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AF Treatment & AnticoagulationDr Matthew Lovell, [email protected] Consultant Cardiologist & Electrophysiologist
!Exeter Heart & Royal Devon and Exeter Hospital
• NICE Guidance for AF
• Release June 2014
• 418 pages + Appendices
• Covers AF treatment, anticoagulation, specialist referral
NICE Guidance
• Very common: lifetime risk for AF at >40 yrs ~ 1 in 4 !
• 2% of total population !
• >1,000,000 cases in UK!
• Prevalence is expected to double over the next twenty five years
AF Epidemiology
AF and AGE
40 50 60 70 80 90
Age (years)
-
-
-
-
-
-
-
-
-
-
-
20
18
16
14
12
10
8
6
4
2
0
Prev
alen
ce (%
)
Framingham Study
Cardiovascular Health Study
Mayo Clinic Study
Western Australia Study
AF will Double by 2025
NICE Screening
• Perform manual pulse palpation in people with:
• palps/SOB/CP/syncope/dizzy
• In patients with risk factors:
• Hypertension, diabetes and IHD
• Opportunistic assessment of such patients for the presence of AF may be prudent
• “Absolutely” irregular RR intervals!
• No distinct P waves on the surface ECG
Diagnosis requires an ECG
NICE AlgorithmAF Diagnosis
Stroke Prevention Rate Control
Rhythm Control
Ablation Therapy
Ongoing Symptoms
Ongoing Symptoms
AF PathwayAF Diagnosis
Stroke Prevention Rate Control
Rhythm Control
Ablation Therapy
Ongoing Symptoms
Ongoing Symptoms
CHADSVASC
Avoid aspirin
Warfarin or NOAC
Assess Bleeding risk
Assess quality of INR
LAA Occlusion
First Line
BB/Ca2+ Combine if symptoms+
Reversible cause CCF from AF
New onset
PerAF: DCCV PAF: Anti-arrhythmics
BB Firstline
CCF:Amiodarone
Flecainide/Sotalol
AF Ablation Pace & Ablate
AFFIRM
Rhythm Control: DCCV
Atrial Fibrillation 605
42 42-45).217 Longer duration of the arrhythmia, greater weight, and higher transthoracic impedance are associated with lower shock success. Left atrial size does not predict the outcome of cardiover-sion (which is successful in 83% of patients with a significantly enlarged left atrium), and neither does advanced age. Studies in older patients have demonstrated that the efficacy rate and the incidence of complications of electrical cardioversion are not sig-nificantly higher than in younger individuals, suggesting that a patient should not be refused electrical restoration of sinus rhythm merely on the grounds of age.218 Age and advanced atrial remodeling are probably more important determinants of the subsequent long-term maintenance of sinus rhythm.
AFL can be converted with a direct current shock as low as 25 to 50 J but because a 100-J shock is almost always successful, it should be considered for the initial shock strength. In AF that has lasted less than 30 days, sinus rhythm can be restored by a shock of 100 J, but it is recommended that cardioversion should be started with the initial shock energy level of 200 J or greater. In those with AF of longer duration, in heavier individuals, or in those with COPD and pulmonary emphysema, an initial setting of 300 to 360 J is appropriate (Figure 42-46). Success may occur on the third or subsequent attempt at an intensity that initially
should not have been automatically applied to their management.
Post hoc analysis of the AFFIRM trial, after correction for any mismatch of baseline characteristics, demonstrated that being in sinus rhythm was an advantage but that use of the then-available antiarrhythmic drugs was associated with increased risk of death.216
In the AF-CHF trial, rate- and rhythm-control strategies were compared specifically in 1376 patients with an ejection fraction (EF) of 35% or less and NYHA class II to IV heart failure.212 Amiodarone was the drug of choice for AF suppression and sinus rhythm maintenance, but sotalol and dofetilide were used in selected cases. The study showed no benefit of rhythm control in addition to optimal medical therapy with regard to the primary endpoint (cardiovascular mortality) (see Figure 42-44, B) as well as prespecified secondary endpoints, including total death, wors-ening heart failure, stroke, and hospitalization.
The closely similar primary endpoint results for the rhythm-control and rate-control strategies were probably caused by a general failure to achieve a clear difference with respect to rhythm and rate status in the two arms of the trials. Ideally, the rhythm-control arm should have comprised patients who were in sinus rhythm, and the rate control arm should have consisted mostly of patients in AF. This was not usually the case; for example, in the AFFIRM trial, only 60% of the rhythm-control arm were main-tained in sinus rhythm, whereas 40% of the rate-control arm had reverted spontaneously to sinus rhythm.
The results of rate-control versus rhythm-control studies high-lighted the limitations of the current therapies to achieve and maintain sinus rhythm. Long-term maintenance of sinus rhythm has proven difficult to achieve in patients with persistent AF, and the method is time consuming and expensive because of the costs of antiarrhythmic drugs and the increased need for hospitaliza-tion. Thus the trend toward rate control on the grounds of safety may be reversed if safer and more effective rhythm control thera-pies become available.
Restoration of Sinus Rhythm
Electrical Cardioversion
The overall success rate is 90% to 95% with electrical cardiover-sion for AF that occurred less than 48 hours earlier and decreases to 72% to 78% if the arrhythmia is present for 1 year (Figure
FIGURE 42-45 Prevalence of unsuccessful electrical cardioversion as a function of duration of the arrhythmia. (Modified from Elhendy A, Gentile F, Khanderia BK, et al: Predictors of unsuccessful electrical cardioversion in atrial fibrillation, Am J Cardiol 89;83–86, 2002.)
30
25
20
15
10
5
0
58
13
22
28
!48 h 48 h"1 mo 1"6 mo 6"12 mo #12 mo
Duration of atrial fibrillation
Uns
ucce
ssfu
l car
diov
ersi
on (
%)
FIGURE 42-46 Electrical cardioversion of atrial fibrillation. DC, Direct current.
25 mm/s 360J SYNC EXTERNAL PADDLES
LEAD II AUTOGAIN DELAYED SYNC
Atrial fibrillationDC
shock Ventricularectopic beat Sinus rhythm
DCCV AF Recurrence
Failure of AAR Drugs
Meta-analysis KPM of Arrhythmia Free Survival
Bonanno et al, J Cardiovasc Med 2010
Pulmonary Vein Triggers
AF Ablation
AF Ablation
AF Ablation
Risk of Ablation• Improve outcomes
• Sinus rhythm 75-80% at 12 months
• Improved symptoms
• Risk of procedure
• 1 in 100 pericardial effusion
• 1 in 400 of CVA
AF and Stroke
Who is at Riskt'It_
FBaF
€t4Ia"gcoIl:@6lL
Y
A a a a=
rr* c\lF-Ut
S <rcoiiFr cao€tr- O
ltrs
-. (6'5 ?.
+rfl x
!Y Q 5_o
(!F€--. tr - >irfi€.-
-^ V
-'-
v/\J,i
e.P.4=L
A' 'AA
--rr-eU6,9trc)
pj
^/
= $1l:C\
• Symptomatic/asymptomatic paroxysmal, persistent or permanent AF
• Atrial flutter
• Those with continuing risk of arrhythmia recurrence after returning to sinus rhythm
Who is at Risk
• CHADS2 score of 0 does not reliably identify AF patients who are ‘truly low-risk'!
• Does not include many common stroke risk factors!
• Use CHADS2VA2SC!
• If CHADS2VA2SC = 0 then use nothing!
• If >= 1/2 then use Warfarin/NOAC
CHADS2 vs CHA2DS2-VASc
cAddressing)stroke)risk:)
CHA2DS23VASc))
Risk)Factor)CCF)/)EF<40% ) ) )1)Hypertension ) ) )1)Age>75 ) ) )2)Diabetes ) ) )1)Stroke/TIA/embolism) )2)Vascular)disease ) )1)Age)65374 ) ) )1)Sex)category)(female)) )1)
Score)))))))))Stroke)rate)(%/yr))0 ) )0)1 ) )1.3)2 ) )2.2)3 ) )3.2)4 ) )4.0)5 ) )6.7)6 ) )9.8)7 ) )9.6)8 ) )6.7)9 ) )15.2)
Modified)from:)Guidelines)on)the)management)of)atrial)fibrillaXon.)EHJ)2010;)31:)236932429)
CHA2DS2-VASc
CHA2DS2-VASc=2, One Yr Risk
Risk 2.2%/yr
1:50
CHA2DS2-VASc=2, 5 Yr Risk
Risk 10%1:10
• Evidence for stroke prevention with aspirin is weak, with potential for harm!
• Major bleeding or ICH not significantly different to that of OAC!
• Use limited to the few patients who refuse any form of OAC!
• ASA + Clopidogrel better efficacy with greater risk of bleeding
Aspirin Not Worth the Risk
Aspirin DataFigure 1. Outcomes Survival Curves
No. at Risk
Oral Anticoagulants
Aspirin
No. at Risk
Oral Anticoagulants
Aspirin
0.25χ2 = 14.7, P<.0010.20
0.15
0.10
0.05
00
1939
2113
1
1409
1514
829
881
432
165
140
348
352
Year
Pro
porti
onW
ith E
vent
Cardiovascular Events
2113
0.25χ2 = 21.7, P<.0010.20
0.15
0.10
0.05
0
Pro
porti
onW
ith E
vent
All Strokes
1939 1413
1525
831
890
163
145
351
358
χ2 = 9.5, P = .02
0
1939
2113
1
1413
1553
821
925
432
158
146
347
365
Year
Major Bleeding
χ2 = 29.5, P<.001
Ischemic Strokes
1939
2113
1415
1526
833
893
165
145
352
358
OralAnticoagulants
Aspirin
χ2 = 0.6, P = .44
0
1939
2113
1
1434
1569
844
938
432
168
153
360
377
Year
Death
χ2 = 2.7, P = .19
Hemorrhagic Strokes
1939
2113
1432
1568
842
935
166
153
359
376
In each plot, the horizontal axis represents time in years. The P value is a log-rank statistic. All strokes included ischemic and hemorrhagic events. Cardiovascular eventsincluded ischemic strokes, myocardial infarctions, systemic emboli, and vascular death. Major bleeding events included intracranial and major systemic bleeds.
Figure 2. Relationship of Therapy With Outcomes in Individual Trials
0 1 3 42Hazard Ratio
Major BleedingP = .87
Ischemic StrokesP = .88
AFASAK 1EAFTPATAFSPAF 2AFASAK 2SPAF 3
Overall
0 1 3 42Hazard Ratio
Cardiovascular EventsP = .96
AFASAK 1EAFTPATAFSPAF 2AFASAK 2SPAF 3
Overall
All StrokesP = .83
0 1 3 42Hazard Ratio
DeathP = .99
Hemorrhagic StrokesP = .98
For each study, the relative effect of oral anticoagulants vs aspirin (with or without low-dose warfarin) is presented for all 6 outcomes as a hazard ratio. Hazard ratiosbelow 1 indicate that oral anticoagulant decreases the risk of the event. Hazard ratios whose 95% confidence interval (error bars) excludes 1 are statistically significantat the 5% level. Because hemorrhagic strokes were uncommon events, a hazard ratio could not be estimated for each study individually. The P value for the DerSimonianand Laird Q statistic, as a measure of heterogeneity, is presented for each outcome in the top right-hand corner. AFASAK indicates Atrial Fibrillation, Aspirin, Antico-agulation study2,3; EAFT, European Atrial Fibrillation Trial5; PATAF, Primary Prevention of Atrial Thromboembolism in patients with Nonrheumatic Atrial Fibrillation inPrimary Care4; SPAF, Stroke Prevention in Atrial Fibrillation studies.7,9
ORAL ANTICOAGULANTS AND ASPIRIN IN ATRIAL FIBRILLATION
©2002 American Medical Association. All rights reserved. (Reprinted) JAMA, November 20, 2002—Vol 288, No. 19 2445
Downloaded From: http://jama.jamanetwork.com/ on 02/23/2014
van Walraven et al, JAMA 2002,
• Do not offer aspirin for stroke prevention
• Only consider dual antiplatelet therapy
• Aspirin and clopidogrel for stroke prevention
• If anticoagulation is contraindicated
• Not tolerated and CHA2DS2-VASc score of =>2
Aspirin NICE 2014
• Anticoagulation may be with NOAC or warfarin
• In those CHA2DS2-VASc score of >=2
• Consider for men CHA2DS2-VASc score = 1
• Taking bleeding risk into account
Anticoagulation NICE 2014
WAll trials ( n=6)
AFASAK I (1)
SPAF (3)
BAATAF (6)
CAFA (7)
SPINAF (8)
EAFT (9)
Relative risk reduction(95% CI)
Adjusted-dose warfarin compared with placebo
050%100% –50% –100%Warfarin better Warfarin worse
All trials ( n=5)
AFASAK I (1)
AFASAK II (12)
EAFT (9)
PATAF (15)
SPAF II (4)
Relative risk reduction(95% CI)
Warfarin compared with aspirin
050%100% –50% –100%Warfarin better Warfarin worse
Warfarin is Effective
Wpatients with a history of AF.84 Efforts to reduce the frequencyof AF through alternative site pacing techniques have demon-strated marginal to no benefit. The one exception may be the use of postoperative pacing to prevent cardiac surgery-associated AF.85,86
THROMBOEMBOLIC PROPHYLAXIS
Stroke represents the most devastating complication of AF,and the percentage of strokes attributable to this arrhythmiaincreases with the increasing age of the population.87 Thus, itis estimated that >35% of strokes in patients >80 years of ageare directly attributable to AF.87 Strokes in patients with AFtend to be more severe than those that result from othercauses, such as carotid artery stenosis, and they carry a highermortality rate.88,89 Several large trials performed in the late1980s and early 1990s clearly demonstrated a very significantbenefit of warfarin therapy for the prevention of strokeamong patients with nonrheumatic AF.90-97 Paroxysmal AFwas shown to have the same annual stroke incidence as per-sistent AF, and the development of stroke was shown to be anongoing risk. These trials also defined several subsets ofpatients with AF who were at a greater risk of stroke thanpatients in whom the arrhythmia existed in isolation (loneAF). The risk of stroke is greatest in patients with prior strokeor TIA (11% per year), and other risk factors include conges-tive heart failure, systolic ventricular dysfunction, hyperten-sion (whether current or treated), older age, and diabetes.98-101
The finding on a transesophageal echocardiogram of denseleft atrial spontaneous contrast, diminished left atrial
appendage velocities, or complex aortic plaque was associatedwith a risk of stroke in excess of 13% per year101-103; many ofthese features were associated with the clinical findings notedearlier and transesophageal imaging is not mandatory for riskstratification. Using a simple point system referred to by anacronym such as the CHADS2, an annual stroke estimate canbe assessed100,104 (Table 24–4). For patients deemed to be atmoderate-to-high risk of stroke, warfarin is indicated, pre-scribed to maintain an INR of 2.0 to 3.0. The role of aspirintherapy in AF is less clear. Low-dose aspirin (81 mg) is noteffective, and the efficacy of higher dose aspirin (325 mg daily)is controversial.105,106
The risk of major bleeding in association with warfarin is low, even in the elderly, if the INR is maintained below3.0.107-109 Tight control of the INR can be facilitated by atten-tion to medications and foods that interact with warfarin(Table 24–5). Unfortunately, despite overwhelmingly con-vincing evidence of the efficacy of warfarin for preventingstroke in AF, a significant number of patients, particularly theelderly, are not prescribed appropriate thromboembolic prophylaxis with warfarin.110-112 This is due more to a miscon-ception of the risk-benefit ratio of anticoagulation in the elderly, in whom thromboembolic strokes are frequent, oftendevastating, and sometimes fatal.
Pericardioversion AnticoagulationThe pericardioversion period represents a special situation interms of thromboembolic risk. After restoration of sinusrhythm, atrial mechanical function may be diminished, andleft atrial appendage-emptying velocities may be even lowerthan they were during AF.113,114 This occurs more frequently ifthe duration of AF is long. The return of atrial function gen-erally occurs in 7 to 14 days after restoration of sinus rhythm,and this is a period of high thromboembolic risk. Thus,anticoagulation is mandated during this time, even if a trans-esophageal echocardiogram showed no thrombus imme-
Arrhythmias/Conduction Disturbances496
Table 24–4 The CHADS2 Scoring System for AssessingAnnualized Stroke Risk
CHADS2 No Aspirin-Score Adjusted Risk (CI)* On Aspirin†
0 1.9 (1.2-3.0) 0.8 (0.4-1.7)1 2.8 (2.0-3.0) 2.2 (1.6-3.1)2 4.0 (3.1-5.1) 4.5 (3.5-5.9)3 5.9 (4.6-7.3) 8.6 (6.8-11.0)4 8.5 (6.3-11.1) 10.9 (7.8-15.2)5 12.5 (8.2-17.5) 12.3 (6.6-22.9)6 18.2 (10.5-27.4) 13.7 (2-97)
Risk of stroke per 100 patient-years among patients notreceiving warfarin. The score is calculated by assigning 1 pointeach for Congestive heart failure, Hypertension, Age ≥75years, Diabetes, and 2 points for prior Stroke or transientischemic attack. The two columns of data are derived fromdifferent cohorts, and the wide confidence intervals with 6points represent a relatively small number of patients with thisscore in this cohort. A simplified scheme classifies patients intolow stroke risk (score 0), moderate risk (score 1-2) and high risk(score 3-6).*Data from Gage BF, Waterman AD, Shannon W et al:Validation of clinical classification schemes for predicting stroke:results from the National Registry of Atrial Fibrillation. JAMA2001;285:2864-70.†Data from Gage BF, van Walraven C, Pearce L, et al: Selectingpatients with atrial fibrillation for anticoagulation: Stroke riskstratification in patients taking aspirin. Circulation2004;110:2287-92.
Table 24–5 Warfarin Interactions
Potentiate Warfarin Inhibit Warfarin
Acetaminophen AzathioprineAmiodarone CarbamazepineAspirin HaloperidolAntibiotics (particularly) Oral contraceptives
Cephalosporins, ciprofloxacin, Phenobarbitalerythromycin metronidazole, Rifampintrimethoprim-sulfamethoxazole, Vitamin K-containing macrolides foods (green leafy
Cimetidine vegetables):Excessive ETOH spinach, broccoli, Fluconazole avocadoNSAIDs Coenzyme QSulfonamides St. John’s wortGingko biloba, ginseng HypothyroidismCongestive heart failure Nephrotic syndrome
EdemaHereditary coumadin
resistance
ETOH, ethanol; NSAIDs, nonsteroidal anti-inflammatory drugs.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
of STrOke in SubjecTs With AtriaL Fibrillation (E)(ARISTOTLE) and Rivaroxaban Once daily oral directfactor Xa inhibition Compared with vitamin Kantagonism for prevention of stroke and EmbolismTrial in Atrial Fibrillation (ROCKET-AF) trials com-pared a new OAC (dabigatran, apixaban or rivarox-aban) with warfarin in patients who were deemedsuitable for VKA therapy, whereas Apixaban VERsusASA to Reduce the risk of strOkES (AVERROES) com-pared apixaban with aspirin in patients deemedunsuitable for VKA therapy. The results of these trialsare summarized in Table 4.
Dabigatran (RE-LY Trial)RE-LY was a noninferiority trial comparing the effi-cacy and safety of dabigatran 150 mg twice daily(b.i.d.), dabigatran 110 mg b.i.d. and warfarin (targetINR 2.0 to 3.0) for stroke prevention in 18 113patients with atrial fibrillation and at least one riskfactor for stroke who were followed for 2 years[22&&,23].
RE-LY efficacy and safety results
Dabigatran 150 mg b.i.d. reduced the rate of theprimary outcome, stroke or systemic embolism, by35% as compared with warfarin [1.11% per year
versus 1.71% per year: relative risk (RR)¼0.65;95% confidence interval (CI) 0.52–0.81; P<0.001for superiority] with a similar risk of major bleeding(3.32% per year versus 3.57% per year; RR¼0.93;95% CI 0.81–1.07; P¼0.32) [23]. Dabigatran 110 mgb.i.d. had similar efficacy to warfarin for strokeprevention (1.54% per year versus 1.71% per year:RR¼0.90; 95% CI 0.74–1.10; P¼0.30 for noninfer-iority) but was associated with a lower risk of majorbleeding (2.87% per year versus 3.57% per year;RR¼0.80; 95% CI 0.70–0.93; P¼0.003) [23].
The rate of hemorrhagic stroke was 0.38% peryear in the warfarin-treated group and was signifi-cantly lower in those who received dabigatran110 mg b.i.d. (0.12% per year; RR¼0.31; 95% CI0.17–0.56; P<0.001) or dabigatran 150 mg b.i.d.(0.10%; RR¼0.26; 95% CI 0.14–0.49; P<0.001)[22&&]. The death rate from vascular causes waslower with dabigatran 150 mg b.i.d. compared withwarfarin (2.28% per year versus 2.69% per year;RR¼0.85; 95% CI 0.72–0.99; P¼0.04) [22&&].
Dabigatran 150 mg b.i.d. compared with war-farin significantly increased major gastrointestinalbleeding (RR¼1.50; 95% CI 1.19–1.89: P<0.001),but there was no increase in gastrointestinal bleed-ing with dabigatran 110 mg b.i.d. compared withwarfarin [22&&]. Dyspepsia was twice as common for
Table 3. HAS-BLED bleeding risk score
HAS-BLED Bleeding Risk Score
Letter Clinical characteristics Score(s)
H Hypertensiona 1
A Abnormal Liverb/Renalc function(1 point each)
1 or 2
S Stroke (previous history, particularlylacunar)
1
B Bleeding predispositiond 1
L Labile INRse 1
E Elderly (Age over 65 years) 1
D Drugsf/Alcoholg (1 point each) 1 or 2
9 (max)
INR, international normalized ratio.aSystolic blood pressure of over 160 mmHg.bChronic hepatic disease (e.g. cirrhosis) or biochemical evidence ofsignificant hepatic derangement (e.g. bilirubin above twice the upper limit ofnormal, in association with aspartate aminotransferase/alanineaminotransferase/alkaline phosphatase above three times the upper limit ofnormal, etc.).cChronic dialysis or renaltransplantation or serum creatinine of 200 mmol/l ormore.dPrevious bleedinghistory and/or predisposition to bleeding, e.g. bleedingdiathesis, anemia, etc.eUnstable/high INRs or poor time in therapeutic range (e.g. under 60%).fDrugs including antiplateletagents and non-steroidal anti-inflammatory drugs.gOver 8 units per week.Adapted with permission from [21].
Vitamin K antagonist
II X IX
IXa
VIIa/TF
Va
Xa
Fibrinogen
Thrombin inhibitor
Xa inhibitor
Fibrin
VIIIa
IIa
FIGURE 1. The oral antithrombotic agents and their sites ofaction.
Clinical trials
334 www.co-cardiology.com Volume 27 " Number 4 " July 2012
Benefit vs Risk
OR
• Reassess anticoagulation for a person with poor anticoagulation control shown by any of the following:
• 2 INR values > 5 or 1 INR value> 8 within the past 6 months
• 2 INR values less than 1.5 within the past 6 months
• TTR less than 65%
Labile INRs
• Novel Oral Anticoagulants
• Alternative to Warfarin
• Stroke prevention in non-valvular AF
• Dabigatran 110/150 mg bd
• Apixaban 5mg bd
• Rivaroxaban 20 mg od
NOACS
• NOACs
• Less interactions, predictable, no monitoring
• Rapid onset/offset
• 20-30% less RR in CVA/embolism
• 30-60% less RR in ICH
• 10-15% less RR in death
• No specific antidotes
NOACs vs Warfarin
1. RE%LY.(NEJM(2009;(361:(1139%1151(2. ROCKET%AF(NEJM(2011;(365:(883%891(3. ARISTOTLE(NEJM(2011;(365:(981%992(
(
the integrity of randomization, leading to potential con-founding and selection bias. Although an intention-to-treatanalysis was provided for the primary efficacy outcome ofcombined stroke and systemic embolism, it was not pro-vided for other efficacy and safety outcomes.4 Conse-quently, ROCKET AF was considered unclear in the do-main of other sources of bias. Importantly, the as-treatedpopulation excluded only 28 of 14,264 patients included inthe intention-to-treat analyses.
ARISTOTLE, another noninferiority trial, used an inten-tion-to-treat analysis for all efficacy outcomes but not forsafety outcomes, for which only patients who received !1dose of study drug were considered.2 It was therefore con-sidered unclear in the domain of other sources of bias. Thesesafety analyses excluded 61 of 18,201 patients included inthe intention-to-treat population.
In each trial, the new oral anticoagulants were found tobe at least noninferior to warfarin for the composite endpoint of stroke (including hemorrhagic stroke) and systemicembolism (Table 2). ARISTOTLE and RE-LY further dem-onstrated the superiority of apixaban and dabigatran, re-spectively, to warfarin with respect to this composite endpoint. All 3 drugs were associated with a significantly de-creased risk for hemorrhagic stroke compared to warfarin.RRs of other secondary efficacy outcomes, including isch-
emic stroke, all-cause mortality, vascular mortality, andmyocardial infarction, were comparable or inconclusive in!2 of the 3 trials. With regard to safety, dabigatran andrivaroxaban were found to have comparable risks for majorbleeding to warfarin, while apixaban demonstrated superi-ority for this outcome. Gastrointestinal bleeding data wereheterogenous among the RCTs. The new oral anticoagulantswere each associated with a decreased risk for intracranialbleeding compared to warfarin.
When data were pooled across RCTs, patients random-ized to new oral anticoagulants had a 22% RR reduction forthe composite end point of stroke and systemic embolismcompared to those randomized to warfarin (RR 0.78, 95%CI 0.67 to 0.92; Figure 2). The risks for ischemic andunidentified stroke (RR 0.87, 95% CI 0.77 to 0.99), hem-orrhagic stroke (RR 0.45, 95% CI 0.31 to 0.68; Figure 2),and all-cause mortality (RR 0.88, 95% CI 0.82 to 0.95;Supplemental Figure 1) were also lower in patients random-ized to new oral anticoagulants compared to patients ran-domized to warfarin. The risk for vascular mortality, usingdata from the RE-LY and ROCKET AF trials, was signif-icantly reduced among those randomized to new oral anti-coagulants (RR 0.87, 95% CI 0.77 to 0.98; SupplementalFigure 1); ARISTOTLE was excluded from this analysisbecause only event rates, rather than count data, were re-
A RE-LY
ROCKET AF
ARISTOTLE
Subtotal (I-squared = 55.9%, p = 0.104)
RE-LY
ROCKET AF
ARISTOTLE
Subtotal (I-squared = 0.0%, p = 0.522)
RE-LY
ROCKET AF
ARISTOTLE
Subtotal (I-squared = 52.2%, p = 0.124)
Study
0.66 (0.53, 0.82)
0.88 (0.75, 1.03)
0.80 (0.67, 0.95)
0.78 (0.67, 0.92)
0.77 (0.61, 0.99)
0.91 (0.73, 1.13)
0.92 (0.75, 1.14)
0.87 (0.77, 0.99)
0.26 (0.14, 0.50)
0.58 (0.37, 0.92)
0.51 (0.35, 0.75)
0.45 (0.31, 0.68)
RR (95% CI)
134/6076
269/7081
212/9120
615/22277
111/6076
156/7061
162/9120
429/22257
12/6076
29/7061
40/9120
81/22257
NOA n/N,
202/6022
306/7090
265/9081
773/22193
142/6022
172/7082
175/9081
489/22185
45/6022
50/7082
78/9081
173/22185
Warfarin n/N,
28.57
37.22
34.20
100.00
27.29
35.93
36.78
100.00
24.45
34.94
40.60
100.00
Weight %
Favors NOA Therapy Favors Warfarin Therapy
1 .25 .5 2 4
B
C
Figure 2. Forest plot for (A) all-cause stroke and systemic embolism, (B) ischemic and unspecified stroke, and (C) hemorrhagic stroke, new oral anticoagulants(NOA) versus warfarin in patients with AF.
457Review/Oral Anticoagulants Versus Warfarin in AF
All stroke/embolism
Ischaemic stroke
Haemorrhagic stroke
ported. Risk for myocardial infarction was similar betweennew oral anticoagulants and warfarin (RR 0.96, 95% CI0.73 to 1.26; Supplemental Figure 2).
Safety outcome analyses included major bleeding, gas-trointestinal bleeding, and intracranial bleeding (Figure 3).Analyses of the risks of major bleeding (RR 0.88, 95% CI0.71 to 1.09) and gastrointestinal bleeding events (RR 1.25,95% CI 0.91 to 1.72) were inconclusive because of wide95% CIs. However, randomization to a new oral anticoag-ulant was associated with a significant reduction in the riskfor intracranial bleeding (RR 0.49, 95% CI 0.36 to 0.66).
Discussion
Our study was designed to compare the efficacy andsafety of new oral anticoagulants to that of warfarin inpatients with AF. Our systematic search identified 3 trials,evaluating the new oral anticoagulants apixaban,2 dabiga-tran,3 and rivaroxaban.4 In our meta-analysis, we found thatthe new oral anticoagulants reduced the risk for a compositeend point of stroke and systemic embolism compared towarfarin. New oral anticoagulants were also found to beassociated with a lower risk for key secondary efficacyoutcomes, including ischemic and unidentified stroke, hem-orrhagic stroke, all-cause mortality, and vascular mortality,compared to warfarin. Our meta-analysis was inconclusive
with respect to major bleeding and gastrointestinal bleedingbut found a substantial decrease in the risk for intracranialbleeding. Overall, our results support the use of the new oralanticoagulants as alternatives to warfarin for long-term an-ticoagulation therapy in patients with AF.
Warfarin is largely underused because of concerns overthe need for systematic monitoring and the risk for bleedingassociated with its use.11 Only 50% to 60% of patients withAF indicated for anticoagulation therapy are estimated toreceive it.11 Furthermore, patients who receive warfarinspend 30% to 50% of the treatment time outside the thera-peutic range.12 There is consequently a need for new agentsthat can function as alternatives to warfarin for long-termanticoagulation in AF. Given the recent approval of dabiga-tran and rivaroxaban for stroke prevention in patients withAF by the United States Food and Drug Administration,13,14
it is essential that evidence comparing the novel treat-ment alternatives to warfarin be available to inform clin-ical decisions.
Bleeding is an important concern in anticoagulation ther-apy. Although warfarin has been shown to lower the riskfor stroke and thromboembolism, it is associated with anincreased risk for potentially life-threatening bleedingevents.15,16 Our results suggest that new oral anticoagu-lants lower the risk for intracranial bleeding and, although
.
RE-LY
ROCKET AF
ARISTOTLE
Subtotal (I-squared = 87.2%, p = 0.000)
RE-LY
ROCKET AF
ARISTOTLE
Subtotal (I-squared = 54.9%, p = 0.109)
RE-LY
ROCKET AF
ARISTOTLE
Subtotal (I-squared = 82.5%, p = 0.003)
Study
0.94 (0.82, 1.07)
1.03 (0.89, 1.18)
0.70 (0.61, 0.81)
0.88 (0.71, 1.09)
0.41 (0.28, 0.60)
0.66 (0.47, 0.92)
0.42 (0.31, 0.59)
0.49 (0.36, 0.66)
1.50 (1.20, 1.89)
1.46 (1.19, 1.78)
0.88 (0.68, 1.14)
1.25 (0.91, 1.72)
RR (95% CI)
399/6076
395/7111
327/9088
1121/22275
36/6076
55/7111
52/9088
143/22275
182/6076
224/7111
105/9088
511/22275
NOA n/N,
421/6022
386/7125
462/9052
1269/22199
87/6022
84/7125
122/9052
293/22199
120/6022
154/7125
119/9052
393/22199
Warfarin n/N,
33.55
33.29
33.15
100.00
30.19
34.23
35.59
100.00
33.49
34.74
31.77
100.00
Weight %
Favors NOA Therapy Favors Warfarin Therapy 1 .25 .5 2 4
A
B
C
Figure 3. Forest plot for (A) major bleeding, (B) intracranial bleeding, and (C) gastrointestinal bleeding, new oral anticoagulants (NOA) versus warfarin inpatients with AF.
458 The American Journal of Cardiology (www.ajconline.org)
Major bleeding
ICH
GI Bleeding
• All 3 NOACS approved for anticoagulation in non-valvular AF
• Dabigatran
• Rivoroxaban
• Apixaban
• No preferences
NICE Approved
• NOACS useful:
• Allergy/intolerance
• INR monitoring impractical
• INR labile
• Those at risk of drug interactions
• People who have never used warfarin (don’t need to try warfarin prior to NOAC)
1
PENINSULA HEART & STROKE NETWORK
This Network guidance is to inform prescribers and other healthcare professionals about the appropriate use of the novel oral anticoagulants (NOACs: dabigatran (Pradaxa®), rivaroxaban (Xarelto®) and apixaban (Eliquis®)) as options for the prevention of stroke and systemic embolism in people with non-valvular atrial fibrillation (AF). This is a new area of prescribing and this guidance sets out the main considerations and patient groups where these alternatives to warfarin may be useful. NICE Guidance for dabigatran and rivaroxaban was issued in 2012 and has been worded almost identically, whilst keeping to the text of their licences. NICE Guidance for apixaban was published in February 2013, and the text is very similar. Note that the age limits mentioned in the guidance are risk factors rather than thresholds for treatment.
Dabigatran (NICE Guidance TA249 issued March 2012)
Dabigatran etexilate is recommended as an option for the prevention of stroke and systemic embolism within its licensed indication, that is, in people with nonvalvular atrial fibrillation with one or more of the following risk factors:
previous stroke, transient ischaemic attack or systemic embolism; left ventricular ejection fraction below 40%; symptomatic heart failure (NYHA Class 2 or more); age 75 or older; OR age 65 or older with one of the following: diabetes mellitus, coronary artery disease or hypertension.
The decision about whether to start treatment with dabigatran should be made after an informed discussion between the clinician and the person about the risks and benefits of dabigatran compared with warfarin. For people who are taking warfarin, the potential risks and benefits of switching to dabigatran should be considered in the light of their level of INR control.
Rivaroxaban (NICE Guidance TA256 issued May 2012) Rivaroxaban is recommended as an option for preventing stroke and systemic embolism within its licensed indication, that is, in people with nonvalvular atrial fibrillation with one or more risk factors such as:
congestive heart failure; hypertension; age 75 or older; diabetes mellitus; prior stroke or transient ischaemic attack
The decision about whether to start treatment with rivaroxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of rivaroxaban compared with warfarin. For people who are taking warfarin, the potential risks and benefits of switching to rivaroxaban should be considered in the light of their level of INR control.
Apixaban (NICE Guidance TA275 issued February 2013) Apixaban is recommended as an option for preventing stroke and systemic embolism within its marketing authorisation, that is, in people with nonvalvular atrial fibrillation with 1 or more risk factors such as:
prior stroke or transient ischaemic attack; age 75 or older; hypertension; diabetes mellitus; symptomatic heart failure.
The decision about whether to start treatment with apixaban should be made after an informed discussion between the clinician and the person about the risks and benefits of apixaban compared with warfarin, dabigatran etexilate and rivaroxaban. For people who are taking warfarin, the potential risks and benefits of switching to apixaban should be considered in light of their level of INR control. Key considerations when choosing between the available oral anticoagulant options 1. Renal Function.
Dabigatran is contraindicated in severe renal impairment (creatinine clearance [CrCl, or the surrogate of eGFR] <30 ml/min), and a lower dose is used in moderate renal impairment and for patients aged over 80 (110 mg BD). Rivaroxaban is contraindicated in people with CrCl / eGFR <15 ml/min, and the dose should be reduced to 15 mg OD for people with CrCl / eGFR 15-49 ml/min. Apixaban is contraindicated for people with CrCl / eGFR <15 ml/min, and the dose should be reduced to 2.5 mg BD for people with CrCl / eGFR 15-29 ml/min, and for people aged ≥80 with serum creatinine >133 µmol/L or weight <60 kg. With all the NOACs drug accumulation can occur with impaired renal function. Renal function should be checked prior to initiation and monitored when necessary, such as when other drugs with renal effects are introduced or altered, or with dehydration/vomiting/diarrhoea. Renal function should be monitored at least annually in patients older than 75 years and in those with renal impairment. Liver function should be checked prior to initiating apixaban. As clinical experience accumulates, these monitoring requirements may be eased.
Peninsula Heart & Stroke Network Guidance Novel oral anticoagulants for the prevention of
stroke and systemic embolism in atrial fibrillation
Bleeding Warfarin vs Rivaroxaban
Piccini et al 2014, Euro Heart Journal
• No difference in bleeding
• No difference in outcomes
30 day Mortality after Major Bleeding
Majeed et al, Circulation 2013
Bleeding Risk• Use the HAS-BLED score to assess the risk of bleeding in
people who are starting or have started anticoagulation.
• Offer modification and monitoring of the following risk factors:
• Uncontrolled hypertension
• Poor control of international normalised ratio (INR) ('labile INRs')
• Concurrent medication, e.g., aspirin or NSAID
• Harmful alcohol consumption
Bleeding Risk: HAS-BLED(i.e. a CHA2DS2-VASc score of 1) may consider aspirin rather thanOAC therapy.
4.1.4 Risk of bleedingAn assessment of bleeding risk should be part of the patient assess-ment before starting anticoagulation. Despite anticoagulation ofmore elderly patients with AF, rates of intracerebral haemorrhageare considerably lower than in the past, typically between 0.1 and0.6% in contemporary reports. This may reflect lower anticoagula-tion intensity, more careful dose regulation, or better control ofhypertension. Intracranial bleeding increases with INR values.3.5–4.0, and there is no increment in bleeding risk with INRvalues between 2.0 and 3.0 compared with lower INR levels.
Various bleeding risk scores have been validated for bleedingrisk in anticoagulated patients, but all have different modalities inevaluating bleeding risks and categorization into low-, moderate-,and high-risk strata, usually for major bleeding risk. It is reasonableto assume that the major bleeding risk with aspirin is similar to thatwith VKA, especially in elderly individuals.56 The fear of falls may beoverstated, as a patient may need to fall !300 times per year forthe risk of intracranial haemorrhage to outweigh the benefit ofOAC in stroke prevention.
Using a ‘real-world’ cohort of 3978 European subjects with AFfrom the EuroHeart Survey, a new simple bleeding risk score,HAS-BLED (hypertension, abnormal renal/liver function, stroke,bleeding history or predisposition, labile INR, elderly (.65),drugs/alcohol concomitantly), has been derived (Table 10).60 Itwould seem reasonable to use the HAS-BLED score to assessbleeding risk in AF patients, whereby a score of ≥3 indicates
‘high risk’, and some caution and regular review of the patient isneeded following the initiation of antithrombotic therapy,whether with VKA or aspirin.
† Congestive heart failure,Hypertension. Age > 75 yearsDiabetes.Stroke/TIA/thrombo-embolism(doubled)
*Other clinically relevantnon-major risk factors:age 65–74, female sex, vascular disease
CHADS2 score > 2†
OAC
OAC (or aspirin)
Nothing (or aspirin)
Age >75 years
>2 other risk factors*
1 other risk factor*
Yes
Yes
Yes
Yes
No
No
No
NoConsider other risk factors*
Figure 4 Clinical flowchart for the use of oral anticoagulation for stroke prevention in AF. AF ¼ atrial fibrillation; OAC ¼ oral anticoagulant;TIA ¼ transient ischaemic attack. A full description of the CHADS2 can be found on page 13.
Table 10 Clinical characteristics comprising theHAS-BLED bleeding risk score
Letter Clinical characteristica Points awarded
H Hypertension 1
A Abnormal renal and liver function (1 point each) 1 or 2
S Stroke 1
B Bleeding 1
L Labile INRs 1
E Elderly (e.g. age >65 years) 1
D Drugs or alcohol (1 point each) 1 or 2
Maximum 9 points
aHypertension’ is defined as systolic blood pressure .160 mmHg. ‘Abnormalkidney function’ is defined as the presence of chronic dialysis or renaltransplantation or serum creatinine ≥200 mmol/L. ‘Abnormal liver function’ isdefined as chronic hepatic disease (e.g. cirrhosis) or biochemical evidence ofsignificant hepatic derangement (e.g. bilirubin .2 x upper limit of normal, inassociation with aspartate aminotransferase/alanine aminotransferase/alkalinephosphatase .3 x upper limit normal, etc.). ‘Bleeding’ refers to previous bleedinghistory and/or predisposition to bleeding, e.g. bleeding diathesis, anaemia, etc.‘Labile INRs’ refers to unstable/high INRs or poor time in therapeutic range (e.g.,60%). Drugs/alcohol use refers to concomitant use of drugs, such as antiplateletagents, non-steroidal anti-inflammatory drugs, or alcohol abuse, etc.INR ¼ international normalized ratio. Adapted from Pisters et al.60
ESC Guidelines 2385
Patient Attitude To Risk of Anticoagulation
LaHaye et al, Thromb Haemost. 2014
• Patients required 15% relative risk reduction in the risk of stroke to consider anticoagulation
• Patients were willing to endure 4.4 major bleeds in order to prevent one stroke
• Do not withhold anticoagulation solely because the person is at risk of having a fall
Falls
shown in the Figure. Overall, the 2 curves are almostsuperimposable, with no statistically significant differencein major bleeds between patients in the 2 groups (P ! .65).
In bivariate analysis, the first major bleed rates did notdiffer significantly between the patients at low and high riskof falls (HR 1.17; 95% confidence interval [CI], 0.59-2.32)(Table 3). However, the number of medications was asso-ciated with a significantly higher first major bleed rate, witha 12% increase for each additional drug being taken (HR1.12; 95% CI, 1.02-1.23). No other covariates were signif-icantly associated with major bleeds.
Multivariable Associations with MajorBleedingAfter adjustment for age and sex, the risk of falls was notstatistically significantly associated with major bleeds (HR1.13; 95% CI, 0.56-2.27) (Table 3). Further adjustment foralcohol abuse, number of drugs, concomitant treatment withantiplatelet agents, and history of stroke or transient ische-mic attack did not change the estimate (HR 1.09; 95% CI,0.54-2.21). Only the number of medications (HR 1.15; 95%CI, 1.04-1.26) and female sex (HR 2.19; 95% CI, 1.00-4.80)were significantly associated with major bleeds.
DISCUSSIONIn this prospective cohort of adult medical patients whoreceived oral anticoagulants, we found that patients on oralanticoagulants at high risk of falls did not have a higher riskof major bleeds than patients at low risk of falls. Overall,only 0.6 fall-related major bleeds per 100 patient-years (3nonfatal subdural hemorrhages) occurred during follow-up,indicating that oral anticoagulants in medical patients whohave a high risk of falls may be safe. The clinical implica-tion of our findings is that a risk of falls, even if high, should
not be an absolute contraindication to oral anticoagulants, asthe benefits of oral anticoagulants are well documented formany diseases. For example, the use of oral anticoagulantsreduces the risk of stroke by approximately two thirds inpatients with atrial fibrillation.19,20
Our findings are consistent with a previous retrospectivestudy of 90 elderly patients treated with oral anticoagulantsfor atrial fibrillation.7 In this study, patients who fell in thepreceding year did not have a higher rate of major bleedsthan patients who did not fall. In a study that retrospectivelyanalyzed 2664 falls in 1861 inpatients, those who receivedoral anticoagulants had a significantly lower rate of hemor-rhagic injuries than those not on oral anticoagulants (6.2%vs 11.3%; P ! .01).8 In another retrospective study of20,000 Medicare beneficiaries with atrial fibrillation, pa-tients at high risk of falls were 1.9 times more likely to havean intracranial hemorrhage.9 However, prescription of war-farin at baseline did not significantly affect the risk ofintracranial hemorrhage. Finally, evidence from a modelingstudy suggested that a patient with atrial fibrillation takingoral anticoagulants would have to fall about 295 times ayear before the risk of fall-related subdural hemorrhagewould outweigh the benefit of stroke prevention.10
In our study, polypharmacy was independently associ-ated with the risk of major bleeds, underscoring the need todiscontinue unnecessary medications or to intensify themonitoring of patients receiving oral anticoagulants. A po-tential explanation is the higher risk of drug interactionsamong patients on oral anticoagulants who receive multipledrug therapies. The use of potentially interacting drugs withwarfarin has been shown to increase the risk of acutebleeds.21
Our study has several strengths. Firstly, we used a pro-spective design and had a 100% follow-up rate. In contrastto prior studies that focused on specific diseases (eg, atrialfibrillation), our study includes a broad patient populationwith various indications for oral anticoagulants, increasingthe generalizability of our findings. Finally, we identifiedpatients at high risk of falls by 2 standardized, validated
Figure Unadjusted time to first major bleeding event curvesaccording to risk of falls (n ! 515).
Table 2 Description of the First Major Bleeding Events,n (%)
EventsHigh Riskof Falls
Low Riskof Falls Total
LocationGastrointestinal 11 (85) 2 (15) 13 (38)Intracerebral 2 (33) 4 (67) 6 (17)Urogenital 3 (60) 2 (40) 5 (14)Ear, nose & throat 3 (75) 1 (25) 4 (11)Muscle hematoma 1 (33) 2 (67) 3 (9)Retroperitoneal 1 (50) 1 (50) 2 (6)Spinal 0 1 (100) 1 (3)Pulmonary 1 (100) 0 1 (3)Total 22 (63) 13 (27) 35 (100)
Fatal bleed 3 2 5Bleed in the context ofover-anticoagulation*
8 1 9
Fall-related bleed 1 2 3
*Defined as an international normalized ratio "3.0.
776 The American Journal of Medicine, Vol 125, No 8, August 2012
Am J Med (2012) 125, 773-778
GRASP-AF Data 2012
• Only 56% high risk patients on OAC
• 35% high risk on anti-platelet only
• 9% high risk not on anything
• 13% high risk coded as contraindicated or declined
Benefits of Better Anticoagulation
• AF and stroke are major health problems
• In AF assess risk with CHA2DS2VASc
• Use Warfarin or NOACs
• Reduce strokes by screening for AF and improving anticoagulation
• Step wise approach for symptom control
Summary
