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Management of Venous Thromboembolism

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The latest guidelines for the management of venous thromboembolism. Includes introduction and management both.

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Management of Venous Thromboembolism

  1. 1. MANAGEMENT OF VENOUS THROMBOEMBOLISM Speaker: Abhishek Agrawal Moderator: Dr. Dharmendra Jain
  2. 2. Introduction Pulmonary Embolism and Deep Venous Thrombosis are a part of the larger entity ‘Venous Thromboembolism’. VTE = DVT + PE Pulmonary Embolism is known as The Great Masquerader.
  3. 3. Epidemiology Incidence of VTE is 1.5 per 1000 person years. Incidence of DVT is approximately twice as that of Pulmonary Embolism. Pulmonary embolism is the third most common cause of hospital-related death and the most common preventable cause of hospital-related death. About half the cases of VTE are idiopathic in nature. Lindblad B, Eriksson A, Bergqvist D: Autopsy-verified pulmonary embolism in a surgical department: Analysis of the period from 1951 to 1988. Br J Surg 1991;78(7):849-852. Braunwald 10th edition Braunwald 10th edition
  4. 4. Modifiable Risk Factors • Obesity • Metabolic syndrome • Cigarette smoking • Hypertension • Abnormal lipid profile • High consumption of red meat and • low consumption of fish, fruits, and • vegetables
  5. 5. Risk Factors • Advancing age • Arterial disease, including carotid and coronary disease • Personal or family history of venous thromboembolism • Recent surgery, trauma, or immobility, including stroke • Congestive heart failure • Chronic obstructive pulmonary disease • Acute infection • Air pollution • Long-haul air travel • Pregnancy, oral contraceptive pills, or postmenopausal hormone replacement therapy • Pacemaker, implantable cardiac defibrillator leads, or indwelling central • venous catheter • Hypercoagulable states • Factor V Leiden resulting in activated protein C resistance • Prothrombin gene mutation 20210 • Antithrombin deficiency • Protein C deficiency • Protein S deficiency Antiphospholipid antibody syndrome
  6. 6. DVT • Distal (calf vein) DVT • Most DVT starts in the calf. In surgical patients, thrombi often begin intraoperatively. In about half of patients, they resolve spontaneously within 72 hours, but in onesixth of patients they extend to involve the proximal veins.5 Isolated calf DVT is usually asymptomatic and does not commonly cause clinically significant PE. Proximal extension of thrombus is more common in patients with symptomatic (compared with asymptomatic) calf vein thrombus and occurs in a quarter of patients within 1 week of presentation.5 The presence of symptoms, and the extent of proximal progression are harbingers for an increased risk of PE. • Proximal (popliteal and thigh) DVT • Symptoms of DVT (pain, swelling, tenderness, and redness) generally do not develop until there is involvement of the proximal leg veins.5 Massive thrombosis can result in vascular compromise and venous gangrene. • About half of patients with symptomatic proximal DVT have clinically silent PE at the time of diagnosis,6 and 10% have symptomatic PE.7,8 The prevalence of PE increases with age, particularly above 70 years.7,8 • Without treatment, a quarter of proximal DVT will propagate during the first 30 days, onefifth regress, and the rest will remain unchanged.6 Without adequate treatment, half the patients will experience recurrent symptomatic VTE within 3 months.9 • With adequate treatment, regression of thrombus occurs during the first week, and recanalisation and resolution of thrombus occurs in about half the patients, generally within the first 3 months.10,11 Resolution of thrombus is less likely in patients with extensive initial thrombosis or cancer. In some cases, thrombus extends into previously unaffected vein segments despite adequate anticoagulation, but this is usually not associated with an increased risk of PE and is of uncertain clinical relevance.
  7. 7. Pathophysiology cont.. PE has the following pathophysiological effects:- Increased pulmonary vascular resistance Impaired gas exchange and hypoxemia Alveolar hyperventilation Increased airway resistance Decreased pulmonary compliance
  8. 8. Clinical Features • Most common symptom – Dyspnea • Most common sign – Tachycardia • Otherwise unexplained dyspnea • Chest pain, either pleuritic or “atypical” • Anxiety • Cough • Tachypnea • Tachycardia • Low-grade fever • Left parasternal lift • Tricuspid regurgitant murmur Accentuated P2 • Hemoptysis • Leg edema, erythema, tenderness SYMPTOMS SIGNS
  9. 9. PULOMONARY EMBOLISM MASSIVE PE SUBMASSIVE PE MILD PE i. Sustained hypotension (systolic blood pressure 90 mm Hg for at least 15 minutes or requiring inotropic support, not due to a cause other than PE ii. Pulselessness or iii. Persistent profound bradycardia (heart rate 40 bpm with signs or symptoms of shock). i. Without systemic hypotension (systolic blood pressure 􏰋90 mm Hg) ii. With either RV dysfunction or myocardial necrosis. Acute PE and the absence of the clinical markers of adverse prognosis that define massive or submassive PE. Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension - A Scientific Statement From the American Heart Association Troponin I > 0.9 ng/mL or troponin T > 0.1 ng/mL BNP > 90 pg/mL or pro-NT BNP > 500 pg/mL
  10. 10. Modified from Piazza G, Goldhaber SZ. Management of submassive pulmonary embolism. Circulation 2010;122:1124-9
  12. 12. Electrocardiogram
  13. 13. D-dimer  The sensitivity of the d-dimer is >80% for DVT (including isolated calf DVT) and >95% for PE.  A normal d-dimer is a useful “rule out” test. Other causes of raised D-dimer o Myocardial infarction o Pneumonia o Sepsis o Cancer o Postoperative state o Second and Third trimester of pregnancy.
  14. 14. CT ANGIOGRAPHY  The overall negative predictive value of a chest CT scan was 99.4%  The CT scan serves as a prognostic and diagnostic test .  Right ventricular enlargement on CT portends a complicated hospital course.  The chest CT scan can also detect other pulmonary diseases that are present in conjunction with PE or that explain a clinical presentation that mimics PE.
  15. 15. When reviewing results of CT, the clinician should look for the following: • Size, location, and extent of thrombus. • Other diagnoses that may coexist with PE or explain PE symptoms: • Pneumonia • Atelectasis • Pericardial effusion/Pneumothorax • Left ventricular enlargement • Pulmonary artery enlargement, suggestive of pulmonary hypertension • Age of thrombus: acute, subacute, chronic • Location of thrombus: pulmonary arteries, pelvic veins, deep leg veins, upper extremity veins • Right ventricular enlargement • Contour of the interventricular septum: whether it bulges toward the left ventricle, thus indicating right ventricular pressure overload Incidental masses or nodules in lung
  16. 16. Echocardiogram Right ventricular enlargement or hypokinesis, especially free wall hypokinesis, with sparing of the apex (the McConnell sign) Interventricular septal flattening and paradoxical motion toward the left ventricle, resulting in a D-shaped left ventricle in cross section Tricuspid regurgitation Pulmonary hypertension with a tricuspid regurgitant jet velocity >2.6 m/sec. Loss of respiratory-phasic collapse of the inferior vena cava with inspiration Dilated inferior vena cava without physiologic inspiratory collapse Direct visualization of thrombus (more likely with transesophageal echocardiography)
  17. 17. Venous Ultrasonography  DVT ----- loss of vein compressibility.  If PE is suspected, DVT can be considered a surrogate for PE.  At least half of patients with PE have no imaging evidence of DVT because the original thrombus may have completely embolised leaving no residue at the original site.  A negative result does not rule out the possibility of PE
  18. 18. Other Modalities  Ventilation Perfusion Scanning  Pulmonary Angiography  Contrast Venography
  19. 19. Differential Diagnosis  Anxiety  Pleurisy  Costochondritis  Pneumonia, bronchitis, asthma, COPD  Myocardial infarction  Pericarditis  Congestive heart failure  Idiopathic pulmonary hypertension
  20. 20. Clinical Decision Rules Low Clinical Likelihood of DVT if Point Score Is Zero or Less; Moderate Likelihood if Score Is 1 to 2; High Likelihood if Score Is 3 or Greater Clinical Variable DVT Score Active cancer 1 Paralysis, paresis, or recent cast 1 Bedridden for >3 days; major surgery <12 weeks 1 Tenderness along distribution of deep veins 1 Entire leg swelling 1 Unilateral calf swelling >3 cm 1 Pitting edema 1 Collateral superficial nonvaricose veins 1 Alternative diagnosis at least as likely as DVT –2
  21. 21. Wells Criteria for clinical likelihood of PE High Probability if >4 score points Clinical Variable PE Score Signs and symptoms of DVT 3.0 Alternative diagnosis less likely than PE 3.0 Heart rate >100/min 1.5 Immobilization >3 days or surgery within 4 weeks 1.5 Prior PE or DVT 1.5 Hemoptysis 1.0 Cancer 1.0
  22. 22. WELLS Criteria for likelihood of PE DVT - 3 Cancer - 1 Immobilization >3 days or surgery within 4 weeks - 1.5 Prior PE or DVT – 1.5 Tachycardia – 1.5 Diagnosis other than PE - 3 Hemoptysis - 1 High Probability if >4 score points Low Probability if <=4 score points
  23. 23. TREATMENT  Oxygenation  Hemodynamic stability  Anticoagulation  Fibrinolysis  IVC filter  Catheter Embolectomy  Surgical Embolectomy
  24. 24. Anticoagulation Heparin is the corner stone of anticoagulation. Heparin at its pentasaccharide sulfation sequence binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation through an increase in the flexibility of its reactive site loop. The activated AT then inactivates coagulation factors thrombin (factor IIa), Xa, IXa, XIa, and XIIa. Target the aPTT between 1.5 and 2.5 times the control value.The therapeutic range of aPTT is 60 to 80 seconds. shorter half-life of UFH is advantageous for patients who might require insertion of an inferior vena caval filter, thrombolysis, or embolectomy.
  25. 25. Low Molecular Weight Heparin LMWHs consist of short chains of polysaccharide (fragments of UFH). It also binds to AT-III to inhibit Factor Xa but it has no effect on Factor II (Thrombin) LMWH therapy is monitored by the anti-factor Xa assay, measuring anti-factor Xa activity.
  26. 26. Heparin and LMWH - MOA
  27. 27. Difference LMWH and UFH UFH LMWH Unpredicatable response  Significant protein binding  Saturable clearance mechanism  Inactivation by platelet factor 4 Predictable response  Less protein binding  Less inactivation by platelet factor 4 Less bioavailability More bioavailability Short half life Long half life Need of regular monitoring No need of regular monitoring Risk of HIT Less risk of HIT
  28. 28. LMWH  In a trial of 672 patients with VTE and cancer, those randomized to dalteparin monotherapy had a much lower VTE recurrence rate than did patients receiving dalteparin as a “bridge” to warfarin: 8.8% versus 17.4%. Lee AY, Levine MN, Baker RI, et al: Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146, 2003.
  29. 29. When monitoring needed in LMWH  The plasma anti-Xa level may be useful in five situations: (1) UFH anticoagulation with baseline elevated aPTT caused by a lupus anticoagulant or anticardiolipin antibodies (2) LMWH dosing in obese patients (3) LMWH dosing in patients with renal dysfunction (4) pregnancy (5) determination of the origin of an unexpected bleeding or clotting problem in patients receiving what appeared to be appropriate anticoagulant dosing.
  30. 30. FONDAPARINUX • Fondaparinux is an anticoagulant pentasaccharide that specifically inhibits activated factor X. By selectively binding to anti- thrombin, fondaparinux potentiates (about 300 times) the neutralization of factor Xa by antithrombin • Fixed-dose, once-daily subcutaneous injection, without the need for coagulation laboratory monitoring or dose adjust- ment.
  32. 32. • Uses:- ① The FDA has approved fondaparinux for initial treatment of acute PE and acute DVT as a bridge to oral anticoagulation with warfarin. ② Fondaparinux is often used off label for the management of suspected or proven heparin-induced thrombocytopenia89 (see later). ③ At times, fondaparinux is used off label as monotherapy without warfarin to treat VTE patients without cancer who cannot tolerate warfarin or who suffer recurrent VTE despite warfarin. The dose for VTE prophylaxis is a fixed low dose of 2.5 mg once daily, regardless of body weight.
  33. 33. WARFARIN • Warfarin is a vitamin K antagonist that prevents gamma- carboxylation activation of coagulation factors II, VII, IX, and X. • Half life of factor VII is 6 hours whereas half life of factor II is 5 days. • Its activity is measured by Prothrombin Time. • The full anticoagulant effect of warfarin may not be apparent for 5 to 7 days, even if the prothrombin time, used to monitor warfarin’s effect, becomes elevated more rapidly. • For VTE patients, the usual target INR range is between 2.0 and 3.0.
  34. 34. Warfarin - MOA
  35. 35. Overlap of Warfarin and LMWH • Warfarin monotherapy decreases the levels of two endogenous anticoagulants, proteins C and S, thus increasing thrombogenic potential. • Warfarin should be overlapped with LMWH to counteract the procoagulant state for at least 5 days, and preferably till the target INR is achieved 2 times 24 hours apart.
  36. 36. Starting dose • Warfarin is traditionally dosed by an “educated guess” coupled with trial and error. • One open-label, randomized trial compared two warfarin ini- tiation nomograms (5 mg versus 10 mg) in 50 patients with acute VTE.95 The median time to two consecutive target INRs was 5 days in both groups (P = 0.69). • Computer-assisted warfarin dosing can be used for better results. Quiroz R, Gerhard-Herman M, Kosowsky JM, et al: Comparison of a single end point to determine optimal initial warfarin dosing (5 mg versus 10 mg) for venous thromboembolism. Am J Cardiol 98:535, 2006.
  37. 37. Warfarin Interactions
  38. 38. Novel Anticoagulants • Immediate onset of action • Short half life • Administration in fixed doses without routine laboratory coagulation monitoring. • Few drug-drug or drug-food interactions • No bridging is needed with a parenteral anticoagulant when they have to be stopped for any diagnostic or surgical procedure.
  39. 39. Dabigatran • It is a direct thrombin inhibitor. • It has been proven noninferior to enoxaparin in three major orthopedic surgery trials of total knee or hip arthroplasty. • In a large-scale trial of acute VTE, dabigatran was noninferior to warfarin. Wolowacz SE, Roskell NS, Plumb JM, et al: Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis. Thromb Haemost 101:77, 2009.
  40. 40. Rivaroxaban • Rivaroxaban is a factor Xa inhibitor. • It has 80% bioavailability. • Half life is 5 to 9 hours. • It is approved for treatment of acute DVT and acute PE as monotherapy . • Its efficacy has proven superior to enoxaparin to prevent VTE after total knee and hip arthroplasty. • Both dabigatran and rivaroxaban are approved in Canada and Europe for VTE prevention after knee or hip arthroplasty. Eriksson BI, Borris LC, Friedman RJ, et al: Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 358:2765, 2008. Lassen MR, Ageno W, Borris LC, et al: Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 358:2776, 2008.
  41. 41. RIVAROXABAN APIXABAN EDOXABAN DABIGATRAN MODE Oral Oral Oral Oral MOA Xa inhibitor Xa inhibitor Xa inhibitor IIa inhibitor Dose VTE Prophylaxis 20 mg OD 2.5 mg BD - 110 mg on day 1 ➡️ 220mg OD Dose VTE Treatment 15 mg BD X 3wks ➡️ 20 mg OD 10 mg BD X 1wk ➡️ 5 mg BD 60 mg OD 150 mg BD Antidote ANDEXANAT ALFA ANDEXANAT ALFA ANDEXANAT ALFA IDARUCIZUMA B
  42. 42. Cancer and VTE – LMWH should be used as monotherapy Unprovoked PE/Proximal leg DVT - Anticoagulation for an indefinite duration with a target INR between 2 and 3. An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 1.5 and 2. Optimal Duration of Anticoagulation CLINICAL SETTING RECOMMENDATION First provoked PE/proximal leg DVT 3 to 6 months First provoked upper extremity DVT or isolated calf DVT 3 months Second provoked VTE Uncertain Second VTE Indefinite duration Cancer and VTE Consider indefinite duration or until cancer is resolved Unprovoked PE/Proximal leg DVT Consider indefinite duration First unprovoked calf DVT 3 months Second unprovoked calf DVT Uncertain
  43. 43. Recurrent VTE • Recurrent VTE has a high fatality rate, especially when it occurs despite ongoing anticoagulation within the first week of diagnosis.115 • Even after completion of a 6-month course of anticoagulation, the case fatality rate for recurrent PE remains high.116
  44. 44. D-dimer in Recurrent VTE • In the placebo group of the PREVENT trial, D-dimer was measured 7 weeks after discontinuation of warfarin in patients with unprovoked VTE.126 The subsequent recurrence rate was twice as high in those with elevated D-dimer levels. • However,an overview of 1888 patients who had unprovoked VTE showed that they had a high 3.5% annual risk of recurrence despite normal D-dimer levels after stopping of anticoagulation.127 Shrivastava S, Ridker PM, Glynn RJ, et al: D-dimer, factor VIII coagulant activity, low-intensity warfarin and the risk of recurrent venous thromboembolism. J Thromb Haemost 4:1208, 2006. Verhovsek M, Douketis JD, Yi Q, et al: Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med 149:481, W494, 2008.
  45. 45. • In a separate meta-analysis of patients with idiopathic VTE, those with normal D-dimer levels measured 1 month after discontinuation of oral anticoagulation had a clinically important 7.2% recurrence rate. • No guideline committee has endorsed the use of D-dimer levels to direct the optimal duration of anticoagulation. Bruinstroop E, Klok FA, Van De Ree MA, et al: Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism: A meta-analysis. J Thromb Haemost 7:611, 2009.
  46. 46. FIBRINOLYSIS • Successful fibrinolysis reverses right heart failure and may result in a lower rate of death and recurrent PE by ① Dissolving much of the anatomically obstructing pulmonary arterial thrombus ② Preventing the continued release of serotonin and other neurohumoral factors that exacerbate pulmonary hypertension ③ Lysing much of the source of the thrombus in the pelvic or deep leg veins, thereby decreasing the likelihood of recurrent PE. • Wide window • Patients who receive thrombolysis up to 14 days after new symptoms or signs maintain an effective response.
  47. 47. Fibrinolytic Agents
  48. 48. Fibrinolytic Agents Fibrinolytic FDA Indication for PE Direct Plasminogen Activator Dosage Fibrin Specificity PAI Resistance Streptokinase Yes No 250 000-IU IV bolus followed by 100 000-IU/h infusion for 12– 24 h - - Urokinase Yes No 4400-IU/kg bolus, followed by 4400 IU 􏰋 kg􏰋1 􏰋 h􏰋1 for 12–24 h - - Alteplase Yes Yes 100-mg IV infusion over 2 h ++ ++ Reteplase No Yes Double 10-U IV bolus† 30 min apart + + Tenecteplase No Yes Weight-adjusted IV bolus over 5 s (30–50 mg with a 5-mg step every 10 kg from 􏰋60 to 􏰋 90 kg) +++ +++
  49. 49. Use of Heparin before and after Thrombolysis 1. Discontinue the continuous infusion of intravenous UFH as soon as the decision has been made to administer thrombolysis. 2. Proceed to order thrombolysis. Use the U.S. Food and Drug Administration–approved regimen of alteplase 100 mg as a continuous infusion during 2 hours. 3. Do not delay the thrombolysis infusion by obtaining an activated partial thromboplastin time (aPTT). 4. Infuse thrombolysis as soon as it becomes available. 5. At the conclusion of the 2-hour infusion, obtain a stat aPTT. 6. If the aPTT is 80 seconds or less (which is almost always the case), 7. resume UFH as a continuous infusion without a bolus. 8. If the aPTT exceeds 80 seconds, hold off from resuming heparin for 4 hours and repeat the aPTT. At this time, the aPTT has virtually always declined to <80 seconds. If this is the case, resume continuous infusion of intravenous UFH without a bolus.
  50. 50. Use of Heparin before and after Thrombolysis STOP IV UFH INFUSION Resume UFH as continous infusion APTT > 80 secAPTT < 80 sec (almost always) Obtain APTT after 2 hours of infusion Give ALTEPLASE 100 mg IV over 2 hour infusion Proceed to thrombolysis. Do not delay thrombolysis for obtaining APTT APTT will be < 80 sec Hold Heparin for 4 hours and repeat APTT
  51. 51. Fibrinolysis in Submassive PE • Death or hemodynamic collapse within 7 days of fibrinolysis is reduced by 56% of patients with submassive PE. • But risk of hemorrhagic stroke is 2% in firbrinolysed patients as compared with 0.2% in patients who only receive heparin. Reference
  52. 52. IVC FILTERS  Indications :- 1) Contraindication to anticoagulation 2) Complication to anticoagulants 3) Failure to achieve target INR inspite of anticoagulation 4) Free floating Ileo-femoral or IVC thrombus  2 types 1) Permanent 2) Retrievable
  53. 53. Normal Venogram Various types of IVC filters
  54. 54. Catheter Embolectomy 1) Thrombus fragmentation 2) Rheolytic thrombectomy 3) Suction thrombectomy 4) Rotational thrombectomyC 5) Conventional catheter-directed thrombolysis (CDT) 6) Pharmacomechanical thrombolysis (PMT).
  55. 55. Limitations 1. Poor maneuverability 2. Mechanical hemolysis 3. Macroembolization 4. Microembolization.
  56. 56. SURGICAL EMBOLECTOMY • Patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction in whom contraindications preclude thrombolysis. • Acute PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale. • Patients refractory to thrombolysis.
  57. 57. Prophylaxis for VTE • PE is the most preventable cause of in- hospital death. • Mechanical Measures – Reduce DVT risk by 60% • Intermittent pneumatic compression devices • Enhance endogenous fibrinolysis • Increase venous blood flow, and graduated compression stockings. • Graduated compression stockings Urbankova J, Quiroz R, Kucher N, et al: Intermittent pneumatic compression and deep vein thrombosis prevention. A meta-analysis in postoperative patients. Thromb Haemost 94:1181, 2005.
  58. 58. Unconventional Approach • VITAMIN E • In Women’s Health Study involving 39,876 women receiving 600 units of vitamin E • 21% reduction in VTE was seen • 44% reduction in patients having prior VTE. • 49% reduction in patients having Factor V Leiden mutation or the prothrombin gene mutation • Vitamin E may reduce VTE risk in women, especially those with a prior history of VTE or with a genetic predisposition. Glynn RJ, Ridker PM, Goldhaber SZ, et al: Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism: Report from the Women’s Health Study. Circulation 116:1497, 2007.
  59. 59. STATINS • In the JUPITER study, 17802 apparently healthy men and women with both low-density lipoprotein cholesterol levels of less than 130 mg/dL and hsCRP levels of 2.0 mg/dL or higher were given Rosuvastatin 20mg/day. • Symptomatic VTE was reduced by 43% in the Rosuvastatin group (P = 0.007). • Thus, Rosuvastatin appears to prevent VTE. Glynn RJ, Danielson E, Fonseca FA, et al: A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 360:1851, 2009.