Antithrombotic Therapy for VTE: CHEST Guidelines 2016 Jennifer Mah, MD March 2016

Case A 44-year-old man is evaluated in follow-up for an episode of unprovoked left proximal leg deep venous thrombosis 3 months ago. Following initial anticoagulation with low- molecular-weight heparin, he began treatment with warfarin. INR testing done every 3 to 4 weeks has shown a stable therapeutic INR. He has mild left leg discomfort after a long day of standing, but it does not limit his activity level. He tolerates warfarin well. Family history is unremarkable, and he takes no other medications. Which of the following is the most appropriate management? Continue anticoagulation indefinitely Discontinue warfarin in another 3 months Discontinue warfarin now Discontinue warfarin and perform thrombophilia testing We will come back to this case at the end of the presentation. [MKSAP17 Heme/Onc question #9]

Objectives Recognize subgroups of VTE Review medications for VTE anticoagulation Learn guidelines for duration of therapy Understand differences in therapy based on type of VTE VTE = venous thromboembolism Recommendations are classified as strong (Grade 1) and weak (Grade 2) based on high- (Grade A), moderate- (Grade B), and low- (Grade C) quality evidence.

Subgroups of VTE Cancer-associated vs No cancer Provoked vs Unprovoked Proximal vs Distal DVT Upper extremity vs Lower extremity DVT VTE includes DVT and PE. This lecture will focus on DVT. We will go into each of these subgroups in more detail. For more information on PEs, please refer to the mini lectures “Pulmonary Embolism, Diagnosis” and “Treatment of Acute Pulmonary Embolism.” DVT = deep venous thrombosis

VTE and No Cancer Use NOAC – preferred! (Grade 2B) Rivaroxaban, apixaban No bridging needed Dabigatran, edoxaban Start with parenteral anticoagulation x5 days If contraindications to NOAC, then use VKA therapy (warfarin) (Grade 2C) Overlap with parenteral anticoagulation x5 days, And INR >2 for 24 hours Parenteral anticoagulants include: heparin gtt, enoxaparin, fondaparinux, bivalirudin, argatroban, etc. NOACs = new oral anticoagulants VKA = vitamin K antagonist

Contraindications to NOACs Extreme BMI (>40) CrCl <30 Significant increased risk of bleeding Remember, NOACs are nonreversible!

Cancer-Associated Thrombosis Use LMWH (Grade 2C) Enoxaparin 1 mg/kg/dose BID Think back to the CLOT trial. LMWH = low-molecular-weight heparin

Provoking Transient Risk Factors for VTE Surgery Estrogen therapy Pregnancy Leg injury Flight >8h

Location of VTE Lower extremity DVT Upper extremity DVT Proximal – Popliteal or more proximal veins Distal – Calf veins Upper extremity DVT Proximal – Axillary or more proximal veins Catheter-associated

Duration of Therapy Proximal DVT or PE Provoked 3 months Unprovoked (Grade 1B) Unprovoked Low bleeding risk Extended therapy (first VTE - Grade 2B, second VTE - Grade 1B) Mod bleeding risk Extended therapy (first VTE - Grade 2B, second VTE - Grade 2B) High bleeding risk 3 months (first VTE - Grade 1B, second VTE - Grade 2B) Isolated Distal DVT Mild symptoms or high bleeding risk Serial imaging x2 weeks (Grade 2C) Extending thrombus Anticoagulate (Grade 1B, 2C) Severe symptoms or risk for extension Anticoagulate (Grade 2C) Cancer-associated Extended therapy (Grade 1B) Upper extremity DVT - Bleeding risk: See next slides. - Extended therapy = long term anticoagulation with periodic (annual) reevaluation of risks/benefits For “Anticoagulate,” use the same anticoagulation tree as for patients with acute proximal DVT. (Grade 1B) Risk factors for extension of isolated distal DVT: See next slides. Basically, this will include anyone who develops distal DVT while inpatient.  Follow the arrow for special considerations for UE DVT therapy.

Special Considerations for Upper Extremity DVT Proximal Anticoagulate Catheter-associated Catheter functional? Catheter still needed? Leave catheter in and anticoagulate Remove and anticoagulate x3 months Yes No These recommendations are based on MKSAP and are not addressed in the CHEST guidelines. No Yes

Risk Factors for Bleeding on Anticoagulant Therapy Age >65 Anemia Age >75 Antiplatelet therapy Previous bleeding Poor anticoagulant control Cancer Comorbidity and reduced functional capacity Metastatic cancer Renal failure Recent surgery Liver failure Frequent falls Thrombocytopenia Alcohol abuse Previous stroke NSAID use Diabetes You might be tempted to use the HAS-BLED score. However it is used for assessing the risk of bleeding in atrial fibrillation management. Low risk 0 risk factors Moderate risk 1 risk factor High risk ≥2 risk factors

Risk Factors for Extension of Distal DVT Positive D-dimer Extensive thrombus >5cm long, involves multiple veins, >7mm diameter Thrombus close to proximal veins No reversible provoking factor Active cancer History of VTE Inpatient status

What if my patient stops anticoagulation? Aspirin is NOT a reasonable alternative to anticoagulation for extended therapy Much less effective at preventing recurrent VTE However, aspirin is better than nothing (Grade 2B)

Recurrent DVT on Anticoagulation If on therapeutic warfarin or NOAC, then switch to enoxaparin temporarily (minimum 1 month) (Grade 2C) Is this really recurrent VTE? Is my patient compliant with therapy? Is there underlying malignancy? If on enoxaparin and compliant, then increase the dose by 25-33% (Grade 2C) - While you are temporarily on lovenox, reassess the patient’s case with the above listed 3 points. - Current guidelines recommend against IVC filter in patients with acute DVT or PE who are treated with anticoagulants (Grade 1B).

Case Revisited A 44-year-old man is evaluated in follow-up for an episode of unprovoked left proximal leg deep venous thrombosis 3 months ago. Following initial anticoagulation with low- molecular-weight heparin, he began treatment with warfarin. INR testing done every 3 to 4 weeks has shown a stable therapeutic INR. He has mild left leg discomfort after a long day of standing, but it does not limit his activity level. He tolerates warfarin well. Family history is unremarkable, and he takes no other medications. Which of the following is the most appropriate management? Continue anticoagulation indefinitely Discontinue warfarin in another 3 months Discontinue warfarin now Discontinue warfarin and perform thrombophilia testing Also, do you agree with using warfarin for anticoagulation?

Duration of Therapy Proximal DVT or PE Provoked 3 months Unprovoked Low to moderate bleeding risk Extended therapy High bleeding risk Isolated Distal DVT Mild symptoms or high bleeding risk Serial imaging x2 weeks Extending thrombus Anticoagulate Severe symptoms or risk for extension Cancer-associated Upper extremity DVT

Case Revisited A 44-year-old man is evaluated in follow-up for an episode of unprovoked left proximal leg deep venous thrombosis 3 months ago. Following initial anticoagulation with low- molecular-weight heparin, he began treatment with warfarin. INR testing done every 3 to 4 weeks has shown a stable therapeutic INR. He has mild left leg discomfort after a long day of standing, but it does not limit his activity level. He tolerates warfarin well. Family history is unremarkable, and he takes no other medications. Which of the following is the most appropriate management? Continue anticoagulation indefinitely Discontinue warfarin in another 3 months Discontinue warfarin now Discontinue warfarin and perform thrombophilia testing This patient had an unprovoked DVT and has a low-bleeding risk. He should be placed on extended therapy, with reassessment every year. NOAC is actually preferred over warfarin.

Summary NOACs are preferred over warfarin for anticoagulation Except if VTE is cancer-associated, then use enoxaparin Duration of therapy is usually 3 months, with extended therapy based on risk factors for recurrent VTE

References Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy For VTE Disease: CHEST Guideline And Expert Panel Report. CHEST. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026. MKSAP 17