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)

• PHYSIOLOGY

• Pulmonary embolism (PE) is a condition where a blood clot in the venous system travels through the circulation and lodges in the lung tissue. Blood clots that cause pulmonary embolisms often originate from a deep vein thrombosis (DVT). DVT and PE are closely related conditions that have common risk factors.
• Lung tissue affected by a pulmonary embolism does not oxygenate properly
• The right side of the heart may also be affected because pressure in the blood vessels that perfuse the lung may rise after a pulmonary embolism. This can cause strain on the right side of the heart.
• Pulmonary embolisms can have a wide range of effects. Massive pulmonary embolisms can cause sudden death while small pulmonary embolism may have no symptoms at all.
• The incidence of pulmonary embolism in the general population ranges from 23 - 69 cases per 100,000 people per year
• The mortality rate for pulmonary embolism varies widely depending on the population studied. On average, PE has a mortality rate of 11% within 2 weeks of diagnosis [1]

• RISK FACTORS FOR PE

• Main risk factors for pulmonary embolism include:
• 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, patients with SVT had a 2.5% incidence of DVT in the first 3 months following SVT diagnosis. Incidence of PE was 0.9% in the same 3 months. At 5 years after SVT diagnosis, risk of VTE was 5-fold higher than patients without a history of SVT. [16]

• DIAGNOSIS

• Symptoms
• Common symptoms of PE are presented in the table below

• Physical exam
• Common physical exam findings in PE are presented in the table below. No single exam finding is diagnostic for PE.

• CT scan
• Multidetector CT scan of the lungs with IV contrast has become the preferred method for diagnosing PE
• Modern CT scanners have a sensitivity of 83% and a specificity of 96% for diagnosing PE [4]

• Ventilation-perfusion (V/Q scan)
• Ventilation-perfusion (V/Q) scans can be used to diagnose PE, but they have fallen out of favor as CT scan technology has improved
• During a V/Q scan, the patient is given an intravenous infusion of radioisotope-labeled albumin particles. The particles travel to the lung tissue where they "light up" the capillary beds. If there is occlusion of a pulmonary artery branch by a PE, then the affected lung tissue will not light up (cold spot) during scintigraphy (procedure for viewing the isotope distribution).
• During the scan, the patient is also given an inhaled radioisotope so that the normal ventilation of the lung can be observed. Some areas of the lung may not ventilate properly because of processes other than PE (ex. reactive vasoconstriction). These areas will have a "ventilation-perfusion match" where neither inhaled or intravenous radioisotope is observed. A PE will cause an area of "ventilation-perfusion mismatch" because the area will have normal ventilation but no perfusion.
• V/Q scan results are reported as normal, near-normal, low, intermediate, and high probability for PE
• Normal V/Q scans rule out PE. High probability scans mean a PE is very likely. The other categories are less useful and require further testing. This is one of the main reasons CT scans are now preferred. [4]
• V/Q scans may be appropriate in patients who cannot receive the iodinated contrast that is required for a CT scan

• Lower extremity ultrasound
• PE and deep vein thrombosis go hand in hand
• Lower extremity ultrasound will show a DVT in 30 - 50% of patients with a PE. A proximal DVT will be detected with ultrasound in 20% of patients with a PE. Diagnosis of a proximal DVT in patients with suspected PE is enough to warrant anticoagulation without further testing.
• Lower extremity ultrasound may be useful in situations where modern CT technology is not available, or in patients who cannot receive the iodinated contrast that is required for a CT scan [4]

• D-dimer
• D-dimer is a degradation product of fibrin cross-linking (see coagulation cascade illustration), and it is used in the diagnosis of PE.
• An elevated D-dimer level can occur when blood clots are being formed. It can also be elevated in other conditions unrelated to a VTE (ex. advanced age, cancer, pregnancy, recent surgery). That being said, the D-dimer test has high sensitivity and low specificity for VTE.

• Age-adjusted D-dimer
• In most laboratories, the upper limit for a normal D-dimer is 500 mcg/L (0.500 mg/L). D-dimer levels rise naturally with age, so the use of age-adjusted D-dimer cutoff values has been recommended. Age-adjusted D-dimer cutoff values are calculated by taking the patient's age (if over 50 years) and multiplying it by 10 mcg/L (mg/L). Studies have found that using age-adjusted limits in patients with low-to-intermediate probability VTE improves the test's specificity with little or no loss of sensitivity. [PMID 26320520, PMID 23645857, PMID 24643601]

• D-dimer with clinical probability tools
• Several studies have looked at different D-dimer cutoff values in combination with PE clinical probability tools to reduce imaging. Those studies 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 patients who present with PE are unstable. Unstable patients will have 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. If CT scan is not available, they should have transesophageal echocardiography to look for right ventricular strain. Patients with unstable PE should also be considered for thrombolysis and embolectomy (see other treatments below). [4]
• Stable patients
• Proceed to Step 2

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

• STEP 3 - Determine probability of PE

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

• Pulmonary embolism rule-out criteria
• The PE rule-out criteria is a set of 8 criteria that if all are met, the risk of PE is very low and testing for PE (e.g. D-dimer, imaging) is not indicated
• Use of the criteria has been validated in trials [PMID 29450523]

• PROVOKED VS UNPROVOKED PE

• Overview
• Extended treatment decisions surrounding PEs are based on whether the PE is considered provoked or unprovoked
• In general, these terms have the following meanings:
• Provoked PE - PE where there is an identifiable risk factor that likely caused the PE
• Unprovoked PE - PE where there is no identifiable risk factor that likely caused the PE


• Defining provoked vs unprovoked
• Risk factors that constitute a provoked PE and ones that do not are not consistently defined across the medical literature. For example, in some studies oral contraceptive use is considered a provoking risk factor and in others, it is not. The same goes for pregnancy and a list of other factors. [6]
• The 2021 ACCP VTE recommendations created two categories of provoking risk factors that they use to make extended treatment recommendations. Those categories are defined below, along with the major risk factors used in the Wells score.


• 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 [27]
• Wells score major risk factors
• Active cancer
• Recently immobilization or surgery (≤ 4 weeks) [4]

• SUBSEGMENTAL PULMONARY EMBOLISM

• Overview
• Subsegmental pulmonary embolisms 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 pulmonary embolisms to increase from 5% of PEs to over 10% of PEs.
• It is uncertain if patients with subsegmental pulmonary embolisms should be anticoagulated. Subsegmental PEs are more likely to be false positives, and they carry a lower risk of recurrent VTE. A study published in 2021 found that 2.1% of patients with one subsegmental PE and no DVT had a recurrent VTE within 90 days. In patients with multiple subsegmental PEs, the incidence was 5.7%. [PMID 34807722] No randomized controlled trials have compared anticoagulation to none in patients with subsegmental PEs.
• The 2021 ACCP guidelines for patients who only have subsegmental PEs are detailed below.


• 2021 ACCP recommendations for subsegmental PE
• Patients at high-risk for recurrent VTE (see below) - anticoagulation
• Patients with low cardiopulmonary reserve and/or marked symptoms that cannot be attributed to another condition - anticoagulation
• Patients at low-risk (see below) for recurrent VTE:
• 1. Perform 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]

• ASYMPTOMATIC PULMONARY EMBOLISM

• Occasionally, asymptomatic PEs are discovered incidentally on imaging that is performed for another reason. Asymptomatic PEs are found on about 1% of outpatient and 4% of inpatient contrast-enhanced CT scans. In most cases, these patients have known malignancy, and the 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]

• TREATMENT | Overview

• Overview
• The treatment of PE can be divided into three phases:
• Acute phase (usually around 5 days) - period where patient is quickly anticoagulated to prevent clot expansion
• Intermediate phase (5 days to 3 - 6 months) - continued anticoagulation to prevent clot expansion and promote dissolution
• Extended phase (> 3 - 6 months) - extended anticoagulation to prevent reoccurrence in appropriate patients

• TREATMENT | Acute phase (first 5 days)

• Overview
• In the acute phase of PE treatment, patients are quickly anticoagulated to stop the clot from spreading. For many years, warfarin was the only oral anticoagulant available. Warfarin takes 3 - 5 days to become therapeutic, so patients have to be covered with quick-acting injectable anticoagulants (typically LMWH) during that period.
• Two newer anticoagulants have a rapid onset of action and do not require injections during the first days of use. Rivaroxaban (Xarelto®) and apixaban (Eliquis®), two Factor Xa inhibitors, are FDA-approved as monotherapy for PE treatment in the acute phase. Two other anticoagulants, dabigatran (Pradaxa®) and edoxaban (Savaysa®), are FDA-approved for treatment after 5 - 10 days of parenteral therapy.

• Outpatient treatment
• The 2021 ACCP guidelines state that patients with low-risk PE 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 treatment at home (PESI calculator)
• The presence of right ventricular dysfunction or increased cardiac biomarker levels should discourage treatment out of the hospital [27]

• Acute phase medications and HIT syndrome
• Heparin-induced thrombocytopenia (HIT) - Heparins can cause a syndrome called Heparin-Induced Thrombocytopenia (HIT). HIT occurs when platelets become activated by antibodies to anti-PF4-heparin complexes (PF4 = platelet factor 4). The activated platelets form clots which can lead to thrombosis (PE, DVT, heart attack, and stroke). When HIT occurs, platelet counts typically fall by 50% from baseline between 5 - 14 days after heparin initiation. Patients who were previously exposed to heparin may see platelet counts drop within 24 hours of exposure. Testing for HIT antibodies can be performed if the condition is suspected. It's important to note that as many as 20% of patients exposed to heparin develop HIT antibodies, but very few of these patients will develop HIT syndrome. A HIT criteria score has been developed to help diagnosis the condition (see 4Ts Score Calculator for HIT). HIT is treated by stopping heparin and switching to a non-heparin anticoagulant. HIT has a mortality of 5 - 10%. [9,22]

• Unfractionated heparin - Typically referred to as "heparin" for short. Heparin works by stimulating antithrombin activity. Antithrombin inhibits Factor IIa (thrombin) and Factor Xa. Unfractionated heparin can cause HIT in 1 - 5% of patients. Unfractionated heparin can be administered by intravenous and subcutaneous routes. Heparin requires lab monitoring with the aPTT. [9] See coagulation inhibition illustration.

• Low molecular weight heparin (LMWH) - Also called "fractionated heparin." LMWHs 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. LMWHs are dosed once daily by subcutaneous injection, and they do not require lab monitoring. Enoxaparin (Lovenox®) is the most widely used LMWH, and it 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%. See coagulation inhibition illustration. [9]

• Fondaparinux (Arixtra®) - Fondaparinux is a synthetic derivative of heparin that activates antithrombin. Fondaparinux stimulates antithrombin inhibition of Factor Xa but not Factor IIa (thrombin). Fondaparinux has a negligible risk of HIT. Some clinicians recommend using fondaparinux for anticoagulation in patients with HIT. It is not FDA-approved for use in HIT syndrome. Fondaparinux is administered once daily by subcutaneous injection, and it does not require lab monitoring. See coagulation inhibition illustration. [9]
• Factor Xa inhibitors - Rivaroxaban and apixaban are Factor Xa inhibitors. Both medications are FDA-approved for the treatment of PE in the acute phase. They are not known to cause HIT syndrome. They are not FDA-approved for use in HIT syndrome. They do not require lab monitoring.
• Argatroban - Argatroban is an intravenous direct thrombin inhibitor. It does not cause HIT syndrome. It is FDA-approved for use in HIT syndrome. It is administered as a continuous IV infusion. Argatroban requires lab monitoring with the aPTT.
• Lepirudin (Refludan®) - Lepirudin is an intravenous direct thrombin inhibitor. It does not cause HIT syndrome. It is FDA-approved for use in HIT syndrome. It is administered by continuous IV infusion. Lepirudin requires lab monitoring with the aPTT.
• Desirudin (Iprivask®) - Desirudin is a subcutaneous direct thrombin inhibitor. It does not cause HIT syndrome. It is not FDA-approved for HIT syndrome. It is administered by twice daily subcutaneous injection. It does not require lab monitoring.
• Bivalirudin (Angiomax®) - Bivalirudin is an intravenous direct thrombin inhibitor. It does not cause HIT syndrome. It is not FDA-approved for use in HIT syndrome. It is administered by continuous IV infusion. Bivalirudin requires lab monitoring with the aPTT.

• 2016 ACCP recommendations
• Patients with no history of HIT - one of the following:
• Factor Xa inhibitors - rivaroxaban (Xarelto®) and apixaban (Eliquis®) may be used in the acute phase because they do not require initial parenteral anticoagulation [20]
• LMWH (preferred over unfractionated heparin) - preferred in patients with cancer
• Fondaparinux (preferred over unfractionated heparin)
• Intravenous or subcutaneous unfractionated heparin
• NOTE: Acute therapy should continue for at least 5 days. If warfarin is to be used for intermediate therapy, then it should be started with injectable therapy. Warfarin typically takes 3-5 days to become therapeutic. Injectable therapy should be continued until the INR is therapeutic (INR of 2 - 3), but not less than 5 days.
• Patients with ongoing HIT
• Direct thrombin inhibitor (argatroban, lepirudin)
• If cardiac surgery or PCI is needed, then use bivalirudin
• Patients with a history of HIT
• Fondaparinux [7]

• 2021 ASH recommendations for patients with active cancer
• Apixaban, rivaroxaban, or LMWH is recommended for treatment during the first week [26]

• TREATMENT | Intermediate phase (5 days to 3 months)

• Overview
• The intermediate phase of treatment involves prolonging anticoagulation for a number of months (typically 3 - 6) so that the PE will not extend and dissolution may occur
• In most cases, patients who require parenteral anticoagulation during the acute phase are switched to oral anticoagulants during the intermediate phase
• The 2011 AHA intermediate recommendations vary slightly from the 2016 ACCP recommendations in that they recommend 6 months of anticoagulation over 3 months in certain patients

• Intermediate phase medications
• Warfarin (Coumadin®) - For a long time, warfarin was the only oral anticoagulant available. The advantage of warfarin is that its efficacy and side effects are well-documented. It is also very cheap. The disadvantages of warfarin are that it requires constant, and often times, frequent lab monitoring and dosage adjustments. Warfarin interacts with a number of medications, and it can also be affected by a person's diet.
• Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) - Factor Xa inhibitors do not require frequent lab monitoring, but they are more expensive than warfarin
• Direct thrombin inhibitors (dabigatran, Pradaxa®) - dabigatran does not require frequent lab monitoring, but it is more expensive than warfarin
• Low molecular weight heparin (LMWH) - Also called "fractionated heparin." LMWHs include enoxaparin (Lovenox®), dalteparin (Fragmin®), and tinzaparin (Innohep®). LMWHs are recommended in patients with cancer, although recent studies have found that warfarin and Factor Xa inhibitors may be equally as effective in this patient population.

• 2021 ACCP recommendations
• Patients without cancer
• The ACCP recommends 3 months of anticoagulation for all types of PEs
• The ACCP recommends dabigatran, rivaroxaban, apixaban or edoxaban as first-line therapies for PE treatment. If these medications are not used, then warfarin with a target INR of 2 - 3 is recommended. [20,27]
• Patients with cancer
• Apixaban, edoxaban, or rivaroxaban for 3 months. Edoxaban and rivaroxaban appear to be associated with a higher risk of GI major bleeding than LMWH in patients with cancer-associated thrombosis (CAT) and a luminal GI malignancy, while apixaban does not. Apixaban or LMWH may be the preferred option in patients with luminal GI malignancies. [27]
• A study published in the JAMA in 2015 compared LMWH to warfarin in cancer patients with VTE [PMID 26284719].
• A study published in the NEJM in 2018 compared LMWH to edoxaban in cancer patients with VTE (see edoxaban for cancer-associated VTE)

• 2021 ASH recommendations for patients with active cancer
• First-line: apixaban, edoxaban, or rivaroxaban
• Second-line: LMWH
• Third-line: vitamin K antagonist [26]

• TREATMENT | Extended phase (> 3 months)

• Overview
• The extended phase of treatment involves continuing anticoagulation beyond the intermediate phase to prevent a recurrence of PE in susceptible patients (see recurrent PE risk below)
• The 2021 ACCP recommendations divide patients into 3 categories based on their provoking risk factors, while previous recommendations used a table that incorporated bleeding risk, first versus second PE, and provoked versus unprovoked. Both guidelines are provided below because they offer two different approaches, and neither has been validated in a prospective trial.
• In most cases, the medication used in the intermediate phase will be continued in the extended phase. Patients should have their risk-benefit ratio reassessed annually.

• 2021 ACCP recommendation
• The 2021 ACCP guidelines state that patients should be divided into 3 groups based on their provoking risk factors (see below)
• Recommendations based on these groups include the following:
• 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.
• In patients receiving extended-phase apixaban, dosing should be 2.5 mg twice daily. In patients receiving 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 recurrent VTE


• 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 [31]
• Unprovoked PE or persistent risk factor (e.g. thrombophilia)

• 2016 ACCP recommendations
• Patients without cancer
• The 2016 ACCP recommendations for extended therapy (see table below) depend on the patient's estimated bleeding risk, whether the PE is provoked or unprovoked, and first versus recurrent. The guidance is based on risk-benefit estimates detailed here - risk-benefit estimation.
• For patients who decline anticoagulants, the ACCP suggests that aspirin be considered since it may help prevent PEs. Aspirin is not as effective as anticoagulants (see aspirin for VTE prevention below) [20]
• Patients with cancer
• The ACCP recommends extended anticoagulation in all patients with active cancer

• 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]

• Summary
• The PADIS-PE study showed that the benefits of extended anticoagulation in patients with first unprovoked PE outweigh the potential risks. It's also important to note that 43% of the subjects were categorized at baseline as "high bleeding risk" by the ACCP bleeding risk criteria. According to the 2016 ACCP guidelines, extended anticoagulation would not have been recommended for these patients.
• During the 24 month post-treatment phase, the risk of VTE in the warfarin group returned to that of the placebo group. This shows that extending initial anticoagulation by 18 months does not appear to lower future VTE risk.

• TREATMENT

• Recurrent PE on anticoagulants
• In rare cases, patients may experience a recurrent PE while they are receiving anticoagulant therapy
• If an on-treatment PE has been confirmed, then an underlying malignancy should be considered
• The ACCP gives the following treatment recommendations for on-treatment PEs
• ACCP recommendations for treating recurrent PEs while on anticoagulants
• In patients receiving warfarin, dabigatran, rivaroxaban, apixaban or edoxaban, switch to LMWH temporarily (defined as at least 1 month)
• In patients receiving 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)

• OTHER TREATMENTS

• Thrombolysis
• Thrombolysis involves infusing a thrombolytic agent (e.g. alteplase, streptokinase, etc.) that causes the PE to dissolve. Thrombolytic agents may be infused systemically (peripheral vein) or in some cases, directly into the clot using a catheter (catheter directed).
• 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, but increased the risk of major bleeding. It 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 "filter" blood clots from the venous blood headed to the lungs. IVC filters may be placed permanently or temporarily using retrievable filters. [25]
• A study published in the JAMA compared anticoagulation to anticoagulation + temporary IVC filter (3 months) in high-risk patients. The study found no benefit of adding an IVC filter to anticoagulation. [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
• Embolectomy involves removing the PE either through open surgery or with devices that 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]

• RISK OF RECURRENT PE

• Overall risk
• The risk of recurrent VTE depends on a number of factors including VTE type (provoked vs unprovoked), sex, VTE site, and other patient-specifc comorbidities
• A number of studies have looked at the risk of recurrent VTE. The first table is from a meta-analysis that looked at recurrence risk during the first year after an event based on VTE type. The second table is from a meta-analysis that followed recurrence rates for up to 10 years in patients who discontinued anticoagulation after a first unprovoked VTE. The third table is from a study that followed VTE risk for 20 years and subdivided the risk based on site of initial VTE.

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

• BLEEDING RISK

• Overview
• Bleeding risk categories used in the ACCP guidelines are based on the risk factors presented below. It's important to note that estimating bleeding risk is an imperfect science, and criteria from different organizations often vary.
• Once the bleeding risk category is determined, it can be used in the risk-benefit estimation below


• 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]

• 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. The table has not been validated in a prospective study, but it does offer a quantitative estimate of bleeding risk and recurrent VTE in different patient populations.

• THROMBOPHILIA TESTING / HYPERCOAGULABLE WORKUP

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

• UNPROVOKED PE AND CANCER RISK

• Overview
• Up to 10% of patients with an unprovoked venous thromboembolism (VTE) are diagnosed with cancer within a year following their event
• This observation causes some providers to order extensive cancer workups in patients with unprovoked venous thromboembolism. Whether this practice is prudent is a matter of debate. [17,18]
• A study published in 2015 in the NEJM compared the effectiveness of two cancer screening approaches in patients with unprovoked venous thromboembolism

• Summary
• The SOME study found no benefit of adding an abdominal and pelvic CT to standard screening in patients with unprovoked VTE
• It's unclear if an unprovoked VTE is a marker of increased cancer risk. In order to evaluate this, a group of patients with unprovoked VTE would have to be compared with a matched control group that underwent all of the same testing. No such study has been performed. The high incidence of cancer in patients diagnosed with VTE may be a product of surveillance bias as opposed to an association of VTE with cancer risk. Some studies have found that the risk of cancer following VTE returns to normal after 6 months. This finding tends to argue against VTE being a marker of increased cancer risk. [18]

• CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION (CTEPH)


• Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a condition which can develop after a patient suffers a PE
• CTEPH occurs when the original blood clot fails to reabsorb. Instead, the clot is replaced over a period of months to years with fibrous tissue that becomes incorporated into the walls of the pulmonary arteries. This causes chronic obstruction of the pulmonary arteries which can lead to right heart strain and failure. [4]
• The incidence of CTEPH after acute PE is unknown, but it has been estimated to occur in 3% of patients
• Up to two-thirds of patients diagnosed with CTEPH have no history of symptomatic PE [7]
• CTEPH is treated with surgical endarterectomy, a procedure where the obstructing material is cut out of the pulmonary arteries. [4]

• ASPIRIN FOR VTE PREVENTION | Secondary prevention

• Overview
• Daily aspirin has been evaluated in the secondary prevention of VTE in several studies
• The WARFASA and ASPIRE studies compared aspirin to placebo in patients with a first episode of unprovoked VTE
• The EINSTEIN CHOICE study compared aspirin to two different doses of rivaroxaban in patients with provoked and unprovoked VTE
• All three studies are presented below. Results from a meta-analysis that combined the WARFASA and ASPIRE studies are also presented.

• STUDY
  Meta-analysis of WARFASA and ASPIRE Trials, NEJM (2012) [PubMed abstract]
• The authors of the ASPIRE study and the WARFASA study performed a pre-specified meta-analysis that combined the two studies
• Results of the meta-analysis showed the following:
• Aspirin reduced the relative risk of recurrent venous thromboembolism by 32% (HR 0.68, 95%CI [CI 0.51 - 0.90], p=0.007)
• There was no significant difference between the two groups in clinically relevant bleeding. Aspirin - 2.92%, Placebo - 1.97% (HR 1.47, 95%CI [0.70 - 3.08], p=0.31) [12]

• Summary
• The ASPIRE study did not show a statistically significant effect of aspirin in preventing recurrent VTE, although there was a trend towards significance with a p-value of 0.09. The study had poor enrollment and was underpowered.
• The WARFASA study, a much smaller study, found a significant effect with aspirin after two years of follow-up
• The meta-analysis that combined the two studies found that aspirin reduced the relative risk of VTE by 32%
• Not surprisingly, the EINSTEIN-CHOICE trial found rivaroxaban to be superior to aspirin for preventing VTE. Also of note, the 10 mg dose of rivaroxaban was as effective as the 20 mg dose.
• Across all 3 studies, the risk of recurrent VTE with daily aspirin was between 4.4 - 6.6% per year. The risk for patients in the EINSTEIN CHOICE trial with a provoked VTE as the index event was slightly lower at 3.6%. In the placebo arms of WARFASA and ASPIRE, the risk of recurrent VTE was 11.2% and 6.5%, respectively.
• Collectively, these three trials help quantify the risk of recurrent VTE for patients who choose to take aspirin over anticoagulation

• ASPIRIN FOR VTE PREVENTION | Primary prevention after TKA / THA

• Overview
• Patients who undergo total hip or knee replacement surgery are at high risk for VTE in the immediate postoperative period
• Anticoagulants like low-molecular weight heparins and Factor Xa inhibitors are often prescribed for 15 - 35 days after surgery to prevent VTE
• A study published in the NEJM in 2018 compared rivaroxaban only to 5 days of rivaroxaban followed by aspirin for VTE prevention in patients undergoing joint replacement surgery. The study is summarized below.

• Summary
• Five days of anticoagulation followed by daily aspirin appears to be a safe and effective alternative to continuous anticoagulation for VTE prophylaxis after joint replacement surgery
• A previous study that compared aspirin to dalteparin came to similar conclusions [PMID 23732713]

• BIBLIOGRAPHY

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• 12 - PMID 23121403 - ASPIRE study
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• 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)