C. Michael Gibson, M.S., M.D. Professor of Medicine Harvard Medical School

Transcription

1 Novel Strategies to Prevent Pulmonary Embolism and DVT: APEX Trial and Substudies C. Michael Gibson, M.S., M.D. Professor of Medicine Harvard Medical School

2 Conflict of Interest Statement 2 Present Research/Grant Funding Angel Medical Corporation Bayer Corp. CSL Behring Google Ikaria, Inc. Janssen Pharmaceuticals Johnson & Johnson Corporation Portola Pharmaceuticals Stealth Peptides, Inc. St. Jude Medical Consultant (all with moderate support) Boston Clinical Research Institute Cardiovascular Research Foundation CSL Behring Gilead Sciences, Inc. The Medicines Company Novo Nordisk Pfizer St. Jude Medical Web MD Consultant (with $0.00 monies received by Dr. Gibson) Bayer Corporation Janssen Pharmaceuticals Johnson & Johnson Corporation Ortho McNeil Spouse: Employee of Boston Clinical Research Institute, she has equity position

3 Learning Objectives 3 Describe the results of the landmark trials in extended duration anticoagulation. Describe the design and rationale of the APEX trial. Describe the risks and benefits of betrixaban based on clinical research.

4 Previous Novel Oral Anticoagulant Trials of Extended Thromboprophylaxis in Acute Medically Ill Patients 4 ADOPT vs. Apixaban MAGELLAN vs. Rivaroxaban RRR=22.8% VTE Events 6 3.1% RRR=12.9% p= % 5.7% p= % Incidence (%) More Major Bleeding % p= % 0.4% Apixaban p< % Rivaroxaban ADOPT: Goldhaber SZ et al. N Engl J Med. 2011;365: MAGELLAN: Cohen AT et al. N Engl J Med. 2013;368: There WILL be off-label and/or investigational discussion in this presentation. Gibson et. al. ISTH SSC 2016 May 27, 2016

5 5 Oral factor Xa inhibitor Renal clearance of administered dose (5%) Renal clearance of absorbed dose (17%) 1 day half-life (19-25 h) Not a substrate for major CYP450 enzymes Rapid onset C max achieved at 3-4 hours Safety and efficacy of 80 mg daily dose of previously described in approximately 1,200 patients in phase I and II studies Connolly S et al. Eur Heart J 2013;34(20): Turpie A et al. Thromb Haemost 2009;101:68-76 Cohen AT et al. Am Heart J 2014; 167: Gibson et. al. ISTH SSC 2016 May 27, 2016

6 APEX Study Design 6 Standard Prophylaxis 10 ± 4 days Extended Prophylaxis days Evaluation Subjects enrolled (N=7,513) R 1:1 40 mg Double blind, double dummy 80 mg Placebo 80 mg Ultrasound & Visit 3 Day 35 (+7 days) Follow-up safety visit 30 Days After Visit 3 (+5 days) Loading dose 160 mg Primary Efficacy Endpoint: Composite of asymptomatic proximal DVT (detected on ultrasound), symptomatic DVT (proximal or distal), non-fatal PE, and VTE-related death through Visit 3 Primary Safety Endpoint: ISTH Major bleeding through 7 days after drug discontinuation Net Clinical Benefit: Composite of primary efficacy and primary safety endpoints Dose adjustments in severe renal insufficiency (CrCl < 30 ml/min): 40 mg PO qd and 20 mg SC qd Gibson et. al. ISTH SSC 2016 May 27, 2016

7 Study Design: Key Inclusion Criteria 7 Age/Risk Factors: 75 yo OR yo with D-dimer 2x ULN OR yo with D-dimer 2x ULN and a history of either VTE, or cancer* Anticipated to be severely immobilized for at least 24 hours after randomization with anticipated length of hospitalization 3 days Hospitalized for one of the following acute presentation: Acute on chronic heart failure decompensation Acute on chronic respiratory failure Acute infection without septic shock Acute rheumatic disorders Acute ischemic stroke (w/ immobilization) *Pre-amendment 3, other risk factors were allowed including: previous history of superficial VT, obesity, varicose veins of lower extremities, hormone therapy, thrombophilia, concomitant use of erythropoiesis stimulating agents There WILL be off-label and/or investigational discussion in this presentation. Gibson et. al. ISTH SSC 2016 May 27, 2016

8 Study Design: Key Exclusion Criteria 8 End stage renal disease with CrCl <15 ml/min, or requiring dialysis (first trial to enroll patients with CrCl <30 ml/min) Anticipated need for prolonged anticoagulation Current intake of dual antiplatelet therapy Anticipated major surgery History of clinically significant bleeding within 6 months prior to enrollment History of IC bleeding, head trauma, or known intracranial lesions History of significant GI, pulmonary or GU bleeding, ongoing chronic PUD or ongoing or acute gastritis within 2 years prior to enrollment Hgb < 10 g/dl (pre-amendment 3); Hgb < 9.5 g/dl or unstable/declining hemoglobin (possible active bleed) (post-amendment 3) Gibson et. al. ISTH SSC 2016 May 27, 2016

9 CONSORT Diagram 9 Randomized (n=7,513) n=3,754 Did not receive any dose of study drug n=3,759 n=34 n=38 mitt population n=3,720 No ultrasound AND no symptomatic event n=3,721 mitt population n=546 n=609 Cohort 3: Overall efficacy population n=3,174 n=3,112 Cohort 3: Overall efficacy population Cohort 2 n=2,893 n=2,842 Cohort 2 Cohort 1 n=1,956 n=1,914 Cohort 1 Cohen et al. N Engl J Med. 2016; 375(6):

10 mitt Efficacy Analysis Including All Patients Who Received Study Drug Including Those with Missing Ultrasound As Included in US FDA Label Cohort 1 D-dimer 2 x ULN P = Cohort 2 D-dimer 2 x ULN or age 75 y P = Cohort 3 Overall efficacy population P = RRR = 20.9% 7.18% RRR = 21.6% RRR = 25.4% Event rate (%) % 6.02% 4.70% 5.99% 4.43% 2 0 n=166 n=132 n=204 n=160 n=223 n=165 (N=2,313) (N=2,314) (N=3,391) (N=3,407) (N=3,720) (3,721) P-values reported using the Mantel-Haenszel test stratified for dosing criteria in Cohort 1 and dosing and entry criteria in Cohort 2 and mitt. mitt defined as patients who received at least one dose of study drug. Symptomatic events from Day 1 till Day 42 or the date of Visit 3, if Visit 3 occurred before Day 42; Asymptomatic DVT between Day 32 and 47. Gibson et. al. ISTH SSC 2016 May 27, 2016

11 Subgroup Analysis: Primary Efficacy Overall Efficacy Population (Cohort 3) 11 Overall Age Age 75 years Age < 75 years Event Rate () Event Rate () 223 / / / / / / 974 Composite of Asymptomatic Proximal DVT, Symptomatic Proximal or Distal DVT, Nonfatal PE, or VTE-related Death RR (95% CI) 0.76 (0.63, 0.92) 0.75 (0.60, 0.95) 0.77 (0.54, 1.09) Gender Male Female 102 / / / / (0.62, 1.09) 0.70 (0.54, 0.92) Additional VTE Risk Factors 2 VTE risk factors < 2 VTE risk factors 114 / / / / (0.51, 0.89) 0.84 (0.64, 1.10) Dosing Criteria No dosing modification P-gp inhibitor Severe renal insufficiency Reason for Hospital Admission Acute decompensated HF Acute infection Acute respiratory failure Acute ischemic stroke Acute rheumatic disorders 180 / / / / / / / / / / / / / / / / (0.56, 0.87) 1.06 (0.67, 1.70) 0.88 (0.40, 1.94) 0.85 (0.62, 1.16) 0.72 (0.50, 1.02) 0.89 (0.53, 1.49) 0.58 (0.34, 1.02) 0.63 (0.22, 1.78) P-value for interaction is non-significant for all analyses. All analysis were stratified for dosing and entry criteria Favors Favors Gibson et. al. ISTH SSC 2016 May 27, 2016

12 Symptomatic VTE All Patients Randomized 12 Composite of Symptomatic Proximal or Distal DVT, Non-Fatal PE, or VTE-related Death Probability of Symptomatic Event (%) Parenteral Therapy Through Visit 3 HR = 0.65 (0.42, 0.99) ARR = 0.51% NNT = % p= % Visit 3 Through End of Trial* HR = 0.56 (0.38, 0.84) ARR = 0.80% NNT = % p= % Time (Days) *End of Trial defined as final follow-up visit ( days after Visit 3) Gibson et. al. ISTH SSC 2016 May 27, 2016

13 Stroke or TIA Modified Intent-to-Treat Population 13 Stroke Type (N=3716) (N=3716) Relative Risk (95% CI) p-value All-cause stroke 0.97% (36) 0.54% (20) 0.56 (0.32, 0.96) Ischemic 0.91% (34) 0.48% (18) 0.53 (0.30, 0.94) Hemorrhagic 0.03% (1) 0.03% (1) 1.00 (0.06, 15.98) 1.00 Uncertain type 0.03% (1) 0.03% (1) 1.00 (0.06, 15.98) 1.00 TIA 0.13% (5) 0.11% (4) 0.80 (0.22, 2.98) 0.74 All-cause stroke or TIA 1.10% (41) 0.65% (24) 0.59 (0.35, 0.97) Gibson et al. Circulation. 2017;135(7):648-55

14 Stroke or TIA Modified Intent-to-Treat Population Received 80 mg 14 Stroke Type (N=2991) (N=2986) Relative Risk (95% CI) p-value All-cause stroke 30 (1.00%) 14 (0.47%) 0.47 (0.25, 0.88) Ischemic 28 (0.94%) 13 (0.44%) 0.47 (0.24, 0.90) Hemorrhagic 1 (0.03%) 0 (0.00%) 0.32 Uncertain type 1 (0.03%) 1 (0.03%) 1.00 (0.06, 16.01) 1.00 TIA 5 (0.17%) 3 (0.10%) 0.60 (0.14, 2.51) 0.48 All-cause stroke or TIA 35 (1.17%) 17 (0.57%) 0.49 (0.27, 0.87) Gibson et al. Circulation. 2017;135(7):648-55

15 Time to Ischemic Stroke Among Subjects with CHF or Ischemic Stroke at Entry Modified Intent-to-Treat Population 15 Gibson et al. Circulation. 2017;135(7):648-55

16 Primary Safety Endpoint: ISTH Major Bleeding Safety Population Major bleeding events (ISTH) through 7 days after drug discontinuation Event rate (%) % p = % n=21 n=25 (N=3,716) (N=3,716) Safety population defined as patients who received at least one dose of active study drug. Analysis by actual treatment. NNH not reported given p=ns. Cohen et al. N Engl J Med. 2016; 375(6):

17 Secondary Safety Endpoint Safety Population Major or clinically relevant non-major bleeding events (ISTH) through 7 days after drug discontinuation 3.12% Event rate (%) % p < n=59 (N=3,716) Safety population defined as patients who received at least one dose of active study drug. Analysis by actual treatment. n=116 (N=3,716) Cohen et al. N Engl J Med. 2016; 375(6):

18 Fatal Bleeding and ICH Safety Population p = % Event rate (%) n=9 0.03% 0.03% n=1 n=1 (N=3,716) (N=3,716) Fatal Bleeding 0.05% n=7 n=2 (N=3,716) ICH (N=3,716) Safety population defined as patients who received at least one dose of active study drug. Analysis by actual treatment. Gibson et. al. ISTH SSC 2016 May 27, 2016

19 19 Unger et al of FDA suggests that net clinical outcome analyses include events that are clinically meaningful and are of similar clinical significance such as fatal or irreversible events. Benefit = Non-hemorrhage CV death + Non-fatal PE + MI + ischemic stroke Harm = Fatal Bleeding + ICH Gibson et. al. ISTH SSC 2016 May 27, 2016

20 Fatal or Irreversible Outcomes All Patients Randomized 20 Non-hemorrhage cardiopulmonary death + Non-fatal PE + MI + ischemic stroke + Fatal bleeding + ICH Through Visit 3 HR = 0.71 (95% CI: ) ARR = 1.18% NNT = 85 Through End of Trial* HR = 0.70 (95% CI: ) ARR = 1.53% NNT = 65 *End of Trial defined as final follow-up visit ( days after Visit 3) Gibson et al. J Am Heart Assoc. 2017;6(7)

21 Fatal or Irreversible Outcomes All Patients Randomized Received 80 mg 21 Non-hemorrhage cardiopulmonary death + Non-fatal PE + MI + ischemic stroke + Fatal bleeding + ICH Through Visit 3 HR = 0.62 (95% CI: ) ARR = 1.47% NNT = 68 Through End of Trial* HR = 0.64 (95% CI: ) ARR = 1.77% NNT = 56 *End of Trial defined as final follow-up visit ( days after Visit 3) Gibson et al. J Am Heart Assoc. 2017;6(7)

22 Primary Efficacy Endpoint Central D-dimer 2 x ULN: MAGELLAN vs. APEX 22 10% MAGELLAN RRR = 29.0% (8.0, 46.0) p< % 9.30% 10% APEX RRR = 29.5% (11.6, 43.9) p= % HR = (95% CI) 8% 8% % 6% 6.50% 6.5% 6% p= 6.4% % 4% 4% 2% 0% 2% n= n= n=125 n=84 n=165 n=118 0% (n=1,348) Rivaroxaban (n=1,285) (n=1,822) (n=1,838) MAGELLAN and APEX analyses through 35 days Cohen A et al. J Throm Haemost. 2014;12: Gibson et. al. ISTH SSC 2016 May 27, 2016

23 Comparison to Previous Novel Oral Anticoagulant Trials of Extended Thromboprophylaxis in Acute Medically Ill Patients 23 8 ADOPT Apixaban MAGELLAN Rivaroxaban RRR = 22.8% p = 0.02 RRR* = 24.0% p<0.001 p* = % APEX Incidence (%) VTE Events Major Bleeding % 5.3% RRR = 12.9% p = % 3.1% 2.7% 0.2% 0.5% 0.4% 0.57% 0.67% 1.1% p=0.04 p<0.001 p=0.55 Apixaban Rivaroxaban * Overall efficacy population analysis used for comparison purposes Gibson et. al. ISTH SSC 2016 May 27, 2016

24 Summary 24 In an mitt analysis that includes all patients treated with study drug performed by the FDA in the label and prespecified in the protocol, reduced the composite endpoint of symptomatic and asymptomatic events as well as symptomatic events was not associated with a significant increase in major, ICH, or fatal bleeding but was associated with more CRNM bleeding reduced stroke reduced fatal or irreversible events Gibson et. al. ISTH SSC 2016 May 27, 2016