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New Oral Anticoagulants the Who, What, When & How Dr. Farooq Faheem

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Importance of stroke prevention in NV-AF patients

Overview of new treatments available Efficacy, clinical & safety data Treatment pathways and guidelines (BNSSG) &

REAL LIFE CASES

Mr. M. R. 62 Years of age

Lives aloneSingle

3Past History1998: Diabetes2004 : Presented with ataxia confusion and headaches ? Cause2007: Slurred speech and confusion : Put down to alcohol intoxification August 2011: Slurred speech, facial drop AF and diagnosed with TIA/CVA and warfarinised4BackgroundSmokes 20 + cpd (mixture of tobacco and cigarettes)

Alcohol up to 2- 3 bottles of cider per day

Hypertension

Echocardiogram: Severe LV dysfunction & Biatrial dilatation

COPD with frequent exacerbations

Obesity with obstructive sleep apnea

Dr. Farooq Faheem5

Background

Lives alone approx. 3 miles from the practiceNo transportNever marriedNot worked since 1998One sister in Weston 8 miles away

6ProgressFrom Sept 2011 to February 2012: did very well with INR testing 20 x INR tests between March 12 to Aug 2012

Average INR 6.3 (Venous 8.9)

? Back to drinking heavily7ProgressDiscussed at Partners meeting following complaints from District Nurses about his:

FEROCIOUS..8NO MORE EXCUSES

9DiscussionsActual visits were twice as many according to District nurses

Would not wake up until late afternoon.

DN unable to get access to the house.

Substantial risk of falls

10Started on NOAC November 2012Added to his Dosette Box

Happy District Nurses!

Latest audit: No blood samples taken as unable to get access to his house11One has to do what one has to do!

12Mrs. D.W. 82 Years of age

Lives alone

13BackgroundActive extremely well and totally asymptomaticHypertension 2006. Ramipril was prescribed.

She never took it!December 2010: near fainting and speech slurred and vacant for approx. 30 minutes

Declined admission, all medications including aspirin Put it down to worrying over Christmas period14BackgroundNever SmokedAlcohol : One/Two units per Year!

HypertensionGrows almost all of her vegetables. Extremely active

Large Family scattered around the UK and the world (Son in Canada, Daughter in France)

Dr. Farooq Faheem15July 2012

Presented with SOBOEShe put it down to gaining a bit of weightAll baseline bloods normalCXR: Normal

16ECG

17ProgressExplained: Very skeptical

Wanted to check herself : ON THE INTERNET!

To discuss with her family

Leaflet for warfarin and NOACs18ProgressFlatly refused to take warfarin

Most of her diet was from her home grown vegetables

Started on NOAC

19One week later.20

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A Worried Doctor!

TOTALLY CHILLED PATIENT!

Asked her to stop medication and return a week later to discuss warfarin AGAIN!22No show..FOUR WEEKS LATER:

WANTED REPEAT PRESCRIPTION FOR..

23What happened?PRESENTED TO EYE CASUALTY AT BRISTOL EYE HOSPITAL THE SAME EVENING. as did not trust my advice!

OPHTALMOLOGIST REASSURED HER: MINOR BRUISING: No long-term consequences

THEY SUGGESTED SHE CONTINUES WITH NOAC24A VERY RELIEVED DOCTOR INDEED!25

Patients with AF have an approximately fivefold increased risk of ischaemic stroke1 2-year age-adjusted incidence of stroke/1,000Individualswith AF*Individualswithout AF Risk ratio=4.8p65), Drugs/alcohol concomitantly; INR: International Normalised Ratio; NSAIDs: Non-steroidal anti-inflammatory drugs; OAC: Oral anticoagulation; ULN: Upper limit of normalReferencesCamm AJ et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369429. Erratum in: Eur Heart J 2011;32:1172. Camm AJ et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: An update of the 2010 ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2012;e-published August 2012, doi:10.1093/eurheartj/ehs253Pisters R et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010;138:1093100.

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Risk factorPointsCongestive heart failure/LV dysfunction+1Hypertension+1Age 75 years+2Diabetes mellitus+1Stroke/TIA/TE+2Vascular disease (MI, aortic plaque, PAD)*+1Age 6574 years+1Sex category (female)+1Cumulative scoreRange 09CHADS2 and CHA2DS2-VASc both available in GRASP-AFhttp://www.improvement.nhs.uk/graspaf/- accessed 07/09/2012ESC 2012 recommendations risk assessment37RecommendationsClassLevelThe CHA2DS2-VASc score is recommended as a means of assessing stroke risk in non-valvular AF.IAAssessment of the risk of bleeding is recommended when prescribing antithrombotic therapy (whether with VKA, NOAC, ASA/clopidogrel, or ASA).IAThe HAS-BLED score should be considered as a calculation to assess bleeding risk, whereby a score 3 indicates high risk.IIaACamm et al. Eur Heart J 2012;e-published August 2012, doi:10.1093/eurheartj/ehs253.Date of Preparation: October 2013. 432UK13PR10268-01. Not for further distribution.AbbreviationsAF: Atrial FibrillationASA: Acetyl salicylic acidCHA2DS2-VASc: Congestive heart failure, Hypertension, Age 75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 6574, and Sex category (female)ESC: European Society of CardiologyHAS-BLED: Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65), Drugs/alcohol concomitantly; INR: International Normalised Ratio NOAC: Novel oral anticoagulantsVKA: Vitamin K antagonistsReferencesCamm AJ et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: An update of the 2010 ESC Guidelines for the management of atrial fibrillation. Eur Heart J 2012;e-published August 2012, doi:10.1093/eurheartj/ehs253.37ESC 2012 recommendations antithrombotic therapy38RecommendationsClassLevelAntithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except in those patients (both male and female) who are at low risk (aged 18,000>14,000>18,000InclusionNonvalvular AF + 1 risk factorNonvalvular AF + 2 risk factors (i.e. moderate to high risk)Nonvalvular AF + 1 risk factorInclusion (CHADS)2.13.52.1Primary EndpointStroke and systemic embolism Stroke and systemic embolism Stroke and systemic embolism Warfarin comparator INR control (mean TTR)64%55%62%PROBE = prospective randomised open blinded end-point; INR = international normalised ratio; TTR = time in therapeutic range47New agents: Stroke, systemic embolism vs warfarinSSE vs warfarin (ITT population)%/yrWarfarin%/yrHR(95% CI)Dabigatran 150 mg1.111.710.65 (0.52-0.81)Dabigatran 110 mg1.541.710.90 (0.74-1.10)Rivaroxaban2.12.40.88 (0.75-1.03)Apixaban1.271.600.79 (0.66-0.95)1. Connolly SJ et al. N Engl J Med 2009;361:113951; 2. Connolly SJ et al. N Engl J Med 2010;363:18751876; 3. Patel MR et al. NEJM 2011;365:88391 and Supplementary Appendix;4. Granger et al. N Eng J Med 2011;365:981-92.Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information.Favours new orals Favours warfarin 0.511.5SSE = stroke and systemic embolism New agents: Ischaemic stroke vs warfarin0.51Ischaemic stroke vs warfarin%/yrWarfarin%/yrHR(95% CI)Dabigatran 150 mg0.861.140.75 (0.58-0.97)Dabigatran 110 mg1.281.141.13 (0.89-1.42)Rivaroxaban1.341.420.94 (0.75-1.17)Apixaban*0.971.050.92 (0.74-1.13)Clinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information.1. Connolly SJ et al. N Engl J Med 2009;361:113951; 2. Connolly SJ et al. N Engl J Med 2010;363:18751876; 3. Patel MR et al. NEJM 2011;365:88391 and Supplementary Appendix;4. Granger et al. N Eng J Med 2011;365:981-92.Favours new orals Favours warfarin1.5*Ischaemic or uncertain type of strokeNew agents: Haemorrhagic stroke vs warfarin1. Connolly SJ et al. N Engl J Med 2009;361:113951; 2. Connolly SJ et al. N Engl J Med 2010;363:18751876; 3. Patel MR et al. NEJM 2011;365:88391 and Supplementary Appendix;4. Granger et al. N Eng J Med 2011;365:981-92.Favours new orals Favours warfarinHaemorrhagic stroke vs warfarin %/yrWarfarin%/yrHR(95% CI)Dabigatran 150 mg0.100.380.26 (0.14-0.49)Dabigatran 110 mg0.120.380.31 (0.17-0.56)Rivaroxaban0.260.440.59 (0.37-0.93)Apixaban0.240.470.51 (0.35-0.75)012.0New agents: Intracranial bleeding vs warfarinClinical Trial Data for information only - no clinical conclusions should be drawn. Please refer to individual product SPCs for further information.1. Connolly SJ et al. N Engl J Med 2009;361:113951; 2. Connolly SJ et al. N Engl J Med 2010;363:18751876; 3. Patel MR et al. NEJM 2011;365:88391 and Supplementary Appendix;4. Granger et al. N Eng J Med 2011;365:981-92.Intracranial bleeding vs warfarin%/yrWarfarin%/yrHR(95% CI)Dabigatran 150 mg0.320.760.41 (0.28-0.60)Dabigatran 110 mg0.230.760.30 (0.19-0.45)Rivaroxaban0.50.70.67 (0.47-0.93)Apixaban0.330.800.42 (0.30-0.58)Favours new orals Favours warfarin012.0Clinical pharmacologyApixaban1Rivaroxaban215 & 20mgDabigatranDabigatran3Mechanism of actionDirect factor Xa inhibitorDirect factor Xa inhibitorDirect thrombin inhibitorOral bioavailability~50%80100% with food~6.5%Pro-drugNoNoYesFood effect on bioavailabilityNoYes (20 mg and 15 mg doses taken with food)NoRenal clearance~27%~33 % *85%DialysisNot recommendedNot dialysableDialysableMean half-life (t1/2)~12 h11-13 h in elderly5-9 h in younger pts 1214 hTmax34 h24 h0.52 h direct renal excretion as unchanged active substanceNo head-to-head clinical trial comparisons between apixaban, rivaroxaban and dabigatran have been performed. The information in this table is based on the SmPCs for apixaban, rivaroxaban and dabigatran. Please refer to the relevant SmPCs for further information1. Apixaban SmPC, September 2013 Available at: http://www.medicines.org.uk/emc/medicine/24988. Date accessed: October 2013. 2. Rivaroxaban SmPC, February 2013. Available at: http://www.medicines.org.uk/emc/medicine/24988. Date accessed: April 2013. 3. Dabigatran Etexilate SmPC, February 2013. Available at: http://www.medicines.org.uk/emc/medicine/20760. Date accessed: April 2013. Date of Preparation: October 2013. 432UK13PR10268-01. Not for further distribution.5252In the ARISTOTLE trial, for every 1000 NVAF patients treated for 1.8 years, apixaban as compared with warfarin prevented:6 strokes15major bleeds8deathsPrespecified hierarchical sequential testing was performed first on stroke/systemic embolism (primary efficacy endpoint) for non-inferiority, then for superiority, then on major bleeding, and finally on death from any cause (secondary endpoint).53Granger et al. N Engl J Med 2011;365:98192.Date of Preparation: October 2013. 432UK13PR10268-01. Not for further distribution.AbbreviationsAF: Atrial fibrillation

ReferencesGranger CB et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:98192.

53Local and National GuidanceBNSSG guidance on anticoagulation in AF

http://www.bnssgformulary.nhs.uk/Local-Guidelines/ESC 2012 recommendations choice of anticoagulant57Non-valvular AFValvular AF*65), Drugs/alcohol concomitantly; INR: International Normalised Ratio; NOAC: novel oral anticoagulants; NVAF: non-valvular atrial fibrillation; OAC: oral anticoagulant; VKA: vitamin K antagonists Adapted from Camm et al. Eur Heart J 2012;33:2719-47(apixaban is not recommended for patients with prosthetic heart valves )

Date of Preparation: October 2013. 432UK13PR10268-01. Not for further distribution.57NOACS for stroke and systemic embolism in non-valvular AFPractical Issues: What do I do in my every day practice?

YVMP Audit of Patients on Rivaroxaban

JULY 2012 To July 2013Before TreatmentFull discussion of CHA2DS2Vasc risks

Leaflets on Warfarin and NOACs

Risks and benefits of ALL drug group explainedBefore Treatment

FBC, ELEC LFTs and Clotting screenPatient sent home to read the leaflets and decide&Ask Dr. Google if he/she or family wished Full documentation in medical records

After treatment startedRepeat FBC Creatinin eGFR, LFTs between 6-12 weeks

Fill in Patient alert card with the prescription

Ask to treat the medications as if on warfarin

Compliance stressed

Up to 31st July 2013 Total of 41 Patients18 Female and 23 Male Age range 52- 893 DVT and 38 AF patientsFour transfer from Warfarin 1 From DabigatranOne patient stopped so far because ? Pruritis65Follow upTwo dose reduction: one eGFR drop and one Chemo affecting renal functionTwo no Post NOACs blood.1 Change from Warfarin b/c of lifestyle: travelling a lot

NO significant Hb or eGFR change otherwise

66When give the choice:All patients have chosen NOACs

Novel instead of Old

The difference?67Absolutely Crucial

How can you support your local clinicians?ANY QUESTIONS?

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