what is new - novel oral anticoagulants – new opportunities in rheumatology - dr i rajendra vara...

Novel oral anticoagulants : New Opportunities in Rheumatology

Dr.I.Rajendra Vara PrasadDM Rheumatology, APLAR Fellow (UK)

Associate ProfessorDepartment of Rheumatology

NIZAMS INSTITUE OF MEDICAL SCIENCES

OUTLINE

• Introduction• Unmet needs of Vitamin K antagonists• Newer Oral Anticoagulants

– Data from phase 3 trials– Data in APS– Indian Data

• Current Indications• Take home message• Question

Introduction

• Vitamin K Antagonists used since 1940s• A number of new oral anticoagulants are now

available • Autoimmune and rheumatologic diseases

associated with hypercoagulability

Coagulation cascade

UNMET NEEDS OF VITAMIN K ANTAGONISTS

Ideal anticoagulant

• Safe and effective• Oral administration• Good pharmacokinetic and pharmacodynamics

profile• No interaction• No adverse events• Wide therapeutic index• Availability of antidotes• Cheap

Bertoletti L, Ollier E, Duvillard C, Delavenne X, Beyens MN, De Magalhaes E, Bellet F, Basset T, Mismetti P, Laporte S. Direct oral anticoagulants: Current indications and unmet needs in the treatment of venous thromboembolism. Pharmacological Research. 2016 Jun 24.

Warfarin

• Predictable anticoagulant effects

• Dose titration and comfort in reversing over-anticoagulation

• Familiarity

R. Shameem, J. Ansell / Best Practice & Research Clinical Haematology 26 (2013) 103–114

Disadvantages of vitamin K antagonists

• Indirect anticoagulant with multiple targets• Slowly onset and offset of action

– Needs bridging therapy• Narrow therapeutic window- Monitoring• Genetics (50-60% variability)

– Cytochrome P450 enzyme, CYP2C9– Vitamin K epoxide reductase complex 1 (VKROC1)


Disadvantages of vitamin K antagonists

• Drug and food interactions– More than 120 drug and food interactions– Maintain a consistent diet

• Variable responsiveness of reagents used in the INR tests

• Reduce protein C/S system


Practical implications

• Under used – <70% of high risk induviduals

• Risk-adjusted percent of time in therapeutic range to be only 58%

• Anticoagulation clinics, computerized tracking systems, and patient self-monitoring or text messages.

Rose AJ. Risk-Adjusted percent time in therapeutic range as a quality indicator for outpatient oral anticoagulation: results of the Veterans Affair Study to Improve Anticoagulation (VARIA). Circ Cardiovasc Qual Outcome 2011;4:22–9.Chow W. Anticoagulation instability with life-threatening complication after dietary modification. Postgrad Med J 1990;66:855–7.

India Data

• Of a total of 1631• Only 17.8% had therapeutic range, 73% being

sub-therapeutic PT/INR values and high complication rates

• Majority of places lack standardized labs• Pressing need for better patient education and

physician/local practitioner update

Kakkar N, Kaur R, John M. Outpatient oral anticoagulant management:an audit of 82 patients. JAPI. 2005;53:847-52.

NEWER ANTICOAGULANTS(NOACs)

NOACs

• Directly and specifically inhibit factor Xa or factor IIa

• Rapid onset of action and sufficiently low biovariability

• Once or twice daily without laboratory monitoring

Coagulation cascade: Anticoagulant effects

Pharmacology

• Oral Direct thrombin Inhibitor – Dabigatran

• Factor Xa Inhibitors – Rivaroxaban– Apixaban – Edoxaban

Lawrence LK Leung, MD. Direct oral anticoagulants: Dosing and adverse effects. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on November 20, 2016.)

Pharmacology

Arachchillage DJ, Cohen H. Use of new oral anticoagulants in antiphospholipid syndrome. Current rheumatology reports. 2013 Jun 1;15(6):1-9.

Renal and hepatic adjustments

Dabigatran Rivaroxaban Apixaban Edoxaban

Renal impairment

Mild +50% +44% +30% +11.6%

Moderate +220% +52% +65% +35%

Severe +530% +64% – +57%

Hepatic impairment

Mild – Not Significant Not significant Not Significant

Moderate Not Significant +127% Not Significant Not Significant

Severe – – – –

Drug Interactions


Laboratory monitoring of NOACs

• Stable pharmacokinetics and pharmacodynamics

• Dabigatran– Normal aPTT is a qualitative marker– Ecarin clotting time provides a quantitative

assessment of dabigatran activity• Rivaroxaban - Anti-factor Xa assays

Sciascia S, Lopez-Pedrera C, Cecchi I, Pecoraro C, Roccatello D, Cuadrado MJ. Non-vitamin K antagonist oral anticoagulants and antiphospholipid syndrome. Rheumatology. 2016 Feb 3:kev445.

Lupus Anticoagulant testing

• LA testing in patients receiving NOACsis unreliable

• False positive dRVVT may occur with rivaroxaban

• Taipan/Ecarin snake venoms, which directly activate prothrombin, can be used to detect LA

• Or after 24 hrs after last dose of Rivaroxaban

Adverse events

• Slightly lower rate of intracranial hemorrhage and death

• Gastrointestinal bleeding– IBD, diverticulosis and angiodysplasia

• Dabigatran (RE-COVER and RE-COVER II trials)– increasing age, reduced renal function, Asian

ethnicity and concomitant antiplatelet therapy• Dyspepsia

Contraindications

• All NOACs should be avoided in pregnancy andduring breastfeeding

• Severe renal and hepatic impairment• Prosthetic heart valves• High body mass index (BMI) >40 kg/m2, or

weight ≥120 kg

Sciascia S, Lopez-Pedrera C, Cecchi I, Pecoraro C, Roccatello D, Cuadrado MJ. Non-vitamin K antagonist oral anticoagulants and antiphospholipid syndrome. Rheumatology. 2016 Feb 3:kev445.

Current approved Indications

• Stroke prevention in patients with atrial fibrillation

• Prevention and management of venous thromboembolic disease

Bertoletti L, Ollier E, Duvillard C, Delavenne X, Beyens MN, De Magalhaes E, Bellet F, Basset T, Mismetti P, Laporte S. Direct oral anticoagulants: Current indications and unmet needs in the treatment of venous thromboembolism. Pharmacological Research. 2016 Jun 24.

Reversal of anticoagulation - dabigatran

• Idarucizumab (humanized dabigatran-specific (Fab) antibody fragments), in two 2.5 gram doses (total = 5 mg) intravenously, no more than 15 minutes apart

• Activated prothrombin complex concentrate, Tranexamic acid, charcoal, Hemodialysis


Reversal of anticoagulation – Xa Inhibitors

• No antidote.• Fresh frozen plasma will not be effective for

any of these• Oral activated charcoal can be used to reverse

all three of these anticoagulants• Ciraparantag and Andexanet alpha in

development


Transitioning Between Anticoagulants

• Warfarin to NOACs – Discontinue the VKA, monitor the PT/INR, and start – Dabigatran once PT/INR is <2.0– Rivaroxaban once PT/INR is <3.0– Apixaban once PT/INR is <2.0– Edoxaban once PT/INR is ≤2.5


Advantages of NOACs

• Fixed dosing and lack of a need for monitoring– once a day (rivaroxaban) or twice a day (dabigatran and

apixaban)

• Not affected by age, gender, or body-weight • Rapid onset and offset(EINSTEIN-DVT) • Less drug interactions• Cost-effectivenessSchulman S. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. NEJM 2009;36:2342–52.Landman G. Oral rivaroxaban for symptomatic venous thromboembolism. NEJM 2011;364(36):2499–510.

Disadvantages of NOACs

• Inability to titrate doses• Prohibitively high cost• No monitoring is possible if needed• Serious bleeding in renal impaired patients

and elderly more than 80 years. • No specific antidote

NOACs in APS

Rivaroxaban in antiphospholipid syndrome

• Thirty-five patients previous VTE ± PTE requiring target INR of 2–3

• Disease duration 9 (1–18) years• Erratic/Subtheurapeutic INR control • Rivaroxaban 20 mg for 10 months• Two women had worsening of menorrhagia

Savino S, Breen K, Hunt BJ. Rivaroxaban use in patients with antiphospholipid syndrome and previous venous thromboembolism. Blood Coagulation & Fibrinolysis. 2015 Jun 1;26(4):476-7.

Rivaroxaban in antiphospholipid syndrome (RAPS) protocol

• Phase II/III prospective non-inferiority RCT • APS patients with or without SLE, on warfarin,

with target INR 2.5 for previous VTE• The primary outcome was percentage change

in endogenous thrombin potential(ETP) from randomisation to day 42

Cohen H, Doré CJ, Clawson S, Hunt BJ, Isenberg D, Khamashta M, Muirhead N. Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE. Lupus. 2015 Sep 1;24(10):1087-94.

RAPS Trial..

RAPS Trial…

• The endogenous thrombinpotential indicated inferiority of rivaroxaban.

• By contrast, peak thrombin concentrations suggested noninferiority.

• 28% of patients in RAPS hadtriple positivity

RAPS Trial…

• Not inferior to that of warfarin• Quality of life (EQ-5D-5L) was significantly

better • No thrombosis or major bleeding were seen.

Serious adverse events occurred in four patients in each group

Limitations of RAPS

• Not designed to confirm clinical efficacy and long-term safety.

• Less aggressive patients were included– 28% of patients in RAPS had triple positivity– Not applicable recurrent venous

thromboembolism ,stroke or other arterial thrombosis

NOACs in VKA refractory cases

• Three patients, recurrence of thrombosis• Severe APS with multiple thrombotic

complications• Failed warfarin or had difficulties adjusting

warfarin dosing to keep INR values within the therapeutic range

Win K, Rodgers GM. New oral anticoagulants may not be effective to prevent venous thromboembolism in patients with antiphospholipid syndrome. American journal of hematology. 2014 Oct 1;89(10):1017-.

Shaefer et al case series

• Three consecutive APS patients who had had no thromboembolism recurrence on warfarin but were switched to NOACs(Dabigatran /Rivaroxaban)

• Two had arterial thrombosis• All three had recurrence

Schaefer JK, McBane RD, Black DF, Williams LN, Moder KG, Wysokinski WE. Failure of dabigatran and rivaroxaban to prevent thromboembolism in antiphospholipid syndrome: a case series of three patients. Thrombosis and haemostasis. 2014;112(5):947-50.

Rivaroxaban In Patients With Antiphospholipid Syndrome: A Series Of 12 Cases(Monitoring INR)

Son M, Wypasek E, Celinska-Lowenhoff M, Undas A. The use of rivaroxaban in patients with antiphospholipid syndrome: a series of 12 cases. Thrombosis research. 2015 May 1;135(5):1035-6.

Thrombotic events in patients with antiphospholipid syndrome treated with rivaroxaban: a series of 8 cases

Signorelli F, Nogueira F, Domingues V, Mariz HA, Levy RA. Thrombotic events in patients with antiphospholipid syndrome treated with rivaroxaban: a series of eight cases. Clinical rheumatology. 2016 Mar 1;35(3):801-5.

INDIAN SCENARIO

Indian scenario• Data analyzed in Indian patients In the Re-

NOVATE II study– Of the 179, 91 received oral dabigatran and 88

received subcutaneous enoxaparin for 28-35 days– Major VTE and VTE-related mortality was

numerically lower in the dabigatran group (7.9%) compared with the enoxaparin group (9.9%)

– Total VTE and all-cause mortality occurred in 18.7% of patients in the dabigatran group and 13.7%

Malhotra R, Babhulkar S, Sanjib KB, Clemens A, Dadi A, Iyer R, Kamath S, Mody B, Mutha S, Reddy G, Shah V. Thromboprophylaxis with dabigatran after total hip arthroplasty in Indian patients: A subanalysis of a double-blind, double-dummy, randomized RE-NOVATE II study. Asian Journal of Surgery. 2016 Apr 30

Outcome LMWH(Enoxaparin)

Oral Anti-coagulant(Dabigatran /Apixaban)

Absoluteriskdifference

P Value

Primary Efficacyoutcome

8(50 patients) 7(50 patients) -1.1 <0.0001

Secondary outcomemajor bleeding

1 2 - 0.04

Minor adverse events were nausea, vomiting, constipation, fever, hypotension etc

Prevention of Deep Vein Thrombosis in Total Knee Replacement

Elumalai Y, Dorai Kumar R, Anand V, Mohan Choudary AP. Comparison of Efficacy of Low Molecular Weight Heparin Versus Oral Anticoagulant in Indian Population for Prevention of Deep Vein Thrombosis in Total Knee Replacement. Orthopedic & Muscular System: Current Research. 2015 Feb 11;2015.

Current indications in APS

14th International Congress on Antiphospholipid Antibodies recommendation for NOACs

• VKA allergy/intolerance• DVT on/off Subtherapeutic anticoagulation

Erkan D, Aguiar CL, Andrade D, Cohen H, Cuadrado MJ, Danowski A, Levy RA, Ortel TL, Rahman A, Salmon JE, Tektonidou MG. 14th international congress on antiphospholipid antibodies task force report on antiphospholipid syndrome treatment trends. Autoimmunity reviews. 2014 Jun 30;13(6):685-96.

Take home messages

• Attractive option• Identifying the ideal patient• More real-world clinical experience• Reversal of anticoagulant effect is challenging

QUESTION

What do you think is the best feature of NOACs compared to warfarin

1. Rapid onset of action2. No need monitoring 3. Very few drug interactions4. No dietary/food restrictions5. No need for dose titration

Thank you

what is new - novel oral anticoagulants – new opportunities in rheumatology - dr i rajendra vara...

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