Dr. Khalid Khan Consultant Cardiologist BCUHB (Wrexham) BCUHB (Wrexham) WCS Spring Meeting 2012
Dr. Khalid KhanConsultant Cardiologist
BCUHB (Wrexham)BCUHB (Wrexham)
WCS Spring Meeting 2012
“When the pulse is irregular and p gtremulous and the beats occur at intervals, then the impulse of life fades; when the then the impulse of life fades; when the pulse is slender (smaller than feeble, but
still perceptible thin like a silk thread) then still perceptible, thin like a silk thread), then the impulse of life is small."
~2000 BC ‐Huang TiNei Ching Su Wen
In the next 4 hours itis estimated that…
10 patients with AF willhave suffered a stroke…
Of these…
ld h8 patients would havebeen at high risk of stroke…
6 patients should havebeen on warfarin…
5 patients will end up inresidential care…
3 patients will go home…
2 patients will die…
www.spafacademy.org.uk
p
VFVF
StrokeStroke
Back door...
CHA2DS2‐VASc criteria Score
Congestive heart failure/left ventricular dysfunction
1
CHA2DS2‐VASc total score
Rate of stroke/other TE (%/year)*
0 0.0Hypertension 1
Age ≥75 yrs 2
Diabetes mellitus 1
1 1.3
2 2.2Diabetes mellitus 1
Stroke/transient ischaemicattack/TE
2
Vascular disease 1
3 3.2
4 4.0
5 6 7Vascular disease(prior myocardial infarction, peripheral artery disease or aortic plaque)
1 5 6.7
6 9.8
7 9.6Age 65–74 yrs 1
Sex category (i.e. female gender)
18 6.7
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.
1 Lip GYH et al. Stroke 2010;41:2731–2738.2 Hart RG et al. Ann Intern Med 2007;146:857–67.TE = thromboembolism
The best or the worst drug in Cardiology
Warfarin better Placebo better
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
100 10050 0 50
All trialsRRR 64%*, ARR 2.7%(95% CI: 49–74%)
Random effects model;
RRR (%)†100 –10050 0 –50
Compared to a 19% RRR, 0.7% ARR for aspirin
Error bars = 95% CI;* p>0.2 for homogeneity;† Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)
Hart RG et al. Ann Intern Med 2007;146:857–67.
50% AF in over 25% low risk patients 75yrs pat e ts
anticoagulated
Only 50% high Only 20% high y 5 grisk patients on warfarin
y grisk over 75yr on warfarin
P d i i di ti i ti t ith k t i lPreadmission medications in patients with known atrial fibrillation who were admitted with acute ischaemic stroke
(high-risk cohort, n=597)( g , )
Sub‐ therapeuticwarfarin, 29%
No antithrombotic29%
Dual antiplatelet
Therapeutic f i %
antiplatelettherapy, 2%
Gladstone DJ et al. Stroke 2009;40:235–240.
warfarin, 10% Single antiplateletagent, 29%
P ib Prescriber reluctance
Patient l t
Genuine Problem! reluctanceProblem!
TherapeuticTherapeuticrange20
Requires dose adjustmentand regular monitoring
Ischaemic stroke
15and regular monitoringstroke
dds ratio
10Intracranial bleed
Od
5
01
ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–e354.
1International normalized ratio (INR)2 83 4 5 6 7
Patient Lifestyle• ComplianceCompliance• Dietary intake of vitamin K• Alcohol intake
M di l IMedical Issues• Numerous drug interactions• Hepatic dysfunctionHepatic dysfunction• Changes in the gut flora
Pharmacogenetics• CYP 2C9 & VKORC1 genes• Tailored therapy
P ib !Prescribers!
“Do you really want some of that rat poison, which means loads of blood tests you can’t drink and you might tests, you can t drink and you might bleed to death or perhaps you might p p y gprefer a baby aspirin which is very
d t ”good too....”
Simple dosing (one size for all)Simple administrationSimple administrationNo / minimal monitoring required
d h dWide therapeutic indexHigh benefitgLow bleeding
Minimal drug / food interactionsMinimal drug / food interactionsPredictable pharmacokinetics
Summary and comparisons
Dabigatran1‐3 Rivaroxaban4,5 Apixaban6,7
Mode of action Factor II Factor X Factor X
Half life 12‐14 hrs 7‐11 hrs 12 hrs
Dosing(in atrial fibrillation)
B.D. O.D. B.D.( )
MetabolismEsterase catalysed hydrolysis
CYP P450 dependant and independent mechanisms
CYP P450
Excretion 85% Renal1/3 Renal 1/4 Renal
Excretion 85% Renal2/3 Hepatic 3/4 Non Renal
Form Capsule Tablet Tablet
150 mg 5 mg
Dose150 mg110 mg (>80 yrs, verapamil or increased bleeding risk)
20 mg15 mg (CrCL 30‐49 ml/min)
5 g2.5 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.
y; y
Dabigatran1‐3 Rivaroxaban4,5 Apixaban6,7
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
InclusionNonvalvular AF + 1 risk factor
Nonvalvular AF + 2 risk factors (i.e. moderate to high risk)
Nonvalvular AF + 1 risk factor
Inclusion (CHADS) 2.1 3.5 2.1
Primary EndpointStroke and systemicembolism
Stroke and systemicembolism
Stroke and systemicembolism
Warfarin comparator INR control (mean TTR)
64% 55% 62%
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.
PROBE = prospective randomised open blinded end‐point; INR = international normalised ratio; TTR = time in therapeutic range
SSE vs. warfarin(ITT population)
%/yr Warfarin%/yr
HR(95% CI)
Dabigatran 150 mg 1.11 1.710.65 (0.52‐
0.81)
Dabigatran 110 mg 1 54 1 710.90 (0.74‐
Dabigatran 110 mg 1.54 1.711.10)
Rivaroxaban 2.1 2.40.88 (0.75‐
1.03)
Apixaban 1.27 1.600.79 (0.66‐
0.95)
0.5 1 1.5SSE = stroke and systemic embolism
Favours new orals Favours warfarin5 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.
Ischaemic stroke vs. Warfarin
%/yrWarfarin%/yr
HR(95% CI)y
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)Rivaroxaban 1.34 1.42 0.94 (0.75 1.17)
Apixaban* 0.97 1.05 0.92 (0.74‐1.13)
0.5 1Favours new orals Favours warfarin
1.5*Ischaemic or uncertain type of stroke
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 stroke vs warfarin
%/yrWarfarin%/yr
HR(95% CI)stroke vs. warfarin %/yr (95% CI)
Dabigatran 150 mg 0.10 0.380.26 (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)
Favours new orals Favours warfarin0 1 2.0
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 vswarfarin
%/yrWarfarin%/yr
HR(95% CI)
warfariny 95
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 1Favours 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 vswarfarin
%/yrWarfarin%/yr
HR(95% CI)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 1.04 (0.90‐1.203 3 4 4 ( 9
Apixaban 2.13 3.09 0.69 (0.60‐0.80)
0.5 1Favours 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 %/yr
Warfarin%/yr
HR(95% CI)
gwarfarin
y%/yr (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 0 5 0 7 0 67 (0 47 0 93)Rivaroxaban 0.5 0.7 0.67 (0.47‐0.93)
Apixaban 0.33 0.80 0.42 (0.30‐0.58)
Favours new orals Favours warfarin0 1 2.0
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 NOACsA t i l bli h dAs soon as trials publishedFollowing approvalsAware of NICE guidelines
Empowered patientp pClear agenda coming in to clinicGood nderstanding of cost and other iss esGood understanding of cost and other issuesAFA and other ‘professional’ website
• Aug 2009 – RELY trial• Sept 2011 – EMA approvalDabigatran • Sept 2011 – EMA approval• March 2012 – NICE TA299
Dabigatran
• Nov 2010 – ROCKET‐AF trial• Dec 2011 – EMA approvalRivaroxaban pp• March 2012 – NICE FAD
Rivaroxaban
• Aug 2011 –ARISTOTLE trial• Not licensed yetApixaban• ?August – NICE
p
The aim of this advice is to promote the safe and effective use of ▼dabigatran within its licensed indication inThe 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 stroke1. 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 CHADS2 risk assessment tool, or more recently introduced CHA2DS2-VASc risk assessment tool (see Appendix 1).
Patients ith a CHADS / CHA DS VASc score ≥ 2 sho ld be initiated on arfarin in the first instancePatients with a CHADS2 / CHA2DS2-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 ▼dabigatran initiation should be undertaken only by Secondary Care clinicians specialising in stroke g y y y p gprevention 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 gy (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: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 IssuesInternational businessmanRemote residence can’t easily get to hospitalRemote residence – can’t easily get to hospital
Dosing difficultiesInnumerate Can’t do /Confused changing doses warfarinPill boxes
d
Can t do /won’t doW f iFear adverse events
Family members problemsRisk of intracranial bleeds
Warfarin
Risk of intracranial bleedsRefusal
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/ p
Lack of confidence/ drug experienceLack of confidence/ drug experience
High bleeding risk/event
High risk but not anticoagulated
Professional reluctanceanticoagulated
Patient reluctance New Agents
Patient difficulty warfarin
g
On WarfarinContinue onWarfarinWarfarin
Loss of income / service primary care?Will t li i t ti l ti li i Will not eliminate anti‐coagulation clinics (immediately)Other conditions needing warfarin (presently)True bleeding or high unacceptable riskTrue bleeding or high unacceptable riskLow risk patientsPatients happy and stable on current Rx
ReversibilityI thi ll bi i ?• Is this really a big issue?
• Antidotes in development
Monitoring?Monitoring?• Don’t do for most other anti‐thrombotics• Crude assessments possible• Crude assessments possible
Clinical scenarios• Cardioversion• EP studies• ACS & PCI – difficult areaACS & PCI difficult area• Confusion doses for other indications (e.g. VTE prophylaxis, DVT/PE Rx)
Duty of care to patientInformed consentInformed consentLaying out of all options – balanced & objectiveRisk and benefits as applicable to patient
Patient choice and partnershipp pLegal status of NICE / AWMSG decisionCannot force warfarin on a patientCannot force warfarin on a patientCan we deny any other treatment i.e. none?Yet to be tested in court…
SPAF remains an unmet needWarfarin remains a good option (tried & tested)Warfarin remains a good option (tried & tested)But for many patients ( & prescribers) not acceptable
N l ti l t ffNew oral anticoagulants offerEquivalent / greater efficacy in SPAF cf. warfarinGreater safety for intracranial bleedsSignificant QOL benefits for many patients
Challenge implementation: Patient vs. Clinician vs. OrganisationgIssue for today – 5 years NOACs will be routine