PULMONARY EMBOLISM

• ACRONYMS AND DEFINITIONS

• aPTT - activated Partial Thromboplastin Time
• 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
• 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.
• VTE - Venous thromboembolism (DVT and PE)

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• 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]

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• RISK FACTORS FOR PE

• Main risk factors for pulmonary embolism:
• Age (> 65 years)
• Immobilization for an extended period (ex. travel, surgery, hospitalization)
• Cancer (see cancer risk and PE below)
• Medications - Oral contraceptives, hormone replacement therapy, SERMs (Evista®, tamoxifen, etc) [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 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]

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• 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

Reference 4

Symptom	Percent of patients with confirmed PE
Shortness of breath	80%
Pleuritic chest pain	52%
Cough	20%
Passing out (syncope)	19%
Chest pain (substernal)	12%
Coughing up blood (hemoptysis)	11%

• 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

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 (bluish discoloration of skin from lack of oxygen)	11%
Fever (> 101.3)	7%

• 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 patients 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 study is detailed here - age-adjusted D-dimer study. Other studies can be found here - PMID 26320520, PMID 23645857
• In 2015, the American College of Physicians recommended that age-adjusted D-dimer cutoff values be used when assessing patients for PE [19]


• 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

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
Coughing up blood (Hemoptysis)	+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:


• High probability
• Perform CT scan
• Intermediate probability
• Order D-dimer
• If D-dimer is elevated, order CT scan
• If D-dimer is normal, PE unlikely [4, 5]
• Low probability
• 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 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]

• 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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• PROVOKED VS UNPROVOKED PE

• When discussing PE, 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


• 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

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• 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 guidelines 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]

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• TREATMENT

• Overview

• The treatment of PE has traditionally been divided into three phases:
• Acute phase (usually around 5 days) - treatment with injectable, quick-acting anticoagulants (ex. heparin, enoxaparin) until warfarin levels are therapeutic
• Intermediate phase (3 - 6 months) - treatment with warfarin (target INR of 2-3)
• Extended phase (indefinite) - extended anticoagulation to prevent reoccurrence in appropriate patients



• Acute phase

• The acute phase of PE treatment involves quickly getting the patient anticoagulated to stop the clot from spreading
• In the past, warfarin was the only oral anticoagulant available. It typically takes 3 - 5 days for warfarin levels to become therapeutic. This means patients have to be covered with quick-acting injectable medications until warfarin levels are therapeutic.
• Rivaroxaban (Xarelto®) and apixaban (Eliquis®), oral Factor Xa inhibitors, are FDA-approved to treat PEs in both the acute and intermediate phases
• Dabigatran (Pradaxa®) and edoxaban (Savaysa®) are FDA-approved for treatment after 5 - 10 days of parenteral therapy
• The AHA guidelines (published 2011) do not mention Factor Xa inhibitors. The ACCP guidelines were updated in 2015 to include recommendations for Factor Xa inhibitors and direct thrombin inhibitors.


• Acute phase medications and HIT syndrome
• The most common medications used in the acute treatment phase of PE are heparin and heparin derivatives
• When discussing heparins, it is important to consider a serious side effect of heparins called HIT syndrome. HIT syndrome can affect medication choice.


• Helpful illustrations:
• Coagulation cascade illustration
• Coagulation inhibition illustration


• 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]
• Low molecular weight heparin (LMWH) - Also called "fractionated heparin." LMWHs include enoxaparin (Lovenox®), dalteparin (Fragmin®), and tinzaparin (Innohep®). LMWH are similar to heparin except that they consist of smaller molecules (hence "low molecular weight") because they have been fractionated (divided into parts). Like heparins, LMWH work by stimulating antithrombin activity. LMWH are the most commonly used medications in acute PE treatment because they can be dosed once daily by subcutaneous injection, and they do not require lab monitoring. The risk of HIT with LMWH is 0.1 - 1.0%. [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. [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.



• 2011 AHA recommendations

• Patients with no history of HIT - one of the following:
• Intravenous or subcutaneous unfractionated heparin
• LMWH
• Fondaparinux
• 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 HIT
• Direct thrombin inhibitor (argatroban, lepirudin, bivalirudin) [8]



• 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]



• Intermediate phase

• The intermediate phase of treatment involves prolonging anticoagulation for a number of months (typically 3 - 6) so that the PE has ample time to dissolve
• Warfarin was the only oral drug available for anticoagulation for a long time. Recently, two new classes of drugs have become available - Factor Xa inhibitors and direct thrombin inhibitors. Both classes of drugs have been found to be effective in the intermediate phase of PE treatment. Both classes are FDA-approved for the intermediate phase of treatment.
• The AHA guidelines (published 2011) do not mention Factor Xa inhibitors. The AHA guidelines mention dabigatran briefly, but they do not include it in their recommendations. The ACCP guidelines (published 2012) discuss rivaroxaban and dabigatran, but they recommend warfarin over both drugs mainly because warfarin has a longer track record.


• 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 disadvantage of warfarin is that it requires constant, and often times, frequent lab monitoring and dosage adjustments. Warfarin interacts with a number of medications (see warfarin drug interactions), and it can also be affected by a person's diet (see warfarin and food).
• Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) - Factor Xa inhibitors are FDA-approved for the intermediate phase treatment of PE. Factor Xa inhibitors do not require frequent lab monitoring, but they are more expensive than warfarin.
• Direct thrombin inhibitors (dabigatran, Pradaxa®) - dabigatran is FDA-approved for the intermediate phase treatment of PE. Dabigatran does not require frequent lab monitoring, but it is more expensive than warfarin.



• 2011 AHA recommendations

• The AHA refers readers to the ACCP and the European Society of Cardiology guidelines for intermediate and extended treatment recommendations in PE [8]



• 2016 ACCP recommendations

• Patients without cancer
• The ACCP recommends 3 months of anticoagulation for all types of PE
• 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 is recommended 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)



• Extended phase

• 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)
• The AHA defers to the ACCP for extended treatment recommendations
• 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 trials) found that extended anticoagulation was beneficial in patients with 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 recommendation may not be appropriate for every patient. Individual patient characteristics need to be considered.
• The recommendations are based on their risk-benefit estimations 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

• * Provoked - recent surgery or transient, nonsurgical risk factor
• Reference 7

provoked vs unprovoked*	First vs second	Bleeding risk (see bleeding risk below)	Extended anticoagulation recommended
provoked	not specified	any	no
unprovoked	first	low or moderate	yes
unprovoked	first	high	no
unprovoked	second	low or moderate	yes
unprovoked	second	high	no
Active cancer - ACCP recommends extended anticoagulation in all patients with active cancer

• Extended phase trials

• For patients with a first, unprovoked PE, the risks of extended anticoagulation (bleeding) have to be weighed against the benefits (lower risk of recurrence)
• One large randomized trial has evaluated the risk/benefit ratio of extended anticoagulation in patients with first, unprovoked PE


• PADIS-PE trial - Six Months vs Extended Oral Anticoagulation After a First Episode of PE, JAMA (2015) [PubMed abstract]
• The PADIS-PE trial enrolled 374 patients with first, unprovoked PE that had been treated for 6 uninterrupted months with a vitamin K antagonist (ex. warfarin)
• Main inclusion criteria: first symptomatic, unprovoked PE (unprovoked PE defined as objectively confirmed PE occurring in the absence of any major reversible risk factor for VTE within 3 months before diagnosis, including surgery with locoregional or general anesthesia lasting more than 30 minutes, trauma with or without plaster cast of the lower limbs, and bed rest for more than 72 hours, and in the absence of active cancer or cancer resolved within the 2 years prior to diagnosis)
• Main exclusion criteria: previous VTE (proximal DVT or PE); bleeding during the initial 6-month anticoagulation; known hypercoagulable disorder; increased bleeding risk (e.g. active gastric ulcer, recent hemorrhagic stroke); platelet count < 100,000/mm³
• Baseline characteristics: average age 58 years; previous distal DVT or superficial vein thrombosis ∼8%; PE treatment prior to enrollment - warfarin ∼67%, other VKA ∼33%; ACCP bleeding risk category - Low 24%, Moderate 32%, High 43%
• Patients were randomized to 1 of 2 groups:
• Group 1 (184 patients) - Warfarin for 18 months (target INR 2 - 3)
• Group 2 (187 patients) - Placebo for 18 months
• PRIMARY OUTCOME: composite of symptomatic recurrent VTE (objectively confirmed nonfatal symptomatic PE or proximal DVT or fatal venous thromboembolism) and nonfatal or fatal major bleeding up to 18 months
• After 18 months, the following was seen:
• Primary outcome: Group 1 - 3.3%, Group 2 - 13.5% (HR 0.22, 95%CI [0.09 - 0.55], p=0.001)
• Recurrent VTE: Group 1 - 1.7%, Group 2 - 13.5% (HR 0.15, 95%CI [0.05 - 0.43], p<0.001)
• Major bleeding: Group 1 - 2.2%, Group 2 - 0.5% (HR 3.96, 95%CI [0.44 - 35.89], p=0.22)
• After the 18 month treatment period, all patients were followed for a median of 24 months without anticoagulant therapy. The risk for the composite outcome was not significantly different at the end of this period (Group 1 - 20.8%, Group 2 - 24%, p=0.22)
• In Group 1, the INR was in the therapeutic range (2 - 3) for 70% of the time
• Findings: Among patients with a first episode of unprovoked pulmonary embolism who received 6 months of anticoagulant treatment, an additional 18 months of treatment with warfarin reduced the composite outcome of recurrent venous thrombosis and major bleeding compared with placebo. However, benefit was not maintained after discontinuation of anticoagulation therapy.


• StraightHealthcare analysis:
• 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.



• Recurrent PE while receiving 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]

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• RISK OF RECURRENT PE

• The risk of recurrent VTE depends on whether the VTE was provoked or unprovoked. The provoking risk factor is also a consideration.
• A number of studies have looked at the risk of recurrent VTE. Information from a meta-analysis on recurrent VTE is presented in the table below.

Reference [6]

Type of VTE	Recurrence rate in first year after treatment of initial VTE (with no extended anticoagulation)
Provoked by surgery	1.0%
Provoked by nonsurgical risk factor	5.8%
Unprovoked VTE	7.9%

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• 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
• An abbreviated version of the table 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 (aspirin, P2Y12 inhibitor)
• Poor anticoagulant control
• Comorbidity and reduced functional capacity
• Recent surgery
• Frequent falls
• Alcohol abuse [7]

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• 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.

• *See bleeding risk category above to determine risk
• Reference [7]

Estimated effect over 5 years of treatment with anticoagulation (% are absolute changes)
		Low bleeding risk*	Intermediate bleeding risk*	High bleeding risk*
First VTE provoked by surgery	Recurrent VTE reduction	↓ 2.6%	↓ 2.6%	↓ 2.6%
	Major bleeding increase	↑ 2.4%	↑ 4.9%	↑ 19.6%
First VTE provoked by a nonsurgical factor/ first unprovoked distal DVT	Recurrent VTE reduction	↓ 13.2%	↓ 13.2%	↓ 13.2%
	Major bleeding increase	↑ 2.4%	↑ 4.9%	↑ 19.6%
First unprovoked proximal DVT or PE	Recurrent VTE reduction	↓ 26.4%	↓ 26.4%	↓ 26.4%
	Major bleeding increase	↑ 2.4%	↑ 4.9%	↑ 19.6%
Second unprovoked VTE	Recurrent VTE reduction	↓ 39.6%	↓ 39.6%	↓ 39.6%
	Major bleeding increase	↑ 2.4%	↑ 4.9%	↑ 19.6%

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• THROMBOPHILIA TESTING / HYPERCOAGULABLE WORKUP

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

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• CANCER RISK AND PE

• CANCER AND VENOUS THROMBOEMBOLISM
• 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


• SOME study - Screening for Occult Cancer in Unprovoked VTE, NEJM (2015) [PubMed abstract]
• The SOME study enrolled 862 patients with a new diagnosis of first unprovoked symptomatic VTE (proximal deep vein thrombosis, pulmonary embolism, or both)
• Main inclusion criteria: unprovoked VTE defined as VTE occurring in the absence of known cancer, current pregnancy, thrombophilia, previous VTE, and recent immobilization
• Main exclusion criteria: weight ≥ 130 kg
• Baseline characteristics: average age 53 years; average weight 90 kg; current or past smoker - 48%; DVT - 67%, PE - 32%, Both - 12%
• Patients were randomized to one of two cancer screenings:
• Group 1 (431 patients) - CBC; CMP; Chest X-ray; Mammography in women > 50 years; PAP in women 18 - 70 years; PSA testing in men > 40 years
• Group 2 (423 patients) - same testing as Group 1 + CT scan of the abdomen and pelvis
• CT scan included a virtual colonoscopy and gastroscopy, biphasic enhanced CT of the liver, parenchymal pancreatography, and uniphasic enhanced CT of the distended bladder
• PRIMARY OUTCOME: confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period.
• After one year, the following was seen:
• New cancer diagnosis: Group 1 - 3.2%, Group 2 - 4.5% (p=0.28)
• Primary outcome: Group 1 - 4 occult cancers were missed, Group 2 - 5 occult cancers were missed (p=1.0)
• There was no significant difference between the two study groups in the mean time to a cancer diagnosis (4.2 months in Group 1 and 4.0 months in Group 2, p=0.88) or in cancer-related mortality (1.4% and 0.9%, p=0.75) [17]
• Findings: The prevalence of occult cancer was low among patients with a first unprovoked venous thromboembolism. Routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit.


• StraightHealthcare analysis:
• The SOME study found no benefit of adding an abdominal and pelvic CT to standard screening in patients with unprovoked VTE. Standard testing in this study varied somewhat from current screening recommendations because it included PSA testing and did not include colon cancer screening.
• 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 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]

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• 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]

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• 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 blood that is headed to the lungs
• IVC filters may be placed permanently or temporarily with the use of retrievable filters
• IVC filters are often used in patients who have contraindications to anticoagulation
• 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. [PubMed abstract]


• 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]

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• ASPIRIN FOR VTE PREVENTION

• Secondary prevention of VTE

• 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.


• WARFASA Study - Aspirin vs Placebo for VTE Prevention, NEJM (2012) [PubMed abstract]
• The WARFASA study enrolled 402 patients with first episode of unprovoked DVT or PE
• Main inclusion criteria: first episode of symptomatic, unprovoked proximal DVT, pulmonary embolism, or both; completed anticoagulation therapy lasting 6 - 18 months
• Main exclusion criteria: cancer; thrombophilia; history of cardiovascular disease requiring aspirin; high risk for bleeding or bleeding during anticoagulation; women with VTE associated with the use of estrogen/progestin therapy
• Baseline characteristics: average age 62 years; average BMI - 27; index event, DVT ∼ 63%, PE ∼ 37%; duration of anticoagulation, 6 months ∼ 34%, 12 months ∼ 55%, 18 months ∼ 10%
• Patients were randomized to 1 of 2 groups:
• Group 1 (205 patients) - Aspirin 100 mg daily
• Group 2 (197 patients) - Placebo
• PRIMARY OUTCOME: Recurrence of thromboembolism (defined as symptomatic, objectively confirmed DVT, PE, or fatal PE) over 2 years
  
• After 2 years, the following was seen:
• Primary outcome (% of patients/year): Group 1 - 6.6%, Group 2 - 11.2% (HR 0.58, 95%CI [0.36 - 0.93], p=0.02)
• Major bleeding or clinically relevant nonmajor bleeding: Group 1 - 4 events, Group 2 - 4 events (HR 0.98, 95%CI [0.24 - 3.96], p=0.97)
• Overall mortality: Group 1 - 6 events, Group 2 - 5 events (HR 1.04, 95%CI [0.32 - 3.42], p=0.95) [11]
• Findings: Aspirin reduced the risk of recurrence when given to patients with unprovoked venous thromboembolism who had discontinued anticoagulant treatment, with no apparent increase in the risk of major bleeding


• ASPIRE Study - Aspirin vs Placebo for VTE Prevention, NEJM (2012) [PubMed abstract]
• The ASPIRE study enrolled 822 patients with first episode of unprovoked DVT or PE
• Main inclusion criteria: first episode of unprovoked DVT involving the popliteal or more proximal veins or an acute pulmonary embolism; completed anticoagulation therapy lasting 6 weeks to 24 months
• Main exclusion criteria: index VTE that occurred ≥ 2 years before enrollment; VTE occurred in the setting of estrogen/progestin therapy
• Baseline characteristics: average age 55 years; index event, DVT - 57%, PE - 28%, both - 14%; duration of anticoagulation ≥ 3 months - 99% of patients
• Patients were randomized to 1 of 2 groups:
• Group 1 (411 patients) - Enteric-coated aspirin 100 mg daily
• Group 2 (411 patients) - Placebo
• The study was originally designed to enroll 3000 patients, but was unable to achieve that number due to poor recruitment
• PRIMARY OUTCOME: Recurrence of thromboembolism (defined as symptomatic, objectively confirmed DVT, PE, or fatal PE)
  
• After a median follow-up of 37.2 months, the following was seen:
• Primary outcome (% of patients/year): Group 1 - 4.8%, Group 2 - 6.5% (HR 0.74, 95%CI [0.52 - 1.05], p=0.09)
• Major or clinically relevant nonmajor bleeding (% of patients/year): Group 1 - 1.1%, Group 2 - 0.6% (HR 1.73, 95%CI [0.72 - 4.11], p=0.22)
• Composite of recurrent VTE, MI, stroke, or cardiovascular death (% of patients/year): Group 1 - 5.2%, Group 2 - 8.0% (HR 0.66, 95%CI [0.48 - 0.92], p=0.01)
• In Group 1, 15% of patients discontinued aspirin. In Group 2, 7% of patients initiated antiplatelet or anticoagulation treatment.
• The poor enrollment of the study left it underpowered to assess the primary outcome [12]
• Findings: In this study, aspirin, as compared with placebo, did not significantly reduce the rate of recurrence of venous thromboembolism but resulted in a significant reduction in the rate of major vascular events, with improved net clinical benefit. These results substantiate earlier evidence of a therapeutic benefit of aspirin when it is given to patients after initial anticoagulant therapy for a first episode of unprovoked venous thromboembolism.


• META-ANALYSIS OF WARFASA AND ASPIRE (2012)
• 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]


• EINSTEIN CHOICE trial - Aspirin vs Rivaroxaban for VTE Prevention, NEJM (2017) [PubMed abstract]
• The EINSTEIN CHOICE trial enrolled 3396 patients with VTE who had completed 6 - 12 months of treatment with anticoagulation
• Main inclusion criteria: Confirmed symptomatic PE and/or DVT treated for 6 to 12 months with anticoagulation without interruption for > 1 week
• Main exclusion criteria: Liver disease with coagulopathy | CrCl < 30 ml/min | Indication for anticoagulant or antiplatelet therapy | High risk of bleeding
• Baseline characteristics: Average age 58 years | Index event: DVT - 51%, PE - 33%, Both - 15% | Provoked VTE - 58%, Unprovoked VTE - 42% | Known thrombophilia - 7% | Previous VTE - 18%
• Patients were randomized to 1 of 3 groups:
• Group 1 (1107 patients) - Rivaroxaban 20 mg once daily
• Group 2 (1127 patients) - Rivaroxaban 10 mg once daily
• Group 3 (1131 patients) - Aspirin 100 mg once daily
• Study drugs were administered for up to 12 months
• PRIMARY OUTCOME: Composite of symptomatic, recurrent fatal or nonfatal venous thromboembolism and unexplained death for which pulmonary embolism could not be ruled out
• After a median follow-up of 351 days, the following was seen:
• Primary outcome: Group 1 - 1.5%, Group 2 - 1.2%, Group 3 - 4.4% (1 vs 3 HR 0.34 95%CI [0.20 – 0.59] | 2 vs 3 HR 0.26 95%CI [0.14 – 0.47])
• Overall mortality: Group 1 - 0.7%, Group 2 - 0.2%, Group 3 - 0.6%
• DVT: Group 1 - 0.8%, Group 2 - 0.6%, Group 3 - 2.6%
• PE: Group 1 - 0.5%, Group 2 - 0.4%, Group 3 - 1.7%
• Provoked index event (primary outcome): Group 1 - 1.4%, Group 2 - 0.9%, Group 3 - 3.6%
• Unprovoked index event (primary outcome): Group 1 - 1.8%, Group 2 - 1.5%, Group 3 - 5.6%
• Major bleeding: Group 1 - 0.5%, Group 2 - 0.4%, Group 3 - 0.3% (1 vs 3 HR 2.01 95%CI [0.50 – 8.04] | 2 vs 3 HR 1.64 95%CI [0.39 – 6.84])
• Findings: Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates.


• StraightHealthcare analysis:
• 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. The 20 mg dose is the current recommended dose for prevention of VTE recurrence.
• 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



• VTE prevention after hip and knee replacement

• Patients who undergo total hip or knee replacement surgery are at high risk for a 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 to 5 days of rivaroxaban followed by aspirin for VTE prevention in patients undergoing joint replacement surgery. The study is summarized below.


• Aspirin vs Rivaroxaban for VTE prophylaxis after Hip or Knee Replacement, NEJM (2018) [PubMed abstract]
• Design: Randomized, controlled trial (N=3424, length - 90 days)
• Baseline characteristics: Average age - 63 years | History of VTE - 2.3% | Hip replacement - 1804 | Knee replacement - 1620
• Treatment:
• Group 1 (1717 patients): Rivaroxaban 10 mg once daily for 14 days following knee replacement or 35 days following hip replacement
• Group 2 (1707 patients): Rivaroxaban 10 mg once daily for 5 days followed by aspirin 81 mg once daily for 9 days following knee replacement or 30 days following hip replacement
• Primary outcomes: Effectiveness - symptomatic VTE confirmed by objective testing within 90 days of randomization; Safety - bleeding, including major or clinically relevant nonmajor bleeding
• Results:
• Symptomatic VTE: Group 1 - 0.70%, Group 2 - 0.64% (diff 0.06%, 95%CI [−0.55 to 0.66], p<0.001 for noninferiority and p=0.84 for superiority)
• Major bleeding: Group 1 - 0.29%, Group 2 - 0.47% (diff 0.18%, 95%CI [−0.65 to 0.29], p=0.42)
• Findings: Among patients who received 5 days of rivaroxaban prophylaxis after total hip or total knee arthroplasty, extended prophylaxis with aspirin was not significantly different from rivaroxaban in the prevention of symptomatic venous thromboembolism


• StraightHealthcare analysis:
• 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

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• BIBLIOGRAPHY

• What is PMID?
• PI = Manufacturer's Package Insert

• #     PMID
  1  -  19109575 - NEJM PE review
  2  -  FDA warning - FDA warning
  3  -  22494827 - Lancet review
  4  -  18757870 - ESC GL for PE
  5  -  19109575 - NEJM PE case
  6  -  20975016 - Ach of IM risk factor for VTE
  7  -  22315268 - ACCP recs for TE - full
  8  -  21422387 - AHA recs for PE
  9  -  2345166 - NEJM HIT review
  10  -  15254285 - NEJM DVT review
  11  -  22621626 - WARFASA study
  12  -  23121403 - ASPIRE study
  13  -  23645857 - age-adjusted d-dimer
  14  -  Ponatinib PI
  15  -  25049279
  16  -  25398934
  17  -  26095467 - SOME study
  18  -  20149076 - incidence of VTE after cancer
  19  -  26414967 - ACP PE best practices
  20  -  26867832 ACCP 2016 VTE GL
  21  -  15900005 - Hypercoagulable workup and VTE risk
  24  -  PMID 29411014 - Evaluating Thrombocytopenia During Heparin Therapy, JAMA (2018)