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

neil.baldwin@nbt.nhs.uk

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