New Perspective in VTE Treatment in Acute Medically Ill Patients: Single vs. Dual Drug Approach. Dr. Johan Kurnianda, SpPD-KHOM

Transcription

1 New Perspective in VTE Treatment in Acute Medically Ill Patients: Single vs. Dual Drug Approach Dr. Johan Kurnianda, SpPD-KHOM

2 VTE : Spectrum of Disease Deep Vein Thrombosis Post Thrombotic Syndrome Pulmonary Embolism Chronic Pulmonary Hypertension

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4 Treatment Goals Prevent the extension of thrombus Prevent of PE Relieved symptoms in the short term Preventing recurrent events in the long term

5 Clinical Scenarios Which acute treatment scheme to use? Which anticoagulants? How long to treat VTE?

6 Case : 1 Mr. G, 59 years old, a farmer with bladder cancer st IV (hepatal-metastasis), PS 2 Chief complaint : dispnoe of a weeks Vital sign : BP : 117/87, HR : 130 RR : 28, T : 36.5 CT angiography : confirmed partial thrombus of apical-segmental right lung artery and partial thrombus apicoposterior segmental left lung artery Previous proximal low extremity DVT + Good liver and kidney funtion

7 What would be your choice for the anticoagulant? A. Vitamin K Antagonist B. Unfractionated heparin C. Low molecule weight heparin D. NOACs

8 Case : 2 Identity Mrs. SN 49 years old, a house wife with active SLE. Chief complaint : dispnoe of a weeks MSCT Thorax : Bilateral pulonary artery embolism. Vital sign : HR 100/mnts, BP 110/70 mmhg, RR 26/mnt, Temp 37,3 C O2 saturation 95 No history of previous VTE, cancer, COPD and CHF Good liver and kidney function

9 What would be your choice for the anticoagulant? A. Vitamin K Antagonist B. Unfractionated heparin C. Low molecule weight heparin D. NOACs

10 Case : 3 Identity Mrs. SR 67 years old, a house wife, with CHF, pneumonia and bed ridden > 5 days Chief complaint : swelling in both lower extremities especially in left lowerextremity. Calf circumference : Right :39 cm,left :35 cm Doppler Ultrasond : Partial thrombus in v. Femoralis sinistra, subtotal thrombus in v. Femoralis to v. poplitea dextra. Clinically stable, CCT 45 ml/min

11 What would be your choice for the anticoagulant? A. Vitamin K Antagonist B. Unfractionated heparin C. Low molecule weight heparin D. NOACs

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13 Burden of VTE in Hospital Patients Why are medical patients so important? 100% VTE risk per patient 75% 50% 25% Examples: SCI THR, TKR other surgery medical patients maj trauma

14 VTE in Medical Patients Medical patients account for: - 80% of fatal PE in hospitals - 60% of symptomatic VTE in hospitals No prophylaxis + routine screening for DVT: DVT 10-20% (greater in stroke) Proximal DVT 4-5%

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18 The promise of new oral anticoagulants Simplified dosing regimen No dietary restrictions Predictable anticoagulation and no need for routine coagulation monitoring Can be given at fixed doses Reduced potential for food and drug interactions Less labour-intensive Less impact on patients daily life Improved compliance Reduced administrative costs Improved quality of life Improved efficacy and safety 1. Raghaven N et al. Drugs Metab Dispos 2009; 2. Shantsila E, Lip GY. Curr Opin Investig Drugs 2008; 3. Mueck W et al. Clin Pharmacokinet 2008; 4. Mueck W et al. Thromb Haemost 2008; 5. Mueck W et al. Int J Clin Pharmacol Ther 2007

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20 Characteristics of New Oral Anticoagulants Drug Dabigatran Rivaroxaban Apixaban Edoxaban Mechanism of action Thrombin inhibitor Factor Xa inhibitor Factor Xa inhibitor Factor Xa inhibitor T1/ hours 5-9 hours 12 hours 6-12 hours Regimen BID QD/BID BID QD Peak to trough ~7 12 (QD) 3-5 ~3 Renal excretion of absorbed drug Potential for drug interactions ~80% 33% 25%-30% 35% P-glycoprotein inhibitor CYP3A4 substrate and P-glycoprotein inhibitor CYP3A4 substrate and P-glycoprotein inhibitor CYP3A4 substrate and P- glycoprotein inhibitor

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23 Rivaroxaban: Phase III Studies Programme in VTE Treatment

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30 EINSTEIN PE: The Only Novel OAC Study to Confirm Early Clot Regression Following Acute PE Following 21 days of rivaroxaban or enoxaparin/vka Baseline PE Complete clot resolution (n=142) 88% Partial clot resolution (n=162) No change (n=43) 12% Worsening 0% Pre-defined safety analysis of the EINSTEIN PE study involving 347 patients with scan-confirmed PE who received a follow up CT or Q scan after 21 days of anticoagulant therapy; *3 patients with symptomatic worsening and confirmed recurrent PE were excluded from this analysis 1. van Es J et al, J Thromb Haemost 2013;11:

31 Significantly Shorter Length of Hospital Stay EINSTEIN DVT Rivaroxaban (n=1731) days* p< # Enoxaparin/VKA (n=1718) EINSTEIN PE Rivaroxaban (n=2419) day* p< # Enoxaparin/VKA (n=2413) Data based on the Global EINSTEIN study population. Includes major variations in hospitalisation practices between countries *Median; # p-values obtained from a stratified Wilcoxon rank-sum test (van Elteren test) stratified by intended treatment duration 1. van Bellen B et al, Curr Med Res Opin 2014;30:

32 Percentage of patients with complete resolution of thrombus Enhanced Clot Regression on Serial Imaging 70% 60% Rivaroxaban Standard of care 50% 40% 30% 20% 10% 0% Day 22 Duration of therapy EOT Predefined imaging outcome of J-EINSTEIN population (n=100). Includes DVT and PE imaging 1. Yamada N et al, Thromb J 2015;13:2

33 EINSTEIN DVT and PE: Conclusions In patients who had acute symptomatic proximal DVT without symptomatic PE, rivaroxaban showed: Non-inferiority to LMWH/VKA for efficacy (HR=0.68; 95% CI ; p<0.001) Similar findings for principal safety outcome between the two groups (HR=0.97; 95% CI ; p=0.77) In patients with acute symptomatic PE DVT, rivaroxaban showed: Non-inferiority to LMWH/VKA for efficacy (HR=1.12; 95% CI ; p non-inferiority =0.003 [margin: 2.0]) Similar findings for principal safety outcome (HR=0.90; 95% CI ; p=0.23) Superiority for major bleeding (HR=0.49; 95% CI ; p=0.003) 1. The EINSTEIN Investigators. N Engl J Med 2010;363:

34 30-day observation period EINSTEIN EXT: Study Design Randomized, double-blind, placebo-controlled, event-driven (n=30), superiority study Confirmed symptomatic DVT or PE completing 6 12 months of rivaroxaban or VKA in EINSTEIN VTE programme Day 1 ~53% N=1197 R Treatment period of 6 or 12 months Rivaroxaban 20 mg od Placebo Confirmed symptomatic DVT or PE completing 6 12 months of VKA ~47% 1. The EINSTEIN Investigators. N Engl J Med 2010;363:

35 Cumulative event rate (%) Enduring Protection Against Recurrent VTE When Treatment is Continued Rivaroxaban n/n (%) 8/602 (1.3) Placebo n/n (%) 42/594 (7.1) Time to event (days) Number of patients at risk Rivaroxaban Placebo Recurrent VTE measured in the ITT population; all analyses were based on the first event 1. The EINSTEIN Investigators. N Engl J Med 2010;363: HR: 0.18 (95% CI ) p<0.001 Placebo (n=594) 82% RRR 8.2% ARR Rivaroxaban (n=602)

36 EINSTEIN EXT: Major Bleeding Rivaroxaban (n=598) Placebo (n=590) n (%) n (%) Major bleeding 4 (0.7)* 0 (0) Bleeding contributing to death 0 (0) 0 (0) Bleeding in a critical site 0 (0) 0 (0) Associated with fall in haemoglobin 2 g/dl and/or transfusion of 2 units 4 (0.7) 0 (0) Gastrointestinal bleeding 3 (0.5) 0 (0) Menorrhagia 1 (0.2) 0 (0) Safety population; *p= The EINSTEIN Investigators. N Engl J Med 2010;363:

37 EINSTEIN EXT: Conclusions In patients who had completed 6 12 months of anticoagulation, rivaroxaban showed: An 82% RRR in the recurrence of VTE (HR=0.18; p<0.001) Absolute risk reduction 5.8%; hence 15 patients need to be treated to prevent one recurrent venous thromboembolic event Low incidence of major bleeding (0.7%; p=0.11; NNH approximately 139) Efficacy and safety results were consistent irrespective of bodyweight and creatinine clearance Modest increase in non-major clinically relevant bleeding (5.4% vs 1.2%) No signal for liver toxicity Oral rivaroxaban 20 mg od could provide clinicians and patients with a simple and effective option for continued anticoagulant treatment 1. The EINSTEIN Investigators. N Engl J Med 2010;363:

38 Real World Evidence for Rivaroxaban in VTE

39 XALIA: A Prospective, Non-interventional Study Objective: collect real-life data in patients with acute DVT treated with rivaroxaban or standard anticoagulation Patients with diagnosis of acute DVT* and with an indication for anticoagulant therapy for 3 months Type, dose and duration of drug used at discretion of attending physician Rivaroxaban for 3 months Investigators to collect data at initial visit, at 1 month and then quarterly # Standard anticoagulation, e.g. initial treatment with LMWH/fondaparinux, followed by VKA or parenteral anticoagulation for 3 months (1 month after end of treatment) Final assessment Primary outcomes Major bleeding events, symptomatic recurrent VTE and all-cause mortality ClinicalTrials.gov NCT ; *After PE EU licence, DVT with concomitant PE permitted; isolated PE excluded #Data were collected at the initial visit and during routine follow-up visits or via mail, telephone, or Ageno W et al, Thromb J 2014;12:16

40 Incidence (% of patients) EINSTEIN DVT and XALIA: Rivaroxaban Outcomes Characteristic 55.8 Age (years) % Male 54.5% 19.4% Previous VTE 24.1% 6.8% Baseline active cancer 5.6% 6.2% Known thrombophilia 6.0% # *Safety population (patients taking 1 dose of study drug); # ITT analysis The EINSTEIN Investigators, N Engl J Med 2010;363:

41 Summary XALIA is a prospective, non-interventional study demonstrating safety and effectiveness of a NOAC for the treatment of VTE in clinical practice Physicians used rivaroxaban in younger patients and those with fewer risk factors for recurrence Crude rates of major bleeding, recurrent VTE and all-cause mortality were low Propensity score-adjusted analyses: rivaroxaban showed similar safety and effectiveness to standard anticoagulation XALIA data are consistent with those from EINSTEIN DVT Patients on rivaroxaban had a shorter duration of hospital stay

42 XALIA-LEA Study Design Objective: collect real-life data in patients with acute DVT and/or PE treated with rivaroxaban or standard anticoagulation from regions not included in the original XALIA study Patients with diagnosis of acute DVT and/or PE and with an indication for anticoagulant therapy for 3 months Type, dose and duration of drug used at discretion of attending physician Rivaroxaban for 3 months Investigators to collect data at initial visit, 1 month and then quarterly * Standard anticoagulation, e.g. initial treatment with LMWH/fondaparinux, followed by VKA or parenteral anticoagulation for 3 months (1 month after end of treatment) Primary outcomes Major bleeding events, symptomatic recurrent VTE and all-cause mortality Final assessment ClinicalTrials.gov NCT ; *Data were collected at the initial visit and during routine follow-up visits or via mail, telephone, or Turpie A. G.G. et al., 26th Biennial International Society on Thrombosis and Haemostasis (ISTH) 2017, 8 13 July 2017, Berlin, Germany

43 XALIA-LEA Enrolment Geograph ic region, n (%) Rivaroxa ban (N=1285) Standard anticoagul ation (N=402) Asia- Pacific Eastern Europe, Middle East and Africa Latin Ame rica 720 (56.0) 167 (41.5) 473 (36.8) 196 (48.8) 92 (7.2) 39 (9.7) Turpie A. G.G. et al., 26th Biennial International Society on Thrombosis and Haemostasis (ISTH) 2017, 8 13 July 2017, Berlin, Germany Total enrolment (safety population in table)

44 XALIA-LEA Primary Outcomes (Adjusted for Covariates) HR= % CI p=0.003 HR= % CI p=0.001 HR= % CI p<0.003 Covariates were selected using a stepwise selection procedure with a threshold of p=0.10 Turpie A. G.G. et al., 26th Biennial International Society on Thrombosis and Haemostasis (ISTH) 2017, 8 13 July 2017, Berlin, Germany

45 Conclusions XALIA-LEA provides data on VTE treatment in regions not studied in XALIA Results for the three primary outcomes demonstrated that rivaroxaban is safe and effective in a broad range of patients, supporting the observations from XALIA and the phase III EINSTEIN studies 1 3 Baseline characteristics between treatment groups were more similar in XALIA-LEA than in XALIA (including age and cancer rates) Increased familiarity with rivaroxaban in clinical practice since the XALIA study may have influenced prescription patterns Major bleeding rates and all-cause mortality were considerably higher in XALIA-LEA compared with XALIA (for the respective rivaroxaban and standard anticoagulation groups) This was possibly due to the higher proportion of patients with PE and known cancer at baseline enrolled in XALIA-LEA 1. ClinicalTrials.gov NCT ; 2. Ageno W et al, Lancet Haematol 2016;3:e12 e21; 3. Prins MH et al, Lancet Haematol 2014;1:e37 e46

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57 Case Case I : male, 59 yo, pulmonary embolism, high PESI score, high burden and active cancer : anticoagulant of choice LMWH, undifinite duration Case 2 : female, 49 yo, pulmonary embolism, low PESI score, clinically stable, underlying disease SLE : anticoagulant of choice NOAC/Rivaroxaban, at least for 3 months with extended option Case 3 : female, 67 yo, extended and provoked DVT, moderate renal function : anticoagulant of choice Rivaroxaban/LMWH with extended option

58 Thank You for Your Kind Attention Questions?