Treatment for VTE should be offered to patients with objectively confirmed DVT or PE, or to those in whom the clinical suspicion is high for the disorder but who have not yet undergone diagnostic testing (see Chapter 9). The management of VTE primarily involves administration of anticoagulants; the goal is to prevent recurrence, extension and embolization of thrombosis and to reduce the risk of post-thrombotic syndrome. Suggested anticoagulation regimens are found in Table 14–16.
Table 14–16.Initial anticoagulation for VTE.1 ||Download (.pdf) Table 14–16. Initial anticoagulation for VTE.1
| || ||Clinical Scenario || |
|Anticoagulant ||Dose/Frequency ||DVT, Lower Extremity ||DVT, Upper Extremity ||PE ||VTE, With Concomitant Severe Kidney Disease2 ||VTE, Cancer-Related ||Comment |
|Unfractionated Heparin |
|Unfractionated heparin ||80 units/kg intravenous bolus, then continuous intravenous infusion of 18 units/kg/h ||× ||× ||× ||× || ||Bolus may be omitted if risk of bleeding is perceived to be elevated. Maximum bolus, 10,000 units. Requires aPTT or heparin anti-Xa monitoring. Most patients: begin warfarin at time of initiation of heparin. |
| ||330 units/kg subcutaneously × 1, then 250 units/kg subcutaneously every 12 hours ||× || || || || ||Fixed-dose; no aPTT monitoring required |
|LMWH and Fondaparinux |
|Enoxaparin3 || |
1 mg/kg subcutaneously every 12 hours
1.5 mg/kg subcutaneously daily
|× ||× ||× || || ||Most patients: begin warfarin at time of initiation of LMWH |
|Dalteparin3 ||200 units/kg subcutaneously once daily for first month, then 150 units/kg/day ||× ||× ||× || ||× ||Preferred LMWH for cancer patients; administer for at least 3–6 months (no transition to warfarin) |
|Fondaparinux ||5–10 mg subcutaneously once daily; use 7.5 mg for body weight 50–100 kg; 10 mg for body weight > 100 kg ||× ||× ||× || || || |
|Direct-Acting Oral Anticoagulants (DOACs) |
|Rivaroxaban ||15 mg orally twice daily with food for 21 days, then 20 mg orally daily with food ||× ||× ||× || ||× || |
Contraindicated if CrCl < 30 mL/min
Monotherapy without need for initial parenteral therapy
Caution in luminal gastrointestinal or genitourinary cancer
|Apixaban ||10 mg orally twice daily for first 7 days, then 5 mg twice daily ||× ||× ||× || ||× || |
Contraindicated if CrCl < 25 mL/min
Monotherapy without need for initial parenteral therapy
|Dabigatran ||5–10 days of parenteral anticoagulation, then begin 150 mg orally twice daily ||× ||× ||× || || || |
Contraindicated if CrCl < 15 mL/min
Initial need for parenteral therapy
|Edoxaban ||5–10 days of parenteral anticoagulation, then 60 mg orally once daily; 30 mg once daily recommended if CrCl is between 15 and 50 mL/min, if weight ≤ 60 kg, or if certain P-gp inhibitors are present ||× ||× ||× || ||× || |
Contraindicated if CrCl < 15 mL/min
Initial need for parenteral therapy
Caution in luminal gastrointestinal or genitourinary cancer
B. Selecting Appropriate Initial Anticoagulant Therapy
Most patients with DVT alone may be treated as outpatients, provided that their risk of bleeding is low, and they have good follow-up. Table 14–17 outlines proposed selection criteria for outpatient treatment of DVT.
Table 14–17.Patient selection for outpatient treatment of DVT. ||Download (.pdf) Table 14–17. Patient selection for outpatient treatment of DVT.
Patients considered appropriate for outpatient treatment
No clinical signs or symptoms of PE and pain controlled
Motivated and capable of self-administration of injections
Confirmed ability to pay for injectable medication (either by insurance or out-of-pocket)
Capable and willing to comply with frequent follow-up
Initially, patients may need to be seen daily to weekly
Potential contraindications for outpatient treatment
DVT involving inferior vena cava, iliac, common femoral, or upper extremity vein (these patients might benefit from vascular intervention)
Active peptic ulcer disease, GI bleeding in past 14 days, liver synthetic dysfunction
Brain metastases, current or recent CNS or spinal cord injury/surgery in the last 10 days, CVA ≤ 4–6 weeks
Familial bleeding diathesis
Active bleeding from source other than GI
Creatinine clearance < 30 mL/min
Patient weighs < 55 kg (male) or < 45 kg (female)
Recent surgery, spinal or epidural anesthesia in the past 3 days
History of heparin-induced thrombocytopenia
Inability to inject medication at home, reliably follow medication schedule, recognize changes in health status, understand or follow directions
Among patients with PE, risk stratification at time of diagnosis should direct treatment and triage. Patients with persistent hemodynamic instability are classified as high-risk patients (previously referred to as having “massive PE”) and have an early PE-related mortality of more than 15%. These patients should be admitted to an intensive care unit and generally receive thrombolysis and anticoagulation with intravenous heparin. Intermediate-risk patients (previously, “submassive PE”) have a mortality rate of up to 15% and should be admitted to a higher level of inpatient care, with consideration of thrombolysis on a case-by-case basis. Catheter-directed techniques, if available, may be an option for patients who are poor candidates for systemic thrombolysis and/or in centers with expertise. Low-risk patients have a mortality rate less than 3% and are candidates for expedited discharge or outpatient therapy.
For hemodynamically stable patients, additional assessment focusing on right ventricular dysfunction is warranted to differentiate between low-risk, low-intermediate risk, and high-intermediate risk PE. The Bova score and the PE severity index (PESI)/simplified PESI accurately identify patients at low risk for 30-day PE-related mortality (Table 14–18) (eTable 14–3) who are potential candidates for expedited discharge or outpatient treatment. Because the Bova score includes serum troponin and evidence of right ventricular dysfunction (by CT or echocardiography), it also identifies patients with high-intermediate risk PE who warrant close monitoring and may require escalation of therapy. An RV/LV ratio less than 1.0 on chest CT angiogram has been shown to have good negative predictive value for adverse outcome but suffers from inter-observer variability. Echocardiography may provide better assessment of right ventricular dysfunction when there is concern. Serum biomarkers such as B-type natriuretic peptide and troponin are most useful for their negative predictive value, and mainly in combination with other predictors.
Table 14–18.Simplified Pulmonary Embolism Severity Index (PESI). ||Download (.pdf) Table 14–18. Simplified Pulmonary Embolism Severity Index (PESI).
| ||Points |
|Age > 80 years old ||1 |
|Cancer ||1 |
|Chronic cardiopulmonary disease ||1 |
|Systolic blood pressure < 100 mm Hg ||1 |
|Oxygen saturation ≤ 90% ||1 |
|Severity Class ||Points ||30-Day Mortality |
|Low risk ||0 ||1% |
|High risk ||≥ 1 ||10% |
eTable 14–3.Pulmonary Embolism Severity Index (PESI). ||Download (.pdf) eTable 14–3. Pulmonary Embolism Severity Index (PESI).
|Risk factor ||Points |
|Age ||No. of years of age |
|Male sex ||10 |
|Cancer ||30 |
|Heart failure ||10 |
|Chronic lung disease ||10 |
|Heart rate > 110 bpm ||20 |
|Systolic blood pressure < 100 mm Hg ||20 |
|Respiratory rate > 30 breaths per minute ||20 |
|Temperature < 36°C ||20 |
|Change in mental status ||60 |
|Oxygen saturation < 90% ||20 |
|Severity class ||Points ||30-day mortality |
|I ||0–65 ||< 1.6% |
|II ||66–85 ||< 3.5% |
|III ||86–105 ||< 7.1% |
|IV ||106–125 ||4–11.4% |
|V ||> 125 ||10–24.5% |
Selection of an initial anticoagulant should be determined by patient characteristics (kidney function, immediate bleeding risk, weight) and the clinical scenario (eg, whether thrombolysis is being considered, active cancer, thrombosis location).
1. Parenteral anticoagulants
In patients in whom parenteral anticoagulation is being considered, LMWHs are more effective than unfractionated heparin in the immediate treatment of DVT and PE and are preferred as initial treatment because of predictable pharmacokinetics, which allow for subcutaneous, once- or twice-daily dosing with no requirement for monitoring in most patients. Accumulation of LMWH and increased rates of bleeding have been observed among patients with severe kidney disease (creatinine clearance less than 30 mL/min), leading to a recommendation to use intravenous unfractionated heparin preferentially in these patients. If concomitant thrombolysis is being considered, unfractionated heparin is indicated. Patients with VTE and a perceived higher risk of bleeding (ie, post-surgery) may be better candidates for treatment with unfractionated heparin than LMWH given its shorter half-life and reversibility. Unfractionated heparin can be effectively neutralized with the positively charged protamine sulfate while protamine may only have partial reversal effect at best on LMWH. Use of unfractionated heparin leads to heparin-induced thrombocytopenia and thrombosis in approximately 3% of patients, so daily complete blood counts are recommended during the initial 10–14 days of exposure.
Weight-based, fixed-dose daily subcutaneous fondaparinux (a synthetic factor Xa inhibitor) may also be used for the initial treatment of DVT and PE, with no increase in bleeding over that observed with LMWH. Its lack of reversibility, long half-life, and renal clearance limit its use in patients with an increased risk of bleeding or kidney disease.
A. DIRECT-ACTING ORAL ANTICOAGULANTS
DOACs have a predictable dose effect, few drug-drug interactions, rapid onset of action, and freedom from laboratory monitoring (Table 14–10). Dabigatran, rivaroxaban, apixaban, and edoxaban are approved for treatment of acute DVT and PE. While rivaroxaban and apixaban can be used as monotherapy eliminating the need for parenteral therapy, patients treated with dabigatran or edoxaban must first receive 5–10 days of parenteral anticoagulation and then be transitioned to the oral agent per prescribing information. Unlike warfarin, DOACs do not require an overlap since these agents are immediately active; the DOAC is started when the parenteral agent is stopped. Compared to warfarin and LMWH, the DOACs are all noninferior with respect to prevention of recurrent VTE; both rivaroxaban and apixaban have a lower bleeding risk than warfarin with LMWH bridge. While DOACs are recommended as first-line therapy for acute VTE according to the CHEST 2016 VTE guidelines, agent selection should be individualized with consideration of kidney function, concomitant medication use, indication, ability to use LMWH bridge therapy, cost, and adherence.
If warfarin is chosen as the oral anticoagulant it will be initiated along with the parenteral anticoagulant, which is continued until INR is in therapeutic range. Most patients require 5 mg of warfarin daily for initial treatment, but lower doses (2.5 mg daily) should be considered for patients of Asian descent, older adults, and those with hyperthyroidism, heart failure, liver disease, recent major surgery, malnutrition, certain polymorphisms for the CYP2C9 or the VKORC1 genes or who are receiving concurrent medications that increase sensitivity to warfarin (eTable 14–4). Conversely, individuals of African descent, those with larger body mass index or hypothyroidism, and those who are receiving medications that increase warfarin metabolism (eg, rifampin) may require higher initial doses (7.5 mg daily). Daily INR results should guide dosing adjustments in the hospitalized patient while at least biweekly INR results guide dosing in the outpatient during the initial period of therapy (Table 14–19). Web-based warfarin dosing calculators incorporating clinical and genetic factors are available to help clinicians choose appropriate starting doses (eg, see www.warfarindosing.org). Because an average of 5 days is required to achieve a steady-state reduction in the activity of vitamin K–dependent coagulation factors, the parenteral anticoagulant should be continued for at least 5 days and until the INR is more than 2.0. Meticulous follow-up should be arranged for all patients taking warfarin because of the bleeding risk associated with initiation of therapy. Once stabilized, the INR should be checked at an interval no longer than every 6 weeks and warfarin dosing should be adjusted by guidelines (Table 14–20) since this strategy has been shown to improve the time patients spend in the therapeutic range and their clinical outcomes. Supratherapeutic INRs should be managed according to evidence-based guidelines (Table 14–21).
eTable 14–4.Commonly used agents and their potential effect on the INR. ||Download (.pdf) eTable 14–4. Commonly used agents and their potential effect on the INR.
Table 14–19.Warfarin dosing adjustment guidelines for initiation of warfarin therapy. ||Download (.pdf) Table 14–19. Warfarin dosing adjustment guidelines for initiation of warfarin therapy.
|Measurement Day ||INR ||Action |
|For Hospitalized Patients Newly Starting Therapy |
|Day 1 || ||5 mg (2.5 or 7.5 mg in select populations1) |
|Day 2 ||< 1.5 ||Continue dose |
| ||≥ 1.5 ||Decrease or hold dose2 |
|Day 3 ||≤ 1.2 ||Increase dose2 |
| ||> 1.2 and < 1.7 ||Continue dose |
| ||≥ 1.7 ||Decrease dose2 |
|Day 4 until therapeutic ||Daily increase < 0.2 units ||Increase dose2 |
| ||Daily increase 0.2–0.3 units ||Continue dose |
| ||Daily increase 0.4–0.6 units ||Decrease dose2 |
| ||Daily increase ≥ 0.7 units ||Hold dose |
|For Outpatients Newly Starting Therapy |
|Measure PT/INR on Day 1 ||Baseline ||Start treatment with 2–7.5 mg |
|Measure PT/INR on Day 3–4 ||< 1.5 ||Increase weekly dose by 5–25% |
| ||1.5–1.9 ||No dosage change |
| ||2.0–2.5 ||Decrease weekly dose by 25–50% |
| ||> 2.5 ||Decrease weekly dose by 50% or HOLD dose |
|Measure PT/INR on Day 5–7 ||< 1.5 ||Increase weekly dose by 10–25% |
| ||1.5–1.9 ||Increase weekly dose by 0–20% |
| ||2.0–3.0 ||No dosage change |
| ||> 3.0 ||Decrease weekly dose by 10–25% or HOLD dose |
|Measure PT/INR on Day 8–10 ||< 1.5 ||Increase weekly dose by 15–35% |
| ||1.5–1.9 ||Increase weekly dose by 5–20% |
| ||2.0–3.0 ||No dosage change |
| ||> 3.0 ||Decrease weekly dose by 10–25% or HOLD dose |
|Measure PT/INR on Day 11–14 ||< 1.6 ||Increase weekly dose by 15–35% |
| ||1.6–1.9 ||Increase weekly dose by 5–20% |
| ||2.0–3.0 ||No dosage change |
| ||> 3.0 ||Decrease weekly dose by 5–20% or HOLD dose |
Table 14–20.Warfarin-dosing adjustment guidelines for patients receiving long-term therapy, with target INR 2–3. ||Download (.pdf) Table 14–20. Warfarin-dosing adjustment guidelines for patients receiving long-term therapy, with target INR 2–3.
|Patient INR ||Weekly Dosing Change |
|Dose change ||Follow-up INR |
|≤ 1.5 ||Increase by 10–15% ||Within 1 week |
|1.51–1.79 ||If falling or low on two or more occasions, increase weekly dose by 5–10%. ||7–14 days |
|1.80–2.29 ||Consider not changing the dose unless a consistent pattern has been observed. ||7–14 days |
|2.3–3.0 (in range) ||No change in dosage. ||28 days (42 days if INR in range three times consecutively) |
|3.01–3.20 ||Consider not changing the dose unless a consistent pattern has been observed. ||7–14 days |
|3.21–3.69 ||Do not hold warfarin. If rising or high on two or more occasions, decrease weekly dose by 5–10%. ||7–14 days |
|3.70–4.99 ||Hold warfarin for 1 day and decrease weekly dose by 5–10%. ||Within 1 week, sooner if clinically indicated |
|5.0–8.99 ||Hold warfarin. Clinical evaluation for bleeding. When INR is therapeutic, restart at lower dose (decrease weekly dose by 10–15%). Check INR at least weekly until stable. ||Within 1 week, sooner if clinically indicated, then weekly until stabilized |
|≥ 9 ||See Table 14–21 || |
Table 14–21.American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for the Management of Supratherapeutic INR. ||Download (.pdf) Table 14–21. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for the Management of Supratherapeutic INR.
|Clinical Situation ||INR ||Recommendations |
|No significant bleed ||Above therapeutic range but < 5.0 || |
| ||≥ 5.0 but < 9.0 || |
| || || |
| || || |
| ||≥ 9.0 || |
| || || |
| || || |
|Serious/life-threatening bleed || || |
3. Duration of anticoagulation therapy
The clinical scenario in which the thrombosis occurred is the strongest predictor of recurrence and, in most cases, guides duration of anticoagulation (Table 14–22). In the first year after discontinuation of anticoagulation therapy, the frequency of recurrent VTE among individuals whose thrombosis occurred in the setting of a transient, major, reversible risk factor (such as surgery) is approximately 3% after completing 3 months of anticoagulation, compared with at least 8% for individuals whose thrombosis was unprovoked, and greater than 20% in patients with cancer. Patients with provoked VTE are generally treated with a minimum of 3 months of anticoagulation, whereas unprovoked VTE should prompt consideration of indefinite anticoagulation provided the patient is not at high risk for bleeding. Merely extending duration of anticoagulation beyond 3 months will not reduce risk of recurrence once anticoagulation is stopped; if anticoagulants are stopped after 3, 6, 12, or 18 months in a patient with unprovoked VTE, the risk of recurrence after cessation of therapy is similar. Individual risk stratification may help identify patients most likely to suffer recurrent disease and thus most likely to benefit from ongoing anticoagulation therapy. Normal D-dimer levels 1 month after cessation of anticoagulation are associated with lower recurrence risk, although some would argue not low enough to consider stopping anticoagulant therapy, particularly in men. One risk scoring system uses body mass index, age, D-dimer, and post-phlebitic symptoms to identify women at lower risk for recurrence after unprovoked VTE. The Vienna Prediction Model, a simple scoring system based on age, sex, D-dimer, and location of thrombosis, can help estimate an individual’s recurrence risk to guide duration of therapy decisions. The following facts are important to consider when determining duration of therapy: (1) men have a greater than twofold higher risk of recurrent VTE compared to women, (2) recurrent PE is more likely to develop in patients with clinically apparent PE than in those with DVT alone and has a case fatality rate of nearly 10%, and (3) proximal DVT has a higher recurrence risk than distal DVT. Laboratory workup for thrombophilia is not recommended routinely for determining duration of therapy because clinical presentation is a much stronger predictor of recurrence risk. The workup may be pursued in patients younger than 50 years, with a strong family history, with a clot in unusual locations, or with recurrent thromboses (Table 14–23). In addition, a workup for thrombophilia may be considered in women of childbearing age in whom results may influence fertility and pregnancy outcomes and management or in those patients in whom results will influence duration of therapy. An important hypercoagulable state to identify is antiphospholipid syndrome because these patients have a marked increase in recurrence rates, are at risk for both arterial and venous disease, in general receive bridge therapy during any interruption of anticoagulation, and should not receive DOACs as first-line antithrombotic therapy due to increased arterial events compared to warfarin. Due to effects of anticoagulants and acute thrombosis on many of the tests, the thrombophilia workup should be delayed in most cases until at least 3 months after the acute event, if indicated at all (Table 14–24). The benefit of anticoagulation must be weighed against the bleeding risks posed, and the benefit-risk ratio should be assessed at the initiation of therapy, at 3 months, and then at least annually in any patient receiving prolonged anticoagulant therapy. While bleeding risk scores have been developed to estimate risk of these complications, their performance may not offer any advantage over a clinician’s subjective assessment, particularly in older individuals. Assessment of bleeding risk is of particular importance when identifying candidates for extended duration therapy for treatment of unprovoked VTE; it is recommended that patients with a high risk of bleeding receive a defined course of anticoagulation, rather than indefinite therapy, even if the VTE was unprovoked.
Table 14–22.Duration of treatment of VTE. ||Download (.pdf) Table 14–22. Duration of treatment of VTE.
|Scenario ||Suggested Duration of Therapy ||Comments |
|Provoked by major transient risk factor (eg, major surgery, major trauma, major hospitalization) ||3 months ||VTE prophylaxis upon future exposure to transient risk factors |
|Cancer-related ||≥ 3–6 months or as long as cancer active, whichever is longer ||LMWH or carefully selected DOAC recommended for initial treatment (see Table 14–16) |
|Unprovoked ||At least 3 months; consider indefinite if bleeding risk allows ||May individually risk-stratify for recurrence with D-dimer, clinical risk scores, and clinical presentation. Consider transition to DOAC secondary prevention dose after initial treatment period. |
|Recurrent unprovoked ||Indefinite || |
|Underlying significant thrombophilia (eg, antiphospholipid antibody syndrome, antithrombin deficiency, protein C deficiency, protein S deficiency, ≥ two concomitant thrombophilic conditions) ||Indefinite ||To avoid false positives, consider delaying investigation for laboratory thrombophilia until 3 months after event |
Table 14–23.Candidates for thrombophilia workup if results will influence management. ||Download (.pdf) Table 14–23. Candidates for thrombophilia workup if results will influence management.
Patients < 50 years of age
Strong family history of VTE
Clot in unusual locations
Women of childbearing age
Suspicion for APS (avoid DOACs if APS is strongly suspected or confirmed)
Table 14–24.Laboratory evaluation of thrombophilia. ||Download (.pdf) Table 14–24. Laboratory evaluation of thrombophilia.
|Hypercoagulable State ||When to Suspect ||Laboratory Workup ||Influence of Anticoagulation and Acute Thrombosis |
|Antiphospholipid antibody syndrome || |
CVA/TIA before age 50 years
Recurrent thrombosis (despite anticoagulation)
Thrombosis at an unusual site
Arterial and venous thrombosis
Livedo reticularis, Raynaud phenomenon, thrombocytopenia, recurrent early pregnancy loss
Anti-cardiolipin IgG and/or IgM medium or high titer (ie, > 40 GPL or MPL, or > the 99th percentile)1
Anti-beta-2 glycoprotein I IgG and/or IgM medium or high titer (> the 99th percentile)1
|Lupus anticoagulant can be falsely positive or falsely negative on anticoagulation |
|Protein C, S, antithrombin deficiencies ||Thrombosis < 50 years of age with family history of VTE ||Screen with protein C activity, free protein S, protein S activity, antithrombin activity ||Acute thrombosis can result in decreased protein C, S and antithrombin activity. Warfarin can decrease protein C and S activity; heparin can decrease antithrombin activity. DOACs can increase protein C, S, and antithrombin activity |
|Factor V Leiden, prothrombin gene mutation ||Thrombosis on OCPs, cerebral vein thrombosis, DVT/PE in white population ||PCR for factor V Leiden or prothrombin gene mutation ||No influence |
|Hyperhomocysteinemia || ||Fasting homocysteine ||No influence |
Secondary prevention (antithrombotic therapy offered after the initial 3–6 months of treatment) should be considered in patients with VTE that is not majorly provoked and is most compelling for those with unprovoked VTE. For most patients who continue to take a DOAC to prevent recurrence, the dose can be reduced to prophylactic intensity after the initial 6–12 months of therapy. In patients deemed poor candidates for ongoing DOAC or warfarin use but who warrant some secondary prevention, low-dose (81–100 mg) aspirin may be used; however, this will provide far less reduction in risk of recurrent VTE with similar bleeding risk.
While LMWH has been the mainstay of treatment for cancer-related VTE based on lower VTE recurrence in cancer patients treated with dalteparin compared with warfarin, studies have shown DOACs (edoxaban, rivaroxaban) to be at least as effective as LMWH for VTE treatment at the expense of increased bleeding, particularly for patients with gastrointestinal cancer. The International Society for Thrombosis and Haemostasis suggests use of speciﬁc DOACs for cancer patients with a diagnosis of acute VTE, no drug-drug interactions, and a low risk of bleeding but suggests use of LMWH for those with a high risk of bleeding, including patients with luminal gastrointestinal cancers with an intact primary tumor, and those at risk for bleeding from the genitourinary or gastrointestinal tract. Clinicians must be aware that chemotherapeutic agents may interact with DOACs and their use should be avoided in cases of potential interactions because there is no easily accessible and reliable way to measure the anticoagulant effect of DOACs.
et al; AMPLIFY-EXT Investigators. Apixaban
for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699–708.
et al; Bova Score Validation Study Investigators. A prospective validation of the Bova score in normotensive patients with acute pulmonary embolism. Thromb Res. 2018 May;165:107–11.
et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016 Jan;41(1):206–32.
JM. Thrombophilia testing and venous thrombosis. N Engl J Med. 2017 Dec 7;377(23):2298.
et al. Reversal of direct oral anticoagulants: guidance from the Anticoagulation Forum. Am J Hematol. 2019 Jun;94(6):697–709.
et al. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med. 2018 May 24;378(21):2010–21.
et al. Simplification of the Pulmonary Embolism Severity Index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med. 2010;170(15):1383–9.
et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e419S–94S.
et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016 Feb;149(2):315–52.
et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018 Sep;16(9):1891–4.
et al. The 2019 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2019 Nov 1;40(42):3453–5.
et al. Direct oral anticoagulant for the prevention of thrombosis in ambulatory patients with cancer: a systematic review and meta-analysis. J Thromb Haemost. 2019 Dec;17(12):2141–51.
et al. Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin
(LMWH) for treatment of cancer associated thrombosis (CAT): a systematic review and meta-analysis. Thromb Res. 2019 Jan;173:158–63.
et al. Rivaroxaban
versus vitamin K antagonist in antiphospholipid syndrome: a randomized noninferiority trial. Ann Intern Med. 2019;171(10):685–94.
et al. Guidance for the treatment of deep vein thrombosis and pulmonary embolism. J Thromb Thrombolysis. 2016 Jan;41(1):32–67. Erratum in: J Thromb Thrombolysis. 2016 Apr;41(3):548.
et al. NCCN Guidelines Insights: Cancer-Associated Venous Thromboembolic Disease, Version 2.2018. J Natl Compr Canc Netw. 2018 Nov;16(11):1289–303.
et al. Guidance for the practical management of warfarin
therapy in the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016 Jan;41(1):187–205.
et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018 Nov 27;2(22):3257–329.
Anticoagulation alone is appropriate treatment for most patients with PE; however, those with high-risk, massive PE, defined as PE with persistent hemodynamic instability, have an in-hospital mortality rate that approaches 30% and absent contraindications, require immediate thrombolysis in combination with anticoagulation (Table 14–25) (Table 14–26). Systemic thrombolytic therapy has been used in carefully selected patients with intermediate-risk, submassive PE, defined as PE without hemodynamic instability but with evidence of right ventricular compromise and myocardial injury. Thrombolysis in this cohort decreases risk of hemodynamic compromise but increases the risk of major hemorrhage and stroke. A lower dose of tPA commonly used for PE treatment has been evaluated in small trials but additional data are needed to recommend its use. Catheter-directed therapy for acute PE may be considered for high-risk or intermediate-risk PE when systemic thrombolysis has failed or as an alternative to systemic thrombolytic therapy.
Table 14–25.Contraindications to thrombolytic therapy for pulmonary embolism. ||Download (.pdf) Table 14–25. Contraindications to thrombolytic therapy for pulmonary embolism.
History of hemorrhagic stroke or stroke of unknown origin
Ischemic stroke in previous 6 months
Central nervous system neoplasm
Major trauma, surgery, or head injury in previous 3 weeks
Transient ischemic attack in previous 6 months
Pregnancy or first postpartum week
Noncompressible puncture sites
Refractory hypertension (systolic blood pressure > 180 mm Hg)
Advanced liver disease
Active peptic ulcer
Table 14–26.Thrombolytic therapies for high risk (massive) pulmonary embolism. ||Download (.pdf) Table 14–26. Thrombolytic therapies for high risk (massive) pulmonary embolism.
|Thrombolytic Agent ||Dose ||Frequency ||Comment |
|High Risk (Massive Pulmonary Embolism) |
|Alteplase (r-TPA) (preferred) ||100 mg ||Continuous intravenous infusion over 2 hours ||Follow with continuous intravenous infusion of unfractionated heparin (see Table 14–16 for dosage) |
|Urokinase ||4400 international units/kg ||Intravenous bolus × 1 followed by 4400 international units/kg continuous intravenous infusion for 12 hours || |
|Streptokinase ||250,000 international units ||250,000 international units intravenously loading dose over 30 min, followed by 100,000 international units/h over 12–24 h || |
In patients with large proximal iliofemoral DVT, data from randomized controlled trials are conflicting on the benefit of catheter-directed thrombolysis in addition to treatment with anticoagulation; the CaVenT trial showed some reduction in risk of postthrombotic syndrome, but the larger ATTRACT trial failed to show reduction in postthrombotic syndrome but did find an increased risk of major bleeding.
et al. Outcomes of catheter-directed therapy plus anticoagulation versus anticoagulation alone for submassive and massive pulmonary embolism. Am J Med. 2019 Feb;132(2):240–6.
et al. Half-dose versus full-dose alteplase
for treatment of pulmonary embolism. Crit Care Med. 2018 Oct;46(10):1617–25.
et al. 2019 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2019 Nov 1;40(42):3453–5.
et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402–11.
et al. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013 Jan 15;111(2):273–7.
et al. Systemic thrombolysis for pulmonary embolism: who and how. Tech Vasc Interv Radiol. 2017 Sep;20(3):162–74.
et al; ATTRACT Trial Investigators. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med. 2017 Dec 7;377(23):2240–52.
D. Nonpharmacologic Therapy
1. Graduated compression stockings
Graduated compressions stockings may provide symptomatic relief to selected patients with ongoing swelling but do not reduce risk of postthrombotic syndrome at 6 months. They are contraindicated in patients with peripheral vascular disease.
2. Inferior vena caval (IVC) filters
There is a paucity of data to support the use of IVC filters for the prevention of PE in any clinical scenario. There are two randomized, controlled trials of IVC filters for prevention of PE. In the first study, patients with documented DVT received full intensity, time-limited anticoagulation with or without placement of a permanent IVC filter. Patients with IVC filters had a lower rate of nonfatal asymptomatic PE at 12 days but an increased rate of DVT at 2 years. In the second study, patients with symptomatic PE and residual proximal DVT plus at least one additional risk factor for severity received full intensity anticoagulation with or without a retrievable IVC filter. IVC filter use did not reduce the risk of symptomatic recurrent PE at 3 months. Most experts agree with placement of an IVC filter in patients with acute proximal DVT and an absolute contraindication to anticoagulation despite lack of evidence to support this practice. While IVC filters were once commonly used to prevent VTE recurrence in the setting of anticoagulation failure, many experts now recommend switching to an alternative agent or increasing the intensity of the current anticoagulant regimen instead. The remainder of the indications (submassive/intermediate-risk PE, free-floating iliofemoral DVT, perioperative risk reduction) are controversial. If the contraindication to anticoagulation is temporary (active bleeding with subsequent resolution), placement of a retrievable IVC filter may be considered so that the device can be removed once anticoagulation has been started and has been shown to be tolerated. Rates of IVC filter retrieval are very low, often due to failure to arrange for its removal. Thus, if a device is placed, removal should be arranged at the time of device placement.
Complications of IVC filters include local thrombosis, tilting, migration, fracture, and inability to retrieve the device. When considering placement of an IVC filter, it is best to consider both short- and long-term complications, since devices intended for removal may become permanent. To improve patient safety, institutions should develop systems that guide appropriate patient selection for IVC filter placement, tracking, and removal.