DVT-PE Nitin Bhatt MD

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DVT-PE Nitin Bhatt MD

  1. 1. DVT-PE <ul><li>Nitin Bhatt MD </li></ul><ul><li>Director, ICU </li></ul><ul><li>VAMC, Reno </li></ul>
  2. 3. Q;3, A 45-year-old woman is evaluated in the emergency department because of the sudden onset of shortness of breath and chest tightness earlier this afternoon. She has been in excellent health and returned 2 days ago from a trip to Japan. On physical examination, her pulse rate is 116/min and respiration rate is 36/min. Cardiopulmonary examination is otherwise unremarkable, and a chest radiograph shows no infiltrates. Measurement of arterial blood gases on room air shows the following: pH 7.48, Paco 2 24 mm Hg, and Pao 2 78 mm Hg; oxygen saturation is 96%. <ul><li>What is the most appropriate immediate next step in this patient’s management? </li></ul><ul><li>( A ) Pulmonary angiogram ( B ) Compression ultrasonography of the lower extremities ( C ) Therapy with diazepam ( D ) Intravenous heparin ( E ) Ventilation-perfusion lung scan </li></ul>
  3. 4. DVT-PE <ul><li>Different stages of same disease </li></ul><ul><li>90%-95% of PE originate from clots in lower extremities </li></ul><ul><li>600,000 per year remain undiagnosed in USA as signs and symptoms are nonspecific </li></ul>
  4. 5. Asymptomatic PE in DVT pts <ul><li>About 40% of patients with venogram proven DVT had asymptomatic PEs when investigated by pulmonary angiogram. </li></ul><ul><li>Ken Moser et al </li></ul>
  5. 6. Of an estimated 200,000 deaths per year in the United States, only 13,000 (6%) occur in patients who have received treatment. The vast majority of patients (94%) who die of pulmonary embolism do not receive treatment because the diagnosis is not made
  6. 7. PE <ul><li>Difficulty of Diagnosis </li></ul><ul><li>Multiple clinical presentations </li></ul><ul><li>Nonspecific signs and symptoms </li></ul><ul><li>Mortality Rates </li></ul><ul><li>With treatment: 5% to 8% (more recent data suggests 2-3%) </li></ul><ul><li>Without treatment: 25% to 30% </li></ul>
  7. 8. Q;3, A 45-year-old woman is evaluated in the emergency department because of the sudden onset of shortness of breath and chest tightness earlier this afternoon. She has been in excellent health and returned 2 days ago from a trip to Japan. On physical examination, her pulse rate is 116/min and respiration rate is 36/min. Cardiopulmonary examination is otherwise unremarkable, and a chest radiograph shows no infiltrates. Measurement of arterial blood gases on room air shows the following: pH 7.48, Paco 2 24 mm Hg, and Pao 2 78 mm Hg; oxygen saturation is 96%. What is the most appropriate immediate next step in this patient’s management? ( A ) Pulmonary angiogram ( B ) Compression ultrasonography of the lower extremities ( C ) Therapy with diazepam ( D ) Intravenous heparin ( E ) Ventilation-perfusion lung scan
  8. 9. Q:3, Ans=D, When venous thromboembolism is strongly suspected, the first action taken should be to administer heparin in a therapeutic dose (in the absence of contraindications to anticoagulation) to prevent new clot formation, allow unopposed fibrinolytic activity to facilitate thrombus resolution, and avoid progression into the pulmonary circulation. Therapy should be started before performing confirmatory diagnostic tests such as a ventilation-perfusion scan, pulmonary angiogram or compression ultrasonography of the lower extremities. Subtherapeutic or delayed anticoagulation is associated with unacceptable recurrence rates of venous thromboembolism, and is a common error in the initial phases of treatment. Although relatively less heparin is required to prevent the coagulation cascade from being initiated, more is required after the cascade is under way. Therefore, early administration of an adequate dose is required. For continuous infusions, the activated partial thromboplastin time should be monitored regularly to ensure that the dose is therapeutic. Inadequate initial heparin therapy also has been associated with late recurrences of thromboembolism. Anxiolytic therapy would not be an appropriate as the initial step in this patient’s manageme
  9. 10. Virchow`s Triad <ul><li>Venous stasis </li></ul><ul><li>Injury to the intima </li></ul><ul><li>Change in the coagulability of blood </li></ul>
  10. 12. Acquired Risk Factors for VTE <ul><li>Surgery and Trauma </li></ul><ul><li>Prolonged Immobilization </li></ul><ul><li>Age greater than 40 </li></ul><ul><li>Obesity, Inflammatory Bowel Disease, CHF </li></ul><ul><li>Cancer , PNH, Nephrotic syndrome </li></ul><ul><li>Myeloproliferative Disorder </li></ul><ul><li>Previous DVT or PE, Air-travel </li></ul><ul><li>Pregnancy and puerperium </li></ul><ul><li>Contraceptives or Hormone Replacement Therapy </li></ul><ul><li>Resistance to Activated Protein-c (not F-5 Leiden) </li></ul><ul><li>Lupus Anticoagulant/ Antiphospholipid antibody </li></ul><ul><li>Mild-moderate Hyperhomocystinemia </li></ul>
  11. 15. Factor V Leiden and VTE <ul><li>9253 randomly selected Danish people, heterozygous and homozygous F V Leiden was associated with hazard ratio for VTE of 3 and 18 respectively, compared to non-carrier population. </li></ul><ul><li>Simultaneous presence of smoking, obesity and old age increased 10 year absolute risk of VTE to 10% and 51% in Heterozygous and homozygous, resp. </li></ul><ul><li>Juul et al, AIM 2004; 140:330-337 </li></ul>
  12. 17. Natural history <ul><li>DVT originates as a platelet nidus near venous valves of lower exremities and grows by accretion of platelets and fibrin </li></ul><ul><li>Newly formed clot more likely to get detached to cause embolism to the FILTER organ, lung, or may be lysed by endogenous lytics </li></ul><ul><li>Organization of venous clots cause damage to venous valves and lead to post-phlebitic syndrome </li></ul>
  13. 18. P.E.:Physiology <ul><li>Hypoxemia in majority, leading to respiratory alkalosis </li></ul><ul><li>V/Q mismatch is predominant cause of hypoxemia, some R  L shunting occurs </li></ul><ul><li>Serotonin from platelets  PVR </li></ul><ul><li>Bronchoconstriction due to mediators from thrombii </li></ul>
  14. 19. P.E.: physiology <ul><li>If no pre-existing cardio-pulmo disease, obstruction of 25-30% of pulmo vascular bed leads to PHTN, >75% obstruction will lead to acute RV failure as normal RV can not generate pressure >50 mm Hg </li></ul><ul><li>Lack of increase in CVP with large P.E. may suggest severe RV failure </li></ul>
  15. 20. PHTN after first episode of PE <ul><li>Excluding patients with persistent risk factors for VTE, in a prospective study of idiopathic or transient risk factor associated PE, about1% risk of chronic thromboembolic pulmonary hypertension was noted, confirmed by pulmonary angiography, 14 to 22 months after acute PE- Becattini et al, Chest 2006;130: 172-5 </li></ul>
  16. 21. Q-9:52 yr woman, 1 yr h/o dyspnea. Heavy smoker in past, h/o HTN.O/E loud P2, elevated JVP,mild bilat ankle edema. CBC, Chem-panel, HIV, ANA , Rh. Titer negative. CXR: prominent Pulm. Arteries, echo: normal EF, RVE, PA-syst pressure 60, PFTs: normal volumes, DLCO 40% pred, V/Q: mild heterogeneity of perfusion, Swan Ganz: RAP 10, RVP 50/10, PAP 50/20, PAOP 26, CI 2. ?DX <ul><li>1, LV diastolic dysfunction </li></ul><ul><li>2, Chronic Pulmonary embolism </li></ul><ul><li>3, Primary pulmonary HTN </li></ul><ul><li>4, Pulmonary veno-occlusive disease </li></ul><ul><li>5, Constrictive pericarditis </li></ul>
  17. 22. A-9=A
  18. 23. DVT: Clinical diagnosis ? <ul><li>Clinical suspicion based on symptoms e.g. leg edema, calf pain, etc., only 30% of clinically suspected to have DVT, ultimately have diagnosis proven. </li></ul><ul><li>Homan`s sign is not specific or sensitive for DVT </li></ul><ul><li>Myositis, cellulitis, hematoma and edmatous state are commonly included in differential diagnosis of DVT </li></ul>
  19. 24. Fedullo and Tapson, NEJM, 9-25-03
  20. 25. Fedullo & Tapson, NEJM 9-25-03 Low=10%, Inter=30% and High=>70%
  21. 26. From JAMA 1/11/06
  22. 27. Prediction of PE in ED. by Gal et al, AIM 7 Feb 2006
  23. 29. DVT <ul><li>Contrast venography </li></ul><ul><li>Compression ultrasound </li></ul><ul><li>Impedence plethysmography </li></ul>
  24. 30. Venogram: Popliteal Vein Thrombosis
  25. 31. Compression ultrasound (Goldhaber) Artery compressed, but vein did not: DVT
  26. 33. CUS in suspected PE? <ul><li>Retrospective analysis of data from prospective study, showed that in patients proven to have PE, >60% had positive CUS. Age >70 and signs and symptoms of DVT were independent predictors of positive CUS </li></ul><ul><li>Girard et al, Chest 2005, P 1593-00 </li></ul>
  27. 34. MRI in Dx Of DVT <ul><li>101 Pts who underwent venogram for diagnosis of dvt were included.All pts with positive venogram and ¼ of those with negative venogram included </li></ul><ul><li>Magnetic Resonance Direct Thrombus Imaging (MRDTI) was used in all patients within 48 hrs of venography and interpreted by 2 reviewers </li></ul><ul><li>Sensitivities and specificities were >90 %. Even isolated calf thrombii had 82-92 % sensitivities. Fraser et al, Ann Int Med 1-15-02 </li></ul>
  28. 35. Pelvic DVT diagnosis by MRA <ul><li>24 patients with proven PE and negative CUS, were studied. </li></ul><ul><li>29% had pelvic DVT </li></ul><ul><li>Common iliac vein involved in 5 patients. </li></ul><ul><li>Stern et al, Chest 2002;122: 115-21 </li></ul>
  29. 36. Pulmonary Embolism, NEJM 7-9-98
  30. 37. Goldhaber, NEJM 7-9-98
  31. 38. SYMPTOMS AND SIGNS IN 117 PATIENTS WITH ACUTE PULMONARY EMBOLISM WITHOUT PRE-EXISTING CARDIAC OR PULMONARY DISEASE (Stein, Chest 1991) 30 TACHYCARDIA>100 37 COUGH 1 CYANOSIS 3 THIRD H.S. 3 PLEURAL RUB Common in PE 4 RIGHT VENR. LIFT *= Significantly More 4 HOMAN`S SIGN 5 WHEEZES 7 TEMP. >38.5*C 4 ANGINA 11 DIAPHORESIS 9 WHEEZING 11 DVT 10 PALPITATIONS 23 LOUD P2 * 13 HEMOPTYSIS 24 FOURTH H.S. * 28 LEG SWELLING 51 RALES (CRACKLES) * 66 PLEURITIC PAIN 70 TACHYPNEA >20/min 73 DYSPNEA % OF PATIENTS SIGNS % OF PATIENTS SYMPTOMS
  32. 41. During fibrinolysis of fibrin, plasmin cleaves factor XIIIa–cross-linked fibrin into an array of intermediate forms. The D-dimer and E fragments are the result of terminal fibrin degradation., P.Bockenstedt, NEJM 9-25-03
  33. 42. Plasma D-Dimer <ul><li>Sensitive but not a specific test for PE, therefore use for excluding PE, not useful to make the diagnosis. </li></ul><ul><li>Not recommended as stand alone test, use with either clinical criteria or V/Q scan or Ultrasound, several diagnostic algorhythms now reported using D-dimer </li></ul>
  34. 43. D-Dimer in diagnosis of VTE: AJRCCM, Feb 2002; 345-8 <ul><li>Strong correlation noted between location of P.E. and D-Dimer concentration, p<0.001 </li></ul><ul><li>Sensitivity of D-Dimer was 93% for excluding segmental or larger P.E. but only 50% for subsegmental P.E. </li></ul>
  35. 44. D-Dime r and Ultrasound in DVT Wells et al,NEJM 9-25-03 <ul><li>Suspected PE cases were excluded </li></ul><ul><li>All patients had clinical stratification as high or low likelihood for DVT </li></ul><ul><li>Low clinical suspicion and negative D-Dimer rules out DVT </li></ul><ul><li>High clinical suspicion but negative D-Dimer and negative US of legs rules out DVT </li></ul><ul><li>39% in D-Dimer group did not need ultrasound, but overall prevalence of DVT-PE was only 15.7% </li></ul>
  36. 45. D Dimer and DVT <ul><li>Low clinical probability and negative D Dimer value rules out DVT effectively. </li></ul><ul><li>High or intermediate clinical probability makes D dimer value unhelpful </li></ul><ul><li>Moderate clinical probability and negative D dimer by HIGH sensitivity assey can have DVT ruled out. (Meta-analysis by Wells et al JAMA Jan 11 2006 p 199-207) </li></ul>
  37. 46. D dimer in evaluation of PE <ul><li>Low clinical probability combined with negative D dimer (SimpliRED whole blood agglutination test) had negative predictive value of 99.5% for excluding PE in a prospective cohort study of ER patients. </li></ul><ul><li>Wells et al AIM 2001;135:98-107 </li></ul><ul><li>In a prospective randomized trial ( Kearon et al, AIM; 2006 p 812-21) low clinical probability and negative d-dimer was associated with <.5% incidence of VTE on follow up. 50% of out-pt and 20% of inpatient fell into this category. </li></ul>
  38. 47. D dimer and PE <ul><li>Negative simplify D-dimer test and a low clinical probability of PE, resulted in 0.7% incidence of VTE on 90 day follow up of ER patients. Kline et al Chest; June 2006, 1417-23 </li></ul>
  39. 48. EKG in a pt with Pulm Embolism, NEJM 7-9-98
  40. 49. PE <ul><li>CXR </li></ul><ul><li>In majority of cases of PE, cxr is abnormal but nondiagnostic e.g. Atelectasis, Small pleural effusion </li></ul><ul><li>Enlarged right descending PA, Decreased pulmonary vascularity (Westermark sign) </li></ul><ul><li>Wedge-shaped peripheral infiltrate (Hampton`s hump) </li></ul><ul><li>Normal </li></ul>
  41. 50. Chest radiograph showing pulmonary infarct in the right lower lobe. This patient had low-grade fever, hemoptysis, and pleuritic chest pain. The ventilation-perfusion scan was read as high probability for pulmonary embolism. A pleural-based density in the lower lobe with the convexity directed toward the hilum signifies pulmonary infarction. This sign is also known as “Hampton’s hump.” From Bone`s Atlas
  42. 51. 67 yr man with 5 days of cough and dyspnea and 1 day of pleuritic pain cxr shows left pleural based infarction at left base. (Hampton`s hump).And avascularity (Westermark`s sign) in RUL. Perfusion scan shows significant corrensponding defects. NEJM 11-1-01
  43. 52. Pulmonary infiltrate and small pl.eff. RLL area from PE, These clear on cxr 2 weeks later (Murray and Nadel)
  44. 53. Normal perfusion scan, excludes PE (Murray & Nadel)
  45. 54. PE by high probability perfusion scan( Murray and Nadel)
  46. 55. PIOPED 10% 98% High or Intermediate or low 52% 82% High or Intermediate 97% 41% High Probability Specificity Sensitivity Scan category
  47. 56. PIOPED: value of clinical assessment Likelihood of P.E. .. Scan…. Clinical suspicion….. 4% 16% 40% Low 16% 28% 66% Intermediate 56% 88% 96% High 0-19% low 20-79% intermediate 80-100% high V/Q Scan Category
  48. 57. V/Q Scan and PE <ul><li>Majority of patients undergoing V/Q scans have NON-DIAGNOSTIC V/Q scans, i.e. do not have normal or high probability V/Q scan </li></ul><ul><li>Majority of patients who have PE do not have high probability V/Q scans </li></ul><ul><li>Majority of patients who are suspected to have PE but later rule out for PE, have abnormal V/Q scans </li></ul>
  49. 58. (Q-8) A 59 yr female is evaluated for dyspnea of acute onset. She was diagnosed to have non-metastatic ca-breast 2 mo ago and c/o fatigue and insomnia since then. T 100, P1105,RR 22, BP 158/88, PSaO2 95% on RA. No JVP, Lung clear, Heart normal, No edema, Abdomen Neg. CXR: neg. EKG: S.tach. V/Q : 2 segmental perfusion defects, minimum ventilation defect. Next ? <ul><li>1, Spiral CT with IV contrast </li></ul><ul><li>2, Thrombolytic RX </li></ul><ul><li>3, IV heparin </li></ul><ul><li>4, Doppler US of lower extremities </li></ul>
  50. 59. Ans:8 = 3 <ul><li>High probability scan and high clinical suspicion=95% PPV for P.E. </li></ul><ul><li>No hemodynamic compromise, no need for thrombolytic therapy </li></ul>
  51. 61. Pleural Effusions in PE <ul><li>60 patients reviewed, 100% exudate </li></ul><ul><li>67% had RBCs >10,000/cc </li></ul><ul><li>60% had predominenet PMNs in differential WBC counts </li></ul><ul><li>18% had pleural fluid eosinophilia >10% </li></ul><ul><li>Retrospective study </li></ul><ul><li>Candeira, Chest 2002;121:465-69 </li></ul>
  52. 62. Spiral CT in PE <ul><li>Spiral cat scan allows for rapid imaging during a single breath hold </li></ul><ul><li>Contrast may be administered peripherally </li></ul><ul><li>Sensitivity is now felt be in 70-80% range while specificity remains >90% </li></ul>
  53. 63. Spiral cat scan in a patient with massive saddle Pulm. Embolism, before and after thrombolytic Rx with TPA. NEJM, 10-10-02
  54. 64. Three advantages of helical CT deserve mention. 1, The value of CT's ability to identify an alternative diagnosis in up to a third of patients with suspected PE 2, As with lung scanning, when the combination of pretest probability and helical CT results yield sufficiently high or low post-test probabilities, the test obviates the need for conventional angiography and its associated higher morbidity. 3, In practice settings in which clinicians can obtain a CT scan more quickly than a lung scan or an angiogram, the use of CT may prevent delays in therapy Matthew B. Stanbrook, MD Brigham and Women's Hospital, Harvard Medical School
  55. 65. CT scan in P.E. Isolated thromboembolism of the subsegmental pulmonary arteries is not unusual, occurring in 6 to 30 percent of patients with embolism in different series. Filling defects involving the main or lobar pulmonary arteries can be considered diagnostic of embolism, whereas a normal CT scan may indicate a substantially reduced likelihood of embolism but cannot be used to rule out the possibility of embolism with the same degree of certainty that a negative ventilation–perfusion scan provides. Outcome studies have demonstrated that withholding anticoagulant therapy in patients with a negative CT scan coupled with a negative ultrasonographic study of the legs is a safe strategy, except in those patients who present with a high clinical probability of embolism Fedullo and Tapson, NEJM 9-25-03
  56. 66. Role of D-dimer, Clinical Prediction and Spiral CAT scan: Christopher study, JAMA 1/11/2006 <ul><li>True management study. 20% incidence of PE. </li></ul><ul><li>Low clinical suspicion plus negative D-dimer, associated with 0.5% incidence of VTE in 3 months </li></ul><ul><li>If Spiral CT (10% single and 90% multidetector-row) negative, 3 month incidence of VTE was 1.3% and fatal PE in 0.5% (in other studies, negative Pulmonary angio was associated with 1.7% VTE and 0.3% fatal PE) </li></ul><ul><li>Work up completed in about 98% and management decision made in 98% with this strategy </li></ul><ul><li>Await further confirmation, some patients had US or v/q scans done before CAT scans. </li></ul>
  57. 67. CT chest and PE <ul><li>Meta-analysis in JAMA (4/27/2005 P 2012-17) included 15 studies and 3500 patients. Risk of recurrent event, in patient with suspected PE but negative spiral CT (single slice or multidetector row scanners used) was similar to that of negative angiography. NPV of negative CT was 99.1% </li></ul><ul><li>An editorial by Hull in JAMA after reviewing Christopher study showing safety of withholding anticoagulation in negative multi-slice CT patients, still recommended caution with this strategy alone until more data seen. Using D dimer and clinical probability with CT data was recommended. </li></ul>
  58. 68. Should CAT scan of chest be accompanied by US of legs to rule out VTE? <ul><li>2004 data suggested this. More recent data seem to show much better NPV with negative CAT scans. At 3 mo follow up, 1.4% VTE and .51% fatal PE (letters to editor, AIM, Moore et al, Meta-analysis AIM 2004;141:866-74). If DVT is also a consideration, combined CT-angio, CT –venography may become available in many hospitals soon. </li></ul>
  59. 69. How long does it take to resolve PEs? <ul><li>% of patients with residual pulmonary embolii is 87% at 8 days, 68% after 6 weeks, 65% after 3 months, 57% after 6 months and 52% after 11 months. The follow up studies were angiograms, CT or V/Q scans. Retrospective review. </li></ul><ul><li>Nijkeuter et al, Chest 2006;129:192-7 </li></ul>
  60. 70. Left pulmonary artery filling defect in PE. (Murray and Nadel)
  61. 71. Pulmonary Angiography: PIOPED data <ul><li>Includes 1111 pts who underwent angiography in PIOPED study </li></ul><ul><li>0.5% mortality and 1% major and 5% minor complications noted, major complications were noted mostly in ICU patients </li></ul><ul><li>PA pressure, volume of contrast and presence of PE did not affect complication rate </li></ul><ul><li>Surveillance showed 0.6% of negative angiogram pts have PE on followup. 96% of angiograms were diagnostic, 3% nondiagnostic 1% incomplete </li></ul>
  62. 72. Indications for Pulmonary Angiogram <ul><li>After reasonable workup substantial suspicion for alternate diagnosis (other than PE) exists </li></ul><ul><li>High clinical suspicion for PE, but low probability V/Q scan and nondiagnostic results of CT and (-) US </li></ul><ul><li>Intermediate clinical probability, (-) CT, high, low or intermediate probability V/Q scan, (-) U.S. </li></ul><ul><li>Low clinical probability, high probability V/Q scan and (-) U.S. </li></ul>
  63. 73. Echocardiogram in pulmonary embolism: Goldhaber, NEJM 7-9-98                                                                                                         
  64. 74. Echocardiogram in PE <ul><li>Right ventricular dilatation </li></ul><ul><li>Right ventricular hypokinesis </li></ul><ul><li>Tricuspid regurgitation </li></ul><ul><li>Bulging of inter ventricular septum into left ventricle </li></ul><ul><li>Reduced LV size with D shaped LV </li></ul>
  65. 75. Fedullo and Tapman, NEJM 9-25-03
  66. 76. Fedullo & Tapman, NEJM 9-25-03
  67. 77. Fedullo and Tapman NEJM 9-25-03 Note: low clinical prob + low prob V/Q may stop workup
  68. 78. Fedullo and Tapman NEJM 9-25-03
  69. 79. Q-10: A 52 yr man c/o mild dyspnea and chest pain after carrying light luggage from car following a 9 hr drive. Has h/o COPD, PUD and Hodgkins Lymphoma in remission x 4 yr after radioRX. Auto-Accident 1 yr ago, had R leg DVT, Rx Heparin x 5 D, then coumadin x 3 mo., P/E, EKG, CXR: unremarkable, V/Q: low probability. ? Next in DX test <ul><li>1, Restart Heparin </li></ul><ul><li>2, ABG </li></ul><ul><li>3, D-Dimer, if high then restart IV Heparin </li></ul><ul><li>4, D-Dimer, if high then US of lower extr. </li></ul>
  70. 80. A-10=4 <ul><li>Pre-test probability of PE is intermediate to high, therefore low probability V/Q scan does not rule out P.E. and 15% likelihood of P.E. remains. </li></ul><ul><li>If D-dimer is negative, may choose repeat US at day 2 and 7 and if negative, do not treat or test further. If D-Dimer AND US are positive, treat for DVT (and P.E.) </li></ul>
  71. 81. Treatment for PE <ul><li>Virchow offered no insights on the treatment or prevention of PE. The first therapy for PE, pulmonary embolectomy, was proposed by Trendelenburg in 1908 </li></ul><ul><li>Dalen, Chest, Nov 2002 </li></ul>
  72. 82. Bed rest in DVT and PE patients <ul><li>No difference in recurrent PE incidence in PE patients or new PE in DVT patients with or without bedrest </li></ul><ul><li>Trujillo-Santos et al, Chest 2005 p 1631-36 </li></ul>
  73. 83. Heparin and PE <ul><li>35 patients with suspected PE randomized to treatment with heparin vs. no heparin </li></ul><ul><li>Untreated group had 5 deaths from PE vs. none in heparin treated group </li></ul><ul><li>Barritt: Lancet 1309, 1960 </li></ul>
  74. 85. Cumulative Probability of Recurrent Venous Thromboembolism in Patients with a Second Episode, According to the Duration of Assigned Anticoagulant Therapy. Schulman et al, NEJM 2-6-1997
  75. 86. Duration of Anticoagulation During therapy with vitamin K antagonists, the risk of recurrence is very effectively reduced — by approximately 90 percent, to 0.7 episode per 100 person-years. In the 6 to 12 months immediately after the discontinuation of therapy, a catch-up phenomenon occurs, resulting in an absolute incidence of recurrence of venous thromboembolism of 5 to 10 percent. This phenomenon has been observed after 3, 6, and 12 months of vitamin K–antagonist therapy and therefore suggests that prolonging this therapy simply delays recurrence until the therapy is stopped, rather than reducing the risk of recurrence. During the subsequent years, the risk of recurrence stabilizes, and the annual incidence of recurrence is 1 to 2 percent. Buller and Prins, NEJM 8-14-03
  76. 87. Bates and Ginsberg, NEJM 7-15-04
  77. 89. What Intensity of Anticoagulation ? low-intensity anticoagulant therapy (INR 1.5 to 1.9) reduces the risk of recurrent thrombosis by about 75 percent, whereas conventional-intensity therapy (INR 2 to 3) reduces this risk by over 90 percent, and no increase in major bleeding ( kearon et al NEJM 8-14-03)
  78. 90. Q;2; A 76-year-old woman with metastatic breast cancer is evaluated because of a 3-day history of swelling of her right leg and pleuritic chest pain. Ultrasonography shows an occlusive thrombus in the femoral vein. Results of a ventilation-perfusion scan are normal, and therapy with continuous intravenous heparin is begun. On the fourth day of heparin therapy and after oral warfarin has been started, the activated partial thromboplastin time is therapeutically prolonged, but the prothrombin time has not yet reached the therapeutic range; at this time, the patient develops dyspnea. On physical examination, her blood pressure is 140/90 mm Hg; she is tachypneic and tachycardic, but the remainder of her cardiopulmonary examination is normal. Chest radiograph shows no abnormalities. Measurement of arterial blood gases reveals new hypoxemia on room air. Ventilation-perfusion scan shows perfusion defects in the entire right lower lobe and the inferior subsegment of the lingula.
  79. 91. Q;2 continued <ul><li>Which one of the following should be part of this patient’s management at this time? </li></ul><ul><li>( A ) Continued observation until warfarin dosing is therapeutic </li></ul><ul><li>(B) Placement of IVC filter </li></ul><ul><li>( C ) Readminister heparin bolus and increase the rate of the continuous infusion </li></ul><ul><li>( D ) Administer an increased dose of warfarin </li></ul>
  80. 92. Q;2 Answer is B <ul><li>This patient had a pulmonary embolism while in the early stages of therapy for recognized venous thrombosis. Heparin therapy is at a dosage in the therapeutic range, and warfarin is not yet therapeutic. The appropriate management strategy would be placement of an IVC-filter, which should prevent recurrent pulmonary embolization. IVC-filters are placed fairly easily transcutaneously and have a low incidence of adverse reactions (5%) and very low associated mortality (≤ 0.1%). Potential complications include malpositioning, infection, air embolization during placement, local wound problems (for example, hematoma formation), perforation of the vena caval wall, migration from the site of placement, and rarely induction of venous thrombosis at the site of insertion. Indications for filter placement include contraindication to anticoagulation, anticoagulation failure or complication (such as in this patient), and pulmonary embolism prophylaxis. It has been reported that the risk of venous thrombosis is increased in the 2 years after an IVC-filter is placed. The risk of recurrent venous thrombosis dictates a full course of therapy with anticoagulation unless specifically contraindicated by hemorrhagic diatheses. </li></ul><ul><li>Because she is adequately anticoagulated with heparin, there is no need to adjust her heparin dosage. Increasing the dose of warfarin is unlikely to have an immediate effect due to the relatively long time required for warfarin to inhibit its target coagulation factors, and it may lead to supratherapeutic effect with an increased risk of bleeding. Because the patient has a large clot persisting in her leg, simple observation does not further reduce her risk of repeat pulmonary embolism. </li></ul>
  81. 93. Venacaval Interruption <ul><li>1: Recurrent PE after 24 hours of adequate anticoagulation </li></ul><ul><li>2: Anticoagulation is contraindicated </li></ul><ul><li>3: Concurrent with pulmonary embolectomy or cardiotomy for PE </li></ul><ul><li>4: In an unstable patient who is unlikely to tolerate recurrence of PE </li></ul>
  82. 94. Urokinase Pulmonary Embolism Trial(UPET) <ul><li>Urokinase resulted in improved resolution of embolii by angiography, lung scan and right sided hemodynamics compared to heparin </li></ul><ul><li>No difference in recurrent PE or 2 week mortality. </li></ul><ul><li>Higher incidence of bleeding with Urokinase </li></ul>
  83. 95. Thrombolytic in PE <ul><li>Indications </li></ul><ul><li>A: Hypotension due to PE </li></ul><ul><li>B: Refractory hypoxemia </li></ul><ul><li>C: Severe DVT in a young patient </li></ul><ul><li>D: ? RV hypokinesis with PE </li></ul>
  84. 96. FDA approved thrombolytic regimens for PE <ul><li>Sreptokinase: 250,000 U bolus over 30 min, then 100,000 U/hr for 24 hours </li></ul><ul><li>Urokinase: 4400 U/kg over 10 min, then 4400 U/kg/hr for 12-24 hours </li></ul><ul><li>TPA: 100 mg over 2 hours </li></ul>
  85. 97. Thrombolytic Rx in Pulm.Embolism NEJM, 10-8-02 Methods We conducted a study of patients with acute pulmonary embolism and pulmonary hypertension or right ventricular dysfunction but without arterial hypotension or shock. The patients were randomly assigned in double-blind fashion to receive heparin plus 100 mg of alteplase or heparin plus placebo over a period of two hours. The primary end point was in-hospital death or clinical deterioration requiring an escalation of treatment, which was defined as catecholamine infusion, secondary thrombolysis, endotracheal intubation, cardio pulmonary resuscitation, or emergency surgical embolectomy or thrombus fragmentation by catheter
  86. 98. Thrombolytics in submassive P.E. <ul><li>Treatment with heparin plus placebo was associated with almost three times the risk of death or treatment escalation compared to the risk associated with heparin plus alteplase (P=0.006). No fatal bleeding or cerebral bleeding occurred in patients receiving heparin plus alteplase. </li></ul><ul><li>(NEJM 10-08-02) </li></ul>
  87. 100. Chart review by Anderson, % of hospitalized patients who received DVT prophylaxis <ul><li>Previous PE 68% </li></ul><ul><li>Old age 34% </li></ul><ul><li>Cancer 29% </li></ul><ul><li>Trauma 39% </li></ul><ul><li>Stroke 30% </li></ul><ul><li>AMI 40% </li></ul><ul><li>Ortopedic surg 39% </li></ul><ul><li>Previous DVT 36% </li></ul><ul><li>Prolonged Immobilization 39% </li></ul><ul><li>Obesity 37% </li></ul><ul><li>LE fracture 34% </li></ul><ul><li>Surgery 34% </li></ul><ul><li>CHF 41% </li></ul>
  88. 101. Q-11: 32 yr BM, 4 mo h/o progressive dyspnea on exertion. P/E High JVP, Large V waves in neck, Holosystolic M at L lower parasternal area. Mild ascitis and bilateral mild ankle edema. High resolution CT shows mosaic perfusion. FVC=83%, FEV1/FVC=75%, TLC=76%,RV=73%, DLCO=22% . ? DX <ul><li>1, IPF </li></ul><ul><li>2, Emphysema </li></ul><ul><li>3, Chronic thrombo-embolic disease </li></ul><ul><li>4, CHF </li></ul><ul><li>5, Cirrhosis of Liver </li></ul>
  89. 102. A-11=3
  90. 103. Q:1 A 63-year-old woman is scheduled to undergo a total knee replacement and needs prophylaxis for deep venous thrombosis. She has no previous history of increased bleeding or of a hypercoagulable state. She takes aspirin, 325 mg/d, for primary prevention of cardiovascular disease and wants to continue taking it; she does not want subcutaneous injections <ul><li>Which one of the following would you recommend for prophylaxis? </li></ul><ul><li>( A ) Aspirin ( B ) Full-dose intravenous heparin ( C ) Intermittent pneumatic compression ( D ) Warfarin ( E ) Elastic stockings </li></ul>
  91. 104. Q :1, Ans:D Warfarin is recommended for prophylaxis for deep venous thrombosis in patients undergoing total knee replacement. There are several regimens for starting prophylaxis in the perioperative period, including one tablet on the night before surgery, or starting with the first dose on the first day after surgery. The target INR is between 2 to 3. Although subcutaneous low-molecular-weight heparin in prophylactic doses is a reasonable alternative to warfarin in this setting, full-dose intravenous unfractionated heparin is not recommended. Total knee replacement surgery carries a risk of calf deep venous thrombosis of 40% to 80%, a risk for proximal deep venous thrombosis of 10% to 20%, a risk for clinical pulmonary embolism of 5% to 10%, and a risk for fatal pulmonary embolism of 1% to 5%. Aspirin is not effective for prophylaxis of deep venous thrombosis. The patient should stop taking aspirin 7 days before this procedure to reduce the risk of bleeding complications. Elastic stockings and pneumatic compression are additive for prophylaxis, but are not sufficient for effective prophylaxis in themselves.
  92. 105. Q;4, A 75-year-old man comes to the emergency department because of a 2-day history of a swollen and tender left calf following a 10-hour automobile trip. Ultrasonography confirms the presence of a deep venous thrombosis of the left calf extending to the popliteal region. The patient has an extensive smoking history, but his medical history is otherwise unremarkable. Physical examination is normal, and a stool specimen is negative for occult blood. The complete blood count, prothrombin time, activated partial thromboplastin time, and routine serum chemistry studies are normal. <ul><li>In addition to a thorough physical examination, which one of the following should be included in the evaluation of this patient? </li></ul><ul><li>(A) CXR </li></ul><ul><li>(B) Abdominal CAT scan </li></ul><ul><li>(C) PSA and Cystoscopy </li></ul><ul><li>(D) Serum CEA level </li></ul>
  93. 106. Q4,Ans=A. Deep venous thrombosis, particularly in an elderly patient, always raises concern about an underlying neoplasm. Although such patients may have an increased incidence of occult malignancy, several studies have demonstrated that an extensive search for a neoplasm rarely yields positive results. A neoplasm amenable to curative therapy is found even more rarely. Therefore, a nondirected and extensive evaluation of this patient for occult malignancy is very unlikely to identify a treatable neoplasm and is not cost effective. However, any clues obtained from the H & P (including a digital rectal examination) suggestive of a neoplasm should be pursued. In this patient, the extensive smoking history justifies a screening CXR despite the lack of symptoms. Since the patient has no other complaints or findings suggestive of an underlying neoplasm (weight loss, stools positive for occult blood, abdominal pain). Therefore, a more extensive evaluation is not indicated. Measurement of the serum carcinoembryonic antigen level may be useful in following the progression of colon cancer once a diagnosis and baseline CEA levels are established but is not sensitive or specific when used as a screening assay.
  94. 107. Q;5 , A 38-year-old man is receiving warfarin therapy for treatment of a deep venous thrombosis of the left leg that he developed 3 weeks ago. He comes for his scheduled prothrombin time INR determination. He denies gingival bleeding, hematuria, nosebleeds, or gastrointestinal disorders but reports a sore throat and fever that started about 1 week ago. He has not been able to swallow and has consequently been on a mostly clear liquid diet for the last week. On physical examination, his temperature is 38.0 °C (100.4 °F). His posterior pharynx is erythematous but without exudate. There are several scattered ecchymoses on the forearms and legs. The remainder of the examination is normal. The laboratory evaluation reveals a hematocrit of 41%; activated partial thromboplastin time of 37 s; and a prothrombin time INR of 6.0.
  95. 108. Q; 5 continued <ul><li>Which of the following is most appropriate for initial management of this patient’s elevated INR? </li></ul><ul><li>( A ) Transfuse two to four units of fresh frozen plasma ( B ) Stop warfarin; give vitamin K, orally ( C ) Stop warfarin; give vitamin K, intravenously ( D ) Stop warfarin; give vitamin K, intramuscularly ( E ) Stop warfarin </li></ul>
  96. 109. Q:5, A=B , This patient has a supratherapeutic INR. The ecchymoses are a minor bleeding complication, but he has a normal hemoglobin level and no evidence of more serious bleeding. The deep venous thrombosis of the left leg is relatively new, and he is at risk of further propagation of the clot if anticoagulation is not maintained. This patient therefore needs to have the warfarin effect lowered without fully reversing the anticoagulation. Vitamin K therapy will correct the INR without the risk associated with transfusing a blood product. Additional vitamin K overrides the warfarin blockade of the γ-carboxylation pathway and results in production of functional clotting factors within hours. The dose of vitamin K determines how much of the warfarin effect will be reversed. A dose of 5 mg of vitamin K will significantly reverse the anticoagulant effect of warfarin within 12 to 24 hours if the patient has good liver function. A 10-mg dose will usually block the warfarin effect completely and interfere with attempts to resume anticoagulation with warfarin. The risk of clotting versus the risk of bleeding determines how much vitamin K to give and how long to withhold the warfarin dose.
  97. 110. Q=5 A=B, continued For patients such as the one described, the dose of vitamin K should be low enough to allow resumption of anticoagulation with warfarin as soon as the INR has dropped into the therapeutic range. Studies have shown that vitamin K, 1 to 2 mg subcutaneously or 2.5 mg orally, will bring the INR into the therapeutic range without causing overcorrection. Low-dose vitamin K should decrease this patient’s INR without placing him at risk for another thrombosis. Fresh frozen plasma is the most rapid way to replace vitamin K clotting factors and reverse the anticoagulation. However, because of the infectious and allergic risks associated with blood products, fresh frozen plasma is only used to reverse warfarin if a patient has a serious bleeding complication or excessive risk of bleeding. Therefore, giving this patient fresh frozen plasma places him at greater long-term risk than the immediate risk imposed by the excessive anticoagulation. Intramuscular medications should not be given to patients with a coagulopathy because these patients have a high risk of developing an intramuscular hematoma. Furthermore, bleeding into the muscle will hamper attempts to resume anticoagulation for the underlying thrombosis. This patient's poor oral intake over the last several days will result in low vitamin K stores. Stopping the warfarin with no other therapy (that is, without replacing vitamin K) will result in a slow reversal of the anticoagulant effect and prolong the risk of bleeding.
  98. 111. Q:6, A 23-year-old otherwise healthy woman has a pulmonary embolism while hospitalized after a motor vehicle accident. She is 8 weeks pregnant. She has completed 1 day of therapy with unfractionated heparin. <ul><li>In addition to completing 5 to 7 days of intravenous administration of unfractionated heparin, which of the following is the next management option for this patient? </li></ul><ul><li>( A ) Unfractionated heparin ( B ) Low-molecular-weight heparin ( C ) Warfarin ( D ) Inferior vena cava filter ( E ) Compression stockings </li></ul>
  99. 112. Q;6, Ans:B <ul><li>Therapy with low-molecular-weight heparin is expensive but is appropriate in the management of deep venous thrombosis (DVT) and pulmonary embolism (PE) when other forms of therapy are ineffective or contraindicated. Low-molecular-weight heparin also has been used for outpatient management of uncomplicated DVT and PE. Intermittent administration of unfractionated heparin has been used for management of PE but has been rejected in recent years because of higher rates of bleeding and recurrent PE compared with continuous administration of heparin. Warfarin therapy is contraindicated during pregnancy because of its teratogenic and fetopathic properties. Insertion of an intravenous filter is not indicated without great risk of reoccurrence of the PE and the inability to use antithrombotic preventive measures. Compression stockings are not practical for patients with lower extremity fractures. </li></ul>
  100. 113. Q;7, A 24-year-old man is evaluated because of a swollen right calf. The calf has been swollen for 1 day. He had a deep venous thrombosis of the opposite leg when he was 17 years old, for which he took warfarin for 3 months. He has never smoked cigarettes. His father also had a deep venous thrombosis, but he is currently in good health. Physical examination shows a tender, swollen, right calf. Doppler studies confirm a deep venous thrombosis. <ul><li>Which of the following is the most likely risk factor for hypercoagulability in this patient? </li></ul><ul><li>( A ) Antiphospholipid antibodies ( B ) Occult malignancy ( C ) Paroxysmal nocturnal hemoglobinuria ( D ) Factor V Leiden mutation ( E ) Homocysteinemia </li></ul>
  101. 114. Q;7,Answer=D <ul><li>This patient requires an evaluation for hypercoagulability state because he has a recurrent thrombosis and because of his young age. The patient's history suggests a genetic cause of hypercoagulability. The most common inherited cause of hypercoagulability in white patients is factor V Leiden mutation, which leads to resistance to activated protein C. Approximately 5% of white patients have this mutation. There are many other inherited causes of hypercoagulability, including genetic deficiencies of protein C, protein S, and antithrombin III. This patient could have had an acquired cause of hypercoagulability, the most common of which is the antiphospholipid antibody syndrome, but this is rarely familial. </li></ul>
  102. 115. Hemorrhage occurs in up to 7 percent of patients during initial treatment; the risk is affected by the heparin dose, the patient's age, and concomitant use or nonuse of thrombolytic and antiplatelet agents. Long-term use of heparin (i.e., longer than one month) can cause osteoporosis. 26 , 27 , 28 Heparin-induced thrombocytopenia is immune-mediated and in 30 to 50 percent of cases is associated with venous or arterial thrombosis. 26 Patients with previous heparin-induced thrombocytopenia should receive alternative anticoagulant agents, such as danaparoid, lepirudin, or argatroban. 26 NEJM 7-15-04
  103. 116. Dalen, Chest, Nov 2002 Mortality of Untreated PE (Clinical Diagnosis) 30–35 Composite 30 1963 Morrell et al 6 35 1961 Hermann et al 5 32 1946 Zilliacus 4 18–25 1969 Coon et al 3 38 1960 Barritt and Jordan 2 Mortality, % Year Source
  104. 117. Dalen, Chest Nov 2002 When to Treat for VTE Diagnosis of DVT by venogram, compression ultrasound, or impedance plethysmography. Echocardiographic diagnosis of clot in main pulmonary artery, right pulmonary artery, or left pulmonary artery, and right ventricular dilatation. Echocardiographic diagnosis of intracardiac thrombus. Positive pulmonary angiogram, positive chest CT, or high probability     V / Q       scan.
  105. 118. Dalen, Chest Nov 2002 When to Withhold Therapy for Suspected PE   Normal chest CT finding   Indeterminate V/Q   scan, or   Normal compression ultrasound legs, or   Normal d-dimer, or Low clinical probability of PE plus: Normal pulmonary angiogram or normal perfusion scan findings
  106. 119. Treatment of VTE Columbus Investigators, 28 1997 Simonneau et al, 27 1997 Thery et al, 25 1992   For PE Hull et al, 21 1992; Prandoni et al, 26 1992 Holm et al, 20 1986   For DVT Low-molecular-weight heparin, subcutaneous None Greenfield et al, 19 1971 Embolectomy, catheter Decousos et al, 18 1998 Mobin-Uddin et al, 17 1969 IVC filter by catheter rt-PA trials, 23 24 1990–98 Bounameaux et al, 16 1985   rt-PA UPET, phase 2, 22 1974 Browse and James, 15 1964   Streptokinase UPET, 14 1973 Hansen et al, 13 1961   Urokinase Thrombolytic agents None Collins et al, 12 1943 IVC ligation Trial Study Group, 74 1995 Duration of anticoagulant Allen et al, 72 1947 Oral anticoagulants Barritt and Jordan, 2 1960 Murray and Best, 9 1938 Unfractionated heparin None Homans, 8 1934 Femoral vein ligation None Trendelenburg, 7 1908 Surgical embolectomy First Randomized Controlled Trial First Clinical Report Treatments
  107. 120. Dalen, Chest, Nov 2002 Incidence of Shock in Patients With PE Documented by Pulmonary Angiography 9.3 753 Totals 6 129 UKEP, 43 1987 10 313 Greenfield and Langham, 42 1984 13 144 Alpert et al, 40 1976 7 167 UPET, 22 1974 With Shock, % Patients, No. Source
  108. 121. Mortality of Angiographically Documented PE With Shock 35 193 Totals 33 rt-PA 24 Gulba et al, 45 1994 30 Catheter embolectomy 46 Greenfield et al, 39 1993 20 rt-PA 15 Diehl et al, 44 1992 42 Embolectomy 78 Meyer et al, 36 1991 32 Anticoagulation and/or IVC interruption 19 Alpert et al, 40 1976 18 Heparin, with or without urokinase 11 UPET, 14 1973, UPET, 22 Mortality, % Treatment no Source
  109. 122. Ximelagatran in VTE JAMA 2005; 293:681-89 <ul><li>Oral, Direct thrombin inhibitor, works rapidly therefore no need for IV therapy. No need to monitor INR </li></ul><ul><li>Compared to LMH + coumadin, it was safe and effective in preventing recurrent VTE over 6 months of therapy after VTE </li></ul><ul><li>10/1240 ACS vs 1/1249 </li></ul><ul><li>Elevated liver enzymes in 9.6% with Ximelagatran therapy </li></ul>

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