Assessment of the Effect of Target Specific Oral Anticoagulants for Treatment of Venous Thromboembolism in Oncology Patients Good morning. My name is Elizabeth Weddendorf and I am a PGY1 Pharmacy Practice Resident at UNC Rex Hospital in Raleigh, NC. Today I will be presenting my research titled Assessment of the Effect of Target Specific Oral Anticoagulants for Treatment of Venous Thromboembolism in Oncology Patients Elizabeth Weddendorf, PharmD PGY1 Pharmacy Practice Resident UNC Rex Healthcare Raleigh, NC elizabeth.weddendorf@unchealth.unc.edu

Disclosure Statement Authors of this presentation have the following to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation. Resident Elizabeth C. Weddendorf, PharmD – nothing to disclose Co-Investigators Rebecca Jones, PharmD, BCPS – nothing to disclose Jeffrey Crane, MD – nothing to disclose W. Russell Laundon, PharmD, MS, BCPS – nothing to disclose Jared Peak, PharmD, BCACP, CPP – nothing to disclose Madison Sasser, PharmD, BCPS – nothing to disclose Wayne Smith, MD – nothing to disclose At this time, the authors of this presentation have nothing to disclose.

UNC Rex Healthcare 660 bed community, acute-care hospital Raleigh, NC Outpatient oncology clinics Wakefield Blue Ridge Lake Boone Trail Cary, NC Garner, NC This study was conducted at UNC Rex Healthcare. Participants received care at our community, acute care-hospital or one of our outpatient oncology clinics located in Raleigh, Cary, or Garner North Carolina.

Background Venous thromboembolism (VTE) is a frequent complication in patients with cancer Risk of VTE varies according to type of cancer Risk of recurrence after a first episode of VTE is higher in patients with cancer compared to those without cancer Type of Cancer Approximate Incidence (%) Ovarian, breast, lymphoma 10 Brain, colon, lung, pancreatic 20 We will begin by discussing some background information and the rational for conducting this study. Venous thromboembolism, or VTE, is a frequent complication occurring in patients with cancer. When compared to the general population, patients with cancer have a 4 to 7 fold higher risk of developing VTE. Approximately 1 out of every5 patients with cancer will have a deep vein thrombosis or pulmonary embolism during their lives. The risk for VTE varies according to the type of cancer, and some of the cancers that confer high risk of VTE are listed in this table. The risk of recurrence after a first episode of VTE is higher in oncology patients compared to non-oncology patients with an annual risk of recurrence up to 25%. Additionally, the incidence of VTE in cancer has been increasing over the past 10 years. Thromb Haemost.2002;87:1076-1077, Thromb Haemost.2002;87:575-579 Circulation.2003;107:I-17-I-2J, Clin Oncol. 2007; 25(1):70-761, Gynecol Oncol. 2007; 105(3):784-790

Background Evidence Based Guidelines Recommendation for Prevention of Recurrent VTE in Cancer American Society of Clinical Oncology (ASCO) Low molecular weight heparin (LMWH) preferred for 3-6 months after initial VTE event Vitamin K antagonists (VKAs) are considered an acceptable alternative if LMWH is not ideal National Cancer Comprehensive Network (NCCN) American College of Chest Physicians (ACCP) The high prevalence of VTE in patients with cancer makes them an important target population for anticoagulant therapy. Current evidence-based guidelines all recommend using low molecular weight heparin first line for the prevention of recurrent VTE in patients with cancer. If administration of low molecular weight heparin is not ideal, vitamin K antagonists are considered an acceptable alternative. However, low molecular weight heparin has been shown to be more efficacious than vitamin K antagonists with less bleeding. Two major clinical trials supporting these recommendations are the CLOT trial and CATCH trial which both found a statistically significant reduction of recurrent VTE with the use of low molecular weight heparin. Trial N Comparison Conclusion CLOT 676 Daltaparin vs warfarin Significant recurrent VTE with warfarin CATCH 900 Tinzaparin vs warfarin Significant reduction in symptomatic DVT with LMWH Ann Oncol. 2011 Sep;22 Suppl 6:vi85-92 ASCO. J Clin Oncol. 2013 Jun 10;31(17):2189-204 Lee AY, et al. JAMA. 2015;314:677-686 Lee AY, et al. NEJM. 2003;349:146-153

Patients with cancer with acute DVT and/or PE CLOT Trial Daltaparin n = 336 Patients with cancer with acute DVT and/or PE N = 676 6 months Daltaparin bridge to VKA (INR 2-3) n = 336 Primary Endpoint: recurrent VTE Secondary endpoint: morality, any bleeding Lee AY, et al. NEJM. 2003;349:146-153

Patients with cancer with acute DVT and/or PE CATCH Trial Tinzaparin n = 449 Patients with cancer with acute DVT and/or PE N = 900 6 months Tinzaparin bridge to VKA (INR 2-3) n = 451 Primary Endpoint: recurrent VTE Secondary endpoint: major bleeding, mortality Lee AY, et al. JAMA. 2015;314:677-686

Background LMWH Pros: stable PK and PD profile, few drug interactions Cons: daily subcutaneous injection for 3 to 6 months VKAs Pros: oral route of administration often preferred Cons: frequent monitoring, complicated dosing regimens, drug and food interactions, and difficulty maintaining therapeutic INR Next lets take a minute to compare and contrast the pros and cons of using low molecular weight heparin and vitamin K antagonists. Low molecular weigth heparin has stable pharmcokinetic and pharmacodynamic properties with few drug interactions. As mentioned previously, patients with cancer will be on anticoagulation therapy for at least 3 to 6 months after the initial VTE occurrence, and daily subcutaneous injections for this length of time may have a negative impact on the patient’s quality of life. For this reason the oral route of vitamin K antagonist may be preferred by some patients. This being said, vitamin K antagonist do require frequent drug monitoring, may have complicated dosing regimens, and have many drug and food interactions. Patients with cancer often have nausea, vomiting, and dietary complications that further complicate warfarin therapy which may result in subtherapeutic INRs. Ann Oncol. 2011 Sep;22 Suppl 6:vi85-92 ASCO. J Clin Oncol. 2013 Jun 10;31(17):2189-204

Background 2016 CHEST guidelines suggest target specific oral anticoagulants (TSOACs) over warfarin for treatment of acute DVT or PE in patients without cancer In patients with DVT or PE with cancer, LMWH is suggested over VKAs and TSOACs Trial Medication Cancer patients (%) RE-COVER Dabigatran vs. warfarin 5 EINSTEIN-DVT EINSTEIN-PE Rivaroxaban vs. enoxaparin + VKA 6.8 4.7 Hokusai-VTE Edoxaban vs. VKA 9.2 AMPLIFY Apixaban vs. enoxaparin + VKA 2.5 In 2016 the antithrombotic CHEST guidelines were updated and currently suggest target specific oral anticoagulants, or TSOACs, which include dabigatran, rivaroxaban, apixaban, and edoxaban, over warfarin for treatment of acute DVT or PE in patients without cancer (Grade 2B). Additionally, they still suggest using LMWH over VKAs (Grade 2B) and TSOACs (Grade 2C) in patients with cancer. This recommendation is based on the rational that the trials published evaluating efficacy and safety of the TSOACs for VTE included few patients with cancer. I have listed the clinical trials evaluating TSOACs for VTE in this table, and as you can all trials contained less than 10% of patients with cancer. N Engl J Med. 2009 Dec 10; 361(24):2342-52, N Engl J Med. 2010 Dec 23; 363(26):2499-510, N Engl J Med. 2012 Apr 5; 366(14):1287-97, N Engl J Med. 2013 Aug 29; 369(9):799-808, N Engl J Med. 2013 Oct 10; 369(15):1406-15, CHEST 2016; 149(2):315-352

Patients with acute VTE RE-COVER Trial dabigatran n = Patients with acute VTE N = 1274 6 months warfarin n = Primary Endpoint: recurrent symptomatic VTE and related deaths Secondary endpoint: acute bleeding events, ACS, other adverse events Dabigatran Warfarin Recurrent VTE 30/1274 (2.4%) 27/1265 (2.1%) Major Bleed 20/1274 (1.6%) 24/1274 (1.9%) Any Bleed 205/1274 (16.1%) 277/1274 (21.9%)

EINSTEIN-DVT and EINSTEIN-PE Rivaroxaban 15 mg BID x 21d, then 20 mg daily Patients with confirmed DVT without symptomatic PE N~ 2900 Patients with confirmed PE without symptomatic DVT N ~3300 30 days Enoxaparin bridge to VKA (INR 2-3) Primary Endpoint: first recurrent VTE Secondary endpoint: first major or non-major clinically relevant bleeding

Symptomatic DVT and/or PE Hokusai-VTE LMWH bridge + edoxaban 60 mg daily Symptomatic DVT and/or PE N = 8292 12 mo LMWH bridge + warfarin Primary Endpoint: symptomatic recurrent VTE and VTE related death Secondary endpoint: major or non-major clinically relevant bleeding during treatment

Symptomatic DVT and/or PE AMPLIFY apixaban 10 mg BID x 7d, then 5 mg BID Symptomatic DVT and/or PE N =4816 6 mo Enoxaparin bridge + warfarin (INR 2-3) Primary Endpoint: symptomatic recurrent VTE and VTE related death Secondary endpoint: bleeding

Background ASCO and NCCN guidelines currently do not recommend use of target specific oral anticoagulants (TSOACs) for treatment cancer-associated VTE TSOACs are an attractive option to treat VTE in oncology patients Oral administration Fixed-dose regimen without routine monitoring Fewer drug and food interactions Some physicians have started prescribing TSOACs for treatment of cancer-associated VTE Furthermore, both the ASCO and NCCN guidelines are in agreement with the 2016 CHEST guidelines and currently do not recommend the use of TSOACs for the prevention of recurrent VTE in patients with cancer. Given the burden of daily injections with LMWH, and the difficulties maintaining therapeutic INRs with warfarin, there is a need for a safe and efficacious alternative. This brings us to the TSOACs. With fewer drug and food interactions, and no monitoring requirements TSOACS an attractive option for treating VTE in within this patient population because they have the potential to simplify treatment and make it less burdensome for patients. At our institution, some physicians have started prescribing TSOACs for the treatment of cancer-associated VTE. Ann Oncol. 2011 Sep;22 Suppl 6:vi85-92 ASCO. J Clin Oncol. 2013 Jun 10;31(17):2189-204

TSOAC Drug Interactions

Purpose To evaluate the recurrence of VTE in oncology patients receiving TSOACs compared to those receiving LMWH This brings us to the purpose of this study which is to evaluate the recurrence of VTE in oncology patients receiving TSOACs compared to those receiving LMWH

Objectives Primary objective Secondary objective Rate of recurrence of VTE in patients taking a TSOAC compared to those receiving LMWH Secondary objective Rate of major bleed A bleeding event causing a decrease in hemoglobin ≥ 2 g/dL Any bleeding event requiring transfusion of 2 or more units of blood Any bleeding event occurring in a critical site (intracranial, intraspinal, intraocular, retroperitoneal or pericardial area) Any bleeding event contributing to patient death The primary objective is rate of recurrence of VTE in patients taking a TSOAC compared to those receiving low molecular weight heparin. The secondary objectives was rate of major bleed defined by the International Society on Thrombosis and Haemostasis (ISTH) Journal of Thrombosis and Haemostasis, 3: 692–694

Methodology Study Design IRB approved Single-center, retrospective, chart review cohort study Patients were identified using ICD-9 and ICD-10 codes This was a single center, IRB-approved, retrospective, chart review cohort study conducted within UNC Rex Healthcare. Patients were identified using ICD-9 and ICD-10 codes, and reports were generated from within the electronic medical record.

Methodology Inclusion criteria Exclusion criteria ≥ 18 years old Diagnosis of active cancer that confers high risk of VTE Ovarian, brain, pancreatic, colon, breast, uterine, lung, and lymphoma Diagnosis of current DVT and/or PE Taking treatment dose of apixaban, dabigatran, rivaroxaban, edoxaban or LMWH Treated at UNC Rex Hospital or outpatient oncology clinic between June 20, 2014 and December 1, 2016 Exclusion criteria < 18 years old Taking warfarin Pregnancy Current incarceration Patients were included in the study if they were adults with a concomitant diagnosis of cancer with high risk of VTE recurrence, which I have listed here, and a diagnosis of VTE, taking treatment dose of a TSOAC or LMWH, and were treated at UNC Rex Hospital or outpatient oncology clinic from the electronic medical record go live date. Patients were excluded if they were younger than 18 years, were taking warfarin, were pregnant, or incarcerated.

Statistics Analysis were conducted with SAS version 9.3 (Copyright © 2012 SAS Institute Inc.) Nominal variables were analyzed using a Chi-square test Series of odds ratios (ORs) and corresponding 95% confidence intervals were analyzed No adjustments were made for multiple comparisons All analysis were conducted using SAS version 9.3. Nominal variables were analyzed using a Chi-square test, and a series of odds ratios and corresponding 95% confidence intervals were analyzed and reported. Because this was a retrospective, hypothesis generating study, no adjustments for multiple comparisons were made.

Enrollment 230 patients assessed for eligibility 79 had orders for TSOAC 151 had orders for LMWH 14 patients excluded 8 cancer diagnosis not included 5 no active cancer diagnosis 1 incarceration 80 patients excluded 39 not treatment dose 16 no current VTE diagnosis 9 did not receive LMWH 8 taking warfarin 5 no active cancer diagnosis 3 cancer diagnosis not included There were 230 patients identified to be assessed for eligibility. 79 patients had orders for a TSOAC and 151 patients had orders for LMWH. The most common reason patients did not meet inclusion criteria were not receiving a treatment dose and not having a concomitant VTE and cancer diagnosis. This resulted in a total of 65 patients being included in the TSOCs analysis and 71 patients being included in the LMWH analysis 65 patients included in TSOAC analysis 71 patients included in LMWH analysis

Patient Characteristics All Patients   TSOAC (n = 65) LMWH (n = 71) Age – Mean (±SD) – year 64.5 (±12.9) 64 (±9.4) Female sex – no. (%) 41 (63.1) 40 (56.3) Male sex – no. (%) 24 (36.9) 31 (43.7) Weight – Mean - kg 81.2 78.8 Creatinine Clearance – no. (%) ≥ 50 ml/min 56 (86.2) 61 (85.9) 49 – 30 ml/min 7 (10.7) 9 (12.7) < 30 ml/min 2 (3.1) 1 (1.4) The characteristics between groups were similar. The average patient was a 64 year old female weighing approximately 80 kg with a CrCl greater than or equal to 50 ml/min.

Patient Characteristics All Patients   TSOAC (n = 65) LMWH (n = 71) Cancer Type – no. (%) Lung 16 (24.6) 25 (35.2) Breast 19 (29.3) 8 (11.3) Colon 12 (18.5) 9 (12.7) Pancreatic 6 (9.2) 15 (21.1) Ovarian 3 (4.6) 7 (9.9) Lymphoma 5 (7.7) 4 (5.6) Uterine 2 (2.8) Brain 1 (1.5) 1 (1.4) Chemotherapy Yes – no. (%) 33 (50.7) 36 (50.7) This table demonstrates the type of cancer for each group. Patients with lung, pancreatic, and ovarian cancer had a higher percentage receiving LMWH where as patients with the other types of cancer were more likely to receive a TSOAC. The percent of patients receiving chemotherapy was the same for both groups.

Patient Characteristics All Patients   TSOAC (n = 65) LMWH (n = 71) Anticoagulant – no. (%) enoxaparin 71 (100) edoxaban 1 (1.5) dabigatran 6 (9.2) rivaroxaban 49 (75.4) apixaban 9 (13.9) This table demonstrates the breakdown of anticoagulant received. All patients in the LMWH received enoxaparin. In the TSOAC group, the majority of patients received rivaroxaban, followed by apixaban, then dabigatran, and only one patient received edoxaban.

Results Outcome All Patients TSOAC (n = 65) LMWH (n = 71)   TSOAC (n = 65) LMWH (n = 71) Overall P-value Odds Ratio (95% CI) Primary efficacy outcome: recurrent VTE No. (%) 4 (6.2) 7 (9.9) p = 0.4286 0.60 (0.17 – 2.15) Secondary safety outcome: major bleed 5 (7.7) 12 (16.9) p = 0.1048 0.41 (0.14 – 1.24) For the primary outcome of recurrent VTE: 6.2% patients who received a TSOAC experienced a recurrent VTE compared to 9.9% patients in the LMWH. This was not found to be a statistically significant difference. For the secondary outcome of major bleed: 7.7% patients in the TSOAC group experienced a major bleed whereas 16.9% patients in the LMWH group experienced a major bleed. This was not found to be a statistically significant difference, either

Discussion Incidence of recurrent VTE was not statistically significant in the TSOAC group compared to current standard of care with LMWH There were more occurrences of major bleed observed in the LMWH group, but this was not found to be statistically significant Limitations Retrospective Coding errors Incomplete medical records Propensity for type 2 error Selection bias In this study the incidence of recurrent VTE was not statistically significant in the TSOAC group compared to the current standard of care with LMWH. Although there were also more occurrences of major bleed observed in the LMWH group compared to the TSOAC group, this finding was not found to be statistically significant, either. There are some limitations that should be considered when interpreting the results of this study including the retrospective design, incomplete medical records, and the possibility of coding errors. Additionally, due to the limited sample size of this study, a power calculation was not performed, and thus there is the propensity for type II error. When evaluating these results one should also consider the possibility of a selection bias. Since use of TSOACs is not considered current standard of care, it is possible there are additional confounding factors for the patients in which physicians chose to prescribe these medications.

Discussion These results suggest TSOACs may be a reasonable option for the treatment of VTE in some patients with cancer Due to the retrospective design and limited sample size of this study, further studies are needed on the topic In conclusion, these results suggest that TSOACs may be a reasonable option for the treatment of VTE in some patients with cancer. However, due to the retrospective design, and the limited sample size of this study, larger randomized control trials are needed on the topic.

Self Assessment Question Is the use of target specific oral anticoagulants efficacious for the treatment of venous thromboembolism within this patient population? Based on the results of this study, the use of target specific oral anticoagulants appear to be efficacious for the treatment of VTE within this patient population Now for the self assessment question: Is the use of target specific oral anticoagulants efficacious for the treatment of venous thromboembolism within the patient population of this study?

SELECT D Trial Rivaroxxaban 15 mg BID x 21 d, then 20 mg Daily Patients with cancer at risk for VTE recurrence N ~ 530; 1:1 Daltaparin 200 IU/kg x 1 mo, then 150 IU/kg Rivaroxxaban 20 mg Daily Residual VTE after 6 months 6 mo vs 12 mo treatment Mostly in the UK. Objective is to determine if rivaroxaban is non-inferior to LMWH placebo Primary Endpoint: recurrent VTE Young A, et al. Thromb Res. 2016; 140(suppl1): S172-S173

HOSUKAI VTE-Cancer Study Trial LMWH 5d bridge with edoxaban 60 mg Patients with cancer and VTE N ~ 1000; 1:1 12 mo Daltaparin 200 IU/kg x 30d, then 150 IU/kg Primary Endpoints: recurrent VTE, major bleeding Van Es N, et al. Thromb Haemost. 2015; 114: 1268-1276

Apixaban vs Dalteparin in Patients with Cancer and VTE Trial Apixaban x7d, then lower dose apixaban Patients with cancer and VTE N ~ 315; 1:1 3 months Daltaparin x 30d, then lower dose daltaprin Primary Endpoint: major bleeding Secondary outcome: recurrent VTE ClinicalTrials.gov. NCT02585713

Assessment of the Effect of Target Specific Oral Anticoagulants for Treatment of Venous Thromboembolism in Oncology Patients Elizabeth Weddendorf, PharmD PGY1 Pharmacy Practice Resident UNC Rex Healthcare Raleigh, NC elizabeth.weddendorf@unchealth.unc.edu