NOACS AND AF PEARLS AND PITFALLS DR LAURA YOUNG HAEMATOLOGIST

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1 NOACS AND AF PEARLS AND PITFALLS DR LAURA YOUNG HAEMATOLOGIST

2 NGAIRE IS 70 YEARS OLD AND IN AF. SHE HAS NO MURMURS, NORMAL BLOOD PRESSURE, EGFR OF 65ML/MIN AND NO SIGNIFICANT PAST MEDICAL HISTORY. REGARDING STROKE RISK, WHICH OF THE FOLLOWING IS THE OPTIMAL STRATEGY FOR NGAIRE AT THIS TIME?

3 A. Warfarin with an INR target of 2-3 B. Dabigatran 150mg twice daily, or a Xa inhibitor if available C. Aspirin 100mg daily D. No treatment required to reduce stroke risk E. Warfarin with an INR target of and aspirin 100mg daily

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5 RISK STRATIFICATION IN AF

6 CHADS 2 score of 0-1: stroke rate (off VKA) CHA 2 DS 2 -VASc 0: 0.8/100py CHA 2 DS 2 -VASc 1:1.8/100py CHA 2 DS 2 -VASc 2: 3.7/100py Olesen Thromb Haemost 2012 Aspirin does not reduce stroke risk or mortality in AF

7 THE MILLION DOLLAR QUESTION WHICH NOAC DO I CHOOSE?

8 FDA Approvals: Awaiting funding assessment for AF?Sept 2014 Rivaroxaban Apixaban VTE & AF Dabigatran AF Approved and fully funded in NZ VTE & AF

9 THINGS THEY HAVE IN COMMON All are fixed doses without monitoring (at the moment!) All are contraindicated with a Creatinine clearance (including weight/gender/age) of <(25-)30ml/min All are direct inhibitors so cannot be reversed by simple replacement of the clotting factor All have lower rates of intracranial haemorrhage than warfarin Tend to have more GI bleeding

10 POINTS OF DIFFERENCE BETWEEN THE NOACS Dose frequency (dabigatran, apixaban bd, rivaroxaban od) Half-life (CrCl) Dabigatran 13h (>80) to 18h (30-50) 80% renal Rivaroxaban 8h (>80) to 9h (30-50) Apixaban 15h (>80) to 17h (30-50) 33% renal 25% renal Apixaban and rivaroxaban were dose adjusted for renal impairment Apixaban had less bleeding complications than warfarin in the randomised trial populations Only apixaban improved overall mortality, but by a very small margin

11 NGAIRE IS NOW 84, IN AF, WITH A HISTORY OF A PREVIOUS CVA; HER INR IS A BIT LABILE ON WARFARIN. HER CREATININE CLEARANCE IS 40ML/MIN. HER CHA 2 DS 2 -VASC IS 5 AND HER HAS-BLED SCORE IS 4. WHICH NOAC???? RISK OF MAJOR BLEEDING ON WARFARIN UP TO 8%/YEAR

12 FROM THE CLINICAL TRIALS Dabigatran does have an interaction between age and bleeding Re-analysis of RE-LY using the European criteria of 150mg in patients <80 with a HAS-BLED of <3 improves the bleeding risk profile; 110mg in this patient Rivaroxaban is equivalent to warfarin in patients >75 or CrCl 30-50ml/min Apixaban is safer than warfarin in those who are older and/or with renal impairment ICH is reduced with all agents in this group IF I could choose.

13 CAVEATS WHEN COMPARING NOACS The trials were all quite different: Apixaban adjusted for age/weight/cr Rivaroxaban adjusted for CrCl Different populations eg Rivaroxaban higher CHADS 2 NO head to head comparisons Real world experience is observational, therefore comorbidity might have influenced treatment choice Little published real world Xa inhibitor experience UNKNOWN if one is superior to the others in high risk populations

14 EMERGENCY REVERSAL Still no optimal strategy We are about to start a single arm clinical trial of a dabigatran reversal agent which in phase II data looks good A combination of prothrombin complex concentrates and activated products may work for Xa inhibitors Clinical trials of Xa reversal products in progress internationally

15 ELECTIVE PROCEDURES WHEN TO STOP No bridging required Minor procedure Major procedure CrCl>50ml/mi n Last dose 24h Last dose 72h CrCl<50ml/mi n Xa inhibitor Last dose 48h Last dose 72h Dabigatran Last dose 48-72h Last dose 96h Modified from ASTH guidelines Int Med J 2014 (Tran et al)

16 CONTRAINDICATIONS TO NOACS Mechanical valves Valvular AF CrCl<25-30ml/min (needs more research/dose adjustment) Pregnant/breastfeeding Hepatic abnormalities..cirrhosis or high transaminases Are NOACs safer in patients who have had an intracranial bleed unknown

17 NGAIRE IS 70 YEARS OLD AND IN AF. SHE HAS NO MURMURS, NORMAL BLOOD PRESSURE, EGFR OF 65ML/MIN AND NO SIGNIFICANT PAST MEDICAL HISTORY. REGARDING STROKE RISK, WHICH OF THE FOLLOWING IS THE OPTIMAL STRATEGY FOR NGAIRE AT THIS TIME?

18 A. Warfarin with an INR target of 2-3 B. Dabigatran 150mg twice daily, or a Xa inhibitor if available C. Aspirin 100mg daily D. No treatment required to reduce stroke risk E. Warfarin with an INR target of and aspirin 100mg daily

19 CONCLUSIONS NOACs are the treatment of choice for stroke prevention in AF CHA 2 DS 2 -VASc stratifies low risk patients and any woman over 65 will have a score of at least 2 In general NOACs are easy to use and have less intracerebral haemorrhage There is however a tendency to more GI bleeding Consideration of renal function is very important and this should be monitored intermittently beware of acute deterioration in illness Elderly patients are high risk for both bleeding and thrombosis, and selection of one NOAC over another is tricky due to lack of head to head comparisons

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21 MONITORING Assays are available for all three NOACs approaching the market Used in hospital for evaluating levels in emergency situations Variability in general coagulation assays

22 RE-LY PK & OUTCOME