PROFESSOR OF MEDICINE TEMPLE UNIVERSITY SCHOOL OF MEDICINE

Transcription

1 PRACTICAL APPROACH TO TREATMENT OF DVT JOSE MISSRI, M.D. PROFESSOR OF MEDICINE CHIEF OF CARDIOLOGY TEMPLE UNIVERSITY SCHOOL OF MEDICINE

2 DVT/PE: Magnitude of the Problem Death 60, ,00 Pulmonary Hypertension 22,000 2 PE 600,000 1 Post-Thrombotic Syndrome 800, ,4 Symptomatic DVT 2 million 1 Asymptomatic DVT 1. Hirsh J et al. Circulation. 1996; 93: Pengo V et al. N Engl J Med. 2004; 350: Brandjes DP et al. Lancet. 1997; 349: Kahn SR et al. J Gen Intern Med. 2000;15: Heit JA et al. Blood. 2005; 106:abstract 910.

3 Venous Thromboembolism b (VTE) It is estimated that 350, to 600, are afflicted by VTE each year. Also, it is estimated that at least 100,000 deaths each year are related to VTE. Pulmonary embolism affects over 1/3 of patients with DVT. The Surgeon General s Call to Action To Prevent DVT/PE 2008

4 Venous Thromboembolism (VTE) In actuality, some suggest the incidence is even higher as some studies suggest that up to half of all DVT s go undiagnosed due to the fact they produce only mild symptoms. Additionally, the diagnosis of PE (identified at time of autopsy) was missed in 50 to 61% of nursing home patients prior to their deaths. The Surgeon General s Call to Action To Prevent DVT/PE 2008

5 Incidence of VTE increases with age rate per 10 00,000 Incidence Ml Male patients t Female patients >80 Age, y Reprinted with permission from Anderson FA, et al. Arch Intern Med. 1991;151:933 8.

6 Post-Thrombotic Venous Reflux Disease Seen in 20-50% of patients t with acute DVT 1 Heart Foot Normal Vein Valve Open Valve Closed Dilated Vein Leaky Valve 1. Deep vein valves become damaged d by thrombus resulting in vein valve failure 2. Reflux or backward flow in the deep veins occurs 3. Pooling of blood causes pressure in leg veins Reproduced with permission of VNUS Medical Technologies, CA 1. Antithrombotic and Thrombolytic Therapy 8 th edition, ACCP Guidelines

7 Swollen, Ulcerated Leg: Post-Thrombotic Image courtesy of Michael Vasquez, MD

8 Who is at Risk?

9 Virchow s Triad: Dr. Rudolf Virchow ) Hypercoagulability 2) Venous Stasis 3) Endothelial Injury/Vessel wall injury

10 Hypercoagulability: Congenital Disorders Protein C &/or Protein S deficiency Factor V Leiden deficiency Antithrombin deficiency Prothrombin G20210A Polymorphism Hyperhomocysteinemia Dysfibrogenemia

11 Hypercoagulability: Acquired Disorders Smoking Pregnancy Oral contraceptives Hormone therapy Malignancy Diabetes Hyperlipidemia Obesity Hyperthyroidism Trauma Surgery Prolonged travel/immobility Nephrotic syndrome Heparin induced Thrombocytopenia Antiphospholipid syndrome Polycythemia Vera Sepsis/SIRS

12 Hypercoagulability: Pregnancy: Increases in factors I, VII, VIII, IX, X, XI Increased platelet count Decreased Protein S and Antithrombin Inhibition of fibrinolytic system by factors from placenta Increased venous stasis secondary to compression of pelvic veins by gravid uterus Segal, JA & Liem, TK. Congenital and Acquired Hypercoagulable Syndromes. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

13 Hypercoagulability: Pregnancy: Virchow s Triad: Risk of thrombosis during postpartum period is 5X greater than during pregnancy. It takes approximately 2 months after delivery for the coagulaiton and fibrinolytic systems to return to normal. Segal, JA & Liem, TK. Congenital and Acquired Hypercoagulable Syndromes. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

14 Hypercoagulability: Malignancy: VTE is a major complicating factor for cancer patients. 1 in 5 cancer patients experience thrombotic event Case controlled study: cancer patients are at 7 times greater risk than general population for VTE - greatest risk with hematologic cancers followed by lung and GI tract cancers. Community oncology April 2008

15 2 Hypercoagulability: Malignancy: Risk for VTE in cancer patients is greater if also has distant metastasis, Factor V Leiden or Prothrombin 20210A mutation. Chemotherapy increases risk for VTE by multiple mechanisms: toxicity on vascular endothelium, release of procoagulants from damaged cancer cells, suppression of natural anticoagulants and fibrinolytics Community oncology April 2008

16 Hypercoagulability: Malignancy: Are patients with non-invasive cancers at increased risk for VTE??? In a study on breast cancer patients, D-Dimer levels were found to be significantly higher in patients with invasive cancer compared with benign breast disease or non-invasive cancer. Community oncology April 2008

17 Venous Stasis: Varicose Veins: phlebitis can migrate to deep venous p g p system thus becoming a DVT.

18 Superficial Phlebitis: clotting of blood in superficial veins (varicose veins). This is not dangerous and typically a self limiting process. Patients are treated with NSAID s for pain control and anti-inflammatory inflammatory benefit. Also moist heat or ice packs may help with comfort.

19 Venous Stasis Migrating Phlebitis: although phlebitis is not dangerous and only requires symptomatic care, patients must be advised to monitor for evidence of propagation of clot up the thigh towards the groin. The patient may notice erythema and/or pain moving up the leg. In such a case venous Doppler's are repeated and if the clot has migrated towards the sapheno-femoral junction, the patient is treated as though + for DVT with systemic anticoagulation.

20 Venous Stasis: Long Haul Travel Economy class syndrome Velocity of venous blood decreases by 2/3 in the seated position (1950 s) 1 1. Ferrari E et al. Travel as a Risk Factor for Venous Thromboembolic Disease A Case-Control Study. Chest. 1999; 115 (2):

21 Venous Stasis the traveler The conclusion was that long duration air travel increased risk of VTE in travelers who had other risk factors for VTE already present. ** Immobility during the flight strongly increased the risk for pulmonary embolism in this group. The reality is immobility is a modifiable risk factor, and thus patients who have other risk factors for VTE should be encouraged to increase mobility during flight. Paganin F et. Al. Venous Thromboembolism in passengers following a 12 hour flight: a case-control study. Aviation Space & Environmental Medicine. 2003; 74 (12):

22 Venous Stasis the traveler How far do you have to go to be at risk? Records of all cases of patients being treated for PE after flying into France were reviewed ( ) Cases identified (from total of 135 million passengers) 2. Incidence of PE was 150 times greater if had flown more than 3100 miles compared to those who traveled shorter distances. 3. Doubling the distance to 6200 miles increased the risk for PE by 3 times compared to 3100 miles. Lapostolle F et al. Severe Pulmonary embolism associated with air travel. New Engl J Med. 2001; 345 (11)

23 Venous Stasis the traveler American College of Chest Physicians Recommendations Long Distance Travel: 1. Avoidance of constrictive clothing around the lower extremities or waist 2. Frequent calf muscle contraction 3. Maintain adequate hydration 4. Use of graduated compression stockings (15-30 mm Hg) 5. For those with other risk factors who are felt to be high risk, a single dose low molecular weight heparin injected prior to departure Antithrombotic and Thrombolytic Therapy 8 th edition, ACCP Guidelines

24 Endothelial Injury Minor Injuries as a Risk Factor for Venous Thrombosis Patients with first episode DVT/PE without recent surgery, cast immobilization, extended bed rest or malignancy, were screened for recent injury (within past 3 months) and presence of Factor V Leiden and Prothrombin 20210A mutation 2471 patients with VTE and 3534 controls 289 VTE pts with recent injury (11.7%) 154 control pts with recent injury (4.4%) Van Stralen KJ, Rosendaal FR, Doggen CJM. Minor Injuries as a Risk Factor for Venous Thrombosis. Arch Intern Med. 2008; 168 (1):

25 Endothelial Injury Minor Injuries as a Risk Factor for Venous Thrombosis Thrombosis was more strongly associated with injury within the past four weeks rather than less recent injury (thus risk from injury seems transient t and disappears by 10 weeks post-injury) 82% of the VTE patients had suffered leg injury, thus thrombosis was more strongly associated with leg injury rather than injury to other body part. (Not likely systemic manifestation of injury since injury to other body parts did not increase risk) Van Stralen KJ, Rosendaal FR, Doggen CJM. Minor Injuries as a Risk Factor for Venous Thrombosis. Arch Intern Med. 2008; 168 (1):

26 Endothelial Injury Partial rupture of muscles (sural muscle) and knee ligament injury were more strongly associated with VTE than were contusions or simple sprains. Risk of VTE was increased 50 fold in those who had injury and Factor V Leiden mutation Risk of VTE was increased 9 fold in those who had injury and Prothrombin 20210A mutation Van Stralen KJ, Rosendaal FR, Doggen CJM. Minor Injuries as a Risk Factor for Venous Thrombosis. Arch Intern Med. 2008; 168 (1):

27 Making the Diagnosis of DVT Timely diagnosis of DVT will help reduced morbidity associated with DVT Post Thrombotic Syndrome and also reduce risk of mortality of PE. Diagnosis of DVT on history and exam alone is not reliable, thus objective testing helps make the diagnosis. Warner WP. Diagnosis of Deep Vein Thrombosis. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

28 Making the Diagnosis of DVT Ascending Contrast Phlebography - gold standard Duplex ultrasonography - most common method at present both sensitive and specific for DVT especially femoral and popliteal vein DVT Radioactive fibrinogen scan & impedance plethysmography p y replaced by ultrasound Warner WP. Diagnosis of Deep Vein Thrombosis. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

29 Making the Diagnosis of DVT Magnetic Resonance Venography: study of choice for pelvic vein DVT. Also allows for evaluation of pelvic pathology such as a tumor compressing the iliac vein. CT Angiography: has become test of choice for PE CT Venography: some issues for diagnosis DVT not seen with MR Venography (difficulties with timing of contrast) Warner WP. Diagnosis of Deep Vein Thrombosis. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

30 Making the Diagnosis of DVT Utility of D-Dimer in the Diagnosis of DVT: D-Dimers are degradation products resulting from plasmin acting on fibrin. The presence of D-Dimer indicates initiation of blood clotting but many conditions other than DVT can give a positive D-Dimer Dimer test result. Thus a positive D-Dimer does not rule in DVT, but a negative test can help exclude the diagnosis. Warner WP. Diagnosis of Deep Vein Thrombosis. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

31 D-Dimer Dimer to predict recurrent VTE New England Journal, Oct 2006 Patients with 1 st episode of unprovoked DVT treated with VKA for at least 3 months D-Dimer was checked one month after anticoagulation was stopped If D-Dimer normal: no more anticoagulation If D-Dimer Dimer abnormal (36%) : patients were randomized no anticoagulation vs. resume treatment Palareti G., Cosmi B, legnani C. et al. D-Dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355:

32 D-Dimer Dimer to predict recurrent VTE Patients with abnormal D-Dimer 15% of those who stopped anticoagulation had recurrent VTE 3% of those who resumed anticoagulation had recurrent VTE Patients with normal D-Dimer 6% of these patients had recurrent VTE Palareti G., Cosmi B, legnani C. et al. D-Dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355:

33 D-Dimer Dimer to predict recurrent VTE Conclusion: Patients with abnormal D-Dimer one month after the discontinuation of anticoagulation have a significant incidence of recurrent venous thromboembolism, which is reduced by the resumption of anticoagulation. The optimal course of anticoagulation in patients with normal D-Dimer levels has not been clearly established. Palareti G., Cosmi B, legnani C. et al. D-Dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355:

34 Treatment of VTE The goals of treatment of VTE are to prevent post-thrombotic syndrome, to prevent recurrent VTE, and to prevent death from PE. 1) Intravenous/subcutaneous eous unfractionated ated heparin, low molecular-weight-heparin (LMWH), factor X inhibitors, with vitamin K antagonist (warfarin) ** Studies show 3 fold increase in recurrent VTE if VKA alone!! 2) Use of graduated d compression stockings 3) Early ambulation no bed rest Pineo GF, & Hull RD. Conventional Treatment of Deep Venous Thrombosis. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

35 Treatment of VTE Intravenous or subcutaneous unfractionated heparin: The anticoagulant response to a standard dose of heparin varies among gpatients. Thus must monitor response by following APTT. Goal APTT is 1.5 times the control Must achieve therapeutic APTT within 24 hours! Failure to do so is associated with 23% recurrence of VTE compared to 4-6% in those therapeutic within 24 hours!! Pineo GF, & Hull RD. Conventional Treatment of Deep Venous Thrombosis. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

36 Treatment of VTE Intravenous or subcutaneous unfractionated heparin: It can be difficult to achieve therapeutic APTT within 24 hours with subcutaneous heparin, thus risking recurrent VTE. Continue heparin until warfarin therapy results in INR is therapeutic for two consecutive days. Heparin does allow for reversal of anticoagulant effect by stopping infusion or use of protamine sulphate if patient requires interventions. Pineo GF, & Hull RD. Conventional Treatment of Deep Venous Thrombosis. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

37 Treatment of VTE Risks: Intravenous or subcutaneous unfractionated heparin: 1. Bleeding: stop infusion; protamine sulphate 2. Heparin Induced Thrombocytopenia (HIT): * Drop in platelet count by 50% *Pltlt Platelet count tfll falls out of normal range (usually less than 100,000) Warkentin TE. The Diagnosis and Treatment of Heparin Induced Thrombocytopenia. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

38 Treatment of VTE Heparin Induced Thrombocytopenia 1. Stop heparin in all forms 2. Send lab test for heparin antibodies 3. Alternative e form of anticoagulation: Argatroban: antithrombin Lepirudin: direct thrombin inhibitor Fondaparinux: inhibits factor Xa Warkentin TE. The Diagnosis and Treatment of Heparin Induced Thrombocytopenia. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

39 Treatment of VTE Low Molecular Weight Heparin: Prolonged half life and predictable clearance allows for dosing once or twice daily. Predictable antithrombotic response based on body weight allows dosing without laboratory monitoring. Less bleeding complications and less HIT than with heparin. (If has + history of HIT, can t use due to cross-reactivityreactivity between LMWH and heparins) Pineo GF, & Hull RD. Conventional Treatment of Deep Venous Thrombosis. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

40 Treatment of VTE Low Molecular Weight Heparin: Studies show LMWH at least as effective as heparin in preventing extension or increasing resolution of thrombus on follow up venography LMWH at least as effective and safe as heparin for treatment of proximal DVT as well as PE Less recurrent VTE and less bleeding when cancer patients with VTE are treated with LMWH for 3-6 months Pineo GF, & Hull RD. Conventional Treatment of Deep Venous Thrombosis. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

41 Treatment of VTE Factor Xa Inhibitor: Rivaroxaban (Xarelto) Indicated for DVT prophylaxis for hip fracture, hip/knee replacement, abdominal surgery Indicated for treatment of DVT Arixtra Prescribing Information. In: Physician s Desk Reference. 62 nd Edition. Montvale, NJ: Thomson Healthcare, 2008;

42 Treatment of VTE Oral Anticoagulants: Warfarin Inhibits vitamin K dependent factors II, VII, IX, X Also inhibits Protein C & S => paradoxical thrombogenic effect Initial changes in INR reflect inhibition of factor VII (short half life), other factors take nearly a week to equilibrate Should avoid green leafy vegetables (spinach, broccoli, cabbage) Contraindicated in pregnancy Pineo GF, & Hull RD. Conventional Treatment of Deep Venous Thrombosis. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

43 Treatment of VTE Oral Anticoagulants: Warfarin Goal INR 2-3 Lower INR ( ) 1 is associated with increased recurrence, embolic risk, but did not decrease risk of bleeding complications Duration of ftherapy for 1 st episode of idiopathic DVT is 3-6 months. Shorter durations of treatment (4-6 weeks) increases recurrence of VTE Pineo GF, & Hull RD. Conventional Treatment of Deep Venous Thrombosis. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

44 Treatment of VTE Vena Cava Filter: When is it indicated? Contraindication to anticoagulation Complication of anticoagulation Recurrent VTE despite therapeutic anticoagulation i History of PE with significant cardio- pulmonary compromise and dis not tfelt likely to tolerate another PE

45 Iliofemoral DVT Changing times = Changing treatments In the past the recommendation for treatment of DVT was Anticoagulation for all with: Calf DVT Femoral-popliteal DVT Iliofemoral DVT Reproduced with permission: Camerota AJ, Keynote address: American College of Phlebology, Nov 2008

46 Iliofemoral DVT Iliofemoral DVT represents a more aggressive thrombotic disorder than infra-inguinal ing inal DVT CT scans of Chest, abdomen, and pelvis are part of routine evaluation! Up to 50% can have asymptomatic PE Need to identify malignancy Need to identify asymptomatic PE (avoid confusion down the line if develops symptoms was this a treatment failure?) Reproduced with permission: Camerota AJ, Keynote address: American College of Phlebology, Nov 2008

47 Iliofemoral DVT CT scans of 16 patients with idiopathic Iliofemoral DVT 69% of patients found to have previously unrecognized cancer on CT scan!!!! Reproduced with permission: Camerota AJ, Keynote address: American College of Phlebology, Nov 2008

48 Iliofemoral DVT Iliofemoral DVT: Anticoagulation Alone After 5 years: 95% Develop Venous Insufficiency Nearly 50% with Venous Claudication 15% Venous Ulceration Markedly reduced d QOL Reproduced with permission: Camerota AJ, Keynote address: American College of Phlebology, Nov 2008

49 Iliofemoral DVT Risk of recurrence with anticoagulation alone: 1149 patients with DVT: Anticoagulated for treatment Recurrence at 3 months: Femoral Vein Thrombosis 5.1% Iliofemoral DVT 11.8% Risk of Recurrence with Iliofemoral DVT nearly equivalent to risk of recurrence of DVT in those with cancer! Reproduced with permission: Camerota AJ, Keynote address: American College of Phlebology, Nov 2008

50 Iliofemoral DVT 2008 American College of Chest Physicians Guidelines: Recommendations now include clot removal Most severe post-thrombotic thrombotic ti morbidity Higher risk of recurrence Reproduced with permission: Camerota AJ, Keynote address: American College of Phlebology, Nov 2008

51 Iliofemoral DVT Benefits of Clot Removal: Thrombolysis: preserves endothelial function and valve competence less residual thrombus than with anticoagulation successful lysis = relief of obstruction & preservation of valve function significant reduction in post-thrombotic morbidity! the greater the success of initial iti treatment, t t the less likely l thrombus will recur. Comorota AJ & Chahwan S. Thrombolytic Therapy for Acute Venous Thrombosis. In Bergan JJ (ed.) The Vein Book. Burlington, Elsevier 2007;

52 Iliofemoral DVT Now for Acute Iliofemoral DVT: Thrombus removal Catheter directed thrombolysis Risks: Major bleeding < 5% Intracranial bleeding rare (< 1%) Pulmonary embolism < 1% Reproduced with permission: Camerota AJ, Keynote address: American College of Phlebology, Nov 2008

53 Iliofemoral DVT Catheter directed thrombolysis Successful thrombolysis: Less post-thrombotic thrombotic symptoms Improve physical functioning Improved quality of life Must anticoagulate after thrombolysis for same duration and same goal linrt to prevent recurrent tthrombosis Lytic failures had same outcomes as those treated with anticoagulation alone. Reproduced with permission: Camerota AJ, Keynote address: American College of Phlebology, Nov 2008

54 Iliofemoral DVT Now for Acute Iliofemoral DVT: Thrombus removal Venous thrombectomy if not candidate for catheter directed thrombolysis: Improved patency Less swelling Fewer post-thrombotic symptoms Must anticoagulate after thrombectomy for same duration and same goal INR to prevent recurrent thrombosis Reproduced with permission: Camerota AJ, Keynote address: American College of Phlebology, Nov 2008

55 Iliofemoral DVT 2008 American College of Chest Physicians Recommendations: In patients with extensive proximal DVT and low risk for bleeding we suggest CDT may be used to reduce acute symptoms and post-thrombotic morbidity After CDT, we recommend the same intensity i and duration of anticoagulant therapy, as for patients who do not undergo CDT After successful CDT, we suggest correction of underlying venous lesions using angioplasty and stents Reproduced with permission: Camerota AJ, Keynote address: American College of Phlebology, Nov 2008

56 Chronic Venous Insufficiency: Compression in addition to anticoagulation for acute DVT: Adding mm Hg Stockings to anticoagulation decreases post-thrombotic th ti syndrome Continue use for at least 2 years Control Stocking Brandies 47% 21% Prandoni 49% 24% Reproduced with permission: Camerota AJ, Keynote address: American College of Phlebology, Nov 2008

57 Key Points 1) VTE is more common than we realize. As our population continues to age, the incidence of VTE is only expected to rise. 2) Despite the convenience of Low Molecular Weight Heparins and Factor Xa inhibitors, simple out patient treatment of DVT is not the best choice for all patients. 3) Patients who present with ilio-femoral DVT without an obvious inciting event (ie long haul travel, recent surgery), you must have high suspicion of underlying malignancy. Over half of these patients t will be found to have cancer once workup is initiated.

58 American College of Chest Physicians Recommendations Early ambulation is preferred to bed rest = quicker resolution of pain and swelling First episode of unprovoked distal DVT, VKA for 3 months Second episode of unprovoked VTE, long term anticoagulation Pts with DVT & cancer, 3-6 months of LMWH, then VKA indefinitely or until cancer resolved. Risk of recurrent VTE is unacceptably high in patients with active cancer that stop anticoagulation. Antithrombotic and Thrombolytic Therapy 8 th edition, ACCP Guidelines

59 American College of Chest Physicians Recommendations Goal range for INR is 2-3 for duration of treatment rather than high intensity range of (no decrease in recurrent VTE with higher INR) Treatment of incidentally noted, asymptomatic DVT is same as for those with symptomatic DVT Severe leg edema due to post-thrombotic syndrome => trial of intermittent pneumatic compression Upper extremity DVT associated with indwelling catheter, need not remove the catheter if it is functional and is still needed. If catheter is removed, still recommend at least 3 months VKA Antithrombotic and Thrombolytic Therapy 8 th edition, ACCP Guidelines

60 American College of Chest Physicians Recommendations No difference in recurrent VTE, bleeding, or mortality with LMWH dosed once vs. twice daily Patients with DVT and renal failure, unfractionated heparin is recommended over LMWH Once daily fondaparinux vs. twice daily enoxaparin: no difference in recurrent VTE, major bleeding, or death Extensive, acute proximal DVT with symptoms < 14 days,, with low risk of bleeding => catheter directed thrombolysis Antithrombotic and Thrombolytic Therapy 8 th edition, ACCP Guidelines

61 American College of Chest Physicians Recommendations DVT due to transient (reversible) risk factor, VKA for 3 months Surgery Cast Immobilization Estrogen Therapy Pregnancy Prolonged dtravel Hospitalization i Rivaroxaban: oral Factor Xa inhibitor for VTE prophylaxis in THR & TKR => less VTE than enoxaparin (both with low rates of bleeding complications) For additional recommendations, treatment of pulmonary embolism or DVT prophylaxis recommendations, please go to the American College of Chest Physicians web site. Chestjournal.org