anticoagulation for atrial fibrillation: who, when, and how?
DESCRIPTION
Anticoagulation for Atrial Fibrillation: Who, When, and How?. August 17, 2013 Elaine M. Hylek , MD, MPH Boston University School of Medicine. Disclosures. Disclosures of Elaine Hylek. TEE depicting a large LAA thrombus attached to the lateral wall . - PowerPoint PPT PresentationTRANSCRIPT
Anticoagulation for Atrial Fibrillation: Who, When, and How?
August 17, 2013Elaine M. Hylek, MD, MPH
Boston University School of Medicine
Disclosures
Employment No conflict of interest to disclose
Research support NIH/NINDS, NIH/NHLBI; Bristol-Myers Squibb-Executive Steering Committee; ARISTOTLE trial; Janssen-Executive Steering Committee; ORBIT-AF Registry
Scientific advisory board Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer
Consultancy No conflict of interest to disclose
Speakers bureau No conflict of interest to disclose
Major stockholder No conflict of interest to disclose
Patents No conflict of interest to disclose
Honoraria Bayer, Boehringer-Ingelheim, Pfizer
Travel support No conflict of interest to disclose
Other No conflict of interest to disclose
Disclosures of Elaine Hylek
Hesse, B. et al. Circulation 2006;113:e456-457e
TEE depicting a large LAA thrombus attached to the lateral wall
Stanford Stroke Center, Albers G
Stanford Stroke Center, Albers G
Prevalence of AF by Age
Feinberg WM. Arch Intern Med. 1995;155(5):469–473
HAZARDS OF WARFARIN
Budnitz D et al. N Engl J Med 2011;365:2002–12
HAZARDS OF WARFARIN
Budnitz D et al. N Engl J Med 2011;365:2002–12
Efficacy and Safety Data for
Target-Specific Oral Anticoagulants
0.01
0.02
0.03
0.05
0.04
Cum
ulat
ive
haza
rd r
ates
RR 0.91(95% CI: 0.74–1.11)
p<0.001 (noninferiority)p=0.34 (superiority)
RR 0.66(95% CI:
0.53–0.82)p<0.001
(superiority)
Years0 0.5 1.0 1.5 2.0 2.5
0.0
WarfarinDabigatran etexilate 110 mgDabigatran etexilate 150 mg
RE-LY: Time to First Stroke/SEE
Connolly SJ et al. N Engl J Med 2009; 361:1139–51
RRR34%
1.11%
1.69%
1.53%
RE-LY Primary Efficacy Outcome Stroke and non-CNS Embolism
Connolly SJ., et al. NEJM Aug 30th 2009. DOI 10.1056/NEJMoa0905561
RR 0.26 (95% CI: 0.14–0.49)p<0.001 (sup)
Hemorrhagic stroke
Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561
RR 0.31 (95% CI: 0.17–0.56)p<0.001 (sup)
Num
ber o
f eve
nts
6,015 6,076 6,022
1412
45
0
10
20
30
40
50
D110 mg BID D150 mg BID Warfarin
0.10%
0.38%RRR69%
RRR74%
0.12%
Dabigatran Etexilate vs Warfarin (RE-LY)
October 19, 2010
FDA Approves Pradaxa to Reduce the Risk of Stroke in Patients with Non-Valvular Atrial
Fibrillation
PRADAXA 150 mg BID-higher rate of major (GI) bleeds and any GI bleeds compared to warfarin.
In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA than with
warfarin.
Rivaroxaban Warfarin Event Rate
Event Rate
HR(95% CI) P-value
On TreatmentN= 14,143
1.70 2.15 0.79 (0.65,0.95) 0.015
ITTN= 14,171 2.12 2.42 0.88
(0.74,1.03) 0.117
Rivaroxabanbetter
Warfarinbetter
ROCKET-AF Primary Efficacy Outcome Stroke and non-CNS Embolism
Event Rates are per 100 Patient-yearsBased on Safety on Treatment or Intention-to-Treat thru Site Notification
PopulationsPatel et al. NEJM 2011;365:883-91
Key Secondary Efficacy OutcomesRivaroxaban Warfarin
Event Rate Event Rate HR (95% CI) P-value
Vascular Death, Stroke, Embolism 3.11 3.63 0.86 (0.74, 0.99) 0.034
Stroke Type Hemorrhagic Ischemic Unknown Type
0.261.340.06
0.441.420.10
0.59 (0.37, 0.93)0.94 (0.75, 1.17)0.65 (0.25, 1.67)
0.0240.5810.366
Non-CNS Embolism 0.04 0.19 0.23 (0.09, 0.61) 0.003
Myocardial Infarction 0.91 1.12 0.81 (0.63, 1.06) 0.121
All Cause Mortality Vascular Non-vascular Unknown Cause
1.871.530.190.15
2.211.710.300.20
0.85 (0.70, 1.02)0.89 (0.73, 1.10)0.63 (0.36, 1.08)0.75 (0.40, 1.41)
0.0730.2890.0940.370
Patel et al. NEJM 2011;365:883-91
Rivaroxaban WarfarinEvent Rate or N (Rate)
Event Rate or N (Rate)
HR (95% CI)
P-value
Major >2 g/dL Hgb drop Transfusion (> 2 units)
Critical organ bleeding Bleeding causing death
3.602.771.650.820.24
3.452.261.321.180.48
1.04 (0.90, 1.20)1.22 (1.03, 1.44)1.25 (1.01, 1.55)0.69 (0.53, 0.91)0.50 (0.31, 0.79)
0.5760.0190.0440.0070.003
Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) 0.019
Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060
Intraventricular 2 (0.02) 4 (0.04)
Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051
Subarachnoid 4 (0.04) 1 (0.01)
Event Rates are per 100 patient-years Based on Safety on Treatment Population
Safety Outcomes Rivaroxaban
Primary OutcomeStroke (ischemic or hemorrhagic) or systemic embolism
Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per yearHR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011
No. at RiskApixaban 9120 8726 8440 6051 3464 1754Warfarin 9081 8620 8301 5972 3405 1768
P (non-inferiority)<0.00121% RRR
Granger C et al. NEJM 2011;365:981–92
Efficacy Outcomes
Outcome
Apixaban(N=9120)
Warfarin(N=9081)
HR (95% CI) P ValueEvent Rate
(%/yr)Event Rate
(%/yr)Stroke or systemic embolism* 1.27 1.60 0.79 (0.66, 0.95) 0.011
Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012
Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42
Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75) <0.001
Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70
All-cause death* 3.52 3.94 0.89 (0.80, 0.998) 0.047
Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81, 0.98) 0.019
Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37
* Part of sequential testing sequence preserving the overall type I error
Granger C et al. NEJM 2011;365:981–92
Bleeding Outcomes
Outcome
Apixaban(N=9088)
Warfarin(N=9052)
HR (95% CI) P ValueEvent Rate(%/yr)
Event Rate(%/yr)
Primary safety outcome: ISTH major bleeding* 2.13 3.09 0.69 (0.60, 0.80) <0.001
Intracranial 0.33 0.80 0.42 (0.30, 0.58) <0.001
Gastrointestinal 0.76 0.86 0.89 (0.70, 1.15) 0.37Major or clinically relevant
non-major bleeding4.07 6.01 0.68 (0.61, 0.75) <0.001
GUSTO severe bleeding 0.52 1.13 0.46 (0.35, 0.60) <0.001
TIMI major bleeding 0.96 1.69 0.57 (0.46, 0.70) <0.001
Any bleeding 18.1 25.8 0.71 (0.68, 0.75) <0.001
* Part of sequential testing sequence preserving the overall type I error
CHADS 2 score = 0 No therapy rather than antithrombotic therapy (Grade 2B)
CHADS 2 score = 1 Oral anticoagulation rather than no therapy or antiplatelet therapy (Grade 1B)
CHADS 2 score = 2 Oral anticoagulation rather than no therapy or other therapies (Grade 1A)
For recommendations in favor of oral AC, we suggest dabigatran 150 mg twice daily rather than VKA therapy (Grade 2B)
You JJ et al. Chest 2012;141(2 Suppl):e531S-75S. PMID: 22315271
ACCP Recommendations for Stroke Prevention Therapy
ESC 2012UPDATE
GUIDELINESFor
ATRIALFIBRILLATION
Camm J et al. Eur Heart J 2012;33:2719–47
2011 ACCF/AHA/HRS Focused Update
Dabigatran is useful as an alternative to warfarin for the prevention of stroke in patients with AF.
• Selection of patients with AF and ≥1 risk factor for stroke who could benefit from treatment with dabigatran as opposed to warfarin should consider individual clinical features, including the ability to comply with twice-daily dosing, availability of an anticoagulation management program, patient preferences, cost, and other factors
Because of the twice-daily dosing and greater risk of non-hemorrhagic side effects with dabigatran, patients already taking warfarin with excellent INR control may have little to gain by switching to dabigatran.
Wann LS et al. Heart Rhythm 2011;8:e1–e8
Hylek, EM. J Cardiovasc Med 2009;10:605-09
Effect of TTR on Primary Endpoints In RELY
Wallentin, et al. Lancet 2010
0.540.590.911.21
10% increase in center algorithm-consistent warfarin dosing predicted a 6.12% increase in TTR (95% CI 5.65-6.59%), and an 8% decrease in rate of the composite clinical outcome (HR 0.92, 95% CI 0.85-1.00).
Translating the Results of Clinical Trials into Clinical Practice
Patient selection
Therapeutic implementation Environment of the healthcare delivery system
Nallamothu, et al. Circulation 2008;118:1294–303
Will we be able to translate trial results to real-world practice?
Property Dabigatran Rivaroxaban Apixaban Edoxaban
Route of admin Oral Oral Oral Oral
Target Thrombin FXa FXa FXa
Dosing Twice daily Once daily Twice daily Once daily
Monitoring required No No No No
Half-life (hrs) 12–17 9–12 8–15 8–11
Mode of elimination Renal 80% Renal ~36% Renal ~25% Renal ~35%
New Oral Anticoagulants: Summary
Definitions:Chronic Kidney Disease and Renal Insufficiency
www.ckdsite.com
I MILD I MOD I SEVERE I
Renal Insufficiency Classification
Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation
Slide courtesy of C Cove
Randomized Trial Age Baseline CrCl
Exclusion CrCl
ARISTOTLE
Apixaban 5 mg bid 70 83% ≥50 <25 ml/min
Warfarin 70 83% ≥50
ROCKET AFRivaroxaban 20 mg qd 73 67 (median) < 30 ml/min
Warfarin 73 67 (median)
RE-LYDabigatran 150 mg bid 72 68 (median) <30 ml/min
Warfarin 72 69 (median)
Pharmacokinetics with Varying Levels of Renal Dysfunction
Kaatz S et al. Am J Hematol 2012 Suppl 1:S141-5. PMID: 22473649
Apixaban Dabigatran Rivaroxaban
Elimination half life with CrCl >80 ml/min 7.6 hr 13.8 hr 8.3 hr
Elimination half life with CrCl 50–79 ml/min 7.3 hr 16.6 hr 8.7 hr
Elimination half life with CrCl 30–49 ml/min 17.6 hr 18.7 hr 9.0 hr
Elimination half life with CrCl <30 ml/min 17.3 hr 27.5 hr 9.5 hr
Periodically assess renal function as clinically indicated (i.e., more frequently in clinical situations that may be associated with a decline in renal function) and adjust therapy accordingly.
Discontinue dabigatran in patients who develop acute renal failure and consider alternative therapy.
In patients with moderate renal impairment (CrCl 30–50 mL/min), concomitant use of the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to produce drug exposure similar to that observed in severe renal impairment. Consider reducing the dose.
JANUARY 2012 UPDATE DABIGATRAN PACKAGE INSERT
Property Dabigatran Rivaroxaban Apixaban Edoxaban
Route of admin Oral Oral Oral Oral
Target Thrombin FXa FXa FXa
Dosing Twice daily Once daily Twice daily Once daily
Monitoring required No No No No
Half-life (hrs) 12–17 9–12 8–15 8–11
Mode of elimination Renal 80% Renal ~36% Renal ~25% Renal ~35%
New Oral Anticoagulants: Summary
Polypharmacy and Non-adherence
• Strongest predictor of non-adherence is the # of medications
• Non-adherence rates estimated 25–50%• Intentional about 75% of the time
Changes in regimen made by patients to:
– increase convenience – reduce adverse effects or – decrease refill expense
Recommended Structured Follow-upFirst month and subsequent 3 month intervals
Pradaxa (dabigatran etexilate mesylate): Drug Safety Communication – Safety Review of Post-Market Reports of Serious Bleeding EventsUPDATED 11/02/2012.
… bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin, which is consistent with observations from the large clinical trial used to approve Pradaxa (the RE-LY trial). FDA is continuing to evaluate multiple sources of data in the ongoing safety review of this issue.
HAS-BLED Bleeding Risk Score
– Hypertension (SBP>160mmHg)
– Abnormal renal/liver fxn (1 pt for each)
– Stroke– Bleeding history or prone– Labile INR (if on warfarin)– Elderly (>65 years)– Drugs (ASA, NSAIDS)/alcohol
(1 pt for each)
• Increasing score associated with ISTH major bleeding (C-index 0.72)
Pisters R et al. Chest 2010;138:1093–100
Hemorrhage Thrombosis
Optimizing Benefit and Reducing Risk
AF stroke associated with a 30-day mortality of 24%.
Swedish AF Cohort; Circulation 2011; 125: 2298-2307
Dabigatran visits,%
2010Q4
2011Q1
2011Q2
2011Q3
2011Q4
Atrial fibrillation 92 72 75 71 63
Venous thromboembolism
0 4 8 3 5
Hypertensive heart disease
8 13 5 15 14
Coronary artery disease 0 3 9 3 6
CVA/TIA 0 0 0 3 3
Valvular disorders 0 0 0 3 0
Kirley K et al. Circ Cardiovasc Qual Outcomes 2012;5:615–21
Effective Use of TSOACs in Clinical Practice
1. Patient selection – ADHERENCE
2. Dose selection – creatinine clearance
3. Determine interval follow-up
4. Assess stability of renal function
5. Blood pressure control
6. Avoidance of concomitant antiplatelet therapy
7. Package insert – avoid potent drug interactions, guidance on transitions
Procedural Management based on Bleeding Risk of Surgery
DABIGATRAN APIXABAN/RIVAROXABAN
Novel Anticoagulants
1. Dabigatran 150 mg BID reduced ischemic stroke
2. Dabigatran 80% renal clearance
3. Dabigatran is associated with small risk of MI, but reduced cardiovascular mortality
4. Dabigatran and rivaroxaban increase GI bleeding
5. Rivaroxaban is once per day and approved Rx for VTE
6. Apixaban reduced stroke, major hemorrhage, and mortality
7. Well-controlled warfarin is associated with low rate of adverse events
Gaps: Practical Considerations
Translation across indication
Atrial fibrillation and valvular heart disease
Atrial fibrillation and ACSAtrial fibrillation and DVT or PE
Select situations in which monitoring would be desirable
Reversibility-trauma, urgent surgery, life-threatening hemorrhage
Guide to the Management ofBleeding in Patients Taking NOAC
Hankey GJ and Eikelboom JW. Circulation. 2011; 123: 1436-1450
Patients with bleeding on NOAC therapy
Mild bleeding Moderate-Severebleeding
Life-threateningbleeding
• Delay next dose or discontinue treatment as appropriate
• Mechanical compression
• Surgical intervention• Fluid replacement and
hemodynamic support• Blood product
transfusion• Oral charcoal • Hemodialysis• ? Prothrombin Complex
Concentrate?(Circulation 2011;124:1573-9)
• Consideration of rFVIIa or PCC
• Charcoal filtration• ? Prothrombin
Complex Concentrate
(Circulation 2011;124:1573-9)
47
WILL THERE BE A CONTINUING ROLE
FOR WARFARIN?
1. Mechanical heart valves2. Cost3. Pregnancy4. Severe renal impairment 5. Drug Interactions6. Lack of acceptance of no monitoring7. Reversal?8. Nonadherence9. Intolerant of novel anticoagulant drug
• Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t1/2, lack of dietary interference, and fewer drug interactions.
• Older individuals with AF are at the highest risk of stroke, the highest risk of hemorrhage, and the highest risk of stopping therapy.
• Further research is needed to inform commonly encountered clinical situations to optimize the effectiveness of these novel agents in routine practice.