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
• DVT - Deep vein thrombosis
• HIT - Heparin-induced thrombocytopenia
• INR - International normalized ratio
• LMWH - Low molecular weight heparin
• 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
• Symptoms of PE are related to lung injury
• Symptoms alone cannot be used to conclusively diagnose a PE
• Common symptoms of PE are presented in the table below

• Physical exam
• There is no physical exam finding that is definitive for a PE diagnosis
• Common physical exam findings in PE are presented in the table below

• 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
• The patient's probability of PE should be taken into account when interpreting the results of a CT scan. In one study, the negative predictive value (NPV) of a CT scan in patients with PE was as follows: Patients with low probability - 96%; Patients with intermediate probability - 89%; Patients with high probability - 60% (NPV is the percent of patients with a negative test who do not have the disease) [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
• The algorithm for diagnosing PE includes the D-dimer blood test
• D-dimer is a degradation product of fibrin cross-linking (see coagulation cascade illustration)
• An elevated D-dimer level can occur when blood clots are being formed. It can also be elevated in other conditions unrelated to DVT (ex. advanced age, cancer, pregnancy, recent surgery).
• The D-dimer test has high sensitivity and low specificity

• Age-adjusted D-dimer
• In most cases, the cutoff value for a normal D-dimer is ≤ 500 mcg/L (0.500 mg/L)
• D-dimer levels rise normally with age so some researchers have recommended using an age-adjusted D-dimer cutoff value
• Several studies have found that using the formula age X 10 mcg/L (mg/L) as a cutoff value in patients over fifty years old improves the specificity of the test with little or no loss of sensitivity. One prospective study that looked at using age-adjusted D-dimer values in patients presenting to the ER with possible PE is detailed below. Two other observational studies that looked at age-adjusted D-dimers are available here - PMID 26320520, PMID 23645857


• STUDY
  Age-adjusted D-dimer Values to Rule Out Pulmonary Embolism, JAMA (2014) [PubMed abstract]
• Design: Prospective study (N=3346 | length = 3 months) in consecutive patients presenting to the ER with clinical suspicion of PE
• Procedure: Patients with high (Geneva) or a likely (Wells) clinical probability proceeded directly to CT scan. Patients with a low/intermediate or unlikely clinical probability had a D-dimer test. Age-adjusted D-dimer values (calculated as age X 10) were used to exclude PE.
• Primary outcome: Failure rate of the diagnostic strategy, defined as the rate of adjudicated symptomatic thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative D-dimer test result according to the age-adjusted cutoff
• Results:
• 2898 patients had unlikely or non-high clinical probability of PE
• 1744 patients had a D-dimer ≥ age-adjusted cutoff and underwent CT scanning
• 817 patients had a D-dimer < 500 μg/L. Of these patients, 1 patient had an adjudicated thromboembolic event during follow-up (0.1%, CI 0% - 0.7%)
• 337 patients had a D-dimer > 500 μg/L, but < age-adjusted cutoff. Of these patients, 1 patient had an adjudicated thromboembolic event during follow-up (0.3%, CI 0.1% - 1.7%)
• Findings: Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism.

• D-dimer with clinical probability
• A study published in 2019 looked at using the D-dimer value combined with the clinical probability of PE to help rule out patients for further testing. The clinical probability of PE was derived from the Wells score, and D-dimer cutoff values of 500 ng/ml (intermediate probability) and 1000 ng/ml (low probability) were used. The study is detailed below.


• STUDY
  Diagnosis of Pulmonary Embolism with D-dimer Adjusted to Clinical Probability , NEJM (2019) [PubMed abstract]
• Design: Randomized controlled trial (N=2017 | length = 3 months) in outpatients and inpatients with symptoms or signs suggestive of pulmonary embolism
• Evaluation: A CT scan was not done in patients who were categorized as Low probability (Wells score 0 - 4, D-dimer < 1000 ng/ml) or Intermediate probability (Wells score 4.5 - 6, 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 C-PTP 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.

• PE diagnostic algorithm
• STEP 1 - Determine if the patient is stable
• Unstable patients
• Unstable patients will have signs of shock and hypotension (ex. SBP < 90 mmHg, blood pressure drop of ≥ 40 mmHg for > 15 minutes, hypoxia)
• About 5 - 10% of PEs will present with shock or hypotension
• These patients should proceed immediately to CT scan. If CT scan is not immediately available, they should have transesophageal echocardiography to evaluate for right ventricular strain.
• Patients with PE who are unstable should be considered for thrombolysis or 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
• When discussing PEs, the terms provoked and unprovoked are often used in the medical literature
• 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


• Definition ambiguity
• Unfortunately, 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 other studies, it is not. Same goes for pregnancy and a list of other factors. [6]
• Distinguishing between a provoked and unprovoked PE is important because the guidelines for extended anticoagulation take this designation into account
• Since there is no consistency in defining provoking risk factors, one solution is to use the major risk factors from the Wells score that are listed below. This definition is still somewhat arbitrary, but it appears to be what the AHA/ACCP guidelines use.
• If one of the following risk factors is present, the PE is considered provoked:
• 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

• 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 around 5% of PEs to over 10% of PEs.
• It is uncertain if patients with subsegmental pulmonary embolisms should be anticoagulated. Subsegmental PEs have a higher likelihood of being false-positives, and they carry a lower risk of recurrent VTE. No randomized controlled trials have compared anticoagulation to no therapy in patients with subsegmental PEs.
• In 2015, the ACCP issued guidelines for patients who only have subsegmental PEs. The guidelines are detailed below.


• 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 [20]

• 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 heparin) during that period.
• Several newer anticoagulants have a quicker 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 to treat PEs in both the acute and intermediate phases.
• Two other anticoagulants, dabigatran (Pradaxa®) and edoxaban (Savaysa®), are FDA-approved for treatment after 5 - 10 days of parenteral therapy

• 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.

• 2016 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]
• Patients with cancer
• LMWH for 3 months
• 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 extending anticoagulation beyond the intermediate phase in order to prevent a recurrence of PE in susceptible patients (see recurrent PE risk below)
• In many patients, the optimal decision to extend or not to extend anticoagulation will not be straightforward
• While there is no validated tool to help make this decision, the ACCP created a table in their latest guidelines that can help quantify the risk-benefit ratio of extended anticoagulation
• To use the table, one must first determine a patient's bleeding risk on anticoagulation (see bleeding risk below)
• Once the bleeding risk category is determined, the risk-benefit estimation table can be used to help quantify the net risk-benefit ratio of anticoagulation while keeping in mind that this is only an estimate and not a validated decision tool. Also of note, a study published in 2015 (see extended phase trial) found that extended anticoagulation was beneficial in patients with a first unprovoked PE. Forty-three percent of the patients in this study were categorized as "high bleeding risk" by the ACCP guidelines. According to the ACCP recommendations, extended anticoagulation would not have been recommended in these patients.
• The table presented in this section is a summary of their recommendations that are based on the risk-benefit estimation table
• In most cases, the medication used in the intermediate phase will be continued in the extended phase
• Patients receiving extended anticoagulation should have their risk-benefit ratio reassessed annually

• 2016 ACCP recommendations
• Patients without cancer
• ACCP recommendations for extended therapy depend on the patient's estimated bleeding risk (see bleeding risk below) and whether the PE is provoked vs unprovoked, and first vs recurrent. These recommendations may not be appropriate for every patient. Individual patient characteristics need to be considered.
• The recommendations are based on their risk-benefit estimates which are detailed below (see risk-benefit estimation below)
• 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 latest ACCP guidelines, extended anticoagulation would not have been recommended for these patients.
• During the 24 month post-treatment phase, 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 risk of VTE.

• 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)

• 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.

• BLEEDING RISK

• ACCP bleeding risk table
• The ACCP presents a table in their guidelines that is meant to help assess a person's risk of bleeding when considering extended anticoagulation. The table has not been validated in any kind of study.
• A truncated version of the recommendation is presented here. It is meant to serve as a starting point in assessing a person's bleeding risk on anticoagulant therapy. It is not a validated method for determining risk. Bleeding risk should be determined on an individual basis while considering a number of factors and their severity.
• Once the risk of bleeding is categorized, this information 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 devised a table in their latest guidelines which helps to estimate the risk/benefit of extended anticoagulation
• The table has not been validated in any type of clinical trial (nor has any other), but it does offer a quantitative estimate of benefit and risk when considering extended anticoagulation
• Given the lack of a validated tool to assess a person's net benefit when considering extended anticoagulation, we felt this table was a good starting point for physicians and patients who need help quantifying the net effect of therapy.
• When using the table, one should keep in mind that it is merely an unvalidated estimate of risk/benefit. The decision for extended therapy should be made on an individual basis after considering a number of risk factors and patient preferences.

• 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]

• OTHER TREATMENTS

• Overview
• Besides anticoagulation, there are a handful of other treatments for PE
• These treatments are typically used in patients who are unstable or who have a contraindication to anticoagulants

• 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 [PubMed abstract].
• 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 a high-risk of bleeding
• 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]

• Inferior Vena Cava (IVC) filters
• IVC filters are devices placed in the inferior vena cava that "filter" blood clots from the venous blood that is headed to the lungs. They are primarily recommended in patients who have a contraindication to anticoagulation. IVC filters may be placed permanently or temporarily with the use of retrievable filters. [25]
• In recent years, the practice of adding IVC filters to anticoagulation in high-risk patients has become more common. The ACCP does not recommend adding IVC filters to most patients who are receiving anticoagulants. They state that a subgroup of patients with severe PE may benefit from adding an IVC, but this is not proven.[20]
• 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 the addition of an IVC filter to anticoagulation. [PMID 25919526]

• 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
• 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]

• 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
• 13 - PMID 23645857 - age-adjusted d-dimer
• 14 - Ponatinib PI
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• 17 - PMID 26095467 - SOME study
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• 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)