Treatment of VTE 2016 Significant Changes University of Oklahoma ACCP Recommendations Treatment of VTE 2016 Significant Changes John Blebea MD MBA Professor of Surgery Department of Surgery University of Oklahoma College of Medicine Tulsa, Oklahoma

Disclosures None

Deep Venous Thrombosis 2

Venous Gangrene

2

Acute Deep Venous Thrombosis Significant clinical problem 600,000 hosp / yr DVT mortality One year 21% PE mortality Three months 18% Deaths 50,000/yr 2

Mortality VTE kills 5X people annually than breast cancer1-4 In-hospital fatality rate of VTE is 12%1 Consider this point, when we compare the death rates for VTE and breast cancer, VTE may kill up to 4 to 5 times more people annually in the United States than breast cancer. In fact, it has been reported that PE is the cause of death in up to 200,000 patients per year in this country alone. In one study conducted by Anderson, et al., the case fatality rate associated with VTE was 12% amongst hospitalized patients. In another study conducted by Kiffin, et al. that followed the development of a PE in elderly patients, the one-year mortality rate was reported to be 39%. Correspondingly, the one-year mortality rate following DVT in elderly patients was 21%. These statistics tell us quite clearly that VTE is responsible for a significant number of deaths especially in our nation’s hospitals. What about other consequences of developing VTE? What about the patients that experience a DVT or PE, yet survive the initial episode? Anderson et al. Arch Intern Med. 1991. ACS. Breast cancer facts and figures. 2001. Kim V, Spandorfer J. Venous Thrombo Emerg. 2001;19:839-59 Bick RL. Drugs. 2000;60:575-95

Economics Cost to treat: $17,114 for a DVT and $18,521 for a PE1 Hospital LOS is > 2X for patients with DVT/PE than those with no VTE 2 ICU LOS is 10X greater for patients with DVT/ PE 1 1 Clagett GP. Incidence of DVT in General Surgical Patients. Chest 1995;113:108S. 2 Ollendorf DA, Vera-Llonch, Oster G. Cost of Venous Thromboembolism Following Major Orthopedic Surgery in Hospitalized Patients. American Journal of Health System Pharmacy 2002;59(18):1750-4. For the unconvinced customer, this slide offers some testimony to the fact that nosocomial pneumonias do cost hospitals. Use this slide as a setup for the report by noting the range of costs for NP. Most facilities will see their incremental cost fall right into that range, which helps verify the data’s validity.

Long-Term Complications Approximately 15 million Americans experience postphlebitic syndrome Symptoms of chronic swelling, pain, and ulceration Increased risk for recurrent VTE Total costs for DVT/PE/post-phlebitic syndrome $2.8-$4.8 billion / year I suspect that it isn’t surprising to you that developing VTE does have long-term health consequences. While VTE encompasses DVT and PE, we also should consider postphlebitic syndrome or PPS – a consequence of DVT. Postphlebitic syndrome, which is characterized by persistent leg pain, chronic swelling, and ulcerations, affects 15 million Americans – and is illustrated in this slide PPS predisposes the patient to recurrent DVT, which may be prevented if thrombosis prophylaxis is routinely and appropriately used and DVT treated effectively. What do we know about the need for prophylaxis of DVT, PE and PPS? What should be occurring in our hospitals and institutions as we treat and care for hospitalized medical patients with restricted mobility in order to prophylax against DVT, which may lead to PE? Bosker et al. http./www.thrombosis-consult.com/ConsensusReports.htm.2004 Geerts et al. Chest. 2001;119:132S-175S. Solucient, Caprini, “Economic Burden of Complications of DVT in the U.S.”, 2003DRG Costs : The DRG Handbook, Solucient.

Clinical Guidelines

Methodology Strength of Recommendations Strong (1) Benefits clearly outweigh risks Weak (2) Benefits closely balanced with risk Guyatt G et al. Chest 2012;141 (2)S:53S-70S

Methodology Quality of Evidence High (A) Randomized trials Moderate (B) Prospective, large series Low (C) Retrospective, single institutions Guyatt G et al. Chest 2012;141 (2)S:53S-70S

Treatment Recommendation Guideline 2. In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, we suggest dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonist (VKA) therapy. [GRADE -2; LEVEL OF EVIDENCE - B] Notes: Although often mistaken as a cosmetic problem, venous insufficiency can produce significant clinical problems for the patient Of the 25 million Americans with venous insufficiency, approximately 7 million exhibit serious symptoms such as edema, skin changes and venous ulcers It is estimated that in America, 72% of women and 42% of men will experience varicose veins by the time they reach their 60s; prevalence is highly correlated to age and gender Kearon C et al. Chest 2016 149(2):315-52

Treatment Recommendation Guideline 9. In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a low or moderate bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy. [GRADE -2; LEVEL OF EVIDENCE - B] 9. In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see text), we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and (ii) high bleeding risk (see text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 1B). Remarks: Patient sex and D-dimer level measured a month after stopping anticoagulant therapy may influence the decision to stop or extend anticoagulant therapy (see text). In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually). Kearon C et al. Chest 2016 149(2):315-52

Treatment Recommendation Guideline 13. In patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension, we suggest serial imaging of the deep veins for 2 weeks over anticoagulation. [GRADE -2; LEVEL OF EVIDENCE - C] Remarks: Patients at high risk for bleeding are more likely to benefit from serial imaging. Patients who place a high value on avoiding the inconvenience of repeat imaging and a low value on the inconvenience of treatment and on the potential for bleeding are likely to choose initial anticoagulation over serial imaging. Kearon C et al. Chest 2016 149(2):315-52

Treatment Recommendation Guideline 18. In patients with acute DVT of the leg, we suggest not using compression stockings routinely to prevent PTS. [GRADE -2; LEVEL OF EVIDENCE - B] Remarks: This recommendation focuses on prevention of the chronic complication of PTS and not on the treatment of symptoms. For patients with acute or chronic symptoms, a trial of graduated compression stockings is often justified. Kearon C et al. Chest 2016 149(2):315-52

Treatment Recommendation Guideline 21. In patients with acute PE associated with hypotension (eg, systolic BP <90 mm Hg) who do not have a high bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy. [GRADE -2; LEVEL OF EVIDENCE - B] Kearon C et al. Chest 2016 149(2):315-52

Treatment Recommendation Guideline 22. In most patients with acute PE not associated with hypotension, we recommend against systemically administered thrombolytic therapy. [GRADE -1; LEVEL OF EVIDENCE - B] Kearon C et al. Chest 2016 149(2):315-52

Treatment Recommendation Guideline 27. In patients with acute upper extremity DVT (UEDVT) that involves the axillary or more proximal veins, we suggest anticoagulant therapy alone over thrombolysis [GRADE -2; LEVEL OF EVIDENCE - C] patients with acute upper extremity DVT (UEDVT) that involves the axillary or more proximal veins, we suggest anticoagulant therapy alone over thrombolysis Kearon C et al. Chest 2016 149(2):315-52

Treatment Recommendation Guideline 24. In most patients with acute PE who are treated with a thrombolytic agent, we suggest systemic thrombolytic therapy using a peripheral vein over CDT [GRADE -2; LEVEL OF EVIDENCE - C] Patients who have a higher risk of bleeding with systemic thrombolytic therapy and who have access to the expertise and resources required to do CDT are likely to choose CDT over systemic thrombolytic therapy. Kearon C et al. Chest 2016 149(2):315-52

New Drugs for DVT/PE 4 Novel Oral Anticoagulants As effective as warfarin (1954) Major benefits - less bleeding - ease of treatment / no injections - predictable bioavailability - fixed dose - no blood testing - no dietary restrictions - fewer drug interactions The most significant recent advance in the treatment of DVT has been the approval and availability of novel oral anticoagulants which have been demonstrated to be just as efficacious as warfarin. Their major benefits have been ease of treatment because they provide a fixed dose regimen, predictable bioavailability, no dietary restrictions, probably fewer drug interactions, less bleeding, and no need for routine blood testing.

Oral Thrombin Inhibitors Dabigatran (Pradaxa) Direct inhibitor Competitive reversible direct and reversible competitive thrombin inhibitor dabigatran (Pradaxa; Boehringer Ingelheim). Dabigatran was the first new oral anticoagulant approved by the Food and Drug Administration (FDA) in more than fifty years to reduce the risk of stroke and systemic embolization in patients with non-valvular atrial fibrillation. Anti-Thrombins

Prospective, randomized, blinded Non-inferiority trial 2,539 patients acute DVT After parenteral anticoagulation - dabigatran 150 mg bid, or - warfarin INR 2.0 -3.0 Duration 6 months The RE-COVER trial examined more than 2,500 patients with acute VTE treated with dabigatran compared to warfarin in a randomized, double-blind trial and found no inferiority of dabigatran and a lower rate of bleeding episodes. On August 28, 2013, the FDA accepted for review a supplemental new drug application from the manufacturer for use of dabigatran in patients with DVT and PE. Based on the results of the RE-COVER trial, and clinicians’ clinical experience for both atrial fibrillation and off-label use for DVT, FDA approval is expected next year. With a half-life of approximately 12 to 14 hours in those with normal renal function, it requires twice daily dosing. A meta-analysis of seven randomized trials suggested that dabigatran was associated with a small but statistically higher risk of myocardial infarction or acute coronary syndrome.

Equivalent efficacy prevention VTE DVT / PE The most significant recent advance in the treatment of DVT has been the approval and availability of novel oral anticoagulants which have been demonstrated to be just as efficacious as warfarin. Their major benefits have been ease of treatment because they provide a fixed dose regimen, predictable bioavailability, no dietary restrictions, probably fewer drug interactions, less bleeding, and no need for routine blood testing. Equivalent efficacy prevention VTE

Bleeding Less total bleeding The most significant recent advance in the treatment of DVT has been the approval and availability of novel oral anticoagulants which have been demonstrated to be just as efficacious as warfarin. Their major benefits have been ease of treatment because they provide a fixed dose regimen, predictable bioavailability, no dietary restrictions, probably fewer drug interactions, less bleeding, and no need for routine blood testing. Less total bleeding

Bleeding Events 134,000 Medicare over age 65 For the Factor Xa inhibitors, prothrombin complex concentrates have been suggested for emergency treatment. However, a possible antidote (Andexanet alfa molecule; Portola Pharmaceuticals), which resembles factor Xa, has had very good early results in healthy volunteers and plans are being made to launch a clinical pivotal study next year. A final consideration for these new drugs will be cost. The cost of therapy with dabigatran, for example, has been estimated to be 60 times higher than that of warfarin, even after including the cost for blood testing and doctor visits for warfarin dose adjustment. 134,000 Medicare over age 65 Treated for atrial fibrillation

Dabigatran trough (ng/ml) Large 5X differences in plasma levels Bleeding CVA/Embolization For the Factor Xa inhibitors, prothrombin complex concentrates have been suggested for emergency treatment. However, a possible antidote (Andexanet alfa molecule; Portola Pharmaceuticals), which resembles factor Xa, has had very good early results in healthy volunteers and plans are being made to launch a clinical pivotal study next year. A final consideration for these new drugs will be cost. The cost of therapy with dabigatran, for example, has been estimated to be 60 times higher than that of warfarin, even after including the cost for blood testing and doctor visits for warfarin dose adjustment. Dabigatran trough (ng/ml) Large 5X differences in plasma levels But monitoring not recommended by company Moore TJ 21-24.

Bleeding Events $650 million paid to settle 4,000 claims For the Factor Xa inhibitors, prothrombin complex concentrates have been suggested for emergency treatment. However, a possible antidote (Andexanet alfa molecule; Portola Pharmaceuticals), which resembles factor Xa, has had very good early results in healthy volunteers and plans are being made to launch a clinical pivotal study next year. A final consideration for these new drugs will be cost. The cost of therapy with dabigatran, for example, has been estimated to be 60 times higher than that of warfarin, even after including the cost for blood testing and doctor visits for warfarin dose adjustment. $650 million paid to settle 4,000 claims

Dabigatran Considerations - twice daily dose of 150mg in U.S. - initial 5-10 days parenteral anticoagulation - twice daily dose of 150mg in U.S. - t ½ 12-17 hours Increased major bleeding risk No specific antidote available - Trauma / emergency interventions - Prothrombin complex concentrate On August 28, 2013, the FDA accepted for review a supplemental new drug application from the manufacturer for use of dabigatran in patients with DVT and PE. Based on the results of the RE-COVER trial, and clinicians’ clinical experience for both atrial fibrillation and off-label use for DVT, FDA approval is expected next year. With a half-life of approximately 12 to 14 hours in those with normal renal function, it requires twice daily dosing. A meta-analysis of seven randomized trials suggested that dabigatran was associated with a small but statistically higher risk of myocardial infarction or acute coronary syndrome.

Idarucizumab Humanized IgG Fab antibody fragment directed against dabigatran; generated from mouse monoclonal antibody Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. Schiele F. Blood 2013 121: 3554-3562 N Engl J Med 373(6):511-520, 2015

Direct Xa Inhibitors Anti-Xa Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Anti-Xa Another new class of oral anticoagulants is the direct Factor Xa inhibitors, rivaroxaban (Xarelto; Bayer), apixaban (Eliquis; Bristol-Meyers-Squibb), and Edoxaban (Lixiana;Daiichi Sankyo).

Rivaroxaban (Xarelto) FDA approved - atrial fibrillation - prophylaxis hip/knee replacement - DVT treatment Once daily dosage - t ½ 5-9 hours Rapid onset of action - No initial parenteral anticoagulation needed - Twice daily dosage initially Rivaroxaban is FDA approved for prophylaxis in patients undergoing hip and knee replacement and for the treatment of both atrial fibrillation and DVT/PE. The EINSTEIN and AMPLIFY clinical studies compared more than 13,000 patients with confirmed symptomatic DVT and PE and found rivaroxaban to be non-inferior to the enoxaparin/warfarin combination treatment and with significantly less major bleeding. Due to its longer half-life, rivaroxaban is given once-daily after the initial three weeks of twice-daily therapy. Another advantage for this medication is that it was not found to cause platelet activation or aggregation in the presence heparin-induced antibodies in vitro, suggesting its potential use in patients with HIT

Randomized, open-label Non-inferiority trial 3,449 patients acute DVT Rivaroxaban - 15 mg bid x 3 weeks, then - 20 mg daily Enoxaparin 1 mg/kg bid x 5 days then warfarin INR 2.0 – 3.0 Duration - 12 months

Recurrent DVT / PE Non-inferior in prevention of VTE (Superiority p = 0.08)

Safety No increase in bleeding

Apixaban (Eliquis) Indications - Atrial fibrillation - Prophylaxis hip/knee replacement - FDA approval for DVT/PE on Aug 14, 2014 Dosage - No heparin bridging needed - 10mg BID x 7 days, then 5mg BID Half-life: 12 hours Apixaban is presently approved only for use in patients with atrial fibrillation but the manufacturer has submitted to the FDA a supplemental application for use in DVT prophylaxis in patients undergoing hip or knee replacement surgery. Edoxaban, which has been approved in Japan since 2011 for prophylaxis, has recently completed a successful phase III non-inferiority study for VTE and is expected to pursue approval for use in the United States

Randomized, double-blind Non-inferiority trial 5,395 patients acute DVT/PE Apixaban - 10 mg bid x 1 week, then - 5 mg bid Enoxaparin 1 mg/kg bid x 5 days then warfarin INR 2.0 – 3.0 Duration - 6 months

Recurrent DVT / PE Non-inferior in prevention of VTE (p < 0.001)

Bleeding Significantly less bleeding (p < 0.001)

Edoxaban (Savaysa) - Approved Jan 2015 for A fib, Rx DVT/PE - Parenteral anticoagulation 5-10 days - 60mg once daily t ½ 10-12 hours Apixaban is presently approved only for use in patients with atrial fibrillation but the manufacturer has submitted to the FDA a supplemental application for use in DVT prophylaxis in patients undergoing hip or knee replacement surgery. Edoxaban, which has been approved in Japan since 2011 for prophylaxis, has recently completed a successful phase III non-inferiority study for VTE and is expected to pursue approval for use in the United States

Edoxaban Non-inferior in prevention of VTE (p < 0.001) Non-inferior Apixaban is presently approved only for use in patients with atrial fibrillation but the manufacturer has submitted to the FDA a supplemental application for use in DVT prophylaxis in patients undergoing hip or knee replacement surgery. Edoxaban, which has been approved in Japan since 2011 for prophylaxis, has recently completed a successful phase III non-inferiority study for VTE and is expected to pursue approval for use in the United States Non-inferior in prevention of VTE (p < 0.001)

Edoxaban Significantly less bleeding (p < 0.005) P < 0.005 Apixaban is presently approved only for use in patients with atrial fibrillation but the manufacturer has submitted to the FDA a supplemental application for use in DVT prophylaxis in patients undergoing hip or knee replacement surgery. Edoxaban, which has been approved in Japan since 2011 for prophylaxis, has recently completed a successful phase III non-inferiority study for VTE and is expected to pursue approval for use in the United States Significantly less bleeding (p < 0.005)

Concerns Cost - 40 - 60x compared to warfarin Renal insufficiency - Cr Cl < 30 ml/min reduce dose by 1/2 - Cr Cl < 15 ml/min probably not use - Edoxaban > 95ml/min not use Compliance - Lose protection if miss one day No specific antidotes - Trauma / emergency interventions - Prothrombin complex concentrate For the Factor Xa inhibitors, prothrombin complex concentrates have been suggested for emergency treatment. However, a possible antidote (Andexanet alfa molecule; Portola Pharmaceuticals), which resembles factor Xa, has had very good early results in healthy volunteers and plans are being made to launch a clinical pivotal study next year. A final consideration for these new drugs will be cost. The cost of therapy with dabigatran, for example, has been estimated to be 60 times higher than that of warfarin, even after including the cost for blood testing and doctor visits for warfarin dose adjustment.

Antidote (Andexanet) Recombinant, inactivated factor Xa molecule that is a direct reversal agent Absorbs anti-Xa anticoagulant so native factor Xa available for hemostasis Drugs it can reverse: Apixaban, edoxaban, rivaroxaban For the Factor Xa inhibitors, prothrombin complex concentrates have been suggested for emergency treatment. However, a possible antidote (Andexanet alfa molecule; Portola Pharmaceuticals), which resembles factor Xa, has had very good early results in healthy volunteers and plans are being made to launch a clinical pivotal study next year. A final consideration for these new drugs will be cost. The cost of therapy with dabigatran, for example, has been estimated to be 60 times higher than that of warfarin, even after including the cost for blood testing and doctor visits for warfarin dose adjustment. Lu G. Nature Med 2013 19(4):446-53. Siegal D. NEJM 2015 373(25):2413-24.

Aripazine Synthetic D-arginine compound designed to bind to heparin, LMWH, new agents Double blind trial 80 healthy volunteers Whole blood clotting time Reversal 10min and persisted 24 hours Clinical trial status: Ongoing healthy volunteer study For the Factor Xa inhibitors, prothrombin complex concentrates have been suggested for emergency treatment. However, a possible antidote (Andexanet alfa molecule; Portola Pharmaceuticals), which resembles factor Xa, has had very good early results in healthy volunteers and plans are being made to launch a clinical pivotal study next year. A final consideration for these new drugs will be cost. The cost of therapy with dabigatran, for example, has been estimated to be 60 times higher than that of warfarin, even after including the cost for blood testing and doctor visits for warfarin dose adjustment. Ansell JE, NEJM November 5, 2014; DOI: 10.1056/NEJMc1411800

Conclusions ACCP updates continue to further define treatment recommendations Integrating use of DOACs Debatable recommendations based on low strength data Further clinical data required Only guidelines – patient care needs to consider individual patient needs and risks new drugs for the treatment of DVT are now available. For patients who have had difficulty maintaining therapeutic levels of anticoagulation while on warfarin, or in whom blood monitoring is problematic, rivaroxaban should be considered. A decrease in the cost of these agents, and the arrival of safe antidotes, will likely replace warfarin in the future.