1. Burden of Stroke in Patients with Atrial Fibrillation and Recent European Guidelines
Prof. Roland KASSAB, MD, FESC
Head of Division of Cardiology, HDF
Congrès de l’Association Médicale Franco-Libanaise
Movenpick Hotel, Beirut,15/07/2011

2. Atrial Fibrillation
First described by Sir William Harvey in 17th century:
observed chaotic motion of atria in open chest animal
ECG findings described in 1909 by Sir Thomas Lewis:
“irregular or fibrillatory waves and irregular ventricular response” or “absent atrial activity
with grossly irregular ventricular response”

3. Continuing Medical Implementation …...bridging the care gap
Atrial Fibrillation
Continuing Medical Implementation …...bridging the care gap

5. Atrial dilatation/stretch Increased vulnerability to AF?
Pathophysiology of AF
?Inflammation
HTN and/or vascular disease
¯Compliance
Mitral regurgitation
Left ventricular hypertrophy
Diastolic dysfunction
Atrial dilatation/stretch
The slide shows a hypothetical construct of the pathophysiology of AF.
In this schematic, atrial dilatation and atrial stretch act as a common denominator in increasing the vulnerability to AF.
To what extent inflammation plays a role is under investigation, but in this substrate the etiologic role of diastolic dysfunction, hypertension, and mitral regurgitation is understandable. Left atrial volume may be a surrogate or marker of multiple other processes that lead to the development of AF, including arteriosclerosis and hypertension.
It is possible that conditions predisposing to increased arterial stiffness may also lead to left atrial dilatation by increasing the impedance to left ventricular ejection.
­Stretch-activated channels
­Dispersion of refractoriness
­Pulmonary vein focal/discharges?
?Inflammation
Increased vulnerability to AF?
Adapted with permission from Gersh BJ, et al. Eur Heart J Suppl. 2005;7(suppl C):C5-C11.
Gersh BJ, Tsang TSM, Barnes ME, Seward JB. The changing epidemiology of non-valvular atrial fibrillation: the role of novel risk factors. Eur Heart J Suppl. 2005;7(suppl C):C5-C11.

6. What Happens When AF Persists?
Electro- physiologic Remodeling
Structural Remodeling
LA and LAA dilatation
Fibrosis
Decrease in Ca++ currents
Shortening of atrial action potential
Increased importance of early activating K+ channels: IKur, IKto
Many studies, in animals and humans, have highlighted the importance of atrial structural and electrical remodeling in the maintenance of atrial fibrillation.
The source of the expression “Atrial fibrillation begets atrial fibrillation” was a 1995 landmark study in which AF was artificially maintained in goats by a fibrillation pacemaker. Over time, initially short episodes of AF (63 seconds) became progressively longer in the animals, leading to episodes lasting over 24 hours.
These and other data have confirmed that maintenance of AF, whether artificial or spontaneous, leads to a shortening of the atrial effective refractory period (AERP). In the Wijffels study, in addition to AERP, the AF-induced animals demonstrated a reversion of physiological rate adaptation, an increase in heart rate, inducibility, and the development of stable AF.
Remodeling explains why “AF begets AF”
Wijffels MCEF, Kirchof CJHJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation. Circulation. 1995;92(7):

7. Atrial Fibrillation Prevalence
Most common sustained cardiac arrhythmia1
Most common diagnosis for arrhythmia-related hospitalization2
Estimated >2.3 million US adults have AF3
Prevalence of AF increases with age and with an aging population4
1 Bialy D et al. J Am Coll Cardiol 1992; 19-41A.
2 Fuster V et al. Circulation 2006; 114:e257-e354
3 Go AS et al. JAMA 2001; 285:
4 Chug SS et al. J Am Coll Cardiol 2001: 37:

8. Projection for Prevalence of Atrial Fibrillation: 5.6 Million by 2050
Projected number of adults with atrial fibrillation in the United States between 1995 and 2050
7.0
6.0
5.42
5.61
5.0
5.16
4.78
4.34
4.0
Adults with atrial fibrillation
in millions
3.80
3.33
3.0
2.94
2.66
2.44
2.0
2.08
2.26
1.0
Upper and lower curves represent the upper and lower scenarios based on sensitivity analyses.
Years
Go AS et al. JAMA. 2001;285:

9. Atrial Fibrillation: Twice as Common as Previously Suspected
Incidence increased 13% over past 20 years
In USA, millions will be affected by 2050
Increasing obesity and increasing age are risk factors that help explain rise in incidence
Miyasaka Y. Circulation 2006; 114:

10. AF Prevalence: Age and Gender
Prevalence of atrial fibrillation with age
Prevalence, percent
Age, years
JAMA 2001; 285: 2370

11. Atrial Fibrillation Is Associated With Increased Mortality
With atrial fibrillation
Without atrial fibrillation
71.3
65.1*
62.4
54.5
51.0*
47.4*
47.5
38.6
Cumulative mortality over 3 years (%)
34.0
36.1*
30.2*
25.4*
Men
Women
Men
Women
Men
Women
65 to 74 years of age
75 to 84 years of age
85 to 89 years of age
* Significantly different from patients with atrial fibrillation (P<.05).
Wolf PA et al. Arch Intern Med. 1998;158:

12. Prevalence per 10,000 persons
Increasing Hospitalizations in the United States When Atrial Fibrillation Is Principal Diagnosis (National Hospital Discharge Survey) 20 40 60 80
100
120
140
Prevalence per 10,000 persons
1985
1987
1989
1991
1993
1995
1997
1999
Year
Age (years)
85+
75 to 84
65 to 74
55 to 64
35 to 54
Wattigney WA et al. Circulation. 2003;108:

14. Atrial Fibrillation Adversely Affects Quality of Life (QoL)
Lower scores = poorer QoL
SF-36 score
Dorian P et al. J Am Coll Cardiol. 2000;36:

15. AF is associated with substantial healthcare costs
Total annual medical costs of AF in the USA estimated as US$6.65 billion (2001)
Healthcare resource utilization included
350,000 hospitalizations
276,000 emergency department visits
234,000 outpatient visits
The bulk of the costs related to direct and indirect inpatient care
23%
44% 4%
29%
Direct inpatient
Indirect inpatient
Drugs
Outpatient
Coyne KS et al. Value Health 2006;9:348–56

16. Atrial Fibrillation: Major Cause of Stroke in the United States
15% of all strokes attributable to atrial fibrillation
75,000 strokes per year attributable to atrial fibrillation
3- to 5-fold increase in risk of stroke in patients with atrial fibrillation
Stroke risk persists even in asymptomatic atrial fibrillation
Go AS et al. JAMA. 2001;285: ; Go AS. Am J Geriatr Cardiol. 2005;14:56-61; Wolf PA et al. Stroke. 1991;22: ; Benjamin EJ et al. Circulation. 1998;98: ; Page RL et al. Circulation. 2003;107:

17. One Sixth of all Strokes Attributable to AF%
AF prevalence
Strokes attributable to AF
Age Range (years)
Framingham Study 10 20 30
50–59
60–69
70–79
80–89
The Framingham Study examined the impact of atrial fibrillation (AF) on stroke incidence in 5,070 participants after 34 years of follow-up.
Results of the study showed that the percentage of strokes attributable to AF increased dramatically with age.1
The investigators of the study concluded that AF is a major cause of stroke, particularly among elderly patients. Therefore, anticoagulation therapy should be a routine part of therapy for these patients.
Wolf et al. Stroke 1991; 22:
Reference:
Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991; 22: 17

18. Nonvalvular Atrial Fibrillation
Stroke Rates Without Anticoagulation
According to Isolated Risk Factors
Stroke Rate
(%/year)
Prior
Stroke/TIA
Age
> 75 years
Hypertension
Female
Diabetes
Heart Failure
 LVEF
Hart RG et al. Neurology 2007; 69: 546. 18

19. Natural History of “Lone” Atrial Fibrillation
No Cardiopulmonary Disease: <60 Years Old
97 Patients
Mean Age = 44
14.8 years
Follow-up
0.35%/yr Stroke
0.40%/yr Mortality
Kopecky S, et al. N Engl J Med 1987; 317:669.

20. Stroke risk persists even in asymptomatic/intermittent AF
The risk of stroke with asymptomatic or intermittent AF is comparable to that with permanent AF1,2
Observed rate of ischaemic stroke1 14
Intermittent AF 12
Sustained AF 10 8
Annual risk of stroke, % 6 4 2
Low
Moderate
High
Stroke risk category
1. Hart RG et al. J Am Coll Cardiol 2000;35:183–7; 2. Flaker GC et al. Am Heart J 2005;149:657–63

21. AF stroke survivors are at increased risk of death
In the Framingham study the 30-day mortality risk after stroke was increased 1.84-fold among patients with AF
Increased risk of death compared with non-AF patients persisted for up to 1 year after stroke
1.0
0.8
Patients without AF
0.6
Survival probability, %
0.4
P <0.001
Patients with AF
0.2
0.0 60
120
180
240
300
360
Days post-stroke
Lin HJ et al. Stroke 1996;27:1760–4

22. AF patients face an increased risk of recurrent stroke10 8
Patients with AF 6
Cumulative probability of recurrence, %
Patients without AF 4
P = 2 2 4 6 8 10 12
Years after first stroke
Marini C et al. Stroke 2005;36:1115–9

23. Decreasing Atrial Fibrillation Burden Is an Important Goal
As with heart failure or angina, success in managing atrial fibrillation is defined as a decrease in:
Decreasing atrial fibrillation burden offers potential to successfully treat atrial fibrillation by:
Decreasing mortality
Decreasing Stroke
Decreasing hospitalizations
Increasing QoL
Frequency of episodes
Duration of episodes
Symptoms during episodes
Prystowsky EN. J Cardiovasc Electrophysiol. 2006;17(suppl 2):S7-S10; Wolf PA et al. Arch Intern Med. 1998;158:

24. Priorities in the Management of AF The Patient Care Pathway
Rhythm Control
Prevention of Thromboembolism
Rate Control

25. Atrial Fibrillation: A Risk Factor for Vascular Events
RISK FACTORS for THROMBOSIS
• Hypertension
• Hyperlipidemia
• Age
• Diabetes Mellitus
• Smoking
Atherosclerosis/Atherothrombosis
Atherosclerosis/Atherothrombosis
Atrial fibrillation (AF) results when the atria of the heart contract and relax at different times, creating a seemingly chaotic, rapid and irregular rhythm.
The condition can be caused by impulses which are transmitted to the ventricles in an irregular fashion or by some impulses failing to be transmitted. This makes the ventricles beat irregularly, which leads to an irregular (and usually fast) pulse in atrial fibrillation.
Underlying causes of AF include dysfunction of the sinus node and a number of heart and lung disorders, including coronary artery disease, rheumatic heart disease, mitral valve disorders, pericarditis and others.
Hyperthyroidism, hypertension and other diseases can cause arrhythmias, as can recent heavy alcohol use. Some cases of AF or flutter occur in the setting of a myocardial infarction or soon after cardiac surgery.
One of the consequences of AF is stroke: about 15% of all strokes are directly attributable to AF, and in patients over 80 years AF is the single leading cause of major stroke.1,2 MI AF MI AF
CHF
CHF
Stroke, MI, Vascular Death
Wolf PA et al. Arch Intern Med 1987; 147:
Leckey R et al. Can J Cardiol 2000; 16:
References:
1. Wolf PA et al. Arch Intern Med 1987; 147:
2. Leckey R et al. Can J Cardiol 2000; 16:

26. Modifiable Risk Factors in Stroke
Relative Risk
Prevalence (%)
Atrial Fib* 1
Hypertension
25-40
Cardiac Disease
10-20
Diabetes
4-8
Smoking
20-40
Alcohol Abuse
5-30
Hyperlipidemia
6-50
Prevalence varies by age, gender, race, ethnicity and stroke risk factor
* AF has the highest relative risk Adapted from Sacco RL. Neurology 1995;45(Suppl 1):S10-S14.
Continuing Medical Implementation …...bridging the care gap

27. Risk Stratification for Patients with AFib-Flutter
Annual Stroke Rate %
AGE
Years
No other Risk Factors
One or More Additional Risk Factors
< 65
1.0
4.9
65-75
4.3
5.7
> 75
3.5
8.1

28. Risk Factor Stratification
High Risk Factors
Moderate Risk Factors
History of CVT/TIA
Age years
Hypertension
Diabetes
Reduced LV Function
CAD without LV dysfunction
Age > 75 years
Mitral stenosis
Prosthetic Heart Valve

29. Predictors of CVA or Embolism
Univariate analysis
LA thrombi RR 1.4
Atrial appendage length 44 (43-45 mm) RR 1.6
Atrial appendage width 23 (22-23mm) RR 2.4
Multivariate analysis
Hypertension RR 3.6
Previous stroke RR 3.7
Age RR 1.1

30. Thrombus in Left Atrial Appendage Associated with Stroke
Thrombus in left atrial appendage is correlated with increased thromboembolic risk in AF
Abnormalities detected by transesophageal echocardiography in the left atrium (LA) and appendage showed that:
impaired atrial emptying associated with atrial fibrillation (AF) leads to stasis and increases the risk of thrombus formation in the left atrium and especially the left-atrial appendage (LAA).1,2
the surface of the newly formed thrombus is itself highly thrombogenic, creating a local hypercoagulable state and promoting its continued development.1,2
exposure to the dynamic circulatory forces within the cardiac chambers promotes embolization of cardiogenic thrombi and subsequent ischemic events in the different arterial beds including stroke and peripheral arterial occlusion.1,2
spontaneous echo contrast, LAA thrombi, LAA peak flow velocities 20 cm/s and complex aortic plaque are independently associated with increased risk of stroke in patients with AF.1,2
Chimowitz. Stroke 1993; 24: 1015
Zabalgoitia. J Am Coll Cardiol 1998; 31: 1622
References:
1. Chimowitz. Stroke 1993; 24: 1015.
2. Zabalgoitia. J Am Col Cardiol 1998; 31: 1622.

31. Stroke Prevention in Atrial Fibrillation: CHADS2
Congestive heart failure
Hypertension
Age > 75 years
Diabetes mellitus
Stroke or TIA
Points Risk of stroke/100pt-years
JAMA 2001;285:2864

32. Stroke Risk Score for Atrial Fibrillation
The CHADS2 Index
Stroke Risk Score for Atrial Fibrillation
Score
(points)
Risk of Stroke
(%/year)
Approximate
Risk threshold for
Anticoagulation
3%/year
Van Walraven C, et al. Arch Intern Med 2003; 163:936.
Go A, et al. JAMA 2003; 290: 2685.
Gage BF, et al. Circulation 2004; 110: 2287.

33. Desirable Characteristics of Pharmacologic Converting Agents
Efficacy
High rate of restoring sinus rhythm with relief of symptoms
Rapid onset of action
Safety
Low rate of adverse effects
Low incidence of drug interactions
Lack of interference with electrical cardioversion

34. Limited efficacy of aspirin in reducing the risk of stroke in patients with AF
Aspirin better
Placebo better
AFASAK
SPAF
EAFT
ESPS II
LASAF
125 mg/d
125 mg QOD
UK-TIA
300 mg/d
1200 mg/d
JAST
RRR = 19% 95% CI: –1 to 35%
All trials
100 50
–50
–100
Relative risk reduction (%)*
Error bars = 95% CI; *Relative risk reduction for all strokes (ischaemic and haemorrhagic) 34
Hart RG et al. Ann Intern Med 2007;146:857–67 34

35. Anticoagulation in Atrial Fibrillation The Standard of Care for Stroke Prevention
Warfarin
Better
Control
Better
AFASAK
Unblinded
SPAF
Unblinded
BAATAF
Unblinded
CAFA
Terminated early
SPINAF
Double-blind; Men only
EAFT
2o prevention; Unblinded
Aggregate
100%
50%
-50%
-100%
Hart R, et al. Ann Intern Med 2007;146:857.

36. Oral Anticoagulant and Aspirin Use in Atrial Fibrillation from 1980 to 2000
Minidose Warfarin Study
AFASAK II
LASAF
EAFT
Oral Anticoagulant
PATAF
SPAF II
Aspirin
SPINAF
SPAF III
Japanese NVAF study
SPAF I
CAFA
BAATAF
AFASAK I
When we superimpose the major clinical trials on antithrombotic therapy in atrial fibrillation, we see that the sharpest increase in use coincided with the publication of the first 6 trials demonstrating that oral anticoagulants significantly reduce stroke risk. A more modest increase in therapy coincided with subsequent trials which further refined the appropriate dosing of therapy.

37. Risk Stratification and Anticoagulation
Stroke Reduction with Warfarin Instead of Aspirin
CHADS2 Score ~
Number of patients Needed-to-treat
to prevent
1 stroke/year 13 42 83
250
EAFT Study Group. Lancet 1993; 324:1255.
Zabalgoitia M, et al. J Am Coll Cardiol 1998; 31:1622.

38. Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reduction
Treatment
Better
Treatment
Worse
Warfarin vs.
Placebo/Control
6 Trials
n = 2,900
Antiplatelet drugs
vs. Placebo
8 Trials
n = 4,876
100%
50%
-50%
Hart R, et al. Ann Intern Med 2007;146:857.

39. Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reductions
Warfarin
Better
Antiplatelet Rx
Better
ACTIVE-W
Anticoagulation vs.
Aspirin + Clopidogrel
n = 6,706
Anticoagulation vs.
Antiplatelet drugs
7 Trials
n = 4,232
100%
50%
-50%
Connolly S, et al. Lancet 2006; 367:1903.
Hart R, et al. Ann Intern Med 2007;146:857.

40. ACTIVE-A Total Stroke Rates
ACTIVE A Medical Advisory Board Meeting_4-09
28% RRR HR (95% CI, 0.62–0.83) p <0.001
0.15
408 (3.3%/year)
Aspirin
ACTIVE.N Engl J Med.May.2009/ p2070 /fig 1B(inset)
0.10
296 (2.4%/year)
Cumulative Incidence
0.05
Clopidogrel + Aspirin
Note: This slide contains off-label information regarding PLAVIX, and should not be used in promotional presentations except in response to unsolicited questions from the audience.
In the ACTIVE A trial, stroke was a component of the composite outcome and occurred in 3.3% of patients per year treated with ASA compared with 2.4% of patients per year treated with PLAVIX plus ASA. This represents a 28% RRR in patients treated with PLAVIX plus ASA vs ASA alone (HR 0.72; 95% CI, 0.62 to 0.83; P<0.001).
0.0
ACTIVE.N Engl J Med.May.2009/ p2070/table 2, p2071/fig 1B 1 2 3 4
Years
Connolly SJ, et al. N Engl J Med 2009; 360:2066.
The ACTIVE trial is sponsored by the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership.
ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360:

41. Hylek, EM et al. N Engl J Med. 2003;349:1019-2614

42. “Most intracranial hemorrhages (62%) occur at INRs < 3.0”
Fang MC et al. Ann Intern Med. 2004;141:745-52

43. Intracerebral Hemorrhage
The Most Feared Complication of Antithrombotic Therapy
>10% of intracerebral hemorrhages (ICH) occur in patients on antithrombotic therapy
Aspirin increases the risk by ~ 40%
Warfarin (INR 2–3) doubles the risk to 0.3– 0.6%/year
ICH during anticoagulation is catastrophic
Hart RG, et al. Stroke 2005;36:1588 43

44. Challenges of Oral Anticoagulation Therapy
Narrow efficacy window + complex kinetics + multiple interactions = hard to use/take
15.0
STROKE
INTRACRANIAL BLEED
10.0
Odds Ratio
There are many challenges associated with oral anticoagulation therapy. These include, a narrow efficacy window, complex kinetics and multiple interactions, which make this therapy hard to use and take.
5.0
1.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
INR
Hylek EM et al. N Eng J Med. 1996; 335(8): 540-6
Hylek EM et al. Ann Intern Med. 1994; 120(11):
References:
Hylek EM et al. N Eng J Med. 1996; 335(8):
Hylek EM et al. Ann Intern Med. 1994; 120(11):

45. Antithrombotic Therapy for Atrial Fibrillation ACC/AHA/ESC Guidelines 2006
Risk Factor
Recommended Therapy
No risk factors
CHADS2 = 0
Aspirin, mg qd
One moderate risk factor
CHADS2 = 1
Aspirin, mg/d or
Warfarin
(INR , target 2.5)
Any high risk factor or
>1 moderate risk factor
CHADS2 >2
or Mitral stenosis
Prosthetic valve
(INR , target 3.0)

46. Rhythm Control Therapies to Maintain Sinus Rhythm
ACC/AHA/ESC 2006 Atrial Fibrillation Guidelines
Rhythm Control Therapies to Maintain Sinus Rhythm
Maintenance of SR
No (or minimal) heart disease
Hypertension
CAD HF
Flecainide
Propafenone
Sotalol
Substantial LVH
Dofetilide
Sotalol
Amiodarone
Dofetilide No
Yes
Amiodarone
Dofetilide
Catheter
ablation
Amiodarone
Catheter
ablation
Catheter
ablation
The recommendations for antiarrhythmic drug (AAD) therapy to maintain sinus rhythm in patients with AF are presented on this slide. Within each box, drugs are listed alphabetically and not in order of suggested use. The vertical flow indicates order of preference under each condition. The seriousness of heart disease proceeds from left to right, and selection of therapy in patients with multiple conditions depends on the most serious condition present.1
For patients with no (or minimal) heart disease, therapy should begin with flecainide, propafenone, or sotalol. If these drugs are not effective, amiodarone or dofetilide may be initiated. If AF persists, treatment with disopyramide, procainamide, or quinidine may be attempted. Nonpharmacologic options may also be considered at this point.1
Patients with heart disease have a greater risk of adverse events with the use of AADs; therapy must be tailored to the type of heart disease and in accordance with safety data in the medical literature. For patients with HF, amiodarone and dofetilide are the drugs of choice. For patients with CAD, a first attempt should be made using sotalol, followed by amiodarone and dofetilide. Disopyramide, procainamide, or quinidine may be used in these patients if the more appropriate drugs fail.1
Hypertensive patients with LV hypertrophy of 1.4 cm or greater can be treated with amiodarone. The first choice for hypertensive patients with LV hypertrophy <1.4 cm is flecainide, or propafenone, followed by amiodarone, dofetilide, or sotalol. If AF persists, these patients can be treated with disopyramide, procainamide, or quinidine.1
In 2009, the FDA approved dronedarone to reduce the risk of CV hospitalization in patients with paroxysmal or persistent AF or AFL, with a recent episode of AF/AFL and associated CV risk factors, who are in sinus rhythm or who will be cardioverted.2
Note: In 2009, the FDA approved dronedarone to reduce the risk of CV hospitalization in patients with paroxysmal or persistent AF or AFL, with a recent episode of AF/AFL and associated CV risk factors, who are in sinus rhythm or who will be cardioverted. Consensus regarding its place in the treatment paradigm is not yet available.
Flecainide
Propafenone
Sotalol
Amiodarone
Catheter
ablation
Amiodarone
Dofetilide
Catheter
ablation
Reproduced with permission from Fuster V, et al. Circulation. 2006;114(7):e257-e354.
Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114(7):e257-e354.
Multaq [package insert]. Bridgewater, NJ: sanofi-aventis; 2009.

47. The new ESC guidelines further differentiated stroke risk & added a bleeding risk stratification
CHADS2
CHA2DS2-VASc
HAS-BLED
Stroke Risk Factor
Score
Congestive Heart Failure 1
Hypertension
Age (> 75 years)
Diabetes
Prior Stroke / TIA 2
Max Score 6
Stroke Risk Factor
Score
Congestive Heart Failure / LV Dysfunction 1
Hypertension
Age (> 75 years) 2
Diabetes
Prior Stroke / TIA / thrombo-embolism
Vascular Disease1
Age 65-74
Sex Category (female)
Max Score 9
Bleeding Risk Factor
Score
Hypertension 1
Abnormal renal or liver function (1 pt. each)
1 or 2
Stroke
Bleeding
Labile INRs
Elderly (age > 65 years)
Drugs or alcohol (1pt. each)
Max Score 9
Note: 1) Prior myocardial infarction, peripheral artery disease, aortic plaque Source: ESC Guidelines for the Management of Atrial Fibrillation, European Heart Journal 2010

48. New approach to thromboprophylaxis

49. Targets for anticoagulant drugs
Intrinsic pathway
(surface contact)
Extrinsic pathway
(tissue damage)
XII
XIIa
Tissue factor XI
XIa IX
VII
IXa
VIIa
VIII
VIIIa
Heparin(s)
Vitamin K antagonists
KEY POINT: The efficacy/safety ratio for currently available therapies is less than satisfactory due to their ill-defined, multitargeted activity. New antithrombotic strategies are needed that offer an improved efficacy/safety profile compared with existing antithrombotic agents.1
Currently available antithrombotic agents include the heparins (UFH and LMWH), vitamin K antagonists (warfarin), and direct thrombin inhibitors (hirudins).2–5
The most widely used agents, heparins and vitamin K antagonists, have a range of actions on various components of the coagulation cascade. This contributes to the unpredictable clinical responses associated with these agents.2–4
Other limitations of currently available antithrombotics include 1–6
High incidence of serious adverse events, particularly bleeding complications
Routine monitoring of coagulation markers may be needed and represents a substantial burden in terms of time and costs
Narrow therapeutic margin
Limited effectiveness in preventing VTE
Factor Xa inhibitors are a novel class of antithrombotic agents designed to selectively target 1 core step in the coagulation cascade, leading to potent effectiveness.7 X Xa V Va
IIa
Direct thrombin inhibitors
Ximelagatran, Dabigatran II
IIa
(Thrombin)
Fibrinogen
Fibrin

50. Investigational Anticoagulant Targets
ORAL
PARENTERAL
TF/VIIa
TFPI (tifacogin)
TTP889 X IX
APC (drotrecogin alfa)
sTM (ART-123)
IXa
VIIIa
Rivaroxaban Apixaban LY YM150
DU-176b Betrixaban
TAK 42 Va AT Xa
Idraparinux
Source: Turpie State of the art presentation EFORT-08 (rivaroxaban, apixaban and dabigatran highlighted and all the others greyed out)
Reference
Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843–1853
All of the drugs in the above figure are to be found in Weitz and Bates (2005) in Figure 2, apart from:
Apixaban – this was called BMS in the original figure
Betrixaban and YM150 – see Graham Turpie’s review paper: Turpie AGG. New oral anticoagulants in atrial fibrillation. Eur Heart J 2008;29:155–165
Otamixaban – Guertin KR, Choi YM. The discovery of the Factor Xa inhibitor otamixaban: from lead identification to clinical development. Curr Med Chem 2007;14:2471–2481
II (thrombin)
DX-9065a Otamixaban
IIa
Dabigatran
APC activated protein C
AT antithrombin
sTM soluble thrombomodulin
TF tissue factor
FPI tissue factor pathway inhibitor
Fibrinogen
Fibrin
Adapted from Weitz JI. Thromb Haemost 2007; 5 Suppl 1:65-7. 50

51. Changes from the previous ACC/AHA/ESC 2006recommendations
2010 Guidelines for the Management of AF The Task Force for the Management of AF of the European Society of Cardiology (ESC)a
Changes from the previous ACC/AHA/ESC
2006recommendations
New guidance in the area of rate control
Advice on how to use the antiarrhythmic drug dronedarone
Formal indications for the use of ablation therapy
Recommendations on “upstream” therapies to prevent the deterioration of AF
Advice on certain “special situations”
In regard to rate control, the ESC guidelines introduced the notion that lenient rate control—that is, a resting heart rate of <110 bpm—is satisfactory and that the resting heart rate does not need to be <80 bpm. This recommendation has been made on the basis of the RACE-2 trial, reported earlier this year.
For rhythm control, the guidelines incorporate the new antiarrhythmic drug dronedarone, which was approved in the United States in 2009, into the recommendations. Catheter ablation also gains a stronger footing as a treatment for AF in the new European guidelines. The guidelines have give a formal indication for ablation therapy, which was implied but not formally recommended in the previous 2006 guidelines. “Potentially provocative” is the suggestion that patients may have an ablation without previous trials of antiarrhythmic drugs if they have paroxysmal AF, no prior heart disease, or are unwilling to take antiarrythmics.
The guidelines also give updated advice on so-called “upstream” therapy that may be prescribed in an attempt to prevent the deterioration of AF, covering the use of ACE inhibitors, angiotensin-receptor blockers ARBs, and statins. The task force also attempts to give advice on a number of “special situations.”
a Developed together with the European Heart Rhythm Association (EHRA) and endorsed by the European Association for Cardio-Thoracic Surgery (EACTS).
Camm AJ, et al. Eur Heart J. 2010;31:
Camm AJ, Kirchhof P, Lip GYH, et al. Guidelines for the management of atrial fibrillation. The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:

55. This slide shows the ESC recommendations for rate and rhythm control in AF.
Camm AJ, Kirchhof P, Lip GYH, et al. Guidelines for the management of atrial fibrillation. The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:

59. Thank you