PULMONARY EMBOLISM

• ACRONYMS AND DEFINITIONS

• ACCP - American College of Chest Physicians
• aPTT - activated Partial Thromboplastin Time
• ASH - American Society of Hematology
• bpm - beats per minute
• CTEPH - Chronic thromboembolic pulmonary hypertension
• DOAC - Direct-acting oral anticoagulant (factor Xa inhibitors, dabigatran)
• DVT - Deep vein thrombosis
• HIT - Heparin-induced thrombocytopenia
• INR - International normalized ratio
• LMWH - Low molecular weight heparin
• OCP - Oral contraceptive pills
• PCI - Percutaneous coronary intervention (heart cath and associated procedures - stents, angioplasty, etc.)
• PE - Pulmonary embolism
• RCT - Randomized controlled trial
• SBP - Systolic blood pressure
• SVT - Superficial vein thrombosis
• Venography - procedure where contrast is injected into the veins and an X-ray is taken. Blood clots in the veins can then be visualized.
• VKA - Vitamin K antagonist (e.g. warfarin)
• VTE - Venous thromboembolism (DVT and PE)

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• EPIDEMIOLOGY

• In the U.S., an estimated 900,000 people (0.1 - 0.3% of the adult population) develop a VTE each year. Sudden death is the presenting symptom in about 25% of PE cases. An individual's risk for PE depends on a number of risk factors that are often identifiable. [28]

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• PHYSIOLOGY

• Pulmonary embolism (PE) is a blood clot that originates in the venous system, travels to the lungs, and lodges in the pulmonary artery. The loss of lung perfusion reduces oxygenation, and in severe cases, death can occur. The heart may also be affected, as rising pulmonary artery pressure can strain the right ventricle, reduce cardiac output, and cause hypotension. A large percentage of PEs come from deep vein thromboses, making the two conditions closely related. [1,29]

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• RISK FACTORS FOR PE

• Age (> 65 years)
• Immobilization for an extended period (ex. travel, surgery, hospitalization)
• Cancer (see cancer risk and PE below)
• Estrogen-containing medications (e.g. oral contraceptives, hormone replacement, SERMs) - see also hormone therapy after VTE [3]
• Human immune globulin products (ex. IVIG, Gamimune®, Sandoglobulin®, Polygam®) [2]
• Ponatinib (Iclusig®) [14]
• Hypercoagulable disorders
• Obesity
• Pregnancy
• Previous PE or DVT
• Cigarette smoking [3]
• First-degree relative with a history of unprovoked VTE - the younger the age of the relative when the VTE occurred, the higher the risk [15]
• Superficial Vein Thrombosis - in one study, 2.5% of patients with an SVT developed a DVT within 3 months of SVT diagnosis; the incidence of PE was 0.9% during the same period. At 5 years, the risk of VTE was 5-fold higher in SVT patients compared to unaffected patients. [16]

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• PROVOKED VS UNPROVOKED PE

• Overview
• Recommendations for providing extended anticoagulation after a PE are based on whether the PE is considered provoked or unprovoked. In general, these terms have the following meanings:
• Provoked PE - PE with a preceding identifiable risk factor
• Unprovoked PE - PE with no preceding identifiable risk factor


• Significant provoking risk factors are not consistently defined across the medical literature. For example, in some studies, oral contraceptive use is considered a significant provoking factor, while in others, it is not. The same goes for pregnancy and a list of other conditions. [6]
• The 2021 ACCP VTE recommendations define two categories of provoking risk factors that are used to make extended anticoagulation recommendations. Those categories are described in the table below, along with major risk factors used in the Wells score.

• References [4,27]

ACCP 2021 PE Risk Factor Categories
PE provoked by a major transient risk factor Surgery with general anesthesia for greater than 30 minutes Confinement to bed in hospital (only bathroom privileges) for at least 3 days with an acute illness Cesarean section
PE provoked by a minor transient risk factor Surgery with general anesthesia for less than 30 minutes Admission to hospital for less than 3 days with an acute illness Confinement to bed out of hospital for at least 3 days with an acute illness Leg injury associated with reduced mobility for at least 3 days Estrogen therapy (OCPs or HRT) Pregnancy and the six weeks after delivery
Major risk factors in the Wells score Active cancer Paralysis or recent immobilization of the lower extremity (this could include prolonged travel) Recently bedridden for ≥ 3 days, or major surgery within previous 12 weeks

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• DIAGNOSIS

• Symptoms
• PE symptoms and their incidence are presented in the table below

• Reference [4]

Symptom	Percent of patients with confirmed PE
Shortness of breath	80%
Pleuritic chest pain	52%
Cough	20%
Syncope	19%
Chest pain (substernal)	12%
Hemoptysis (coughing up blood)	11%

• Physical exam
• Physical exam findings in PE are presented in the table below

• Reference [4]

Physical exam finding	Percent of patients with confirmed PE
Rapid respiratory rate (≥ 20/min)	70%
Rapid heart rate (≥ 100/bpm)	52%
Symptoms of DVT (see DVT diagnosis)	20%
Cyanosis	11%
Fever (> 101.3)	7%

• CT scan
• Multidetector lung CT with IV contrast is the preferred method for diagnosing PE, with a sensitivity of close to 100% in some studies and a specificity of 96% [4,28]

• Ventilation-perfusion (V/Q scan)
• Ventilation-perfusion (V/Q) scans, where V represents alveolar ventilation and Q represents alveolar perfusion, can be used to diagnose a PE. Ventilation (V) on a V/Q scan is observed using an inhaled radioisotope, and perfusion (Q) is measured with an intravenous infusion of radioisotope-labeled albumin particles. If a PE is present, affected lung tissue will show reduced perfusion with normal ventilation, creating a high V/Q ratio, while unaffected areas will have a low V/Q ratio because they are overperfused by diverted blood. This shift in the normal ratios is called a V/Q mismatch.
• V/Q scan results are reported as the probability of a PE with normal, near-normal, low, intermediate, and high categories. Normal V/Q scans rule out a PE, while high-probability scans make a PE very likely. The other categories are less useful and require further testing; this is one of the main reasons CT scans are now preferred. V/Q scans may be appropriate in patients who cannot receive iodinated contrast for a CT scan. [4,30]

• Lower extremity ultrasound
• PE patients will have an accompanying lower extremity DVT on ultrasound 30 to 50% of the time. If suspicion for a PE is high, and other testing (e.g. CT scan, V/Q scan) is inconclusive or contraindicated, a lower extremity ultrasound may be informative. [4]

• D-dimer
• D-dimer, a degradation product of fibrin cross-linking whose levels rise during clot formation (see coagulation cascade illustration), can be helpful in diagnosing a PE. An elevated D-dimer is sensitive for a PE, but not specific, as a number of other conditions can cause elevations (e.g. advanced age, cancer, pregnancy, recent surgery). Therefore, a normal D-dimer essentially rules out a PE in many patients, while a high level is nonspecific and requires further testing.

• Age-adjusted D-dimer
• D-dimer levels rise naturally with age, so older patients have higher levels. In most laboratories, the upper limit of normal for a D-dimer is 500 mcg/L (0.500 mg/L). Studies have found that using age-adjusted cutoff levels in patients 50 and older increases the specificity of the test without sacrificing sensitivity, and some experts argue that age-adjusted levels should be the standard. [PMID 26320520, PMID 23645857, PMID 24643601].
• The formula for calculating an age-adjusted level is as follows:
• Age-adjusted D-dimer cutoff = patient's age (if 50 or older) X 10 mcg/L [Online calculator]

• D-dimer with clinical probability tools
• Several studies have looked at the effects of combining D-dimer values with clinical probability tools in an effort to reduce unnecessary imaging. A study incorporating the Wells criteria and one using the YEARS score are detailed below..

• STUDY
  Combination of the D-dimer and the Wells Criteria to Rule Out PE, NEJM (2019) [PubMed abstract]
• Design: Prospective study (N=2017 | length = 3 months) in outpatients and inpatients with symptoms or signs suggestive of pulmonary embolism
• Evaluation: CT scan was not performed if patients met one of the following criteria:
• Low probability (Wells score 0 - 4 and D-dimer < 1000 ng/ml)
• Intermediate probability (Wells score 4.5 - 6 and D-dimer < 500 ng/ml)
• Primary outcome: Symptomatic, objectively verified venous thromboembolism, which included pulmonary embolism or deep vein thrombosis up to 3 months after evaluation
• Results:
• No patients who were ruled out for CT scan by the criteria above were found to have VTE during follow-up. Of these patients, 315 had a low probability Wells score and a D-dimer level of 500 to 999 ng/ml.
• Of all the patients who were evaluated, 7.4% had PE on initial testing
• Findings: A combination of a low clinical pretest probability and a d-dimer level of less than 1000 ng per milliliter identified a group of patients at low risk for pulmonary embolism during follow-up.

• STUDY
  Combination of of YEARS Score and Adjusted D-dimer to Rule Out PE, JAMA (2021) [PubMed abstract]
• Design: Cluster-randomized, crossover study (N=1414 | length = 3 months) in patients presenting to the ER with clinical suspicion of PE (e.g. acute onset of chest pain, worsening acute dyspnea, and/or syncope)
• Evaluation: Patients with a pulmonary embolism rule-out criteria (PERC) score of 0 were excluded, as were patients with a high pretest probability of PE as determined by subjective physician assessment. CT imaging was not performed if patients met one of the following criteria:
• YEARS score^✝ of 0 and D-dimer < 1000 ng/ml
• YEARS score^✝ ≥ 1 and D-dimer less than the age-adjusted D-dimer threshold
• ^✝YEARS score ranges from 0 to 3 with 1 point for each of the following: PE is the most likely diagnosis, hemoptysis, and clinical sign of DVT.
• Primary outcome: Venous thromboembolism (VTE) at 3 months
• Results:
• In the control group, only age-adjusted D-dimer thresholds were used (no YEARS criteria)
• Primary outcome: D-dimer + YEARS - 0.15%, Control - 0.80% (noninferior)
• Findings: Among ED patients with suspected PE, the use of the YEARS rule combined with the age-adjusted D-dimer threshold in PERC-positive patients, compared with a conventional diagnostic strategy, did not result in an inferior rate of thromboembolic events.

• PE diagnostic algorithm
• STEP 1 - Determine if the patient is stable
• Unstable patients
• Five to ten percent of PE patients present with signs of shock and hypotension (e.g. SBP < 90 mmHg, blood pressure drop of ≥ 40 mmHg for > 15 minutes, hypoxia). Unstable patients should proceed immediately to CT scan, and right ventricular function should be evaluated with echocardiography. Treatment with thrombolysis and embolectomy should be considered. [4]
• Stable patients
• Proceed to Step 2

• STEP 2 - Assess patient's probability of PE using Wells score

• Reference [4,5]

Finding / History	Points
Signs and symptoms of DVT	+3
Heart rate > 100 bpm	+1.5
Recently immobilization or surgery (≤ 4 weeks)	+1.5
Previous PE or DVT	+1.5
Hemoptysis (coughing up blood)	+1
Cancer	+1
Pulmonary embolism more likely than alternative diagnosis	+3

• STEP 3 - Determine probability of PE

• Reference [4]

Wells Score	PE probability
< 2	Low probability
2 - 6	Intermediate probability
≥ 7	High probability

• STEP 4 - Based on the patient's probability, do the following:

• Reference [19]

Probability	Testing
High	Perform CT scan
Intermediate	Order D-dimer If D-dimer is elevated, order CT scan If D-dimer is normal, PE unlikely [4, 5]
Low	If patient meets all Pulmonary embolism rule-out criteria (see below), do not order D-dimer or imaging studies (probability of PE < 1%) If patient does not meet all rule-out criteria, order D-dimer [19]

• Pulmonary embolism rule-out criteria
• The PE rule-out criteria is a set of 8 findings that make the probability of a PE less than 1% if all are met. A trial validating the criteria is available here - PMID 29450523.

• Reference [19]

Pulmonary Embolism Rule-Out Criteria
Age < 50 years
Initial heart rate < 100 beats/min
Initial oxygen saturation > 94% on room air
No unilateral leg swelling
No hemoptysis
No surgery or trauma within 4 weeks
No history of VTE
No estrogen use

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• SUBSEGMENTAL PULMONARY EMBOLISM

• Overview
• Subsegmental PEs are small emboli in the periphery of the lung. Advances in CT angiography have made it possible to detect filling defects as small as 2 - 3 mm, causing the diagnosis of subsegmental PEs to increase from 5% of all PEs to over 10%.
• The treatment of subsegmental PEs is debatable, as they are more likely to be false positives and carry a low risk of recurrent VTE. A study published in 2021 found that the risk of recurrent VTE in patients with one untreated subsegmental PE and no DVT was 2.1% over 90 days; in patients with multiple untreated subsegmental PEs, the risk was 5.7%. [PMID 34807722]
• The 2021 ACCP recommendations for subsegmental PEs are provided below


• 2021 ACCP recommendations for subsegmental PE
• Patients at high risk for recurrent VTE (see below) should be treated with anticoagulation
• Patients with low cardiopulmonary reserve and/or marked symptoms that cannot be attributed to another condition should be treated with anticoagulation
• For patients at low risk for recurrent VTE, do the following:
• 1. Perform an ultrasound of the legs to rule out proximal DVT. In patients with central venous catheters, also rule out upper extremity DVT.
• 2. If no DVT is found, clinical surveillance is recommended over anticoagulation. Clinical surveillance entails one or more follow-up ultrasounds to detect an evolving DVT. [20]


• High risk for recurrent VTE defined as having any of the following:
• Hospitalization or reduced mobility for another reason
• Active cancer (particularly if metastatic or being treated with chemotherapy)
• No reversible risk factor for VTE such as recent surgery
• Pregnancy [20,27]

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• ASYMPTOMATIC PULMONARY EMBOLISM

• Occasionally, PEs have no symptoms and are discovered incidentally on imaging performed for another reason. Asymptomatic PEs are seen in about 1% of outpatient and 4% of inpatient contrast-enhanced CT scans. In most cases, these patients have known malignancy, and imaging has been ordered for cancer staging or monitoring.
• The 2021 ACCP guidelines state that the initial and long-term management of asymptomatic PEs should be the same as symptomatic PEs [27]

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• TREATMENT | Anticoagulation

• PE treatment is divided into three phases:
• Initiation phase (5 - 10 days) - period where the patient is quickly anticoagulated to prevent clot expansion
• Treatment phase (3 months) - continued anticoagulation to prevent clot expansion and promote dissolution
• Extended phase (beyond 3 months) - extended anticoagulation to prevent reoccurrence in appropriate patients

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• TREATMENT | Initiation phase (5 - 10 days)

• Initiation phase (5 - 10 days)
• In the initiation phase, patients are quickly anticoagulated to stop the clot from spreading. For many years, warfarin, which takes 3 - 5 days to become therapeutic and requires coverage with quick-acting injectable therapy during that time, was the only oral anticoagulant available. Rivaroxaban and apixaban, two newer DOACs, have a rapid onset of action and do not require injections during the first days of use. Two other DOACs, dabigatran and edoxaban, are FDA-approved for treatment after 5 - 10 days of parenteral therapy.

• Outpatient treatment
• The 2021 ACCP guidelines state that patients with low-risk PEs can be treated as outpatients. The guidelines do not give definitive criteria for "low-risk PE" but suggest the following:
• Clinical decision rules such as the Pulmonary Embolism Severity Index (PESI), either the original form with a score < 85 or the simplified form with a score of 0, can help to identify low-risk patients who are suitable for home treatment (PESI calculator)
• The presence of right ventricular dysfunction or increased cardiac biomarker levels should discourage outpatient treatment [27]

• ACCP 2021 recommendations
• Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) or dabigatran are preferred over warfarin. Parenteral therapy is not required with apixaban and rivaroxaban, whereas 5 to 10 days are recommended with dabigatran and edoxaban.
• Patients with subsegmental PE - see subsegmental PE
• Patients with antiphospholipid syndrome - warfarin (target INR 2.5) is preferred with initial parenteral therapy
• Patients with cancer - Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) are preferred over LMWH. Edoxaban and rivaroxaban appear to be associated with a higher risk of GI major bleeding than LMWH in patients with cancer-associated thrombosis and a luminal GI malignancy, while apixaban does not. Apixaban or LMWH may be the preferred option in patients with luminal GI malignancies (see Factor Xa inhibitors for cancer-associated VTE treatment) [27]

• ASH 2021 recommendations for patients with active cancer
• Apixaban, rivaroxaban, or LMWH is recommended for treatment during the first week [26]
• Studies
• Factor Xa inhibitors for cancer-associated VTE treatment
• A study published in 2015 comparing tinzaparin, a LMWH, to warfarin in cancer patients with acute VTE found no significant difference between the therapies for recurrent VTE or major bleeding at 6 months. [PMID 26284719]

• Heparins
• Unfractionated heparin - typically referred to as "heparin" for short. Heparin works by activating antithrombin, which in turn, inhibits Factor IIa (thrombin) and Factor Xa (coagulation inhibition illustration). Heparin can be administered intravenously or subcutaneously and requires aPTT monitoring. It causes HIT in 1 - 5% of patients. [9]

• Low molecular weight heparin (LMWH) - LMWHs, also called "fractionated heparin," include enoxaparin (Lovenox®), dalteparin (Fragmin®), and tinzaparin (Innohep®). LMWHs are similar to heparin except that they consist of smaller molecules (hence "low molecular weight") because they have been fractionated (divided into parts). Like heparin, LMWHs work by stimulating antithrombin activity (see coagulation inhibition illustration). LMWHs are given by subcutaneous injection, and they do not require lab monitoring. Enoxaparin (Lovenox®), the most widely used LMWH, is dosed 1 mg/kg every 12 hours for VTE treatment and 40 mg once daily for VTE prevention. The risk of HIT with LMWH is 0.1 - 1.0%. [9]

• Fondaparinux (Arixtra®) - fondaparinux is a synthetic heparin derivative that activates antithrombin, but unlike heparins where Factor Xa and IIa are inhibited, only Factor Xa is inhibited when antithrombin is stimulated by fondaparinux (see coagulation inhibition illustration). Fondaparinux carries a negligible risk of HIT, and some experts recommend its use in HIT patients; however, it is not FDA-approved for this indication. Fondaparinux is administered once daily by subcutaneous injection and does not require lab monitoring. [9]

• Heparin-induced thrombocytopenia (HIT)
• Heparins can cause a syndrome called heparin-induced thrombocytopenia (HIT) that is marked by the development of antibodies to complexes of platelet factor 4 (PF4) and heparin. Anti-PF4 antibodies can activate platelets, causing thrombosis and platelet depletion. During HIT, platelet counts typically fall by 50% between 5 and 14 days after heparin initiation; patients with previous heparin exposure may see counts drop within 24 hours. If HIT is suspected, testing for anti-PF4 antibodies can be performed; however, a positive test has low specificity, as antibodies are present in up to 20% of heparin-exposed patients, but only a small fraction of these patients will develop HIT. To help make a diagnosis, a calculator has been developed that estimates the probability of HIT based on 4 findings (see 4Ts Score Calculator for HIT). HIT, which has a mortality of 5 - 10%, is treated by stopping heparin and switching to a non-heparin anticoagulant. [9,22]

• Non-heparins
• Argatroban - argatroban is a direct thrombin inhibitor FDA-approved for VTE treatment in patients with HIT syndrome. It is administered via continuous IV infusion and requires aPTT monitoring.
• Bivalirudin (Angiomax®) - bivalirudin is a direct thrombin inhibitor FDA-approved for use during PCI in patients with HIT syndrome. It is administered via continuous IV infusion and requires aPTT monitoring.

• Parenteral therapy treatment recommendations
• Patients with no history of HIT:
• LMWH or fondaparinux are preferred. Intravenous or subcutaneous unfractionated heparin may also be used.
• Therapy should last at least 5 days. See initiating warfarin for recommendations on dosing warfarin.
• Patients with ongoing HIT
• Direct thrombin inhibitor (argatroban)
• If cardiac surgery or PCI is needed, then use bivalirudin
• Patients with a history of HIT
• Fondaparinux [7]

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• TREATMENT | Treatment phase (3 months)

• Treatment phase (3 months)
• During the treatment phase, acute-phase anticoagulation is extended for a total of 3 months to facilitate clot reabsorption. Patients who received parenteral therapy during the acute phase are typically switched to oral therapy.

• ACCP 2021 recommendations
• All patients should be treated for 3 months with the anticoagulant they received in the initiation phase [27]

• ASH 2021 recommendations for patients with active cancer
• First-line: apixaban, edoxaban, or rivaroxaban
• Second-line: LMWH
• Third-line: vitamin K antagonist [26]
• Studies
• Factor Xa inhibitors for cancer-associated VTE treatment
• A study published in 2015 comparing tinzaparin, a LMWH, to warfarin in cancer patients with acute VTE found no significant difference between the therapies for recurrent VTE or major bleeding at 6 months. [PMID 26284719]

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• TREATMENT | Extended phase (beyond 3 months)

• Extended phase (beyond 3 months)
• After 3 months of treatment, extended anticoagulation is used to prevent VTE recurrence, which can be as high as 8% in the first year after an unprovoked VTE. The 2021 ACCP recommendations for extended anticoagulation divide VTEs into the following three categories:
• VTE provoked by a major transient risk factor (see major and minor risk factor definitions)
• VTE provoked by a minor transient risk factor
• Unprovoked VTE or persistent risk factor (e.g. thrombophilia)

• 2021 ACCP recommendation
• NOTE: see ACCP categories for definitions of major and minor transient risk factors
• Patients with a major transient risk factor should not receive extended coagulation
• Patients with a minor transient risk factor should not receive extended coagulation
• Patients with an unprovoked PE or persistent risk factor (e.g. thrombophilia) should receive extended coagulation with a DOAC. If a DOAC cannot be used, a vitamin K antagonist should be offered. Patients with antiphospholipid syndrome should receive warfarin.
• Extended-phase apixaban dosing should be 2.5 mg twice daily, and extended-phase rivaroxaban dosing should be 10 mg once daily.
• In patients with an unprovoked proximal DVT or PE who stop anticoagulant therapy, taking low-dose daily aspirin may help to prevent VTE recurrence [27]
• A quantitative estimate of the risks and benefits of extended therapy is available here - risk-benefit estimation

• 2021 ASH recommendations for patients with active cancer
• Extended anticoagulation is recommended in all cancer patients with VTE
• Apixaban, edoxaban, rivaroxaban, or LMWH may be used [26]

• Recurrent PE while taking anticoagulants
• Recurrent VTE while receiving anticoagulant therapy is rare, and affected patients should be evaluated for the following: (1) is the VTE truly a recurrent VTE, (2) anticoagulant compliance, (3) possibility of an underlying malignancy. The ACCP gives the following treatment recommendations:
• In patients receiving warfarin or a DOAC, switch to LMWH temporarily (defined as at least 1 month)
• In patients receiving long-term LMWH, increase the dose of LMWH by about one-quarter to one-third [20]

• Anticoagulant + antiplatelet therapy
• Patients with a PE who have coronary artery disease have indications for both anticoagulation and antiplatelet therapy. Recommendations for antithrombotic therapy in these patients are provided at the links below.
• Triple therapy recommendations (patients who are < 12 months since ACS, PCI, or CABG)
• Stable coronary artery disease (patients who are > 12 months since ACS, PCI, or CABG)

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• OTHER TREATMENTS

• Thrombolysis
• Thrombolytic agents (e.g. alteplase, streptokinase), administered systemically or directly into a clot through a catheter, can be used to dissolve a PE
• A study published in 2014 compared thrombolysis to placebo in normotensive patients with right ventricular dysfunction following a PE. The study found that thrombolysis decreased the risk of hemodynamic decompensation, increased the risk of major bleeding, and had no effect on overall mortality. [PMID 24716681].
• 2021 ACCP guidelines recommend systemic thrombolytic therapy in the following patients:
• Patients with acute PE associated with hypotension (e.g. systolic BP < 90 mmHg) who do not have high bleeding risk
• Select patients with acute PE who deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk [20,27]

• Inferior Vena Cava (IVC) filters
• IVC filters are devices placed in the inferior vena cava that capture venous blood clots, preventing them from reaching the lungs. IVC filters may be placed permanently or temporarily using retrievable filters. [25]
• A study published in 2015 compared anticoagulation to anticoagulation + a temporary IVC filter (3 months) in PE patients at high risk for recurrence. The study found no benefit of adding the IVC filter. [PMID 25919526]
• 2021 ACCP recommendations
• IVC filters should only be used in patients with acute VTE (e.g. diagnosed in the preceding 1 month) in whom anticoagulants are contraindicated. In these patients, the IVC filter should be promptly removed when anticoagulant therapy has been instituted.
• IVC filters should not be combined with anticoagulation in most patients. Because it is uncertain if there is benefit to placement of an IVC filter in anticoagulated patients with severe PE (e.g. with hypotension), our recommendation against insertion of an IVC filter in patients with acute PE who are anticoagulated may not apply to this select subgroup of patients. [20,27]

• Embolectomy
• PEs can be removed directly through open surgery or with devices run through a catheter. These procedures require a certain expertise that is not widely available.
• 2021 ACCP guidelines recommend possible embolectomy in the following patients:
• In patients with acute PE associated with hypotension and who have a high bleeding risk, failed systemic thrombolysis, or shock that is likely to cause death before systemic thrombolysis can take effect (e.g. within hours), if appropriate expertise and resources are available, we suggest catheter assisted thrombus removal (mechanical interventions ± direct thrombolysis) over no such intervention [20,27]

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• RISK OF RECURRENT VTE

• Overall risk
• The risk of recurrent VTE is strongly tied to the presence or absence of a provoking risk factor. The first table below shows the 1-year risk of recurrence based on provoking risk factors in patients who received no extended anticoagulation. The second table gives cumulative incidences of recurrent VTE over 10 years in patients who discontinued anticoagulation after a first unprovoked VTE.

• Patients were treated with at least 3 months of anticoagulation
• Reference [6]

Recurrence rate in first year after stopping anticoagulation
Type of VTE	Recurrence
Provoked by surgery	1.0%
Provoked by nonsurgical risk factor	5.8%
Unprovoked VTE	7.9%

• Reference [23]

Cumulative recurrent VTE risk for patients who discontinued anticoagulation after a first unprovoked VTE
Time	VTE (Men)	VTE (Women)
2 years	18.3%	13.6%
5 years	28.6%	21.2%
10 years	41.2%	28.8%

• Reference [24]

Cumulative recurrent VTE risk by initial VTE site for patients with first unprovoked VTE who were not anticoagulated
Time	Distal DVT	Proximal DVT	PE
10 years	17%	37%	34%
20 years	30%	47%	44%

• Recurrent VTE after stopping estrogen-containing OCPs
• A systemic review and meta-analysis published in 2022 examined the risk of recurrent VTE in women diagnosed with estrogen-provoked VTE. The review included 14 studies where women with a VTE thought to be provoked by an estrogen-containing OCP received acute treatment for at least 3 months and were then followed after they discontinued anticoagulation. The overall rate of recurrent VTE after stopping anticoagulation was 1.57% per year. In studies where all patients stopped hormonal use or were strongly encouraged to do so (N=8), the recurrence rate was 1.31% per year. The rate among studies that included patients with high-risk thrombophilias (N=4) was 1.95% per year, compared to 1.40% per year among studies that excluded these women. [PMID 35108438]
• Summary
• This observational study provides meaningful information on the risk of VTE recurrence in females who experience a VTE while taking estrogen-containing OCPs. OCP use is considered a minor transient risk factor in the most recent ACCP guidelines, and extended anticoagulation is not recommended. Given that the overall risk of recurrence in these women was 1.57% per year, this analysis supports their recommendation.

• Recurrent VTE after negative D-dimer
• D-dimer levels are useful in diagnosing a VTE. Some studies have shown they can also predict VTE recurrence, with elevated levels after VTE treatment indicating greater risk. The study below evaluated the utility of D-dimer testing to predict future VTE risk.

• STUDY
  D-dimer testing to predict recurrent VTE in patients with first unprovoked VTE, Ann of IM (2015) [PubMed abstract]
• The study enrolled 410 adults with first unprovoked VTE who had completed 3 - 7 months of anticoagulation
• Patients had a D-dimer test during treatment, and if it was negative, anticoagulation was stopped. A second test was performed 1 month later, and if it was also negative, anticoagulation was held indefinitely (N=321). Recurrent VTE risk in patients with two negative tests is detailed in the table below, with women subdivided into whether their first VTE occurred during estrogen therapy (OCPs or HRT).

• Estrogen women were taking estrogen-containing OCPs or hormone replacement therapy when their first VTE occurred
• ^✝Five-year results were reported in a separate study [PMID 31033194]
• References [26,28]

Risk of recurrent VTE after negative D-dimer testing
Follow-up	Men	Non-estrogen Women	Estrogen Women
Average of 2.2 years	18.3%	11%	0%
Median of 5 years✝	29.7%	17%	2.3%

• Summary
• In the study above, D-dimer testing was not helpful in identifying patients at lower risk for VTE, as recurrence rates in negative patients were similar to those in untested populations

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• RISK-BENEFIT ESTIMATION

• ACCP risk-benefit estimation
• The ACCP published a table in their 2012 guidelines that estimates the risk and benefits of extended anticoagulation. Although the data has not been validated in a prospective study, it does offer a quantitative estimate of bleeding and recurrent VTE risk in patients treated with long-term anticoagulation.

• Categories of major bleeding risk:
• Low-risk: 0 risk factors
• Moderate-risk: 1 risk factor
• High-risk: ≥ 2 risk factors


• Risk factors for bleeding:
• Age > 65 years
• Age > 75 years (NOTE: An 80 year old would have 2 risk factors by age (> 65 and 75) and a 70 year old would have one risk factor by age)
• Previous bleeding
• Cancer
• Metastatic cancer (NOTE: A person with localized cancer would have one risk factor by cancer and a person with metastatic cancer would have 2 risk factors by cancer)
• Kidney failure
• Liver failure
• Low platelets (thrombocytopenia)
• Previous stroke
• Diabetes
• Anemia
• Antiplatelet therapy
• Poor anticoagulant control
• Comorbidity and reduced functional capacity
• Recent surgery
• Frequent falls
• Alcohol abuse [7]

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• THROMBOPHILIA TESTING / HYPERCOAGULABLE WORKUP

• See thrombophilia testing for recommendations on testing patients with VTE for hypercoagulable disorders

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• UNPROVOKED PE AND CANCER RISK

• Overview
• Up to 10% of patients with an unprovoked VTE are diagnosed with cancer within a year of their event. This association causes some providers to perform extensive cancer workups in affected patients. To test the validity of this approach, a study published in 2015 compared standard cancer screening to standard screening + CT of the abdomen/pelvis in patients with first unprovoked VTE.

• Summary
• The SOME study found no benefit of adding an abdominal and pelvic CT to standard cancer screening in patients with a first unprovoked VTE. It's unclear if an unprovoked VTE is a marker of increased cancer risk or if the higher incidence of cancer diagnosis after VTE is secondary to surveillance bias.

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• CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION (CTEPH)


• Chronic thromboembolic pulmonary hypertension (CTEPH) is a condition that occurs when a PE fails to completely reabsorb and is replaced over months to years with fibrous tissue that becomes incorporated into the artery wall. Blood flow is obstructed, and over time, pulmonary hypertension and right heart failure can develop.
• The incidence of CTEPH after PE is around 3 - 5%, and up to two-thirds of affected patients have no history of symptomatic PE.
• CTEPH is treated with surgical endarterectomy, a procedure where the obstructing material is surgically removed from the pulmonary artery. [4,7]

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• ASPIRIN FOR VTE PREVENTION

• See aspirin for VTE prevention

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• BIBLIOGRAPHY

• 1 - PMID 19109575 - NEJM PE review
• 2 - FDA warning
• 3 - PMID 22494827 - Lancet review
• 4 - PMID 18757870 - ESC GL for PE
• 5 - PMID 19109575 - NEJM PE case
• 6 - PMID 20975016 - Ach of IM risk factor for VTE
• 7 - PMID 22315268 - ACCP recs for TE - full
• 8 - PMID 21422387 - AHA recs for PE
• 9 - PMID 2345166 - NEJM HIT review
• 10 - PMID 15254285 - NEJM DVT review
• 11 - PMID 22621626 - WARFASA study
• 12 - PMID 23121403 - ASPIRE study
• 13 - PMID 23645857 - age-adjusted d-dimer
• 14 - Ponatinib PI
• 15 - PMID 25049279 - Factors that predict thrombosis in relatives of patients with venous thromboembolism, Blood (2014)
• 16 - PMID 25398934 - Risk of venous and arterial thrombotic events in patients diagnosed with superficial vein thrombosis: a nationwide cohort study, Blood (2015)
• 17 - PMID 26095467 - SOME study
• 18 - PMID 20149076 - incidence of VTE after cancer
• 19 - PMID 26414967 - ACP PE best practices
• 20 - PMID 26867832 ACCP 2016 VTE GL
• 21 - PMID 15900005 - Hypercoagulable workup and VTE risk
• 22 - PMID 29411014 - Evaluating Thrombocytopenia During Heparin Therapy, JAMA (2018)
• 23 - PMID 31340984 - Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis, BMJ (2019)
• 24 - PMID 27696701 - The long-term recurrence risk of patients with unprovoked venous thromboembolism: an observational cohort study J Thromb Haemost (2016)
• 25 - PMID 32919823 - Society of Interventional Radiology Clinical Practice Guideline for Inferior Vena Cava Filters in the Treatment of Patients with Venous Thromboembolic Disease: Developed in collaboration with the American College of Cardiology, American College of Chest Physicians, American College of Surgeons Committee on Trauma, American Heart Association, Society for Vascular Surgery, and Society for Vascular Medicine, J Vasc Interv Radiol (2020)
• 26 - PMID 33570602 - American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer, Blood Advances (2021)
• 27 - PMID 34352278 - Executive Summary: Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report, Chest (2021)
• 28 - CDC Data and Statistics on Venous Thromboembolism
• 29 - Medscape, Pulmoanry embolism
• 30 - PMID 28144061 - Mechanisms of hypoxemia, Lung India (2017)