Anjan K. Chakrabarti, M.D., Shalin J. Patel, M.D., Payal Kohli, M.D., Jacob A. Udell, M.D., M.P.H, Priyamvada Singh M.B.B.S., Lakshmi Gopalakrishnan M.B.B.S., Varun Kumar M.B.B.S., C. Michael Gibson, M.S., M.D.
Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center (AKC, SJP, LG, VK, CMG), Harvard Medical School, Boston, MA; TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital (PK, JAU), Harvard Medical School, Boston, MA; and the PERFUSE Angiographic Core Laboratories and Data Coordinating Center, Beth Israel Deaconess Medical Center (PS) in Boston, MA
Corresponding Author: C. Michael Gibson, M.S., M.D. , Beth Israel Deaconess Medical Center, Cardiovascular Division, 185 Pilgrim Road, Farr 319, Boston, MA 02215.
Non-valvular atrial fibrillation is the most common arrhythmia encountered in clinical practice and is associated with substantial healthcare costs. The risk of thromboembolic stroke is 3-5 times higher in patients with atrial fibrillation compared with the general population. Until the recent emergence of direct thrombin (factor IIa) and factor Xa inhibitors, antithrombotic therapy for atrial fibrillation was achieved with antiplatelet agents or vitamin K antagonists, which are considered cost-effective strategies when compared to no treatment. Now newer agents, such as the direct thrombin inhibitor dabigatran, can lower thromboembolic events and reduce the risk of fatal and intracerebral hemorrhage compared with warfarin, in addition to eliminating the need for costly therapeutic monitoring. Multiple analyses have shown that dabigatran, when compared with warfarin therapy that achieves a time in therapeutic range (TTR) consistent with previous large-scale trials, is a cost-effective approach to antithrombotic therapy in atrial fibrillation, ranging from $16,385 to $86,000 per quality-adjust life-year (QALY) gained. It has been shown to be especially cost-effective (QALY < $50,000) for high stroke-risk patients, those with a CHADS2 score of > 3 (barring excellent INR control) and for lower-risk patients with a CHADS2 of 2 but concomitant high risk of hemorrhage. In addition, factor Xa inhibitors, such as rivaroxaban (recently approved by the Federal Drug Administration [FDA]) and apixaban, may exhibit the same cost savings as dabigatran in terms of reduction of bleeding and elimination of therapeutic level monitoring costs. Going forward, the use of these agents and their role in thromboembolic stroke prophylaxis will need to be evaluated on a patient-by-patient basis, balancing consideration of the patient's stroke and bleeding risks, as well as quality of life post-therapy.
Atrial fibrillation is the most common arrhythmia seen in clinical practice with a prevalence of over three million in the United States, a number that is estimated to rise to over 7.5 million by 2050.1 It has a substantial impact on the healthcare delivery system and poses a significant economic, morbidity, and mortality burden.2-4 In fact, 1 in every 4 people will be affected by atrial fibrillation during their lifetime.5 The risk of thromboembolic stroke, perhaps the most feared complication of atrial fibrillation, is 3-5 times higher in patients with non-valvular atrial fibrillation than the general population.6,7 Thromboemoblic events due to atrial fibrillation are more severe with respect to distribution of ischemic territory and duration of transient ischemic events than those caused by atherosclerotic carotid disease.8, 9 The embolic source in atrial fibrillation begins with static blood in the left atrium or left atrial appendage which, along with endothelial dysfunction and altered hemodynamics, predisposes to clot formation and subsequent embolization, potentially resulting in ischemic stroke or systemic organ infarction.10, 11 Atrial dimensions and hemodynamics lead to the formation of larger particles than those associated with shedding from atheroembolic carotid disease, and consequently higher mortality and disability.8, 9
The combination of high prevalence and morbid outcomes in atrial fibrillation has motivated a great deal of research in the area of antithrombotic therapies, which have been shown to significantly reduce the risk of thromboembolic stroke.12, 13 Early trials investigating antithrombotic therapies for stroke prophylaxis found that they were very effective in patients with all forms of non-valvular atrial fibrillation: paroxysmal, persistent or permanent.14 Interestingly, regardless of underlying arrhythmia treatment strategy (rate vs. rhythm control), antithrombotic therapies have shown a significant benefit with respect to reducing thromboembolic stroke; specifically, restoration of sinus rhythm alone has not been shown to reduce thromboembolic strokes in patients with atrial fibrillation. In fact, patients managed with a rhythm control strategy without antithrombotic therapy experienced the highest rates of thromboembolic events.15, 16 With an aging population in the United States, the population-based need for antithrombotic therapy amongst patients with atrial fibrillation is substantial.17 A cost-effective solution for decreasing the population-wide burden of thromboembolism, particularly in the current climate of efficient health care delivery, is increasingly important.
Determining whether a therapy is "cost-effective" historically involved estimating the "cost per year of life saved" by calculating the cost to save a life, estimating how many years that person will live, and dividing the cost to save the life by the number of years the person will live.18 In general, an estimate of what society is willing to pay for, and therefore what is determined to be cost-effective, is $50,000 per year of life saved.19 To put this in perspective historically, hemodialysis costs approximately $129,000 per year of life saved.20 Given the substantial patient-level morbidity and population-level costs associated with embolic stroke (permanent disability, intensive rehabilitation, and risk of hospitalization for co-morbidities related to stroke), a more useful measurement of a cost-effective therapy in atrial fibrillation may be the "quality-adjusted life-year" (QALY), first used in 1976 by Zeckhauser and Shepard to indicate a health outcome measurement unit that combines duration and quality of life.21, 22 QALYs adjust a patient’s life expectancy based on the levels of health-related quality of life they are predicted to experience throughout the course of their life, or part of it. In general, it is calculated by obtaining quality-of-life estimates, known as "utilities," and by interviewing patients using the "trade-off method" to determine utilities for various scenarios, health outcomes, and deficits. Each expected life year is then multiplied by this "utility" factor, the sum of which are QALYs.22 In the case of atrial fibrillation and thromboembolic disease, where the burden of neurological disability can be high, utilities for neurologic deficits can be compared to the consequences of taking antithrombotic therapy and multiplied by life expectancy to determine QALY. This method has been previously employed for atrial fibrillation by Gage, et al.23 Similar methods have been used to analyze the cost-effectiveness of novel antithrombotic therapies and can be used for emerging therapies.
Aspirin and Anti-Platelet Therapies – Inexpensive, but Are They Effective?
Until the recent emergence of direct thrombin inhibitors and factor Xa inhibitors, antithrombotic therapy in atrial fibrillation was achieved with aspirin or warfarin, and in some cases aspirin with another antiplatelet therapy, including a thienopyridine such as clopidogrel, or a thromboxane synthase inhibitor such as dipyridamole. Aspirin had been shown in early studies to reduce thromboembolic stroke when compared to placebo.12,24-26 In the early clinical trials, which compared the efficacy of aspirin against no therapy in stroke prophylaxis for atrial fibrillation, only one trial achieved statistical significance in lowering thromboembolic stroke. A subsequent landmark meta-analysis concluded the risk of thromboembolic stroke was reduced by twenty percent with aspirin vs. placebo in patients with atrial fibrillation.25 Because the relative risk of stroke from atrial fibrillation increases long-term when additional comorbidities are present, patients can be stratified to aspirin therapy using the CHADS2 risk score. The CHADS2 risk score is a multivariate risk model that has been validated in various patient populations for primary prevention of stroke in patients with atrial fibrillation.14, 27 The presence of each of the following risk factors proportionally adds one point to the future stroke risk score, including chronic heart failure (the "C" in the CHADS2 acronym), hypertension ("H"), advanced age >=75 ("A"), diabetes mellitus ("D"), and prior stroke or TIA (which carries twice the weight of the other risk factors, hence the "S2"). Future risk of ischemic stroke is expressed in number of events per 100 person years of follow-up, with or without antithrombotic therapy, and increases as one’s score increases from 0 to 6. Those with a score of 0 or 1, and therefore a low stroke risk, were deemed more appropriate for aspirin therapy because the risk of stroke is low as compared with the risk of bleeding from antithrombotic therapy (which also increases with additional comorbidities).Contemporary analyses demonstrate that CHADS2 may not be comprehensive enough to accurately estimate stroke risk, particularly in the CHADS2 low-range of a morbid population; as a result, the CHADS2VASc score was developed. The CHADS2VASc score can further risk stratify patients with a CHADS2 score of 0 or 1 adding an additional point each in the presence of atherosclerotic vascular disease ("V"), age between 65-74 years (the second "A"), or female sex category ("Sc"). 28 This revised score not only refines the selection of patients appropriate for antiplatelet therapy, but also allows for more accurate risk stratification in this population.
When compared to other antithrombotic therapies, aspirin is quite inexpensive; in fact it costs only $35.97 for a one-year supply. However, its effectiveness in stroke prophylaxis in atrial fibrillation on a population level is diminishing. Olesen, et al. have shown that the benefit of warfarin therapy outweighs complications in all patients with atrial fibrillation except those at lowest risk of thromboembolic events (i.e. CHADS2VASc of 0).24, 29 Another cost-effectiveness analysis of aspirin performed by Gage, et al. similarly demonstrated that aspirin is only as cost-effective as warfarin in low-risk populations (i.e. CHADS2 score of 0). Specifically, in a low-risk population, the quality-adjusted life expectancy was estimated to be 6.70 years with warfarin therapy, 6.69 years with aspirin therapy, and 6.51 years with no therapy. Warfarin was not cost-effective in this population but aspirin actually saved money, at a 10-year cost (including the cost of prophylaxis, stroke, transient ischemic attacks, hemorrhage, and death in 1994 dollars) of $5400 versus $6300 for no therapy. This strategy did not prove cost-effective in other higher risk groups.23
Dual antiplatelet therapy with aspirin and clopidogrel, estimated to cost $1799.88 for a one-year supply until clopidogrel becomes generic as expected in May 2012, was assessed in the ACTIVE trial for stroke prophylaxis in atrial fibrillation. ACTIVE A, which compared clopidogrel with placebo in patients already receiving aspirin, showed combined therapy with aspirin and clopidogrel further reduced thromboembolic stroke in patients with atrial fibrillation, but at a trade-off of higher bleeding risk when compared to aspirinalone.30 Alternatively, ACTIVE W, which compared a strategy of clopidogrel plus aspirin to oral anticoagulation therapy, established that warfarin was superior thromboembolic prophylaxis compared to aspirin/clopidogrel without a significant difference in bleeding complications.31 As noted by Hankey, et al., while aspirin/clopidogrel may be superior to aspirin alone in terms of thromboembolic stroke prevention, it is unlikely to be more cost-effective until clopidogrel loses patent protection.32 Other reports have confirmed that dual-antiplatelet therapy does not appear to be a cost-effective strategy.33
Warfarin has been established as effective therapy for the prevention of thromboembolic stroke in patients with atrial fibrillation. Indeed, stroke prophylaxis with warfarin is superior to aspirin in several clinical trials.12, 26, 34 Warfarin has subsequently been the therapy of choice for stroke prophylaxis in non-valvular atrial fibrillation in those who can tolerate its associated side effects, drug interactions, and INR monitoring. However, because warfarin is associated with increased risk of bleeding, patients and clinicians have had to face difficult decisions regarding the safety of anticoagulation therapy in clinical practice. In addition, warfarin requires frequent monitoring to maintain a narrow therapeutic window, has a slow onset of action with several days required to reach therapeutic levels, has significant medication interactions, and adversely affects quality of life by requiring lifestyle modifications to avoid injury and interaction with meals.
Although the annual cost of warfarin is only $109.50, the cumulative cost including therapeutic level monitoring must also be considered in its total cost. The cost of monitoring includes the number of annual visits (an average of 16), registered nurse's (RN) and general practitioner’s (GP) time, home testing, and blood sample collection, analysis and transportation. Inclusive of all costs, the cost of monitoring is estimated to be $2,134 per patient per year in the first year, with a subsequent drop to $1,170 per year as long as a stable level of therapeutic level is maintained.35When compared to aspirin, Gage, et al. demon strated in 1994 that warfarin is more cost-effective in both moderate- and high-risk patients with atrial fibrillation.23 Specifically in moderate-risk patients, the cost-effectiveness of warfarin therapy compared with aspirin therapy was $8000 (range, $200 to $30000) per QALY gained. Warfarin was also more cost-effective compared to no therapy in the moderate- and high-risk patient groups.
Over the last two years, there have been significant developments in antithrombotic therapy (i.e. direct thrombin inhibitors and factor Xa inhibitors), which now provide an alternative and potentially more cost-effective therapy for stroke prophylaxis without the burden of therapeutic level monitoring or slow onset of action.
Novel direct thrombin inhibitors have recently emerged as an alternative to warfarin for stroke prophylaxis in atrial fibrillation. Dabigatran is a potent, direct, competitive inhibitor of thrombin, which has an absolute bioavailability of 6.5%, a serum half-life of 12 to 17 hours, and does not require regular therapeutic monitoring. The RE-LY trial, which compared dabigatran to warfarin in patients with atrial fibrillation, showed that dabigatran 150 mg twice daily was superior to warfarin therapy by reducing thromboembolic events, and fatal and intracerebral hemorrhage.36 Subsequent cost-effectiveness analyses have demonstrated that when the total cost of administering warfarin is taken into account, and the cost savings associated with dabigatran's reduction in stroke are factored in, dabigatran may be a more cost-effective therapy for stroke prophylaxis in atrial fibrillation and may offer more quality-adjusted life-years than other alternatives (see Figure 1).33
Figure 1: QALY Added Compared to No Therapy for Stroke Prophylaxis in Atrial Fibrillation.*Data presented is for Base Case as Analyzed by Shah et al, and Represents the Typical Patient in the RE-LY Study
A "back of the envelope" analysis has demonstrated the cost-effectiveness of dabigatran compared to warfarin in atrial fibrillation.37 Compared to warfarin, with an annual cost of drug acquisition and monitoring of approximately $1,761 per year, the annual cost of dabigatran comes at $2,884 per year38, which makes the annual additional cost of dabigatran over warfarin approximately $1,123 per year. However, the rate of stroke per year in RE-LY was 1.57% for warfarin and 1.01% for 150 mg of dabigatran; therefore, there is a 0.56% lower annual rate of stroke.36 It should also be noted that there was a small but statistically significant reduction in mortality (0.5% per year) associated with dabigatran therapy, and there were also numerically (but not statistically significantly) fewer major bleeds (3.4% vs 3.1% per year). With this mortality benefit, 200 patients will have to be treated with dabigatran instead of warfarin per year to save one life. For a population sample of 200 patients, extra medication cost of dabigatran would be $224,600, and dabigatran would be expected to reduce yearly incidence of stroke by 1.12 compared to warfarin (200 patients x 0.56%), which would equate to a cost saving of $112,000 if Center for Disease Control (CDC) estimates for cost of stroke ($100,000 per year) are maintained.37, 39 Similarly, dabigatran would be able to reduce yearly personal incidence of major GI bleed by 0.6 events per year or $4800 per year (estimated cost of bleeding event $8000).37,40,41 Dabigatran would increase the yearly incidence of MI by 0.42 in a 200 patient population, which would cost an additional $2800 per year (estimated cost of MI $7000).37 The overall cost of dabigatran treatment in 200 patients, to save one life, would therefore be $110,600. It would therefore take 2.2 years to reach the $50,000 per life saved per year threshold for dabigatran to be cost-effective (unpublished data Dr. C. Michael Gibson).37
Separate analyses have been performed by Freeman, et al. and Shah, et al., which estimated cost per QALY gained with dabigatran 150mg to be $45,372 and $86,000, respectively.33, 42 The latter may be a more accurate estimate as the authors explicitly modeled dyspepsia, calibrated their mortality rates to those of RE-LY, and stratified their results by INR control, the CHADS2 score, and the HEMORR2HAGES bleeding risk score.43 Both studies found that dabigatran 150 mg would be cost-effective (QALY < $50,000) for high-risk patients with a CHADS2 score of > 3 (unless INR control was excellent) and for patients with a CHADS2 of 2 and high estimated risk of hemorrhage with warfarin. Overall, it appears that while there is some variability in QALY, there is a consensus that dabigatran is a cost-effective stroke prophylaxis therapy strategy for patients at high risk of a thromboembolic event with atrial fibrillation (see Figure 2).
It should be noted that these conclusions assume a time in therapeutic range (TTR) in the warfarin-treated arm that is consistent with previous literature. Several prospective trials have shown that patients with atrial fibrillation treated with warfarin stay in therapeutic range only 61-68% of the time.44, 45 Patients with a TTR over 75% have a thromboembolic event rate of only 1.07% per year, which is similar to the thromboembolic event rate in patients treated with dabigatran 150 mg in RE-LY.36, 46 This was reinforced by Wallentin, et al., who demonstrated that 150 mg dabigatran was not superior to warfarin at reducing the risk of non-hemorrhagic stroke at higher TTR quartiles.47 These results highlight the importance of considering TTR for a given patient population when making cost-effectiveness comparisons between novel therapies and warfarin.
Figure 2: Dollars Spent on various Therapies per QALY in the United States.**Data Ranges presented are Based on Analyses by Gage et al, Shah et al, and Gibson et al.
Another promising class of antithrombotic drugs are the factor Xa inhibitors. These therapies are similar to direct thrombin inhibitors in that they do not require laborious therapeutic monitoring and have a relatively fast onset of action. Rivaroxaban, a factor Xa inhibitor, was recently approved for use in atrial fibrillation by the FDA.48 This agent was shown in the ROCKET-AF trial to be non-inferior to warfarin in thromboembolic stroke prophylaxis, while having lower rates of fatal and intracerebral bleeding.49 To date, rivaroxaban has been shown to be a cost-effective therapy in the reduction of venous thromboembolism after total hip replacement in Canada; in fact the therapy was shown to provide quality-of-life benefit at a lower cost than enoxapaFigure rin, and this may translate to stroke prophylaxis in atrial fibrillation.50 In the United Kingdom (UK) and Europe, the National Institute for Health and Clinical Excellence (NICE) are deliberating whether rivaroxaban is cost-effective utilizing a provisional cost in the UK of once daily rivaroxaban ($3.24 per day), or an annual cost of $1200.51
Table 1: Clinical studies of alcohol and atrial fibrillation
Apixaban, another novel factor Xa inhibitor, may prove to be the most cost-effective antithrombotic for use with atrial fibrillation given the overwhelming efficacy and safety reported in the ARISTOTLE trial. ARISTOTLE evaluated apixaban compared with warfarin for stroke prophylaxis in atrial fibrillation and noted significantly lower rates of all-cause mortality, thromboembolic stroke, and intracerebral hemorrhage.52 The emerging data on this novel therapy and its potential utility in atrial fibrillation is very favorable; however the cost associated with apixaban has not yet been announced by its manufacturer making any cost-effectiveness estimates premature.
In the absence of finalized cost data in the United States, Figure 3 demonstrates what the cost per life saved vs. annual drug cost for this class of medications would be with variable mortality benefits (ranging from 5-15% relative risk reduction). The ROCKET-AF, RE-LY, and ARISTOTLE52 trials all demonstrate similar mortality, stroke, and major bleeding benefit over warfarin therapy; as a result, the "back of the envelope" analysis used to generate Figure 3 makes the same cost assumptions presented for the dabigatran analysis and holds bleeding and stroke rate reductions constant. This analysis highlights the approximate $2300 threshold for annual drug cost leading to actual cost saving based on reduction of mortality, stroke, and major bleeding over warfarin.
Figure 3: Cost per life saved based on annual drug costs when compared to warfarin therapy
As the burden of atrial fibrillation and its morbidity continue to grow, so will the need for cost-effective novel therapies. Until recently, the most effective therapy for thromboembolic stroke prophylaxis in nonvalvular atrial fibrillation has been warfarin. While warfarin does add quality-adjusted life-years when compared to aspirin or no therapy, its many shortcomings including slow-onset of action and tedious therapeutic level monitoring, are finally being overcome by the novel direct thrombin inhibitors and factor Xa inhibitors. Questions remain regarding the performance of these drugs when applied to the general population as opposed to those represented in large clinical trials. In adaddition, the cost-effectiveness of these antithrombotic therapies will weigh heavily on their price and "
effectiveness. As a result, the use of these agents and their role in thromboembolic stroke prophylaxis will need to be evaluated on a patient-by-patient basis, taking into consideration the patient’s stroke risk, risk of bleeding, medication compliance, and quality of life post-therapy (see Table 1). If these agents emerge as safe and cost-effective therapies after the benefit of post-marketing surveillance data, they will pave the way for further innovation in the medical care of this expanding population
1. Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial fibrillation and flutter in the united states. Am J Cardiol. 2009;104:1534-1539.
2. Coyne KS, Paramore C, Grandy S, Mercader M, Reynolds M, Zimetbaum P. Assessing the direct costs of treating nonvalvular atrial fibrillation in the united states. Value Health. 2006;9:348-356.
3. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: Incidence, risk factors, and prognosis in the manitoba follow-up study. Am J Med. 1995;98:476-484.
4. Stewart S, Hart CL, Hole DJ, McMurray JJ. Population prevalence, incidence, and predictors of atrial fibrillation in the renfrew/paisley study. Heart. 2001;86:516-521.
5. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D’Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Lifetime risk for development of atrial fibrillation: The framingham heart study. Circulation. 2004;110:1042-1046.
6. Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: Population-based estimates. Am J Cardiol. 1998;82:2N-9N.
7. Wolf PA, Dawber TR, Thomas HE, Jr., Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: The framingham study. Neurology. 1978;28:973-977.
8. Anderson DC, Kappelle LJ, Eliasziw M, Babikian VL, Pearce LA, Barnett HJ. Occurrence of hemispheric and retinal ischemia in atrial fibrillation compared with carotid stenosis. Stroke; a journal of cerebral circulation. 2002;33:1963-1967 9. Harrison MJ, Marshall J. Atrial fibrillation, tias and completed strokes. Stroke. 1984;15:441-442.
10. Heppell RM, Berkin KE, McLenachan JM, Davies JA. Haemostatic and haemodynamic abnormalities associated with left atrial thrombosis in non-rheumatic atrial fibrillation. Heart. 1997;77:407-411.
11. Kamath S, Blann AD, Chin BS, Lip GY. Platelet activation, haemorheology and thrombogenesis in acute atrial fibrillation: A comparison with permanent atrial fibrillation. Heart. 2003;89:1093-1095.
12. Stroke prevention in atrial fibrillation study. Final results. Circulation. 1991;84:527-539.
13. van Walraven C, Hart RG, Singer DE, Laupacis A, Connolly S, Petersen P, Koudstaal PJ, Chang Y, Hellemons B. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: An individual patient meta-analysis. JAMA. 2002;288:2441-2448.
14. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: Results from the national registry of atrial fibrillation. JAMA. 2001;285:2864-2870 15. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, Said SA, Darmanata JI, Timmermans AJ, Tijssen JG, Crijns HJ. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002;347:1834-1840.
16. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, Kellen JC, Greene HL, Mickel MC, Dalquist JE, Corley SD. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825-1833.
17. Go AS, Hylek EM, Chang Y, Phillips KA, Henault LE, Capra AM, Jensvold NG, Selby JV, Singer DE. Anticoagulation therapy for stroke prevention in atrial fibrillation: How well do randomized trials translate into clinical practice? JAMA : the journal of the American Medical Association. 2003;290:2685-2692.
18. Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the panel on cost-effectiveness in health and medicine. JAMA : the journal of the American Medical Association. 1996;276:1253-1258.
19. Lee TT, Solomon NA, Heidenreich PA, Oehlert J, Garber AM. Cost-effectiveness of screening for carotid stenosis in asymptomatic persons. Annals of internal medicine. 1997;126:337-346 20. Hamel MB, Phillips RS, Davis RB, Desbiens N, Connors AF, Jr., Teno JM, Wenger N, Lynn J, Wu AW, Fulkerson W, Tsevat J. Outcomes and cost-effectiveness of initiating dialysis and continuing aggressive care in seriously ill hospitalized adults. Support investigators. Study to understand prognoses and preferences for outcomes and risks of treatments. Annals of internal medicine. 1997;127:195-202.
21. Zeckhauser R, DS S. Where now for saving lives? . Law and Contemporary Problems. 1976;40:5-45.
22. Sassi F. Calculating qalys, comparing qaly and daly calculations. Health policy and planning. 2006;21:402-408.
23. Gage BF, Cardinalli AB, Albers GW, Owens DK. Cost-effectiveness of warfarin and aspirin for prophylaxis of stroke in patients with nonvalvular atrial fibrillation. JAMA : the journal of the American Medical Association. 1995;274:1839-1845 .
24. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery CA, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P. Guidelines for the management of atrial fibrillation: The task force for the management of atrial fibrillation of the european society of cardiology. Eur Heart J. 2010;Oct;31:2369-2429.
25. Hart RG PL, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-867.
26. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The copenhagen afasak study. Lancet. 1989;1:175-179.
27. Go AS, Hylek EM, Chang Y, Phillips KA, Henault LE, Capra AM, Jensvold NG, Selby JV, Singer DE. Anticoagulation therapy for stroke prevention in atrial fibrillation: How well do randomized trials translate into clinical practice? JAMA. 2003;290:2685-2692 28. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH, Vahanian A, Auricchio A, Bax J, Ceconi C, Dean V, Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas PE, Widimsky P, Agladze V, Aliot E, Balabanski T, Blomstrom-Lundqvist C, Capucci A, Crijns H, Dahlof B, Folliguet T, Glikson M, Goethals M, Gulba DC, Ho SY, Klautz RJ, Kose S, McMurray J, Perrone Filardi P, Raatikainen P, Salvador MJ, Schalij MJ, Shpektor A, Sousa J, Stepinska J, Uuetoa H, Zamorano JL, Zupan I. Guidelines for the management of atrial fibrillation: The task force for the management of atrial fibrillation of the european society of cardiology (esc). Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2010;12:1360-1420 29. Olesen JB, Lip GY, Lindhardsen J, Lane DA, Ahlehoff O, Hansen ML, Raunso J, Tolstrup JS, Hansen PR, Gislason GH, Torp-Pedersen C. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: A net clinical benefit analysis using a ‘real world’ nationwide cohort study. Thromb Haemost. 2011;106:739-749.
30. Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Yusuf S. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trialwith irbesartan for prevention of vascular events (active w): A randomised controlled trial. Lancet. 2006;367:1903-1912.
31. Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M, Chrolavicius S, Yusuf S. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360:2066-2078.
32. Hankey GJ. Replacing aspirin and warfarin for secondary stroke prevention: Is it worth the costs? Current opinion in neurology. 2010;23:65-72.
33. Shah SV, Gage BF. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation. 2011;123:2562-2570.
34. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke prevention in atrial fibrillation ii study. Lancet. 1994;343:687-691 35. Bjorholt I, Andersson S, Nilsson GH, Krakau I. The cost of monitoring warfarin in patients with chronic atrial fibrillation in primary care in sweden. BMC family practice. 2007;8:6.
36. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial fibrillation. The New England journal of medicine. 2009;361:1139-1151.
37. C. Michael Gibson. Last Modified October 13. Estimates of cost per year of life save for dabigatran. Http://www.Wikidoc.Org/index.Php/estimates_of_cost_per_year_of_life_saved_for_dabigatran.
38. Huston L. Pradaxa (dabigatran) pricing starts to emerge. cardiosource.org. 2010 39. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, Finkelstein EA, Hong Y, Johnston SC, Khera A, Lloyd-Jones DM, Nelson SA, Nichol G, Orenstein D, Wilson PW, Woo YJ. Forecasting the future of cardiovascular disease in the united states: A policy statement from the american heart association. Circulation. 2011;123:933-944.
40. Ghate SR, Biskupiak J, Ye X, Kwong WJ, Brixner DI. All-cause and bleeding-related health care costs in warfarin-treated patients with atrial fibrillation. Journal of managed care pharmacy : JMCP. 2011;17:672-684.
41. Kim MM, Metlay J, Cohen A, Feldman H, Hennessy S, Kimmel S, Strom B, Doshi JA. Hospitalization costs associated with warfarin-related bleeding events among older community-dwell ing adults. Pharmacoepidemiology and drug safety. 2010;19:731-736.
42. Freeman JV, Zhu RP, Owens DK, Garber AM, Hutton DW, Go AS, Wang PJ, Turakhia MP. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation. Annals of internal medicine. 2011;154:1-11.
43. Gage BF, Yan Y, Milligan PE, Waterman AD, Culverhouse R, Rich MW, Radford MJ. Clinical classification schemes for predicting hemorrhage: Results from the national registry of atrial fibrillation (nraf). American heart journal. 2006;151:713-719 44. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke prevention in atrial fibrillation iii randomised clinical trial. Lancet. 1996;348:633-638.
45. Diener HC. Stroke prevention using the oral direct thrombin inhibitor ximelagatran in patients with non-valvular atrial fibrillation. Pooled analysis from the sportif iii and v studies. Cerebrovascular diseases. 2006;21:279-293.
46. White HD, Gruber M, Feyzi J, Kaatz S, Tse HF, Husted S, Albers GW. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: Results from sportif iii and v. Archives of internal medicine. 2007;167:239-245 47. Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S, Connolly SJ. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: An analysis of the re-ly trial. Lancet. 2010;376:975-983.
48. Walsh S. Fda approves xarelto to prevent stroke in people with common type of abnormal heart rhythm. 2011.
49. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. The New England journal of medicine. 2011;365:883-891.
50. Diamantopoulos A, Lees M, Wells PS, Forster F, Ananthapavan J, McDonald H. Cost-effectiveness of rivaroxaban versus enoxaparin for the prevention of postsurgical venous thromboembolism in canada. Thrombosis and haemostasis. 2010;104:760-770 51. Nainggolan L. K’s nice wants more data on rivaroxaban in af. theheart.org. 2012;2012.
52. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L. Apixaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine. 2011;365:981-992.