1 Indications for Using Newer Oral Agents and a Comparison to Warfarin In Patients with Atrial Fibrillation Louis Evan Teichholz, M.D. Vice-Chairman, Heart and Vascular Hospital Chief, Division of Cardiology, HackensackUMC April 3, 2014
2 Presenter Disclosure Information Louis Evan Teichholz, MD Indications for Using Newer Oral Agents and a Comparison to Warfarin Financial Disclosure: No relevant financial relationships exist Unlabeled/Unapproved Uses Disclosure: None
3 TEST YOUR AWARENESS First read the sentence in the box below: FINISHED FILES ARE THE RE- SULT OF YEARS OF SCIENTIF- IC STUDY COMBINED WITH THE EXPERIENCE OF MANY YEARS Now count the F s in the sentence. Count them only once and do not go back and count them again.
4 Atrial Fibrillation and Stroke Left ventricular hypertrophy, diastolic dysfunction, and diabetes were common in all hypertensive patients with stroke. In conclusion, hypertensive patients with these risk factors should undergo prolonged electrocardiographic event monitoring to identify occult intermittent AF so measures can be taken to prevent a second stroke and possibly a first stroke. (Haft and Teichholz. Am J Cardiol 2008;102: ) The incidence of AF in patients with stroke is higher in those with other risk factors for stroke and thus may be a common mechanism whereby stroke risk factor cause stroke. Stroke patients in NSR especially with other risk factors should be monitored for AF (Haft and Teichholz. J. Atrial Fib 2013;6:Issue 2) The AF burden threshold which confers increased thromboembolism risk is not precisely defined, but might be as brief as several minutes to several hours. The advent of novel anticoagulation medications, which offer the promise of improved efficacy along with superior safety profiles might warrant more aggressive identification of patients who might benefit from these therapies. (Glotzer and Ziegler. Can J Cardiol 2013;29:S14-23)
5 Summary of evidence-based guideline update: Prevention of stroke in non-valvular atrial fibrillation: Report of the Guideline Development Subcommittee of the American Academy of Neurology Culebras et al. Neurology 2014;82: In patients with recent cryptogenic stroke, cardiac rhythm monitoring probably detect previously undetected NVAF at rate ranging fro 0% to 23% (weighted mean 10.7%) with detection rate probably related to duration of monitoring.
6 2.66 Million people with AF 461,000 hospital discharges At 80yo: lifetime risk of 26%M, 23%W Increases risk of stroke 4 to 5 fold Accounts for 15% to 20% of strokes
7 CHA 2 DS 2 VASc vs. CHADS 2 Scores
8 Anticoagulation Decisions based on Risk Score (CHADS 2 or CHA 2 DS 2 VASc) Score Risk Anticoagulation Therapy Considerations 0 Low None or Aspirin Aspirin daily (?75-325mg) 1 Moderate Aspirin or Warfarin* Aspirin daily or raise INR to , depending on patient preference* >=2 Moderate Warfarin* Raise INR to , unless or High contraindicated* * Or use of newer oral anticoagulant
10 History of Warfarin 1930s: cows hemorrhaging after eating spoiled sweet clover silage 1939: bishydroxycoumarin (dicoumarol) identified 1948: potent form as rodenticide Called Warfarin (Wisconsin Alumni Research Foundation) Anticoagulant in humans? No, too toxic!? 1951: Army inductee s failed attempt at suicide with high dose of warfarin rodenticide Clinical use for over 60 years
11 In the clinical use of warfarin and in the studies comparing warfarin to the newer oral agents, what percentage of time were patients within the therapeutic range (INR 2 to 3)? % % % % % 0% 0% 0% 0% 0%
12 Warfarin & Atrial Fibrillation Warfarin reduces stroke risk by 68% Narrow therapeutic index drug with increased risk of hemorrhagic complications Requires monitoring of PT or the INR with Optimal INR: Warfarin is underutilized, prescribed to ~50%
13 A National Assessment of Warfarin Anticoagulation Therapy for Stroke Prevention in Atrial Fibrillation Dlott et al. DOI: /CIRCULATIONAHA (on-line 2/3/14) QUEST laboratory database. 138,319 patients from 37,939 physicians = 2,683,674 results Patients with >2 mos therapy, INR >1.2 and dx of AF TTR (time in therapeutic range) defined as : Mean TTR with < 6 mos. testing was 47.6% and rose to 57.5% with > 6 mos. testing. No. of patients tested per practice positively associated with TTR
14 Antithrombotics and stroke reduction in atrial fibrillation
15 Limitations of warfarin Frequent monitoring necessitating regular clinic Attendance (or use of POS device) Narrow therapeutic window Slow onset and offset of action, requiring 3 6 days to reach therapeutic levels Long half-life Numerous drug and dietary interactions Genetic polymorphisms exist which confer increased sensitivity or resistance to warfarin Unpredictable pharmacodynamics and pharmacokinetics leading to inter and intra-individual variability in dose and metabolism
16 Risk of Intracranial Hemorrhage in Outpatients Adapted from: Hylek EM, Singer DE, Ann Int Med 1994;120:
17 Lowest Effective Intensity for Warfarin Therapy for Stroke Prevention in Atrial Fibrillation INR below 2.0 results in a higher risk of stroke Hylek EM, et al. NEJM 1996;335:
19 Characteristics of the ideal anticoagulant Equivalent efficacy to warfarin at least Predictable response Wide therapeutic window Low inter and intra-patient variability Fixed oral dosing (Once daily) Low potential for drug and dietary interactions No need for regular coagulation monitoring Fast onset and offset of action Low incidence and severity of adverse effects Available and effective antidote Low cost
21 RE-LY In patients with atrial fibrillation, dabigatran (Pradaxa ) given at a dose of 110 mg twice a day was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg twice a day, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. ROCKET-AF In patients with atrial fibrillation, rivaroxaban (Xarelto ) at a dose of 20 mg once a day was non-inferior to warfarin for the prevention of stroke or systemic embolism. There was no significant betweengroup difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. ARISTOTLE In patients with atrial fibrillation, apixaban (Eliquis ) at a dose of 5 mg. twice a day was superior to warfarin in the primary efficacy endpoint of stroke and systemic embolism and was superior to warfarin in the primary safety endpoint of major bleeding.
22 Dabigatran = Pradaxa Rivaroxabon = Xarelto Apixaban = Eliquis Comparable Primary Efficacy Endpoints of Stroke or Systemic Embolism Comparable Primary Safety Endpoints of Major Bleeding J Am Coll Cardiol 2012;59:
23 Time in Therapeutic Range (TTR) RE-LY ROCKET AF ARISTOTLE 64% 67% warfarinexperienced 61% warfarinnaïve Mean 55% Median 58% Mean 62% Median 66%
24 Which of the following is NOT a potential limitation of the use of newer oral anticoagulants? 1. No well studied commercially available antidote(s) 2. Expensive 3. Lack of validated clinically available tests to monitor anticoagulant effect 4. Long duration of action 5. Use on patients with significant renal insufficiency 0% 0% 0% 0% 0%
26 Comparison of Agents
29 Potential Limitations of New Oral Anticoagulants. No well studied commercially available antidote(s) Expense All about $335/mo. (Special cards, etc.) Warfarin (5 mg) ~ $26 /mo; Coumadin (5 mg) ~ $55 /mo Lack of validated clinically available tests to monitor anticoagulant effect? One size fits all. No head-to-head studies of new agents? Guidelines for triple therapy? Renal issues True long-term cost-effectiveness Cost-effective analyses based on trial data may not reflect real-world clinical practice
30 The Effect of Dabigatran Plasma Concentrations and Patient Characteristics on the Frequency of Ischemic Stroke and Major Bleeding in Atrial Fibrillation Patients Reilly et al JACC 2014;63: Ischemic stroke and bleeding outcomes were correlated with dabigatran plasma concentrations. [Levels related to renal function, age, weight, and gender] Age was the most important covariate. [Other: ASA use, diabetes] Individual benefit-risk might be improved by tailoring dabigatran dose after considering selected patient characteristics. ONE SIZE FITS ALL???
31 Antidotes under development 4 and 3 factor prothrombin complexes (?) Monoclonal antibody against dabigantran (adabi-fab) Recombinant protein (PRT064445) for Xa inhibitors Andexanet alfa (Portola) for Xa (apixaban) PER 997 universal reversal agent
32 Cost-effectiveness of new agents. Cost will be a major barrier to use for the new agents Warfarin is an established and cheap generic drug Only dabigatran has been compared to warfarin in cost effectiveness analyses, both with favorable results for the new drug One analysis suggested high-dose dabigatran was cost-effective as long as the cost was less than $13.70 (roughly double the current US pricing) A further analysis suggested that dabigatran was cost-effective in high-risk stroke patients unless they had exceptionally good INR control Cost-effective analyses based on trial data may not reflect real-world clinical practice Collateral costs (including physician time for dose adjustments and patient transport to clinics) must be incorporated into future analyses More experience with the new agents is mandatory before meaningful conclusions on their cost effectiveness can be made
33 Retail Cost Comparison for 30 Day Supply Drug Dosage Cost Warfarin 5 mg $25.74 Coumadin 5 mg $55.06 Rivaroxabon 20 mg qd $ Dabigatran 150 mg bid $ Apixaban 5 mg bid $ Rivaroxabon = Xarelto Dabigatran = Pradaxa Apixaban = Eliquis
34 Worldwide Sales (1 st half 2013) Dabigatran = Pradaxa = ~ $827 Million Rivaroxabon = Xarelto = ~ $847 Million Apixaban = Eliquis = ~ $ 34 Million (1 st yr) Coumadin = ~ $500 Million
35 New Oral Anticoagulants in Atrial Fibrillation and in Acute Coronary Syndromes ESC Working Group on Thrombosis Task Force on Anticoagulants in Heart Disease Position Paper JACC 2012; 59: The availability, as of now, of 3 new treatment alternatives for stroke prevention in patients with nonvalvular atrial fibrillation is a great step forward to further improve outcomes and quality of life. Compared with warfarin, these new alternatives have important advantages, with their lower risk of intracranial bleeding, no clear interactions with food, fewer interactions with medications, and no need for frequent laboratory monitoring and dose adjustments. Therefore, these new oral anticoagulants will be preferred alternatives to VKAs for many patients with atrial fibrillation and an increased risk of stroke. However, still further information is needed on how to prioritize the patients deriving greater benefits from the novel agents. More information is also needed on the transition between different agents, interruption for procedures and/or surgery, anticoagulation during cardioversion and ablation procedures, and dosing in renal failure.
36 There is also a need for more information on how to manage patients with bleeding because there are no specific antidotes for any of the new agents. Generally available tools to determine the anticoagulant effect (e.g., thrombin time or anti-xa activity) may be needed when these compounds become widely used. Adherence might be a larger issue in the real-life setting than in clinical trials. Therefore, there needs to be agreement on how these patients should be followed on an individual level and how the efficacy and safety of these new treatments can be determined at a health care system level. Because these are lifelong treatments, there is also a need for assessing long-term efficacy and safety over decades in the real-life setting. The cost of the drug at the patient level might be an obstacle to their use, although the cost-effectiveness at a societal level might be tolerable in comparison with other recently accepted novel treatments. New Oral Anticoagulants in Atrial Fibrillation and in Acute Coronary Syndromes ESC Working Group on Thrombosis Task Force on Anticoagulants in Heart Disease Position Paper JACC 2012; 59:
37 Summary of evidence-based guideline update: Prevention of stroke in non-valvular atrial fibrillation: Report of the Guideline Development Subcommittee of the American Academy of Neurology Culebras et al. Neurology 2014;82:
38 Indirect Comparisons of New Oral Anticoagulant Drugs for Efficacy and Safety When Used for Stroke Prevention in Atrial Fibrillation Gregory Y. H. Lip, MD, Torben Bjerregaard Larsen, MD, PHD, Flemming Skjøth, PHD, Lars Hvilsted Rasmussen, MD, PHD (J Am Coll Cardiol 2012;60:738 46) Notwithstanding the limitations of an indirect comparison study, we found no profound significant differences in efficacy between apixaban and dabigatran etexilate (both doses) or rivaroxaban. Dabigatran 150 mg BID was superior to rivaroxaban for some efficacy endpoints, whereas major bleeding was significantly lower with dabigatran 110 mg BID or apixaban. Only a head-to-head direct comparison of the different new OACs would fully answer the question of efficacy/safety differences between the new drugs for stroke prevention in AF.
39 Danger Ahead: Watch Out for Indirect Comparisons! [Editorial] Christopher P. Cannon, MD, and Payal Kohli, MD JACC 2012;60: We have entered an exciting new era of anticoagulation with multiple new oral anticoagulants becoming available for use as potential replacements for warfarin, the vitamin K antagonist that has been the only oral agent available for 50 years. This straightforward and statistically sound analysis of the data strongly supports the use of the newer agents over warfarin, as a class. In general, the authors appear to be saying that there are more similarities between these agents than differences, as has also been previously noted. However, because of the statistical limitations of such comparisons, although of some interest, we feel the differences they report on some endpoints are not robust enough to be relied upon for the clinical care of patients. Instead, we would turn to direct evidence from trials and the indications put forth by the FDA to select the appropriate agent, at the dose tested, for use in the patient population studied within the trial.
40 Current and New Oral Antithrombotics in Non-valvular Atrial Fibrillation: A Network Meta-analysis of 79,808 Patients Dogliotti et al. Heart 2014;100: RCT s with 79,808 patients Random effects model within Bayesian framework using Markov Chain Monte Carlo simulation to calculate pooled outcome ratios for eight treatments. In simulated comparisons, the novel oral anticoagulants ranked better the Vitamin K antagonists or antiplatelet therapies for prevention of stroke, ischemic stroke or systemic embolism and mortality.
42 Shared Decision Making should play an important role in the selection of an appropriate agent for anticoagulation in patients with atrial fibrillation. 1. TRUE 2. FALSE 0% 0% 1 2
43 Recommendations Culebras et al. Neurology 2014;82: Clinicians might obtain cardiac rhythm studies for prolonged periods (1 or more weeks) in patients with cryptogenic stroke without known NVAF to increase the yield of identification of patients with occult NVAF (level C) Clinicians should use a risk stratification scheme to help identify patients with NVAF who are at higher risk for stroke or at no clinically significant risk. However, clinicians should not rigidly interpret anticoagulation thresholds suggested by these tools as being definitive indicators of which patients require anticoagulation (level B) In clinical trials, the new oral anticoagulants are non-inferior or superior to warfarin for reducing stroke and in most patients the reduction in ischemic stroke outweighs the risk of bleeding complications. [They do not generally distinguish in general warfarin or any of the newer oral agents except as reported below (level B)]
44 Recommendations Culebras et al. Neurology 2014;82: Clinicians might recommend that patients taking warfarin whose condition is well-controlled continue warfarin treatment rather than switch to treatment with a new oral anticoagulant (Level C) Clinicians should administer dabigatran, rivaroxaban, or apixaban to patients who have NVAF requiring anticoagulant medication and are at higher risk of intracranial bleeding. (Level B) Clinicians should offer dabigatran, rivaroxaban, or apixaban to patients unwilling or unable to submit to frequent periodic testing of INR levels (Level B) Clinicians should routinely offer oral anticoagulants to elderly patients (aged 75 years) with NVAF if there is no history of recent unprovoked bleeding or intracranial hemorrhage.
45 Patient Values and Preferences (Shared Decision Making) An important consideration when deciding on a therapeutic strategy for stroke prophylaxis in patients with AF is that of patient preference. Patients will, generally speaking, be taking the prescribed therapies for the duration of their lives so it is crucial that they are adequately informed. Evidence suggests that well-informed patients are more compliant with therapy and have better outcomes.
46 Shared Decision Making in Atrial Fibrillation Seaborg, Hess, Coylewright et al. Circulation, 2014;129: SDM characterized by patient participation in clinical decision making is a potentially powerful tool to increase the patientcentered nature of AF management. SDM in AF involves patients and their clinicians actively engaging in the assessment of the risks and benefits of various treatment options for symptom control and stroke prevention and determining which course of action best fits the patient s circumstances, goals, and preferences. Patients with AF appear uniquely posed to benefit from SDM, given the number of sensible options available. Further work is needed in this area to ascertain the extent to which SDM implementation can improve the quality of care and life for patients with this very common disease.
47 Canadian Cardiovascular Congress Debate: Is warfarin dead for stroke prevention in atrial fibrillation? (Reported in Medscape.com Oct 21, 2013) Dr. Paul Dorian (Univ of Toronto): Warfarin is an effective rat poison but is obsolete for preventing stroke in AF Dr. L. Brent Mitchell (Univ of Calgary): Warfarin is the appropriate choice for stroke prevention in many patients with AF, so warfarin is not dead Co-chair Dr. Jafna Cox (Dalhousie Univ): If you have a patient who is doing absolutely fine on warfarin I agree and I think most experts agree there is no compelling reason to switch. However, the newer agents are easier to use in appropriate patients who have an issue with INR monitoring, food interactions, and drug interactions.
49 Irrespective of whether the AF pattern is paroxysmal, persistent, or permanent
52 In the clinical use of warfarin and in the studies comparing warfarin to the newer oral agents, what percentage of time were patients within the therapeutic range (INR 2 to 3)? % % % % % 0% 0% 0% 0% 0%
53 Which of the following is NOT a potential limitation of the use of newer oral anticoagulants? 1. No well studied commercially available antidote(s) 2. Expensive 3. Lack of validated clinically available tests to monitor anticoagulant effect 4. Long duration of action 5. Use on patients with significant renal insufficiency 0% 0% 0% 0% 0%
54 Shared Decision Making should play an important role in the selection of an appropriate agent for anticoagulation in patients with atrial fibrillation. 1. TRUE 2. FALSE 0% 0% 1 2
55 Targets of Novel Anticoagulants for Long-Term Use J Am Coll Cardiol 2012;59: