VTE Guidelines: 2016 update Kelsey Van Gorkom, Pharm.D. PGY-2 Geriatric Specialty Pharmacy Resident, CAVHS AAHP Fall Seminar September 29th, 2016

Disclosures None

Objectives Review the changes to the CHEST guidelines for VTE treatment. Evaluate landmark trials leading to the approval of direct oral anticoagulants and use in VTE. Construct a treatment plan to include selection of the appropriate anticoagulant and treatment duration.

Abbreviations DOAC: direct oral anticoagulant VTE: venous thromboembolism DVT: deep vein thrombosis PE: pulmonary embolism PTS: post-thrombotic syndrome CDT: catheter directed thrombolysis LMWH: low molecular weight heparin UFH: unfractionated heparin

Proximal DVT Distal DVT Intro-VTE 3rd most common cause of cardiovascular morbidity and mortality Proximal DVT accounts for ~80% Typical treatment: anticoagulation therapy and compression stockings Enden, T et al. Lancet. 2012;379:31-38. Bashir R, et al. JAMA Intern Med. 2014;174(9):1494-1501. Image: S.Standring, ed. Overview of veins of the lower limb. In: Grays Anatomy, 39th ed, 2005, figure 110.5, page 1403, Elsevier Ltd.

Virchow’s Triad Hypercoagulability Stasis of blood flow Factor V Leiden Hyperhomocysteinemia Protein C/S def Antithrombin def Malignancy Estrogen therapy Pregnancy Atrial fibrillation Left ventricular dysfunction Bed rest Paralysis Venous obstruction Endothelial injury Atherosclerosis Vascular injury/trauma Abnormal or mechanical heart valve Indwelling vascular catheter

Post-thrombotic syndrome (PTS) Pain, swelling, heaviness, edema, ulcerations 20-50% of patients with proximal DVT Occurs with anticoagulation and compression stockings therapy Quality of life impairment Bashir R, et al. JAMA Intern Med. 2014;174(9):1494-1501.

Key changes in the 2016 VTE update DOACs are suggested over warfarin for initial and long-term treatment of VTE in patients without cancer (Grade 2B) Routine use of compression stockings is no longer recommended to prevent PTS (Grade 2B) Subsegmental pulmonary embolism Who should/should not receive therapy Kearon et al. CHEST. 2016;149(2):315-352.

Key changes in level of evidence Discouragement of IVC filter use in anticoagulated patients Evaluation of indefinite anticoagulant therapy after a first unprovoked VTE based on risk vs benefit Discouragement of thrombolytic therapy in PE patients who are not hypotensive and are not deteriorating on anticoagulation Kearon et al. CHEST. 2016;149(2):315-352.

DOACs vs. warfarin In patient with VTE and no cancer: Dabigatran, rivaroxaban, apixaban, or edoxaban over VKA (Grade 2B) Lower risk of bleeding Comparable recurrent VTE risk reduction 2010 Pradaxa 2011 Xarelto 2012 CHEST 9th ed 2012 Eliquis 2014 Edoxaban

Landmark trials Dabigatran Rivaroxaban Apixaban Edoxaban RE-COVER (2009) RE-COVER II (2014) Rivaroxaban EINSTEIN-DVT (2010) EINSTEIN-PE (2012) Apixaban AMPLIFY (2013) Edoxaban HOKUSAI-VTE (2013)

RE-COVER Randomized, double-blind, double dummy, non-inferiority trial Dabigatran 150mg BID or LMWH/warfarin with goal INR 2-3 Enrollment from 2006-2008, follow up ~6 months Primary endpoint (efficacy): recurrent VTE or VTE related death Secondary endpoints (safety): bleeding events, ACS Result: dabigatran noninferior to warfarin in recurrent VTE and related deaths and major bleeding Schulman S, et al. N Engl J Med. 2009;361(24):2342-2352.

RE-COVER: VTE or VTE- related death 2.4% in dabigatran group 2.1% in warfarin group HR 1.10 (95% CI 0.65 to 1.84) Schulman S, et al. N Engl J Med. 2009;361(24):2342-2352.

RE-COVER: Bleeding rates Major bleeding: 1.6% in dabigatran group 1.9% in warfarin group HR 0.82 (95% CI 0.45 to 1.48) Non-major bleeding: 5.6% in dabigatran group 8.8% in warfarin group HR 0.63 (95% CI 0.47-0.84) Schulman S, et al. N Engl J Med. 2009;361(24):2342-2352.

RE-COVER 2 Randomized, double blind, double dummy trial Dabigatran 150mg BID or LMWH/warfarin with goal INR 2-3 Enrollment from 2008-2010, ~6 month follow up Primary outcome: recurrent VTE and VTE related death Secondary outcomes (safety): major bleeding, clinically relevant nonmajor bleeding Higher incidence of GI bleeds, ACS in dabigatran group Results: dabigatran non-inferior to warfarin in VTE recurrence and related death and major bleeding Schulman S, et al. Circulation. 2014;129:764-772

RECOVER 2: VTE or VTE related death 2.3% in dabigatran group 2.2% in warfarin group HR 1.08 (95% CI 0.64 to 1.80) Schulman S et al. Circulation. 2014;129:764-772.

RECOVER 2: Bleeding rates Major bleeding: 1.2% in dabigatran group 1.7% in warfarin group HR 0.69 (95% CI 0.36 to 1.32) Any bleeding: 15.6% in dabigatran group 22.1% in warfarin group HR 0.67 (95% CI 0.56-0.81) Schulman S, et al. Circulation. 2014;129:764-772

Dabigatran Dosing (following 5-10 days parenteral anticoagulation) 150mg PO twice daily CrCl ≤30mL/min: no recommendations available CrCl <50mL with concomitant PGP inhibitors: avoid use Drug interactions: Dronedarone, ketoconazole, verapamil, amiodarone Use with caution in patients with CAD Dabigatran. Micromedex 2.0. Accessed August 20, 2016.

EINSTEIN-DVT Randomized, open-label, event-driven, noninferiority trial Rivaroxaban 15mg BID x 21 days, then 20mg daily vs LMWH/VKA Randomized, double-blind, event-drive superiority trial Rivaroxaban 20mg daily vs placebo for additional 6 or 12 months Enrollment from: 2007-2009 Primary endpoint (efficacy): recurrent VTE Secondary endpoint (safety): clinically relevant bleeding Results: rivaroxaban noninferior to LMWH/VKA in VTE recurrence and major bleeding Bauersachs R, et al. N Engl J Med. 2010;363(26):2499-2510

EINSTEIN DVT: VTE or VTE related death 2.1% in rivaroxaban group 3% in LMWH/VKA group HR 0.68 (95% CI 0.44-1.04) Bauersachs R, et al. N Engl J Med. 2010;363(26):2499-2510

EINSTEIN DVT: Bleeding rates 8.1% in rivaroxaban group 8.1% in LMWH/VKA group HR 0.97 (95% CI 0.76-1.22) Bauersachs R, et al. N Engl J Med. 2010;363(26):2499-2510

EINSTEIN-PE Randomized, open-label, event-drive, non-inferiority trial Rivaroxaban 15mg BID x21days vs LMWH/VKA Enrollment from 2007-2011 Primary outcome (efficacy): recurrent VTE Secondary outcome (safety): major or clinically relevant nonmajor bleeding Results: rivaroxaban noninferior to warfarin in VTE recurrence and superior in major bleeding Buller HR, et al. N Engl J Med. 2012;366(14):1287-1297

EINSTEIN PE: VTE 2.1% in rivaroxaban group 1.8% in LMWH/VKA group HR 1.12 (95% CI 0.75-1.68) Buller HR, et al. N Engl J Med. 2012;366(14):1287-1297

EINSTEIN PE: Bleeding rates 1.1% in rivaroxaban group 2.2% in LMWH/VKA group HR 0.49 (95% CI 0.31-0.79) Buller HR, et al. N Engl J Med. 2012;366(14):1287-1297

Rivaroxaban Dosing CrCl < 30ml/min: avoid use Drug interactions: 15mg BID x 21days, then 20mg daily Take with food to increase absorption CrCl < 30ml/min: avoid use Drug interactions: Dronedarone, ketoconazole, verapamil, amiodarone Rivaroxaban. Micromedex 2.0. Accessed August 20, 2016.

AMPLIFY Randomized, double-blind, noninferiority trial Apixaban 10mg BID x 7 days, then 5mg BID compared to SQ enoxaparin followed by warfarin 2008-2012 Primary endpoint (efficacy): recurrent VTE or death related to VTE Secondary endpoint (safety): major bleeding and major bleeding Result: apixaban noninferior for VTE recurrence, superior in major bleeding Agnelli G, et al. N Engl J Med. 2013;369(9):799-808

AMPLIFY: VTE or VTE-related death 2.3% in apixaban group 2.7% in warfarin RR 0.84 (95% CI 0.60 to 1.18) Agnelli G, et al. N Engl J Med. 2013;369(9):799-808

AMPLIFY: major bleeding 0.6% in apixaban group 1.8% in warfarin group RR 0.31 (95% CI -1.7 to -0.6) Agnelli G, et al. N Engl J Med. 2013;369(9):799-808

Apixaban Dosing Dose adjustments Drug interactions: 10mg twice daily x 7 days, then 5mg twice daily Dose adjustments No dose adjustments recommended SCr >2.5mg/dL or CrCl<25mL/min excluded from clinical trials Drug interactions: Clarithromycin, ketoconazole, ritonavir Apixaban. Micromedex 2.0. Accessed August 20, 2016.

HOKUSAI-VTE Randomized, double-blind, noninferiority trial Edoxaban 60mg daily vs edoxaban 30mg daily vs warfarin Enrollment from 2010-2012, 3 to 12 month follow up Primary outcome (efficacy): recurrent VTE Secondary outcome (safety): major or clinically relevant nonmajor bleeding Results: edoxaban noninferior to warfarin for VTE recurrence, superior to warfarin for major bleeding Buller HR, et al. N Engl J Med. 2013;365(15):1406-1415

HOKUSAI-VTE: VTE 3.2% in edoxaban group 3.5% in warfarin group HR 0.89 (95% CI 0.7 to 1.13) PE subgroup: 3.3% in edoxaban group 6.2% in warfarin group HR 0.52, (95%CI 0.28-0.98) Buller HR, et al. N Engl J Med. 2013;365(15):1406-1415

HOKUSAI VTE: Bleeding rates 8.5% in edoxaban group 10.3% in warfarin group HR 0.81 (95% CI 0.71 to 0.94) Buller HR, et al. N Engl J Med. 2013;365(15):1406-1415

Edoxaban Dosing Dose adjustments Drug interactions 60mg PO once daily following 5-10 days parenteral anticoagulation <60kg: 30 mg once daily Dose adjustments < 60kg: 30mg once daily CrCl 15-50 mL/min: 30mg once daily CrCl <15 mL/min: avoid use Drug interactions Use with specific PGP inhibitors: 30mg once daily Verapamil, quinidine, azithromycin, clarithromycin, erythromycin, itraconazole, ketoconazole Edoxaban. Micromedex 2.0. Accessed August 20, 2016.

Warfarin Place in therapy: VKA recommended over LMWH (Grade 2C) in patients without cancer who do not take a DOAC VKA recommended over LMWH (Grade 2C) Kearon et al. CHEST. 2016;149(2):315-352.

LMWH Place in therapy: Patients with VTE and cancer Recommend LMWH over VKA, DOACs (Grade 2C) Kearon et al. CHEST. 2016;149(2):315-352.

Aspirin Since AT9, 2 trials have compared ASA with placebo for prevention of recurrent VTE Place in therapy “In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE (Grade 2B).” Kearon et al. CHEST. 2016;149(2):315-352.

INSPIRE study Aspirin for the prevention of recurrent venous thromboembolism Randomized, double blind, placebo controlled trial 1224 patients Aspirin EC 100mg: 616 patients Placebo: 608 patients Primary outcome: recurrent VTE Secondary outcome: major bleeding Simes J, et al. Circulation. 2014;130:1062-1071.

INSPIRE Results Primary outcome: recurrent VTE Aspirin 5.1% Placebo 7.5% HR 0.58 (95% CI 0.40-0.84) Secondary outcome: major bleeding Aspirin 1.1% Placebo 0.7% HR 1.5 (95% CI 0.72-3.14) Simes J, et al. Circulation. 2014;130:1062-1071.

Preferred anticoagulant Notes Cancer LMWH Factor Preferred anticoagulant Notes Cancer LMWH Want to avoid parenteral therapy Rivaroxaban; apixaban VKA, edoxaban, dabigatran require initial parenteral anticoagulation Once daily therapy preferred Rivaroxaban; edoxaban; VKA Liver disease with coagulopathy DOACs CI if INR raised due to liver disease CrCl <30 mL/min VKA DOACs and LMWH CO with severe renal impairment CAD VKA; rivaroxaban; apixaban; edoxaban ACS more often with dabigatran than with VKA Hx GI bleeding; dyspepsia VKA; apixaban Dabigatran had high incidence of dyspepsia and GIB; rivaroxban and edoxaban may be associated with higher rate of GIB compared to VKA Kearon et al. CHEST. 2016;149(2):315-352.

Recurrent VTE VTE recurrence while on VKA, dabigatran, rivaroxaban, apixaban, or edoxaban Recommend treating with LMWH for at least 1 month (Grade 2C) Recurrent VTE on long-term LMWH Increase dose of LMWH by 25-33% (Grade 2C) Evaluate: Compliance Underlying malignancy True recurrence Kearon et al. CHEST. 2016;149(2):315-352.

1st deep vein thrombosis (DVT) with transient risk factor Indication Duration of Therapy 1st deep vein thrombosis (DVT) with transient risk factor 3 months (Grade 1B) 1st unprovoked DVT proximal Low to moderate bleed risk High bleed risk Chronic (2B) 3 months (1B) 1st unprovoked DVT distal 2nd unprovoked DVT Chronic(1B) 3 months (2B) Kearon C, et al. CHEST 2016; 149(2):315-352.. You J, et al. CHEST 2012; 133:531S-575S .

1st pulmonary embolism (PE) with transient risk factor 3 months (1B) Indication Duration of Therapy 1st pulmonary embolism (PE) with transient risk factor 3 months (1B) 1st unprovoked PE Low to moderate bleed risk High bleed risk Chronic (2B) 2nd unprovoked PE Chronic (1B) 3 months (2B) Kearon C, et al. CHEST 2016; 149(2):315-352.. You J, et al. CHEST 2012; 133:531S-575S .

Compression stockings “…we suggest not using compression stockings routinely to prevent PTS (Grade 2b)” 2014 RCT found that routine use did not reduce PTS May use for acute or chronic symptoms Previously recommended to use for 2 years following Kahn, et al. Lancet. 2014;383(9920):880-888. Kearon et al. CHEST. 2016;149(2):315-352.

Compression stockings to prevent post-thrombotic syndrome Multicenter, randomized, placebo-controlled trial Enrollment 2004 to 2010 Compression stockings: 410 patients Placebo: 396 patients Primary outcome: diagnosis of PTS at 6 months or later Compression stockings: 14.2% PTS Placebo: 12.7% PTS HR 1.13 (95% CI 0.73-1.76) Results: routine use of graduated compression stockings did NOT reduce PTS or have other important benefits Kahn SR, et al. Lancet. 2014;383(9920):880-8

Subsegmental PE Subsegmental PE : no involvement of more proximal pulmonary arteries Likely to have risen from a small DVT US to exclude proximal DVT “Whether the risk of progressive or recurrent VTE is high enough to justify anticoagulation in patients with subsegmental PE is uncertain.” Kearon et al. CHEST. 2016;149(2):315-352.

Subsegmental PE Low risk for recurrent VTE High risk for recurrent VTE Clincial surveillance over anticoagulation (Grade 2c) High risk for recurrent VTE Hospitalized/ reduced mobility Active cancer No reversible risk factor for VTE Anticoagulation over clinical surveillance (Grade 2c) Kearon et al. CHEST. 2016;149(2):315-352.

Acute PE Treat at home or early discharge recommended over standard discharge (Grade 2B) Low risk Clinically stable No recent bleeding No renal/hepatic impairment No severe thrombocytopenia Expected to be compliant Previously recommended early discharge over standard discharge Kearon et al. CHEST. 2016;149(2):315-352.

Systemic thrombolytic therapy “In most patients with acute PE not associated with hypotension, we recommend against systemically administered thrombolytic therapy (Grade 1B).” “In selected patients with acute PE who deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2C).” Cardiac biomarkers Vital signs Tissue perfusion Kearon et al. CHEST. 2016;149(2):315-352.

Fibrinolysis for patients with intermediate-risk PE Randomized, double-blind, placebo-controlled Tenecteplase and heparin or heparin alone Primary outcome: death or hemodynamic decompensation Secondary outcome: extracranial bleeding, ischemic or hemorrhagic stroke Results: Thrombolytic therapy prevented cardiovascular collapse but increased major bleeding “no convincing net benefit from thrombolytic therapy” Thrombolysis in patients who developed cardiovascular collapse after initially being treated with anticoagulant alone showed benefit Kearon et al. CHEST. 2016;149(2):315-352.

Catheter directed thrombolysis Localized delivery of thrombolytic agents directly into the thrombus Possibly more effective in achieving local resolution of the thrombus Reduces bleeding complications Various types of catheters used “For patients who require thrombolytic therapy and do not have a high risk of bleeding, the AT10 panel favored systemic thrombolytic therapy over CDT…higher quality of evidence to support systemic…” Enden, T et al. Lancet. 2012;379:31-38. Image: https://www.fairview.org/HealthLibrary/Article/41271

CDT for PE In patients with acute PE who are treated with a thrombolytic agent, we suggest systemic thrombolytic therapy using a peripheral vein over CDT (Grade 2C).” “In patients with acute PE associated with hypotension and who have (i) high bleeding risk, (ii) failed systemic thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (eg, within hours), if appropriate expertise and resources are available, we suggest catheter-assisted thrombus removal over no such intervention (Grade 2C).” Kearon et al. CHEST. 2016;149(2):315-352.

CDT CAVENT trial 2012 Bashir, et al. 2014 Open-label, randomized controlled trial (189 patients) CDT plus LMWH/VKA vs LMWH/ VKA Assessed venous patency and bleeding following DVT CDT reduced PTS, appears to be cost-effective Bashir, et al. 2014 Retrospective review (3649 patients) CDT associated with increase in transfusions, intracranial bleeds, PE, vena cava filter insertion Long term outcomes and PTS not reported Kearon et al. CHEST. 2016;149(2):315-352. Enden, T et al. Lancet. 2012;379:31-38. Bashir R, et al. JAMA Intern Med. 2014;174(9):1494-1501.

Patients most likely to benefit from CDT Iliofemoral DVT Symptoms for <14 days Good functional status Life expectancy ≥1 year Low risk of bleeding Kearon et al. CHEST. 2016;149(2):315-352.

Pulmonary Thromboembolectomy “In selected patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are identified by an experienced thromboendarterectomy team, we suggest pulmonary thromboendarterectomy over no pulmonary thromboendarterectomy (Grade 2C).” Kearon et al. CHEST. 2016;149(2):315-352.

IVC filter NOT recommended in combination with patients on anticoagulation (Grade 1B). Based on results of PREPIC2 trial IVC plus anticoagulation No reduction in recurrent PE Kearon C, et al. CHEST. 2016;149(2):315-353 Mismetti P et al. JAMA. 2015;313(16):1627-35.

Acknowledgements David Dillinger, Pharm.D., BCACP

Question Which of the following are not classified as an anticoagulant indicated in VTE? Apixaban Warfarin Edoxaban Clopidogrel

References Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. NEJM. 2009;361:2342-2352. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-72. Bauersachs R, Berkowitz S, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. NEJM.2010;363(26):2499- 2510. Doi:10.1056/NEJMoa1007903. Buller H, Prins M, Lensing A, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. NEJM.2012;366(14):1287-1297. Doi: 10.1056/NEJMoa1007903. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. NEJM. 2013;369:799-808 Buller HR, Decousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-15. Simes J, Becattini C, Agnelli G, et al. Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE Collaboration. Circulation. 2014;130:1062-1071. Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383(9920):880-888. Enden T, Haig Y, Klow NE, et al. Long-term outcome after additionalcatheter-directed thrombolysis versus standard treatment for acuteiliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet. 2012;379(9810):31-38. Bashir R, Zack CJ, Zhao H, Comerota AJ, Bove AA. Comparative outcomes of catheter-directed thrombolysis plus anticoagulation vs anticoagulation alone to treat lower-extremity proximal deep vein thrombosis. JAMA Intern Med. 2014;174(9):1494-1501.

Image: http://www.pharmacy-tech-resources.com/images/Questions.jpg