Neue Antikoagulantien bei spontaner und Tumor-assoziierter VTE Paul Kyrle Univ. Klinik f. Innere Medizin I AKH/Medizinische Universität Wien

Treatment of VTE: past, present and future Heparin Vitamin K antagonists Heparin Dabigatran/Edoxaban Rivaroxaban/Apixaban

Treatment of VTE acutesubacuteextended up to 2 weeks up to months> 6 months

Schulman, N Engl J Med 2009 Recurrent VTE and related death RE-COVER - Dabigatran for acute/subacute VTE Non-inferiority p<0.001

RE-COVER - Dabigatran for acute/subacute VTE Schulman, N Engl J Med 2009 Bleeding

EINSTEIN-DVT - Rivaroxaban for acute DVT EINSTEIN Investigators, N Engl J Med 2010 Recurrent VTE and related death HR=0.68 (95% CI: 0.44–1.04) p<0.001 for non-inferiority p=0.08 for superiority

Clinically significant bleeding EINSTEIN-DVT - Rivaroxaban for acute DVT EINSTEIN Investigators, N Engl J Med 2010

EINSTEIN-PE Büller et a., NEJM 2012

EINSTEIN-PE Büller et a., NEJM 2012

EINSTEIN-PE Büller et a., NEJM 2012

Oral Rivaroxaban for the Treatment of Symptomatic Venous Thromboembolism: A Pooled Analysis of the EINSTEIN DVT and EINSTEIN PE Studies Harry R Büller on behalf of the EINSTEIN Investigators

EINSTEIN DVT and EINSTEIN PE studies Randomized, open-label, event-driven, non-inferiority studies of identical design with a priori specified combined analyses  Primary efficacy outcome: first recurrent VTE  Principal safety outcome: first major or non­-major clinically relevant bleeding 1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499–510; 2. The EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–97 15 mg bid Confirmed DVT without symptomatic PE 1 N=3449 N=8282 Rivaroxaban Day 1Day 21 Enoxaparin bid for at least 5 days + VKA, INR 2.0–3.0 Confirmed PE with or without symptomatic DVT 2 N=4833 Predefined treatment period of 3, 6, or 12 months 20 mg od 30-day post-study treatment period Rivaroxaban R

Rivaroxaban (N=4150) Enoxaparin/VKA (N=4131) Males, %5554 Age, mean, years ± SD57±17 Weight, n (%) ≤50 kg75(1.8)92(2.2) >50–100 kg3477(84)3432(83) ≥100 kg590(14)605(15) Creatinine clearance, ml/min (%) <3010(0.2)11(0.3) 30–49322(8)311(8) 50–791030(25)992(24) ≥802748(66)2787(67) Index VTE, n (%) DVT1699(41)1690(41) PE1793(43)1804(44) DVT and PE615(15)597(15) Unprovoked VTE, n (%)2003(48)2048(50) Previous VTE, n (%)791(19)819(20) Active cancer, n (%)232(6)198(5) EINSTEIN DVT and EINSTEIN PE pooled analysis: patient characteristics ITT population

Rivaroxaban (N=4150) Enoxaparin/VKA (N=4131) n %n% First symptomatic recurrent VTE Fatal PE2<0.11 Death (PE cannot be excluded) DVT and PE1<0.12 DVT only PE only EINSTEIN DVT and EINSTEIN PE pooled analysis: primary efficacy outcome Hazard ratio ITT population Rivaroxaban superior Rivaroxaban non-inferior Rivaroxaban inferior 1.75 p=0.41 for superiority (two-sided) p< for non-inferiority (one-sided)

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; p non-inferiority < Mean time in therapeutic range = 61.7% ITT population

EINSTEIN DVT and EINSTEIN PE pooled analysis: principal safety outcome Number of patients at risk Rivaroxaban Enoxaparin/VKA Cumulative event rate (%) Rivaroxaban N=4130 Enoxaparin/VKA N= Time to event (days) First major or clinically relevant non-major bleeding Rivaroxaban n/N (%) Enoxaparin/VKA n/N (%) HR (95% CI) p-value 388/4130 (9.4) 412/4116 (10.0) 0.93 (0.81–1.06) p=0.27 Safety population

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 (%) First major bleeding Rivaroxaban n/N (%) Enoxaparin/VKA n/N (%) HR (95% CI) p-value 40/4130 (1.0) 72/4116 (1.7) 0.54 (0.37–0.79) p=0.002 Safety population

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< Intraocular3<0.13 Pericardial002<0.1 Intra-articular004<0.1 Adrenal/pulmonary/abdominal3<0.12 Fall in hemoglobin ≥2 g/dl and/or transfusions ≥2 units EINSTEIN DVT and EINSTEIN PE pooled analysis: types of major bleeding *Some patients had >1 event

Outcome RivaroxabanEnoxaparin/VKA HR (95% CI) n/N% % Recurrent VTE Fragile21/ / (0.39–1.18) Non-fragile65/ / (0.70–1.38) Major bleeding Fragile10/ / (0.13–0.54) Non-fragile30/ / (0.49–1.29) EINSTEIN DVT and EINSTEIN PE pooled analysis: outcomes in fragile patients* *Age >75 years or CrCl <50 ml/min or body weight ≤50 kg

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 EINSTEIN PE pooled analysis: clot size and recurrent VTE

EINSTEIN DVT and EINSTEIN PE pooled analysis: conclusions  In patients with acute symptomatic DVT and/or PE, rivaroxaban showed:  Non-inferiority versus enoxaparin/VKA for efficacy  Similar incidence rates to enoxaparin/VKA for the principal safety outcome  Superiority for major bleeding  Consistent efficacy and safety results irrespective of age, body weight, gender, renal function, cancer, and severity of DVT/PE  Single-drug approach: no LMWH needed

Treatment of VTE - conclusion acutesubacuteextended up to 2 weeks up to months > 6 months NOACS as safe and effective NOACS as effective, but safer

Risk of recurrence after unprovoked VTE Kyrle, Rosendaal & Eichinger, Lancet 2010

Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA in EINSTEIN VTE program Rivaroxaban 20 mg od Placebo Day 1 R N=1,197 Treatment period of 6 or 12 months 30-day observational period Confirmed symptomatic DVT or PE completing 6 or 12 months of VKA ~53% ~47% Randomized, double-blind, placebo-controlled, event-driven (n=30), superiority study EINSTEINext - Rivaroxaban for extended thromboprophylaxis after VTE Study design EINSTEIN Investigators, NEJM 2011

Continued treatment EINSTEIN-DVT - Rivaroxaban for acute DVT EINSTEIN Investigators, N Engl J Med 2010

Continued treatment EINSTEIN-DVT - Rivaroxaban for acute DVT EINSTEIN Investigators, N Engl J Med major bleeds no major bleeds

AMPLIFY - Extended Agnelli, NEJM 2012

AMPLIFY - Extended Agnelli, NEJM 2012

RESONATE

Time to first VTE or VTE-related death

Risk of first onset of any bleeding

13/1430 Major bleeding 0.9% 1.8% HR 0.52 (95% CI: 0.27–1.02) 25/1426 Percentage p = On treatment 48% RRR RRR, relative risk reduction.

VKA in cancer patients Prandoni, Blood 2002

VKA in cancer patients

CLOT (Lee, NEJM 2003) Major bleeding: Dalteparin 19/338 (6%) VKA 12/335 (4%) p = 0.3

VTE and cancer  ACCP 2012 LMWH over VKA (2B) VKA over NOACs (2C) Dalteparin –once daily 200 IU/kg body weight s.c. –dose reduction to % of therapeutic dose after 4 weeks

EINSTEIN DVT and EINSTEIN PE pooled analysis: outcomes in patients with cancer Outcome RivaroxabanEnoxaparin/VKA HR (95% CI) n/N% % Recurrent VTE Cancer6/ / (0.22–1.80) No cancer 80/ / (0.67–1.24) Major bleeding Cancer 6/ / (0.21–1.77) No cancer34/ / (0.35–0.80)

RE-COVER Dabigatran in VTE cancer patients D W

Advantages of NOACs in cancer patients with VTE oral route  better quality of life/adherence short half-life  better flexibility at least as effective and safe as VKA

Caveats für using NOACs in cancer patients with VTE Small patient numbers in clinical trials Generalizability of trial data (low-risk pts) Oral route in pts with nausea, vomiting and diarrhea Interaction with chemotherapy No on-going trials, neither with LMWH nor with NOACs

Summary as effective as LMWH/VKA less (major) bleeding single drug approach (rivaroxaban, apixaban) effective in VTE long-term prevention (up to 1 year) suitable for selected cancer patients NOACs for treatment of VTE