New Oral Anticoagulants: Breakthrough or Just Another Bleeding Mess?
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New Oral Anticoagulants: Breakthrough or Just Another Bleeding Mess?

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The following slides were presented as part of a debate between Dr. Marc Carrier and Dr. Jafna Cox at the Family Medicine Forum 2013 in Vancouver, British Columbia.

The following slides were presented as part of a debate between Dr. Marc Carrier and Dr. Jafna Cox at the Family Medicine Forum 2013 in Vancouver, British Columbia.

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  • Matchar DB, Samsa GP, Cohen SJ, Oddone EZ, Jurgelski AE. Improving the quality of anticoagulation of patients with atrial fibrillation in managed care organizations: results of the managing anticoagulation services trial. Am J Med 2002;113:42-51Bungard TJ, Ackman JL, Ho G, Tsuyuki RT. Adequacy of anticoagulation in patients with atrial fibrillation coming to a hospital. Pharmacotherapy2000;20:1060-5.
  • SSED110 0.90 (.74-1.10) <0.001, 0.01Ischemic StrokeD110 1.11 (0.88-1.39) 0.35D150 0.76 (0.59-0.97) 0.03Riva 0.94 (0.75,1.17) 0.581Apix 0.92 (0.74-1.13) 0.42
  • ICH:D110 0.30 (0.19-0.45) <0.001
  • Overall mortalityD110 0.91 (0.80-1.03) 0.13D150 0.88 (0.77-1.00) 0.051Riva 0.85 (0.70-1.02) 0.073Apix 0.89 (0.80-0.998) 0.047CV mortalityD110 0.90 (0.77-1.06) 0.21D150 0.85 (0.72-0.99) 0.04Riva 0.89 (0.73-1.10) 0.289Apix 0.89 (0.76-1.04)
  • Low stroke risk: Guidelines3-5 recommend that AF patients at lowest risk of stroke (CHADS2 = 0 and no additional risk factors) receive no antithrombotic therapy, as the risks usually outweigh the potential benefits.3-5 Indeed, antithrombotic therapy is associated with an increased risk of major bleeding that may also lead to serious consequences; therefore, the beneficial effect of therapy on the risk of stroke should always be weighed against a patient’s risk of hemorrhage.3 However, patients presenting with additional risk factors not considered in the CHADS2 score (i.e., age between 65 and 74 years, female sex and presence of vascular disease) may benefit from antithrombotic therapy, in which case ASA or anticoagulants are recommended.3-5 Alternative treatment options: Antiplatelet agents demonstrate benefits in stroke prevention, but are considered less effective than anticoagulant therapy for this purpose.7,15,47 A potentially lower risk of bleeding however positions ASA as a reasonable low-cost alternative to anticoagulants in some patients with an intermediate to low risk of stroke.3-5 The combination of ASA + clopidogrel is also considered an alternative in the occasional patients who cannot be treated with an anticoagulant, or who present with particular comorbidities, as long as the risk of bleeding is low.3-5,7
  • When a patient receiving an oral anticoagulant agent is to undergo a surgical or diagnostic procedure that has a risk of major bleeding, the risk of a thromboembolic event occurring while the antithrombotic agent is reduced or stopped must be weighed against the goal of a reduced risk of major bleeding.Consideration should be given to the route of clearance and half-life of the drug. In addition, the patient’s renal function should be assessed. The use of other concomitant medications which may increase bleeding risk, such as ASA, NSAIDs and clopidogrel, should also be taken into account.ReferencesCrowther MA & Wallentin TE. Managing bleeding in anticoagulation patients with a focus on novel therapeutic agents. J Thromb Haemostat 2009;7 (Suppl 1):107-110.van Ryn J, et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity.Thromb Haemostat 2010;103:1116-1127.Pradax Product Monograph 2010, Boehringer Ingelheim Canada Ltd.
  • Since approximately 80% of dabigatran is eliminated via the kidneys, a determination of renal function combined with bleeding risk is important in deciding when to discontinue dabigatran therapy. Dabigatran should be discontinued at least 24 hours prior to any elective surgery depending on the degree of renal impairment and risk of bleeding. In patients with normal renal function (CrCl >50 to ≤ 80 ml/min) and moderate bleeding risk, dabigatran should be discontinued 1-2 days prior to surgery, in those with normal renal function and high risk of bleeding where complete hemostasis may be required, dabigatran should be discontinued 2-3 days before surgery. In patients with moderate renal impairment (CrCl 31-50 ml/min) and moderate risk of bleeding, dabigatran should be discontinued 3-4 days prior to surgery, in those with moderate renal impairment and high risk of bleeding, again, where complete hemostasis may be required, dabigatran should be discontinued 4-5 days before surgery. In patients with severe renal impairment (CrCl < 30 ml/min) and moderate or high risk of bleeding, dabigatran should be discontinued at least 4-5 days prior to and preferably more than 5 days before surgery. These patients should have dabigatran permanently discontinued unless their renal function improves. In addition, patients with severe renal impairment should have a delay in surgery, if at all possible, and/or haemodialysis or other measures should be considered prior to surgery as their risk of bleeding will be elevated.ReferencesAdapted from:van Ryn J, et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemostat 2010;103:1116-1127.Pradax Product Monograph 2010, Boehringer Ingelheim Canada Ltd.
  • www.cadth.ca/clots

New Oral Anticoagulants: Breakthrough or Just Another Bleeding Mess? New Oral Anticoagulants: Breakthrough or Just Another Bleeding Mess? Presentation Transcript

  • New Oral Anticoagulants: Breakthrough or Just Another Bleeding Mess? Debate between Dr. Marc Carrier and Dr. Jafna Cox at #FMF2013 November 8, 2013
  • The following slides were presented as part of a debate at the Family Medicine Forum 2013 in Vancouver, British Columbia.
  • • Dr. Cox and Dr. Carrier served as expert clinical advisors on CADTH’s Preventing Stroke in Patients with Atrial Fibrillation project that focused on the clinical and cost-effectiveness of warfarin, the new oral anticoagulants (NOACs), and antiplatelets in the prevention of stroke in Afib. • We enjoyed their lively debates during the project and felt that they needed to be heard by a larger audience — especially family physicians faced with decisions of which agent to choose for their patients.
  • New Oral Anticoagulants: Breakthrough or Just another Bleeding Mess? Marc Carrier MD MSc FRCPC Thrombosis Program Ottawa Hospital Research Institute
  • Objectives • Is evidence for the new oral anticoagulants (NOACs) impressive, or is it hype? • More effective for all patients? • Safe? » Major bleeding? » Other complications? • How relevant are clinical practice guidelines that disregard cost (and evidence)? • How difficult is it to treat a bleed with the new drugs?
  • Warfarin the underdog! • Is NOT rat poison – Rats have evolved (and so should you…) • Advantages of warfarin – Active by the oral route – Once daily dosing – Can be monitored • Surgeries • Bleeding episodes • Recurrent events • Adherence – Rapidly-acting antidote available – Low cost
  • Is evidence for the NOACs impressive, or is it hype? Efficacy data
  • Warfarin is highly effective for the prevention of stroke in patients with atrial fibrillation Hart et al Ann Intern Med. 2007;146:857-867
  • Drug Brand name Target Peak (h) Half- life (h) Bio Renal excr. (%) Drug interactions Dabigatran Pradaxa® Factor IIa 1.5 14 - 17 8% > 80% P-glycoprotein Rivaroxaban Xarelto® Factor Xa 2 - 3 7 - 11 80% 33% CYP3A4 P-glycoprotein Apixaban Eliquis ® Factor Xa 3 8 – 14 66% 25% CYP3A4 P-glycoprotein Edoxaban Lixiana ® Factor Xa 4 8 - 11 45% 35% CYP3A4 P-glycoprotein NOACs
  • RE-LY ROCKET AF ARISTOTLE Sample size 18,113 14,264 18,201 Population Non-valvular A fib CHADS ≥ 1 Non-valvular A fib CHADS ≥ 2 Non-valvular A fib CHADS ≥ 1 NOACs Dabigatran 110 mg or 150 mg BID Rivaroxaban 20 mg OD Apixaban 5 mg BID Design Open RCT with two doses of double-blind dabigatran Double-blind Double-blind 1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010; 4.Granger CB et al, 2011. Trials Comparing NOACs vs. Warfarin
  • Are NOACs really more effective? Wallentin L. Lancet. 2010 Sep 18;376(9745):975-83.
  • Are NOACs good anticoagulants? Other high risk populations • Mechanical heart valves • Trial terminated early after enrolling 252 patients – Dabigatran 150, 220 or 300 mg PO BID – Warfarin • Increased rates of thromboembolic and bleeding complications with NOACs Eikelboom JW et al N Engl J Med. 2013 Sep 26;369(13):1206-14.
  • Are NOACs good anticoagulants? Other high risk populations • Secondary prevention of VTE Castellucci L et al BMJ. 2013 Aug 30;347:f5133.
  • Is evidence for the new oral anticoagulants impressive, or is it hype? Safety data
  • Are NOACs really safer? Wallentin L. Lancet. 2010 Sep 18;376(9745):975-83.
  • New or unknown side effects? MI or ACS Uchino K et al. Arch Intern Med 2012;172(5):397-402.
  • Need more real world data! • Carefully selected patients enrolled in Phase III clinical trials are not fully representative of real-world patients • Especially for adherence! – Need for studies assessing adherance over time and in different clinical settings – Schulman S. J Thromb Haemost 2013;11:1295-9. • Current phase 4 data registries only include highly selected patient population • Low risk of MI, low risk of bleeding, etc. • Southworth MR, et al. N Engl J Med 2013;368:14; 1272-74. • Connolly SJ et al. Circulation 2013 Jul 16;128(3):237-43. • Larsen TB et al. J Am Coll Cardiol 2013;61:2264-73.
  • Need more real world data! • More phase IV clinical studies are needed to provide more generalizable data. Until then patient selection is important
  • How relevant are clinical practice guidelines that disregard cost (and evidence)?
  • Oral anticoagulation is not candy! CHADS2 = 0 *Aspirin is a reasonable alternative in some as indicated by risk/benefit CHADS2 = 1 CHADS2 ≥ 2 No anti- thrombotic Assess Thromboembolic Risk (CHADS2) No additional risk factors for stroke Increasing stroke risk ASA OAC* OAC* OAC Either female sex or vascular disease Age ≥ 65 yrs or combination of female sex and vascular disease Skanes AC, et al. Can J Cardiol 2012;28:125-136.
  • How relevant are clinical practice guidelines that disregard cost/evidence • What is the evidence for CHADS 0? • Unknown benefit (unknown risk/benefit) • But known cost!! – Annual cost of NOACs from $1,147.53 to $1,289.44 (for life!) • Changing practice based on absence of data… – Hard to actually do trials once the practice has changed – $$ for industry without known benefit • What is the evidence for rivaroxaban in CHADS1?
  • No blood monitoring is an advantage of NOACs but it is also a major disadvantage…
  • Ms MT • Ms. MT is on dabigatran 150 mg po bid. Her CrCl is 35 cc/min. She is fell and presented to ER with left hip fracture • Basic coagulation parameters 1. Thrombin time > 60 s 2. INR normal 3. PTT 45 s • When can the surgery be done? Keep in mind that morbidity/mortality is increased if delayed by > 48 hours • Does it manner if the anesthesiologist want to do a spinal?
  • Ms MT • Ms. MT is on rivaroxaban 20 mg po daily. Her CrCl is 45 cc/min. She presented to ER with new acute stroke symptoms. Investigations showed that she would be a candidate for thrombolytics. • Last dose of rivaroxaban was 12 hours ago. • Basic coagulation parameters 1. Thrombin time normal 2. INR normal 3. PTT normal 4. Anti-Xa is 0.4 • Can she receive thrombolytics?
  • How difficult is it to treat a bleed with the new drugs?
  • What is the evidence that it controls bleeding?
  • What is the evidence that it controls bleeding? • Rabbit data • Pragst I et al. J Thromb Haemost 2012 10: 1841–1848 • RCT of 10 non-bleeding healthy volunteers receiving prothrombin complex (Octoplex/beriplex) • FII, FVII, FIX, FX - 50 IU/kg • Eerenberg ES et al. Circulation. 2011 Oct 4;124(14):1573-9. • “Spiked” serum analyses with FEIBA • FII, FVIIa, FIX, FX – 25 to 50 IU/Kg • Marlu R et al. Thromb Haemost 2012 Aug;108(2):217-24.
  • What is the evidence that it controls bleeding? • Hooray!! Some bleeding patients data – Level 1 ;) Case series of 4 bleeding patients who received FEIBA • Industry has done RCT enrolling over 50,000 patients to receiving NOAC without any data antidote or reversal • We need to tailor our practice using data of a case series involving 4 patients!!!
  • Conclusions • NOACs not more effective or safe than warfarin if good time in therapeutic range • Phase III clinical trials are not fully representative of real- world patients • Many questions remain around bleeding and perioperative management of NOACs • More research on adherence is needed
  • Conclusions • Good old warfarin might still be the number #1 drug of choice...especially for long-term treatment
  • Jafna L. Cox, MD, FRCPC, FACC Heart and Stroke Foundation of Nova Scotia Endowed Chair in Cardiovascular Outcomes Research Professor of Medicine and of Community Health and Epidemiology, CDHA/Dalhousie University Past ACC Governor, Atlantic Provinces New Oral Anticoagulants: Breakthrough or Just Another Bleeding Mess?
  • Disclosure • Dr Cox – Has served on advisory boards for AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Pfizer, and Sanofi-Aventis – Has participated in research funded by Bayer, Merck, Pfizer and Sanofi-Aventis – Has served as/is a consultant to the Nova Scotia Department of Health, the New Brunswick Department of Health, the Public Health Agency of Canada, and the Canadian Agency for Drugs and Technologies in Health – Is a member of the Canadian Cardiovascular Society’s Atrial Fibrillation Guidelines Panel and Chair of its Atrial Fibrillation Quality Indicator Subcommittee
  • Antiplatelet drugs vs. Placebo Warfarin vs. Placebo/Control 100% 50% 0 - 50% 6 Trials n = 2,900 8 Trials n = 4,876 Treatment Better Treatment Worse Hart RG et al. Ann Intern Med 2007; 146: 857 RRR 64% RRR 19% Antithrombotic Therapy for AF: Efficacy of Existing Stroke Risk Reduction Therapy Warfarin vs. Aspirin: RRR 39%
  • • Warfarin is highly effective for stroke prevention in AF – reduces risk by 64% – but its use is problematic – Associated with significant increase in intracranial and other haemorrhage, especially in the elderly – Only about 1 in 4 patients are optimally treated • Registries show that only 50-60% of eligible patients receive warfarin • In clinical trials, time in therapeutic range (TTR) is 60-68%; in general practice, TTR is typically <50% Warfarin for Stroke Prevention in AF Hart Ann Int Med 2007;146:857; Hylek Stroke 2006;37:1075; Singer Chest 2008;133:546S; Gladstone Stroke 2009;40:235; CCS guidelines 2004; Matchar Am J Med 2002;113:42; Bungard Pharmacotherapy 2000;20:1060
  • 60 35 34 55 64 51 49 54 34 67 59 45 43 0 20 40 60 80 100 WarfarinUse(%)Underuse of Oral Anticoagulation in AF: Results from Recent Studies 2005-061999-2000 2007-10 Go Ann Intern Med 1999;131:927 Nieuwlaat Eur Heart J 2006;27:3018 Friberg Eur Heart J 2006;27:1954 Glazer Arch Intern Med 2007:167 Samsa Arch Intern Med 2000;160:967 Hylek Stroke 2006;37:1075 Monte Eur Heart J 2006;27:2217 Walker Heart Rhythm 2008;5:1365 Gage Stroke 2000;31:822 Hylek Stroke 2006;37:1075 Boulanger Int J Clin Pract 2006;60:258 Zimetbaum Am J Med 2010;123:446 Waldo J Am Coll Cardiol 2005;46:1729 Birman-Deych Stroke 2006;37:1070
  • Use of Oral Anticoagulation in AF: Results from a Global Registry Healey et al. ESC 2011 Appropriate use of OAC continues to remain low. When OAC is used, INR control is suboptimal. 65.1 44.8 63.5 38.7 55.8 36.9 39.9 10.5 43.6 0 20 40 60 80 100 % OAC Use in CHADS2 ≥2 53.5 43.5 66.9 59.1 46.8 39.5 33.9 36.1 38.4 0 20 40 60 80 100 % Time in Therapeutic Range* *based on 3 most recent INR values Based on 15,174 patients presenting to an Emergency Department with AF/AFL between Jan. 2008 and Apr. 2011
  • Adding Insult to Injury: Patient Persistence With Warfarin for Atrial Fibrillation Gomes T, et al. Arch Intern Med 2012; 172: 1-3 43% stop in 2 years, 61% stop in 5 years (median 2.9 years) Ontario patients > 66 years of age, 1997-2008 (N= 125,195)
  • Warfarin and ASA/Antiplatelets are Commonly Associated With Adverse Events Drug Annual Estimate of Hospitalizations % ED Visits Resulting in Hospitalization Oral hypoglycemics 10,656 (10.7%) 51.8% Warfarin 33,171 (33.3%) 46.2% Oral antiplatelets 13,263 (13.3%) 41.5% Insulins 13,854 (13.9%) 40.6% ED=emergency department Budnitz DS et al. N Engl J Med 2011; 365: 2012-12 Annual US National Estimates of Hospitalizations and ED Visits Resulting in Hospitalization in Adults ≥65 Years of Age (2007-2009)
  • Key Factors in Physician Underutilization Of VKAs in AF • Lifestyle issues – Need for regular monitoring, lifestyle restrictions, compliance and other patient factors • Resource challenges – Lack of availability of a coordinated anticoagulant outpatient monitoring process or clinic • Perceived bleeding risk – Concern about risk of hemorrhage, not always appropriately balanced against risk of stroke
  • Go AS, et al. Ann Intern Med 1999; 131: 927–934 Age (years) 35.4 44.3 57.360.758.1 0 20 40 60 80 100 WarfarinUse(%) <55 55-64 65-74 75-84 >85 Rate of Warfarin Use Within 3 Months of Diagnosis of AF An Age-Related Risk-Treatment Paradox With Warfarin Use in SPAF • Risk of stroke in AF patients increases with age – 1.5% per year in 50-59 year olds – 23.5% in 80-89 year olds
  • Anticoagulation and Risk of Falls in the Elderly – Putting Matters in Perspective • A patient with a 5% annual stroke risk from AF would need to fall 295 times in a year for the calculated risk of subdural hematoma from falling to outweigh the stroke reduction benefit of warfarin Arch Intern Med 1999; 159:677-685
  • Stroke Prevention in the Elderly With AF Remains A Challenge – Fear of Bleeding Hylek EM, et al. Circulation 2007; 115: 2689-2696 Major Hemorrhage on Warfarin in First Year of Therapy Among Elderly Patients with AF
  • New Oral Anticoagulants for SPAF • Direct Thrombin Inhibitors – Dabigatran • Factor Xa Inhibitors – Rivaroxaban • Phase III data published Aug. 2011 – Apixaban • Phase III data published Aug. 2011 – Edoxaban • Phase III data expected Nov. 2013 http://www.clinicaltrials.gov/ct2/search Adapted from Turpie Eur Heart J 2008; 29:155 Xa IIa TF/VIIa X IX IXa VIIIa Va II FibrinFibrinogen Rivaroxaban Apixaban Edoxaban TTP889 Warfarin sites of action Dabigatran
  • Prevention of Stroke Connolly N Engl J Med 2010; 363: 1876; Patel N Engl J Med 2011; 365: 883; Granger N Engl J Med 2011; 365: 981 0.50 0.75 1.00 1.25 1.50 Dabigatran 110 mg BID Dabigatran 150 mg BID HR (95% CI) Warfarin betterComparator better Rivaroxaban 20 mg QD Apixaban 5 mg BID 0.29 <0.001 0.12 0.01 Stroke or Systemic Embolism Ischemic Stroke Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD Apixaban 5 mg BID 0.35 0.03 0.59 0.42 Superiority p-value
  • Reducing the Bleeding Risk HR (95% CI) Warfarin betterComparator better 0.50 0.75 1.00 1.250.25 Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD Apixaban 5 mg BID Intracranial Haemorrhage ISTH Major Bleeding Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD Apixaban 5 mg BID Superiority p-value <0.001 <0.001 0.02 <0.001 0.003 0.31 0.58 <0.001 Connolly N Engl J Med 2010; 363: 1876; Patel N Engl J Med 2011; 365: 883; Granger N Engl J Med 2011; 365: 981
  • Sensitivity Analysis – Major Bleeding Apixaban 5 mg BID versus Adjusted Dose Warfarin Dabigatran 110 mg BID versus Adjusted Dose Warfarin Dabigatran 150 mg BID versus Adjusted Dose Warfarin Rivaroxaban 20 mg OD versus Adjusted Dose Warfarin No treatment/Placebo versus Adjusted Dose Warfarin Low Dose Aspirin (≤ 100 mg OD) versus Adjusted Dose Warfarin Medium Dose Aspirin (> 100 mg and ≤ 300 mg OD)versus Adjusted Dose Warfarin Clopidogrel 75 mg OD & Low dose Aspirin (≤ 100 mg OD) versus Adjusted Dose Warfarin 0.69(0.6,0.8) 0.71(0.61,0.81) 0.8(0.69,0.93) 0.8(0.69,0.93) 0.93(0.8,1.08) 0.93(0.81,1.08) 1.03(0.89,1.19) 1.03(0.89,1.19) 0.33(0.08,1.08) 0.21(0.06,0.62) 1.05(0.6,1.86) 0.77(0.57,1.04) 1.78(0.62,5.59) 0.73(0.48,1.11) 1.1(0.83,1.46) 1.19(0.92,1.54)
  • Mortality 0.50 0.75 1.00 1.25 1.50 Dabigatran 110 mg BID Dabigatran 150 mg BID HR (95% CI) Warfarin betterComparator better Rivaroxaban 20 mg QD Apixaban 5 mg BID Superiority p-value 0.13 0.051 0.073 0.047 All-Cause Mortality Cardiovascular Mortality Dabigatran 110 mg BID Dabigatran 150 mg BID Rivaroxaban 20 mg QD Apixaban 5 mg BID 0.21 0.04 0.29 NR NR: Not Reported Connolly N Engl J Med 2010; 363: 1876; Patel N Engl J Med 2011; 365: 883; Granger N Engl J Med 2011; 365: 981
  • Major Clinical Recommendations for Antithrombotic Management in AF Risk of stroke Canadian Guidelines CCS American Guidelines ACCP European Guidelines ECS Low (CHADS2 = 0) Higher risk* = OAC Dabigatran, rivaroxaban, apixaban recommended over warfarin.† Lower risk* = ASA Lowest risk* = No therapy No therapy Higher risk* = OAC Lowest risk* = No therapy Intermediate (CHADS2 = 1) OAC Dabigatran, rivaroxaban, apixaban recommended over warfarin.† OAC Dabigatran recommended over warfarin.‡ OAC Dabigatran, rivaroxaban, apixaban recommended over warfarin. High (CHADS2 ≥2) OAC Dabigatran, rivaroxaban, apixaban recommended over warfarin.† OAC Dabigatran recommended over warfarin.‡ OAC Dabigatran, rivaroxaban, apixaban recommended over warfarin. ASA = acetylsalicylic acid; OAC = oral anticoagulants; VKA = vitamin K antagonist. * Based on the consideration of other risk factors (age 65-74 years, female sex and presence of vascular disease). † Preference for newer agents less clear in patients under warfarin with stable INR and no bleeding complications. ‡ At the time the American Guidelines were published (2012), only dabigatran received regulatory approval for use in AF and therefore, the Guidelines do not make recommendations for apixaban and rivaroxaban.
  • Persistence Among Patients with Non-Valvular AF Beginning Dabigatran or Warfarin 0 10 20 30 40 50 60 70 80 90 100 6 months 12 months Dabigatran Warfarin %ofpatientspersistentontherapy Zalesak M, et al. Higher persistence in newly diagnosed nonvalvular atrial fibrillation patients treated with dabigatran versus warfarin. Circ Cardiovasc Qual Outcomes 2010; 3: 624-631. Assembled into propensity-score matched pairs (each N=1745) • At 6 months: - 72 % of patients still persistent with dabigatran treatment - 53% of patients still persistent with warfarin treatment • At 12 months: - 63% of patients still persistent with dabigatran treatment - 39% of patients still persistent with warfarin treatment Newly diagnosed AF patients: 1,775 on warfarin and 3,370 on dabigatran (identified from US Department of Defense claims database)
  • Mean Time to Switch or Discontinue From Original Prescription 131 149 168 0 30 60 90 120 150 180 Warfarin Dabigatran (110&150mg) Rivaroxaban (20mg) Daysoninitialtherapy Initial drug therapy Evers et al, Real life treatment persistence with newer oral anticoagulants and potential strokes avoided in patients with atrial fibrillation [abstract]. Eur Heart J 2013; 34S
  • Anticoagulants and Antidotes • There is no antidote for any of the new oral anticoagulants However, there is also no immediate antidote for warfarin! – Vitamin K takes time to work (12 or more hours), far too long if the patient is presenting with an intracranial haemorrhage • By 12-24 hours of stopping a NOAC, hemostasis will have normalized – PCC therapy rapidly corrects INR in most patients on warfarin, yet with debatable prognostic impact – Antidotes for the Factor Xa inhibitors are in development • Benefit shown in mice with apixaban, betrixaban, rivaroxaban • Phase 2 studies in humans have begun Pandit TN, et al. Am J Hematol 2012; 87: S56-62; Dowlatshahi. Stroke 2012; 43: 1812; Lu et al. Nat Med 2013; 19: 446-452
  • Warfarin-Associated ICH: Poor Prognosis Despite Anticoagulation Reversal Dowlatshahi. Stroke 2012; 43: 1812 Canadian PCC (prothrombin complex concentrate) Registry: • N=141 anticoagulation associated intracerebral hemorrhages • 72% with INR < 1.5 within < 1h; yet 42% mortality (50% of cases)
  • • Warfarin is an effective agent that has long served as our foundation for anticoagulation in AF • Warfarin has important limitations that contribute to underutilization and poor INR control – 3 of 4 patients with AF are unprotected or poorly protected against stroke • New agents offer important safety and efficacy advantages over warfarin • Warfarin will continue to play an important role: – For other indications (e.g., prosthetic valves) – In patients with renal impairment (i.e., CrCl < 15 ml/min) A Cardiologist’s Perspective: On The Shifting Role of Warfarin
  • • Compared with warfarin, each of the 3 new agents: – Are at least as effective in preventing stroke/systemic embolism – Are associated with less intracranial bleeding – Are associated with similar or less major bleeding – Offer greater ease of use • Many patients will benefit from the advantages offered by these drugs that ideally should be started by primary care or emergency department physicians rather than cardiologists A Cardiologist's Perspective: On The Evolving Treatment Paradigm for SPAF
  • • It’s just too bad that • You wouldn’t necessarily get there on time • Comfort would be a significant problem • Forget about “hands free” anything • And who needs seat belts, automatic transmission, parking/lane change/braking assist, etc., anyway? If the only cars available were from the 1950s you’d still get to where you needed to be; well, maybe 2/3 of the time… Why Bother To Innovate?
  • Why Bother To Innovate? • If you are unlucky enough to crash you will probably survive • And while you are unlikely ever to be able to replace any broken parts, well… just get someone else to drive you the next time Safety and convenience are overrated and not worth the money; you’ll still get from point A to point B… Maybe...
  • • Imagine if the novel anticoagulants had been established therapy for some 6 decades and a new drug appeared that: – Was unpredictable in terms of patient therapeutic response – Had slow therapeutic onset and offset – Had a narrow therapeutic window – Required close monitoring via frequent blood tests – Required frequent dose adjustment – Was plagued by drug-drug and drug-food interactions – Was associated with more intracranial haemorrhage – Resulted in a 10% increase in mortality Would anyone in their right mind think it had a chance of getting to market and, if it did, would anyone prescribe it? Some Final Insane Musings
  • Thank You
  • Choice of Anticoagulant Based on Patient Characteristics Adapted/modified from Weitz & Gross, Hematology 2012:536-40 Characteristic Drug Choice Rationale Mechanical or valvular AF Warfarin New agents not studied Liver dysfunction with elevated INR Warfarin New agents require hepatic metabolism Poor compliance Warfarin or nothing Missed doses of greater consequence with shorter acting agents Stable on warfarin Warfarin Consider switching at patient request CrCl < 30 mL/min Warfarin Such patients were excluded from trials with new agents CrCl of 30-50 mL/min Rivaroxaban or Apixaban Oral Xa inhibitors are less affected by impaired renal function than dabigatran Dyspepsia or upper GI complaints Rivaroxaban or Apixaban Dyspepsia in up to 10% given dabigatran Recent GI bleed Apixaban More GI bleeding with dabigatran (150 mg BID) or rivaroxaban than with warfarin Recent ischemic stroke on Warfarin Dabigatran Dabigatran (150 mg BID) associated with lowest risk of ischemic stroke vs warfarin Recent acute coronary syndrome Rivaroxaban or Apixaban Small MI signal with dabigatran
  • NOACs and Poor Kidney Function
  • CrCl (mL/min) Age Range (years) 0% 20% 40% 60% 80% 100% 20-39 40-59 60-69 ≥70 ≥90 60-89 30-59 15-29 Kidney Function Declines With Advancing Age
  • The Risk Factors for CKD are Commonly Found in Patients with AF Risk Factor for Stroke in AF (CHA2DS2-Vasc) Congestive Heart Failure Hypertension Age ≥ 75 Diabetes Mellitus Stroke/TIA/Thromboembolis m Vascular Disease Age 65-74 Female Risk Factors (CKD) Heart Disease Hypertension Age ≥ 65 Diabetes Mellitus Smoking Obesity Family history of kidney disease High cholesterol African-American, Native- American or Asian-American race Haroun et al. J Am Soc Nephrol 14: 2934–2941, 2003; http://www.mayoclinic.com/health/kidney-failure/DS00682/DSECTION=risk-factors; Lip, GY, et al. Stroke 2010; 46: 2731
  • The Risk of Stroke and Bleeding Increases with Declining Renal Function – Real World Data Olesen et al. N Engl J Med 2012; 367: 625-35 Data from 132,372 patients with a diagnosis of non- valvular atrial fibrillation using Danish national registries Stroke/thromboembolism Bleeding Eventrate/100personyears No Renal Disease Non end-stage CKD 10 8 6 4 2 0
  • Measuring and Monitoring Renal Function with NOAC Anticoagulants • NOAC studies used creatinine clearance (CrCl) to assess renal function • For prescribing and monitoring patients on NOAC, use CrCl not creatinine • With NOAC, check kidney function: • Every 6 months for most patients • Every 3 months for those who have CrCl < 50 • With every acute, especially dehydrating, illness • Important: for fragile patients calculate CrCl and not GFR (they can be very different in older patients) Pharmacologic properties Rivaroxaban (Xarelto®) Dabigatran (Pradaxa®) Apixaban (Eliquis®) Mechanism of action Direct factor Xa inhibitor Direct factor IIa (thrombin) inhibitor Direct factor Xa inhibitor Renal clearance 33% 85% 27% 1. Xarelto® PM, June 2013; 2. Pradaxa ® PM November, 2012; 3. Eliquis® PM November, 2012; 4. FDA Eliquis Drug Approval Package, Clinical Pharmacology/Biopharmaceutics Review
  • New OACs: Total Drug Exposure (AUC) with Declining Renal Function Apixaban (27% cleared renally†)3 Dabigatran (85% cleared renally)2 Rivaroxaban (33% cleared renally*)1 AUCratiovs.NormalRenalFunction * active drug † Factoring in the absolute bioavailability of apixaban, ~ 50 % of the systemically available dose is eliminated in urine4 1. Xarelto® PM, July 18, 2012 ; 2. Pradaxa ® PM November 12, 2012; 3. Eliquis® PM November 27, 2012; 4. FDA Eliquis Drug Approval Package, Clinical Pharmacology/Biopharmaceutics Review
  • Perioperative and Bleeding Management
  • Practical Considerations: Perioperative Management of Anticoagulant Therapy • Alteration of oral anticoagulant regimen may not be necessary for most patients undergoing low risk procedures: – Dental procedures (including extractions of up to 4 teeth), joint and soft tissue injections, arthrocentesis, cataract surgery, upper endoscopy or colonoscopy with/without biopsy • For other invasive and surgical procedures, oral anticoagulation needs to be withheld: – Decision on whether to pursue an aggressive strategy of perioperative administration of IV heparin or SQ low molecular-weight heparin should be individualized based on an estimation of the patient’s risks of thromboembolism and bleeding and the patient’s preference Douketis J, et al. Chest 2008;133:299S-339S; Dunn AS and Turpie AGG. Arch Intern Med 2003;163:901-908
  • • Determine renal function (CrCl or eGFR) • Determine drug half-life • Evaluate stroke and bleeding risks – Decide timing of temporary discontinuation – Consider any need for bridging therapy – Plan timing of resumption of therapy • Re-evaluate after surgical or diagnostic procedure Crowther MA & Warkentin TE. J Thromb Haemostat 2009;7 (Suppl 1):107-110 van Ryn J, et al. Thromb Haemostat 2010;103:1116-1127 Cairns et al. Can J Card 2011 27:74-90 Practical Considerations: Perioperative Management of Anticoagulant Therapy
  • Practical Considerations: Perioperative management – Summary of CCS Guidelines Cairns et al. Can J Card 2011 27:74-90 Patient with AF Undergoing Surgical or Diagnostic Procedure With Major Bleeding Risk Very Low to Moderate Stroke Risk* High Stroke Risk** Low Bleeding Risk High Bleeding Risk Low Bleeding Risk High Bleeding Risk Continue Antithrombotic (INR <3 if warfarin) Stop Antithrombotic Preprocedure Reinstitute when risk of bleeding reduced Continue OAC or stop OAC and bridge with UFH or LMWH perioperatively Stop OAC and bridge with UFH or LMWH perioperatively¶ * CHADS2 ≤ 2 ** Mechanical valve, recent stroke or TIA, rheumatic valve disease, CHADS2 ≥ 3 ¶ Stop 12 to 24 hours preprocedure , restart when hemostasis secure and bridge to therapeutic OAC
  • • For dabigatran: – If CrCl ≥ 30 ml/min and patient is at low risk of bleeding, withhold dabigatran for ≥ 24 hours; restart the evening after the procedure – If CrCl < 30 ml/min and if the procedure is complicated, withhold dabigatran for 2-5 days; consider switching the patient to warfarin after the procedure • For apixaban and rivaroxaban: – If CrCl ≥ 30 ml/min and patient is at low risk of bleeding, withhold for ≥ 24 hours; restart the evening after the procedure – If CrCl < 30 ml/min and if the procedure is complicated, withhold for ≥ 36 hours; consider switching the patient to warfarin after the procedure 1. Pradax Product Monograph 2010, Boehringer Ingelheim Canada Ltd 2. Xarelto Product Monograph 2012, Bayer Inc (Canada) Practical Considerations: If a Novel Anticoagulant Must be Stopped Before a Procedure
  • New OACs: Total Drug Exposure (AUC) with Declining Renal Function Apixaban (27% cleared renally†)3 Dabigatran (85% cleared renally)2 Rivaroxaban (33% cleared renally*)1 AUCratiovs.NormalRenalFunction * active drug † Factoring in the absolute bioavailability of apixaban, ~ 50 % of the systemically available dose is eliminated in urine4 1. Xarelto® PM, July 18, 2012 ; 2. Pradaxa ® PM November 12, 2012; 3. Eliquis® PM November 27, 2012; 4. FDA Eliquis Drug Approval Package, Clinical Pharmacology/Biopharmaceutics Review
  • Renal Function: Timing of Dabigatran Discontinuation Prior to Procedure Renal function (CrCl ml/min) Half-life, hours (range) Timing of discontinuation of dabigatran before surgery Moderate bleeding risk High bleeding risk > 50 to ≤ 80 15 (12–34) 1–2 days 2–3 days 31–50 18 (13–23) 3–4 days 4–5 days ≤ 30* 27 (22–35) 4–5 days > 5 days *Dabigatran is contraindicated for use in patients with severe renal impairment (CrCl < 30ml/min) Adapted from: 1. van Ryn J, et al. Thromb Haemostat 2010;103:1116-1127 2. Pradax Monograph 2010, Boehringer Ingelheim Canada Ltd
  • Measures to Take for Bleeding on NOAC Direct thrombin inhibitors (dabigatran) – Ask about last intake + dosing regimen – Estimate normalization of hemostasis • Normal renal function: 12-24 hours • CrCl 50-80 ml/min: 24-36 hours • CrCl 30-50 ml/min: 36-48 hours • CrCl <30 ml/min: ≥48 hours FXa inhibitors (apixaban, rivaroxaban) – Ask about last intake + dosing regimen – Normalization of hemostasis: 12-24 hours Heidbuchel H, et al. Europace 2013; 15: 625-51 Assess whether a NOAC is in circulation: • Check PTT for dabigatran • Check PT for rivaroxaban • No clear method for apixaban
  • Dabigatran and MI Risk
  • Efficacy and Safety Endpoints Across Trials Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med 2011;365:883; Granger N Engl J Med 2011;365:981; CADTH Report 2012 (Odds Ratio, 95% CI) 0.10 1.00 10.00 Apixaban 5 mg bid Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 20 mg od Apixaban 5 mg bid Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 20 mg od Apixaban 5 mg bid Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 20 mg od Apixaban 5 mg bid Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 20 mg od Apixaban 5 mg bid Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 20 mg od All-cause Stroke/SE Major Bleeding All-cause Mortality Intracranial Hemorrhage Myocardial Infarction
  • Myocardial Infarction in RELY Connolly NEJM 2009;361:1139 *Connolly NEJM 2010;363:1876 D 110mg Annual rate D 150mg Annual rate W Annual rate Myocardial Infarction 0.72% P=0.07 0.74% P=0.048 0.53% D 110mg Annual rate D 150mg Annual rate W Annual rate D 110 mg vs. W RR 95% CI P D 150 mg vs. W RR 95% CI P Myocardial Infarction 0.82% (0.72%) 0.81% (0.74%) 0.64% (0.53%) 1.29 0.96-1.75 0.09 (0.07) 1.27 0.94-1.71 0.12 (0.048)
  • Mak K-H. BMJ Open 2012;2:e001592. doi:10.1136/bmjopen-2012-001592 Dabigatran Rivaroxaban Apixaban P=0.021 P<0.001 P=0.333
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