associated with Reduced Mobility for ≥3 Days
In Patients with Venous Thromboembolism Diagnosed in the Absence of Transient Provocation (Unprovoked Venous Thromboembolism or Provoked by Persistent Risk Factor), Extended-Phase Anticoagulation with a DOAC is Recommended (Strong Recommendation, Moderate-Certainty Evidence)
In Patients with Venous Thromboembolism Diagnosed in the Absence of Transient Risk Factor (Unprovoked Venous Thromboembolism or Provoked by a Persistent Risk Factor) Who Cannot Receive a DOAC, Extended-Phase Anticoagulation with Coumadin is Recommended (Weak Recommendation, Moderate-Certainty Evidence)
The Recommendation to Offer Extended-Phase Anticoagulation Would Not Automatically Imply that All Patients with Unprovoked Venous Thromboembolism Receive Extended Therapy
Patient Preference and Predicted Risk of Recurrent Venous Thromboembolism or Bleeding Should Also Influence the Decision to Proceed with, or Continue, Extended-Phase Anticoagulation Therapy
Patients Who Receive Extended-Phase Anticoagulation Should Have This Decision Reevaluated at Least Annually, and at Times of Significant Change in Health Status
Extended-Phase anticoagulation Does Not Have a Predefined Stop Date
However, Studies of Extended-Phase anticoagulation Monitored Patients for Durations of About 2-4 yrs
Although Most Patients in These Studies Did Not Stop Anticoagulation Therapy at the End of Follow-Up, the Risk-to-Benefit Balance of Continuing Extended Anticoagulation Therapy Beyond THis Time is Uncertain
In Patients Offered Extended-Phase Anticoagulation, Use of Reduced-Dose Apixaban (2.5 mg BID) or Rivaroxaban (10 mg qday) is Recommended Over Full-Dose Apixaban or Rivaroxaban (Weak Recommendation, Very Low-Certainty Evidence)
In Patients Offered Extended-Phase Anticoagulation, Reduced-Dose DOAC (Apixaban 2.5 mg BID or Rivaroxaban 10 mg qday) is Recommended Over Aspirin or No Therapy (Strong Recommendation, Low-Certainty Evidence) and Rivaroxaban is Recommended Over Aspirin (Weak Recommendation, Moderate-Certainty Evidence)
Rivaroxaban is the Only DOAC to Be Directly Compared to Aspirin for Secondary Prevention of Venous Thromboembolism
Several Other DOACs, as Well as Coumadin, are Also Acceptable for Secondary Prevention (Extended-Phase Therapy) After Venous Thromboembolism
In Patients with an Unprovoked Proximal Deep Venous Thrombosis or Acute Pulmonary Embolism Who are Stopping Anticoagulation and Do Not Have a Contraindication to Aspirin, Aspirin is Recommended Over No Aspirin to Prevent Recurrent Venous Thromboembolism (Weak Recommendation, Low-Certainty Evidence)
Because Aspirin Has Been Shown to Be Much Less Effective at Preventing Recurrent Venous Thromboembolism than Anticoagulants, and Because Some Anticoagulants Confer a Similar Risk of Bleeding to Aspirin, We Do Not Consider Aspirin a Reasonable Alternative to Anticoagulation in Patients Who Want Extended Therapy
However, if a Patient Has Decided to Stop Anticoagulation, Prevention of Recurrent Venous Thromboembolism is One of the Benefits of Aspirin Which Needs to Be Balanced Against Aspirin’s Risk of Bleeding and Inconvenience
Use of Aspirin Should Also Be Reevaluated
Specific Treatment of Acute Pulmonary Embolism with Hypotension
Therapeutic Choices
Systemic Thrombolytic Therapy
Systemic Thrombolytic Therapy Accelerates Resolution of Pulmonary Embolism (with More Rapid Lowering of Pulmonary Artery Pressure, Improved Hypoxemia, and Resolution of Perfusion Scan Defects)
However, Systemic Thrombolytic Therapy Also Increases the Risk of Hemorrhage
Catheter-Based Thrombus Removal Without Thrombolytic Therapy (Suction Thrombectomy)
Commercial Suction Thrombectomy Catheters
FlowTriever: 20 Fr sheath
Indigo: 4/6/8 Fr sheath
Catheter-Based (Mechanical-Only) Techniques for Thrombus Removal Involve Fragmentation of the Thrombus Using Various Types of Catheters (Some of Which are Designed for this Purpose)
Thrombus Fragmentation Results in Distal Displacement of the Thrombus with/without Suctioning and Removal of Some of the Thrombus Through the Catheter
Catheter-Directed Thrombolysis Uses Approximately 33% of the Dose of Thrombolytic That Systemic Thrombolysis Uses (Lowering the Risk of Hemorrhage in Brain, Gastrointestinal Trac, etc)
Catheter-Directed Thrombolysis Achieves Higher Local Concentrations of Thrombolytics at the Site of the Pulmonary Embolism and Also Facilitates Thrombus Fragmentation and Permeability Via the Catheter
Systematic Review of Venoarterial Extracorporeal Membrane Oxygenation in Massive Acute Pulmonary Embolism (Crit Care Med, 2021) [MEDLINE]
Venoarterial Extracorporeal Membrane Oxygenation Has an Emerging Role in the Management of Massive Acute Pulmonary Embolism-Related Cardiac Arrest with 61% Survival
Systemic Thrombolysis Preceding Venoarterial Extracorporeal Membrane Oxygenation Did Not Confer a Statistically Significant Increase in the Risk of Death, Yet Age >65 y/o and Cannulation During Cardiopulmonary Resuscitation were Associated with a 3-Fold and 6-Fold Risks of Death, Respectively
Absolute Contraindications to Systemic Thrombolytic Therapy (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
History of Ischemic Cerebrovascular Accident (CVA) within Last 3 mos (Excluding Cerebrovascular Accident within the Last 3-4.5 hrs) (see Ischemic Cerebrovascular Accident)
Malignant Intracranial Neoplasm
History of Traumatic Brain Injury (TBI)/Facial Trauma within Last 3 mos (see Traumatic Brain Injury)
Severe Uncontrolled Hypertension on Presentation (Systolic BP >180 mm Hg, Diastolic BP >100 mm Hg)
Traumatic/Prolonged (>10 min) Cardiopulmonary Resuscitation (CPR) within Last 3 wks (see Cardiopulmonary Resuscitation)
For Streptokinase/Anistreplase, Prior Exposure (>5 Days Prior) or Prior Allergic Reaction to these Agents
Clinical Efficacy of Systemic Thrombolysis in Acute Pulmonary Embolism
Meta-Analysis of Thrombolyis in Acute PE (JAMA, 2014) [MEDLINE]: meta-analysis (16 trials, n = 2115)
Thrombolysis Decreased the Mortality Rate (2.17%), as Compared to Anticoagulation Alone (3.89%)
No Mortality Benefit was Observed in Patients >65 y/o, a Population in Whom the Risk of Hemorrhage was the Greatest
Thrombolysis Decreased the Risk of Recurrent PE (1.17%) as Compared to Anticoagulation Alone (3.04%)
Thrombolysis Increased the Risk of Major Hemorrhage (9.2%), as Compared to Anticoagulation Alone (3.4%)
No Significant Difference in Major Hemorrhage in Patients ≤65 y/o
Thrombolysis Increased the Risk of Intracranial Hemorrhage (1.5%), as Compared to Anticoagulation Alone (0.2%)
PEITHO Trial of Thrombolytics in Intermediate-Risk Pulmonary Embolism (NEJM, 2014) [MEDLINE]: RCT of tenecteplase (n = 1006), intention-to-treat analysis in normotensive, intermediate-risk PE patients (RV dysfunction on Echo or CT, elevated serum troponin)
Thrombolysis Decreased Hemodynamic Decompensation (2.6%), as Compared to Placebo Group (5.6%)
Thrombolysis (1.2%) Had No Impact on 7-Day Mortality Rate, as Compared to Placebo Group (1.8%)
Thrombolysis Had No Impact on the 30-Day Mortality Rate
Thrombolysis Increased the Risk of Major Hemorrhage and Stroke
Death or Hemodynamic Decompensation Occurred in 2.6% of Patients in the Tenecteplase Group vs 5.6% of Patients in the Placebo Group (Odds Ratio 0.44; 95% Confidence Interval: 0.23-0.87; P = 0.02)
Mean Time Between Randomization and Death/Hemodynamic Compensation was 1.79 ± 1.6 Days in the Heparin Only (Placebo) Arm
Therefore, in Patients with Intermediate Risk Acute Pulmonary Embolism, Anticoagulation with Unfractionated Heparin/Low Molecular Weight Heparin for 2-3 Days Seems Reasonable Before Switching to Oral Anticoagulation (Eur Heart J, 2020) [MEDLINE]
Clinical Efficacy of Catheter-Directed Therapy in Acute Pulmonary Embolism
Catheter-Based Thrombus Removal Without Thrombolytic Therapy (Suction Thrombectomy)
Percutaneous Mechanical Thrombectomy with the FlowTriever System was Safe and Effective in Patients with Acute Intermediate-Risk Pulmonary Embolism, with Significant Improvement in RV/LV Ratio and Minimal Major Bleeding
Indigo
EXTRACT PE Trial (JACC Cardiovasc Interv, 2021) [MEDLINE]
In this Prospective, Multicenter Study, the Indigo Aspiration System was Associated with a Significant Reduction in the RV/LV Ratio and a Low Major Adverse Event Rate in Submassive Pulmonary Embolism
Intraprocedural Thrombolytic Drugs were Avoided in 98.3% of Patients
Catheter-Directed Thrombolysis
EkoSonic
ULTIMA Randomized Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis in Acute Pulmonary Embolism (Circulation, 2014) [MEDLINE]:
In Intermediate Risk Patients, Catheter-Directed Thrombolysis was Superior to Anticoagulation Alone in Reversing Right Ventricular Dilatation at 24 hrs (With No Increase in Risk of Bleeding Complications)
SEATTLE II Trial (JACC Cardiovasc Interv, 2015) [MEDLINE]
Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis Decreased RV Dilation, Reduced Pulmonary Hypertension, Decreased Anatomic Thrombus Burden, and Minimized Intracranial Hemorrhage in Patients with Acute Massive and Submassive Pulmonary Embolism
Treatment with Using a Ultrasound Catheter-Directed Thrombolysis with Shorter Delivery Duration and Lower-Dose tPA was Associated with Improved Right Ventricular Function and Reduced Clot Burden, as Compared with baseline
Major Bleeding Rate was Low, But One Intracranial Hemorrhage Event Did Occur
Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]
High-Risk Acute Pulmonary Embolism (Characterized by Hemodynamic Instability)
In Suspected High-Risk Acute Pulmonary Embolism, Intravenous Anticoagulation with Unfractionated Heparin (Including Weight-Adjusted Bolus) is Recommended without Delay (Class I, Level C)
Systemic Thrombolytic Therapy is Recommended (Class I, Level B)
In Patients in Whom Thrombolysis is Contraindicated or Has Failed, Surgical Pulmonary Embolectomy is Recommended (Class I, Level C)
In Patients in Whom Thrombolysis is Contraindicated or Has Failed, Percutaneous Catheter-Directed Treatment Should Be Considered (Class IIa, Level C)
Norepinephrine and/or Dobutamine Should Be Considered (Class IIa, Level C)
In Patients with Refractory Circulatory Collapse or Cardiac Arrest, Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO) May Be Considered, in Combination with Surgical Embolectomy or Catheter-Directed Treatment (Class IIb, Level C)
In Patients with Hemodynamic Deterioration on Anticoagulation Treatment, Rescue Thrombolytic Therapy (Class I, Level B) or Alternatively, Surgical Embolectomy or Percutaneous Catheter-Directed Treatment (Class IIa, Level C), are Recommended
Recommendations for Systemic Thrombolysis (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]
Consider Full-Dose Systemic Thrombolytics in the Following Groups
High-Risk Acute Pulmonary Embolism without Contraindications to Systemic Thrombolytics
Consider Reduced-Dose Systemic Thrombolytics in the Following Groups
High-Risk Acute Pulmonary Embolism with Relative Contraindications to Thrombolysis
Selected Intermediate to High-Risk Acute Pulmonary Embolism with Evidence of or Risk of Clinical Deterioration Based on Vital Signs, Severity of Right Ventricular Dysfunction, Tissue Perfusion, and/or Gas Exchange, and Presence of Low Bleeding Risk
Consider Systemic Thrombolytics in Patients with Cardiac Arrest and Suspected Acute Pulmonary Embolism
Consider Systemic Thrombolytics in Selected Patients with Intermediate or High-Risk Acute Pulmonary Embolism with Thrombus-in-Transit
Recommendations for Catheter-Directed Therapy (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]
Consider Catheter-Directed Thrombolysis in the Following Groups
Intermediate to High-Risk Acute Pulmonary Embolism with Risk for Clinical Deterioration Based on Vital Signs, Severity of Right Ventricular Dysfunction, Tissue Perfusion, and/or Gas Exchange, and without Absolute Contraindication to Thrombolysis
High-Risk Acute Pulmonary Embolism with Relative Contraindications to Systemic Thrombolysis<
Consider Catheter Embolectomy in the Following Groups
Intermediate to High-Risk Acute Pulmonary Embolism with Risk for Clinical Deterioration Based on Vital Signs, Severity of Right Ventricular Dysfunction, Tissue Perfusion, and/or Gas Exchange, with Absolute or Relative Contraindications to Thrombolysis
High-Risk Acute Pulmonary Embolism with Absolute Contraindications to Systemic Thrombolysis
After Failed Systemic Thrombolysis or Catheter-Directed Thrombolysis
Thrombus-in-Transit in the Right Atrium or Right Ventricle (AngioVac System)
Recommendations for Surgical Embolectomy (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]
High-Risk Acute Pulmonary Embolism with Contraindications to, or Failure of Systemic Thrombolysis or Catheter-Directed Thrombolysis
Intermediate to High Risk Acute Pulmonary Embolism, with Contraindications to, or Failure of Systemic Thrombolysis or Catheter-Directed Thrombolysis, with Risk for Clinical Deterioration Based on Vital Signs, Severity of Right Ventricular Dysfunction, Tissue Perfusion, and/or Gas Exchange
Right Heart Thrombi, Especially with Large Thromboembolic Burden
Thrombus-in-Transit Across a Patent Foramen Ovale (PFO)
Recommendations for Mechanical Hemodynamic Support (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]
Consider Mechanical Mechanical Hemodynamic Support in High-Risk Acute Pulmonary Embolism with Cardiac Arrest, Refractory Shock, and/or Contraindications to or Failure of Systemic Thrombolysis
Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
For Patients with Acute Pulmonary Embolism and Hemodynamic Compromise, Use of Thrombolytic Therapy Followed by Anticoagulation is Recommended Over Anticoagulation Alone (Strong Recommendation, Low Certainty in the Evidence
In this Case, the High Mortality of Patients with Acute Pulmonary Embolism and Hemodynamic Compromise, as Well as the Potential Lifesaving Effect of Thrombolytics, Warranted a Strong Recommendation
For Patients with Acute Pulmonary Embolism with Echocardiography and/or Biomarkers Compatible with Right Ventricular Dysfunction But without Hemodynamic Compromise (Submassive Pulmonary Embolism), Anticoagulation Alone is Recommended Over the Routine Use of Thrombolysis in Addition to Anticoagulation (Conditional Recommendation, Low Certainty in the Evidence
Thrombolysis is Reasonable to Consider for Submassive Pulmonary Embolism and Low Risk for Bleeding in Selected Younger Patients or for Patients at High Risk for Decompensation Due to Concomitant Cardiopulmonary Disease
Patients with Submassive Pulmonary Embolism Should Be Monitored Closely for the Development of Hemodynamic Compromise
For Patients with Acute Pulmonary Embolism in Whom Thrombolysis is Considered Appropriate, Use of Systemic Thrombolysis is Recommended Over Catheter-Directed Thrombolysis (Conditional Recommendation, Very Low Certainty in the Evidence)
This Recommendation Reflects Uncertainty About Catheter-Directed Thrombolysis for Acute Pulmonary Embolism Rooted in the Paucity of Randomized Trial Data and Variability in Procedural Experience Across Centers
In Centers with the Appropriate Infrastructure, Clinical Staff, and Procedural Experience, Catheter-Directed Thrombolysis May Be an Alternative to Systemic Thrombolysis, Especially for Patients with an Intermediate to High Risk for Bleeding, Because the Total Dose and Duration of Administration of Thrombolytic Agents are Lower When Delivered by Catheter
In Patients with Acute Pulmonary Embolism Associated with Hypotension (Systolic Blood Pressure <90 mm Hg) Who Do Not Have a High Bleeding Risk, Systemic Thrombolytic Therapy is Recommended (Weak Recommendation, Low-Certainty Evidence)
Studies of Systemically Administered Thrombolytic Therapy Have Utilized Different Agents at Varying Doses
Due to Lack of Comparative Data Between These Approaches, No Agent/Dosing Strategy is Favored Over Another
In Most Patients with Acute Pulmonary Embolism Which is Not Associated with Hypotension, Systemic Thrombolytic Therapy is Not Recommended (Strong Recommendation, Low-Certainty Evidence
In Selected Patients with Acute Pulmonary Embolism Who Clinically Deteriorate After Starting Anticoagulation But Have Yet to Develop Hypotension and Who Have an Acceptable Bleeding Risk, Systemically Administered Thrombolytic Therapy is Recommended (Weak Recommendation, Low-Certainty Evidence)
Deterioration (Which Has Not Resulted in Hypotension) May Include Any of the Following
Progressive Tachycardia
Decrease in Systolic Blood Pressure (But Remains >90 mm Hg)
Increase in Jugular Venous Pressure
Worsening Gas Exchange
Signs of Shock (Cold Sweaty Skin, Reduced Urine Output, Confusion)
Progressive Right Heart Dysfunction (on Echocardiogram)
Increase in Cardiac Biomarkers
In Patients with Acute Pulmonary Embolism Who are Treated with a Thrombolytic Agent, Systemic Thrombolytic Therapy Using a Peripheral Vein is Recommended Over Catheter-Directed Thrombolysis (Weak Recommendation, Low-Certainty Evidence)
No Randomized Trials or Observational Studies Have Compared Contemporary Catheter-Assisted Thrombus Removal with Systemic Thrombolytic Therapy
In Patients with Acute Pulmonary Embolism Associated with Hypotension Who Also Have High Bleeding Risk, Failed Systemic Thrombolysis, or Shock Which is Likely to Cause Death Before Systemic Thrombolysis Can Take Effect (within Hours), if Appropriate Expertise and Resources are Available, Catheter-Directed Therapy is Suggested (Weak Recommendation, Low-Certainty Evidence)
Specific Treatment of Asymptomatic Acute Pulmonary Embolism
Rationale
Asymptomatic Pulmonary Embolism is Diagnosed in About 1% of Outpatients and About 4% of Inpatients Who Have Contrast-Enhanced Chest CT Scans (Chest, 2021) [MEDLINE]
Most Asymptomatic Pulmonary Emboli are Found in Patients with Known Malignancy and are Reported on CT Scans Which Have Been Obtained for Another Indication (Such as Cancer Staging, Surveillance, or Treatment Response Evaluation) (Chest, 2021) [MEDLINE]
About 50% Involve the Lobar or More Central Pulmonary Arteries, While the Remaining 50% Involve More Distal Pulmonary Arteries (Chest, 2021) [MEDLINE]
In Patients Who are Incidentally Found to Have Asymptomatic Pulmonary Embolism, the Standard Initiation and Treatment with Anticoagulation is Recommended, as for Patients with Symptomatic Acute Pulmonary Embolism (Weak Recommendation, Moderate-Certainty Evidence
Specific Treatment of Acute Subsegmental Pulmonary Embolism
Rationale/Background
Improvements in Computed Tomography (CT Angiography) Have Led to Increased Diagnosis of Subsegmental Pulmonary Emboli
Subsegmental Pulmonary Emboli Have Increased from Approximately 5% to >10% of All Detected Pulmonary Emboli
Due to Small Size of Subsegmental Pulmonary Emboli, They are More Likely to Be a False-Positive Finding than a Pulmonary Embolism in the Segmental/More Proximal Pulmonary Arteries
Subsgmental Pulmonary Embolism is More Likely to Be a Real Finding if the Following Features are Present
Computed Tomography (CT) Pulmonary Artery Angiogram is of High Quality with Good Opacification of the Distal Pulmonary Arteries
Presence of Multiple Intraluminal Defects
Defects Involve More Proximal (Larger) Subsegmental Arteries
Defects are Seen on >1 Image
Defects are Surrounded by Contrast, Rather than Adherent to Pulmonary Artery Walls
Defects are Seen on >1 Projection
Patient is Symptomatic (as Opposed to Pulmonary Embolism Being an Incidental Finding)
Presence of High Clinical Pretest Probability for Pulmonary Embolism
Elevated Plasma D-Dimer without Another Explanation
Since a True Subsegmental Pulmonary Embolism is Likely to Have Arisen From a Small Deep Venous Thrombosis, the Risk of Progressive or Recurrent Venous Thromboembolism Without Anticoagulation is Expected to Be Lower Than in Patients with a Larger Pulmonary Emboli
Subsequent Evaluation of Acute Subsegmental Pulmonary Embolism Should Include Lower Extremity Venous Doppler Studies to Classify the Patient According to One of the Following
Subsegmental Acute Pulmonary Embolism + No Lower Extremity Proximal Deep Venous Thrombosis + Low Risk of Recurrent Venous Thromboembolism
Factors Associated with Low Risk of Recurrent Venous Thromboembolism
Absence of Active Cancer
Normal Mobility
Outpatient Status
Presence of Reversible Risk Factor for Venous Thromboembolism (Recent Surgery, etc)
Clinical Surveillance (with Serial Lower Extremity Dopplers, etc) is Recommended Over Anticoagulation (Weak Recommendation, Low-Certainty Evidence)
Presence of High Risk of Bleeding May Favor Clinical Surveillance Strategy Over Anticoagulation
Subsegmental Acute Pulmonary Embolism + No Lower Extremity Proximal Deep Venous Thrombosis + High Risk of Recurrent Venous Thromboembolism
Factors Associated with High Risk of Recurrent Venous Thromboembolism
Active Cancer (Especially if Metastatic or on Chemotherapy)
Decreased Mobility
Hospitalization
Absence of Reversible Risk Factor for Venous Thromboembolism (Recent Surgery, etc)
Anticoagulation is Recommended Over Clinical Surveillance (Weak Recommendation, Low-Certainty Evidence)
Presence of Low Cardiopulmonary Reserve May Favor Anticoagulation Over Surveillance Strategy
Specific Treatment of Low-Risk Acute Pulmonary Embolism
Criteria
Criteria for Outpatient Treatment of Acute PE (or Early Discharge to Home)
Clinically Stable with Good Cardiopulmonary Reserve
No Specific Contraindications, Such as Recent Bleeding, Severe Renal Disease, Severe Liver Disease, or Severe Thrombocytopenia (Platelets <70k)
Patient is Expected to be Compliant with Treatment
Patient Feels Well Enough to Be Treated at Home
Other Criteria-Pulmonary Embolism Severity Index (PESI): score <85
Other Criteria-Simplified Pulmonary Embolism Severity Index (Simplified PESI): score 0
Other Factors Which Might Merit Inpatient Treatment Instead of Outpatient Treatment
Increased Cardiac Biomarker Levels
Presence of Right Ventricular Dysfunction Recommendations (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) (Chest, 2021) [MEDLINE]
In Patients with Low-Risk Acute Pulmonary Embolism, Outpatient Treatment is Recommended (Provided There is Access to Medications, Ability to Access Outpatient Care, and Adequate Home Circumstances (Strong Recommendation, Low-Certainty Evidence)
Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]
Carefully Selected Patients with Low-Risk Acute Pulmonary Embolism Should Be Considered for Early Discharge and Continuation of Treatment at Home, if Proper Outpatient Care and Anticoagulant Treatment Can Be Provided (Class IIa, Level A)
Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
For Patients with Acute Pulmonary Embolism with a Low Risk for Complications, Offering Home Treatment is Recommended Over Hospital Treatment (Conditional Recommendation, Very Low Certainty in the Evidence
At Best, Clinical Prediction Scores Have a Moderate Ability to Predict Patient Outcomes and, Therefore, Do Not Replace Clinical Judgment
However, They May Help to Select Patients at Low Risk for Complications
Pulmonary Embolism Severity Index (PESI) and Simplified PESI Have Been the Most Widely Validated Scores
This Recommendation Does Not Apply to Patients Who Have Other Conditions Which Might Require Hospitalization, Have Limited or No Home Support, Cannot Afford Medications, or Have a History of Poor Compliance
Patients with Submassive Pulmonary Embolism (Intermediate-High Risk) or Massive Pulmonary Embolism (High-Risk) or at High Risk for Bleeding and Those Requiring Intravenous Analgesics May Benefit from Initial Treatment in the Hospital
Specific Treatment of Recurrent Venous Thromboembolism While Not on Anticoagulation
Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
For Patients Who Develop Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by a Transient Risk Factor and Have a History of Previous Unprovoked Venous Thromboembolism or Venous Thromboembolism Provoked by a Chronic Risk Factor, Use of Indefinite Antithrombotic Therapy is Recommended Over Stopping Anticoagulation After Completing Primary Treatment (Conditional Recommendation, Moderate Certainty in the Evidence)
For Patients Who Develop Deep Venous Thrombosis and/or Acute Pulmonary Embolism Provoked by a Transient Risk Factor and Have a History of a Previous Venous Thromboembolism Also Provoked by a Transient Risk Factor, Stopping Anticoagulation After Completion of Primary Treatment is Recommended Over Indefinite Antithrombotic Therapy (Conditional Recommendation, Moderate Certainty in the Evidence
For Patients with a Recurrent Unprovoked Deep Venous Thrombosis and/or Acute Pulmonary Embolism, Indefinite Antithrombotic Therapy is Recommended Over Stopping Anticoagulation After Completion of Primary Treatment (Strong Recommendation, Moderate Certainty in the Evidence)
Specific Treatment of Recurrent Venous Thromboembolism While on Anticoagulation (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) (Chest, 2016) [MEDLINE]
Rationale
Risk of Recurrent Venous Thromboembolism Decreases Rapidly After Starting Anticoagulation
Based on This, a Recurrence Soon After Therapy Can Generally Be Managed by Increasing the Intensity of Anticoagulation
When Oral Anticoagulation is Managed Well, the Risk of Recurrence is Approximately 2 Per 100 Patient-Years (Blood, 2017) [MEDLINE]
The Main Reasons for Breakthrough Events are Underlying Disease and Subtherapeutic Drug Levels
Recommendations (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]
Treatment of Recurrent Venous Thromboembolism on a Non-Low Molecular Weight Heparin (Coumadin or Oral Agent)
Switch to Low Molecular Weight Heparin is Recommended, at Least Temporarily (Grade 2C Recommendation)
Treatment of Recurrent Venous Thromboembolism on a Low Molecular Weight Heparin
Higher Dose of Low Molecular Weight Heparin (by 25-33%) is Recommended (Grade 2C Recommendation)
Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
For Patients with Breakthrough Deep Venous Thrombosis and/ or Acute Pulmonary Embolism During Therapeutic Coumadin Treatment, Use of Low Molecular Weight Heparin is Recommended Over DOAC Therapy (Conditional Recommendation, Very Low Certainty in the Evidence)
Patients Who Present with a New Venous Thromboembolism Event During Therapeutic Coumadin Treatment Should Be Further Investigated to Identify Potential Underlying Etiologies
This Recommendation Does Not Apply to Patients Who Develop Breakthrough Venous Thromboembolism in the Setting of Poor INR Control, in Whom a DOAC May Be a Reasonable Option
Inferior Vena Cava Filter Use in the Management of Venous Thromboembolism Has Increased Over the Last Few Decades (Arch Intern Med, 2010) [MEDLINE] (Am J Med, 2011) [MEDLINE]
Although Most IVC Filters are Currently Designed to Be Retrieved, Many Remain in Patients for Extended Durations or Permanently, Even When the Original Reason for IVC Filter Placement Has Resolved (Chest, 2021) [MEDLINE]
Anticoagulation Failure: objectively documented extension of existing deep venous thrombosis (or new deep venous thrombosis) or pulmonary embolism while therapeutically anticoagulated
Failure of Previous Device to Prevent Pulmonary Embolism (Due to Central Extension of Thrombus Through an Existing Inferior Vena Cava Filter or Recurrent Pulmonary Embolism)
In Association with Thrombectomy, Embolectomy, or Lytic Therapy
Prophylaxis with No Thromboembolic Disease
Prophylaxis with Thromboembolism in Addition to Anticoagulation
Technique
Filter Positioning
Inferior Vena Cava Filters are Typically Placed Infrarenally, Since Suprarenal Filters May Lead to Renal Vein Compromise, if They Become Clotted
Retrievable Inferior Vena Cava Filters
May Remain in Place for Approximately 2 mos
There is No Data to Support One Inferior Vena Cava Filter Brand Over Another
Clinical Efficacy
Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group (PREPIC) Trial (NEJM, 1998) [MEDLINE]
At 2 Years, Inferior Vena Cava Filter Had No Impact on the Rate of Symptomatic Pulmonary Embolism or Mortality Rate
However, Inferior Vena Cava Filter Placement Increased the Rate of Recurrent Deep venous Thrombosis
Randomized, Open-Label PREPIC2 Trial of IVC Filter Added to Anticoagulation in Severe Acute PE Requiring Hospitalization (JAMA, 2015) [MEDLINE]
Retrievable Inferior Vena Cava Filter Has No Clinical Cenefit Over Anticoagulation Alone (in Terms of Decreasing the Risk of Recurrent Pulmonary Embolism at 3/6 Months or 3-Month/6-Month Mortality Rate)
Based on These Data, Inferior Vena Cava Filter is Not Indicated in Anticoagulated Acute Pulmonary Embolism Patients on the Basis of Poor Cardiopulmonary Reserve, Large Clot Burden, or Suspected Risk of Recurrence
Recommendations (European Society of Cardiology and European Respiratory Society Guidelines for the Diagnosis and Management of Acute Pulmonary Embolism, 2019) (Eur Heart J, 2020) [MEDLINE]
Inferior Vena Cava (IVC) Filters Should Be Considered in Patients with Acute Pulmonary Embolism and Absolute Contraindications to Anticoagulation (Class IIa, Level C)
Inferior Vena Cava (IVC) Filters Should Be Considered in Cases of Acute Pulmonary Embolism Recurrence Despite Therapeutic Anticoagulation (Class IIa, Level C)
Routine Use of Inferior Vena Cava (IVC) Filters is Not Recommended (Class III, Level A)
Recommendations for Inferior Vena Cava (IVC) Filter (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]
Consider an Inferior Vena Cava (IVC) Filter for Patients with Contraindications to or Failure of Therapeutic Anticoagulation and for Highly Selected Patients with Intermediate or High-Risk Acute Pulmonary Embolism
Consider an Inferior Vena Cava (IVC) Filter in Select Patients When Large, Free-Floating, Proximal DVT is Identified
Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
For Patients with Proximal Deep Venous Thrombosis and Significant Preexisting Cardiopulmonary Disease, as Well as for Patients with Acute Pulmonary Embolism and Hemodynamic Compromise, Anticoagulation Alone is Recommended Over Anticoagulation Plus Inferior Vena Cava (IVC) Filter Placement (Conditional Recommendation, Low Certainty in the Evidence)
These Recommendations Apply to Patients Who are Eligible to Receive Anticoagulation
For Patients with a Contraindication to Anticoagulation, Insertion of a Retrievable Inferior Vena Cava (IVC) Filter May Be Indicated with Retrieval as Soon as the Patient is Able to Receive Anticoagulation
In Patients with Acute Lower Extremity Deep Venous Thrombosis, Inferior Vena Cava (IVC) Filter is Not Recommended in Addition to Anticoagulation (Strong Recommendation, Moderate-Certainty Evidence)
Because it is Uncertain if There is Benefit to Placement of an Inferior Vena Cava (IVC) Filter in Anticoagulated Patients with High-Risk Acute Pulmonary Embolism (with Hypotension), the Recommendation Against Insertion of an Inferior Vena Cava (IVC) Filter in Patients with Acute Pulmonary Embolism Who are Anticoagulated May Not Apply to this Select Subgroup of Patients
In Patients with Acute Lower Extremity Proximal Deep Venous Thrombosis and a Contraindication to Anticoagulation, Inferior Vena Cava (IVC) Filter is Recommended (Strong Recommendation, Moderate-Certainty Evidence)
In These Patients, the Inferior Vena Cava (IVC) Filter Should Be Promptly Removed When Anticoagulation Has Been Instituted
Specific Treatment of Lower Extremity Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis)
Outpatient vs Inpatient Therapy
Criteria for Outpatient Therapy (Patient Must Have All of These to Be Considered for Outpatient Therapy)
Hemodynamically Stable
Low Risk of Hemorrhage
No Renal Insufficiency
Feasible Administration/Monitoring of Anticoagulation at Home (Adequate Mental Capacity to Manage Medications and Monitoring, Adequate Living Conditions, Caregiver Support, Telephone Access, etc)
Contraindications to Outpatient Therapy (Can Fam Physician, 2005) [MEDLINE]
Massive Deep Venous Thrombosis (Iliofemoral Deep Venous Thrombosis, Phlegmasia Cerulea Dolens, etc)
Concurrent Symptomatic Pulmonary Embolism
High Risk of Hemorrhage on Anticoagulation
Comorbid Conditions or Other Factors Which Require Inpatient Care
Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
For Patients with Uncomplicated Deep Venous Thrombosis, Offering Home Treatment is Recommended Over Hospital Treatment (Conditional Recommendation Based, Low Certainty in Evidence)
Recommendation Does Not Apply to Patients Who Have Other Conditions Which Might Require Hospitalization, Have Limited or No Home Support, Cannot Afford Medications, or Have a History of Poor Compliance
Patients with Limb-threatening Deep Venous Thrombosis or a High Risk for Bleeding and Those Requiring Intravenous Analgesics May Benefit from Initial Treatment in the Hospital
Ambulation
Ambulation is Indicated as Soon as Possible (Despite the Theoretical Risk for Embolization)
Usually a Gradual Increase in Ambulation is Advisable
Ambulation Has Not Been Demonstrated to Increase the Risk of Fatal Pulmonary Embolism (XXXXXXXXX)
Graduated Compression Stockings
Rationale
May Provide Symptomatic Relief and Facilitate Ambulation
Theoretical Goal of Therapy is the Prevention of Post-Phlebitic Syndrome (Although Data are Conflicting as to Their Efficacy in this Regard)
Contraindications
Allergy to the Stocking Material
Inability to Apply Stockings
Severe Arterial Insufficiency
Skin Ulceration
Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
For Patients with Deep Venous Thrombosis, with or without an Increased Risk for Postthrombotic Syndrome, the Routine Use of Compression Stockings is Not Recommended (Conditional Recommendations, Very Low Certainty in the Evidence)
Although the Majority of Patients May Not Benefit from the Use of Stockings to Reduce the Risk of Postthrombotic Syndrome, Stockings May Help to Reduce Edema and pain associated with Acute Deep Venous Thrombosis in Selected Patients
In Patients with Acute Lower Extremity Deep Venous Thrombosis, Use of Routine Compression Stockings to Prevent Post-Thrombotic Syndrome is Not Recommended (Weak Recommendation, Low-Certainty Evidence)
No Evidence Exists that the Use of Graduated Compression Stockings Following Deep Venous Thrombosis Reduces the Risk for Recurrent Deep Venous Thrombosis
Presence of Free-Floating Thrombus in Deep Venous Thrombosis
Free-Floating Thrombus Occurs in 10% of All Deep Venous Thromboses (J Vasc Surg, 1990) [MEDLINE]
Only 13% are Associated with Clinically-Significant Pulmonary Emboli by V/Q Scan (Usually the Pulmonary Embolism Occurred Before the Diagnosis of the Free-Floating Thrombus)
Most Free-Floating Thrombi Followed Noninvasively by Duplex Scanning Do Not Embolize, But Rather Become Attached to the Vein Wall or Resolve
Assuming Adequate Anticoagulation with Unfractionated Heparin/Low Molecular Weight Heparin (Nadroparin Calcium), Studies Suggest that Presence of DVT with Free-Floating Thrombus Does Not Increase the Risk of Acute Pulmonary Embolism (Arch Intern Med, 1997) [MEDLINE]
However, Similar Studies Have Not Been Done Using Direct Oral Anticoagulants
This is Critical Since Direct Oral Anticoagulants May Have Slower Onsets of Action Than Heparins
Apixaban Has a Peak Onset of Action of 3-4 hrs (see Apixaban)
Rivaroxaban Does Not reach Peak Plasma Levels Until 2-4 hrs Later (see Rivaroxaban)
Catheter-Directed Thrombolysis of Acute Lower Extremity Deep Venous Thrombosis (see Deep Venous Thrombosis)
Clinical Efficacy
Retrospective Analysis of Catheter-Directed Thrombolysis for Lower Extremity DVT (JAMA Int Med, 2014) [MEDLINE]
Catheter-Directed Thrombolysis of Lower Extremity DVT is Associated with 2x-Increased Risk of Transfusion, 3x-Increased Risk of Intracranial Hemorrhage, 1.5x-Increased Risk of Acute PE, and 2x-Increased Risk of IVC Filter Insertion: long-term outcomes were not reported
Indications (Patients Most Likely to Benefit from Catheter-Directed Thrombolysis of Lower Extremity DVT) (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]
Failure of Anticoagulation
Good Functional Status
Iliofemoral DVT/Phlegmasia Cerulea Dolens
Life Expectancy of At Least 1 Year
Low Risk of Hemorrhage
Symptoms for <14 Days
Recommendations (American Society of Hematology Guidelines for the Management of Venous Thromboembolism, 2020) (Blood Adv, 2020) [MEDLINE]
In Most Patients with Proximal Deep Venous Thrombosis, Anticoagulation Therapy Alone is Recommended Over Thrombolytic Therapy in Addition to Anticoagulation (Conditional Recommendation, Low Certainty in the Evidence)
Thrombolysis is Reasonable to Consider for Patients with Limb-Threatening Deep Venous Thrombosis (Phlegmasia Cerulea Dolens) and for Selected Younger Patients at Low Risk for Bleeding with Symptomatic Deep Venous Thrombosis Involving the Iliac and Common Femoral Veins (Higher Risk for More Severe Postthrombotic Syndrome)
Patients in These Categories Who Value Rapid Resolution of Symptoms, are Averse to the Possibility of Postthrombotic Syndrome, and Accept the Added Risk of Major Bleeding May Prefer Thrombolysis
Use of Thrombolysis Should Be Rare for Patients with Deep Venous Thrombosis Limited to Veins Below the Common Femoral Vein
For Patients with Extensive Deep Venous Thrombosis in Whom Thrombolysis is Considered Appropriate, Use of Catheter-Directed Thrombolysis is Recommended Over Systemic Thrombolysis (Conditional Recommendation, Very Low Certainty in the Evidence)
In Patients with Acute Lower Extremity Deep Venous Thrombosis, Anticoagulation Alone is Recommended Over Interventional (Thrombolytic, Mechanical, or Pharmacomechanical) Therapy (Weak Recommendation, Moderate-Certainty Evidence)
Treatment of Isolated Distal (Calf) Deep Venous Thrombosis (Chest, 2021) (Chest Antithrombotic Therapy for VTE Disease 2021 Guidelines) [MEDLINE]
Rationale
Approximately 15% of Untreated Distal Deep Venous Thromboses Will Ultimately Extend Proximally into the Popliteal Vein and May Cause Acute Pulmonary Embolism (Chest, 2016) [MEDLINE]
Patients at High Risk for Bleeding are More Likely to Benefit from Serial Imaging
General Factors Which Favor Anticoagulation
Active Cancer
Elevated Plasma D-Dimer (Particularly When Markedly So without an Alternative Explanation) (see Elevated Plasma D-Dimer)
Extensive Thrombosis (Involving Multiple Veins >5 cm in Length, >7 mm in Maximum Diameter)
Highly Symptomatic Patient
History of Venous Thromboembolism
Inpatient Status
No Reversible Provoking Factor for Deep Venous Thrombosis
General Factors Which Favor Serial Lower Extremity Imaging
Thrombus Confined to Muscular Calf Veins (i.e. Soleus, Gastrocnemius)
Moderate/High Risk of Bleeding
Patient Prefers to Avoid Anticoagulation
Isolated Distal Deep Venous Thrombosis without Severe Symptoms or Risk Factors for Extension (See Below)
Serial Lower Extremity Dopplers x 2 wks are Recommended (Weak Recommendation, Moderate-Certainty Evidence)
Serial Lower Extremity Dopplers Should Be Performed Once Weekly or with Worsening Symptoms
During Surveillance
If Thrombus Does Not Extend within the Distal Veins, Anticoagulation is Not Recommended (Strong Recommendation, Moderate-Certainty Evidence)
If Thrombus Extends within the Distal Veins, Anticoagulation is Suggested (Weak Recommendation, Very Low-Certainty Evidence)
If Thrombus Extends into the Proximal Veins, Anticoagulation is Recommended (Strong Recommendation, Moderate-Certainty Evidence)
Isolated Distal Distal Deep Venous Thrombosis with Severe Symptoms or Risk Factors for Extension (See Below)
Anticoagulation is Recommended (Weak Recommendation, Low-Certainty Evidence)
Risk Factors for Extension of Distal Deep Venous Thrombosis
Active Cancer
Elevated Plasma D-Dimer (Particularly When Markedly So without an Alternative Explanation) (see Elevated Plasma D-Dimer)
Extensive Thrombosis (Involving Multiple Veins, >5 cm in Length, >7 mm in Maximum Diameter)
History of Venous Thromboembolism
Inpatient Status
No Reversible Provoking Factor for Distal Deep Venous Thrombosis
Thrombosis Close to Proximal Veins
Note: Thrombosis Confined to the Muscular Veins of the Calf (Soleus, Gastrocnemius) has a Lower Risk of Extension than Thrombosis that Involves the Axial (True Deep: Peroneal, Tibial) Veins
Treatment of Lower Extremity Superficial Venous Thrombosis (SVT)
In Patients with Lower Extremity Superficial Venous Thrombosis (SVT) at Increased Risk of Clot Progression to Deep Venous Thrombosis or Acute Pulmonary Embolism (Per the Factors Below), Anticoagulation for 45 Days is Recommended Over No Anticoagulation (Weak Recommendation, Moderate-Certainty Evidence)
Factors Which Favor the Use of Anticoagulation in Patients with Superficial Venous Thrombosis
Active Cancer
Extensive Superficial Venous Thrombosis
History of Venous Thromboembolism or Superficial Venous Thrombosis
Involvement Above the Knee (Particularly if Close to the Saphenofemoral Junction)
Involvement of the Greater Saphenous Vein
Recent Surgery
Severe Symptoms
In Patients with Superficial Venous Thrombosis Who are Treated with Anticoagulation, Fondaparinux (2.5 mg Daily) is Recommended Over Other Anticoagulant Regimens Such as Prophylactic or Therapeutic Dose Low Molecular Weigh Heparins (Weak Recommendation, Low-Certainty Evidence)
In Patients with Superficial Venous Thrombosis Who Refuse or are Unable to Use Parenteral Anticoagulation, Rivaroxaban 10 mg Daily is Recommended as a Reasonable Alternative to Fondaparinux (2.5 mg Daily) (Weak Recommendation, Low-Certainty Evidence)
Specific Treatment of Upper Extremity Deep Venous Thrombosis
Anticoagulation
Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
Anticoagulation is Recommended for Upper Extremity Deep Venous Thrombosis Involving the Axillary or More Proximal Veins
Catheter-Directed Thrombolysis of Upper Extremity Deep Venous Thrombosis Which Involves Axillary or More Proximal Veins
Indications (Patients Most Likely to Benefit from Catheter-Directed Thrombolysis of Upper Extremity DVT) (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]
Good Functional Status
Life Expectancy of ≥1 Year
Low Risk of Hemorrhage
Severe Symptoms
Symptoms Present for <14 Days
Thrombus Involving Most of the Axillary and Subclavian Vein
Recommendations (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]
Anticoagulation is Recommended Over Catheter-Directed Thrombolysis in Upper Extremity Deep Venous Thrombosis (Grade 2C Recommendation)
In Patients Who Undergo Catheter-Directed Thrombolysis of Upper Extremity Deep Venous Thrombosis, the Same Intensity/Duration of Anticoagulation is Recommended as in Those Who Do Not Undergo Thrombolysis (Grade 1B Recommendation)
Follow-Up of Acute Pulmonary Embolism
Recommendations for Follow-Up of Acute Pulmonary Embolism (Consensus Practice from the PERT Consortium, 2019) (Clin Appl Thromb Hemost, 2019) [MEDLINE]
Acute Pulmonary Embolism Patients Should Have a Short Interval Follow-Up Visit (2 wks-3 mos) Post-Pulmonary Embolism, or Sooner if Symptoms or Patient Complexity Suggest the Need for This
Expert Follow-Up with the PERT Team is Recommended
The Initial Post-Discharge Visit Should Focus on the Patient’s Clinical Status, Anticoagulation Regimen (Type, Dose, Duration, Compliance, and Tolerance), Consideration for Inferior Vene Cave Filter Removal, Evaluation of Thrombophilia and Age-Appropriate Cancer Screening
Patients with Persistent or Recurrent Symptoms, Particularly After 3 mos, Merit Follow-Up Testing
If Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is Highly Suspected or Confirmed, the Patient Should Be Referred to an Expert CTEPH Center
References
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 2012
Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):7S-47S. doi: 10.1378/chest.1412S3 [MEDLINE]
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American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 2016
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General
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Thrombolytics
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