Oral Rivaroxaban for the Treatment of Symptomatic Venous Thromboembolism: A Pooled Analysis of the EINSTEIN DVT and EINSTEIN PE Studies Anthonie WA Lensing on behalf of the EINSTEIN Investigators

Venous thromboembolism  1-2 new cases per 1000 per year  If no or inadequate anticoagulant treatment is given  recurrent thrombotic complications in 20-30%  Heparin/vitamin K antagonist (VKA)  VKA has a slow onset of action; heparin is needed for the first week of treatment  VKA has an unpredictable anticoagulant effect, requiring –frequent INRs and dose adjustments  Heparin/VKA recurrent VTE rate: ~ 3% at 6 mo

Rivaroxaban  Specific, direct factor Xa inhibitor  High oral bioavailability  Rapid onset of action  Half-life: 7–11 hours  Only 1/3 renally cleared  Small change in exposure with varying bodyweight  Wide therapeutic window  Absorption limited if > 50 mg

Rivaroxaban Can Rivaroxaban be given in a fixed dose without the requirement for monitoring and replace heparin and VKA treatment in DVT/PE patients?

1. N Engl J Med 2010;363:2499; 2. N Engl J Med 2012;366:1287–97. EINSTEIN DVT and EINSTEIN PE studies Randomised, open-label, event-driven, non-inferiority studies of identical design with a priori specified combined analyses 15 mg bid DVT without PE N=3449 N=8282 Rivaroxaban Day 1Day 21 Enoxaparin bid for at least 5 days + VKA, INR 2.0–3.0 PE with or without DVT N=4833 Predefined treatment period of 3, 6, or 12 months 20 mg od 30-day post-study treatment period Rivaroxaban R

EINSTEIN DVT and EINSTEIN PE pooled analysis: primary efficacy outcome Number of patients at risk Rivaroxaban Enoxaparin/VKA Rivaroxaban N=4150 Enoxaparin/VKA N= Time to event (days) Cumulative event rate (%) HR=0.89, 95% CI 0.66 – 1.19 p non-inferiority, < Prins MH et al. Thromb J 2013;11:21

Clot size and recurrent VTE

EINSTEIN PE: Repeat CT scan at 3 weeks in 264 patients Rivaroxaban N=135 Enoxaparin/VKA N=129 Complete resolution59 (44%)57 (44%) Partial resolution61 (45%)58 (45%) No change15 (11%)12 (9%) Deteriorated00 Van Es, et al. JTH, 11: 679–85

RivaroxabanEnoxaparin/VKA n/N% % Limited ≤25% of vasculature of a single lobe, popliteal vein only 11/ / Intermediate47/ / Extensive multiple lobes and >25% of entire pulmonary vasculature; involving common femoral/ iliac vein 28/ / EINSTEIN DVT and PE pooled analysis: Clot size and recurrent VTE Prins MH et al. Thromb J 2013;11:21

EINSTEIN DVT and EINSTEIN PE pooled analysis: major bleeding Number of patients at risk Rivaroxaban Enoxaparin/VKA Rivaroxaban N=4130 Enoxaparin/VKA N= Time to event (days) Cumulative event rate (%) Prins MH et al. Thromb J 2013;11:21

Outcome Rivaroxaban (N=4130) Enoxaparin/VKA (N=4116) HR (95% CI) p-value n%n% Major bleeding* (0.37–0.79) p=0.002 EINSTEIN DVT and EINSTEIN PE pooled analysis: types of major bleeding Prins MH et al. Thromb J 2013;11:21 *Some patients had >1 event

Outcome Rivaroxaban (N=4130) Enoxaparin/VKA (N=4116) HR (95% CI) p-value n%n% Major bleeding* (0.37–0.79) p=0.002 Fatal3< Retroperitoneal001<0.1 Intracranial2<0.14 Gastrointestinal/thorax1<0.13 In a critical site Retroperitoneal1< Intracranial3< Pericardial002<0.1 Other Fall in hemoglobin ≥2 g/dl and/or transfusions ≥2 units Gastrointestinal EINSTEIN DVT/PE: types of major bleeding *Some patients had >1 event Prins MH et al. Thromb J 2013;11:21

Apixaban vs rivaroxaban for treatment of VTE  AMPLIFY  mono-therapy with apixaban 10 mg bid/7 days followed by 5 mg bid for 6 months  stringent exclusion criteria  EINSTEIN DVT/PE  mono-therapy with rivaroxaban15 mg bid/21 days followed by 20 mg od during 3, 6 or 12 months  limited screen of exclusion criteria  Results of the EINSTEIN DVT/PE and AMPLIFY may have been influenced by differences in study design and patient selection.

Apixaban vs rivaroxaban for treatment of VTE Einstein DVT/PE rivaroxaban Amplify apixaban Recurrent VTE NOAC vs LMWH/VKA 86 (2.1%) vs 95 (2.3%) RR 0.90 ( ) 59 (2.3%) vs 71 (2.7%) RR 0.84 ( ) Major bleeding NOAC vs LMWH/VKA 40 (1.0%) vs 72 (1.7%) RR 0.55 ( ) 15 (0.6%) vs 49 (1.8%) RR 0.31 ( )

Adaptation of Einstein using Amplify inclusion/exclusion criteria AmplifyEinstein DVT/PE EINSTEIN adaptation Patients affected Treatment Duration 6 months3, 6, or 12 months Exclude 3-month Censor at 6 mths N=660 N=4940 Exclusion criteria Patients with transient risk factorsIncludedExcludeN=2221 Hemoglobin < 9 gr/dlNo limitationExclude <9 gr/dlN=104 ALT > 2 times ULNALT ≥ 3 times ULNExclude >2 ULNN=163 Total bilirubin >1.5 times ULNNo limitationExclude >1.5N=71 Requiring ASA >165 mg/dayASA was discouragedExclude >165 mgN=20 Platelet count < 100 x10 9 No limitationExclude<100x10 9 N=81 < 6 mths bleeding: intracranial /intraocular/ GI/proven ulcer; < 1 week: stroke/ neurosurgery or planned major surgery/ intracranial neoplasm/AV malformation or aneurysm/hemorrhagic tendencies high risk of bleeding excluded Exclude N=67

Einstein patients who were (cohort 1) and were not (cohort 2) eligible for Amplify Einstein cohort 1Einstein cohort 2 Recurrent VTE NOAC vs LMWH/VKA 38 (1.5%) vs 61 (2.3%) RR 0.63 ( ) p= (2.6%) vs 27 (2.3%) RR 1.08 ( ) p=0.76 Major bleeding NOAC vs LMWH/VKA 22 (0.8%) vs 46 (1.7%) RR 0.48 ( ) p= (1.3%) vs 12 (1.1%) RR 1.13 ( ) p=0.76

Prohemostatic treatments in patients with severe bleeding in EINSTEIN

EINSTEIN DVT/PE: Clinical presentation of major bleeding Major bleeding Rivaroxaban n=45 VKA n=79 Category 1 Controllable 18 (40.0%)17 (21.5%) Category 2 Not serious but requires measures to control 19 (42.2%)34 (43.0%) Category 3 Serious 7 (15.6%)26 (32.9%) Category 4 Fatal 1 (2.2%)2 (2.5%) Category 3+4 rivaroxaban vs VKA: odds ratio 0.39, 95% CI: ; p=0.04) Eerenberg et al. J. Thromb Haemost 2015;13:1590-6

Einstein DVT/PE: Clinical course of major bleeding Major bleedingRivaroxaban n=45VKA n=79 Category 1 Uncomplicated 17 (37.8%)21 (26.6%) Category 2 Stable 19 (42.2%)33 (41.8%) Category 3 Unstable 5 (11.1%)17 (21.5%) Category 4 No life saving attempts made 4 (8.9%)8 (10.1%) Category 3+4 rivaroxaban vs VKA: odds ratio 0.81, 95% CI 0.30 to 2.13, p= 0.66 Eerenberg et al. J. Thromb Haemost 2015;13:1590-6

EINSTEIN DVT/PE Prohaemostatic measures Rivaroxaban n=45 Enox/VKA n=79 Vitamin K130 FFP411 Prothrombin complex 29 rFVIIa10 Eerenberg et al. J. Thromb Haemost 2015;13:1590-6

EINSTEIN DVT/PE: conclusions  In patients with acute symptomatic DVT and/or PE, rivaroxaban showed:  Non-inferiority versus enoxaparin/VKA for efficacy  Approximately 50% reduction for major bleeding  Single-drug approach: no LMWH needed  21 days of bid treatment more effective than 7 days?

Outcome RivaroxabanEnoxaparin/VKA HR (95% CI) n/N% % Recurrent VTE Fragile21/ / (0.39–1.18) Non-fragile 65/ / (0.70–1.38) Major bleeding Fragile 10/ / (0.13–0.54) Non-fragile30/ / (0.49–1.29) EINSTEIN DVT/PE: outcomes in fragile patients* *Age >75 years, CrCl <50 ml/min, or body weight ≤50 kg Prins MH et al. Thromb J 2013;11:21

Renal function

Renal function, exposure and half-life Rivaroxaban *Dabigatran Renal impairment Increase exposure Prolongation half-life (hr) Increase exposure Prolongation half-life (hr) mild44% %+ 2.8 moderate52% %+ 4.9 severe64% % * Similar for apixaban, edoxaban

EINSTEIN DVT/PE: Recurrent VTE and kidney function p trend =0.001 Bauersachs et al. Thromb J 2014;12:25

EINSTEIN DVT/PE: Major bleeding and kidney function p trend =0.92 p trend =0.01 Bauersachs et al. Thromb J 2014;12:25

EINSTEIN DVT/PE: Major bleeding in patients taking NSAIDs or aspirin

Methods  1884 (22.8%) received NSAIDs  1202 (14.6%) received aspirin  Days counted as “on” or “off” days:  Adjustment for confounders  Incidence per 100 patient-years and hazard ratios by Cox model

Major bleeding RivaroxabanEnoxaparin-VKA EventsPt-yEvents/100 pt-y EventsPt-yEvents/100 pt- y NSAID NSAID – * * HR = 2.6 (1.2 ‒ 5.4) HR = 2.3 (1.3 ‒ 4.0) ASA ASA – * * HR = 1.5 (0.6 ‒ 3.6)HR = 1.5 (0.7 ‒ 3.1) * Significant differences Davidson BL et al. JAMA 2014;

NSAIDS/ASA during VTE treatment  Physicians should inform patients about increased bleeding risk with these commonly used drugs and advise curtailing their casual use

Conclusions  Concomitant anticoagulant/NSAID or ASA is associated with increased risk of major bleeding  Increase in bleeds was similar for rivaroxaban and enoxaparin-VKA  Physicians should inform patients about increased bleeding risk with these commonly used drugs and advise curtailing their casual use

VTE and cancer

Venous thromboembolism and cancer Approximately 10–20% of VTE cases occur in patients with either active cancer or a history of cancer Cancer patients with VTE are recommended to receive long-term LMWH monotherapy –ACCP 2012 grade 2B (weak with underlying evidence of moderate quality) OutcomeDalteparinDalteparin/VKAHR (95% CI) n/N% % Recurrent VTE 27/ / (0.30–0.77) Major bleeding19/ /3353.6~1.6 (0.7–3.4) Clot study 1 1.Lee et al, 2003; 2. Kearon et al, 2012; 3. Konstantinides et al, 2014.

Venous thromboembolism and cancer Long-term LMWH is often not used based on medical, economic and quality of life considerations –LMWH followed by long-term VKA is often prescribed in practice In EINSTEIN DVT/PE, rivaroxaban was compared with enoxaparin/VKA –Patients with cancer were not excluded

Classification of patients with cancer Patients with cancer were classified as: –Active cancer at baseline (diagnosis or treatment < 6 months or recurrent or metastatic cancer) –Active cancer during the study (a new diagnosis of cancer) –A history of cancer (all other) Prins MH et al. Lancet Haematology 2014;1:e37–46

VTE and cancer Active cancer at baseline (n=462) Active cancer during study (n=193) History of cancer (n=469) No known cancer: (n=7157) 8281 patients randomised N Engl J Med 2010;363:2499; N Engl J Med 2012;366:1287–97; Prins MH et al. Lancet Haematology 2014;1:e37–46.

VTE and cancer: outcomes No known cancer RivaroxabanEnoxaparin/VKAHR (95% CI) Recurrent VTE, n (%)65/3563 (1.8)70/3594 (1.9)0.93 (0.66–1.30) Major bleeding, n (%)31/3546 (0.9)53/3582 (1.5)0.58 (0.37–0.91) Mortality, n (%)33/3563 (0.9)42/3594(1.2)0.77 (0.49–1.22) Prins MH et al. Lancet Haematology 2014;1:e37–46

VTE and cancer: outcomes History of cancer RivaroxabanEnoxaparin/VKAHR (95% CI) Recurrent VTE, n (%)5/233 (2.1)5/236 (2.1)0.98 (0.28–3.43) Major bleeding, n (%)1/231 (0.4)4/236 (1.7)0.23 (0.03–2.06) Mortality, n (%)5/233 (2.1)4/236 (1.7)1.12 (0.30–4.22) Prins MH et al. Lancet Haematology 2014;1:e37–46

VTE and cancer: outcomes Active cancer* RivaroxabanEnoxaparin/VKAHR (95% CI) Recurrent VTE, n (%)16/354 (4.5)20/301 (6.6)0.67 (0.35–1.30) Major bleeding, n (%)8/353 (2.3)15/298 (5.0)0.42 (0.18–0.99) Mortality, n (%)58/354 (16.4)53/301 (17.6)0.93 (0.64–1.35) *At baseline or diagnosed during the study Prins MH et al. Lancet Haematology 2014;1:e37–46

Major bleeding and renal function in patients with cancer p trend =0.92 p trend =0.01 Prins MH et al. Lancet Haematology 2014;1:e37–46

VTE in cancer Compared with standard therapy in patients with acute VTE, a fixed dose rivaroxaban only regimen had: –Similar efficacy –Lower incidence of major bleeding –Similar mortality Rivaroxaban is an alternative to standard therapy in cancer patients when a physician decides against LMWH

Conclusions Compared with standard therapy in patients with active cancer and VTE, rivaroxaban had: –Similar efficacy –Lower incidence of major bleeding –Similar mortality Rivaroxaban is an alternative to standard therapy when a physician decides against long-term LMWH A head-to-head comparison of rivaroxaban with LMWH in patients with cancer and VTE is warranted Prins MH et al. Lancet Haematology 2014;1:e37–46

EINSTEIN DVT/PE: conclusions  In patients with acute symptomatic DVT and/or PE, rivaroxaban showed:  Non-inferiority versus enoxaparin/VKA for efficacy  Approximately 50% reduction for major bleeding  Consistent efficacy and safety results irrespective of age, body weight, gender, renal function, cancer, severity of DVT/PE, and treatment of first/recurrent VTE  Single-drug approach: no LMWH needed

Laboratory assessment of rivaroxaban  Inhibition of Factor Xa and plasma rivaroxaban levels are closely correlated  Assays (particularly chromogenic assays) that measure inhibition of Factor Xa activity can quantify rivaroxaban plasma concentrations  Standardization of these assays to measure rivaroxaban involves the use of rivaroxaban calibrators and controls  Standardized assay kits are now commercially available for clinical use, e.g. –BIOPHEN Factor X Chromogenic –STA® Liquid Anti-Xa and STA® rivaroxaban calibrator and control [Diagnostica Stago] –Technochrom anti-Xa and Technoview rivaroxaban calibrator and control [Technoclone GmbH, Vienna, Austria].

From VKA to rivaroxaban Start rivaroxaban if INR below 3.0 from rivaroxaban to VKA rivaroxaban contributes to an elevated INR, but normalizes in 24 hrs Give rivaroxaban and VKA concurrently until INR ≥ 2.0 Obtain INR 24 hrs after previous rivaroxaban dose (but prior to the next dose!) from heparins to rivaroxaban Give rivaroxaban at the time the next heparin dose would be given from rivaroxaban to heparins Give first heparin dose at the time the next rivaroxaban dose would be taken Converting from or to rivaroxaban