Dr. Khalid Khan Consultant Cardiologist

Dr. Khalid Khan Consultant Cardiologist BCUHB (Wrexham) WCS Spring Meeting 2012

When the pulse is irregular and tremulous and the beats occur at intervals, then the impulse of life fades; when the pulse is slender (smaller than feeble, but still perceptible, thin like a silk thread), then the impulse of life is small." ~2000 BC Huang Ti Nei Ching Su Wen

In the next 4 hours it is estimated that 10 patients with AF will have suffered a stroke Of these 8 patients would have been at high risk of stroke 6 patients should have been on warfarin 5 patients will end up in residential care 3 patients will go home 2 patients will die www.spafacademy.org.uk

VF Stroke Back door...

CHA 2 DS 2 VASc criteria Score Congestive heart failure/ 1 left ventricular dysfunction Hypertension 1 CHA 2 DS 2 VASc total score Rate of stroke/other TE (%/year)* 0 0.0 1 1.3 Age 75 yrs 2 Diabetes mellitus 1 2 2.2 Stroke/transient ischaemic 2 3 3.2 attack/te 4 4.0 Vascular disease 1 (prior myocardial infarction, 5 67 6.7 peripheral artery disease or aortic 6 9.8 plaque) 7 9.6 Age 65 74 yrs 1 8 6.7 Sex category 1 (i.e. female gender) 9 15.2 * Theoretical rates without therapy: assuming that warfarin provides a 64% relative reduction in TE risk (2.7% ARR), based on Hart et al. TE = thromboembolism 1 Lip GYH et al. Stroke 2010;41:2731 2738. 2 Hart RG et al. Ann Intern Med 2007;146:857 67.

The best or the worst drug in Cardiology

Warfarin better Placebo better AFASAK SPAF BAATAF CAFA SPINAF EAFT All trials RRR 64% *, ARR 2.7% (95% CI: 49 74%) 100 50 0 50 100 RRR (%) Random effects model; Error bars = 95% CI; * p>0.2 for homogeneity; Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic) Compared to a 19% RRR, 0.7% ARR for aspirin Hart RG et al. Ann Intern Med 2007;146:857 67.

50% AF in over 75yrs 25% low risk patients ts anticoagulated Only 50% high risk patients on warfarin Only 20% high risk over 75yr on warfarin

Preadmission i medications in patients t with known atrial fibrillation who were admitted with acute ischaemic stroke (high-risk cohort, n=597) Sub therapeutic warfarin, 29% No antithrombotic 29% Therapeutic warfarin, 10% Dual antiplatelet therapy, 2% Single antiplatelet agent, 29% Gladstone DJ et al. Stroke 2009;40:235 240.

Prescriber reluctance Genuine Problem! Patient reluctance

20 15 Ischaemic stroke Therapeutic range Requires dose adjustment and regular monitoring Od dds ratio 10 5 Intracranial bleed 1 0 1 2 3 4 5 6 7 8 International normalized ratio (INR) ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257 e354.

Patient Lifestyle Compliance Dietary intake of vitamin K Alcohol intake Mdi Medical Issues Numerous drug interactions Hepatic dysfunction Changes in the gut flora Pharmacogenetics CYP 2C9 & VKORC1 genes Tailored therapy Prescribers!

Do you really want some of that rat poison, which means loads of blood tests, you can t drink and you might bleed to death or perhaps p you might prefer a baby aspirin which is very good too...

Simple dosing (one size for all) Simple administration No / minimal monitoring required Wide therapeutic index High benefit Low bleeding Minimal drug / food interactions Predictable pharmacokinetics

Summary and comparisons

Dabigatran 1 3 Rivaroxaban 4,5 Apixaban 6,7 Mode of action Factor II Factor X Factor X Half life 12 14 hrs 7 11 hrs 12 hrs Dosing (in atrial fibrillation) Metabolism Excretion B.D. O.D. B.D. Esterase catalysed hydrolysis 85% Renal CYP P450 dependant and independent mechanisms CYP P450 1/3 Renal 1/4 Renal 2/3 Hepatic 3/4 Non Renal Form Capsule Tablet Tablet Dose 150 mg 110 mg (>80 yrs, verapamil or increased bleeding risk) 20 mg 15 mg (CrCL 30 49 ml/min) 5 mg 2.5 mg (2 or more: >80yr; weight <60 kg; Cr >1.5 mg/dl) B.D. = twice daily; O.D. = once daily 1. Ezekowitz MD et al. Am Heart J 2009;157:805 10; 2. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 4. Rocket Investigators. Am Heart J 2010;159:340 347; 5. Patel MR et al. NEJM 2011;365:883 91; 6. Lopes et al. Am Heart J 2010;159:331 9; 7. Granger et al. N Eng J Med 2011;365:981 92.

Dabigatran 1 3 Rivaroxaban 4,5 Apixaban 6,7 Study RE LY ROCKET AF ARISTOTLE Design PROBE Double Blind Double Blind Follow up 2 yrs 1.5 yrs 1.5 yrs Population size >18,000 >14,000 >18,000 Inclusion Nonvalvular AF + 1 risk factor Nonvalvular AF + 2 risk factors (i.e. moderate to high risk) Inclusion (CHADS) 2.1 3.5 2.1 Nonvalvular AF + 1 risk factor Primary Endpoint Warfarin comparator INR control (mean TTR) Stroke and systemic embolism Stroke and systemic embolism 64% 55% 62% Stroke and systemic embolism PROBE = prospective randomised open blinded end point; INR = international normalised ratio; TTR = time in therapeutic range 1. Ezekowitz MD et al. Am Heart J 2009;157:805 10; 2. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 4. Rocket Investigators. Am Heart J 2010;159:340 347; 5. Patel MR et al. NEJM 2011;365:883 91; 6. Lopes et al. Am Heart J 2010;159:331 9; 7. Granger et al. N Eng J Med 2011;365:981 92.

SSE vs. warfarin (ITT population) %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg 1.11 1.71 Dabigatran 110 mg 1.54 1.71 Rivaroxaban 2.1 2.4 Apixaban 1.27 1.60 0.65 (0.52 0.81) 0.90 (0.74 1.10) 0.88 (0.75 1.03) 0.79 (0.66 0.95) SSE = stroke and systemic embolism 0.5 1 1.5 Favours new orals Favours warfarin 1. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3. Patel MR et al. NEJM 2011;365:883 91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365:981 92.

Ischaemic stroke vs. Warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg 0.86 1.14 0.75 (0.58 0.97) Dabigatran 110 mg 1.28 1.14 1.13 (0.89 1.42) Rivaroxaban 1.34 1.42 0.94 (0.75 1.17) Apixaban* 0.97 1.05 0.92 (0.74 1.13) *Ischaemic or uncertain type of stroke 0.5 1 Favours new orals Favours warfarin 1.5 1. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3. Patel MR et al. NEJM 2011;365:883 91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365:981 92.

Haemorrhagic %/yr Warfarin HR stroke vs. warfarin %/yr (95% CI) Dabigatran 150 mg 0.10 0.38 0.26 (0.14 0.49) Dabigatran 110 mg 0.12 0.38 0.31 (0.17 0.56) Rivaroxaban 0.26 0.44 0.59 (0.37 0.93) Apixaban 0.24 0.47 0.51 (0.35 0.75) 0 1 2.0 Favours new orals Favours warfarin 1. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3. Patel MR et al. NEJM 2011;365:883 91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365:981 92.

All cause mortality vs warfarin %/yr Warfarin HR %/yr (95% CI) Dabigatran 150 mg 3.64 4.13 0.88 (0.77 1.00) Dabigatran 110 mg 3.75 4.13 0.91 (0.80 1.03) Rivaroxaban 1.87 2.21 0.85 (0.70 1.02) Apixaban 3.52 3.94 0.89 (0.80 0.99) 0.5 1 Favours new orals Favours warfarin 1.5 1. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3. Patel MR et al. NEJM 2011;365:883 91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365:981 92.

Major bleeding vs Warfarin HR %/yr warfarin %/yr (95% CI) Dabigatran 150 mg 3.32 3.57 0.93 (0.81 1.07) Dabigatran 110 mg 2.87 3.57 0.80 (0.70 0.93) Rivaroxaban 3.6 3.4 34 1.04 (0.90 1.20 Apixaban 2.13 3.09 0.69 (0.60 0.80) 0.5 1 Favours new orals Favours warfarin 1.5 1. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3. Patel MR et al. NEJM 2011;365:883 91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365:981 92.

Intracranial bleeding vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg 0.32 0.76 0.41 (0.28 0.60) Dabigatran 110 mg 0.23 0.76 0.30 (0.19 0.45) Rivaroxaban 05 0.5 07 0.7 067 0.67 (0.47 0.93) 093) Apixaban 0.33 0.80 0.42 (0.30 0.58) 0 1 2.0 Favours new orals Favours warfarin 1. Connolly SJ et al. N Engl J Med 2009;361:1139 51; 2. Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3. Patel MR et al. NEJM 2011;365:883 91 and Supplementary Appendix; 4. Granger et al. N Eng J Med 2011;365:981 92.

Patients asking for NOACs As soon as trials published Following approvals Aware of NICE guidelines Empowered patient Clear agenda coming in to clinic Good understanding of cost and other issues AFA and other professional website

Dabigatran Aug 2009 RELY trial Sept 2011 EMA approval March 2012 NICE TA299 Rivaroxaban Nov 2010 ROCKET AF trial Dec 2011 EMA approval March 2012 NICE FAD Apixaban Aug 2011 ARISTOTLE trial Not licensed yet?august NICE

The aim of this advice is to promote the safe and effective use of dabigatran within its licensed indication in BCUHB for the prevention of stroke and systemic embolism for patients with nonvalvular atrial fibrillation. The advice: 1. Warfarin, with dose titrated to a target INR of 2 to 3, remains the anticoagulant of choice for stroke prevention in AF. The focus of AF management should be to identify patients with AF and undertake stroke risk assessment using the CHADS 2 risk assessment tool, or more recently introduced CHA 2 DS 2 - VASc risk assessment tool (see Appendix 1). Patients with a CHADS 2 / CHA 2 DS 2 -VASc score 2 should be initiated on warfarin in the first instance, unless contraindicated. 2. In warfarin naive patients, if there are compelling reasons (see below) not to initiate warfarin then dabigatrang initiation should be undertaken only by Secondary Care clinicians specialising in stroke prevention in AF (eg Cardiology or the Stroke team). However in this group of patients continued prescribing by General Practitioners is appropriate i.e. dabigatran's BRAG List designation for stroke prevention in AF is AMBER WITHOUT SHARED CARE. Compelling reasons include patients who are: Unable to take warfarin due to allergy or contraindications (that is not otherwise a contraindication to anti-coagulant therapy in general). Note that a bleeding risk that would lead to contra-indication of warfarin would also contra-indicate dabigatran. 3. For patients prescribed warfarin previously dabigatran will only be considered as an alternative to warfarin for stroke prevention in AF in patients who are: Unable to achieve an INR within the target therapeutic range (TTR) for at least 50% of the time over a period of 6 months (excluding first month after initiation) on warfarin. The TTR can be calculated automatically with most INR monitoring software systems.

Travel Issues International businessman Remote residence can t easily get to hospital Dosing difficulties Innumerate Can t do / Confused changing doses warfarin Pill boxes won t do d Warfarin Fear adverse events Family members problems Risk of intracranial bleeds Refusal QOL dietary restrictions Good pt vs. Bad patient (rewarded)

Simple defined population type Good clinical trial Approval for use Select difficult patients (outside trial) Uncertain / poor outcomes Lack of confidence/ drug experience

High risk but not anticoagulated High bleeding risk/event Professional reluctance Patient reluctance New Agents Patient difficulty warfarin On Warfarin Continue on Warfarin

Loss of income / service primary care? Will not eliminate i anti coagulation lti clinics i (immediately) Other conditions needing warfarin (presently) True bleeding or high unacceptable risk Low risk patients Patients happy and stable on current Rx

Reversibility Is this really a big issue? Antidotes in development Monitoring? Don t do for most other anti thrombotics Crude assessments possible Clinical scenarios Cardioversion EP studies ACS & PCI difficult area Confusion doses for other indications (e.g. VTE prophylaxis, DVT/PE Rx)

Duty of care to patient Informed consent Laying out of all options balanced & objective Risk and benefits as applicable to patient Patient choice and partnership p Legal status of NICE / AWMSG decision Cannot force warfarin on a patient Can we deny any other treatment i.e. none? Yet to be tested in court

SPAF remains an unmet need Warfarin remains a good option (tried & tested) But for many patients ( & prescribers) not acceptable New oral anticoagulants t offer Equivalent / greater efficacy in SPAF cf. warfarin Greater safety for intracranial bleeds Significant QOL benefits for many patients Challenge implementation: Patient vs. Clinician vs. Organisation Issue for today 5 years NOACs will be routine