Mechanism of Action of New Oral Anticoagulants New anticoagulants

ORAL PARENTERAL TF/VIIa TFPI (tifacogin) TTP889 X IX

Apixaban IXa APC (drotrecogin alfa) Rivaroxaban VIIIa sTM (ART-123) Edoxaban Va Betrixaban AT YM150 Xa Fondaparinux TAK 442 Idraparinux

II DX-9065a

Dabigatran IIa

Fibrinogen Fibrin

Adapted from Weitz JI & Bates SM. J Thromb Haemost 2005;3:1843-1853. 2 Targets for anticoagulants

ORAL PARENTERAL DIRECT INDIRECT TF/VIIa

X IX VKAs inhibit the hepatic synthesis of several IXa coagulation factors VIIIa Va AT Rivaroxaban Fondaparinux Apixaban Xa Edoxaban Betrixaban AT LMWH

II AT UFH Dabigatran IIa AZD 0837 Fibrinogen Fibrin

Adapted from Weitz et al, 2005; Weitz et al, 2008 3 3 Targets of new oral anticoagulants

Xll Xl lX TF VIIIa VII Direct factor Xa inhibitors Xa • Rivaroxaban • Apixaban Va Direct thrombin inhibitors IIa • Dabigatran

I

Fibrin Clot

Adapted from Ansell J. J Thromb Haemost 2007;5(suppl 1):60-64. Turpie AGG. Arterioscler Thromb Vasc Biol 2007;27:1238-1247. 4 Currently Available Anticoagulants: An Overview of Properties

• Narrow therapeutic window • Proven efficacy in • A perception that incidence venous thrombosis and severity of bleeding and • Less proof available in side effects are high arterial thrombosis • Many food and drug interactions* • Unpredictable response* • High intra- and interindividual variability*

• Dose adjustment required • Slow on- and offset of action* • Routine monitoring required* † *Warfarin • Parenteral/subcutaneous administration required †Heparins

5 Clinical pharmacology of apixaban, rivaroxaban and dabigatran

Apixaban1 Rivaroxaban2 Dabigatran3 Direct factor Xa Direct factor Xa Direct thrombin Mechanism of action inhibitor inhibitor inhibitor Absolute availability ~50% 80–100% ~6.5% Route of Oral Oral Oral administration Pro-drug No No Yes Food effect No No No Renal clearance ~27% ~33 % 85%

Mean half-life (t1/2) ~12 h 7–11 h ~12–14 h

Tmax 3-4 h 2–4 h 0.5–2 h

No head-to-head comparisons between apixaban, rivaroxaban and dabigatran have been performed in a randomised clinical trial setting. The information in this table is based on the SmPCs for apixaban, rivaroxaban and dabigatran. Please refer to the SmPCs for further information.

1. Apixaban SmPC June 2011 2. Rivaroxaban SmPC March 2011 3. Dabigatran SmPC August 2011 6 Stroke prevention in non-valvular AF: studies with non-VKA anticoagulants

Study completed/reported Study ongoing/not reported

Licensed for use in the UK

Rivaroxaban Dabigatran Apixaban Edoxaban

AVERROES3 (vs. ASA) ROCKET-AF1 RE-LY 2 ENGAGE-AF (vs. warfarin) (vs. warfarin) ARISTOTLE4 (vs. warfarin) (vs. warfarin)

1. Patel MR et al. NEJM published online August 2011 2. Connolly SJ et al. NEJM 2009;361: 1139-1151 3. Connolly SJ et al. NEJM published online February 2011 4. Granger et al. NEJM published online August 2011

7 Development status of Anticoagulants1

Licensed indication Phase III study completed Phase III study in progress No study ongoing Rivaroxaban Dabigatran Apixaban

RE-NOVATE ADVANCE VTE prevention RECORD RE-MODEL 1 - 3 in orthopaedic 1 - 4 surgery

AVERROES Stroke ROCKET AF RE-LY prevention in AF ARISTOTLE

EINSTEIN DVT RE-COVER RE-MEDY VTE treatment AMPLIFY

EINSTEIN PE RE-SONATE

VTE prevention ADOPT MAGELLAN medically ill

ATLAS TIMI APPRAISE-2

ACS 51 stopped

www.clinicaltrials.gov

8 9 Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism

P (non-inferiority)<0.001 21% RRR

Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011

No. at Risk Apixaban 9120 8726 8440 6051 3464 1754 Warfarin 9081 8620 8301 5972 3405 1768

10 Major Bleeding ISTH definition

31% RRR

Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, 0.60–0.80); P<0.001

No. at Risk Apixaban 9088 8103 7564 5365 3048 1515 Warfarin 9052 7910 7335 5196 2956 1491

11 12 13 Intra-cranial bleeding rates RR 0.31 (95% CI: 0.20–0.47) p<0.001 (sup) RR 0.40 (95% CI: 0.27–0.60) 90 p<0.001 (sup) 80 87 0,74 %

70

60 RRR RRR 69% 60% 50 40

30 36 Number Number of events 20 27 0,30 % 0,23 % 10 0 D110 mg BID D150 mg BID Warfarin

Connolly SJ., et al. NEJM published online on Aug 30th 2009. Dabigatran etexilate is in clinical development and not licensed for DOI 10.1056/NEJMoa0905561 clinical use in stroke prevention for patients with atrial fibrillation 14 15 16 17 Market Share

The new anticoagulants appear to work.

More expensive than warfarin – will undergo economic analysis to decide who should go on to these drugs.

18 Dabigatran 110 Dabigatran 150 RELY Warfarin mg mg

CHADS2 Mean 2.1 2.2 2.1 0-1 (%) 32.6 32.2 30.9 2 (%) 34.7 35.2 37.0 3+ (%) 32.7 32.6 32.1

ROCKET AF Rivaroxaban Warfarin

CHADS2 Mean 3.5 3.5 2 (%) 13 13 3 (%) 43 44 3+ 4 (%) 29 28 87% 5 (%) 13 12 6 (%) 2 2

ARISTOTLE Rivaroxaban Warfarin

CHADS2 Mean 2.1 2.1 0-1 (%) 34 34 2 (%) 35.8 35.8 3+ (%) 30.2 30.2

C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011 19 Comparison of Trial Metrics

RE-LY ROCKET AF ARISTOTLE Time in 64% Mean 55% Mean 62% Therapeutic 67% warfarin- Median 58% Median 66% experienced Range (TTR) 61% warfarin-naïve

Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011 C. Michael Gibson, M.S., M.D. 20 Patient Profile – NUH Trust

. NUH Trust currently manages 6,732 active patients.

. Approximately 130,000 dose adjustments undertaken per year.

Patients with indication “AF” only, with an INR range of “2.0-3.0”

. Group makes up approximately 43% of total active patients.

. Average age of patient group is 76 years.

. Average time the patients have been on therapy is 6 years.

. Average percentage time in range for group is 75%.

. Average percentage of patients with TIR < 65% is 24%. Information obtained from NUH Trust DAWN CDSS system on 07/09/2011 21 Service Considerations

. How do we decide who is suitable for new anticoagulants?

. How will we support patients on new agents?

. How will we keep track of patients on new anticoagulants?

– Bleeding and clotting events, renal function, compliance reviews etc

– General practice / Anticoagulation Clinics involvement

– Admissions into Acute Trusts [including Trauma events]

22 What guidance is available for prescribers and Anticoagulation Service Teams?

Local policy / procedures [TIR < 65%]

Economic considerations

23 Can we afford the new anticoagulants

24 NICE Guidance on Dabigatran Emphasizes Need for Cost-Effectiveness Data

Appraisal Committee's preliminary recommendations 1.1 The Committee is minded not to recommend the use of dabigatran etexilate for the prevention of stroke and systemic embolism in people with atrial fibrillation.

The manufacturer of dabigatran etexilate should provide the following for the second Appraisal Committee meeting: A cost-effectiveness analysis of the sequential regimen outlined above, comparing dabigatran etexilate with warfarin using relative risks from the whole RE-LY trial population rather than from the post hoc subgroup analysis. The analysis should include sensitivity analyses using a range of assumptions of international normalised ratio (INR) monitoring costs such as those used by the Evidence Review Group (ERG) (£279.36, £241.54 and £115.14) in addition to the cost stated in the manufacturer's submission (£414.90).

C. Michael Gibson, M.S., M.D. 25 A “Back of the Envelope” Assessment of the Potential Cost Effectiveness of Dabigatran (Pradaxa) in Non- Valvular Atrial Fibrillation

C. Michael Gibson, M.S., M.D.

26 . Cost-Effectiveness of Dabigatran Compared With Warfarin for Stroke Prevention in Atrial Fibrillation.

. The incremental cost-effectiveness ratios compared with warfarin was $45,372 per QALY for high-dose dabigatran.

Freeman JV et al. Cost-Effectiveness of Dabigatran Compared With Warfarin for Stroke Prevention in Atrial Fibrillation. Ann Intern Med. 2011 Jan 4;154(1):1-11. Epub 2010 Nov 1. 27 What Variables Were Used to Calculate the Cost of INR Monitoring?

. Variables included in estimating the cost of INR monitoring were: – The actual number of annual visits was used (average 16 visits) – The cost in an RNs time and a GPs time were calculated in each case – The cost of home testing was included (which was more expensive than office testing) – The cost of a patient who did not show up for an appointment was included – The cost of the laboratory staff in taking the blood sample – The cost of analyzing the sample – The sample transportation costs – Limitations: – Based on 2003 costs – Does not reflect costs of INR performed elsewhere outside of GP office – Does not include patient transportation costs, or the societal costs of a patient’s time off from work!

Björholt et al, BMC Family Practice 2007, 8:6doi:10.1186/1471- 2296-8-6. http://www.biomedcentral.com/1471-2296/8/6/ C. Michael Gibson, M.S., M.D. 28 How Much Is A Year of Life Worth?

While estimates of what governments are willing to pay for are generally about $50,000 per year of life saved, hemodialysis costs approximately $129,000 per year of life saved.

C. Michael Gibson, M.S., M.D. http://www.time.com/time/health/article/0,8599,1808049,00.html 29 How Much Is A Year of Life Worth?

“Our Department of Transport, for instance, has a cost-per-life- saved threshold for new road schemes of about 1.5 million GBP per life, or around 30,000 GBP per life year gained. The judgment of our health economists is that somewhere in the region of 20,000-30,000 GBP ($31,600 USD to $47,400 USD) per quality-adjusted life year is the [threshold], but it's not a strict limit.” Sir Michael Rawlins

Chairman of the UK‟s NICE (National Institute for Health and Clinical Excellence) C. Michael Gibson, M.S., M.D. http://www.time.com/time/health/article/0,8599,1888006,00.html#ixzz13Z0tUMuG 30

What Do We Spend In Society To Save A Life?

Dollars Spent To Save A Life A Save To Spent Dollars

New York Times, January 29, 1995, p. F3. C. Michael Gibson, M.S., M.D. http://www.cbe.wwu.edu/Krieg/Econ.%20Documents/how_much_for_a_life.htm 31 Predictions

. Evidence that up to 40% of patients – usually elderly that should be on an anticoagulant drug – are NOT. . With increasing awareness and audit of GP databases – more people being anticoagulated – perhaps first line new anticoagulant. . Truly unstable patients – is < 65% TTR the best cut- off? . Short term e.g cardioversion. . Bridging therapy for high risk patients. . The educated, broadsheet reading pressure group.

32 Prevalence of Atrial Fibrillation ATRIA Study

11.1 12 Women (n=7801) 10.3 Men (n=10,173)

10 9.1

8 7.3 7.2

6 5.0 5.0

4 3.0 3.4 Prevalence (%) Prevalence 1.7 1.7 2 0.9 1.0 0.1 0.2 0.4 0 <55 55-59 60-64 65-69 70-74 75-79 80-84 >85 Age (years)

Go A, et al. JAMA 2001; 285:2370. 33 Patient Profile – NUH Trust

. NUH Trust currently manages 6,732 active patients.

. Approximately 130,000 dose adjustments undertaken per year.

Patients with indication “AF” only, with an INR range of “2.0-3.0”

. Group makes up approximately 43% of total active patients.

. Average age of patient group is 76 years.

. Average time the patients have been on therapy is 6 years.

. Average percentage time in range for group is 75%.

. Average percentage of patients with TIR < 65% is 24%. Information obtained from NUH Trust DAWN CDSS system on 07/09/2011 34 For the forseeable future

Majority of current AF patients will remain on warfarin.

VTE patients will remain on warfarin.

Heart Valve patients will remain on warfarin.

The rest.

35 Challenges of the new anticoagulant drugs

Medication non-adherence is high across all disease states

Percentage of patients who continue treatment beyond first month

36 37 What needs to be highlighted to a patient starting new anticoagulants?

. Importance of adherence – No effect on AF symptoms – Especially for patients switching from warfarin who are used to being monitored

. Signs and symptoms of bleeding, including bruising

. Dyspepsia – take with food

. Carry the Patient Alert card and alert any HCPs

of your medication 38 Heartmind Patient Support programme . Offered to patients already prescribed Pradaxa® for SPAF.

. Support and tools to help them live better with AF.

. Supports the HCPs original conversation once they have left the surgery/hospital and enrolled.

. Content can be opted in and out by the patient:

– 6 magazines over a 7 month rolling programme

– Themed fold-outs [e.g. stroke information]

– Nurse-led call centre, website and emails, SMS

– Digital and magnet reminders

– Investigating videos and spoken word.

39 Monitoring patients on New Anticoagulants [NUH Trust]

. Central database of patients – Interactions transmitted to general practice – Events monitored, recorded and reported

– Seamless transition between CDSS modules 40 Is it valuable to have a central database?

. Education/help resource for patients.

. Education/help resource for health care professionals.

. Local audit/clinical development

41 Current Anticoagulants services

. Will need to continue modified/unmodified.

. Roles of staff will extend to include all anticoagulants.

. No further investment.

. Expand into the other „needy‟ areas of thrombosis work – thromboprophylaxis/VTE/Pregancy

42