- ACRONYMS AND DEFINITIONS
- ACCP - American College of Chest Physicians
- aPTT - activated Partial Thromboplastin Time
- ASH - American Society of Hematology
- bpm - beats per minute
- CTEPH - Chronic thromboembolic pulmonary hypertension
- DOAC - Direct-acting oral anticoagulant (factor Xa inhibitors, dabigatran)
- DVT - Deep vein thrombosis
- HIT - Heparin-induced thrombocytopenia
- INR - International normalized ratio
- LMWH - Low molecular weight heparin
- OCP - Oral contraceptive pills
- PCI - Percutaneous coronary intervention (heart cath and associated procedures - stents, angioplasty, etc.)
- PE - Pulmonary embolism
- RCT - Randomized controlled trial
- SBP - Systolic blood pressure
- SVT - Superficial vein thrombosis
- Venography - procedure where contrast is injected into the veins and an X-ray is taken. Blood clots in the veins can then be visualized.
- VKA - Vitamin K antagonist (e.g. warfarin)
- VTE - Venous thromboembolism (DVT and PE)
- PHYSIOLOGY
- Pulmonary embolism (PE) is a condition where a blood clot in the venous system travels through the circulation and lodges in the lung tissue. Blood clots that cause pulmonary embolisms often originate from a deep vein thrombosis (DVT). DVT and PE are closely related conditions that have common risk factors.
- Lung tissue affected by a pulmonary embolism does not oxygenate properly
- The right side of the heart may also be affected because pressure in the blood vessels that perfuse the lung may rise after a pulmonary embolism. This can cause strain on the right side of the heart.
- Pulmonary embolisms can have a wide range of effects. Massive pulmonary embolisms can cause sudden death while small pulmonary embolism may have no symptoms at all.
- The incidence of pulmonary embolism in the general population ranges from 23 - 69 cases per 100,000 people per year
- The mortality rate for pulmonary embolism varies widely depending on the population studied. On average, PE has a mortality rate of 11% within 2 weeks of diagnosis [1]
- RISK FACTORS FOR PE
- Age (> 65 years)
- Immobilization for an extended period (ex. travel, surgery, hospitalization)
- Cancer (see cancer risk and PE below)
- Estrogen-containing medications (e.g. oral contraceptives, hormone replacement, SERMs) - see also hormone therapy after VTE [3]
- Human immune globulin products (ex. IVIG, Gamimune®, Sandoglobulin®, Polygam®) [2]
- Ponatinib (Iclusig®) [14]
- Hypercoagulable disorders
- Obesity
- Pregnancy
- Previous PE or DVT
- Cigarette smoking [3]
- First-degree relative with a history of unprovoked VTE - the younger the age of the relative when the VTE occurred, the higher the risk [15]
- Superficial Vein Thrombosis - in one study, 2.5% of patients with an SVT developed a DVT within 3 months of SVT diagnosis; the incidence of PE was 0.9% during the same period. At 5 years, the risk of VTE was 5-fold higher in SVT patients compared to unaffected patients. [16]
- PROVOKED VS UNPROVOKED PE
- Overview
- Recommendations for providing extended anticoagulation after a PE are based on whether the PE is considered provoked or unprovoked. In general, these terms have the following meanings:
- Provoked PE - PE with a preceding identifiable risk factor
- Unprovoked PE - PE with no preceding identifiable risk factor
- Significant provoking risk factors are not consistently defined across the medical literature. For example, in some studies, oral contraceptive use is considered a significant provoking factor, while in others, it is not. The same goes for pregnancy and a list of other conditions. [6]
- The 2021 ACCP VTE recommendations define two categories of provoking risk factors that are used to make extended anticoagulation recommendations. Those categories are described in the table below, along with major risk factors used in the Wells score.
ACCP 2021 PE Risk Factor Categories |
---|
PE provoked by a major transient risk factor
|
PE provoked by a minor transient risk factor
|
Major risk factors in the Wells score
|
- DIAGNOSIS
- Symptoms
- Common symptoms of PE are presented in the table below
Symptom | Percent of patients with confirmed PE |
---|---|
Shortness of breath | 80% |
Pleuritic chest pain | 52% |
Cough | 20% |
Syncope | 19% |
Chest pain (substernal) | 12% |
Hemoptysis (coughing up blood) | 11% |
- Physical exam
- Common physical exam findings in PE are presented in the table below. No single exam finding is diagnostic for PE.
Physical exam finding | Percent of patients with confirmed PE |
---|---|
Rapid respiratory rate (≥ 20/min) | 70% |
Rapid heart rate (≥ 100/bpm) | 52% |
Symptoms of DVT (see DVT diagnosis) |
20% |
Cyanosis | 11% |
Fever (> 101.3) | 7% |
- CT scan
- Multidetector CT scan of the lungs with IV contrast has become the preferred method for diagnosing PE
- Modern CT scanners have a sensitivity of 83% and a specificity of 96% for diagnosing PE [4]
- Ventilation-perfusion (V/Q scan)
- Ventilation-perfusion (V/Q) scans can be used to diagnose PE, but they have fallen out of favor as CT scan technology has improved
- During a V/Q scan, the patient is given an intravenous infusion of radioisotope-labeled albumin particles. The particles travel to the lung tissue where they "light up" the capillary beds. If there is occlusion of a pulmonary artery branch by a PE, then the affected lung tissue will not light up (cold spot) during scintigraphy (procedure for viewing the isotope distribution).
- During the scan, the patient is also given an inhaled radioisotope so that the normal ventilation of the lung can be observed. Some areas of the lung may not ventilate properly because of processes other than PE (ex. reactive vasoconstriction). These areas will have a "ventilation-perfusion match" where neither inhaled or intravenous radioisotope is observed. A PE will cause an area of "ventilation-perfusion mismatch" because the area will have normal ventilation but no perfusion.
- V/Q scan results are reported as normal, near-normal, low, intermediate, and high probability for PE
- Normal V/Q scans rule out PE. High probability scans mean a PE is very likely. The other categories are less useful and require further testing. This is one of the main reasons CT scans are now preferred. [4]
- V/Q scans may be appropriate in patients who cannot receive the iodinated contrast that is required for a CT scan
- Lower extremity ultrasound
- PE and deep vein thrombosis go hand in hand
- Lower extremity ultrasound will show a DVT in 30 - 50% of patients with a PE. A proximal DVT will be detected with ultrasound in 20% of patients with a PE. Diagnosis of a proximal DVT in patients with suspected PE is enough to warrant anticoagulation without further testing.
- Lower extremity ultrasound may be useful in situations where modern CT technology is not available, or in patients who cannot receive the iodinated contrast that is required for a CT scan [4]
- D-dimer
- D-dimer, a degradation product of fibrin cross-linking whose levels rise during clot formation (see coagulation cascade illustration), can be helpful in diagnosing a PE. An elevated D-dimer is sensitive for a PE, but not specific, as a number of other conditions can cause elevations (e.g. advanced age, cancer, pregnancy, recent surgery). Therefore, a normal D-dimer essentially rules out a PE in many patients, while a high level is nonspecific and requires further testing.
- Age-adjusted D-dimer
- D-dimer levels rise naturally with age, so older patients have higher levels. In most laboratories, the upper limit of normal for a D-dimer is 500 mcg/L (0.500 mg/L). Studies have found that using age-adjusted cutoff levels in patients 50 and older increases the specificity of the test without sacrificing sensitivity, and some experts argue that age-adjusted levels should be the standard. [PMID 26320520, PMID 23645857, PMID 24643601].
- The formula for calculating an age-adjusted level is as follows:
- Age-adjusted D-dimer cutoff = patient's age (if 50 or older) X 10 mcg/L [Online calculator]
- D-dimer with clinical probability tools
- Several studies have looked at the effects of combining D-dimer values with clinical probability tools in an effort to reduce unnecessary imaging. A study incorporating the Wells criteria and one using the YEARS score are detailed below..
- STUDY
- Design: Prospective study (N=2017 | length = 3 months) in outpatients and inpatients with symptoms or signs suggestive of pulmonary embolism
- Evaluation: CT scan was not performed if patients met one of the following criteria:
- Low probability (Wells score 0 - 4 and D-dimer < 1000 ng/ml)
- Intermediate probability (Wells score 4.5 - 6 and D-dimer < 500 ng/ml)
- Primary outcome: Symptomatic, objectively verified venous thromboembolism, which included pulmonary embolism or deep vein thrombosis up to 3 months after evaluation
- Results:
- No patients who were ruled out for CT scan by the criteria above were found to have VTE during follow-up. Of these patients, 315 had a low probability Wells score and a D-dimer level of 500 to 999 ng/ml.
- Of all the patients who were evaluated, 7.4% had PE on initial testing
- Findings: A combination of a low clinical pretest probability and a d-dimer level of less than 1000 ng per milliliter identified a group of patients at low risk for pulmonary embolism during follow-up.
- STUDY
- Design: Cluster-randomized, crossover study (N=1414 | length = 3 months) in patients presenting to the ER with clinical suspicion of PE (e.g. acute onset of chest pain, worsening acute dyspnea, and/or syncope)
- Evaluation: Patients with a pulmonary embolism rule-out criteria (PERC) score of 0 were excluded, as were patients with a high pretest probability of PE as determined by subjective physician assessment. CT imaging was not performed if patients met one of the following criteria:
- YEARS score✝ of 0 and D-dimer < 1000 ng/ml
- YEARS score✝ ≥ 1 and D-dimer less than the age-adjusted D-dimer threshold
- ✝YEARS score ranges from 0 to 3 with 1 point for each of the following: PE is the most likely diagnosis, hemoptysis, and clinical sign of DVT.
- Primary outcome: Venous thromboembolism (VTE) at 3 months
- Results:
- In the control group, only age-adjusted D-dimer thresholds were used (no YEARS criteria)
- Primary outcome: D-dimer + YEARS - 0.15%, Control - 0.80% (noninferior)
- Findings: Among ED patients with suspected PE, the use of the YEARS rule combined with the age-adjusted D-dimer threshold in PERC-positive patients, compared with a conventional diagnostic strategy, did not result in an inferior rate of thromboembolic events.
- PE diagnostic algorithm
- STEP 1 - Determine if the patient is stable
- Unstable patients
- Five to ten percent of patients who present with PE are unstable. Unstable patients will have signs of shock and hypotension (e.g. SBP < 90 mmHg, blood pressure drop of ≥ 40 mmHg for > 15 minutes, hypoxia).
- Unstable patients should proceed immediately to CT scan. If CT scan is not available, they should have transesophageal echocardiography to look for right ventricular strain. Patients with unstable PE should also be considered for thrombolysis and embolectomy (see other treatments below). [4]
- Stable patients
- Proceed to Step 2
- STEP 2 - Assess patient's probability of PE using Wells score
Finding / History | Points |
---|---|
Signs and symptoms of DVT | +3 |
Heart rate > 100 bpm | +1.5 |
Recently immobilization or surgery (≤ 4 weeks) | +1.5 |
Previous PE or DVT | +1.5 |
Hemoptysis (coughing up blood) | +1 |
Cancer | +1 |
Pulmonary embolism more likely than alternative diagnosis | +3 |
- STEP 3 - Determine probability of PE
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:
Probability | Testing |
---|---|
High |
|
Intermediate |
|
Low |
|
- 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]
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 |
- SUBSEGMENTAL PULMONARY EMBOLISM
- Overview
- Subsegmental pulmonary embolisms are small emboli in the periphery of the lung. Advances in CT angiography have made it possible to detect filling defects as small as 2 - 3 mm, causing the diagnosis of subsegmental pulmonary embolisms to increase from 5% of PEs to over 10%.
- It is uncertain if patients with subsegmental pulmonary embolisms should be anticoagulated. Subsegmental PEs are more likely to be false positives, and they carry a lower risk of recurrent VTE. A study published in 2021 found that 2.1% of patients with one subsegmental PE and no DVT had a recurrent VTE within 90 days. In patients with multiple subsegmental PEs, the incidence was 5.7%. [PMID 34807722] No randomized controlled trials have compared anticoagulation to none in patients with subsegmental PEs.
- The 2021 ACCP guidelines for patients who only have subsegmental PEs are detailed below.
- 2021 ACCP recommendations for subsegmental PE
- Patients at high-risk for recurrent VTE (see below) - anticoagulation
- Patients with low cardiopulmonary reserve and/or marked symptoms that cannot be attributed to another condition - anticoagulation
- Patients at low-risk (see below) for recurrent VTE:
- 1. Perform ultrasound of the legs to rule out proximal DVT. In patients with central venous catheters, also rule out upper extremity DVT.
- 2. If no DVT is found, clinical surveillance is recommended over anticoagulation. Clinical surveillance entails one or more follow-up ultrasounds to detect an evolving DVT. [20]
- High-risk for recurrent VTE defined as having any of the following:
- Hospitalization or reduced mobility for another reason
- Active cancer (particularly if metastatic or being treated with chemotherapy)
- No reversible risk factor for VTE such as recent surgery
- Pregnancy [20,27]
- ASYMPTOMATIC PULMONARY EMBOLISM
- Occasionally, asymptomatic PEs are discovered incidentally on imaging that is performed for another reason. Asymptomatic PEs are found on about 1% of outpatient and 4% of inpatient contrast-enhanced CT scans. In most cases, these patients have known malignancy, and the imaging has been ordered for cancer staging or monitoring.
- The 2021 ACCP guidelines state that the initial and long-term management of asymptomatic PEs should be the same as symptomatic PEs [27]
- TREATMENT | Anticoagulation
- PE treatment is divided into three phases:
- Initiation phase (5 - 10 days) - period where the patient is quickly anticoagulated to prevent clot expansion
- Treatment phase (3 months) - continued anticoagulation to prevent clot expansion and promote dissolution
- Extended phase (beyond 3 months) - extended anticoagulation to prevent reoccurrence in appropriate patients
- TREATMENT | Initiation phase (5 - 10 days)
- Initiation phase (5 - 10 days)
- In the initiation phase, patients are quickly anticoagulated to stop the clot from spreading. For many years, warfarin, which takes 3 - 5 days to become therapeutic and requires coverage with quick-acting injectable therapy during that time, was the only oral anticoagulant available. Rivaroxaban and apixaban, two newer DOACs, have a rapid onset of action and do not require injections during the first days of use. Two other DOACs, dabigatran and edoxaban, are FDA-approved for treatment after 5 - 10 days of parenteral therapy.
- Outpatient treatment
- The 2021 ACCP guidelines state that patients with low-risk PEs can be treated as outpatients. The guidelines do not give definitive criteria for "low-risk PE" but suggest the following:
- Clinical decision rules such as the Pulmonary Embolism Severity Index (PESI), either the original form with a score < 85 or the simplified form with a score of 0, can help to identify low-risk patients who are suitable for home treatment (PESI calculator)
- The presence of right ventricular dysfunction or increased cardiac biomarker levels should discourage outpatient treatment [27]
- ACCP 2021 recommendations
- Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) or dabigatran are preferred over warfarin. Parenteral therapy is not required with apixaban and rivaroxaban, whereas 5 to 10 days are recommended with dabigatran and edoxaban.
- Patients with subsegmental PE - see subsegmental PE
- Patients with antiphospholipid syndrome - warfarin (target INR 2.5) is preferred with initial parenteral therapy
- Patients with cancer - Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) are preferred over LMWH. Edoxaban and rivaroxaban appear to be associated with a higher risk of GI major bleeding than LMWH in patients with cancer-associated thrombosis and a luminal GI malignancy, while apixaban does not. Apixaban or LMWH may be the preferred option in patients with luminal GI malignancies (see Factor Xa inhibitors for cancer-associated VTE treatment) [27]
- ASH 2021 recommendations for patients with active cancer
- Apixaban, rivaroxaban, or LMWH is recommended for treatment during the first week [26]
- Studies
- Factor Xa inhibitors for cancer-associated VTE treatment
- A study published in 2015 comparing tinzaparin, a LMWH, to warfarin in cancer patients with acute VTE found no significant difference between the therapies for recurrent VTE or major bleeding at 6 months. [PMID 26284719]
- Heparins
- Unfractionated heparin - typically referred to as "heparin" for short. Heparin works by activating antithrombin, which in turn, inhibits Factor IIa (thrombin) and Factor Xa (coagulation inhibition illustration). Heparin can be administered intravenously or subcutaneously and requires aPTT monitoring. It causes HIT in 1 - 5% of patients. [9]
- Low molecular weight heparin (LMWH) - LMWHs, also called "fractionated heparin," include enoxaparin (Lovenox®), dalteparin (Fragmin®), and tinzaparin (Innohep®). LMWHs are similar to heparin except that they consist of smaller molecules (hence "low molecular weight") because they have been fractionated (divided into parts). Like heparin, LMWHs work by stimulating antithrombin activity (see coagulation inhibition illustration). LMWHs are given by subcutaneous injection, and they do not require lab monitoring. Enoxaparin (Lovenox®), the most widely used LMWH, is dosed 1 mg/kg every 12 hours for VTE treatment and 40 mg once daily for VTE prevention. The risk of HIT with LMWH is 0.1 - 1.0%. [9]
- Fondaparinux (Arixtra®) - fondaparinux is a synthetic heparin derivative that activates antithrombin, but unlike heparins where Factor Xa and IIa are inhibited, only Factor Xa is inhibited when antithrombin is stimulated by fondaparinux (see coagulation inhibition illustration). Fondaparinux carries a negligible risk of HIT, and some experts recommend its use in HIT patients; however, it is not FDA-approved for this indication. Fondaparinux is administered once daily by subcutaneous injection and does not require lab monitoring. [9]
- Heparin-induced thrombocytopenia (HIT)
- Heparins can cause a syndrome called heparin-induced thrombocytopenia (HIT) that is marked by the development of antibodies to complexes of platelet factor 4 (PF4) and heparin. Anti-PF4 antibodies can activate platelets, causing thrombosis and platelet depletion. During HIT, platelet counts typically fall by 50% between 5 and 14 days after heparin initiation; patients with previous heparin exposure may see counts drop within 24 hours. If HIT is suspected, testing for anti-PF4 antibodies can be performed; however, a positive test has low specificity, as antibodies are present in up to 20% of heparin-exposed patients, but only a small fraction of these patients will develop HIT. To help make a diagnosis, a calculator has been developed that estimates the probability of HIT based on 4 findings (see 4Ts Score Calculator for HIT). HIT, which has a mortality of 5 - 10%, is treated by stopping heparin and switching to a non-heparin anticoagulant. [9,22]
- Non-heparins
- Argatroban - argatroban is a direct thrombin inhibitor FDA-approved for VTE treatment in patients with HIT syndrome. It is administered via continuous IV infusion and requires aPTT monitoring.
- Bivalirudin (Angiomax®) - bivalirudin is a direct thrombin inhibitor FDA-approved for use during PCI in patients with HIT syndrome. It is administered via continuous IV infusion and requires aPTT monitoring.
- Parenteral therapy treatment recommendations
- Patients with no history of HIT:
- LMWH or fondaparinux are preferred. Intravenous or subcutaneous unfractionated heparin may also be used.
- Therapy should last at least 5 days. See initiating warfarin for recommendations on dosing warfarin.
- Patients with ongoing HIT
- Direct thrombin inhibitor (argatroban)
- If cardiac surgery or PCI is needed, then use bivalirudin
- Patients with a history of HIT
- Fondaparinux [7]
- TREATMENT | Treatment phase (3 months)
- Treatment phase (3 months)
- During the treatment phase, acute-phase anticoagulation is extended for a total of 3 months to facilitate clot reabsorption. Patients who received parenteral therapy during the acute phase are typically switched to oral therapy.
- ACCP 2021 recommendations
- All patients should be treated for 3 months with the anticoagulant they received in the initiation phase [27]
- ASH 2021 recommendations for patients with active cancer
- First-line: apixaban, edoxaban, or rivaroxaban
- Second-line: LMWH
- Third-line: vitamin K antagonist [26]
- Studies
- Factor Xa inhibitors for cancer-associated VTE treatment
- A study published in 2015 comparing tinzaparin, a LMWH, to warfarin in cancer patients with acute VTE found no significant difference between the therapies for recurrent VTE or major bleeding at 6 months. [PMID 26284719]
- TREATMENT | Extended phase (beyond 3 months)
- Extended phase (beyond 3 months)
- After 3 months of treatment, extended anticoagulation is used to prevent VTE recurrence, which can be as high as 8% in the first year after an unprovoked VTE. The 2021 ACCP recommendations for extended anticoagulation divide VTEs into the following three categories:
- VTE provoked by a major transient risk factor (see major and minor risk factor definitions)
- VTE provoked by a minor transient risk factor
- Unprovoked VTE or persistent risk factor (e.g. thrombophilia)
- 2021 ACCP recommendation
- NOTE: see ACCP categories for definitions of major and minor transient risk factors
- Patients with a major transient risk factor should not receive extended coagulation
- Patients with a minor transient risk factor should not receive extended coagulation
- Patients with an unprovoked PE or persistent risk factor (e.g. thrombophilia) should receive extended coagulation with a DOAC. If a DOAC cannot be used, a vitamin K antagonist should be offered. Patients with antiphospholipid syndrome should receive warfarin.
- Extended-phase apixaban dosing should be 2.5 mg twice daily, and extended-phase rivaroxaban dosing should be 10 mg once daily.
- In patients with an unprovoked proximal DVT or PE who stop anticoagulant therapy, taking low-dose daily aspirin may help to prevent VTE recurrence [27]
- 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]
- The PADIS-PE trial enrolled 374 patients with a first unprovoked PE that had been treated for 6 uninterrupted months with a vitamin K antagonist
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%
Randomized treatment 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
Results
Duration: 18 months | |||
Outcome | Warfarin | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 3.3% | 13.5% | HR 0.22, 95%CI [0.09 - 0.55], p=0.001 |
Recurrent VTE | 1.7% | 13.5% | HR 0.15, 95%CI [0.05 - 0.43], p<0.001 |
Major bleeding | 2.2% | 0.5% | HR 3.96, 95%CI [0.44 - 35.89], p=0.22 |
|
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.
- 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.
- OTHER TREATMENTS
- Thrombolysis
- Thrombolysis involves infusing a thrombolytic agent (e.g. alteplase, streptokinase, etc.) that causes the PE to dissolve. Thrombolytic agents may be infused systemically (peripheral vein) or in some cases, directly into the clot using a catheter (catheter directed).
- A study published in 2014 compared thrombolysis to placebo in normotensive patients with right ventricular dysfunction following a PE. The study found that thrombolysis decreased the risk of hemodynamic decompensation, but increased the risk of major bleeding. It had no effect on overall mortality [PMID 24716681].
- 2021 ACCP guidelines recommend systemic thrombolytic therapy in the following patients:
- Patients with acute PE associated with hypotension (e.g. systolic BP < 90 mmHg) who do not have high bleeding risk
- Select patients with acute PE who deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk [20,27]
- Inferior Vena Cava (IVC) filters
- IVC filters are devices placed in the inferior vena cava that "filter" blood clots from the venous blood headed to the lungs. IVC filters may be placed permanently or temporarily using retrievable filters. [25]
- A study published in the JAMA compared anticoagulation to anticoagulation + temporary IVC filter (3 months) in high-risk patients. The study found no benefit of adding an IVC filter to anticoagulation. [PMID 25919526]
- 2021 ACCP recommendations
- IVC filters should only be used in patients with acute VTE (e.g. diagnosed in the preceding 1 month) in whom anticoagulants are contraindicated. In these patients, the IVC filter should be promptly removed when anticoagulant therapy has been instituted.
- IVC filters should not be combined with anticoagulation in most patients. Because it is uncertain if there is benefit to placement of an IVC filter in anticoagulated patients with severe PE (e.g. with hypotension), our recommendation against insertion of an IVC filter in patients with acute PE who are anticoagulated may not apply to this select subgroup of patients. [20,27]
- Embolectomy
- Embolectomy involves removing the PE either through open surgery or with devices that run through a catheter
- These procedures require a certain expertise that is not widely available
- 2021 ACCP guidelines recommend possible embolectomy in the following patients:
- In patients with acute PE associated with hypotension and who have a high bleeding risk, failed systemic thrombolysis, or shock that is likely to cause death before systemic thrombolysis can take effect (e.g. within hours), if appropriate expertise and resources are available, we suggest catheter assisted thrombus removal (mechanical interventions ± direct thrombolysis) over no such intervention [20,27]
- RISK OF RECURRENT PE
- Overall risk
- The risk of recurrent VTE depends on a number of factors including VTE type (provoked vs unprovoked), sex, VTE site, and other patient-specifc comorbidities
- A number of studies have looked at the risk of recurrent VTE. The first table is from a meta-analysis that looked at recurrence risk during the first year after an event based on VTE type. The second table is from a meta-analysis that followed recurrence rates for up to 10 years in patients who discontinued anticoagulation after a first unprovoked VTE. The third table is from a study that followed VTE risk for 20 years and subdivided the risk based on site of initial VTE.
Recurrence rate in first year after treatment of initial VTE with no extended anticoagulation | |
---|---|
Type of VTE | Recurrence |
Provoked by surgery | 1.0% |
Provoked by nonsurgical risk factor | 5.8% |
Unprovoked VTE | 7.9% |
Cumulative recurrent VTE risk for patients who discontinued anticoagulation after a first unprovoked VTE | ||
---|---|---|
Time | VTE (Men) | VTE (Women) |
2 years | 18.3% | 13.6% |
5 years | 28.6% | 21.2% |
10 years | 41.2% | 28.8% |
Cumulative recurrent VTE risk by initial VTE site for patients with first unprovoked VTE who were not anticoagulated | |||
---|---|---|---|
Time | Distal DVT | Proximal DVT | PE |
10 years | 17% | 37% | 34% |
20 years | 30% | 47% | 44% |
- Recurrent VTE after stopping estrogen-containing OCPs
- A systemic review and meta-analysis published in 2022 examined the risk of recurrent VTE in women with a history of estrogen-provoked VTE. The review included 14 studies where women with a VTE thought to be provoked by estrogen-containing OCPs received acute treatment for at least 3 months and were then followed after they discontinued anticoagulation. The overall annual rate of recurrent VTE after stopping anticoagulation was 1.57%. In studies where all patients definitely stopped hormonal use after the first VTE or were strongly encouraged to do so (N=8), the annual rate was 1.31%. The annual rate among studies that included patients with high-risk thrombophilia (N=4) was 1.95%, compared to 1.40% among studies that excluded these women. [PMID 35108438]
- Summary
- This observational study provides some meaningful information on the risk of VTE recurrence in females who experience a VTE while taking estrogen-containing OCPs. OCP use is considered a minor transient risk factor by the most recent ACCP guidelines, and chronic anticoagulation is not recommended. Given that the overall annual risk of recurrence in these women was 1.57%, this analysis supports their recommendation.
- BLEEDING RISK
- Overview
- Bleeding risk categories used in the ACCP guidelines are based on the risk factors presented below. It's important to note that estimating bleeding risk is an imperfect science, and criteria from different organizations often vary.
- Once the bleeding risk category is determined, it can be used in the risk-benefit estimation below
- Categories of major bleeding risk:
- Low-risk: 0 risk factors
- Moderate-risk: 1 risk factor
- High-risk: ≥ 2 risk factors
- Risk factors for bleeding:
- Age > 65 years
- Age > 75 years (NOTE: An 80 year old would have 2 risk factors by age (> 65 and 75) and a 70 year old would have one risk factor by age)
- Previous bleeding
- Cancer
- Metastatic cancer (NOTE: A person with localized cancer would have one risk factor by cancer and a person with metastatic cancer would have 2 risk factors by cancer)
- Kidney failure
- Liver failure
- Low platelets (thrombocytopenia)
- Previous stroke
- Diabetes
- Anemia
- Antiplatelet therapy
- Poor anticoagulant control
- Comorbidity and reduced functional capacity
- Recent surgery
- Frequent falls
- Alcohol abuse [7]
- RISK-BENEFIT ESTIMATION
- ACCP risk-benefit estimation
- The ACCP published a table in their 2012 guidelines that estimates the risk and benefits of extended anticoagulation. The table has not been validated in a prospective study, but it does offer a quantitative estimate of bleeding risk and recurrent VTE in different patient populations.
Estimated effect over 5 years of Extended anticoagulation vs No extended anticoagulation (% differences are absolute) | ||||
---|---|---|---|---|
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% |
- 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
- The SOME study enrolled 862 patients with a new diagnosis of first unprovoked symptomatic VTE
Main inclusion criteria
- First unprovoked VTE (proximal DVT, PE, or both)
- Unprovoked VTE defined as VTE occurring in the absence of known cancer, current pregnancy, thrombophilia, previous VTE, and recent immobilization
Main exclusion criteria
- Age < 18 years
- Weight ≥ 130 kg
- Ulcerative colitis
- Glaucoma
Baseline characteristics
- Average age 53 years
- Average weight 90 kg
- Current or past smoker - 48%
- Index event: DVT - 67% | PE 32% | Both - 12%
Randomized treatment groups
- 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.
Results
Duration: 1 year | |||
Outcome | Screening | Screening + CT | Comparisons |
---|---|---|---|
New cancer diagnosis | 3.2% | 4.5% | p=0.28 |
Primary outcome | 4 occult cancers were missed | 5 occult cancers were missed | p=1.0 |
Mean time to cancer diagnosis | 4.2 months | 4 months | p=0.88 |
Cancer-related mortality | 1.4% | 0.9% | p=0.75 |
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.
- Summary
- The SOME study found no benefit of adding an abdominal and pelvic CT to standard screening in patients with unprovoked VTE
- It's unclear if an unprovoked VTE is a marker of increased cancer risk. In order to evaluate this, a group of patients with unprovoked VTE would have to be compared with a matched control group that underwent all of the same testing. No such study has been performed. The high incidence of cancer in patients diagnosed with VTE may be a product of surveillance bias as opposed to an association of VTE with cancer risk. Some studies have found that the risk of cancer following VTE returns to normal after 6 months. This finding tends to argue against VTE being a marker of increased cancer risk. [18]
- CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION (CTEPH)
- Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a condition which can develop after a patient suffers a PE
- CTEPH occurs when the original blood clot fails to reabsorb. Instead, the clot is replaced over a period of months to years with fibrous tissue that becomes incorporated into the walls of the pulmonary arteries. This causes chronic obstruction of the pulmonary arteries which can lead to right heart strain and failure. [4]
- The incidence of CTEPH after acute PE is unknown, but it has been estimated to occur in 3% of patients
- Up to two-thirds of patients diagnosed with CTEPH have no history of symptomatic PE [7]
- CTEPH is treated with surgical endarterectomy, a procedure where the obstructing material is cut out of the pulmonary arteries. [4]
- ASPIRIN FOR VTE PREVENTION
- BIBLIOGRAPHY
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- 9 - PMID 2345166 - NEJM HIT review
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- 17 - PMID 26095467 - SOME study
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- 21 - PMID 15900005 - Hypercoagulable workup and VTE risk
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- 23 - PMID 31340984 - Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis, BMJ (2019)
- 24 - PMID 27696701 - The long-term recurrence risk of patients with unprovoked venous thromboembolism: an observational cohort study J Thromb Haemost (2016)
- 25 - PMID 32919823 - Society of Interventional Radiology Clinical Practice Guideline for Inferior Vena Cava Filters in the Treatment of Patients with Venous Thromboembolic Disease: Developed in collaboration with the American College of Cardiology, American College of Chest Physicians, American College of Surgeons Committee on Trauma, American Heart Association, Society for Vascular Surgery, and Society for Vascular Medicine, J Vasc Interv Radiol (2020)
- 26 - PMID 33570602 - American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer, Blood Advances (2021)
- 27 - PMID 34352278 - Executive Summary: Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report, Chest (2021)