1. 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.

2. Annual Cost of Pradaxa and Warfarin Cost per day of Pradaxa: $7.90 Cost per day of Pradaxa: $7.90 Annual cost of Pradaxa: $2,884 Annual cost of Pradaxa: $2,884 (http://cardiobrief.org/2010/10/26/pradaxa-dabigatran-pricing-starts-to-emerge/#more-6874(http://cardiobrief.org/2010/10/26/pradaxa-dabigatran-pricing-starts-to-emerge/#more-6874) (http://cardiobrief.org/2010/10/26/pradaxa-dabigatran-pricing-starts-to-emerge/#more-6874 Cost per day of warfarin: $0.30 Cost per day of warfarin: $0.30 Annual cost of warfarin: $109.50 Annual cost of warfarin: $109.50 (http://www.pharmacychecker.com/Pricing.asp?DrugName=Warfarin&DrugId=19462&DrugStrengthId=31 721 ) http://www.pharmacychecker.com/Pricing.asp?DrugName=Warfarin&DrugId=19462&DrugStrengthId=31 721http://www.pharmacychecker.com/Pricing.asp?DrugName=Warfarin&DrugId=19462&DrugStrengthId=31 721 Annual cost of INR monitoring for warfarin: $2,134 in the first year, $1,170 in the second year, an average of $1,652 per year Annual cost of INR monitoring for warfarin: $2,134 in the first year, $1,170 in the second year, an average of $1,652 per year (http://www.biomedcentral.com/1471-2296/8/6/) http://www.biomedcentral.com/1471-2296/8/6/ Annual cost of drug acquisition and monitoring of warfarin is therefore $1,761 per year Annual cost of drug acquisition and monitoring of warfarin is therefore $1,761 per year C. Michael Gibson, M.S., M.D.

3. What Variables Were Used to Calculate the Cost of INR Monitoring? Variables included in estimating the cost of INR monitoring were: 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/http://www.biomedcentral.com/1471-2296/8/6/ C. Michael Gibson, M.S., M.D.

4. Incremental Increase in Cost Per Year (Per Patient) for Pradaxa over Warfarin Annual cost of pradaxa:$2,884 minus Annual cost of warfarin and monitoring:$1,761 Annual additional cost for pradaxa =$1,123 C. Michael Gibson, M.S., M.D.

5. Costs To Save One Life Given the 0.5% mortality reduction (which was of borderline statistical significance (p=0.051) for the 150 mg dose), you would need to treat 200 patients for one year to save one life. Given the 0.5% mortality reduction (which was of borderline statistical significance (p=0.051) for the 150 mg dose), you would need to treat 200 patients for one year to save one life. That one year of therapy in 200 patients would cost an additional 200 X $1,123 or $224,600. That one year of therapy in 200 patients would cost an additional 200 X $1,123 or $224,600. C. Michael Gibson, M.S., M.D.

6. How Long Does The Person Whose Life You Saved Go On To Live With Atrial Fibrillation? In order to calculate the cost per year of life saved, we need to estimate how long the person whose life you just saved will go on to live with atrial fibrillation In order to calculate the cost per year of life saved, we need to estimate how long the person whose life you just saved will go on to live with atrial fibrillation The average age of patients in RE-LYwas 71.4 years. The average years of life a female can expect to live beyond 71 years is 14 years and a male is 13 years based on US census life tables:The average age of patients in RE-LYwas 71.4 years. The average years of life a female can expect to live beyond 71 years is 14 years and a male is 13 years based on US census life tables: (http://www.census.gov/compendia/statab/cats/births_deaths_marriages_divorces/life_expectancy.html ). http://www.census.gov/compendia/statab/cats/births_deaths_marriages_divorces/life_expectancy.html Survival of atrial fibrillation patients may be less than the usual 13.5 years for a 71 year oldSurvival of atrial fibrillation patients may be less than the usual 13.5 years for a 71 year old The survival of an atrial fibrillation patient may depend upon co- morbidities The survival of an atrial fibrillation patient may depend upon co- morbidities Although post CABG atrial fibrillation may have a limited impact on survival, some conditions such as systolic heart failure that are associated with atrial fibrillation are associated with a 1.9 fold higher risk of dying Although post CABG atrial fibrillation may have a limited impact on survival, some conditions such as systolic heart failure that are associated with atrial fibrillation are associated with a 1.9 fold higher risk of dying (http://eurheartj.oxfordjournals.org/content/26/13/1303.abstract?ijkey=72f6b7eab8464404e3699b19453c0d442a2f7692&keytype2=tf_ipsecsha)(http://eurheartj.oxfordjournals.org/content/26/13/1303.abstract?ijkey=72f6b7eab8464404e3699b19453c0d442a2f7692&keytype2=tf_ipsecsha)http://eurheartj.oxfordjournals.org/content/26/13/1303.abstract?ijkey=72f6b7eab8464404e3699b19453c0d442a2f7692&keytype2=tf_ipsecsha Given that the risk of dying is doubled, let’s assume the survival is halved to 6.75 years. Given that the risk of dying is doubled, let’s assume the survival is halved to 6.75 years. This will yield a conservative estimate of cost effectiveness This will yield a conservative estimate of cost effectiveness C. Michael Gibson, M.S., M.D.

7. Cost Per Year Of Life Saved With Pradaxa Therefore, $224,600 in costs divided by those 6.75 years the person whose life was saved goes on to live equates toTherefore, $224,600 in costs divided by those 6.75 years the person whose life was saved goes on to live equates to $33,274 per year of life saved C. Michael Gibson, M.S., M.D.

8. Cost Per Year of Life Saved Might Be Even Less Because Of The Reduced Costs Of Stroke And Major Bleeding Associated with Pradaxa Treatment What are the cost savings if there is a reduction in stroke? What are the cost savings if there is a reduction in stroke? The lifetime cost of all cause stroke is estimated by the CDC to be $100,000. (http://www.cdc.gov/dhdsp/cdcynergy_training/content/activeinformation/resources/Cost_of_HD.pdf)The lifetime cost of all cause stroke is estimated by the CDC to be $100,000. (http://www.cdc.gov/dhdsp/cdcynergy_training/content/activeinformation/resources/Cost_of_HD.pdf)http://www.cdc.gov/dhdsp/cdcynergy_training/content/activeinformation/resources/Cost_of_HD.pdf The rate of stroke per year was 1.57% for warfarin and 1.01% for 150 mg of pradaxa. Therefore, there is a 0.56% lower rate of stroke per year. In our population of 200 patients, there would be expected to be 1.12 fewer strokes. The rate of stroke per year was 1.57% for warfarin and 1.01% for 150 mg of pradaxa. Therefore, there is a 0.56% lower rate of stroke per year. In our population of 200 patients, there would be expected to be 1.12 fewer strokes. If each stroke costs $100,000 over the lifetime of the patient then preventing 1.12 fewer cases with pradaxa would save $112,000 C. Michael Gibson, M.S., M.D.

9. Cost Per Year of Life Saved Might Be Even Less With Reduced Costs Associated with Reduced Stroke and Major Bleeding What are the cost savings if there is a reduction in major bleeding? What are the cost savings if there is a reduction in major bleeding? In addition to the small but statistically significant reduction in mortality associated with pradaxa therapy, there were also numerically (but not statistically significantly) fewer major bleeds (3.4% vs 3.1% per year). In addition to the small but statistically significant reduction in mortality associated with pradaxa therapy, there were also numerically (but not statistically significantly) fewer major bleeds (3.4% vs 3.1% per year). The cost of a major bleed is estimated to be $8000 (personal communication Dr. David Cohen). The cost of a major bleed is estimated to be $8000 (personal communication Dr. David Cohen). The costs of treating 200 patients with pradaxa would be reduced slightly by preventing 0.6 major bleeds or $4,800 dollars. C. Michael Gibson, M.S., M.D.

10. What Are The Costs Associated With The Higher Rate of MI For Pradaxa? There was an increased risk of MI of 0.21% (p=0.048) for pradaxa vs warfarin (0.74%-0.53%/yr) There was an increased risk of MI of 0.21% (p=0.048) for pradaxa vs warfarin (0.74%-0.53%/yr) The cost of a significant q wave MI is $7000 (Source: Dr. David Cohen) The cost of a significant q wave MI is $7000 (Source: Dr. David Cohen) Treatment of the 200 patients with pradaxa would yield 0.4 of an MI at an increased cost of $2800. C. Michael Gibson, M.S., M.D.

11. What Happens When You Account For The Cost Of Complications (Stroke, Major bleeding and MI) Treating 200 patients with pradaxa for a year costs an additional $224,600 over warfarin Treating 200 patients with pradaxa for a year costs an additional $224,600 over warfarin Among 200 treated patients, there is a cost reduction of $112,000 due to 1.12 fewer stroke cases with pradaxa Among 200 treated patients, there is a cost reduction of $112,000 due to 1.12 fewer stroke cases with pradaxa Among 200 treated patients, there is a cost reduction of $4,800 due to 0.6 fewer major bleeds Among 200 treated patients, there is a cost reduction of $4,800 due to 0.6 fewer major bleeds Among 200 treated patients, there is a cost increase of $2,800 due to 0.4 MI cases Among 200 treated patients, there is a cost increase of $2,800 due to 0.4 MI cases The total additional cost of pradaxa treatment inclusive of complications in 200 patients is $110,600 The cost per year of life saved assuming 6.75 years of survival is $16,385 C. Michael Gibson, M.S., M.D.

12. How Long Would A Patient With Atrial Fibrillation Need To Survive For The Therapy To Be Cost Effective? If society views $50,000 / year of life saved as cost effective If society views $50,000 / year of life saved as cost effective If it costs society $110,600 to save that life when the costs of complications are factored in If it costs society $110,600 to save that life when the costs of complications are factored in Then the survival of atrial fibrillation patients must only exceed 2.2 years for the therapy to be cost effective ($110,600 to save a life of someone who lives 2.2 years = $50,000 per year of life saved) Then the survival of atrial fibrillation patients must only exceed 2.2 years for the therapy to be cost effective ($110,600 to save a life of someone who lives 2.2 years = $50,000 per year of life saved) Most 71 year old atrial fibrillation patients survive more than 2.2 years Most 71 year old atrial fibrillation patients survive more than 2.2 years C. Michael Gibson, M.S., M.D.

13. What If We Model The Cost Effectiveness Based on All Cause Stroke Instead of Mortality There was a reduction in all cause stroke from 1.57%/yr for warfarin to 1.01%/yr for pradaxa, a 0.56% / year reduction. There was a reduction in all cause stroke from 1.57%/yr for warfarin to 1.01%/yr for pradaxa, a 0.56% / year reduction. You would need to treat 179 patients with pradaxa to prevent one stroke. You would need to treat 179 patients with pradaxa to prevent one stroke. This would incur an incremental cost of 179 X $1,123 or $200,535. This would incur an incremental cost of 179 X $1,123 or $200,535. On the other hand, the lifetime cost of all cause stroke is estimated by the CDC to be $100,000. (http://www.cdc.gov/dhdsp/cdcynergy_training/content/activeinformation/resources/Cost_of_HD.pdf) On the other hand, the lifetime cost of all cause stroke is estimated by the CDC to be $100,000. (http://www.cdc.gov/dhdsp/cdcynergy_training/content/activeinformation/resources/Cost_of_HD.pdf)http://www.cdc.gov/dhdsp/cdcynergy_training/content/activeinformation/resources/Cost_of_HD.pdf The net total cost would therefore be $100,535The net total cost would therefore be $100,535 Patients with stroke have a 2.3 fold higher mortality, so survival was estimated to be 13.5 / 2.3 = 5.8 years Patients with stroke have a 2.3 fold higher mortality, so survival was estimated to be 13.5 / 2.3 = 5.8 years(http://stroke.ahajournals.org/cgi/content/abstract/24/6/796) $17,333 per year of stroke free life saved C. Michael Gibson, M.S., M.D.

14. Limitations The estimates are driven by “point estimates”. A 0.5% improvement in mortality is small, and this point estimate may be unstable (the p value is 0.051). The estimates are driven by “point estimates”. A 0.5% improvement in mortality is small, and this point estimate may be unstable (the p value is 0.051). Patients with atrial fibrillation may live longer than the 6.75 years assumed here. A longer survival time would reduce the cost per year of life saved. Patients with atrial fibrillation may live longer than the 6.75 years assumed here. A longer survival time would reduce the cost per year of life saved. No quality adjusted life expectancy data is presented. No quality adjusted life expectancy data is presented. These data mix present cost with future costs. These data mix present cost with future costs. Some cost estimates are old. Some cost estimates are old. There may be heterogeneity in costs of stroke, bleeding and MI throughout the world. There may be heterogeneity in costs of stroke, bleeding and MI throughout the world. C. Michael Gibson, M.S., M.D.

15. 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) http://www.time.com/time/health/article/0,8599,1888006,00.html#ixzz13Z0tUMuG C. Michael Gibson, M.S., M.D.

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

17. What Do We Spend In Society To Save A Life? http://www.cbe.wwu.edu/Krieg/Econ.%20Documents/how_much_for_a_life.htm New York Times, January 29, 1995, p. F3. Dollars Spent To Save A Life C. Michael Gibson, M.S., M.D.

18. Cost Effectiveness: A Lesson From My Son’s Lemonade Stand Dad: I think I will have a glass of lemonade. Son: Here you go. Dad: That was good! I think I will have another one. Son: You can’t have another one. Dad: But the sign says “all you can drink” Son: That is what I am saying dad, that is all you can drink! Let’s make sure we have a clear societal understanding of “All you can drink” C. Michael Gibson, M.S., M.D.

19. Cost Effectiveness Conclusions The annual difference in costs between pradaxa and warfarin once the cost of monitoring is accounted for is approximately $1,123 US dollars The annual difference in costs between pradaxa and warfarin once the cost of monitoring is accounted for is approximately $1,123 US dollars The estimated cost per year of life saved ($33,000 per year of life saved) is likely to fall within the range of acceptable cost effectiveness ($50,000 per year of life saved) The estimated cost per year of life saved ($33,000 per year of life saved) is likely to fall within the range of acceptable cost effectiveness ($50,000 per year of life saved) The cost to prevent all cause stroke appears to be acceptable as well The cost to prevent all cause stroke appears to be acceptable as well While significant reductions in stroke and borderline significant reductions in mortality were observed, the point estimates were infrequent (around 0.5%) which may adversely impact the certainty of cost effectiveness estimates While significant reductions in stroke and borderline significant reductions in mortality were observed, the point estimates were infrequent (around 0.5%) which may adversely impact the certainty of cost effectiveness estimates C. Michael Gibson, M.S., M.D.

20. Present Research/Grant Funding Abbott; Angel Medical Corporation; Astra Zeneca; Atrium Medical Systems; Baxter; Bayer Corp. Cardica, Inc.; FibroGen, Inc.; Fold Rx; Genentech, Inc.; INO Therapeutics, Inc.; Johnson & Johnson Corporation; Lantheus Medical Imaging; Portola Pharmaceuticals; Sanofi-Aventis; Schering Plough Corporation Consultant and Speaking Engagements Acusphere, Inc.; Angel Medical Systems; Archemix Corporation; Ascenta Therapeutics; Atrium Medical Corporation; Bayer Corporation; Boehringer Ingelheim; Cardica Inc.; Heartscape Technologies, Inc.; ICON Medical Imaging; Jim Moran Heart and Vascular Research Institute; Johnson & Johnson Corporation; Medicure, Inc.; Merck; Novartis Pharmaceutical Corporation; Portola Pharmaceuticals, Inc.; Sanofi-Aventis Pharmaceuticals; Schering Plough Corporation; St. Jude Medical; The Medicines Company Royalties as a Contributor UpToDate in Cardiovascular Medicine; Pocket Medicine Disclosures I would like to thank Dr. David Cohen and Matt Reynolds for critiquing these slides Dr. Gibson has received research grant support from virtually all manufacturers of antiplatelets and antithrombins and many device manufacturers C. Michael Gibson, M.S., M.D.