The case for switching to the The case for switching to the emerging oral anticoagulants in emerging oral anticoagulants in
Atrial FibrillationAtrial Fibrillation
Dr Neil BaldwinConsultant Physician & Clinical Lead for Stroke
North Bristol NHS TrustBristol
AF prevalence increases with age
3. Go AS, et al. JAMA 2001;285:2370-2375
Age
AF
pre
va
len
ce
(%)
General population
>60 years >80 years
9
8
7
6
5
4
3
2
1
0
Treatment options for Atrial Treatment options for Atrial FibrillationFibrillation
Anti-platelet TreatmentsAnti-platelet TreatmentsAspirinAspirinClopidogrelClopidogrel
AnticoagulantsAnticoagulants
• WarfarinWarfarin• DabigatranDabigatran• RiveroxibanRiveroxiban• ApixabanApixaban
Mechanical Left Atrial Appendix occluderMechanical Left Atrial Appendix occluder
Aspirin v placeboAspirin v placebo
Aspirin is generally regarded asAn ineffective treatment
But its safer
Or is it?
Random effects model;Random effects model;Error bars = 95% CI;Error bars = 95% CI;
**pp>0.2 for homogeneity;>0.2 for homogeneity;†† Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic)
Warfarin has been hard to beatWarfarin has been hard to beat
Hart RG et al. Ann Intern Med 2007;146:857–67
Warfarin betterWarfarin better Placebo betterPlacebo better
RRR (%)RRR (%)††
100100 ––1001005050 00 ––5050
AFASAKAFASAK
SPAFSPAF
BAATAFBAATAF
CAFACAFA
SPINAFSPINAF
EAFTEAFT
All trialsAll trialsRRR 64%RRR 64%**
(95% CI: 49–74%)(95% CI: 49–74%)
Frenchay AF Thromboprophylaxis Frenchay AF Thromboprophylaxis
Criteria 2: Thromboprophylaxis prior to admission
Anticoagulation 22%
Antiplatelet 44%
Both 28%
None 6%
ESSC project Aliya Rahman N Baldwin 2010
DBG2919 | August 2011
How are AF patients at risk of stroke currently being managed?
Gladstone, D. J. et al. Stroke 2009;40:235–240
Preadmission medications in patients with known Atrial fibrillation who were admitted with acute ischemic stroke (high-risk cohort, n=597)
Therapeuticwarfarin, 10%
Sub-therapeuticwarfarin, 29% Single antiplatelet
agent, 29%
Dual antiplatelettherapy, 2%
No antithrombotic29%
DBG2919 | August 2011
Warfarin and its challenging therapeutic window
ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354and Eur Heart J 2006;27:1979–2030
1
International normalized ratio (INR)
Od
ds
rati
o
2
15
8
10
5
01
3 4 5 6 7
Intracranial bleed
Therapeuticrange
20
Requires dose adjustmentand regular monitoringStroke
Why time in therapeutic range (TTR) matters
0 500 1000 1500 2000
Survival to stroke (days)
0.6
0.7
0.8
0.9
1.0
Cu
mu
lati
ve s
urv
ival
71–100%
Warfarin group
61–70%51–60%41–50%31–40%<30%Non warfarin
Morgan CL et al. Thrombosis Research 2009;124:37–41
Individual TTR: main determinant of quality of anticoagulation and predictor of clinical outcome
Veeger et al: Brit J Haematol 2005;128:513
Black – above range
Light Grey – within range
Dark grey – below range
Warfarin is not widely usedWarfarin is not widely used
Waited over 50 years for a new oral Waited over 50 years for a new oral anticoagulant....anticoagulant....
SPAF trials versus WarfarinSPAF trials versus Warfarin
Dabigatran
Rivaroxaban
ApixabanDabigatran Rivaroxaban Apixaban
Study RELY Rocket Aristotle
Design PROBE Double Blind Double Blind
Follow up 2 yrs 1.5yrs 1.5yrs
Population size
>18,000 >14,000 >18,000
Inclusion Non valvular AF + 1 risk factor
Non valvular AF + 2 risk factor (i.e. moderate to high risk)
Non valvular AF + 1 risk factor
Inclusion (CHADs)
2.1 3.5 2.1
Primary Endpoint
Stroke and systemic embolism
Stroke and systemic embolism
Stroke and systemic embolism
Warfarin comparator INR control (mean TTR)
64% 55% 62%
Ezekowitz et al. Am Heart J 2009;157 and Connolly et al, N Eng J Med 2009; 361 Rocket investigators, Am Heart J 2010; 159 and Patel et al, N Eng J Med 2011; 365Lopes et al. Am Heart J 2010; 159 and Granger et al, N Eng J Med 2011; 365
Date of preparation: January 2012
0.010.01
0.020.02
0.030.03
0.050.05
0.040.04
Cu
mu
lati
ve h
azar
d r
ates
Cu
mu
lati
ve h
azar
d r
ates
RR 0.91RR 0.91(95% CI: 0.74–1.11)(95% CI: 0.74–1.11)pp<0.001 (NI)<0.001 (NI)pp=0.34 (Sup)=0.34 (Sup)
RR 0.65RR 0.65(95% CI: 0.53–0.82)(95% CI: 0.53–0.82)pp<0.001 (NI)<0.001 (NI)pp<0.001 (Sup)<0.001 (Sup)
YearsYears00 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5
0.00.0
WarfarinWarfarinDabigatran etexilate 110 mgDabigatran etexilate 110 mgDabigatran etexilate 150 mgDabigatran etexilate 150 mg
RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superiorRR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior
Dabigatran - Time to first stroke / SSEDabigatran - Time to first stroke / SSE
Connolly SJ Connolly SJ et al.et al. NEJM NEJM published online on Aug 30published online on Aug 30 thth 2009. DOI 10.1056/NEJMoa0905561 2009. DOI 10.1056/NEJMoa0905561
RRRRRR35%35%
RR 0.41RR 0.41(95% CI: 0.27–0.60)(95% CI: 0.27–0.60)p<0.001 (Sup) p<0.001 (Sup)
RR 0.31RR 0.31(95% CI: 0.20–0.47)(95% CI: 0.20–0.47)p<0.001 (Sup) p<0.001 (Sup)
Cu
mu
lati
ve h
azar
d r
ates
Cu
mu
lati
ve h
azar
d r
ates
YearsYears
0.00.0
0.010.01
0.020.02
00 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5
RE-LY (dabigatran):RE-LY (dabigatran): Time to first intra-cranial bleed Time to first intra-cranial bleed
RRRRRR59%59%
RRRRRR69%69%
WarfarinWarfarinDabigatran etexilate 110 mgDabigatran etexilate 110 mgDabigatran etexilate 150 mgDabigatran etexilate 150 mg
Connolly SJ Connolly SJ et al.et al. NEJM NEJM published online on Aug 30published online on Aug 30 thth 2009. DOI 10.1056/NEJMoa0905561 2009. DOI 10.1056/NEJMoa0905561
Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patientsDabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patientswith Atrial fibrillationwith Atrial fibrillation
RR, relative risk; CI, confidence interval; Sup, superiorRR, relative risk; CI, confidence interval; Sup, superior
Major bleeding risk compared to warfarin
RR 0.93 (95% CI: 0.81–1.07)
RR 0.80 (95% CI: 0.70–0.93)
% p
er
year
RRR7%
ARR0.25%
RRR20%ARR
0.70%
0
1.0
2.0
4.0
342 / 6,015
2.87
D110 mg BID
399 / 6,076
3.32
D150 mg BID
421 / 6,022
3.57
Warfarin
p=0.32 (sup)
p=0.003 (sup)
3.0
3.5
2.5
1.5
0.5
19. Connolly SJ et al. N Engl J Med 2009; 361:1139–115120. Connolly et al. N Engl J Med 2010; 363:1875–1876
Most common adverse eventsMost common adverse eventsDabigatran 110 mgDabigatran 110 mg
%%Dabigatran 150 mgDabigatran 150 mg
%%WarfarinWarfarin
%%
Dyspepsia*Dyspepsia* 11.811.8 11.311.3 5.85.8
Dyspnoea Dyspnoea 9.39.3 9.59.5 9.79.7
Dizziness Dizziness 8.18.1 8.38.3 9.49.4
Peripheral edema Peripheral edema 7.97.9 7.97.9 7.87.8
Fatigue Fatigue 6.66.6 6.66.6 6.26.2
Cough Cough 5.75.7 5.75.7 6.06.0
Chest pain Chest pain 5.25.2 6.26.2 5.95.9
Arthralgia Arthralgia 4.54.5 5.55.5 5.75.7
Back pain Back pain 5.35.3 5.25.2 5.65.6
Nasopharyngitis Nasopharyngitis 5.65.6 5.45.4 5.65.6
DiarrhoeaDiarrhoea 6.36.3 6.56.5 5.75.7
Urinary tract infection Urinary tract infection 4.54.5 4.84.8 5.65.6
Upper respiratory tract infectionUpper respiratory tract infection 4.84.8 4.74.7 5.25.2
*Occurred more commonly on dabigatran *Occurred more commonly on dabigatran pp<0.001<0.001
Connolly SJ Connolly SJ et al. NEJMet al. NEJM published online on Aug 30 published online on Aug 30thth 2009. DOI 10.1056/NEJMoa0905561 2009. DOI 10.1056/NEJMoa0905561
Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patientsDabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patientswith Atrial fibrillationwith Atrial fibrillation
Rivaroxaban - primary endpointRivaroxaban - primary endpoint
Patel et al, N Eng J Med 2011; 365
Rivaroxaban Warfarin Rivaroxaban vs. Warfarin
SSE* # No. / 100 pts yrs
# No. / 100 pts yrs
ARR HR P =
Safety, as treated
189 1.7 243 2.2 0.5 0.79 (0.65-0.95)
0.02(sup)
Intention to treat
269 2.1 306 2.4 0.3 0.88(0.75-1.03)
0.12(sup)
*SSE (Stroke, Systemic Embolism) Date of preparation: January 2012
Rivaroxaban - safety endpointRivaroxaban - safety endpoint
Patel et al, N Eng J Med 2011; 365Date of preparation: January
2012
Apixaban – primary endpointApixaban – primary endpoint
Apixaban Warfarin Apixaban vs. Warfarin
# %/YR # %/YR ARR HR P =
SSE* 212 1.27 265 1.60 0.33 0.79 0.01(sup)
Granger et al, N Eng J Med 2011; 365 *SSE (Stroke, Systemic Embolism)Date of preparation: January
2012
Apixaban – safety endpointsApixaban – safety endpoints
Granger et al, N Eng J Med 2011; 365
Apixaban Warfarin Apixaban vs. Warfarin
# %/YR # %/YR ARR HR P =
MajorBleeding
327 2.13 462 3.09 0.96 0.69(0.60-0.80)
<0.001
Major + Clinical relevantBleeding
613 4.07 877 6.01 1.94 0.68(0.61-0.75)
<0.001
GIBleeding
105 0.76 119 0.86 0.10 0.89(0.70-1.15)
0.37
Date of preparation: January 2012
New agents versus warfarinNew agents versus warfarin
SSE* vs. Warfarin(ITT population)
ARR HR
D150 0.60 0.65 (0.52-0.81)
D110 0.17 0.90 (0.74-1.10)
Rivaroxaban 0.30 0.88 (0.75-1.03)
Apixaban 0.33 0.79 (0.66-0.95)
Haemorrhagic stroke vs. Warfarin
ARR HR
D150 0.28 0.26 (0.14-0.49)
D110 0.26 0.31 (0.17-0.56)
Rivaroxaban 0.18 0.59 (0.37-0.93)
Apixaban 0.23 0.51 (0.35-0.75)Connolly et al, N Eng J Med 2009; 361 and Vol. 363 No.19
Patel et al, N Eng J Med 2011; 365Granger et al, N Eng J Med 2011; 365
Stroke, Systemic Embolism
Date of preparation: January 2012
Haemorrhagic stroke
New agents versus warfarinNew agents versus warfarin
Intracranial Bleeding
ARR HR
D150 0.44 0.41 (0.28-0.06)
D110 0.53 0.30 (0.19-0.45)
Rivaroxaban
0.20 0.67 (0.47-0.93)
Apixaban 0.47 0.42 (0.30-0.58)Connolly et al, N Eng J Med 2009; 361 and Vol. 363 No.19
Patel et al, N Eng J Med 2011; 365 Granger et al, N Eng J Med 2011; 365
Major Bleeding
ARR HR
D150 0.25 0.93 (0.81-1.07)
D110 0.70 0.80 (0.70-0.93)
Rivaroxaban -0.20 1.04 (0.90-1.20)
Apixaban 0.96 0.69 (0.60-0.80)
Date of preparation: January 2012
Major Bleeds
Intracranial bleeding
Benefits of New AgentsBenefits of New Agents
Dabigatran 150 mg bd and Apixaban 5mg bd have Dabigatran 150 mg bd and Apixaban 5mg bd have superior efficacy to Warfarin.superior efficacy to Warfarin.
Dabigatran 110mg bd and Riveroxiban 20mg od are Dabigatran 110mg bd and Riveroxiban 20mg od are non inferior to Warfarin.non inferior to Warfarin.
All four agents and doses are superior to Warfarin in All four agents and doses are superior to Warfarin in reducing Intracranial haemorrhages.reducing Intracranial haemorrhages.
Dabigatran 110mg bd and Apixaban 5mg bd are Dabigatran 110mg bd and Apixaban 5mg bd are superior to Warfarin in avoiding major haemorrhagesuperior to Warfarin in avoiding major haemorrhage
Benefits of New AgentsBenefits of New Agents
Warfarin in avoiding major bleedsWarfarin in avoiding major bleeds
All three drugs are oral agentsAll three drugs are oral agents
Short half life means rapid onset of actionShort half life means rapid onset of action
All three do not require monitoring (Major perceived All three do not require monitoring (Major perceived
benefit for patients)benefit for patients)
Few known drug interactionsFew known drug interactions
Disadvantages of the new agentsDisadvantages of the new agents
Short half life means concordance of treatment Short half life means concordance of treatment regime is important otherwise patients will be regime is important otherwise patients will be undertreatedundertreated
Lack of monitoring will prevent patients Lack of monitoring will prevent patients concordance being checkedconcordance being checked
Lack of a test of coagulation may be a problem if Lack of a test of coagulation may be a problem if patients present with acute bleeding patients present with acute bleeding
Lack of an agreed protocol for managing acute Lack of an agreed protocol for managing acute bleedingbleeding
Differences in the proposed management of bleeding Differences in the proposed management of bleeding complicationscomplications
““The Cost is greater than The Cost is greater than Warfarin”Warfarin”
Dabigatran £2.52/dayDabigatran £2.52/day
Riveroxiban £2.10/dayRiveroxiban £2.10/day
Have we really understood the true cost of anticoagulation Have we really understood the true cost of anticoagulation with Warfarin?with Warfarin?
Frequency of INR TestsFrequency of INR TestsNeed for District Nurse visits for phlebotomy Need for District Nurse visits for phlebotomy Full cost of bleeding complicationFull cost of bleeding complication
ICHICHMajor bleedingMajor bleedingAdmissions with high INR Admissions with high INR Urgent clinic attendances Urgent clinic attendances
Have we understood the cost of increased stroke for Have we understood the cost of increased stroke for patients not ant coagulated because of “Fear of patients not ant coagulated because of “Fear of Warfarin?Warfarin?
Difference in the estimated number of events over 5 Difference in the estimated number of events over 5 yr if 10,000 patients over 80 switched to dabigatranyr if 10,000 patients over 80 switched to dabigatran
No Rx ASA W re-ly
IS -960 -280 -37
ICH 12 -82 -206
ECH 341 -95 -44
AMI -48 -24 50
Cost/QALY £6,334 £15,643 £16,072
Annual cost £228 £308 £266
Difference in the estimated number of events over 5 Difference in the estimated number of events over 5 yr if 10,000 patients over 80 switched to dabigatranyr if 10,000 patients over 80 switched to dabigatran
ASA W re-ly W 50-60%
W 40-50%
IS -280 37 15 -14
ICH -82 -206 -230 -239
ECH -95 -44 -216 -329
AMI -24 50 47 43
Cost/QALY £15,643 £16,072 £12,604 £10,719
Annual cost
£308 £266 £245 £230
As TTR falls the incremental benefits of introducing Dabigatran are •Reductions in the number of Ischaemic stroke •Reductions in ICH•Reduction in ECH•Fall in net cost
Net clinical benefit and Net clinical benefit and componentscomponents
CharacteristicDabi
110 mg
Dabi
150 mgWarfarin
P-value
110 vs. W
P-value
150 vs. W
Number of patients (n) 6015 6076 6022
Net Clinical Benefit 7.34 7.11 7.91 0.09 0.02
- Stroke / SSE
- Death
- MBE
- PE
- MI
1.54
3.75
2.87
0.12
0.82
1.11
3.64
3.32
0.15
0.81
1.71
4.13
3.57
0.10
0.64
<0.001 (NI)
0.30 (sup)
0.13
0.003
0.71
0.09
<0.001 (NI)
<0.001 (sup)
0.051
0.32
0.30
0.12
All data represents %/year
Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151.
What about other preventative treatments
Proteos for Osteoporosis £312 per year
Candesartan 32 mg £ 192 per year
HRT patches £384 per year
Where should we focus the use of new Where should we focus the use of new agents?agents?
Patients with Atrial Fibrillation and at least a Patients with Atrial Fibrillation and at least a CHADS score of 1.CHADS score of 1.
Patients who are documented to be allergic or Patients who are documented to be allergic or intolerant to Coumarins intolerant to Coumarins
Where should we focus the use of new Where should we focus the use of new agents?agents?
Failure to maintain adequate time in therapeutic Failure to maintain adequate time in therapeutic rangerange
Patients who continue to need INR monitoring more Patients who continue to need INR monitoring more frequently than every two weeksfrequently than every two weeks
Patients in whom the practicality of INR monitoring Patients in whom the practicality of INR monitoring is burdensomeis burdensome
Warfarin and its challenging therapeutic window
ACC/AHA/ESC guidelines: Fuster V et al. Circulation 2006;114:e257–354and Eur Heart J 2006;27:1979–2030
1
International normalized ratio (INR)
Od
ds
rati
o
2
15
8
10
5
01
3 4 5 6 7
Intracranial bleed
Therapeuticrange
20
Requires dose adjustmentand regular monitoringStroke
Stroke / SSE
19. Connolly SJ., et al. N Engl J Med 2009; 361:1139-115120. Connolly et al. N Engl J Med 2010; 363:1875-1876
% p
er
year
183 / 6,015 134 / 6,076 202 / 6,022
RRR35%ARR
0.60%
RRR10%ARR
0.17%
1.54
0
0.3
0.6
0.9
1.2
1.5
1.8
D110 mg BID
1.11
D150 mg BID
1.71
Warfarin
RR 0.65 (95% CI: 0.52–0.81)
RR 0.90 (95% CI: 0.74–1.10)
p<0.001 (sup)
p<0.001 (NI)
RR, Relative risk; CI, confidence interval; Sup, superior
Time to first intra-cranial bleed
RRR70%ARR0.53%
RR 0.41(95% CI: 0.28–0.60)p<0.001 (Sup)
RR 0.30(95% CI: 0.19–0.45)p<0.001 (Sup)
Cu
mu
lati
ve h
azar
d r
ates
Years
0.0
0.01
0.02
0 0.5 1.0 1.5 2.0 2.5
RRR59%ARR0.44%
WarfarinDabigatran etexilate 110 mgDabigatran etexilate 150 mg
19. Connolly SJ et al. N Engl J Med 2009; 361:1139–115120. Connolly et al. N Engl J Med 2010; 363:1875–1876
Should we focus the use of new agents Should we focus the use of new agents on patients with recent TIA?on patients with recent TIA?
Patients with recent TIAPatients with recent TIA
High risk of early stroke recurrenceHigh risk of early stroke recurrence Immediate prescription will lead to immediate cover Immediate prescription will lead to immediate cover
compared to delayed cover with Warfarincompared to delayed cover with Warfarin
Patients with recent cardio embolic stroke > 14 daysPatients with recent cardio embolic stroke > 14 days
The ‘pitch’
Newly diagnosed, treatment-naïve AF patients should be offered a new oral anticoagulants
• Its more effective than Warfarin• Its rapid onset ensures early protection• Its is simpler to use • Its much easier for patients
The ‘pitch’
Patients stable on warfarin should be switched to a new oral anticoagulant?
Thank you
Myocardial infarctionMyocardial infarction
The rate of myocardial infarction was higher with both doses of The rate of myocardial infarction was higher with both doses of dabigatran than with warfarin.dabigatran than with warfarin.
Definition not reported in Re-ly but adjudicated Definition not reported in Re-ly but adjudicated Enzyme rise / ECG change Enzyme rise / ECG change No difference in mortalityNo difference in mortality
It may be that warfarin provides better protection It may be that warfarin provides better protection against coronary ischemic events than dabigatran, and against coronary ischemic events than dabigatran, and warfarin is known to reduce the risk of myocardial warfarin is known to reduce the risk of myocardial infarction.infarction.
Rates of myocardial infarction were similar between Rates of myocardial infarction were similar between patients with Atrial fibrillation who received warfarin patients with Atrial fibrillation who received warfarin and those on ximelagatran, another direct thrombin and those on ximelagatran, another direct thrombin inhibitor.inhibitor.
The explanation for this finding is therefore uncertain.The explanation for this finding is therefore uncertain.
Use of dabigatran in clinical "real world" Use of dabigatran in clinical "real world" practicepractice
Non-adherence Non-adherence is likely to undermine therapeutic outcomes in "real world" is likely to undermine therapeutic outcomes in "real world"
practice because of a reduction in patient adherence practice because of a reduction in patient adherence Drug interactions.Drug interactions.
Although identified drug interactions are few at this point, it Although identified drug interactions are few at this point, it can be anticipated that at least some additional medications can be anticipated that at least some additional medications will interact with dabigatran will interact with dabigatran
Safety vs efficacy at extremes of body weight Safety vs efficacy at extremes of body weight
Renal and/or hepatic disease Renal and/or hepatic disease Other adverse effects Other adverse effects
may be identified as wide-spread use occursmay be identified as wide-spread use occurs Medico-legal issues Medico-legal issues
may arise when major bleeding occurs with this drug that may arise when major bleeding occurs with this drug that cannot be monitored or reversed. cannot be monitored or reversed.
Cost Cost