Acute Pulmonary Embolism (PE)

Epidemiology

Incidence

  • The Incidence of Pulmonary Embolism Has Increased with the Increased Use of CT Pulmonary Artery Angiogram for the Diagnosis of Pulmonary Embolism (see Computed Tomography Pulmonary Artery Angiogram, [[Computed Tomography Pulmonary Artery Angiogram]])
    • Increasing Incidence of Acute Pulmonary Embolism (Arch Intern Med, 2011) [MEDLINE]
      • 1993-1998: 62 cases per 100k
      • 1998-2005: 112 cases per 100k
    • Autopsy Incidence of Acute Pulmonary Embolism: evidence of old PE is found in 25-30% of all autopsies

Risk Factors for Venous Thromboembolism

General Comments

  • Same Risk Factors as for Deep Venous Thrombosis (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])
    • Risk Factor Can Be Identified in >80% of Patients with Venous Thrombosis: more than one factor may often be present
      • 50% of thrombotic events in patients with inherited hypercoagulable states are associated with an additional risk factor (pregnancy, surgery, prolonged immobilization, oral contraceptives)

Inherited Risk Factors (see Hypercoagulable States, [[Hypercoagulable States]])

  • General Comments
    • Factor V Leiden Gene Mutation and Prothrombin Gene Mutation Account for 50-60% of Inherited (Primary) Hypercoagulable States
  • Antithrombin Deficiency (see Antithrombin Deficiency, [[Antithrombin Deficiency]])
  • Dysfibrinogenemia (see Dysfibrinogenemia, [[Dysfibrinogenemia]]): rare
  • Factor V Leiden (see Factor V Leiden, [[Factor V Leiden]])
  • Factor XII Deficiency (see Factor XII Deficiency, [[Factor XII Deficiency]])
  • Family History of Venous Thromboembolism: strong risk factor
  • Heparin Cofactor II Deficiency: unclear risk factor
  • Hereditary Hemorrhagic Telangiectasia (HHT) (Osler-Weber-Rendu Syndrome) (see Hereditary Hemorrhagic Telangiectasia, [[Hereditary Hemorrhagic Telangiectasia]])
    • Epidemiology: associated with decreased serum iron levels and increased plasma factor VIII levels (Thorax, 2012) [MEDLINE]
  • Plasminogen Deficiency: unclear risk factor
  • Protein C Deficiency (see Protein C Deficiency, [[Protein C Deficiency]])
  • Protein S Deficiency (see Protein S Deficiency, [[Protein S Deficiency]])
  • Prothrombin Gene Mutation (see Prothrombin Gene Mutation, [[Prothrombin Gene Mutation]])

Acquired Risk Factors (see Hypercoagulable States, [[Hypercoagulable States]])

  • Active Tuberculosis (see Tuberculosis, [[Tuberculosis]])
  • Age: hazard ratio of 1.7 (95 percent confidence interval: 1.5 to 2.0) for every decade of life after age 55 (ARIC and CHS studies)
  • Antiphospholipid Antibody Syndrome (see Antiphospholipid Antibody Syndrome, [[Antiphospholipid Antibody Syndrome]])
  • Asthma (see Asthma, [[Asthma]])
  • Central Intravenous Catheters
    • Central Venous Catheter (CVC) (see Central Venous Catheter, [[Central Venous Catheter]])
    • Peripherally Inserted Central Catheter (PICC) (see Peripherally Inserted Central Catheter, [[Peripherally Inserted Central Catheter]])
      • Meta-Analysis Comparing PICC Line with Central Venous Catheter (Lancet, 2013) [MEDLINE]
        • PICC Lines Had a Higher Risk of Venous Thrombosis than Central Venous Catheters, Especially in Patients Who are Critically Ill or in Those with Cancer
        • PICC Lines Had No Risk of Acute PE
  • Chronic Kidney Disease (CKD), Especially with Hemodialysis (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
  • Chronic Myeloproliferative Diseases (see Chronic Myeloproliferative Diseases, [[Chronic Myeloproliferative Diseases]])
    • Myeloproliferative Neoplasms
      • Essential Thrombocythemia (see Essential Thrombocythemia, [[Essential Thrombocythemia]])
      • Polycythemia Vera (see Polycythemia Vera, [[Polycythemia Vera]])
        • Epidemiology: venous thrombosis occurs in 7% of polycythemia vera cases (Leukemia, 2013) [MEDLINE]
        • Physiology: hyperviscosity and qualitative platelet defects
  • Chronic Psoriasis (see Psoriasis, [[Psoriasis]])
  • Congenital Venous Malformation of the Inferior Vena Cava
  • Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
  • Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
    • Epidemiology
      • Longitudinal Investigation of Thromboembolism Etiology (LITE) Study (2002) Demonstrated that Diabetes Mellitus Increased the Risk of Venous Thromboembolism (Adjusted Hazard Ratio 1.5) (Arch Intern Med, 2002) [MEDLINE]
      • Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.18), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
  • Hyperhomocysteinemia (see Hyperhomocysteinemia, [[Hyperhomocysteinemia]])
  • Hyperlipidemia (see Hyperlipidemia, [[Hyperlipidemia]])
    • Epidemiology
      • Longitudinal Investigation of Thromboembolism Etiology (LITE) Study (2002) Indicated that Alcohol Use, Hypertension, Hyperlipidemia, Physical Inactivity, and Tobacco Abuse were Not Associated with an Increased Risk of Venous Thromboembolism (Arch Intern Med, 2002) [MEDLINE]
      • Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.18), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
  • Hypertension (see Hypertension, [[Hypertension]])
    • Epidemiology
      • Longitudinal Investigation of Thromboembolism Etiology (LITE) Study (2002) Indicated that Alcohol Use, Hypertension, Hyperlipidemia, Physical Inactivity, and Tobacco Abuse were Not Associated with an Increased Risk of Venous Thromboembolism (Arch Intern Med, 2002) [MEDLINE]
      • Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.18), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
  • Hyperviscosity States (see Hyperviscosity, [[Hyperviscosity]])
  • Immobilization
    • Bedrest
    • Critical Illness (Especially with Mechanical Ventilation)
      • Risk of Deep Venous Thrombosis in Mechanically-Ventilated Patients is 5-10%, Despite Adequate DVT Prophylaxis (J Intensive Care Med, 2006) [MEDLINE] (Crit Care MED, 2005) [MEDLINE] (NEJM, 2011) [MEDLINE]
    • Extended Travel (“Travelers’ Thrombosis”)
      • Travel (Air, Train, Auto) for >4 hrs is Associated with Increased Risk of Deep Venous Thrombosis (Aviat Space Environ Med, 2014) [MEDLINE]
      • Incidence of Pulmonary Embolism Following Air Travel is Correlated with the Distance Traveled (NEJM, 2001) [MEDLINE]
    • Lower Extremity Fracture/Injury
  • Infection
    • Sepsis (see Sepsis, [[Sepsis]])
      • Multicenter Prospective Study of Risk Factors for and Incidence of Venous Thromboembolism in Severe Sepsis/Septic Shock (Chest, 2015) [MEDLINE]
        • Despite Guideline-Recommended DVT Prophylaxis, the Incidence of Venous Thromboembolism was 37.2% in Patients with Severe Sepsis/Septic Shock
        • Most Venous Thromboembolism Events were Clinically Significant (Defined as Pulmonary Embolism, Proximal DVT, and/or Symptomatic Distal DVT) and were Associated with an Increased Length of Stay (18.2 ± 9.9 days vs 13.4 ± 11.5 days, P < 0.05)
        • Mortality was Higher in Patients with Acute Venous Thromboembolism, But this Did Not Reach Statistical Significance
        • Insertion of a CVC and Longer Mechanical Ventilation Duration were Significant Venous Thromboembolism Risk Factors
        • There was No Difference in the Incidence of Venous Thromboembolism Incidence Between Patients Receiving Pharmacologic Prophylaxis vs Sequential Compression Devices (37.3% vs 36.3%)
        • There was No Difference in the Incidence of Venous Thromboembolism Incidence Between Patients Receiving Low Molecular Weight Heparin Prophylaxis vs Unfractionated Heparin Prophylaxis (33.3% vs 41.3%)
    • Varicella-Zoster Virus (VZV) )(see Varicella-Zoster Virus, [[Varicella-Zoster Virus]])
      • Epidemiology: has been reported in children (Pediatr Infect Dis J, 2015) [MEDLINE]
  • Inflammatory Bowel Disease (see Inflammatory Bowel Disease, [[Inflammatory Bowel Disease]])
  • Liver Disease (see Cirrhosis, [[Cirrhosis]])
    • Epidemiology: there is a high (6.3%) risk of venous thromboembolism in hospitalized liver disease patients, despite abnormal coagulation parameters [MEDLINE]
  • Lower Extremity Venous Insufficiency (see Lower Extremity Chronic Venous Disease, [[Lower Extremity Chronic Venous Disease]])
  • Malignancy: clinical venous thromboembolism occurs in 5% of patients with cancer
    • Co-Incidence of DVT and Malignancy: 20% of patients with DVT have a known active malignancy
    • Risk of Venous Thrombembolism in Course of Cancer: highest risk during initial hospitalization, at the onset of chemotherapy, and at the time of disease progression
    • Presence of a Central Venous Catheter: futher compounds the risk of malignancy-associated venous thromboembolism
    • Common Sites of Malignancies at Time of Venous Thromboembolism Diagnosis: most cancers (78%) are diagnosed before the diagnosis of the DVT
      • Lung Cancer: 17%
      • Pancreatic Cancer: 10%
      • Colorectal cancer: 8%
      • Renal Cancer: 8%
      • Prostate Cancer: 7%
  • May-Thurner Syndrome (May-Thurner Syndrome, [[May-Thurner Syndrome]])
    • Physiology: compression of the left common iliac vein between the overlying right common iliac artery and underlying vertebral body
  • Nephrotic Syndrome (see Nephrotic Syndrome, [[Nephrotic Syndrome]])
  • Obesity (see Obesity, [[Obesity]])
    • Epidemiology
      • Longitudinal Investigation of Thromboembolism Etiology (LITE) Study (2002) Demonstrated that Obesity Increased the Risk of Venous Thromboembolism Using Age/Race/Sex-Adjusted Hazard Ratios for BMI (BMI <25 = 1.0, BMI 25-30 = 1.5, BMI 30-35 = 2.2, BMI 35-40 = 1.5, and BMI ≥40 = 2.7) (Arch Intern Med, 2002) [MEDLINE]
      • Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.18), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
      • Obesity Increased the Risk of Pulmonary Embolism (Relative Risk 2.03), But Decreased the Mortality of Pulmonary Embolism in Hospitalized Patients (Thromb Res, 2011) [MEDLINE]
  • Obstructive Sleep Apnea (OSA) (see Obstructive Sleep Apnea, [[Obstructive Sleep Apnea]])
  • Ovarian Hyperstimulation Syndrome (see Ovarian Hyperstimulation Syndrome, [[Ovarian Hyperstimulation Syndrome]])
  • Paget-Schroetter Syndrome (see Paget-Schroetter Syndrome, [[Paget-Schroetter Syndrome]])
    • Physiology: underlying venous compression at the thoracic outlet
  • Paroxysmal Nocturnal Hemoglobinuria (PNH) (see Paroxysmal Nocturnal Hemoglobinuria, [[Paroxysmal Nocturnal Hemoglobinuria]])
  • Pregnancy (see Pregnancy, [[Pregnancy]])
    • Incidence of DVT is equal throughout pregnancy (first trimester: 22%/second trimester: 41%/third trimester: 37%)
    • Incidence of PE during pregnancy: 34% occur pre-partum, 66% occur post-partum (82% of these follow C-section)
    • Increased risk of DVT in left leg during pregnancy (possibly due to left common iliac vein compression by overlying right iliac artery)
    • ASA does not affect risk of DVT in pregnancy (even in presence of anti-phospholipid Ab syndrome)
  • Polycystic Ovary Syndrome (see Polycystic Ovary Syndrome, [[Polycystic Ovary Syndrome]])
  • Presence of Central Venous Catheter (CVC) (see Central Venous Catheter, [[Central Venous Catheter]])
  • Prior Thrombotic Event: major risk factor
  • Recent Arterial Cardiovascular Event (Within 3 Months): short-term increase in venous thromboembolism risk
  • Recent Major Surgery
    • Cancer Surgery
    • Major Vascular Surgery
    • Neurosurgery
    • Orthopedic Surgery
      • Total Hip Replacement: 30-day risk of symptomatic non-fatal venous thromboembolism is 2.5% [MEDLINE][MEDLINE]
      • Total Knee Replacement: 30-day risk of symptomatic non-fatal venous thromboembolism is 1.4% [MEDLINE][MEDLINE]
  • Renal Transplant (see Renal Transplant, [[Renal Transplant]])
  • Rheumatologic Disease/Vasculitis (see Vasculitis, [[Vasculitis]])
    • Behcet’s Disease (see Behcet’s Disease, [[Behcets Disease]])
    • Eosinophilic Granulomatosis with Polyangiitis (EGPA) (Churg-Strauss Syndrome) (see Eosinophilic Granulomatosis with Polyangiitis, [[Eosinophilic Granulomatosis with Polyangiitis]])
    • Giant Cell Arteritis (Takayasu Arteritis) (see Giant Cell Arteritis, [[Giant Cell Arteritis]])
      • Incidence of Venous Thromboembolism (DVT or PE) was 13.3 per 1000 Person-Years with Incidence Rate Ratio of 3.58 (2.33-5.34, CI 95%) (Ann Rheum Dis, 2016) [MEDLINE]
    • Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) (see Granulomatosis with Polyangiitis, [[Granulomatosis with Polyangiitis]])
    • Microscopic Polyangiitis (see Microscopic Polyangiitis, [[Microscopic Polyangiitis]])
    • Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis, [[Rheumatoid Arthritis]])
    • Scleroderma (see Scleroderma, [[Scleroderma]])
      • Scleroderma Increases the Risk of Venous Thromboembolism (Rheumatology-Oxford, 2014) [MEDLINE] and (Arthritis Care Res-Hoboken, 2016) [MEDLINE]: increased risk appears to be the highest in the first year after the diagnosis of scleroderma
  • Superficial Thrombophlebitis/Superficial Venous Thrombosis (SVT) (see Superficial Venous Thrombosis, [[Superficial Venous Thrombosis]])
    • Epidemiology: SVT may occur in patients with inherited/acquired hypercoagulable states
    • Clinical
      • Occult DVT: occult DVT is present in 7-32% of superficial thrombophlebitis cases (suggests that screening of these patients with LE dopplers may be warranted)
      • Recurrence of SVT: 24% of cases have recurrent SVT [MEDLINE]
      • Later Development of DVT: 32% of SVT cases develop DVT at median interval of 4 years [MEDLINE]
  • Trauma of Any Etiology
    • Physiology: decreased lower extremity venous blood flow, decreased fibrinolysis, and immobilization
  • Drugs/Toxins
    • Bevacizumab (Avastin) (see Bevacizumab, [[Bevacizumab]])
      • Epidemiology: increased risk of venous and arterial events
    • Corticosteroids (see Corticosteroids, [[Corticosteroids]]):
      • Dutch Population-Based Case-Control Study of Danish Adults (Over 7 Year Period) [MEDLINE]: n= 38,765 Danish adults who developed venous thromboembolism (with n = 387,650 controls)
        • Systemic vs Non-Systemic Steroids: risk of venous thromboembolism was highest with use of systemic glucocorticoids, as compared to a relatively lower risk with inhaled or gastrointestinal glucocorticoids
        • Time of Onset-Related Effect: risk of venous thromboembolism was highest with new use of glucocorticoids (incidence ratio 3.06), as compared to continuing or past use
        • Dose-Effect: risk of venous thromboembolism increased with increasing cumulative doses of the glucocorticoids
        • Possible Study Flaws: study may not have been able to fully account for all of the confounding risks of venous thrombombolism related to the underlying disease itself (for which the glucocorticoids were prescribed): the underlying disease may have increased the risk of venous thromboembolism or the increased risk of immobility (which could indirectly increase the risk of venous thromboembolism)
      • United States Population-Based Retrospective Cohort Study of the Risks of Short-Term Corticosteroid Use in Adults (BMJ, 2017) [MEDLINE]
        • One in Five American Adults in a Commercially-Insured Plan were Given at Least One Outpatient Short-Term Corticosteroid Course During the Three Year Study (2012-2014): mostly for upper respiratory tract infections, spinal conditions, and allergies
        • Within 30 Days of Initiation, Short-Term Use of Corticosteroids Increased the Risk of Sepsis (Incidence Rate Ratio 5.30, 95% CI: 3.80-7.41), Venous Thromboembolism (Incidence Rate Ratio 3.33, 95% CI: 2.78 to 3.99), and Fractures (Incidence Rate Ratio 1.87, 95% CI: 1.69 to 2.07): increased risk persisted at prednisone equivalent doses of <20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture)
    • Erythropoiesis-Stimulating Agents
    • Heparin-Induced Thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia, [[Heparin-Induced Thrombocytopenia]])
    • Hormone Replacement Therapy (see Estrogen, [[Estrogen]])
    • Intravenous Drug Abuse (IVDA) (see Intravenous Drug Abuse, [[Intravenous Drug Abuse]]): due to femoral injection of drugs
    • Lenalidomide (Revlimid) (see Lenalidomide, [[Lenalidomide]])
    • Nonsteroidal Anti-Inflammatory Drugs (NSAID’s) (see Nonsteroidal Anti-Inflammatory Drug, [[Nonsteroidal Anti-Inflammatory Drug]])
      • Epidemiology
        • Systematic Review and Meta-analysis (Rheumatology, 2015) [MEDLINE]: NSAID’s increase risk of venous thromboembolism with RR of 1.80 (95% CI: 1.28-2.52)
    • Oral Contraceptives (OCP) (see Oral Contraceptives, [[Oral Contraceptives]])
    • Prothrombin Complex Concentrate-3 Factor (Profilnine SD) (see Prothrombin Complex Concentrate-3 Factor, [[Prothrombin Complex Concentrate-3 Factor]])
    • Prothrombin Complex Concentrate-4 Factor (Kcentra, Beriplex, Confidex) (see Prothrombin Complex Concentrate-4 Factor, [[Prothrombin Complex Concentrate-4 Factor]])
    • Tamoxifen (see Tamoxifen, [[Tamoxifen]])
    • Testosterone (see Testosterone, [[Testosterone]])
    • Thalidomide (see Thalidomide, [[Thalidomide]])
    • Tobacco Abuse (see Tobacco, [[Tobacco]])
    • Epidemiology
      • Longitudinal Investigation of Thromboembolism Etiology (LITE) Study (2002) Indicated that Alcohol Use, Hypertension, Hyperlipidemia, Physical Inactivity, and Tobacco Abuse were Not Associated with an Increased Risk of Venous Thromboembolism (Arch Intern Med, 2002) [MEDLINE]
      • Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.18), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
      • Cigarette smoking >25 cigarettes per day increases risk

Physiology

Virchow’s Triad: Contributors to the Development of Venous Thromboembolism

  • Alteration in Blood Flow: stasis
  • Vascular Endothelial Injury
  • Alteration in Constituents of Blood: inherited or acquired hypercoagulable state

Lower Extremity Venous Anatomy

Superficial Veins

  • Greater Saphenous Vein Above or Below the Knee
  • Non-Saphenous Veins
  • Small Saphenous Vein
  • Telangiectasias/Reticular Veins

Deep Veins

  • Inferior Vena Cava (IVC)
  • Iliac Veins
    • Common Iliac Vein
    • External Iliac Vein
    • Internal Iliac Vein
  • Pelvic Veins
    • Broad Ligament Vein
    • Gonadal Vein
    • Other Pelvic Veins
  • Femoral Veins
    • Common Femoral Vein
    • Deep Femoral Vein
  • Popliteal Vein
  • Crural Calf Veins
    • Anterior Tibial Vein: less common site of distal DVT
    • Posterior Tibial Vein: more common site of distal DVT
    • Peroneal Vein: more common site of distal DVT
  • Muscular Calf Veins: less common site of distal DVT
    • Gastrocnemius Vein
    • Soleal Vein
    • Other Muscular Calf Veins

Perforator Veins

  • Thigh Perforator Vein
  • Calf Perforator Vein

Upper Extremity Venous Anatomy

Superficial Veins

  • Basilic Vein
    • Common site of PICC placement
  • Cephalic Vein
  • Median Antebrachial Vein
  • Median Antecubital Vein
  • Accessory Cephalic Vein

Deep Veins

  • Radial Vein
  • Ulnar Vein
  • Interosseous Vein: in the forearm
  • Brachial Vein
    • Common site for PICC-related DVT
  • Axillary Vein
    • Common site for PICC-related DVT
  • Subclavian Vein
    • Common site for PICC-related DVT
  • Internal Jugular Vein
    • Most common site for CVC-related deep venous thrombosis

Lower Extremity Deep Venous Thrombosis

  • Calf Vein (Distal) DVT
    • Progression: left untreated, distal DVT will progress to proximal DVT in approximately 33% of cases
      • Usually progresses within the first 2 wks after diagnosis: if extension does not occur in the first 2 wks, it is unlikely to occur
      • Limited muscular calf vein distal DVT has a low risk of extension without treatment (risk of extension: 3%), as compared to extensive thrombosis of multiple calf veins (risk of extension: 15%)
    • Risk of Pulmonary Embolism with Distal DVT: risk of distal DVT embolization is approximately 50% the risk of proximal DVT embolization [MEDLINE]
  • Proximal DVT: thrombi in lower extremities develop within minutes, then organize, and fibrinolyse (stabilizing within 7-10 days)
    • Risk of Pulmonary Embolism with Proximal DVT: the risk of (symptomatic or asymptomatic) PE is approximately 50%
    • Highest Risk Period for Embolization of Proximal DVT: within first few days after DVT formation

Upper Extremity Deep Venous Thrombosis

Source of Pulmonary Embolism

  • In Situ Pulmonary Artery Thrombosis: rare
  • Lower Extremity Deep Venous Thrombosis (DVT): accounts for >95% of pulmonary embolism cases
    • Larger lower extremity veins (iliac, femoral, popliteal) are the source of most clinically significant pulmonary emboli
  • Pelvic Vein Deep Venous Thrombosis (DVT)
  • Arteriovenous Hemodialysis Fistula (see Arteriovenous Hemodialysis Fistula, [[Arteriovenous Hemodialysis Fistula]]): thrombectomy (including cases with paradoxical arterial embolism) may lead to pulmonary embolism
  • Upper Extremity Deep Venous Thrombosis (DVT): usually near venous valves

Clinical Consequences of Acute Pulmonary Embolism

  • Pulmonary Infarction: occurs in 10% of cases (since bronchial artery collateral vessels usually supply blood)
    • Physiology: inflammatory response in the lung and adjacent visceral/parietal pleura -> results in pleuritic chest pain and hemoptysis
  • Abnormal Gas Exchange
    • Mechanical Obstruction of Pulmonary Vascular Bed, Resulting in Alteration of V/Q Ratio: hypoxemia
    • Surfactant Dysfunction and Atelectasis, Resulting in Functional Intrapulmonary Shunting: hypoxemia
    • Inflammation Resulting in Respiratory Drive Stimulation: hypocapnia with respiratory alkalosis
  • Increased Pulmonary Vascular Resistance Due to Mechanical Obstruction of Pulmonary Vascular Bed and Hypoxic Pulmonary Vasoconstriction: obstruction of only 33% of pulmonary vasculature produces pulmonary hypertension, due to pulmonary arterial vasoconstriction (in addition, when obstruction of the pulmonary vascular bed approaches 75 percent, the right ventricle must generate a systolic pressure >50 mmHg to preserve adequate pulmonary artery flow)
    • Right Ventricular Dilation/Flattening of the Interventricular Septum
    • Decreased Flow from the Right Ventricle and Right Ventricular Dilation Decrease Left Ventricular Preload
    • Decreased Left Ventricular Stroke Volume and Decreased Cardiac Output: hypotension
  • Increased Alveolar Dead Space Fraction: due to occluded vasculature with remaining ventilation
    • Most Patients with Acute PE Have Alveolar Dead Space Fraction >20% and Positive D-Dimer
    • Most Patients with Normal Alveolar Dead Space (<20%) and Negative D-Dimer Do No Have Acute PE

Resolution of Acute Pulmonary Embolism

  • Embolus in the Pulmonary Vasculature Lyses over Hours-Days

Diagnosis

Electrocardiogram (EKG) (see Electrocardiogram, [[Electrocardiogram]])

  • See Below

Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]])

  • Hypocapnia with Respiratory Alkalosis: due to hyperventilation due to pulmonary hypertension
  • Hypoxemia with Elevated A-a Gradient: due to V/Q mismatch/intrapulmonary shunt/decreased CO with low SvO2
    • However, 18% of cases have pO2 between 85-100 mmHg
    • Up to 6% of cases have a normal A-a gradient
    • Presence of SaO2 <95% at Time of Diagnosis: increased risk of in-hospital complications (respiratory failure, cardiogenic shock, and death)

Pleural Fluid (see Thoracentesis, [[Thoracentesis]])

  • Pattern
  • Appearance
    • Hemorrhagic: in some cases
      • this is not a considered a contraindication to anticoagulants or thrombolytics
  • Pleural Fluid Eosinophilia (see Pleural Effusion-Cell Count Patterns, [[Pleural Effusion-Cell Count Patterns]]): may be seen in cases where effusion is bloody

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])

  • DLCO: decreased (due to loss of capillary blood volume)
    • May be the only PFT abnormality

Chest X-Ray (CXR)/Chest CT Patterns (see Chest X-Ray, [[Chest X-Ray]] and Chest Computed Tomography, [[Chest Computed Tomography]])

  • Features
    • Atelectasis (see Atelectasis, [[Atelectasis]])
    • Alveolar Infiltrate (see Pneumonia, [[Pneumonia]]): may cavitate in some cases
    • Cardiomegaly: seen in 50% of cases
    • Enlarged PA and Enlarged RV: seen with large PE only
    • “Hampton’s Hump”: wedge-shaped infiltrate in area of PE (appears 12-36 hours later)
      • May cavitate
    • “Westermark Sign”: wedge-shaped area of vascular clearing in area of PE
    • Pleural Effusion: seen in 47% of cases
      • Usually unilateral and small: 86% are only blunted CPA
      • May precede infiltrates (50% of acute PE’s with effusion have associated parenchymal infiltrates)
      • Usually reach maximum size in first 3 days (enlargement after that suggests recurrent PE or other complication)
    • Normal CXR: most common pattern

Ventilation/Perfusion (V/Q) Scan (see Ventilation-Perfusion Scan, [[Ventilation-Perfusion Scan]])

  • Overall diagnostic accuracy of V/Q is poor (ranges from 15-86%) in 72% of all patients, insufficient to diagnose PE or exclude the diagnosis of PE
  • Normal scan: virtually excludes diagnosis of PE
  • Low probability scan: low clinical prob + low prob V/Q = 4% probability of PE
    -Note: if clinical prob is high, low prob V/Q has 40% probability of PE
  • Intermediate probability scan: ranges from 15-66% probability of PE (depending on clinical prob)
  • High probability scan: high clinical prob + high prob V/Q = 95% probability of PE (these patients can be treated with heparin, thrombolytics without pulmonary angio)
    • Note: if clinical prob is low, high prob V/Q has 56% probability of PE

Pulmonary Artery Angiogram (see Pulmonary Artery Angiogram, [[Pulmonary Artery Angiogram]])

  • Indications
    • Gold Standard Diagnostic Test: negative pulmonary angiogram excludes clinically relevant PE
  • Adverse Effects: generally safe in patients without acute, severe pulmonary hypertension
    • Procedure-Related Mortality: <2%
    • Procedure-Related Morbidity: 5% (due mainly to catheter insertion-related complications, contrast reactions, arrhythmias, respiratory failure)
    • Radiation Exposure: greater than that from CT pulmonary angiogram
  • Angiographic Patterns
    • “Rat Tail Configuration”: vessel tapers to a point
    • “Filling Defects”: may be seen in most cases
    • “Abrupt Cut-Off”: may be seen in complete occlusion

Computed Tomography Pulmonary Artery Angiogram (CTPA) (see Computed Tomography Pulmonary Artery Angiogram, [[Computed Tomography Pulmonary Artery Angiogram]])

  • Sensitivity: 86% in large (main/lobar/segmental) vessels (75% in all vessels)
  • Specificity: 91% in large (main/lobar/segmental) vessels (89% in all vessels)
  • CT Pulmonary Angiogram Has Traditionally Been Considered Most Accurate for Large/Main/Lobar/Segmental PE’s and Less Accurate for Smaller/Peripheral Subsegmental PE’s: however, there is improved detection of PE by multi-detector CT pulmonary angiogram (9.4%) vs single-detector CT pulmonary angiogram (4.7%)
  • Low Risk of PE Following a Negative CT Pulmonary Angiogram: <2% risk of PE in 3-month F/U in patients with negative CT angio + low-intermediate clinical probability + negative LE dopplers
    • This risk increases to 5% if clinical probability is high

Clinical Efficacy

  • Grading of CT Signs of Right Ventricular Dysfunction in Acute PE (AJR Am J Roentgenol, 2010) [MEDLINE]
    • Volumetric Determination of the Right Ventricular Volume/Left Ventricular Volume Ratio: most reproducible/least user-dependent of the CT measurements (as compared to septal bowing or IVC reflux) -> ratio >1.2 is suggestive of RV strain
  • Grading of Intermediate-Risk Pulmonary Embolism Patients (Eur Respir J, 2014) [MEDLINE]
    • SBP 90-100 mm Hg: 2 pts
    • Elevated Troponin: 2 pts
    • RV Dysfunction (by Echocardiogram or CT): 2 pts
    • HR ≥100 BPM: 1 pt
    • Scoring: range 0-7
      • Stage I (0-2 points)
        • 3.6% risk for in-hospital PE-related complications
        • 4.2% risk for 30-day PE-related complications
        • 1.7% 30-day PE-related mortality
      • Stage II (3-4 points)
        • 9.7% risk for in-hospital PE-related complications
        • 10.8% risk for 30-day PE-related complications
        • 5.0% 30-day PE-related mortality
      • Stage III (>4 points)
        • 28.0% risk for in-hospital PE-related complications
        • 29.2% risk for 30-day PE-related complications
        • 15.5% 30-day PE-related mortality
  • Retrospective Review of CT Pulmonary Artery Angiograms in Tertiary Care Hospital (AJR Am J Roentgenol, 2015) [MEDLINE]: n = 937 CT pulmonary artery angiogram studies
    • Acute PE was Diagnosed in 18.6% of CT Pulmonary Artery Angiograms
    • There was Discordance Between the Chest Radiologist and the Original Radiologist in 25.9% of Cases
      • Discordance Occurred More Commonly When the Original Reported PE was Solitary (46.2% of Solitary PE’s were Considered Negative on Retrospective Review) and Located in a Segmental/Subsegmental Pulmonary Artery (26.8% of Segmental and 59.4% of Subsegmental PE’s were Considered Negative on Retrospective Review)

Gadolinium-Enhanced Magnetic Resonance Venogram and Pulmonary Artery Angiogram (MRA) (see Magnetic Resonance Imaging, [[Magnetic Resonance Imaging]])

Advantages

  • No Exposure to Iodinated Radiographic Contrast
  • No Radiation Exposure

Disadvantages

  • Magnetic Resonance Venogram and Pulmonary Artery Angiogram Have High Rates of Technically Inadequate Studies [MEDLINE]: technically inadequate studies were found in 25% (range: 11-52%) of studies performed in the PIOPED III Study (2010), depending on the center
    • Due to the large number of technically inadequate studies in PIOPED III, magnetic resonance venography and pulmonary angiogram only identified 57% of patients with pulmonary embolism
    • Vascular opacification and motion artifact are the principal factors which influence interpretability of MRA [MEDLINE]: some centers appear to obtain better images (for unclear reasons)
  • Technically Adequate Magnetic Resonance Pulmonary Angiogram
    • Sensitivity: 78%
    • Specificity: 99%
  • Technically Adequate Magnetic Resonance Pulmonary Angiogram + Magnetic Resonance Venogram: combination has significantly higher sensitivity than magnetic resonance pulmonary angiogram alone (however, only 52% of patients had technically inadequate results)
    • Sensitivity: 92%
    • Specificity: 96%

Recommendations

  • Magnetic Resonance Pulmonary Artery Angiogram and Venogram Studies Should Only be Performed in Centers with Local Expertise

Lower Extremity Venogram (see Lower Extremity Venogram, [[Lower Extremity Venogram]])

  • Indications: gold standard for diagnosis of lower extremity DVT

Lower Extremity Compression Venous Doppler Ultrasound (see Lower Extremity Compression Venous Doppler Ultrasound, [[Lower Extremity Compression Venous Doppler Ultrasound]])

Clinical Efficacy

  • Systematic Review and Meta-Analysis of Risk Stratification of Patients with Acute PE Based on Presence/Absence of Lower Extremity DVT (Chest, 2016) [MEDLINE]

    • In Patients Diagnosed with Acute Symptomatic PE, Concomitant DVT was Significantly Associated with an Increased Risk of Death within 30 days of the PE Diagnosis, as Compared to Those without a Concomitant Lower Extremity DVT (6.2% vs 3.8%)
  • May detect DVT

  • 3% false-positive rate
  • Only 29% of patients with PE (diagnosed by V/Q or angiogram) have DVT by U/S
  • Incidence of symptomatic DVT-PE is <1% in those with negative whole leg LE U/S during a 3 months of F/U period
  • Serial Ambulatory U/S Studies: 2-week monitoring (to assess for extension), without anticoagulation, may be indicated for patients with isolated calf vein DVT + adequate cardiopulmonary reserve + non-high prob V/Q scan [Hull; Arch Int Med, 1989] -> <3% of patients had PE during F/U period
  • Results cannot be generalized to patients with limited cardiopulmonary reserve or patients with a documented PE

Lower Extremity Impedance Plethysmography (IPG)

  • Indications: sensitive for above the knee DVT

Lower Extremity Radiofibrinogen Study

  • Indications: sensitive for calf/lower thigh DVT

Serum Brain Natriuretic Peptide (BNP) (see Serum Brain Natriuretic Peptide, [[Serum Brain Natriuretic Peptide]])

  • May Be Elevated
    • Magnitude of increase in BNP correlates with risk of subsequent complications and prolonged hospitalization
    • BNP >90 pg/ml (within 4 hrs of presentation): associated with adverse outcomes (death, cardioplumonary resuscitation, mechanical ventilation, pressor therapy, thrombolysis, and embolectomy)
    • BNP <50 pg/ml (within 4 hrs of presentation): benign clinical course in 95% of cases
  • Sensitivity: 60%
  • Specificity: 62%

Clinical Data

  • Grading of Factors Associated with 30-Day Frequency of Adverse Events in Prep Study (Am J Respir Crit Care Med, 2010) [MEDLINE]
    • Altered Mental Status: OR 6.8 (95% CI: 2.0-23.3)
    • Shock on Admission: OR 2.8 (95% CI: 1.1-7.5)
    • Cancer: OR 2.9 (95% CI: 1.2-6.9)
    • Elevated BNP: OR 1.3 for an increase of 250 ng/L (95% CI: 1.1-1.6)
    • Echocardiographic Right Ventricular Volume/Left Ventricular Volume Ratio: OR 1.2 for an increase of 0.1 (95% CI: 1.1-1.4)

Serum Troponin (see Serum Troponin, [[Serum Troponin]])

  • May Be Elevated: due to acute right heart overload
    • Not useful for diagnosis, but offers prognostic information (elevated troponin is associated with increased incidence of prolonged hypotension + increased 30-day mortality)
    • Troponin I: elevated in 30% of moderate-large PE
    • Troponin T: elevated in 50% of moderate-large PE

Clinical Efficacy

  • Grading of Pulmonary Embolism Using Right Ventricular Dysfunction and Troponin Levels (Chest, 2013) [MEDLINE]
    • Right Ventricular Dysfunction and Elevated Troponin Level: these criteria have an incremental prognostic value for risk stratification in hemodynamically-stable patients with acute pulmonary embolism
  • Grading of Intermediate-Risk Pulmonary Embolism Patients (Eur Respir J, 2014) [MEDLINE]
    • SBP 90-100 mm Hg: 2 pts
    • Elevated Troponin: 2 pts
    • RV Dysfunction (by Echocardiogram or CT): 2 pts
    • HR ≥100 BPM: 1 pt
    • Scoring: range 0-7
      • Stage I (0-2 points)
        • 3.6% risk for in-hospital PE-related complications
        • 4.2% risk for 30-day PE-related complications
        • 1.7% 30-day PE-related mortality
      • Stage II (3-4 points)
        • 9.7% risk for in-hospital PE-related complications
        • 10.8% risk for 30-day PE-related complications
        • 5.0% 30-day PE-related mortality
      • Stage III (>4 points)
        • 28.0% risk for in-hospital PE-related complications
        • 29.2% risk for 30-day PE-related complications
        • 15.5% 30-day PE-related mortality

Elevated Serum NT-proBNP level + Elevated Serum Troponin (see Serum Brain Natriuretic Peptide, [[Serum Brain Natriuretic Peptide]] and Serum Troponin, [[Serum Troponin]])

  • Provide prognostic information
  • Troponin-T >0.07 µg/L + NT-proBNP >600 ng/L is associated with 33% 40-day mortality (as compared to 0% mortality with NT-proBNP level <600 ng/L)

Plasma D-Dimer (see Plasma D-Dimer, [[Plasma D-Dimer]])

Assay/Interpretation

  • Rationale: D-dimer is the degradation product of cross-linked fibrin
  • “Sensitive” D-Dimer Assays: quantitative or semiquantitative newer generation assays
    • Rapid Enzyme-Linked Immunosorbent Assay (ELISA)
    • Immunoturbidimetric Assay
    • Latex Agglutination Assay
  • Normal D-Dimer Level: <500 ng/mL (<0.5 μg/mL or <500 μg/L) Fibrinogen Equivalent (FE) Units
  • Sensitivity/Specificity
    • Sensitivity: 80-100% (Cochrane Database Syst Rev, 2016) [MEDLINE]
      • In the ANTELOPE Study, the Sensitivity of D-Dimer was Lower in Subsegmental Pulmonary Embolism (53%), as Compared to Large Main, Lobar, and Segmental Pulmonary Embolism (93%) (Am J Respir Crit Care Med, 2002) [MEDLINE]
      • D-Dimer Has a High Negative Predictive Value
    • Specificity: 23-63% (Cochrane Database Syst Rev, 2016) [MEDLINE]

Clinical Efficacy

  • European ADJUST-PE Study of Age-Adjusted D-Dimer Levels in the Diagnosis of Pulmonary Embolism (JAMA, 2014) [MEDLINE]
    • Age-Adjusted D-Dimer (Only for Patients ≥50 y/o): defined as 10 x age
    • Compared with a Fixed D-Dimer Cutoff of 500 μg/L (500 ng/mL), the Combination of a Pre-Test Clinical Probability Assessment and Age-Adjusted D-Dimer Cutoff was Associated with a Larger Number of Patients in Whom Pulmonary Embolism Could Be Considered Ruled Out with a Low Likelihood of Subsequent Clinical Venous Thromboembolism
  • Systematic Review of Use of D-Dimer to Exclude the Diagnosis of Pulmonary Embolism (Cochrane Database Syst Rev, 2016) [MEDLINE]
    • Negative D-Dimer is Valuable to Rule Out the Diagnosis of Pulmonary Embolism in Patients Who Present in the Accident and Emergency Setting with Low Pre-Test Probability
      • Sensitivity: 80-100%
      • Specificity: 23-63%
    • Evidence from One Trial Suggests that Utility May Be Lower in Older Patient Populations, But There was No Evidence to Support Using an Increased Diagnostic Threshold in Patients >65 y/o
  • Systematic Review and Meta-Analysis of Wells Criteria and D-Dimer Testing in the Diagnosis of Pulmonary Embolism (Ann Intern Med, 2016) [MEDLINE]
    • In Patients with an “Unlikely” Pre-Test Probability of Pulmonary Embolism, Age-Adjusted D-Dimer Testing is Associated with a 5% Increase in the Proportion of Patients with Suspected Pulmonary Embolism in Whom Imaging Can Be Safely Withheld, as Compared to Fixed D-Dimer Testing
  • Interval Likelihood Ratios for Plasma D-Dimer (Acad Emerg Med, 2017) [MEDLINE]
    • If the Pre-D-Dimer Probability of PE is 15% (Intermediate Pre-Test Probability), Only a D-DImer <500 ng/mL Will Result in a Post-Test Probability <3%
    • Consequently, Given a Pre-Test Probability of 15% (Intermediate Pre-Test Probability) and a CT Pulmonary Artery Angiogram Threshold of 3%, a Strategy to Obtain CT Pulmonary Artery Angiogram for D-Dimer ≥500 ng/ mL is Consistent with the Interval Likelihood Ratios Reported

Echocardiogram (see Echocardiogram, [[Echocardiogram]])

  • General Comments
    • Only 30-40% of Acute PE’s Have Positive Echocardiographic Evidence of PE: percentage is higher in cases of massive PE
  • Features
    • Features of RV Strain/Overload: present in 30-40% of patients with acute PE (higher percentage in patients with massive PE)
      • Decreased RV Ejection Fraction
      • RV Enlargement
      • Tricuspid Regurgitation: Doppler of TR jet allows estimation of PA pressure
    • Pulmonic Regurgitation
    • RV Thrombus: >35% patients with RV thrombus develop PE, but only 4% of PE patients have an RV thrombus
    • McConnell’s Sign (77% sensitivity for diagnosis of acute PE): regional wall motion abnormalities that spare the RV apex
    • Normal LV Ejection Fraction: usually seen

Clinical Data

  • Grading of Factors Associated with 30-Day Frequency of Adverse Events in Prep Study (Am J Respir Crit Care Med, 2010) [MEDLINE]
    • Altered Mental Status: OR 6.8 (95% CI: 2.0-23.3)
    • Shock on Admission: OR 2.8 (95% CI: 1.1-7.5)
    • Cancer: OR 2.9 (95% CI: 1.2-6.9)
    • Elevated BNP: OR 1.3 for an increase of 250 ng/L (95% CI: 1.1-1.6)
    • Echocardiographic Right Ventricular Volume/Left Ventricular Volume Ratio: OR 1.2 for an increase of 0.1 (95% CI: 1.1-1.4)
  • Grading of Pulmonary Embolism Using Right Ventricular Dysfunction and Troponin Levels (Chest, 2013) [MEDLINE]
    • Right Ventricular Dysfunction and Elevated Troponin Level: these criteria have an incremental prognostic value for risk stratification in hemodynamically-stable patients with acute pulmonary embolism
  • Grading of Intermediate-Risk Pulmonary Embolism Patients (Eur Respir J, 2014) [MEDLINE]
    • SBP 90-100 mm Hg: 2 pts
    • Elevated Troponin: 2 pts
    • RV Dysfunction (by Echocardiogram or CT): 2 pts
    • HR ≥100 BPM: 1 pt
    • Scoring: range 0-7
      • Stage I (0-2 points)
        • 3.6% risk for in-hospital PE-related complications
        • 4.2% risk for 30-day PE-related complications
        • 1.7% 30-day PE-related mortality
      • Stage II (3-4 points)
        • 9.7% risk for in-hospital PE-related complications
        • 10.8% risk for 30-day PE-related complications
        • 5.0% 30-day PE-related mortality
      • Stage III (>4 points)
        • 28.0% risk for in-hospital PE-related complications
        • 29.2% risk for 30-day PE-related complications
        • 15.5% 30-day PE-related mortality

Swan-Ganz Catheter (see Swan-Ganz Catheter, [[Swan-Ganz Catheter]])

  • RA: normal (at rest)
  • RV-SYS: moderately elevated (with normal RV-EDP)
  • PA-SYS and PA-DIA: moderately elevated (severe elevations suggest CTEPH, since vascular remodeling is required to raise pressures this high/acute severe elevations will also produce rapid RV failure)
  • PA-SaO2: lack of “step-up” excludes intracardiac shunt
  • PCWP: normal (reflects normal LA and LV-EDP)
  • CO: normal-decreased (at rest)
  • PVR: may be elevated

Clinical Decision Rules for the Diagnosis of Acute Pulmonary Embolism

Wells Criteria/Modified (Dichotomized) Wells Criteria (BMJ, 2015) [MEDLINE]

  • Criteria
    • Clinical Symptoms of DVT (Leg Swelling, Pain with Palpation): 3.0 pts
    • Other Diagnosis Less Likely than Pulmonary Embolism: 3.0 pts
    • Heart Rate >100 bpm: 1.5 pts
    • History of DVT/PE: 1.5 pts
    • Immobilization (≥3 Days) or Surgery in Previous 4 Weeks: 1.5 pts
    • Hemoptysis: 1.0 pt
    • Malignancy: 1.0 pt
  • Wells Criteria Scoring
    • Low Probability of Pulmonary Embolism: <2 pts
    • Intermediate/Moderate Probability of Pulmonary Embolism: 2-6 pts
    • High Probability of Pulmonary Embolism: >6 pts
  • Modified (Dichotomized) Wells Criteria Scoring
    • Pulmonary Embolism Unlikely: ≤4 pts
    • Pulmonary Embolism Likely: >4 pts

Simplified Wells Criteria

  • Criteria
    • Clinical Symptoms of DVT (Leg Swelling, Pain with Palpation): 1 pt
    • Other Diagnosis Less Likely than Pulmonary Embolism: 1 pt
    • Heart Rate >100 bpm: 1 pt
    • History of DVT/PE: 1 pt
    • Immobilization (≥3 Days) or Surgery in Previous 4 Weeks: 1 pt
    • Hemoptysis: 1 pt
    • Malignancy: 1 pt
  • Simplified Wells Criteria Scoring
    • Pulmonary Embolism Unlikely: ≤1 pt
    • Pulmonary Embolism Likely: >1 pt

Revised Geneva Score

  • Criteria
    • Age > 65 y/o: 1 pt
    • Previous Deep Venous Thrombosis/Pulmonary Embolism: 3 pts
    • Surgery (Under General Anesthesia) or Fracture of Lower Extremity in Last Month: 2 pts
    • Cancer (Solid or Hematologic; Currently Active or Considered Cured for <1 Year): 2 pts
    • Unilateral Lower Extremity Pain: 3 pts
    • Hemoptysis: 2 pts
    • Heart Rate 75-94: 3 pts
    • Heart Rate ≥95: 5 pts
    • Pain on Lower Extremity Deep Venous Palpation and Unilateral Edema: 4 pts
  • Revised Geneva Scoring
    • Low Probability of Pulmonary Embolism: <4 pts
    • Intermediate/Moderate Probability of Pulmonary Embolism: 4-10 pts
    • High Probability of Pulmonary Embolism: >10 pts

Simplified Revised Geneva Score

  • Criteria
    • Age > 65 y/o: 1 pt
    • Previous Deep Venous Thrombosis/Pulmonary Embolism: 1 pt
    • Surgery (Under General Anesthesia) or Fracture of Lower Extremity in Last Month: 1 pt
    • Cancer (Solid or Hematologic; Currently Active or Considered Cured for <1 Year): 1 pt
    • Unilateral Lower Extremity Pain: 1 pt
    • Hemoptysis: 1 pt
    • Heart Rate 75-94: 1 pt
    • Heart Rate ≥95: 2 pts
    • Pain on Lower Extremity Deep Venous Palpation and Unilateral Edema: 1 pt
  • Simplified Revised Geneva Scoring
    • Pulmonary Embolism Unlikely: ≤2 pts
    • Pulmonary Embolism Likely: >2 pts

Kline Rule (Ann Emerg Med, 2002) [MEDLINE]

  • Algorithmic Approach Which May Also Be Used

Pisa Model (Am J Respir Crit Care Med, 2008) [MEDLINE]

  • Age
    • Age 57–67: coefficient 0.80 (Odds Ratio = 2.23)
    • Age 68–74: coefficient 0.87 (Odds Ratio = 2.38)
    • Age ≥75: coefficient 1.14 (Odds Ratio = 3.11)
  • Male Sex: coefficient 0.60 (Odds Ratio = 1.82)
  • Risk Factors
    • Immobilization: coefficient 0.42 (Odds Ratio = 1.53)
    • Deep Venous Thrombosis (Ever): coefficient 0.64 (Odds Ratio = 1.90)
  • Preexisting Diseases
    • Cardiovascular coefficient –0.51 (Odds Ratio = 0.60)
    • Pulmonary: coefficient –0.89 (Odds Ratio = 0.41)
  • Symptoms
    • Dyspnea (Sudden Onset): coefficient 2.00 (Odds Ratio = 7.38)
    • Orthopnea: coefficient –1.51 (Odds Ratio = 0.22)
    • Chest Pain: coefficient 1.01 (Odds Ratio = 2.74)
    • Fainting/Syncope: coefficient 0.66 (Odds Ratio = 1.93)
    • Hemoptysis: coefficient 0.93 (Odds Ratio = 2.52)
  • Signs
    • Unilateral Leg Swelling: coefficient 0.80 (Odds Ratio = 2.23)
    • Fever >38°C ( >100.4°F): coefficient –1.47 (Odds Ratio = 0.23)
    • Wheezes: coefficient –1.20 (Odds Ratio = 0.30)
    • Crackles: coefficient –0.61 (Odds Ratio = 0.54)
  • Electrocardiogram
    • Acute Cor Pulmonale (Includes ≥1 of the Following EKG Abnormalities: S1Q3T3, S1S2S3, Negative T-Waves in Right Precordial Leads, Transient Right Bundle Branch Block, or Pseudoinfarction Pattern): coefficient 1.96 (Odds Ratio = 7.11)
  • Constant: coefficient –3.43
  • Calculation
    • Add All of the Coefficients + Constant –3.43 to Obtain a Sum Score
    • Probability of Pulmonary Embolism = [1 + exp(–sum)]–1

Clinical Utility of Diagnostic Algorithms for the Diagnosis of Acute Pulmonary Embolism

Clinical Data

  • Prospective Observational Study of the Accuracy of Clinical Gestalt in the Diagnosis of Acute Pulmonary Embolism (Chest, 2005) [MEDLINE]
    • Accurate Determination of the Pretest Probability of Acute Pulmonary Embolism Appears to Increase with Clinical Experience
    • However, the Difference in Accuracy Between Inexperienced and Experienced Physicians is Not Sufficiently Large to Distinguish Between the Two When Determining Whether Clinical Gestalt or a Clinical Prediction Rule Should Be Used to Determine the Pretest Probability of Acute Pulmonary Embolism
  • Dutch Prospective Cohort Christopher Study Using Algorithm Combining Clinical Probability, D-Dimer, and Computed Tomography in the Diagnosis of Pulmonary Embolism (JAMA, 2006) [MEDLINE]: patients were followed for 3 mos
    • Initial Modified Wells Criteria Scoring: patients were categorized into “pulmonary embolism unlikely” vs “pulmonary embolism likely” groups
      • “Unlikely Group”: underwent D-dimer testing -> if D-dimer was normal, pulmonary embolism was considered excluded
      • All Others (“Likely” Group” or Those with Positive D-Dimer): underwent CT pulmonary angiogram to diagnose or exclude pulmonary embolism
    • Diagnostic Strategy Using Modified Wells Criteria, D-Dimer Testing, and CT Pulmonary Angiogram was Safe and Effective in the Diagnosis of Pulmonary Embolism
  • Dutch (Prometheus Study Group) Prospective Cohort Study of Clinical Decision Rules in the Diagnosis of Pulmonary Embolism (Ann Intern Med, 2011) [MEDLINE]
    • All 4 Clinical Decision Rules (Wells Rule, Revised Geneva Score, Simplified Wells Rule, and Simplified Revised Geneva Score) Had Similar Performance for the Exclusion of Acute Pulmonary Embolism in Combination with a Normal D-Dimer Result
  • Systematic Review and Meta-Analysis of Pulmonary Embolism Rule Out Criteria (PERC) in Acute Pulmonary Embolism (Emerg Med J, 2013) [MEDLINE]
    • Overall Proportion of Missed Pulmonary Emboli by Using PERC was Only 0.3%
    • PERC Had 97% Sensitivity and 22% Specificity: indicates that 22% of D-dimer tests could have been safely avoided had the PERC been universally applied
  • Dutch Study of the Accuracy of Clinical Decision Rules in the Diagnosis of Acute Pulmonary Embolism in Patients with a Delayed Clinical Presentation (Am J Respir Crit Care Med, 2013) [MEDLINE]
    • Pulmonary Embolism Can Be Safely Excluded Based on Clinical Decision Rules and D-Dimer Testing in Patients with a Delayed Clinical Presentation
    • Patients with a Delayed Clinical Presentation More Frequently Had a Centrally-Located Pulmonary Embolism
    • Cumulative Rates of Recurrent Venous Thromboembolism and Mortality Were Not Different for Patients with and without a Delayed Clinical Presentation
  • Study of the Yield of CT Pulmonary Artery Angiogram When Providers Used Well Criteria-Based Clinical Decision Support in the ED (Radiology, 2016) [MEDLINE]
    • Odds of Diagnosis of Acute Pulmonary Embolism was 2x Higher (Yield: 11.2% of Studies) When Providers Adhered to Wells Criteria-Based Clinical Decision Support, as Compared to Providers who Overrode the Clinical Decision Support (Yield: 4.2% of Studies)
      • Wells Criteria ≤4: providers were recommended to initially use D-dimer testing (since the probability of acute PE is low in this population, if D-dimer level is normal)
      • Providers Who Overrode the Clinical Decision Support Ordered a CT Pulmonary Angiogram in Patients with Wells Criteria ≤4 and Negative D-Dimer (or Did Not Perform D-Dimer Testing)
  • French Randomized PROPER Trial Using Pulmonary Embolism Rule-Out Criteria (PERC) in Low-Risk Emergency Department Patients (JAMA, 2018) [MEDLINE]
    • In Patients at Very Low-Risk with Suspected Pulmonary Embolism, PERC Strategy vs Conventional Strategy Had Similar Rates of Thromboembolic Events Over 3 mo
    • PERC Strategy is Safe for Use in Very Low-Risk Patients Presenting to the Emergency Department

Recommendations (American College of Physicians Guidelines for the Evaluation of Patients with Suspected Pulmonary Embolism, 2015) (Ann Intern Med, 2015) [MEDLINE]

  • Use Validated Clinical Prediction Rules (or Clinical Gestalt) to Estimate the Pretest Probability of Pulmonary Embolism
    • Clinical Gestalt: the overall accuracy of an experienced clinician’s gestalt appears to be similar to that of clinical decision rules (however, clinical decision rules allow standardization for evaluation of suspected acute pulmonary embolism by clinician’s who less frequently evaluate patient’s with suspected acute pulmonary embolism)
    • Clinical Decision Rules
      • Wells Criteria or Modified (Dichotomized) Wells Criteria
      • Revised Geneva Score or Revised Simplified Geneva Score
      • Kline Rule
      • Pisa Model
  • Low Pre-Test Probability of Pulmonary Embolism + Meets All Pulmonary Embolism Rule Out Criteria (PERC)
    • D-Dimer and Imaging Studies are Not Recommended
    • Pulmonary Embolism Rule Out Criteria (PERC) (Ann Emerg Med, 2004) [MEDLINE]: pre-test probability with score = 0 is <1%
      • Age <50 y/o: 0= meets criterion, 1 = does not meet criterion
      • Initial Heart Rate <100 bpm: 0= meets criterion, 1 = does not meet criterion
      • Initial SaO2 >94% (on Room Air): 0= meets criterion, 1 = does not meet criterion
      • Absence of Unilateral Leg Swelling: 0= meets criterion, 1 = does not meet criterion
      • Absence of Hemoptysis: 0= meets criterion, 1 = does not meet criterion
      • Absence of Surgery/Trauma within 4 wks: 0= meets criterion, 1 = does not meet criterion
      • Absence of History of Venous Thromboembolism: 0= meets criterion, 1 = does not meet criterion
      • Absence of Estrogen Use: 0= meets criterion, 1 = does not meet criterion
  • Intermediate Pre-Test Probability of Pulmonary Embolism + Does Not Meet All Pulmonary Embolism Rule Out Criteria (PERC)
    • Initial High-Sensitivity D-Dimer (But Not Imaging Study) is Recommended as the Initial Diagnostic Test
      • Use Age-Adjusted D-Dimer Thresholds (Age x 10) Rather than Generic 500 ng/ml Threshold in Patients >50 y/o
      • If D-Dimer is Below the Age-Adjusted Cutoff, Do Not Use Imaging Study
  • High Pre-Test Probability of Pulmonary Embolism
    • CT Pulmonary Artery Angiogram (But Not D-Dimer) is Recommended
    • Ventilation/Perfusion (V/Q) Scan Should Be Reserved for Patients with Contraindication to CT Pulmonary Artery Angiography (or When CT Pulmonary Artery Angiography is Not Available)


Clinical Grading/Risk Stratification of Pulmonary Embolism Severity

  • Grading of CT Signs of Right Ventricular Dysfunction in Acute PE (AJR Am J Roentgenol, 2010) [MEDLINE]

    • Volumetric Determination of the Right Ventricular Volume/Left Ventricular Volume Ratio: most reproducible/least user-dependent of the CT measurements (as compared to septal bowing or IVC reflux) -> ratio >1.2 is suggestive of RV strain
  • Grading of Factors Associated with 30-Day Frequency of Adverse Events in Prep Study (Am J Respir Crit Care Med, 2010) [MEDLINE]

    • Altered Mental Status: OR 6.8 (95% CI: 2.0-23.3)
    • Shock on Admission: OR 2.8 (95% CI: 1.1-7.5)
    • Cancer: OR 2.9 (95% CI: 1.2-6.9)
    • Elevated BNP: OR 1.3 for an increase of 250 ng/L (95% CI: 1.1-1.6)
    • Echocardiographic Right Ventricular Volume/Left Ventricular Volume Ratio: OR 1.2 for an increase of 0.1 (95% CI: 1.1-1.4)
  • Grading of Low-Risk Pulmonary Embolism with Simplified Pulmonary Embolism Severity Index (sPESI) (2010) [MEDLINE]

    • Simplified Pulmonary Embolism Severity Index (sPESI): has similar prognostic accuracy and clinical utility and greater ease of use, as compared with the original PESI
  • Grading of Pulmonary Embolism Using Right Ventricular Dysfunction and Troponin Levels (Chest, 2013) [MEDLINE]

    • Right Ventricular Dysfunction and Elevated Troponin Level: these criteria have an incremental prognostic value for risk stratification in hemodynamically-stable patients with acute pulmonary embolism
  • Grading of Intermediate-Risk Pulmonary Embolism Patients (Eur Respir J, 2014) [MEDLINE]

    • SBP 90-100 mm Hg: 2 pts
    • Elevated Troponin: 2 pts
    • RV Dysfunction (by Echocardiogram or CT): 2 pts
    • HR ≥100 BPM: 1 pt
    • Scoring: range 0-7
      • Stage I (0-2 points)
        • 3.6% risk for in-hospital PE-related complications
        • 4.2% risk for 30-day PE-related complications
        • 1.7% 30-day PE-related mortality
      • Stage II (3-4 points)
        • 9.7% risk for in-hospital PE-related complications
        • 10.8% risk for 30-day PE-related complications
        • 5.0% 30-day PE-related mortality
      • Stage III (>4 points)
        • 28.0% risk for in-hospital PE-related complications
        • 29.2% risk for 30-day PE-related complications
        • 15.5% 30-day PE-related mortality

Clinical Manifestations

Cardiovascular Manifestations

Arrhythmias

  • Atrial Fibrillation (AF) (see Atrial Fibrillation, [[Atrial Fibrillation]])
    • Epidemiology
      • Large Prospective Registry of Acute Pulmonary Embolism Patients (Eur Respir J, 2005) [MEDLINE]
        • Atrial Arrhythmias, Complete Right Bundle Branch Block, Peripheral Low Voltage, Pseudoinfarction Pattern (Q Waves in III and aVF), ST Segment Changes (Elevation or Depression) in Left Precordial Leads are Associated with Increased Risk of Mortality in Acute PE: 29% of patients with at least one of these findings on hospital admission did not survive to hospital discharge
      • Norwegian Tromso Study of the Association Between Venous Thromboembolism and Atrial Fibrillation (J Am Heart Assoc, 2014) [MEDLINE]
        • Venous Thromboembolism was Associated with an Increased Future Risk of Atrial Fibrillation: 9.3% of patients with venous thromboembolism developed subsequent atrial fibrillation
        • Risk of Atrial Fibrillation was Particularly High in the First 6 Months After the Venous Thomboembolism Event (Hazard Ratio 4.00, 95% CI: 2.21-7.25) and in Those with Pulmonary Embolism (Hazard Ratio 1.78, 95% CI: 1.13-2.8)
      • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med. 2015) [MEDLINE]
        • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
      • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
        • Presence of S1Q3T3 Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.38, 95% CI: 2.46-4.66, P <0.001)
        • Presence of Complete RBBB (But Not Incomplete RBBB) Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.90, 95% CI: 2.46-6.20, P <0.001)
        • Presence of T-Wave Inversion in Precordial/Inferior Leads Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.62, 95% CI: 1.19-2.21, P = 0.002)
        • Presence of Right Axis Deviation Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.24, 95% CI: 1.86-5.64, P <0.001)
        • Presence of Atrial Fibrillation Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.96, 95% CI: 1.45-2.67, P <0.001)
  • Sinus Bradycardia (see Sinus Bradycardia, [[Sinus Bradycardia]])
    • Epidemiology
      • Sinus Bradycardia is Associated with a Poor Prognosis in Acute PE
  • Sinus Tachycardia (see Sinus Tachycardia, [[Sinus Tachycardia]])
    • Epidemiology
      • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med. 2015) [MEDLINE]
        • Sinus Tachycardia was Present in 38% of Acute PE Cases
        • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
      • Retrospective Review of EKG Changes in Acute Pulmonary Embolism ( J Emerg Med, 2017) [MEDLINE]
        • Sinus Tachycardia Occurs in 25% of Acute PE Cases
      • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
        • Presence of Sinus Tachycardia Predicted Increased Adjusted 30-Day Mortality in Acute PE
  • Supraventricular Tachycardia (SVT) (see Supraventricular Tachycardia, [[Supraventricular Tachycardia]])

Electrocardiographic (EKG) Abnormalities (see Electrocardiogram, [[Electrocardiogram]])

  • General Comments
    • Normal EKG is Present in Many Cases of Acute PE
    • While EKG Abnormalities are Common in Acute PE, They are Usually Non-Specific and Non-Diagnostic (Am J Cardiol, 2000) [MEDLINE]
    • Retrospective Review of EKG Changes in Acute Pulmonary Embolism ( J Emerg Med, 2017) [MEDLINE]
      • No Change in EKG was Observed in 25% of Acute PE Cases
  • Peripheral Low Voltage
    • Epidemiology
      • Large Prospective Registry of Acute Pulmonary Embolism Patients (Eur Respir J, 2005) [MEDLINE]
        • Atrial Arrhythmias, Complete Right Bundle Branch Block, Peripheral Low Voltage, Pseudoinfarction Pattern (Q Waves in III and aVF), ST Segment Changes (Elevation or Depression) in Left Precordial Leads are Associated with Increased Risk of Mortality in Acute PE: 29% of patients with at least one of these findings on hospital admission did not survive to hospital discharge
      • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
        • Low-Voltage in Limb/Precordial Leads Did Not Predict Increased In-Hospital Mortality
  • P-Pulmonale
    • Epidemiology
      • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
        • Presence of P-Pulmonale Did Not Predict Increased In-Hospital Mortality in Acute PE
  • Pseudoinfarction Pattern (Q Waves in III and aVF)
    • Epidemiology
      • Large Prospective Registry of Acute Pulmonary Embolism Patients (Eur Respir J, 2005) [MEDLINE]
        • Atrial Arrhythmias, Complete Right Bundle Branch Block, Peripheral Low Voltage, Pseudoinfarction Pattern (Q Waves in III and aVF), ST Segment Changes (Elevation or Depression) in Left Precordial Leads are Associated with Increased Risk of Mortality in Acute PE: 29% of patients with at least one of these findings on hospital admission did not survive to hospital discharge
  • Right Axis Deviation (RAD)
    • Epidemiology
      • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
        • Right Axis Deviation Predicted Increased In-Hospital Mortality in Acute PE
  • Right Bundle Branch Block (see Right Bundle Branch Block, [[Right Bundle Branch Block]])
    • Epidemiology
      • Large Prospective Registry of Acute Pulmonary Embolism Patients (Eur Respir J, 2005) [MEDLINE]
        • Atrial Arrhythmias, Complete Right Bundle Branch Block, Peripheral Low Voltage, Pseudoinfarction Pattern (Q Waves in III and aVF), ST Segment Changes (Elevation or Depression) in Left Precordial Leads are Associated with Increased Risk of Mortality in Acute PE: 29% of patients with at least one of these findings on hospital admission did not survive to hospital discharge
      • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med. 2015) [MEDLINE]
        • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
      • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
        • Presence of S1Q3T3 Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.38, 95% CI: 2.46-4.66, P <0.001)
        • Presence of Complete RBBB (But Not Incomplete RBBB) Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.90, 95% CI: 2.46-6.20, P <0.001)
        • Presence of T-Wave Inversion in Precordial/Inferior Leads Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.62, 95% CI: 1.19-2.21, P = 0.002)
        • Presence of Right Axis Deviation Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.24, 95% CI: 1.86-5.64, P <0.001)
        • Presence of Atrial Fibrillation Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.96, 95% CI: 1.45-2.67, P <0.001)
  • “RV Strain” Findings
    • Physiology
      • EKG Findings Indicating “RV Strain” (Due to RV Hypertrophy or Dilatation)
        • ST Depression and T-Wave Inversion in the Right Precordial Leads, V1-V3 (and Sometimes V4)
        • ST Depression and T-Wave Inversion in Inferior Leads, II, III, and AVF: III is the most rightward facing lead
    • Epidemiology
      • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med. 2015) [MEDLINE]
        • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
      • Study of the Incidence of RV Strain-Related Electrocardiographic Changes from the Italian Pulmonary Embolism Registry (Thromb Res, 2018) [MEDLINE]: RV strain/ischemia findings examined in the study included complete or incomplete right bundle branch block, S1Q3 pattern, T-wave inversion in leads V1- V3 (V4), inferior (II/III/AVF) ST-segment elevation, and Qr pattern in lead V1
        • At Least One of the RV Strain/Ischemia Findings was Present in 53.1% of Acute PE Cases (high risk patients: at least one finding was present in 74.8% of cases, intermediate-risk (BP 90-100) patients: at least one finding was present in 73.5% of cases, intermediate-risk (BP >100) patients: at least one finding was present in 56.5% of cases, and low-risk patients: at least one finding was present in 28.2% of cases)
        • Right Bundle Branch Block Occurred in 22.4% of Acute PE Cases
        • S1Q3 Occurred in 24.4% of Acute PE Cases
        • T-Wave Inversion in V1-V3 (V4) Occurred in 28.4% of Acute PE Cases
        • Inferior ST Elevation Occurred in 6.2% of Acute PE Cases
        • V1 Qr Pattern Occurred in 6.8% of Acute PE Cases
  • S1Q3T3 Pattern
    • Epidemiology
      • S1Q3T3 Pattern Occurs Infrequently in Acute PE: occurs in <10% of cases
      • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med. 2015) [MEDLINE]
        • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
      • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
        • Presence of S1Q3T3 Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.38, 95% CI: 2.46-4.66, P <0.001)
        • Presence of Complete RBBB (But Not Incomplete RBBB) Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.90, 95% CI: 2.46-6.20, P <0.001)
        • Presence of T-Wave Inversion in Precordial/Inferior Leads Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.62, 95% CI: 1.19-2.21, P = 0.002)
        • Presence of Right Axis Deviation Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.24, 95% CI: 1.86-5.64, P <0.001)
        • Presence of Atrial Fibrillation Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.96, 95% CI: 1.45-2.67, P <0.001)
  • ST-Segment Changes (Elevation or Depression)
    • Epidemiology
      • Large Prospective Registry of Acute Pulmonary Embolism Patients (Eur Respir J, 2005) [MEDLINE]
        • Atrial Arrhythmias, Complete Right Bundle Branch Block, Peripheral Low Voltage, Pseudoinfarction Pattern (Q Waves in III and aVF), ST Segment Changes (Elevation or Depression) in Left Precordial Leads are Associated with Increased Risk of Mortality in Acute PE: 29% of patients with at least one of these findings on hospital admission did not survive to hospital discharge
      • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med. 2015) [MEDLINE]
        • ST Elevation in aVR was Present in 36% of Acute PE Cases
        • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
      • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
        • Presence of ST Elevation in V1 Predicted Increased Adjusted In-Hospital Mortality in Acute PE
  • T-Wave Inversion/Flattening
    • Epidemiology
      • Systematic Review and Meta-Analysis of EKG Findings Which Predict Circulatory Shock in Acute Pulmonary Embolism (Acad Emerg Med. 2015) [MEDLINE]
        • T-Wave Inversion in Lead V1 was Present in 38% of Acute PE Cases
        • Findings Consistent with RV Strain (Heart Rate >100 bpm, S1Q3T3 Pattern, Complete RBBB, Inverted T-Waves in V1-V4, ST Elevation in aVR, and Atrial Fibrillation) are Associated with Increased Risk of Circulatory Shock and Death
      • Retrospective Review of EKG Changes in Acute Pulmonary Embolism ( J Emerg Med, 2017) [MEDLINE]
        • T-Wave Inversion/Flattening (Most Commonly in the Inferior Leads) is the Most Common EKG Finding in Acute PE: occurs in 33% of cases
      • Systematic Review and Meta-Analysis of Prognostic Value of EKG Findings in Acute Pulmonary Embolism (Clin Cardiol, 2017) [MEDLINE]
        • Presence of S1Q3T3 Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.38, 95% CI: 2.46-4.66, P <0.001)
        • Presence of Complete RBBB (But Not Incomplete RBBB) Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.90, 95% CI: 2.46-6.20, P <0.001)
        • Presence of T-Wave Inversion in Precordial/Inferior Leads Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.62, 95% CI: 1.19-2.21, P = 0.002)
        • Presence of Right Axis Deviation Predicted Increased In-Hospital Mortality in Acute PE (OR: 3.24, 95% CI: 1.86-5.64, P <0.001)
        • Presence of Atrial Fibrillation Predicted Increased In-Hospital Mortality in Acute PE (OR: 1.96, 95% CI: 1.45-2.67, P <0.001)

Cardiac Physical Exam Findings

  • Accentuated P2
    • Epidemiology: accentuated P2 occurs in 23% of cases
  • Fourth Heart Sound (S4) (see Fourth Heart Sound, [[Fourth Heart Sound]])
    • Epidemiology: S4 occurs in 24% of cases

Hemodynamic Findings

  • Hypotension/Cardiogenic Shock (see Hypotension, [[Hypotension]] and Cardiogenic Shock, [[Cardiogenic Shock]]))
    • Epidemiology: hypotension occurs in 8% of acute PE cases
  • Syncope (see Syncope, [[Syncope]])
    • Epidemiology
      • Systematic Review and Meta-Analysis of Incidence of Acute PE in Patients with Syncope (Am J Emerg Med, 2017) [MEDLINE]: n = 12 studies
        • Pooled Estimate of Incidence of Acute PE in Patients with Syncope Presenting to the ED: 0.8%
        • Pooled Estimate of Incidence of Acute PE in Hospitalized Patients with Syncope: 1%

Pulmonary Manifestations

  • Cough (see Cough, [[Cough]]): occurs in 37% of cases
  • Dyspnea (see Dyspnea, [[Dyspnea]]): occurs in 73% of cases
  • Hemoptysis (see Hemoptysis, [[Hemoptysis]]): occurs in 13% of cases
    • Physiology: due to pulmonary infarction
  • Hypocapnia with Respiratory Alkalosis (see Respiratory Alkalosis, [[Respiratory Alkalosis]])
  • Hypoxemia (see Hypoxemia, [[Hypoxemia]])
  • Pleural Rub
    • Physiology: due to pulmonary infarction
  • Pleuritic Chest Pain (see Chest Pain, [[Chest Pain]]): occurs in 66% of cases
  • Pulmonary Hypertension/Acute Cor Pulmonale (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
    • Physiology: due to acute pulmonary hypertension with resulting right ventricular failure
  • Rales: occur in 51% of cases
  • Systolic/Continuous Murmur Over Lung: due to due to shunt of blood around pulmonary embolism
  • Tachypnea (see Tachypnea, [[Tachypnea]]): occurs in 70% of cases
  • Wheezing (see Obstructive Lung Disease, [[Obstructive Lung Disease]])
    • Physiology: due to platelet release of serotonin

Other Manifestations

  • Fever (see Fever, [[Fever]]): in association with pulmonary infarction

Treatment

Strength of Clinical Indication for Anticoagulation in Lower Extremity Proximal vs Distal Deep Venous Thrombosis

  • Comparative Risks of Pulmonary Embolism: the risk of pulmonary embolism is higher with proximal lower extremity DVT than with distal lower extremity DVT
    • Over 90% of Pulmonary Emboli Arise from the Proximal Lower Extremity Veins (Lancet, 1974) [MEDLINE] (Acta Chir Scand Suppl, 1977) [MEDLINE]
    • Comparative Mortality Rates (Data from OPTIMEV Study) (Thromb Haemost, 2009) [MEDLINE]
    • Proximal Lower Extremity DVT: 8% mortality rate
    • Distal Lower Extremity DVT: 4.4% mortality rate

General Goals of Anticoagulation

  • Prevention of Early Complications of Venous Thromboembolism: the benefits of anticoagulation are greatest during the initial period of anticoagulation
    • Acute Pulmonary Embolism (PE)
    • Clot Extension: anticoagulation inhibits clot extension
    • Death: anticoagulation decreases risk of DVT recurrence and mortality rate [MEDLINE]
  • Prevention of Late Complications of Venous Thromboembolism
    • Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (see Chronic Thromboembolic Pulmonary Hypertension, [[Chronic Thromboembolic Pulmonary Hypertension]])
    • Recurrent Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])
      • Anticoagulation Decreases the Risk of DVT Recurrence and Mortality Rate [MEDLINE]
      • Anticoagulation Decreases the Risk of Recurrent Venous Thromboembolism to 3.4% and Risk of Fatal Venous Thromboembolism to 0.4% [MEDLINE]
      • Systematic Review and Meta-Analysis of Anticoagulation Regimens for Venous Thromboembolism (JAMA, 2014)[MEDLINE]: n = 45 trials (44,989 patients)
        • No Statistically Significant Differences (in Terms of Safety/Efficacy) Between Anticoagulation Regimens (Low Molecular Weight Heparin/Coumadin, Unfractionated Heparin/Coumadin, Fondaparinux/Coumadin, Low Molecular Weight Heparin with Dabigatran/Edoxaban, Apixaban, Rivaroxaban, or Low Molecular Weight Heparin Alone)
        • Combination of Unfractionated Heparin/Coumadin Appeared to Have the Highest Risk of Venous Thromboembolism Recurrence (Hazard Ratio 1.42)
        • Apixaban/Rivaroxaban Regimens were Associated with the Lowest Risk of Hemorrhage
    • Post-Thrombotic (Post-Phlebitic) Syndrome (see Post-Thrombotic Syndrome, [[Post-Thrombotic Syndrome]])

Initial Treatment of Venous Thrombembolism (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

Requirements for Initial Parenteral Anticoagulation with Specific Long-Term Anticoagulants

  • Parenteral Anticoagulation is Indicated Prior to Coumadin
    • Conversion from Parenteral Anticoagulation to Coumadin
      • Coumadin Should Be Started Concurrently with Parenteral Anticoagulation, Rather Than Waiting (Grade 2C Recommendation) [MEDLINE]: start coumadin 5 mg qday (with a lower dose used in elderly or those with a high risk of bleeding, malnutrition, debility, congestive heart failure, or liver disease)
      • Coumadin Should Be Overlapped with Parenteral Anticoagulation for at Least 4-5 Days
      • Parenteral Anticoagulation Can Be Discontinued When INR Remains >2 for at Least 2 Consecutive Days
  • Parenteral Anticoagulation is Indicated Prior to Dabigatran (Pradaxa)
    • Conversion from Unfractionated Heparin Drip/Argatroban Drip to Dabigatran (Pradaxa) (see Dabigatran, [[Dabigatran]]): start dabigatran as soon as drip is stopped
    • Conversion from Low Molecular Weight Heparin (Enoxaparin, Dalteparin, Tinzaparin) or Fondaparinux to Dabigatran (Dabigatran) (see Dabigatran, [[Dabigatran]]): start dabigatran approximately 2 hrs prior to next scheduled dose of subcutaneous agent
  • Parenteral Anticoagulation is Indicated Prior to Edoxaban (Savaysa, Lixiana)
    • Conversion from Unfractionated Heparin/Argatroban Drip to Edoxaban (Savaysa, Lixiana) (see Edoxaban, [[Edoxaban]]): discontinue heparin/argatroban drip and initiate edoxaban 4 hrs later
    • Conversion from Low Molecular Weight Heparin (Enoxaparin, Dalteparin, Tinzaparin) to Edoxaban (Savaysa, Lixiana) (see Edoxaban, [[Edoxaban]]): discontinue low molecular weight heparin and initiate edoxaban at the time of the next scheduled administration of low molecular weight heparin
  • Parenteral Anticoagulation is Not Indicated Prior to Apixaban (Eliquis)/Rivaroxaban (Xarelto) (see Apixaban, [[Apixaban]] and Rivaroxaban, [[Rivaroxaban]])

Parenteral Anticoagulants

  • Argatroban (Acova) (see Argatroban, [[Argatroban]])
  • Fondaparinux (Arixtra) (see Fondaparinux, [[Fondaparinux]])
  • Low Molecular Weight Heparins (see Low Molecular Weight Heparins, [[Low Molecular Weight Heparins]])
    • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]]): Grade 2C Recommendation
    • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]])
    • Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]])
  • Unfractionated Heparin (see Heparin, [[Heparin]])

Parenteral Anticoagulant Dosing in Morbid Obesity (see Obesity, [[Obesity]])

  • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]])
    • Proposed Dosing Regimen (NEJM, 2014) [MEDLINE]
      • Dose = 0.75 mg/kg (Actual Body Weight) Has Been Suggested for Patients with a Body Mass Index (BMI) >40 or Weight >200 kg (441 lb)
    • Monitoring with Anti-Factor Xa Activity (see Anti-Factor Xa Activity, [[Anti-Factor Xa Activity]]): should be considered in this population
  • Heparin (see Heparin, [[Heparin]])
    • Proposed Dose Adjustment Formulas (Pharmacotherapy, 2010) [MEDLINE]
      • Dosing Weight = Ideal Body Weight + 0.3 (Actual Body Weight – Ideal Body Weight)
      • Dosing weight = Ideal Body Weight + 0.4 (Actual Body Weight – Ideal Body Weight)

Risk Stratification for Anticoagulation-Associated Hemorrhage

  • Risk Factors for Anticoagulation-Associated Hemorrhage
    • Age >65-75 y/o
    • Anemia (see Anemia, [[Anemia]])
    • Antiplatelet Therapy
    • Cancer/Metastatic Cancer
    • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
    • Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
    • Ethanol Abuse (see Ethanol, [[Ethanol]])
    • Frequent Falls
    • History of Hemorrhage
    • History of Stroke (see Ischemic Cerebrovascular Accident, [[Ischemic Cerebrovascular Accident]])
    • Liver Disease (see Cirrhosis, [[Cirrhosis]])
    • Nonsteroidal Anti-Inflammatory Drugs (NSAID) (see Nonsteroidal Anti-Inflammatory Drug, [[Nonsteroidal Anti-Inflammatory Drug]])
    • Poor Anticoagulant Control
    • Recent Surgery
    • Reduced Functional Capacity
    • Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])
  • Absolute Risk of Major Hemorrhage
    • Anticoagulation Duration: 0-3 mo
      • Low Risk (0 Risk Factors)
        • Baseline Risk of Hemorrhage = 0.6%
        • Increased Risk of Hemorrhage = 1.0%
        • Total Risk of Hemorrhage = 1.6%
      • Moderate Risk (1 Risk Factors)
        • Baseline Risk of Hemorrhage = 1.2%
        • Increased Risk of Hemorrhage = 2.0%
        • Total Risk of Hemorrhage = 3.2%
      • High Risk (At Least 2 Risk Factors)
        • Baseline Risk of Hemorrhage = 4.8%
        • Increased Risk of Hemorrhage = 8.0%
        • Total Risk of Hemorrhage = 12.8%
    • Anticoagulation Duration: After First 3 mo
      • Low Risk (0 Risk Factors)
        • Baseline Risk of Hemorrhage = 0.3%/year
        • Increased Risk of Hemorrhage = 0.5%/year
        • Total Risk of Hemorrhage = 0.8%/year
      • Moderate Risk (1 Risk Factors)
        • Baseline Risk of Hemorrhage = 0.6%/year
        • Increased Risk of Hemorrhage = 1.0%/year
        • Total Risk of Hemorrhage = 1.6%/year
      • High Risk (At Least 2 Risk Factors)
        • Baseline Risk of Hemorrhage = at least 2.5%/year
        • Increased Risk of Hemorrhage = at least 4.0%/year
        • Total Risk of Hemorrhage = at least 6.5%/year

Long-Term Treatment of Venous Thromboembolism without Cancer (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

Recommended Agents

  • First-Line Agents: Novel Oral Anticoagulants
    • Apixaban (Eliquis) (see Apixaban, [[Apixaban]]): Grade 2B Recommendation
    • Dabigatran (Pradaxa) (see Dabigatran, [[Dabigatran]]): Grade 2B Recommendation
    • Edoxaban (Savaysa, Lixiana) (see Edoxaban, [[Edoxaban]]): Grade 2B Recommendation
    • Rivaroxaban (Xarelto) (see Rivaroxaban, [[Rivaroxaban]]): Grade 2B Recommendation
  • Second-Line Agents
    • Coumadin (see Coumadin, [[Coumadin]]): Grade 2C Recommendation
      • Recommended INR Range: 2-3 (Grade 1B Recommendation) (ACCP Antithrombotic Guidelines; Chest, 2012) [MEDLINE]
  • Third-Line Agents: Low Molecular Weight Heparins (see Low Molecular Weight Heparins, [[Low Molecular Weight Heparins]])
    • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]]): Grade 2C Recommendation
    • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]]): Grade 2C Recommendation
    • Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]]): Grade 2C Recommendation

Long-Term Treatment of Venous Thromboembolism with Cancer (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

Recommended Agents

  • First-Line Agents: Low Molecular Weight Heparins (see Low Molecular Weight Heparins, [[Low Molecular Weight Heparins]])
    • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]]): Grade 2C Recommendation
    • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]]): Grade 2C Recommendation
    • Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]]): Grade 2C Recommendation
  • Second-Line Agents
    • Coumadin (see Coumadin, [[Coumadin]]): Grade 2C Recommendation
      • Recommended INR Range: 2-3 (Grade 1B Recommendation) (ACCP Antithrombotic Guidelines; Chest, 2012) [MEDLINE]
    • Apixaban (Eliquis) (see Apixaban, [[Apixaban]]): Grade 2C Recommendation
    • Dabigatran (Pradaxa) (see Dabigatran, [[Dabigatran]]): Grade 2C Recommendation
    • Edoxaban (Savaysa, Lixiana) (see Edoxaban, [[Edoxaban]]): Grade 2C Recommendation
    • Rivaroxaban (Xarelto) (see Rivaroxaban, [[Rivaroxaban]])): Grade 2C Recommendation

Clinical Efficacy

  • Systematic Review and Meta-Analysis of Treatment of Venous Thromboembolism in Patients with Cancer (Lancet Oncol, 2008) [MEDLINE]
    • Long-Term Full-Dose Low Molecular Weight Heparin is More Effective than Coumadin in the Secondary Prophylaxis of Venous Thromboembolism in Patients with Cancer of Any Stage, Performance Status, or Prognosis
    • Optimum Treatment Duration is Unclear, But Because the Prothrombotic Tendency Will Persist in Patients with Advanced Cancer, Indefinite Treatment is Generally Recommended

Specific Duration of Anticoagulation (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Proximal DVT/Acute PE, Provoked by Surgery: 3 months (Grade 1B Recommendation)
  • Proximal DVT/Acute PE, Provoked by Non-Surgical Transient Risk Factor: 3 months (Grade 1B Recommendation)
  • Distal DVT, Unprovoked: 3 months (Grade 1B recommendation), assuming that anticoagulation is desired by the patient
  • Distal DVT, Provoked by Surgery or by a Non-Surgical Transient Risk Factor: 3 months (Grade 2C Recommendation), assuming that anticoagulation is desired by the patient
  • First Unprovoked Proximal DVT/Acute PE
    • Low/Moderate Bleeding Risk (See Risk Factors for Hemorrhage Above): indefinite anticoagulation (Grade 2B Recommendation)
    • High Bleeding Risk (See Risk Factors Above): 3 months (Grade 1B Recommendation)
  • Second Unprovoked Proximal DVT/Acute PE
    • Low Bleeding Risk: indefinite anticoagulation (Grade 1B Recommendation)
    • Moderate Bleeding Risk: indefinite anticoagulation (Grade 2B Recommendation)
    • High Bleeding Risk: 3 months (Grade 2B Recommendation)
  • Proximal DVT/Acute PE with Cancer
    • Low/Moderate Bleeding Risk: indefinite anticoagulation (Grade 1B Recommendation)
    • High Bleeding Risk: indefinite anticoagulation (Grade 2B Recommendation)

Specific Clinical Features Which May Influence the Choice of Specific Initial/Long-Term Anticoagulants (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Cancer: preferred anticoagulant(s) -> low molecular weight heparin
  • When Parenteral Therapy Cannot Be Used: preferred anticoagulant(s) -> apixaban, rivaroxaban
    • Coumadin, Dabigatran, and Edoxaban Require Initial Parenteral Anticoagulant Therapy Prior to Their Use
  • Once Daily Oral Therapy is Preferred: preferred anticoagulant(s) -> edoxaban, rivaroxaban, coumadin
  • Liver Disease with Coagulopathy (see Cirrhosis, [[Cirrhosis]]): preferred anticoagulant(s) -> low molecular weight heparin
    • Novel Oral Anticoagulants are Contraindicated if INR is Elevated Due to Liver Disease
    • Coumadin is Difficult to Control and INR May Not Reflect Anti-Thrombotic Effect in Liver Disease
  • Chronic Kidney Disease (CrCl <30 mL/min) (see Chronic Kidney Disease, [[Chronic Kidney Disease]]): preferred anticoagulant(s) -> coumadin
    • Novel Oral Anticoagulants and Low Molecular Weight Heparins are Contraindicated with Severe Renal Insufficiency
    • Dosing of Novel Oral Anticoagulants are Variable, Dependent on the Agent
    • Systematic Review/Meta-Analysis Comparing Rates of Hemorrhage of Novel Oral Anticoagulants vs Coumadin When Used in the Setting of Renal Insufficiency (Chest, 2016) [MEDLINE]
      • CrCl 50-80 mL/min: novel oral anticoagulants had a significantly decreased risk of major bleeding, as compared to coumadin
      • CrCl <50 mL/min: novel oral anticoagulants had a non-significantly decreased risk of major bleeding, as compared to coumadin
      • Apixaban had the lowest rate of major bleeding in this subgroup (see Apixaban, [[Apixaban]])
  • Coronary Artery Disease (CAD) (see Coronary Artery Disease, [[Coronary Artery Disease]]): preferred anticoagulant(s) -> coumadin, apixaban, edoxaban, rivaroxaban
    • Coronary Artery Events Occur More Frequently with Dabigatran than with Coumadin: this is not seen with other novel oral anticoagulants
    • If Possible, Antiplatelet Therapy (for Coronary Artery Disease) Should Be Avoided in Patients on Anticoagulants Because of Increased Risk of Bleeding
  • Dyspepsia/Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]]): preferred anticoagulant(s) -> coumadin, apixaban
    • Dabigatran Increases Dyspepsia
    • Dabigatran, Rivaroxaban, and Edoxaban May Be Associated with Higher Risk of Gastrointestinal Hemorrhage than Coumadin: data supporting this is from atrial fibrillation trials (but VTE trials do not support this
  • Poor Patient Compliance: preferred anticoagulant(s) -> coumadin
    • INR Monitoring Can Help to Detect Poor Patient Compliance
  • Thrombolytic Therapy Use: preferred anticoagulant(s) -> unfractionated heparin drip
    • There is a More Experience with Unfractionated Heparin Use in Patients Treated with Thrombolytic Therapy
  • Reversal Agent Required: preferred anticoagulant(s) -> coumadin, unfractionated heparin drip, dabigatran
  • Pregnancy (see Pregnancy, [[Pregnancy]]): preferred anticoagulant(s) -> low molecular weight heparin
    • There is a Potential for Other Agents to Cross the Placenta in Pregnancy
      • Coumadin is Teratogenic
  • Cost/Coverage Issues: preferred anticoagulant(s) -> variable
    • Cost-Effectiveness of Rivaroxaban Compared to Enoxaparin/Coumadin in Treatment of Venous Thrombembolism (J Med Econ, 2014) [MEDLINE]: rivaroxaban cost $2,448 per-patient less and was associated with 0.0058 more QALY’s compared with enoxaparin + coumadin
    • Cost-Effectiveness of Novel Oral Anticoagulants, Compared to Coumadin, in Non-Valvular Atrial Fibrillation and Venous Thromboembolism (J Med Econ, 2015) [MEDLINE]: medical costs are reduced when novel oral anticoagulants are used instead of coumadin for the treatment of non-valvular atrial fibrillation/venous thromboembolism, with apixaban being associated with the greatest reduction in medical costs
    • UK Study of Cost-Effectiveness of Rivaroxaban Compared to Enoxaparin/Coumadin in Treatment of Venous Thrombembolism (Thromb J, 2015) [MEDLINE]: rivaroxaban was a cost-effective choice for acute treatment of venous thromboembolism and secondary prevention of venous thromboembolism, compared with low molecular weight heparin/coumadin treatment, regardless of the treatment duration

ANTICOAG PREF

Specific Treatment of Acute Pulmonary Embolism with Hypotension

Rationale

  • Systemic Thrombolytic Therapy Accelerates Resolution of Pulmonary Embolism (with More Rapid Lowering of Pulmonary Artery Pressure, Improved Hypoxemia, and Resolution of Perfusion Scan Defects): however, systemic thrombolytic therapy also increases the risk of hemorrhage
  • Catheter-Directed Thrombolysis Uses Approximately 33% of the Dose of Thrombolytic That Systemic Thrombolysis Uses: effectively lowering bleeding risk
    • Catheter-Directed Thrombolysis Achieves Higher Local Concentrations of Thrombolytics at the Site of the PE and Also Facilitates Thrombus Fragmentation and Permeability Via the Catheter

Agents

  • Alteplase (Activase) (see Alteplase, [[Alteplase]])
    • Administration: xxxx

Major Contraindications to Systemic Thrombolytic Therapy

  • Active Hemorrhage
  • Coagulopathy/Bleeding Diathesis (see Coagulopathy, [[Coagulopathy]])
  • Diabetic Retinopathy (see Diabetic Retinopathy, [[Diabetic Retinopathy]])
  • History of Intracranial Hemorrhage
  • History of Ischemic CVA <3 mo Ago (see Ischemic Cerebrovascular Accident, [[Ischemic Cerebrovascular Accident]])
  • Recent Brain/Spinal Surgery
  • Recent Head Trauma with Fracture/Traumatic Brain Injury (TBI) (see Traumatic Brain Injury, [[Traumatic Brain Injury]])
  • Structural Intracranial Disease

Relative Contraindications to Systemic Thrombolytic Therapy

  • Age >75 y/o
  • Anticoagulation: coumadin, etc
  • Black Race
  • Diastolic BP >110
  • Female Sex
  • History of Ischemic CVA >3 mo Ago (see Ischemic Cerebrovascular Accident, [[Ischemic Cerebrovascular Accident]])
  • Low Body Weight
  • Pericarditis/Pericardial Effusion
  • Pregnancy (see Pregnancy, [[Pregnancy]])
  • Recent Invasive Procedure
  • Recent Non-Intracranial Hemorrhage
  • Recent Surgery
  • Systolic BP >180
  • Traumatic Cardiopulmonary Resuscitation (CPR) (see Cardiopulmonary Resuscitation, [[Cardiopulmonary Resuscitation]])

Clinical Efficacy of Systemic Thrombolysis in Acute Pulmonary Embolism

  • Meta-Analysis of Thrombolyis in Acute PE (JAMA, 2014) [MEDLINE]: meta-analysis (16 trials, n = 2115)
    • Thrombolysis Decreased the Mortality Rate (2.17%), as Compared to Anticoagulation Alone (3.89%)
      • No Mortality Benefit was Observed in Patients >65 y/o, a Population in Whom the Risk of Hemorrhage was the Greatest
    • Thrombolysis Decreased the Risk of Recurrent PE (1.17%) as Compared to Anticoagulation Alone (3.04%)
    • Thrombolysis Increased the Risk of Major Hemorrhage (9.2%), as Compared to Anticoagulation Alone (3.4%)
      • No Significant Difference in Major Hemorrhage in Patients ≤65 y/o
    • Thrombolysis Increased the Risk of Intracranial Hemorrhage (1.5%), as Compared to Anticoagulation Alone (0.2%)
  • PEITHO Trial of Thrombolytics in Intermediate-Risk Pulmonary Embolism (NEJM, 2014) [MEDLINE]: RCT of tenecteplase (n = 1006), intention-to-treat analysis in normotensive, intermediate-risk PE patients (RV dysfunction on Echo or CT, elevated serum troponin)
    • Thrombolysis Decreased Hemodynamic Decompensation (2.6%), as Compared to Placebo Group (5.6%)
    • Thrombolysis (1.2%) Had No Impact on 7-Day Mortality Rate, as Compared to Placebo Group (1.8%)
    • Thrombolysis Had No Impact on the 30-Day Mortality Rate
    • Thrombolysis Increased the Risk of Major Hemorrhage and Stroke

Clinical Efficacy of Catheter-Directed Thrombolysis in Acute Pulmonary Embolism

  • Randomized Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis in Acute PE (Circulation, 2014) [MEDLINE]:
    • In Intermediate Risk Patients, Catheter-Directed Thrombolysis was Superior to Anticoagulation Alone in Reversing RV Dilatation at 24 hrs (With No Increase in Risk of Bleeding Complications)

Recommendations (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Systemic Thrombolytic Therapy is Indicated for Acute PE with Hypotension (Grade 2B Recommendation)
  • Systemic Thrombolytic Therapy is Recommended Over Catheter-Directed Thrombolysis for Acute PE with Hypotension (Grade 2C Recommendation)
    • However, the Bleeding Risk May Indicate Catheter-Directed Thrombolysis in Centers Where Local Expertise is Present
  • Systemic Thrombolytic Therapy Can Also Be Considered in Patient Who Deteriorates After Starting Anticoagulation (Significant Hypoxemia, Poor Tissue Perfusion, etc), But Who Has Not Developed Hypotension Yet

Specific Treatment of Acute Subsegmental Pulmonary Embolism

Rationale/Background

  • Improvements in CT Angiography Have Led Increased Diagnosis of Subsegmental PE’s: subsegmental PE’s have increased from approximately 5% to more than 10% of all detected PE’s
  • Due to Small Size of Subsegmental PE’s, They are More Likely to Be a False-Positive Finding than a PE in the Segmental/More Proximal Pulmonary Arteries
    • Subsgmental PE is More Likely to Be a Real Finding if the Following Features are Present
      • CT Pulmonary Artery Angiogram is of High Quality with Good Opacification of the Distal Pulmonary Arteries
      • There are Multiple Intraluminal Defects
      • Defects Involve More Proximal (Larger) Subsegmental Arteries, Defects are Seen on >1 Image
      • Defects are Surrounded by Contrast, Rather than Adherent to Pulmonary Artery Walls
      • Defects are Seen on >1 Projection
      • Patient is Symptomatic (as Opposed to PE Being an Incidental Finding)
      • There is a High Clinical Pretest Probability for PE
      • Plasma D-Dimer is Elevated without Another Explanation
  • Since a True Subsegmental PE is Likely to Have Arisen From a Small DVT, the Risk of Progressive or Recurrent VTE Without Anticoagulation is Expected to Be Lower Than in Patients with a Larger PE

Recommendations (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Subsequent Evaluation of Acute Subsegmental Pulmonary Embolism Should Include Lower Extremity Venous Doppler Studies to Classify the Patient According to One of the Following
  • Subsegmental Acute Pulmonary Embolism + No Proximal DVT + Low Risk of Recurrent Venous Thrombembolism: clinical surveillance (with serial LE Dopplers, etc) is recommended over anticoagulation (Grade 2C Recommendation)
    • Factors Associated with Low Risk of Recurrent Venous Thromboembolism
      • Absence of Active Cancer
      • Normal Mobility
      • Outpatient Status
      • Presence of Reversible Risk Factor for Venous Thromboembolism (Recent Surgery, etc)
    • Presence of High Risk of Bleeding May Favor Clinical Surveillance Strategy Over Anticoagulation
  • Subsegmental Acute Pulmonary Embolism + No Proximal DVT + High Risk of Recurrent Venous Thrombembolism: anticoagulation is recommended over clinical surveillance (Grade 2C recommendation)
    • Factors Associated with High Risk of Recurrent Venous Thromboembolism
      • Active Cancer (Especially if Metastatic or on Chemotherapy)
      • Decreased Mobility
      • Hospitalization
      • Absence of Reversible Risk Factor for Venous Thromboembolism (Recent Surgery, etc)
    • Presence of Low Cardiopulmonary Reserve May Favor Anticoagulation Over Surveillance Strategy

Specific Treatment of Low-Risk Acute Pulmonary Embolism

Criteria

  • Criteria for Outpatient Treatment of Acute PE (or Early Discharge to Home)
    • Clinically Stable with Good Cardiopulmonary Reserve
    • No Specific Contraindications, Such as Recent Bleeding, Severe Renal Disease, Severe Liver Disease, or Severe Thrombocytopenia (Platelets <70k)
    • Patient is Expected to be Compliant with Treatment
    • Patient Feels Well Enough to be Treated at Home
  • Other Criteria-Pulmonary Embolism Severity Index (PESI): score <85
  • Other Criteria-Simplified Pulmonary Embolism Severity Index (Simplified PESI): score 0
  • Other Factors Which Might Merit Inpatient Treatment Instead of Outpatient Treatment
    • Increased Cardiac Biomarker Levels
    • Presence of Right Ventricular Dysfunction

Recommendations (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Low Risk PE Patients May Be Treated at Home or Discharged Early (Such as After the First 5 Days of Treatment)

Specific Treatment of Recurrent Venous Thromboembolism While on Anticoagulation

Rationale

  • Risk of Recurrent Venous Thromboembolism Decreases Rapidly After Starting Anticoagulation: based on this, a recurrence soon after therapy can generally be managed by increasing the intensity of anticoagulation

Risk Factors for Recurrent Venous Thromboembolism

Recommendations (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Treatment of Recurrent Venous Thromboembolism on a Non-Low Molecular Weight Heparin (Coumadin or Oral Agent): switch to low molecular weight heparin is recommended, at least temporarily (Grade 2C recommendation)
  • Treatment of Recurrent Venous Thromboembolism on a Low Molecular Weight Heparin: higher dose of low molecular weight heparin (by 25-33%) is recommended (Grade 2C recommendation)

Specific Use of Aspirin for Extended Treatment of Venous Thromboembolism

Recommendations (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • For Unprovoked Proximal DVT/Acute PE, When Anticoagulation is Stopped, Aspirin is Recommended (if There is No Contraindication) to Decrease Recurrence Risk of Venous Thromboembolism (Grade 2B Recommendation)
    • Aspirin is Far Less Effective than Anticoagulation and is Therefore, Not a Substitute for Anticoagulation

Inferior Vena Cava (IVC) Filter Placement (see Inferior Vena Cava Filter, [[Inferior Vena Cava Filter]])

Historical Perspective

  • IVC filter use in the management of venous thromboembolism has increased over the last few decades [MEDLINE] [MEDLINE]

Indications for Inferior Vena Cava Filter

  • Absolute Contraindication to Anticoagulation
    • Active Hemorrhage
    • Fall Risk: particularly in older patient
    • History of Intracranial Hemorrhage
    • Major Trauma
    • Recent or Planned Emergency Surgery/Procedure
    • Severe Coagulopathy (see Coagulopathy, [[Coagulopathy]])
    • Severe or Uncontrolled Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])
    • Severe Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]]): platelet count <50k
    • Unstable Aortic Dissection (see Aortic Dissection, [[Aortic Dissection]])
  • Relative Contraindication to Anticoagulation
    • Intracranial/Spinal Tumor
    • Large Abdominal Aortic Aneurysm with Severe Hypertension (see Abdominal Aortic Aneurysm, [[Abdominal Aortic Aneurysm]])
    • Mild or Controlled Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])
    • Mild-Moderate Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]]): platelet count <150k
    • Stable Aortic Dissection (see Aortic Dissection, [[Aortic Dissection]])
  • Complication of Anticoagulation
    • Anticoagulation Failure: objectively documented extension of existing DVT (or new DVT) or PE while therapeutically anticoagulated
    • Coumadin Skin Necrosis (see Coumadin, [[Coumadin]])
    • Drug Reaction
    • Hemorrhage (Major or Minor)
    • Heparin-Induced Thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia, [[Heparin-Induced Thrombocytopenia]])
    • Poor Compliance with Anticoagulation Regimen
  • Failure of Previous Device to Prevent Pulmonary Embolism: central extension of thrombus through an existing filter or recurrent PE
  • In Association with Thrombectomy, Embolectomy, or Lytic Therapy
  • Prophylaxis with No Thromboembolic Disease
  • Prophylaxis with Thromboembolism in Addition to Anticoagulation

Technique

  • Filter Positioning: IVC filters are typically placed infrarenally, since suprarenal filters may lead to renal vein compromise, if they become clotted
  • Retrievable Inferior Vena Cava Filters: may remain in place for approximately 2 mo
  • There is No Data to Support One IVC Filter Brand Over Another

Clinical Efficacy

  • Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group (PREPIC) Trial (NEJM, 1998) [MEDLINE]
    • At 2 years, IVC filter had no impact on the rate of symptomatic PE or mortality rate
    • However, IVC filter placement increased the rate of recurrent DVT
  • Randomized, Open-Label PREPIC2 Trial of IVC Filter Added to Anticoagulation in Severe Acute PE Requiring Hospitalization (JAMA, 2015) [MEDLINE]: retrievable IVC filter had no clinical benefit over anticoagulation alone (in terms of decreasing the risk of recurrent PE at 3/6 months or 3-month/6-month mortality rate)
    • Based on these data, IVC filter is not indicated in anticoagulated acute PE patients on the basis of poor cardiopulmonary reserve, large clot burden, or suspected risk of recurrence

Recommendations (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • For Patients with Venous Thromboembolism Treated with Anticoagulation, IVC Filter Placement is Not Recommended

Specific Treatment of Lower Extremity Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])

Ambulation

  • Ambulation is Indicated as Soon as Possible (Despite the Theoretical Risk for Embolization): usually a gradual increase in ambulation is advisable
    • Ambulation Has Not Been Demonstrated to Increase the Risk of Fatal Pulmonary Embolism

Graduated Compression Stockings

  • Rationale: may provide symtomatic relief and facilitate ambulation
    • Theoretical goal of therapy is the prevention of post-phlebitic syndrome (although data are conflicting as to their efficacy in this regard)
  • Contraindications
    • Allergy to the Stocking Material
    • Inability to Apply Stockings
    • Severe Arterial Insufficiency
    • Skin Ulceration
  • Recommendations (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]
    • Graduated Compression Stockings are Not Recommended in Acute DVT to Prevent Post-Thrombotic Syndrome (Grade 2B Recommendation): however they may be used for patients with acute/chronic DVT symptoms

Catheter-Directed Thrombolysis of Acute Lower Extremity Deep Venous Thrombosis (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])

  • Clinical Efficacy
    • Retrospective Analysis of Catheter-Directed Thrombolysis for Lower Extremity DVT (JAMA Int Med, 2014) [MEDLINE]
      • Catheter-Directed Thrombolysis of Lower Extremity DVT is Associated with 2x-Increased Risk of Transfusion, 3x-Increased Risk of Intracranial Hemorrhage, 1.5x-Increased Risk of Acute PE, and 2x-Increased Risk of IVC Filter Insertion: long-term outcomes were not reported
  • Indications (Patients Most Likely to Benefit from Catheter-Directed Thrombolysis of Lower Extremity DVT) (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]
    • Failure of Anticoagulation
    • Good Functional Status
    • Iliofemoral DVT/Phlegmasia Cerulea Dolens
    • Life Expectancy of At Least 1 Year
    • Low Risk of Hemorrhage
    • Symptoms for <14 Days
  • Recommendations (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]
    • Anticoagulation is Recommended Over Catheter-Directed Thrombolysis for Lower Extremity DVT (Grade 2C recommendation)
      • Patients who put a high value on the prevention of post-thrombotic (post-phlebitic) syndrome and lower value on initial complexity, cost, and risk of bleeding may choose catheter-directed thrombolysis (see Post-Thrombotic Syndrome, [[Post-Thrombotic Syndrome]])

Treatment of Isolated Distal (Calf) Deep Venous Thrombosis (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Rationale: approximately 15% of untreated distal DVT’s will ultimately extend proximally into the popliteal vein and may cause acute PE [MEDLINE]
  • Isolated Distal DVT without Severe Symptoms or Risk Factors for Extension: serial LE Dopplers x 2 wks are recommended (Grade 2C recommendation)
    • During Surveillance
      • Thrombus Extends within the Distal Veins -> Anticoagulation is Suggested (Grade 2C recommendation)
      • Thrombus Extends into the Proximal Veins -> Anticoagulation is Recommended (Grade 1B recommendation)
  • Isolated Distal DVT with Severe Symptoms or Risk Factors for Extension: anticoagulation is recommended (Grade 2C recommendation)
    • Risk Factors for Extension of Distal DVT
      • Active Cancer
      • Extensive Thrombosis
        • Involving Multiple Veins
        • More than 5 cm in Length
        • More than 7 mm in Maximum Diameter
      • History of Venous Thromboembolism
      • Inpatient Status
      • No Reversible Provoking Factor for DVT
      • Positive Plasma D-Dimer (see Plasma D-Dimer, [[Plasma D-Dimer]]): particularly when markedly elevated without an alternative reason
      • Thrombosis Close to Proximal Veins: thrombosis confined to the muscular veins of the calf (soleus, gastrocnemius) has a lower risk of extension than thrombosis that involves the axial (true deep: peroneal, tibial) veins

Specific Treatment of Upper Extremity Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])

Anticoagulation

  • Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Anticoagulation is Recommended for Upper Extremity Deep Venous Thrombosis Involving the Axillary or More Proximal Veins

Catheter-Directed Thrombolysis of Upper Extremity Deep Venous Thrombosis Which Involves Axillary or More Proximal Veins

  • Indications (Patients Most Likely to Benefit from Catheter-Directed Thrombolysis of Upper Extremity DVT) (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]
    • Good Functional Status
    • Life Expectancy of ≥1 Year
    • Low Risk of Hemorrhage
    • Severe Symptoms
    • Symptoms Present for <14 Days
    • Thrombus Involving Most of the Axillary and Subclavian Vein
  • Recommendations (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]
    • Anticoagulation is Recommended Over Catheter-Directed Thrombolysis in Upper Extremity Deep Venous Thrombosis (Grade 2C Recommendation)
    • In Patients Who Undergo Catheter-Directed Thrombolysis of Upper Extremity Deep Venous Thrombosis, the Same Intensity/Duration of Anticoagulation is Recommended as in Those Who Do Not Undergo Thrombolysis (Grade 1B Recommendation)

Prognosis

  • Mortality Rate: <10% of all PE’s result in death
    • 90% of deaths due to PE occur within the first 1-2 hrs
  • Contribution of Pulmonary Embolism to US Death Rate [MEDLINE]: PE’s account for 100k deaths per year in the US
    • Deaths from Acute PE are Declining [MEDLINE]

References

American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 2012

  • Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):7S-47S. doi: 10.1378/chest.1412S3 [MEDLINE]
  • Introduction to the ninth edition: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):48S-52S. doi: 10.1378/chest.11-2286 [MEDLINE]
  • Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):53S-70S. doi: 10.1378/chest.11-2288 [MEDLINE]
  • Patient values and preferences in decision making for antithrombotic therapy: a systematic review: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e1S-e23S. doi: 10.1378/chest.11-2290 [MEDLINE]
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  • Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e531S-e575S. doi: 10.1378/chest.11-2304 [MEDLINE]
  • Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e576S-e600S. doi: 10.1378/chest.11-2305 [MEDLINE]
  • Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e601S-e636S. doi: 10.1378/chest.11-2302 [MEDLINE]
  • Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e637S-e668S. doi: 10.1378/chest.11-2306 [MEDLINE]
  • Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e669S-e690S. doi: 10.1378/chest.11-2307 [MEDLINE]
  • VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e691S-e736S. doi: 10.1378/chest.11-2300 [MEDLINE]
  • Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e737S-e801S. doi: 10.1378/chest.11-2308 [MEDLINE]

American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 2016

  • Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-52. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7 [MEDLINE]

General

  • Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet. 1960 Jun 18;1(7138):1309-12 [MEDLINE]
  • Source of non-lethal pulmonary emboli. Lancet. 1974 Feb 16;1(7851):258-9 [MEDLINE]
  • Deep vein thrombosis and pulmonary embolism. An autopsy study with multiple regression analysis of possible risk factors. Acta Chir Scand Suppl. 1977;478:1-120 [MEDLINE]
  • Genetic risk factors for superficial vein thrombosis. Thromb Haemost. 1999;82(4):1215 [MEDLINE]
  • A prospective study of venous thromboembolism after major trauma. N Engl J Med 1994; 331:1601–1606 [MEDLINE]
  • A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7):409 [MEDLINE]
  • Vena caval filters: a comprehensive review. Blood. 2000;95(12):3669 [MEDLINE]
  • Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty. N Engl J Med. 2000;343(24):1758 [MEDLINE]
  • Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet. 2001;358(9275):9 [MEDLINE]
  • Deep vein thrombosis and its prevention in critically ill adults. Arch Intern Med 2001;161:1268–1279 [MEDLINE]
  • Pulmonary embolism mortality in the United States, 1979-1998: an analysis using multiple-cause mortality data. Arch Intern Med. 2003;163(14):1711 [MEDLINE]
  • Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005; 172:1041-1046 [MEDLINE]
  • Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med. 2005 Jul;33(7):1565-71 [MEDLINE]
  • Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006;295(2):172 [MEDLINE]
  • Clinical Practice: Acute pulmonary embolism. N Engl J Med 2008;359:2804–2813 [MEDLINE]
  • Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study. Thromb Haemost. 2009 Sep;102(3):493-500. doi: 10.1160/TH09-01-0053 [MEDLINE]
  • RIETE Investigators. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170: 1383–1389 [MEDLINE]
  • Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest. 2010;137(5):1145 [MEDLINE]
  • Gadolinium-enhanced magnetic resonance angiography for pulmonary embolism. A multicenter prospective study (PIOPED III). Ann Intern Med 2010;152:434-443 [MEDLINE]
  • Reproducibility of CT signs of right ventricular dysfunction in acute pulmonary embolism. AJR Am J Roentgenol 2010; 194:1500-1506 [MEDLINE]
  • Prognostic factors for pulmonary embolism: the PREP study, a prospective multicenter cohort study. Am J Respir Crit Care Med 2010; 181:168-173 [MEDLINE]
  • Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med. 2010 May 4;152(9):578-89. doi: 10.7326/0003-4819-152-9-201005040-00008 [MEDLINE]
  • Deep vein thrombosis: a clinical review. J Blood Med. 2011; 2: 59–69 [MEDLINE]
  • Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med. 2011;171(9):831 [MEDLINE]
  • Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants’ data from seven trials. BMJ. 2011 May 24;342:d3036. doi: 10.1136/bmj.d3036 [MEDLINE]
  • Obesity and pulmonary embolism: the mounting evidence of risk and the mortality paradox.  Thromb Res. 2011;128:518–523 [MEDLINE]
  • Impact of vena cava filters on in-hospital case fatality rate from pulmonary embolism. Am J Med. 2012 May;125(5):478-84. Epub 2012 Feb 4 [MEDLINE]
  • Factors in the technical quality of gadolinium enhanced magnetic resonance angiography for pulmonary embolism in PIOPED III. Int J Cardiovasc Imaging. 2012 Feb;28(2):303-12. doi: 10.1007/s10554-011-9820-7. Epub 2011 Feb 24 [MEDLINE]
  • A meta-analysis of anticoagulation for calf deep venous thrombosis. J Vasc Surg. 2012 Jul;56(1):228-37.e1; discussion 236-7. doi: 10.1016/j.jvs.2011.09.087. Epub 2011 Dec 29 [MEDLINE]
  • Use of Glucocorticoids and Risk of Venous Thromboembolism: A Nationwide Population-Based Case-Control Study. JAMA Intern Med. 2013 Apr 1:1-1 [MEDLINE]
  • Acute pulmonary embolism: external validation of an integrated risk stratification model. Chest 2013 Jun 13. doi: 10.1378/chest.12-2938 [MEDLINE]
  • Identification of intermediate-risk patients with acute symptomatic pulmonary embolism. Eur Respir J. 2014 Sep;44(3):694-703. doi: 10.1183/09031936.00006114. Epub 2014 Apr 2 [MEDLINE]
  • Vena cava filters in unstable elderly patients with acute pulmonary embolism. Am J Med. 2014 Mar;127(3):222-5. Epub 2013 Nov 23 [MEDLINE]
  • Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism: a systematic review and meta-analysis. Rheumatology (Oxford). 2015 Apr;54(4):736-42. doi: 10.1093/rheumatology/keu408. Epub 2014 Sep 24 [MEDLINE]
  • Diagnostic prediction models for suspected pulmonary embolism: systematic review and independent external validation in primary care. BMJ. 2015;351:h4438 [MEDLINE]
  • Trends in incidence versus case fatality rates of pulmonary embolism: Good news or bad news? Thromb Haemost. 2016 Jan;115(2):233-5. Epub 2015 Dec 03 [MEDLINE]

Risk Factors

  • Severe pulmonary embolism associated with air travel. N Engl J Med. 2001 Sep 13;345(11):779-83 [MEDLINE]
  • Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med. 2002;162(10):1182 [MEDLINE]
  • Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation. 2008;117(1):93 [MEDLINE]
  • Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia. Thorax. 2012 Apr;67(4):328-33. Epub 2011 Dec 14 [MEDLINE]
  • Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27(9):1874. Epub 2013 Jun 6 [MEDLINE]
  • Systemic sclerosis increases the risks of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study. Rheumatology (Oxford). 2014;53(9):1639 [MEDLINE]
  • Travelers’ thrombosis. Aviat Space Environ Med. 2014 Feb;85(2):191-4 [MEDLINE]
  • A meta-analysis of the risk of venous thromboembolism in inflammatory rheumatic diseases. Arthritis Res Ther. 2014 Sep 25;16(5):435. doi: 10.1186/s13075-014-0435-y [MEDLINE]
  • VTE incidence and risk factors in patients with severe sepsis and septic shock.  Chest.  2015;148:1224–1230 [MEDLINE]
  • Vascular Complications of Varicella: Description of 4 Cases and a Review of Literature. Pediatr Infect Dis J. 2015 Nov;34(11):1256-9. doi: 10.1097/INF.0000000000000855 [MEDLINE]
  • Venous thromboembolic events in systemic vasculitis. Ann Rheum Dis. 2015 Mar;74(3):e27. doi: 10.1136/annrheumdis-2014-206849. Epub 2014 Nov 7 [MEDLINE]
  • Microscopic polyangiitis: A little-known new risk factor of venous thrombosis. J Mal Vasc. 2015 Dec;40(6):406-7. doi: 10.1016/j.jmv.2015.07.106. Epub 2015 Aug 28 [MEDLINE]
  • The risk of deep venous thrombosis and pulmonary embolism in giant cell arteritis: a general population-based study. Ann Rheum Dis. 2016 Jan;75(1):148-54. doi: 10.1136/annrheumdis-2014-205665. Epub 2014 Sep 29 [MEDLINE]
  • Risk of Pulmonary Embolism and Deep Venous Thrombosis in Systemic Sclerosis: A General Population-Based Study. Arthritis Care Res (Hoboken). 2016 Feb;68(2):246-53 [MEDLINE]
  • Deep Vein Thrombosis as Initial Manifestation of Whipple Disease. Case Rep Gastroenterol. 2016 Nov 7;10(3):640-645. eCollection 2016 Sep-Dec [MEDLINE]
  • Consider Behcet’s disease in young patients with deep vein thrombosis. Respir Med Case Rep. 2016 Apr 14;18:41-4. doi: 10.1016/j.rmcr.2016.04.002. eCollection 2016 [MEDLINE]
  • Portal Venous Thrombosis: Eosinophilic Vasculitis. J Clin Diagn Res. 2017 Mar;11(3):OD04-OD05. doi: 10.7860/JCDR/2017/25235.9575. Epub 2017 Mar 1 [MEDLINE]
  • Cerebral venous sinus thrombosis in Behçet’s disease: a retrospective case-control study. Clin Rheumatol. 2017 Jun 14. doi: 10.1007/s10067-017-3718-2 [MEDLINE]
  • Behcet Disease Initially Presenting as Deep Venous Thrombosis: A Case Report. J Pediatr Hematol Oncol. 2017 Apr 21. doi: 10.1097/MPH.0000000000000830 [MEDLINE]
  • Clinical associations with venous thromboembolism in anti-neutrophil cytoplasm antibody-associated vasculitides. Rheumatology (Oxford). 2017 May 1;56(5):704-708. doi: 10.1093/rheumatology/kew465 [MEDLINE]

Deep Venous Thrombosis (DVT) Prophylaxis (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])

  • Cost-effectiveness of ultrasound in preventing femoral venous catheter-associated pulmonary embolism. Am J Respir Crit Care Med 2003;168:1481–1487 [MEDLINE]
  • Efficacy of deep venous thrombosis prophylaxis in the medical intensive care unit. J Intensive Care Med. 2006 Nov-Dec;21(6):352-8 [MEDLINE]
  • Intermittent pneumatic compression or graduated compression stockings for deep vein thrombosis prophylaxis? A systematic review of direct clinical comparisons. Ann Surg. 2010 Mar;251(3):393-6. doi: 10.1097/SLA.0b013e3181b5d61c [MEDLINE]
  • PROTECT Trial: Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med. 2011 Apr 7;364(14):1305-14. doi: 10.1056/NEJMoa1014475 [MEDLINE]
  • Screening and prevention of venous thromboembolism in critically ill patients: a decision analysis and economic evaluation. Am J Respir Crit Care Med. 2011 Dec 1;184(11):1289-98. doi: 10.1164/rccm.201106-1059OC [MEDLINE]
  • LIFENOX: Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. doi: 10.1056/NEJMoa1111288 [MEDLINE]
  • Unfractionated heparin versus low molecular weight heparin for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Rev. 2012 Sep 12;9:CD007557. doi: 10.1002/14651858.CD007557.pub2 [MEDLINE]
  • DVT Surveillance Program in the ICU: Analysis of Cost-Effectiveness. PLoS One. 2014 Sep 30;9(9):e106793. doi: 10.1371/journal.pone.0106793. eCollection 2014 [MEDLINE]
  • Cost-effectiveness of Dalteparin vs Unfractionated Heparin for the Prevention of Venous Thromboembolism in Critically Ill Patients. JAMA. 2014 Nov 1. doi: 10.1001/jama.2014.15101 [MEDLINE]

Upper Extremity Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])

  • The long term clinical course of acute deep vein thrombosis of the arm: prospective cohort study. BMJ. 2004;329:484-5 [MEDLINE]
  • Upper extremity DVT in oncological patients: analysis of risk factors. Data from the RIETE registry. Exp Oncol. 2006;28:245-7
  • Upper extremity deep venous thrombosis. Semin Thromb Hemost. 2006;32:729-36 [MEDLINE]
  • Current perspective of venous thrombosis in the upper extremity. J Thromb Haemost. 2008;6:1262-6 [MEDLINE]
  • Accuracy of diagnostic tests for clinically suspected upper extremity deep vein thrombosis: a systematic review. J Thromb Haemost. 2010;8:684-92 [MEDLINE]
  • Safety and feasibility of a diagnostic algorithm combining clinical probability, d-dimer testing, and ultrasonography for suspected upper extremity deep venous thrombosis: a prospective management study. Ann Intern Med. 2014 Apr 1;160(7):451-7. doi: 10.7326/M13-2056 [MEDLINE]

Diagnosis

Electrocardiogram (EKG) (see Electrocardiogram, [[Electrocardiogram]])

  • The electrocardiographic manifestations of pulmonary embolism. J Emerg Med. 1988;6(4):301 [MEDLINE]
  • Clinical characteristics of patients with acute pulmonary embolism. Am J Cardiol. 1991;68(17):1723 [MEDLINE]
  • The ECG in pulmonary embolism. Predictive value of negative T waves in precordial leads–80 case reports. Chest. 1997;111(3):537 [MEDLINE]
  • Diagnostic value of the electrocardiogram in suspected pulmonary embolism. Am J Cardiol. 2000;86(7):807 [MEDLINE]
  • Prognostic value of the ECG on admission in patients with acute major pulmonary embolism. Eur Respir J. 2005;25(5):843 [MEDLINE]
  • Findings From 12-lead Electrocardiography That Predict Circulatory Shock From Pulmonary Embolism: Systematic Review and Meta-analysis. Acad Emerg Med. 2015 Oct;22(10):1127-37. Epub 2015 Sep 22 [MEDLINE]
  • New Electrocardiographic Changes in Patients Diagnosed with Pulmonary Embolism. J Emerg Med. 2017;52(3):280. Epub 2016 Oct 11 [MEDLINE]
  • The value of electrocardiography in prognosticating clinical deterioration and mortality in acute pulmonary embolism: A systematic review and meta-analysis. Clin Cardiol. 2017 Oct;40(10):814-824. doi: 10.1002/clc.22742. Epub 2017 Jun 19 [MEDLINE]
  • Prognostic significance of electrocardiogram at presentation in patients with pulmonary embolism of different severity. Thromb Res. 2018 Jan 31;163:123-127. doi: 10.1016/j.thromres.2018.01.025 [MEDLINE]

Plasma D-Dimer (see Plasma D-Dimer, [[Plasma D-Dimer]])

  • ANTELOPE Study. Embolus location affects the sensitivity of a rapid quantitative D-dimer assay in the diagnosis of pulmonary embolism. Am J Respir Crit Care Med. 2002;165(3):345 [MEDLINE]
  • Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA. 2014 Mar 19;311(11):1117-24. doi: 10.1001/jama.2014.2135 [MEDLINE]
  • D-dimer test for excluding the diagnosis of pulmonary embolism. Cochrane Database Syst Rev. 2016 Aug 5;(8):CD010864. doi: 10.1002/14651858.CD010864.pub2 [MEDLINE]
  • Wells Rule and d-Dimer Testing to Rule Out Pulmonary Embolism: A Systematic Review and Individual-Patient Data Meta-analysis. Ann Intern Med. 2016 Aug;165(4):253-61. Epub 2016 May 17 [MEDLINE]
  • A Test in Context: D-Dimer. J Am Coll Cardiol. 2017 Nov 7;70(19):2411-2420. doi: 10.1016/j.jacc.2017.09.024 [MEDLINE]
  • D-dimer Interval Likelihood Ratios for Pulmonary Embolism. Acad Emerg Med. 2017 Jul;24(7):832-837. doi: 10.1111/acem.13191. Epub 2017 Jun 14 [MEDLINE]

CT Pulmonary Artery Angiogram (see xxxx, [[xxxx]])

  • Overdiagnosis of Pulmonary Embolism by Pulmonary CT Angiography. AJR Am J Roentgenol. 2015 Aug;205(2):271-7. doi: 10.2214/AJR.14.13938 [MEDLINE]
  • Yield of CT Pulmonary Angiography in the Emergency Department When Providers Override Evidence-based Clinical Decision Support. Radiology. 2016 Sep 30:151985 [MEDLINE]

Clinical Decision Rules

  • Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost. 2000;83:416-20 [MEDLINE]
  • Criteria for the safe use of D-dimer testing in emergency department patients with suspected pulmonary embolism: a multicenter US study. Ann Emerg Med. 2002;39:144-152 [MEDLINE]
  • Impact of a rapid rule-out protocol for pulmonary embolism on the rate of screening, missed cases, and pulmonary vascular imaging in an urban US emergency department. Ann Emerg Med. 2004 Nov;44(5):490-502 [MEDLINE]
  • Clinical gestalt and the diagnosis of pulmonary embolism: does experience matter? Chest. 2005;127:1627-30 [MEDLINE]
  • Simple and accurate prediction of the clinical probability of pulmonary embolism. Am J Respir Crit Care Med. 2008;178:290-294 [MEDLINE]
  • Further validation and simplification of the Wells clinical decision rule in pulmonary embolism. Thromb Haemost. 2008;99:229-34 [MEDLINE]
  • Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected pulmonary embolism. Ann Emerg Med. 2011 Jun;57(6):628-652.e75. doi: 10.1016/j.annemergmed.2011.01.020 [MEDLINE]
  • Performance of 4 clinical decision rules in the diagnostic management of acute pulmonary embolism: a prospective cohort study. Ann Intern Med. 2011;154:709-18 [MEDLINE]
  • Pulmonary embolism rule-out criteria (PERC) in pulmonary embolism—revisited: a systematic review and meta-analysis. Emerg Med J. 2013;30:701-6 [MEDLINE]
  • Impact of delay in clinical presentation on the diagnostic management and prognosis of patients with suspected pulmonary embolism. Am J Respir Crit Care Med. 2013 Jun 15;187(12):1369-73. doi: 10.1164/rccm.201212-2219OC [MEDLINE]
  • Evaluation of Patients With Suspected Acute Pulmonary Embolism: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. 2015 Nov 3;163(9):701-11. doi: 10.7326/M14-1772. Epub 2015 Sep 29 [MEDLINE]
  • Risk stratification of patients with acute symptomatic pulmonary embolism based on presence or absence of lower extremity DVT:  systematic review and meta-analysis.  Chest.  2016;149:192–200 [MEDLINE]
  • Wells Rule and d-Dimer Testing to Rule Out Pulmonary Embolism: A Systematic Review and Individual-Patient Data Meta-analysis. Ann Intern Med. 2016 Aug;165(4):253-61. Epub 2016 May 17 [MEDLINE]
  • Clinical Decision Rules for Pulmonary Embolism in Hospitalized Patients: A Systematic Literature Review and Meta-analysis. Thromb Haemost. 2017;117(11):2176 [MEDLINE]
  • Effect of the Pulmonary Embolism Rule-Out Criteria on Subsequent Thromboembolic Events Among Low-Risk Emergency Department Patients: The PROPER Randomized Clinical Trial. JAMA. 2018 Feb 13;319(6):559-566. doi: 10.1001/jama.2017.21904 [MEDLINE]

Clinical Manifestations

  • Syncope in patients with pulmonary embolism. JAMA. 1977;238(23):2509 [MEDLINE]
  • Venous thromboembolism increases the risk of atrial fibrillation: the Tromso study. J Am Heart Assoc. 2014;3(1):e000483. Epub 2014 Jan 2 [MEDLINE]
  • Prevalence of pulmonary embolism in patients presenting with syncope. A systematic review and meta-analysis. Am J Emerg Med. 2017 Sep 14. pii: S0735-6757(17)30740-4. doi: 10.1016/j.ajem.2017.09.015 [MEDLINE]

Treatment

General

  • Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53 [MEDLINE]
  • Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials. Ann Intern Med. 2004 Feb 3;140(3):175-83 [MEDLINE]
  • Enoxaparin in the treatment of deep vein thrombosis with or without pulmonary embolism: an individual patient data meta-analysis. Chest. 2005 Oct;128(4):2203-10 [MEDLINE]
  • Management of venous thromboembolism in patients with advanced cancer: a systematic review and meta-analysis. Lancet Oncol. 2008 Jun;9(6):577-84. doi: 10.1016/S1470-2045(08)70149-9 [MEDLINE]
  • Clinical Practice: Acute pulmonary embolism. N Engl J Med 2008;359:2804–2813 [MEDLINE]
  • Fondaparinux and the management of heparin-induced thrombocytopenia: the journey continues.  Ann Pharmacother  2009;43:1636–1646 [MEDLINE]
  • Unfractionated heparin dosing for venous thromboembolism in morbidly obese patients: case report and review of the literature.  Pharmacotherapy. 2010 Mar;30(3):324. doi: 10.1592/phco.30.3.324 [MEDLINE]
  • Use of Glucocorticoids and Risk of Venous Thromboembolism: A Nationwide Population-Based Case-Control Study. JAMA Intern Med. 2013 Apr 1:1-1 [MEDLINE]
  • Cost-effectiveness of rivaroxaban compared with enoxaparin plus a vitamin K antagonist for the treatment of venous thromboembolism. J Med Econ. 2014 Jan;17(1):52-64. doi: 10.3111/13696998.2013.858634. Epub 2013 Nov 14 [MEDLINE]
  • Fibrinolysis for patients with intermediate risk pulmonary embolism.  N Engl J Med 2014;370:1402–1411 [MEDLINE]
  • Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA. 2014 Sep 17;312(11):1122-35. doi: 10.1001/jama.2014.10538 [MEDLINE]
  • Unfractionated heparin dosing for therapeutic anticoagulation in critically ill obese adults.  J Crit Care 2015;30:395–399 [MEDLINE]
  • Comparison of differences in medical costs when new oral anticoagulants are used for the treatment of patients with non-valvular atrial fibrillation and venous thromboembolism vs warfarin or placebo in the US. J Med Econ. 2015 Jun;18(6):399-409. doi: 10.3111/13696998.2015.1007210. Epub 2015 Feb 9 [MEDLINE]
  • Cost-effectiveness analysis of treatment of venous thromboembolism with rivaroxaban compared with combined low molecular weight heparin/vitamin K antagonist. Thromb J. 2015 Jun 11;13:20. doi: 10.1186/s12959-015-0051-3. eCollection 2015 [MEDLINE]
  • Major Bleeding and Hemorrhagic Stroke with Direct Oral Anticoagulants in Patients with Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials. Chest. 2016,(): doi:10.1016/j.chest.2015.12.029 [MEDLINE]

Inferior Vena Cava (IVC) Filter (see Inferior Vena Cava Filter, [[Inferior Vena Cava Filter]])

  • A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep vein thrombosis: Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7):409-415 [MEDLINE]
  • PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation. 2005;112(3):416-422 [MEDLINE]
  • A population-based study of inferior vena cava filters in patients with acute venous thromboembolism. Arch Intern Med. 2010;170(16): 1456-1462 [MEDLINE]
  • Increasing use of vena cava filters for prevention of pulmonary embolism. Am J Med. 2011;124(7):655-661 [MEDLINE]
  • PREPIC2 Trial. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015 Apr 28;313(16):1627-35. doi: 10.1001/jama.2015.3780 [MEDLINE]

Embolectomy

  • Pulmonary embolectomy: a 20-year experience at one center. Ann Thorac Surg 1991; 51:232-236
  • Medical compared with surgical treatment for massive pulmonary embolism. Lancet 1994; 343:565-577

Thrombolytics

  • Urokinase pulmonary embolism trial. A national cooperative study. Circulation 1973; 47,48 (suppl 2):1-108
  • Alteplase versus heparin in acute pulmonary embolism: randomized trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993; 34:507-511
  • Thrombolytic therapy for pulmonary embolism. Cochrane Database System Rev. 2009;(3): CD004437 [MEDLINE]
  • Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014 Jun 18;311(23):2414-21. doi: 10.1001/jama.2014.5990 [MEDLINE]
  • PEITHO Trial: Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097 [MEDLINE]
  • Systematic review and meta-analysis for thrombolysis treatment in patients with acute submassive pulmonary embolism. Patient Prefer Adherence. 2014;8:275-282 [MEDLINE]
  • Comparative outcomes of catheter-directed thrombolysis plus anticoagulation vs anticoagulation alone to treat lower-extremity proximal deep vein thrombosis. JAMA Intern Med. 2014;174(9):1494-1501 [MEDLINE]
  • Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism.  Circulation 2014;129:479–486 [MEDLINE]
  • Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2015 Sep 30;9:CD004437. doi: 10.1002/14651858.CD004437.pub4 [MEDLINE]
  • Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-52. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7 [MEDLINE]