Updates in Diagnosis & Management of VTE

Updates in Diagnosis & Management of VTE Financial Disclosures-NONE TRACY MINICHIELLO, MD CHIEF, ANTICOAGULATION& THROMBOSIS SERVICE- SAN FRANCISCO VAMC PROFESSOR OF MEDICINE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO Objectives THESE SHOULD BE AT YOUR FINGERTIPS Approach to subsegmental PE, calf vein DVT and superficial vein thrombosis Determine duration of anticoagulation for VTE Review options for secondary prevention of VTE Manage anticoagulation in cancer patients Kearon et al. Chest. 2016;149(2):315-352. Doherty et al. JACC 2017 1

Volume 41, Issue 1, January 2016 Special Issue: Management of Venous Thromboembolism: Clinical Guidance from the Anticoagulation Forum Subsegmental PE A 77 yo man had undergoes colectomy for recurrent bleeding from diverticulosis. On POD # 3 he becomes tachycardic to the 110s. WBC is elevated.the surgical team orders an abdominal CT which shows a fluid collection concerning for early abscess. It also shows an isolated RLL subsegmental PE. A dedicated CTa shows a single isolated RLL subsegmenral PE. Do you anticoagulate this patient? a) Sure, it is a PE. b) No this is incidental. Let s pretend we don t know it is there c) Couldn t you start with an easy question? It is really early. Isolated Subsegmental PE Isolated Subsegmental PE Definition: PE shown on CT angiography that occurred in a subsegmental branch but no larger order of vessels. The subsegmental PE may involve one or more than one subsegmental branch Identification of ISSPE has tripled over past decade 2

Isolated Subsegmental PE Subsegmental PE IS IT REAL? ISSPE is more likely to be TRUE if.good quality scan, mult defects, centrally located, d-dimer elevated, seen on mult cuts, patient symptomatic vs incidental;high pretest prob of PE Get u/s of bilateral lower extrem (upper if CVC) Consider risk of recurrence-higher if not post op; immobile; active cancer IF high bleed risk don t AC: get serial u/s Kearon et al. Chest. 2016;149(2):315-352. A 77 yo man had undergoes colectomy for recurrent bleeding from diverticulosis. On POD # 3 he becomes tachycardic to the 110s. WBC is elevated.the surgical team orders an abdominal CT which shows a fluid collection concerning for early abscess. It also shows an isolated RLL subsegmental PE. A dedicated CTa shows a single isolated RLL subsegmenral PE. Do you anticoagulate this patient? a) Sure, it is a PE. b) No this is incidental. Lets pretend we don t know it is there c) Couldn t you start with an easy question? It is really early. Incidental PE Incidental PE in Cancer A 77 yo man is 2 weeks s/p laproscopic nephrectomy for renal cell CA. He received LMWH for 5 days post op but this was discontinued when he developed melena. An EGD showed a peptic ulcer. He has a staging CT which shows no disease but shows a RUL subsegmental pulmonary artery filling defect. Do you anticoagulated this patient? a) No, that did not go well last time b) Yes, it is a PE c) Easier questions remember?? 3

Incidental PE in Cancer Incidental PE LOCATION Proximal DVT or main, lobar segmental or multiple subsegmental PE ISSPE with proximal DVT ISSPE with distal DVT or no DVT RECOMMENDATION AC for at least 6 months AC for at least 6 months Case be case;consider risk of bleeding/ recurrent thrombosis, patient preference. If no anticoagulation serial U/S to detect thrombus A 77 yo man is 2 weeks s/p laproscopic nephrectomy for renal cell CA. He received LMWH for 5 days post op but this was discontinued when he developed melena. An EGD showed a peptic ulcer. He has a staging CT which shows no disease but does show a RUL subsegmental pulmonary artery filling defect. Do you anticoagulated this patient? a) No, that did not go well last time b) Yes, it is a PE c) Easier questions remember?? Calf Vein DVT A 37 year old man presents with right calf pain one week after being kicked in calf during a soccer game. On exam right calf is 2 cm> left. U/S shows DVT in the peroneal vein. What anticoagulation regimen do you recommend? 1. Rivaroxaban 15 mg BID x 21 days then 20 mg daily to complete 3 months of therapy 2. Prophylactic dosing of LMWH or DOAC 3. No anticoagulation, return in one week for repeat ultrasound of lower extremity. 4. Um, is that a deep vein? The guy sitting next to me wants to know. Also includes gastroc and soleus veins 4

Calf Vein DVT-CHEST 2016 Calf Vein DVT-CHEST 2016 AC Forum clinical guidance We suggest treatment of distal DVT with anticoagulation versus observation. We suggest a duration of therapy 3 months. Risk factors for extension: d-dimer +, extensive thrombosis close to proximal veins; active cancer, prior VTE, inpatient Kearon et al. Chest. 2016;149(2):315-352. Streiff MB et al. J Thromb Thrombolysis. 2016;41:32-67.. Calf Vein DVT Calf Vein DVT 1 st DVT, no cancer, outpatient only 6 weeks LMWH and GCS vs placebo and GCS U/S at 3-7 days and 42 days Outcome progression to proximal DVT or PE No difference in VTE, increased risk of bleeding Righini et al. Lancet Haematol 2016;3: e556 62 A 37 year old man presents with right calf pain on week after being kicked in calf during a soccer game. On exam right calf is 2 cm> left. U/S shows DVT in the peroneal vein. What anticoagulation regimen do you recommend? 1. Rivaroxaban 15 mg BID x 21 days then 20 mg daily to complete 3 months of therapy 2. Prophylactic dosing of LMWH or DOAC 3. No anticoagulation, return in one week for repeat ultrasound of lower extremity. 4. Um, is that a deep vein? The guy sitting next to me wants to know. 5

Superficial Vein Thrombosis Superficial Vein Thrombosis CHEST Guidelines A 55 year old woman presents with painful swelling over anterior left thigh. On exam she has a palpable cord concerning for SVT. She has an u/s which shows thrombosis of the greater saphenous vein extending from the calf proximally and terminating 6 cm from the deep femoral vein. What do you recommend? a. Prophylactic fondaparinux b. Prophylactic rivaroxaban c. Full dose DOAC or warfarin d. NSAIDS and ice Factors that favor the use of AC : extensive SVT; above the knee, close to saphenofemoral junction; severe symptoms; involvement of the greater saphenous vein; history of VTE or SVT; active cancer; recent surgery In patients with superficial vein thrombosis of the lower limb of at least 5 cm in length, we suggest the use of a prophylactic dose of fondaparinux or LMWH for 45 days over no anticoagulation (Grade 2B). Kearon C et al. Chest. 2012 CALISTO TRIAL- fonda vs placebo Primary outcome 1% vs 6% Superficial Vein Thrombosis Superficial Vein Thrombosis >400 pts symptomatic SVT riva 10 mg v fonda 2.5mg Symptomatic above the knee SVT of at least 5 cm length + other risk factor (>65, male,hx VTE, cancer, autoimmune disease, non-varicose veins) No difference in primary efficacy outcome After 6 weeks 7% recurrence risk in high risk patients (v 1.2% in CALISTO) Full dose anticoagulation for at LEAST 6 weeks 6

Superficial Vein Thrombosis Duration of Anticoagulation for VTE A 55 year old woman presents with painful palpable swelling over anterior left thigh. On exam she has a palpable cord concerning for SVT. She has an u/s which shows thrombosis of the greater saphenous vein extending from the calf proximally and terminating 2 cm from the deep femoral vein. What anticoagulant regimen do you recommend? a. Prophylactic fondaparinux b. Prophylactic rivaroxaban c. Full dose DOAC or warfarin d. Nsaids and ice A 57 year old man presents with unprovoked PE. He has no other PMHx. He is started on rivaroxaban. How long should he remain on anticoagulation? 1) One year 2) 6 months 3) 3 months 4) Indefinitely 5) At least until I sign out Risk of VTE Recurrence After Anticoagulation Is Stopped Risk of VTE Recurrence After AC Is Stopped Characteristic Recurrence at 1 y Recurrence at 5 y Major provoked (transient) Minor provoked (transient) 1% 3% 5% 15% Unprovoked 10% 30% Cancer 20% Major transient risk factors Major surgery, trauma Minor transient risk factors Pregnancy, minor surgery, longhaul air travel, immobilization Nontransient risk factors Active cancer, severe thrombophilia, inflammatory bowel disease Independent Predictors of VTE Recurrence 1,2 Increasing patient age Increasing BMI Male gender Active cancer Second episode of unprovoked VTE + D-dimer after stopping anticoagulation PE higher risk for recurrent PE Other Helpful Tools Age- and sex-adjusted D- dimer cutoff levels 3 Clinical prediction tools 4 DASH Vienna Men Continue and HER- DOO2 Kearon C et al. Blood. 2014;123(12):1794-1801. 2. Heit JA. Nat Rev Cardiol. 2015;12(8):464-474. 27 1. Kearon C et al. Blood. 2014;123:12. 2. Heit JA. Nat Rev Cardiol. 2015;12(8):464-474. 3. Palareti G et al. Int J Lab Hematol. 2016;38(1):42-49. 4. Kyrle PA et al. Thromb Haemost. 2012;108:1061-1064. 28 7

Duration of Anticoagulation for VTE: 2016 CHEST and AC Forum Guidelines/Guidance VTE and Bleeding Risk: 2016 CHEST Guideline Risk of Major Bleeding After 3 Mo of Anticoagulation, %/y Indication CHEST 2016 1 AC Forum 2016 2 1st provoked VTE 3 mo 3 mo (surgical) a 3 mo (medical) 1st unprovoked VTE Extended b Extended 2nd unprovoked VTE Extended b Extended VTE + cancer Extended b Extended a Unless risk factors for recurrence persist b No scheduled stop date, unless high bleeding risk. Kearon C et al. Chest. 2016;149(2):315-352. Streiff MB et al. J Thromb Thrombolysis. 2016;41:32-67. 29 Low (0 risk factors) Moderate (1 risk factor) High ( 2 risk factors) Baseline risk 0.3 0.6 2.5 Increased risk 0.5 1.0 4.0 Total risk 0.8 1.6 6.5 Risk Factors for Bleeding with Anticoagulation Age >65 y Age >75 y Previous bleeding Cancer Renal or hepatic failure Thrombocytopenia Previous stroke Diabetes Anemia Antiplatelet therapy Poor anticoagulation control Recent surgery Frequent falls Alcohol abuse NSAID use Reprinted from Chest, 149(2), Kearon C et al, Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report, 315-352, with permission from the American College of Chest Physicians. 30 Options for Secondary Prevention of VTE Agent Risk Reduction Regimen None 0% Full-dose anticoagulation 1-3 ~80-90% Low dose DOAC₂ ~80% Warfarin INR 2 3; maintenance dosing dabigatran, rivaroxaban, apixaban, edoxaban Apixaban 2.5 mg BID Rivaroxaban 10mg QD Low-intensity warfarin 3 75% Warfarin INR 1.5 1.9 ASA 4 32% 100 mg po daily CHEST 2016: In patients with an unprovoked proximal VTE who are stopping anticoagulant therapy and do not have a contraindication to ASA we suggest ASA..to prevent recurrent VTE 1. Agnelli G et al. N Engl J Med. 2013;368:699-708. 2. EINSTEIN INVESTIGATORS N Engl J Med 363;26 3. Kearon C et al. N Engl J Med. 2003;349:631-639. 4. Brighton TA et al. N Engl J Med. 2012;367:1979-1987. 31 8.8% 1.7% Agnelli etal NEJM 2013 8

Weitz et al. N Engl J Med March 2017 After 6-12 months of anticoagulation for VTE Provoked (~60%) or unprovoked (~40%) Clinical equipose about indefinite AC therapy One year follow up Weitz et al. N Engl J Med March 2017 Rivaroxaban 20 mg Rivaroxaban 10 mg All Provoked VTE Recurrent VTE BLEED 1.5% 1.4% 1.5% 3.3% 1.2% 0.9% 1.0% 2.4% ASA 81 mg 4.4% 3.6% 8.8% 2.0% ASA for Secondary VTE Prevention Duration of Anticoagulation for VTE ASA is not considered a reasonable alternative to anticoagulant therapy in patients who want extended duration therapy A 57 year old man presents with unprovoked PE. He has no other PMHx. He is started on rivaroxaban. How long should he remain on anticoagulation? 1) One year 2) 6 months 3) 3 months 4) Indefinitely 5) At least until I sign out 9

DOACS in Cancer 58 yo male presents to ED with chest pain and shortness of breath. CT reveals large bilateral PE. Vitals are stable. He has adenocarcinoma of the lung and is undergoing chemotherapy. Which of the following do you recommend for initial PE treatment? a. Enoxaparin b. IV UFH-> warfarin c. Enoxaparin-> dabigatran d. Rivaroxaban 15 mg BID x21 days then 20 mg daily DOACs and VTE in Cancer Vedovati et al CHEST 2016 Treatment of Cancer-related VTE In case control study rivaroxaban as effective in cancer v. non cancer patients for VTE Mult ongoing RCTs now CHEST 2016 VTE + cancer recommendations: 2 LMWH over VKA (Grade 2B) (DOAC or VKA okay patients not treated with LMWH) DOACS in Cancer 58 yo male presents to ED with chest pain and shortness of breath. CT reveals large bilateral PE. Vitals are stable. He has adenocarcinoma of the lung and is undergoing chemotherapy. Which of the following do you recommend for initial PE treatment? a. Enoxaparin b. IV UFH-> warfarin c. Enoxaparin-> dabigatran d. Rivaroxaban 15 mg BID x21 days then 20 mg daily Bott-Kitslaar Am J Med 2016. Kearon C et al. Chest. 2016. 39 10

Thrombocytopenia Cancer and VTE Our 58 yo man with new PE, adenoc CA of the lung undergoing chemo has a platelet count of 65 at initiation of low molecular weight heparin but he is on a downward trajectory as expected from chemo infused last week. On HD #3 his platelet count is 42K. You: 1) Stop enoxaparin 2) Switch to half dose enoxaparin 3) Switch to prophylactic enoxaparin 4) Transfuse with platelets 4) Go into an empty room and shout Why is it ALWAYS during my shift??? HIT O points O points O points O points Thrombocytopenia Cancer and VTE Thrombocytopenia Cancer and VTE Our 58 yo man with new PE, adenoc CA of the lung undergoing chemo has a platelet count of 65 at initiation of anticoagulation but he is on a downward trajectory as expected from chemo infused last week. On HD #3 his platelet count is 42K. You: 1) Stop enoxaparin 2) Switch to half dose enoxaparin 3) Switch to prophylactic enoxaparin 4) Transfuse with platelets 4) Go into an empty room and say Why is it ALWAYS during my shift??? 11

Pulmonary Embolism and Syncope Pulmonary Embolism and Syncope D-dimer and Wells ~40% ~40% PE identified in 17% of all patients, ~ 25% of those with no clear etiology More likely if tachycardia, tachypnea, signs DVT, prior VTE, cancer and no alternative explanation for syncope Get d-dimer and Wells in patients hospitalized for syncope? Incidental Rate of in all comers including those not admitted was < 4% Average age 76 Take Home Points ISSPE-1 st is it real? 2 nd is there a DVT? 3 rd is patient high risk? Duration of anticoagulation for VTE dictated by status of risk factors at time of event Low dose rivaroxaban or apixaban are options for secondary prevention of VTE in select patients Consider withholding anticoagulation and opting for follow up U/S in low risk calf vein thrombosis 6 weeks of low dose rivaroxaban is an option for treatment of SVTconsider longer duration if high risk Cancer associated VTE should be treated with LMWH-if parenteral therapy not an option DOAC or warfarin acceptable Thrombocytopenia in cancer patients with VTE should prompt adjustment in anticoagulation regimen or platelet transfusion Patients hospitalized for syncope should have pre-test probability of PE and d-dimer assessed. WORKSHOP IVC filters Incidental PE Does this patient need to be bridged? Thrombophilia work up Management of patient with recurrent VTE despite therapeutic anticoagulation PICC line thrombosis and more Heparin-induced thrombocytopenia 12