Acute Pulmonary Embolism: Treatment and Prophylaxis Gregory Piazza and Samuel Z. Goldhaber Circulation 2006;114;42-47

  A 66-year-old man, history of deep venous thrombosis (DVT)   Sx : acute dyspnea   V/S : normotensive, tachycardia of 110 bpm, SaO2 76% on RA   Lab   EKG : sinus tachycardia   BNP and cardiac troponin levels : elevated   CT with contrast : a large saddle pulmonary embolus and increased diameter of the right ventricle (RV)   Tx : unfractionated heparin IV bolus followed by continuous Infusion → several hours later, the patient became progressively more hypotensive and hypoxemic   TTE : RV dilatation and hypokinesis → intravenous fibrinolysis → rapid improvement in hemodynamics and oxygenation Case presentation

  Pulmonary embolism (PE) : represents a spectrum of syndromes   small peripheral emboli causing pleuritic pain   massive PE resulting in cardiogenic shock or cardiac arrest   Some may rapidly deteriorate and manifest systemic hypotension, cardiogenic shock, and sudden death despite therapeutic levels of anticoagulation   Risk stratification to identify such patients : a critical component of care   The International Cooperative Pulmonary Embolism Registry (ICOPER)   age > 70 years   cancer, congestive heart failure, chronic obstructive pulmonary disease   systolic blood pressure less than 90 mm Hg → significant predictors of increased mortality   Elevated cardiac biomarkers : correlate with the presence of RV dysfunction → a powerful independent predictor of early mortality Risk Stratification

  Patients with PE and Elevated cardiac biomarkers : should undergo TTE to test for the presence of RV dysfunction   Cardiac troponins : released as a result of microinfarction due to RV pressure overload   BNP : secreted from cardiac myocytes in response to RV stress   Echocardiography : imaging test of choice for risk stratification of patients with PE → patients with RV dysfunction on echocardiography : increased risk of hypotension, cardiogenic shock, and early death   RV enlargement as detected by chest CT   Measurements from a reconstructed CT 4-chamber view, RV enlargement (ratio of RV to LV dimension of greater than 0.9) : a significant independent predictor of 30-day mortality Risk Stratification

An algorithm approach to the risk stratification of patients with acute pulmonary embolism Risk Stratification

MANAGEMENT

  Normal blood pressure, no evidence of RV dysfunction : stable hospital course with anticoagulation alone   Submassive PE (normotensive, evidence of RV dysfunction) : elevated risk for adverse events and early mortality   Massive PE Management - Classification

  Fibrinolysis or embolectomy in either massive or submassive PE   The Food and Drug Administration (FDA)   t-PA (alteplase) 100 mg administered as a continuous infusion over 2 hours   Requires screening for contraindications d/t bleeding risk (3.0% for intracranial hemorrhage) Management - Primary Therapy

DrugMethod Streptokinase 30 분 이상 : 25,000 U 후 24 시간 동안 시간당 100,000 Ub,c 30 분 이상 : 25,000 U 후 12 시간 동안 시간당 100,000 U 1~2 시간 이상 : 1,500,000 U Urokinase 10 분 이상 4,400 U/kg 후 24 시간 동안 4,400 U/kg/hb 10 분 이상 4,400 U/kg 후 12 시간 동안 4,400 U/kg/hb 10 분 이상 1,000,000 U 후 11 분 이상 2,000,000 U Alteplase (t-PA) 2 시간 이상 : 100mg Reteplase 30 분 간격으로 두 번 10 U

  Absolute Contraindication   활동성 내출혈   최근의 자발적 두개내 출혈   Relative Contraindication   대수술, 분만, 장기생검 or 10 일 이내의 혈관천자   2 달 이내의 허혈성 뇌졸중   10 일 이내의 위장관 출혈   15 일 이내의 심각한 외상   1 달 이내의 신경외과 또는 안과 수술   조절되지 않는 고혈압 (SBP > 180mmHg, DBP>110mmHg)   최근의 심폐소생술   혈소판 < 100,000/mm3, PT 50%   임신   세균성 심내막염   당뇨병성 출혈성 망막병증 Management - Primary Therapy

  Surgical embolectomy   In patients with massive or submassive PE   Fibrinolysis is contraindicated or failed   Paradoxical embolism, persistent right heart thrombi   Hemodynamic or respiratory compromise requiring cardiopulmonary resuscitation   Catheter-based pulmonary embolectomy   Fibrinolysis and open surgical embolectomy are contraindicated   Successful when applied to fresh thrombus within the first 5 days of symptoms of PE Management - Primary Therapy

  IV unfractionated heparin   Bolus followed by continuous infusion   Titrated to a target aPTT of 2 to 3 times the upper limit of normal (approximately 60 to 80 seconds)   Preferred in patients undergoing fibrinolysis or embolectomy   Heparin is withheld during the administration of t-PA and not restarted until the aPTT level less than twice the upper limit of normal Management - Anticoagulation

  Low-molecular-weight heparins (LMWHs)   As safe and effective as IV unfractionated heparin   LMWH monotherapy without oral anticoagulation : may be preferable in patients with malignancy   Advantages over unfractionated heparin   longer half-life   increased bioavailability   More predictable dose response   dosed by weight, administered subcutaneously → usually not require dose adjustments or laboratory monitoring   laboratory monitoring benefit in   chronic kidney disease ( LMWHs : renally cleared)   massive obesity, pregnancy   Unanticipated bleeding or thromboembolism despite correct weight- based dosing of LMWH Management - Anticoagulation

  heparin-induced thrombocytopenia (HIT)   Results from heparin-dependent immunoglobulin G antibodies   Decrease in platelet count greater than 50% of baseline → should raise concern about possible HIT and discontinuation of all heparin   Typically occurs within 4 to 14 days of heparin exposure   Occur earlier if previously exposed to heparin   If HIT is suspected or confirmed → administer a direct thrombin inhibitor such as argatroban or lepirudin Management - Anticoagulation

  Fondaparinux   Synthetic pentasaccharide with anti-Xa activity   Approved by the FDA for the initial treatment of venous thromboembolism including PE   Subcutaneous administration on a once-daily basis   Dose : fixed doses of 5 mg for <50 kg 7.5 mg for 50 ~ 100 kg 10 mg for >100 kg   No dose adjustment with laboratory coagulation tests   Cleared through the renal route – contraindicated in patients with severe renal disease   No side effect of HIT Management - Anticoagulation

  Warfarin   Oral vitamin K antagonists   Usually initiated simultaneously with heparin, LMWH, or fondaparinux   Overlapped for at least 5 days until full therapeutic efficacy   The target INR : between 2.0 and 3.0   Consideration of drug–food, drug–alcohol, drug– drug interactions   The optimal duration : depends on the risk of recurrent VTE   No reversible causes → chronic ill course with a high risk of recurrence after completion of standard anticoagulation   Inferior vena cava (IVC) filter indication   Anticoagulation is contraindicated   Recurrent PE despite adequate anticoagulation   Undergoing open surgical embolectomy Management - Anticoagulation

An approach to therapy for acute pulmonary embolism Management

PREVENTION

  Protocol of prophylaxis : still inconsistent   The risk of VTE persists after hospital discharge especially postoperative patients → use of extended VTE prophylaxis for 4 to 6 weeks in patients undergoing oncological or orthopedic surgery   Prophylactic regimens   Mechanical prophylactic devices : compression stocking, intermittent pneumatic compression → increase venous blood flow and enhance endogenous fibrinolysis   Pharmacological prophylaxis : subcutaneous unfractionated heparin, LMWH, warfarin, and fondaparinux Prevention

  Safety and efficacy of various VTE prophylactic regimens   Daily subcutaneous enoxaparin : safely reduce the risk of VTE   LMWH dalteparin (5000 IU subcutaneously once daily) : halved the rate of VTE, with a low risk of bleeding   Fondaparinux (2.5 mg subcutaneously once daily) : reduced the risk of VTE by 47% The Arixtra for Thromboembolism Prevention in a Medical Indications Study (ARTEMIS)   Prophylaxis with warfarin or LMWH in the prevention of VTE among orthopedic patients (hip replacement, major knee surgery, hip fracture)   Extended-duration prophylaxis with enoxaparin : reduced the risk of VTE in abdominal or pelvic surgery for malignancy Enoxaparin and Cancer (ENOXACAN) II study Prevention