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Thrombolytic therapy in pulmonary embolism

Thrombolytic therapy in pulmonary embolism. Presented by Ri 胡儀峰 Instructor: P 柯文哲. Chief complaint. A 59 year-old woman, for another treatment to pulmonary embolism with respiratory failure status post intubation. Brief history.

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Thrombolytic therapy in pulmonary embolism

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  1. Thrombolytic therapy in pulmonary embolism Presented by Ri 胡儀峰 Instructor: P 柯文哲

  2. Chief complaint • A 59 year-old woman, for another treatment to pulmonary embolism with respiratory failure status post intubation

  3. Brief history • She has history of Af with RVR on regular medicine control. • Abdominal fullness was noted in Nov.2005 and abdominal echo revealed a solid mass at left side of pelvis, 7 cm in size and hydronephrosis. • She was transferred to 三軍總 hospital on Nov.26.2005. Debulking with retroperitoneal tumor excision and LN dissection was done Dec.2.2005. • Post operative course was smooth but left leg edema was noted.

  4. Brief history • Sudden onset of shortness of breath was noted on Dec.10.2005. • Respiratory failure was noted and intubation was done. • Chest CT showed low density filling defect, 4 cm, in the pulmonary trunk , left main pulmonary artery and bilateral pulmonary with suspected pulmonary embolism. • Heparin has been adminstrated since Dec.17.2005. She was transferred to NTUH for further management on Dec.24.2005.

  5. Past history • 1. HTN (+) , DM: nil • 2. Smoking(-), Alcoholism (-) • 3. Surgery: Retroperitoneal SCC with right inguinal LN metastasis, s/p debulking with retroperitoneal tumor excision and LN dissection in Dec.2005 • 4. Allergy: denied • 5. Family history: non-contributory

  6. Course and management • After transferred to ICU, fever was noted and Tazocin was administrated. • Fever work-up was done and sputum culture revealed Pseudomonus aeruginosa. • Cardiac echo revealed LVEF: 72% with mild MR and moderate TR. Duplex revealed bilateral DVT(L<R). • Sudden onset of dyspnea with desasuration was noted. Auto peep was found. Ventilator with pressure control with muscle relaxant were administrated.

  7. Course and management • Chest, abdomen, pelvis and lower extremity CT showed left main trunk embolization, left iliac mass at previous OP area and massive thrombus of common iliac vein, left femoral, and left popliteal vein. • IVC filter with t-PA catheter thrombolysis was done. Hypotension and deoxygenation were noted, in spite of high inotropic agents use. • DNR was signed on 12/26. The patient died of sepsis, pulmonary embolism and retroperitoneal SCC at 13:25pm on Dec.26.2005.

  8. Introduction • Deep vein thrombosis (DVT) and acute pulmonary embolism (PE) are two manifestations of the same disorder, venous thromboembolism. • DVT of the lower extremity is subdivided into either calf vein or proximal vein (popliteal, femoral, or iliac vein) thrombosis.

  9. Introduction • Proximal vein thrombosis is of greater importance clinically, since it is more commonly associated with serious disease. • Over 90 percent of cases of acute PE are due to emboli emanating from the proximal veins of the lower extremities.

  10. GENERAL OBJECTIVES • Prevent further clot extension, acute PE, and recurrence of thrombosis, late complications ( postphlebitic syndrome and chronic thromboembolic pulmonary hypertension). • Anticoagulant therapy is indicated for patients with symptomatic proximal DVT, since pulmonary embolism will occur in approximately 50 percent of untreated individuals, most often within days or weeks of the event

  11. Treatment of acute pulmonary embolism and DVT • HEPARIN THERAPY -- Unfractionated heparin --Low molecular weight heparin • ORAL ANTICOAGULANT THERAPY -- Warfarin • THROMBOLYTIC THERAPY -- Urokinase -- Streptokinase -- Alteplase • INFERIOR VENA CAVAL INTERRUPTION

  12. HEPARIN • Simultaneous initiation of heparin (either unfractionated or low-molecular weight) and oral warfarin --The standard anticoagulant regimen for venous thromboembolism in all medically stable patients.

  13. HEPARIN • Monitor the response, using either the activated partial thromboplastin time (aPTT) or heparin levels, and to titrate the dose to the individual patient. • Critical therapeutic level of heparin, as measured by the aPTT, is 1.5 times the mean of the control value or the upper limit of the normal aPTT range, with a target range (aPTT ratio) of 1.5 to 2.5

  14. HEPARIN • Experimental studies and clinical trials have established that the efficacy of heparin therapy depends upon achieving a critical therapeutic level of heparin within the first 24 hours of treatment, usually via a continuous heparin infusion • Heparin infusion of 1000 IU/hr and who had an aPTT ratio of <1.5 times control for three days or more threefold increase in the risk of recurrent venous thromboembolism

  15. Low molecular weight heparin • Greater bioavailability when given by subcutaneous injection • The duration of the anticoagulant effect is greater (once or twice daily) • The anticoagulant response is highly correlated with body weight, permitting administration of a fixed dose -- Laboratory monitoring is not necessary except in pregnancy, morbid obesity and renal failure • Less likely to induce thrombocytopenia

  16. THROMBOLYSIS FOR PE

  17. INDICATIONS Patients with massive PE associated with hemodynamic compromise are reasonable candidates for intravenous thrombolytic therapy.

  18. Echocardiography • May reveal findings which strongly suggest massive and hemodynamically significant PE: -- Right ventricular dilation and/or hypokinesis. Even in the absence of systemic hypotension or profound hypoxemia • Such findings suggest the need for aggressive intervention, including consideration of thrombolytic therapy. This criterion for administration of lytic agents is not utilized by all practitioners, and remains the subject of investigation. Grifoni, S, Olivotto, I, Cecchini, P, et al. Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation 2000; 101:2817.

  19. CONTRAINDICATIONS • These should be particularly scrutinized if lytic therapy is considered

  20. Therapeutic regimens of Acute PE

  21. General guidelines for administration Buller, HR, Agnelli, G, Hull, RD, et al. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:401S.

  22. About administration • Intravenous route -- primary method of delivery • Rapid infusion -- Shorter regimens may not only prove efficacious but also reduce the risk of hemorrhagic complications • Catheter-directed therapy -- for massive PE, may induce major bleeding

  23. Catheter-directed therapy • Local delivery of streptokinase -- Extensive lysis (by perfusion scan and pulmonary arteriography at 12 to 24 hour follow-up) • Intrapulmonary versus peripheral alteplase -- no advantage over the intravenous route • Direct delivery into clot --Enhanced thrombolysis, relatively low doses (in an animal model of PE) -- Could prove advantageous over the intravenous route

  24. THROMBOLYSIS FOR PE Urokinase versus heparin (By Urokinase Pulmonary Embolism Trial (UPET)) • Thrombolysis was hastened in patients receiving UK compared with those treated with heparin when pulmonary arteriograms and lung perfusion scans were examined 24 hours after treatment -- The difference between the two groups diminished -- No difference in the frequency of recurrent PE or in mortality rate within two weeks of therapy • Bleeding complications in this trial were relatively high. Further experience with thrombolytic therapy has suggested that adverse effects are reduced. • One limitation to this study : small number of patients with potentially life-threatening embolic disease (only 7 percent classified as having massive PE with shock). The Urokinase Pulmonary Embolism Trial: A national cooperative study. Circulation 1973; 47(Suppl II):1.

  25. THROMBOLYSIS FOR PE Urokinase versus heparin • Phase 2 of the UPET evaluated 12 and 24 hour infusions of UK and a 24 hour infusion of SK -- No difference in mortality was demonstrated among the treatment groups. -- The extent of thrombolysis was greater than that in heparin-treated patients. -- Thrombolytic therapy was associated with more rapid reduction of vascular obstruction and earlier hemodynamic improvement. Urokinase-Streptokinase Embolism Trial: Phase 2 results. A cooperative study. JAMA 1974; 229:1606.

  26. THROMBOLYSIS FOR PE Alteplase versus heparin • A randomized controlled trial of alteplase plus heparin versus placebo plus heparin was conducted in 256 patients. -- Therapy with alteplase was associated with a decreased need for escalation of therapy (10 versus 25 percent ) -- In-hospital mortality did not differ significantly between groups. • Limitations of this study include possible undertreatment of the control group, because heparin was not dosed according to weight. -- In addition, because only about 30 percent of patients in each group had echocardiographic evidence of right ventricular dysfunction, it is possible that the study was underpowered to detect a treatment effect specific to these patients. Konstantinides, S, Geibel, A, Heusel, G, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002; 347:1143

  27. THROMBOLYSIS FOR PE Alteplase versus urokinase • One study compared alteplase (100 mg administered intravenously over two hours) with a 24-hour infusion of UK (2000 U per pound bolus followed by continuous infusion at 2000 U/pound per hour). The primary end points were improvement by pulmonary arteriography at two hours and by perfusion scan at 24 hours. -- Moderate or marked improvement on arteriogram at two hours was much more common in patients treated with alteplase (59 versus 13 percent). -- The alteplase-treated patients had received the entire dose of thrombolytic therapy (100 mg of alteplase) by the time of the two hour outcome measurement whereas the UK-treated patients had received only part of the total dosage to be administered.-- Improvement in lung scan reperfusion at 24 hours was identical in the two treatment groups. Goldhaber, SZ, Kessler, CM, Heit, J, et al. A randomized controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 1988; 2:293.

  28. THROMBOLYSIS FOR PE Alteplase versus urokinase • At present, the alteplase regimen in which 100 mg is administered intravenously over two hours is the most rapidly administered protocol that is currently approved for use in the United States

  29. Long-term outcome • Almost all studies have demonstrated the superiority of thrombolysis (in particular with alteplase) over heparin in terms of resolution of both radiographic and hemodynamic abnormalities when measurements were made within the first 24 hours, this advantage appears to be short-lived. • Repeat echocardiograms obtained seven days after treatment of 40 patients with either heparin or alteplase revealed no significant differences in ventricular dimensions. In addition, the trials have not demonstrated a difference either in mortality rate or in resolution of symptoms. Konstantinides, S, Tiede, N, Geibel, A, et al. Comparison of alteplase versus heparin for resolution of major pulmonary embolism. Am J Cardiol 1998; 82:966.

  30. Long-term outcome • Measurement of diffusing capacity and capillary volumes at two weeks and one year after treatment showed that patients receiving thrombolytic therapy had higher diffusing capacity and lung capillary volumes compared to those receiving heparin. • Follow-up of the same group of 23 patients for an average of seven years following initial therapy showed that patients who had been treated with thrombolytic therapy had lower pulmonary artery pressure and pulmonary vascular resistance compared to patients who had received heparin. • The clinical significance of these changes awaits further prospective trials. Sharma, GVRK, Burleson, VA, Sasahara, AA. Effect of thrombolytic therapy on pulmonary-capillary blood volume in patients with pulmonary embolism. N Engl J Med 1980; 303:842. Sharma, GVRK, Folland, ED, McIntyre, KM, et al. Longterm hemodynamic benefit of thrombolytic therapy in pulmonary embolic disease (abstract). J Am Coll Cardiol 1990; 15:65A.

  31. RECOMMENDATIONS • The use of thrombolytic agents in the treatment of venous thromboembolism -- individualized and requires further investigation. • Hemodynamically unstable PE or massive iliofemoral thrombosis -- the best candidates for thrombolytic therapy.

  32. Conclusion • The primary therapy for acute pulmonary embolism is anticoagulation with heparin and warfarin to prevent additional thromboembolism. • Thrombolysis, why not? -- Heparin for well-tolerated PEs : extremely good prognosis -- Inherent risk of thrombolysis : bleeding -- The most effective thrombolytic period missed (extensive bronchial collateral circulation )

  33. Conclusion • The role of thrombolytic therapy in the management of acute massive pulmonary embolism remains controversial • Although there is more rapid dissolution of venous thromboemboli, the risk of serious bleeding with thrombolysis remains a concern( intracerebral hemorrhage occurs more frequently with thrombolytic agents than with heparin).

  34. Conclusion • Thrombolytic therapy can play an important role in the management of acute pulmonary embolism: -- PE associated with systemic hypotension in the absence of absolute contraindications. -- Echcardiographic evidence of thrombus in the right ventricle -- Severely compromised oxygenation, respiratory failure

  35. Conclusion • Catheter-directed therapy with low-dose thrombolytic therapy can be considered • Direct intraembolic therapy may be superior to intravenous therapy • Acceptable time window for administration 2 weeks • The shorter interval between the onset of symptoms and the initiation of therapy, the greater response

  36. Thank you for your attention!

  37. RECOMMENDATIONS • From the evidence-based recommendations of the Seventh American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy Buller, HR, Agnelli, G, Hull, RD, et al. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:401s

  38. RECOMMENDATIONS • Therapy of acute deep vein thrombosis or pulmonary embolism should be initiated with IV heparin adjusted to prolong the APTT to a range that corresponds to a plasma heparin level of 0.3 to 0.7 U/mL

  39. RECOMMENDATIONS • Heparin therapy should be continued for at least five days. • Oral anticoagulation should be overlapped with heparin therapy for four to five days. • Heparin and warfarin therapy can be initiated simultaneously, with heparin therapy discontinued on day five or six if the INR has been therapeutic for two consecutive days. • Longer periods of initial heparin therapy may be considered in the case of massive pulmonary embolism or iliofemoral thrombosis.

  40. RECOMMENDATIONS • LMW heparin may be used in place of unfractionated heparin. • Dosing requirements are individualized for each product.

  41. RECOMMENDATIONS • Long-term anticoagulation should be continued for at least 12 weeks using oral anticoagulants to prolong the INR to 2.0 to 3.0.

  42. RECOMMENDATIONS • First thromboembolic event in the context of a reversible risk factor -- treated for three to six months • Idiopathic first thromboembolic event -- full six months of treatment. • Recurrent venous thrombosis or a continuing risk factor -- treated indefinitely.

  43. RECOMMENDATIONS • IVC filter placement is recommended when -- anticoagulation is contraindicated -- recurrent thromboembolism despite adequate anticoagulation -- chronic recurrent embolism with pulmonary hypertension -- situations with a high-risk of recurrent embolization -- conjunction with the performance of pulmonary embolectomy or endarterectomy

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