What are the current guidelines for diagnosis, risk stratification, treatment, and follow‑up of acute pulmonary embolism?

Current Guidelines for Acute Pulmonary Embolism

Diagnosis

Clinical Probability Assessment

Use a validated prediction rule (Wells or revised Geneva score) to stratify every patient with suspected PE into low, intermediate, or high clinical probability before ordering any tests. 1

• Immediately assess for hemodynamic instability (shock or systolic BP < 90 mm Hg for ≥15 minutes) to identify high‑risk PE requiring urgent reperfusion therapy. 1
• Both three‑level (low/intermediate/high) and two‑level (PE unlikely/PE likely) schemes are acceptable for clinical probability assessment. 1
• The revised Geneva score assigns points for: prior VTE (3), heart rate 75‑94 bpm (3) or ≥95 bpm (5), recent surgery or fracture (2), hemoptysis (2), active cancer (2), unilateral leg pain (3), pain on deep venous palpation with unilateral edema (4), age >65 years (1). 1

D‑dimer Testing

• Measure D‑dimer only in patients with low or intermediate clinical probability using a highly sensitive assay; never measure D‑dimer in high‑probability patients because a normal result does not safely exclude PE. 1
• Age‑adjusted D‑dimer cut‑offs (age × 10 µg/L for patients >50 years) maintain >97% sensitivity while significantly increasing specificity. 2
• In low‑ or intermediate‑probability patients, a normal D‑dimer permits exclusion of PE without further testing. 1

Imaging Strategy

• Computed tomography pulmonary angiography (CTPA) is the first‑choice imaging test for hemodynamically stable patients with an elevated D‑dimer or high clinical probability. 1
• Accept a PE diagnosis when CTPA shows a segmental or more proximal filling defect in patients with intermediate or high clinical probability. 1
• Reject a PE diagnosis when CTPA is normal in patients with low or intermediate clinical probability. 1
• Ventilation‑perfusion (V/Q) scintigraphy is a valid alternative when CTPA is contraindicated (contrast allergy, renal impairment); a normal perfusion scan excludes PE. 1
• Do not perform CT venography as an adjunct to CTPA. 1
• Do not use magnetic resonance angiography to rule out PE. 1
• Identification of a proximal deep‑vein thrombosis by compression ultrasound in a patient with suspected PE confirms VTE and justifies anticoagulation. 1
• For suspected high‑risk PE, perform bedside echocardiography or emergency CTPA depending on local availability. 1

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Risk Stratification

High‑risk PE is defined by shock, cardiac arrest, obstructive shock, or persistent hypotension (systolic BP <90 mm Hg for ≥15 minutes) and carries early mortality that may exceed 30%. 1

• High‑risk patients require immediate reperfusion therapy. 1

Intermediate‑risk PE comprises hemodynamically stable patients with evidence of right‑ventricular (RV) dysfunction (on echocardiography or CTPA) and/or elevated cardiac biomarkers (troponin, BNP/NT‑proBNP). 1

• Intermediate‑high risk: both RV dysfunction and biomarker elevation. 1
• Intermediate‑low risk: one of the two. 1

Low‑risk PE: hemodynamically stable without RV dysfunction or biomarker elevation; these patients are candidates for early discharge and outpatient treatment. 1

• Use validated clinical prediction tools such as the Pulmonary Embolism Severity Index (PESI) or simplified PESI (sPESI) to estimate 30‑day mortality risk. 2
• For very low‑risk patients, apply the PERC (Pulmonary Embolism Rule‑Out Criteria) to identify those in whom testing risks outweigh PE risk (approximately 1%), with pooled sensitivity of 97%. 2

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Acute Treatment

High‑Risk (Hemodynamically Unstable) PE

Administer systemic thrombolytic therapy immediately to all high‑risk PE patients who do not have a high bleeding risk. 1

• Initiate intravenous unfractionated heparin (UFH) without delay, including a weight‑adjusted bolus (80 IU/kg or 5,000–10,000 units), even before imaging confirmation. 1, 3
• UFH continuous infusion: 18 IU/kg/h (or 1,300 IU/h standard dose). 3
• Target activated partial thromboplastin time (aPTT) = 1.5–2.5 × control (≈45–75 seconds); check aPTT 4–6 hours after bolus, 6–10 hours after any dose change, then daily once therapeutic. 3
• Alteplase dosing: 100 mg infused over 2 hours, or 0.6 mg/kg over 15 minutes (maximum 50 mg) if cardiac arrest is imminent. 1, 2
• Meta‑analyses show a significant reduction in mortality or recurrence in patients with massive PE treated with thrombolysis (OR 0.45; 95% CI 0.22–0.92). 4
• Surgical pulmonary embolectomy is indicated when thrombolysis is absolutely contraindicated or fails to improve hemodynamics within one hour. 1
• Provide rescue thrombolysis if hemodynamic deterioration occurs despite anticoagulation. 1
• Catheter embolectomy or thrombus fragmentation may be considered if surgery is not immediately available, though safety and efficacy are not well documented. 4

Hemodynamic Support Measures

• Administer high‑flow oxygen for correction of hypoxemia. 4
• Vasopressor agents are recommended for hypotensive patients. 4
• Dobutamine and dopamine may be used in patients with low cardiac output and normal blood pressure. 4
• Avoid aggressive fluid challenge—this may worsen right ventricular failure. 4

Intermediate‑ and Low‑Risk (Hemodynamically Stable) PE

Start anticoagulation immediately in patients with high or intermediate clinical probability while diagnostic work‑up proceeds. 1

• For parenteral anticoagulation in hemodynamically stable patients, prefer low‑molecular‑weight heparin (LMWH) or fondaparinux over UFH. 1, 3
• Do not use systemic thrombolysis as routine primary treatment in intermediate‑ or low‑risk PE. 1
• Standard anticoagulation with close monitoring for deterioration is recommended for intermediate‑high risk PE patients. 2
• Low‑risk patients can be safely managed with ambulatory anticoagulation using tools like the Hestia criteria to identify suitable candidates. 2

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Oral Anticoagulation Selection

Prefer a non‑vitamin‑K oral anticoagulant (NOAC)—apixaban, rivaroxaban, edoxaban, or dabigatran—over a vitamin K antagonist (VKA) when initiating oral therapy. 1, 3

Rivaroxaban

• 15 mg orally twice daily for the first 21 days, then 20 mg once daily thereafter. 3
• Single‑drug regimen; no parenteral lead‑in required. 3
• EINSTEIN‑PE trial: non‑inferior to enoxaparin/warfarin for preventing recurrent VTE (2.1% vs 1.8%; HR 1.12), with significantly lower major bleeding (1.1% vs 2.2%; HR 0.49; P=0.003). 3
• Hospital length of stay: 45% discharged ≤5 days vs 33% with enoxaparin/VKA (p<0.0001). 3

Apixaban

• 10 mg orally twice daily for the first 7 days, then 5 mg twice daily thereafter. 3
• Single‑drug regimen; no parenteral lead‑in required. 3

Dabigatran and Edoxaban

• Require a 5‑day lead‑in with therapeutic LMWH before switching to the oral agent. 3

Vitamin K Antagonist (Warfarin)

• If a VKA is chosen, overlap with parenteral anticoagulation until the INR reaches 2.0–3.0 on two consecutive measurements taken at least 24 hours apart (target INR ≈2.5). 1, 3
• Continue parenteral agent for at least 5 days and until INR is therapeutic for 2 consecutive days. 3
• Initiate warfarin with a starting dose of 10 mg daily in younger adults (<60 years) and ≤5 mg daily in older adults. 3

Contraindications to NOACs

• Do not use NOACs in patients with severe renal impairment (creatinine clearance <25–30 mL/min) or antiphospholipid antibody syndrome; these patients must receive a VKA indefinitely. 1, 3
• NOACs are contraindicated during pregnancy and lactation. 1, 3
• Concurrent use of strong P‑glycoprotein and CYP3A4 inhibitors (e.g., ritonavir, ketoconazole) contraindicates NOACs. 3

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Duration of Anticoagulation

All patients with PE require therapeutic anticoagulation for a minimum of 3 months, followed by mandatory reassessment at 3–6 months to decide on continuation. 1, 3

Provoked PE

• Discontinue anticoagulation after 3 months in patients whose first PE was provoked by a major transient/reversible risk factor (e.g., surgery, trauma, immobilization, pregnancy). 1, 3

Unprovoked PE

• Extend anticoagulation indefinitely beyond 3 months for unprovoked PE when bleeding risk is low‑to‑moderate; the annual recurrence risk exceeds 5%. 1, 3
• After the first 6 months, a reduced dose of apixaban (2.5 mg twice daily) or rivaroxaban (10 mg daily) may be used for extended anticoagulation. 1

Recurrent VTE

• Continue oral anticoagulation indefinitely in patients with recurrent VTE (≥1 prior episode) not related to a major transient risk factor. 1, 3

Antiphospholipid Antibody Syndrome

• Continue VKA therapy indefinitely in patients with antiphospholipid antibody syndrome; NOACs are contraindicated. 1, 3

Cancer‑Associated Thrombosis

• Extended monotherapy with therapeutic LMWH (minimum 6 months and continued as long as cancer is active) is preferred over warfarin or NOACs. 3
• Edoxaban or rivaroxaban may be considered as alternatives to LMWH, with caution in gastrointestinal cancers due to increased bleeding risk. 1

Pregnancy

• Use therapeutic fixed‑dose LMWH based on early‑pregnancy weight throughout gestation. 1, 3
• LMWH should be continued for at least 6 weeks after delivery or for 3 months from the index PE episode, whichever is longer. 3
• Post‑partum, warfarin may be initiated and does not preclude breastfeeding. 3

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Inferior Vena Cava (IVC) Filter Placement

Do not routinely place IVC filters; reserve them only for patients with absolute contraindications to anticoagulation (e.g., active major bleeding) or who experience recurrent PE despite adequate anticoagulation. 1, 3

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Follow‑Up and CTEPH Screening

Re‑examine all patients 3–6 months after acute PE to evaluate persistent dyspnea, functional limitation, signs of VTE recurrence, cancer, or bleeding complications. 1

• Schedule regular follow‑up visits at yearly intervals for patients on extended anticoagulation. 1
• Re‑assess drug tolerance, adherence, hepatic/renal function, and bleeding risk at each visit. 1, 3
• If persistent or new‑onset dyspnea or functional limitation is present at the 3–6 month review, perform ventilation‑perfusion scintigraphy to detect mismatched perfusion defects suggestive of chronic thromboembolic pulmonary hypertension (CTEPH). 1
• Refer symptomatic patients with persistent perfusion defects to a specialized CTEPH center, incorporating echocardiography, natriuretic peptide levels, and/or cardiopulmonary exercise testing. 1
• Follow‑up imaging is not routinely required in asymptomatic patients but may be considered in those with risk factors for CTEPH (unprovoked PE, large perfusion defects, RV dysfunction, hypothyroidism, diabetes). 1

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Critical Pitfalls to Avoid

• Never delay anticoagulation in high‑ or intermediate‑probability PE while awaiting diagnostic confirmation. 1
• Never measure D‑dimer in high‑clinical‑probability patients; proceed directly to imaging. 1, 2
• Never use NOACs in severe renal impairment (<25–30 mL/min) or antiphospholipid antibody syndrome; a VKA is mandatory. 1, 3
• Never lose patients to follow‑up after acute PE; routine reassessment at 3–6 months is essential for detecting CTEPH and guiding anticoagulation duration. 1
• Never ignore persistent dyspnea, as it may indicate CTEPH requiring specialized evaluation. 1
• Never discontinue anticoagulation at 3 months in unprovoked PE without weighing bleeding risk; the annual recurrence exceeds 5%. 1
• Never withhold thrombolysis in massive PE solely because of contraindications; in life‑threatening situations, traditional contraindications should be set aside. 1
• Never use INR to monitor rivaroxaban activity, as INR does not correlate reliably with drug levels. 3