A place for new oral anticoagulants in medicine: a fast evolving story

Transcription

1 A place for new oral anticoagulants in medicine: a fast evolving story Prof Beverley Hunt MB ChB, FRCP, FRCPath, MD Chair of Thrombosis & Haemostasis, King s College, London Medical Director of Lifeblood: the thrombosis charity

2 Conflicts of interest None I have not taken any funding from pharmaceutical companies producing anticoagulant drugs since 2010 I am medical director of Thrombosis UK. In 2014 the trustees voted not take any funding from pharmaceutical companies

3 Objectives Discuss old vs. new Reversing agents Politics!

4 So what is wrong with Warfarin? Pros Huge clinical experience Highly efficacious VTE treatment and secondary prevention; stroke prevention in AF; mechanical valves Predictably reversible (Vit K; PCCs e.g. Beriplex) Cons Bleeding risk is high Prolonged effect, bridging is as nightmare Pharmacokinetics unpredictable Requires regular INR monitoring Drug interactions Food interactions including alcohol

5 The Narrow Therapeutic Window of Warfarin Odds ratio for event 10 5 Ischaemic stroke Target INR Intracranial bleeding International normalized ratio 8.0 Adapted from Wann et al. Circulation 2011;123;e269-e367

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7 So what is a perfect anticoagulant? Effective Oral Fast onset of action Short half life Predictable pharmacokinetics No drug/food interactions Fully reversible Do the DOACs fulfill these criteria?

8 Alternatives to Vitamin K antagonists NOACs NOACs TSOACs DOACs New Oral Novel Anticoagulants Oral Anticoagulants Non-VKA Oral Anticoagulants s Target Specific Oral Anticoagulants Direct oral anticoagulants

9 DOACs predictable dose response no need for routine monitoring reduced need for dose adjustment no food interactions limited drug interactions

10 So where are they licensed? Dabigatran Rivaroxaban Apixaban Prevention of VTE post Hip & Knee Replacement Prevention of Stroke in AF Treatment of acute VTE Prevention of recurrence of VTE Acute Coronary Syndrome SmPC Dabigatran, Rivaroxaban, Apixaban Plus edoxaban

11 So what do NICE (& Scottish Medicines Agency) agree they do? Prevention of VTE post Hip & Knee Replacement Dabigatran Rivaroxaban Apixaban TA157 TA170 TA245 Prevention of Stroke in AF TA249 TA256 TA275 Treatment of acute VTE TA327 TA287 TA341 Prevention of recurrence of VTE TA237 TA287 TA341 Acute Coronary Syndrome TA335 SmPC Dabigatran, Rivaroxaban, Apixaban

12 Coagulation & direct oral anticoagulants (DOACs) tissue factor:viia IX VIIIa IXa X Va Xa rivaroxaban apixaban edoxaban prothrombin thrombin dabigatran fibrinogen fibrin

13 RE-LY Study (18,000 patients) Stroke / SSE 1.8 RR 0.91 (95% CI: ) p<0.001 (NI) RR 0.66 (95% CI: ) p<0.001 (sup) % per year RRR 34% D110 mg BID D150 mg BID Warfarin 182 / 6, / 6, / 6,022 New Engl J 2009; 361: 1139

14 Haemorrhagic stroke RR 0.31 (95% CI: ) 50 p<0.001 (sup) RR 0.26 (95% CI: ) p<0.001 (sup) Number of events RRR 69% RRR 74% % % % 0 D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022

15 DOACs versus warfarin in patients with AF Study All-cause Stroke and sytemic embolism RE-LY ROCKET AF ARISTOTLE Subtotal (I-squared = 55.9%, p = 0.104) RR (95% CI) 0.66 (0.53, 0.82) 0.88 (0.75, 1.03) 0.80 (0.67, 0.95) 0.78 (0.67, 0.92) Ischemic and unspecified stroke RE-LY ROCKET AF ARISTOTLE Subtotal (I-squared = 0.0%, p = 0.522) Hemorrhagic stroke RE-LY ROCKET AF ARISTOTLE Subtotal (I-squared = 52.2%, p = 0.124) 0.77 (0.61, 0.99) 0.91 (0.73, 1.13) 0.92 (0.75, 1.14) 0.87 (0.77, 0.99) 0.26 (0.14, 0.50) 0.58 (0.37, 0.92) 0.51 (0.35, 0.75) 0.45 (0.31, 0.68) RE-LY: dabigatran; ROCKET AF: rivaroxaban; ARISTOTLE: apixaban Favors NOA Therapy Favors Warfarin Therapy Miller SC et al. April 27,Am J Cardiol 2012

16 Pharmacodynamics of new oral direct inhibitors Taken from Kaatz et al Am J Hematol 2012;S141

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18 NICE AF QSs ask all AF patients at risk of stroke are offered VKA & DOAC & doc & pt make joint decision..

19 Myths of the DOACs -What patients are told! We do not have the experience with these new drugs! We can not monitor these new drugs! We can not reverse these drugs and you will just bleed! They will bankrupt the NHS! The Clinical Commissioning group says no! You must try warfarin before you can have them! If you wont try warfarin you can not have them! You can only have them if your warfarin is poorly controlled! You must take them regularly This is actually true!

20 Guideline for Management of Acute Deep Vein Thrombosis in Non Pregnant Patients Consider referring to Vascular Surgery SpR (via switchboard) for catheter-directed thrombolytic therapy if symptomatic iliofemoral DVT with symptoms <14 days duration AND good functional status AND a life expectancy of 1 year or more AND a low risk of bleeding Table 1: Contra-indications to Rivaroxaban Significant liver disease Pregnancy of Breastfeeding Creatinine clearance <30mls/min Concomitant use of cytochrome P-450 3A4 inhibitors: eg fluconazole, anti-retrovirals Currently not recommended in active cancer patients should receive enoxaparin or UFH Table 2: Provoking factors for DVT Yes Is rivaroxaban suitable? (See table 1 for contra-indications) Yes Is egfr >30mls/minute? No No No Prescribe UFH (See unfractionated heparin infusion guideline) Any of the following are considered to be transient risk factors within 3 months of DVT: Surgery Trauma Acute medical illness Long haul flight (>4 hours) Significant immobility Pregnancy or post partum Hormonal therapy (OCP or HRT) Prescribe rivaroxaban 15mg bd for three weeks, then 20mg od Prescribe enoxaparin thereafter (15mg od if creat 1.5mg/kg once daily clearance 30-49ml/min). Arrange for patient to be seen on the next working day by Thrombosis Nurse Specialist ( thrombosishelp@gstt.nhs.uk or Bleep 0122). Please provide patient name, DOB, hospital number and their contact telephone number. Ensure enough rivaroxaban or enoxaparin is supplied. Patients prescribed enoxaparin will be switched to warfarin, except those with active cancer, who will continue enoxaparin for entire duration of anticoagulation). All patients with unprovoked DVT (see table 2 for provoking factors) will be reviewed by the Thrombosis Team regarding the need for further investigations & duration of anticoagulation (table 4). Table 3: Are further investigations needed? - Those with provoked DVT do not require further investigation. - For unprovoked DVT consider: 1: Investigations for cancer If patient is >40 years old: perform history, full physical examination, chest X-ray,FBC, liver function tests, calcium and urinalysis. (CT Abdo/pelvis and mammogram if above normal). 2: Thrombophilia testing There is no role for thrombophilia screening if it is not planned to stop anticoagulation. If it is planned to stop treatment, screen for antiphospholipid antibodies. Screen for hereditary thrombophilia if patients have a first degree relative with previous VTE. Table 4: Duration of anticoagulation Provoked: Three months if first calf or proximal lower limb DVT. At least 6 months if proximal DVT and cancer is provoking factor for DVT Unprovoked: Three months if calf DVT. At least 6 months treatment if first proximal lower limb DVT, and indefinite depending on risk of recurrence DTC ref 12035q. Review by Mar 2014

21 Efficacy/safety separate for Xa and IIa Van Es et al. Blood 2014

22 NICE s Incremental Cost-effectiveness Ratios (ICER) for rivaroxaban in secondary prevention of venous thromboembolism Patient group ICER ( /QALY) Meaning 3 months anticoagulation RIV dominates Rivaroxaban is cost saving and more effective than standard of care 6 months anticoagulation 3,200 Rivaroxaban cost-effective 12 months anticoagulation 14,900 Rivaroxaban cost-effective Long term 19,400 Rivaroxaban cost-effective Cancer N/A N/A NICE. Technology appraisal guidance 261. July 2012

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24 Different set of drug interactions from VKAs NOT metabolised by cytochrome P450 Low protein binding BUT Affected by drugs using P-glycoprotein Inhibitors- azole antimicrobials &HIV protease inhibitors Substrates- digoxin, midazolam Inducers- rifampicin

25 Drug interactions

26 Bridging DOACs -timing of last dose Renal function (CrClml/min Low risk Anti Xas Rivaroxaban, apixaban, edoxaban High risk AntiXas Low risk surgery Anti Iia dabigatran High risk surgery Dabigatran >80 24hrs 48hrs 24 hrs hrs 48hrs hrs 48hrs Post op-use LMWH to bridge until bleeding risk is low

27 Limitations of DOACs Specific antidotes not available yet Assessment of anticoagulant activity is complicated Adherence difficult to assess

28 DOACs in Patients with Active Cancer & VTE 10% of all VTE have active cancer Current Rx is full dose LMWH Few patients studied (total of 962) Comparator was warfarin and not LMWH

29 Cancer & DOACs Van Es et al. Blood 2014

30 Impact of rivaroxaban and dabigatran on commonly used coagulation tests. PT (INR) APTT Fibrinogen Thrombin T Ecarin clotting Dabigatran /no change* Rivaroxaban No change No change No change Effect dependent on dose, time since Rx and renal function Standard effect of dabigatran is APTT hours after stopping APTT And giving FFP will NOT reverse the prolonged tests.. *Thrombin-based fibrinogen assays can yield falsely low fibrinogen levels in the presence of high concentrations of direct thrombin inhibitors.

31 Can the lab help? 1) Management depends on the severity of bleeding 2) The time of last dose of NOAC should be determined and the half-life can be estimated from measurement of serum creatinine and calculation of CrCl 3) The anticoagulant activity can be determined semiquantitively by PT/INR affected by anti Xas Thrombin time by dabigatran 4) BUT only rivaroxaban has a linear relationship with PT 5) Many labs now measure quantative= functional activity anti Xa activity (similar to LMWHs)

32 Effect of rivaroxaban on coagulation assays Samama et al Thromb Haemostas 2010;103:815

33 Other areas to explore? All successful studies in patients normally with INR target of 2-3 RAPS study rivaroxaban in APS patients with previous DVT or PE & INR target of 2-3 Does not give constant 24/7 anticoagulation but peaks & troughs In a phase 2 trial, patients with mechanical heart valves were randomly assigned to receive either dabigatran or warfarin for anticoagulation. Dabigatran was associated with higher rates of ischemic stroke (5%, vs. 0% with warfarin) and major bleeding (4% vs. 2%). Eikelboom J et al New Engl J Med 2013

34 Bleeding with NOACs Comparative data Reversing Antidotes Clinical trials

35 Bleeding components Van Es et al. Blood 2014

36 Bleeding rates in new users of dabigatran and warfarin Oct 2010-Dec 2011 (Mini Sentinel database) Southworth et al, Editorial New Engl J Med 14 th March 2013 Dabigatran Warfarin Analysis Patients Event Incidence per 100,00 Patients Event 100,000 GI haemorrhage with AF 10, , Intracranial haemorrhage 10, , Reassuringly similar rates to RE-LY

37 Antidotes for DOACs Dabigatran-directed antibody Andexanet alfa

38 Andexanet Alfa Recombinant factor Xa with (a) active site serine replaced with alanine, and (b) Gla-domain deleted Serves as a decoy by binding factor Xa inhibitors Lu G et al., Nat. Med. 19;446, 2013

39 Mechanism of Action of Andexanet alfa Yeh C et al., Circ. Res. 113:945, 2013

40 DabiFab Antibody= idaruzicumab =Prazbind Fab fragment of a humanized mouse antibody against dabigatran Binds dabigatran, but not thrombin No anticoagulant or procoagulant activity Licensed in the UK, Europe & North America Schiele F et al., Blood 121:3554, 2013

41 Current management of bleeding Stop drug with DOAC Consider activated charcoal Manage as per other bleeders Consider PCC 50iu/Kg Use Prazbind in life threatening bleeding with dabigatran if available

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