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Atrial Fibrillation

Atrial fibrillation (AF) is one of the most common arrhythmias and predisposes patients to devastating thromboembolic complications. At least 2.3 million adults in the US have AF.  It is more prevalent in older individuals and the  morbidity and mortality from the complications of AF increases with age.  Over the past two decades, the incidence rate has climbed by 13% per year; by the year 2050, it is estimated that 12-16 million individuals in the US will be affected by AF.  The advancing age of the population and increased prevalence of diabetes are two major factors contributing to this expected rise.1
 
AF risk factors include genetic predisposition, environment, and lifestyle (Table 1). 2,3 Disease prevalence is greater with advancing age and among men (Figure 1).2  However, women suffer stroke from AF more often than men.
 
Table 1:  Atrial Fibrillation Risk Factors 2

    •    Thyroid disease
    •    Valvular heart disease
    •    Pulmonary embolism and pulmonary hypertension
    •    Congenital heart disease
    •    Cardiomyopathy
    •    Heart surgery
    •    Chronic lung disease (chronic obstructive pulmonary disease, asthma)
    •    Obesity
    •    Diabetes
    •    Medications
    •    Sleep apnea
    •    Excessive alcohol consumption or alcohol withdrawal
    •    Cigarette or stimulant use (such as caffeine)
    •    Periods of extreme stress, fatigue, or acute medical illness
 
Figure 1: Atrial Fibrillation Prevalence: Age and Gender 

AF-figure 1
AF is characterized by an irregular and often rapid heart rate (often ranging from 130 to 200 beat/min compared with the normal 60-80 beats/min). In addition to the rapid heart rate, AF results in a  loss of organized atrial contraction which can diminish cardiac output by approximately 20% and may cause fatigue.  Loss of organized atrial activity, in turn, results in stasis and formation of blood clots within the left atrium.  The potential for systemic thromboembolism from the heart into the cerebral arteries enhances the risk of ischemic stroke.  The risk of stroke secondary to AF averages 15% and increases with age, rising to about 20% to 25%  in patients between the ages of 80-89 years.
 
The majority of AF patients suffer from one or more of the following common symptoms including:
    •    Irregular and/or rapid heartbeat
    •    Chest discomfort or pain
    •    Heart palpitations (irregular or fast heart rate)
    •    Dizziness
    •    Sweating
    •    Shortness of breath
    •    Anxiety
    •    Exercise intolerance/fatigue
    •    Fainting
 
Complications of AF include death, stroke, visceral or peripheral artery embolism, decreased quality of life and exercise capacity, and heart failure.5, 3 AF doubles the mortality rate compared to an age and gender matched population, and mortality is 9 times higher during the first 4 months after diagnosis.3
 
Part of the therapeutic strategy for treating AF patients include pharmacological and non-pharmacological interventions to control rate and rhythm.  Pharmacologic interventions include the use of antiarrhythmic agents to restore the atria to sinus rhythm as well as the use of beta-blockers, calcium channel blockers, or digitalis to control the ventricular rate.  Electrical cardioversion and radiofrequency catheter ablation are non-pharmacological approaches to restoring normal sinus rhythm. Atrioventricular nodal ablation with pacemaker placement or implantation of an atrial defibrillator are invasive therapeutic approaches.3
 
Irrespective of the approach to controlling heart rate and rhythm, AF remains a risk factor for thromboembolic disease, in particular stroke, and anticoagulant therapy is strongly recommended for most patients.6
 

Atrial Fibrillation and Stroke Prevention

About 15% of strokes are caused by emboli due to atrial fibrillation.  Most of these embolic strokes are preventable if adequate anticoagulation is utilized.6
 
Table 2: Summary of Annual Event Rates for Strokes from ATHENA Trial (n= 2327) 7

Rate

Total strokes

3%

Stroke-related hospitalizations

2%

Ischemic stroke

2%

Hemorrhagic stroke

0%

Other stroke

0%

Fatal stroke

1%

Stroke or TIA

4%

Stroke, ACS or CV death

9%

Stroke, ACS, or death

11%


Studies have demonstrated that anticoagulant therapy such as with warfarin reduces the risk of stroke in AF patients approximately 65% (Table 3).Treatment with antiplatelet agents such as aspirin are less effective. The decision to recommend anticoagulation for a patient with AF is dependent on the patient’s underlying risk of stroke as determined by the CHADS2 and CHA2DS2-VASc scores (Table 4).

Table 3: Reduction of Ischemic Stroke in AF Patients Treated with Warfarin 8

INR

Person-yr*

Stoke
(95% CI)
(N=152)

 

Rate/100 person-yr

Person-yr*

Intracranial Hemorrhage
(95% CI)
(N=58)

Rate/100 person-yr

<1.5

556

7.7 (5.7-10.4)

561

0.5 (0.2-1.7)

1.5-1.9

2847

1.9 (1.4-2.4)

2867

0.3 (0.1-0.6)

2.0-2.5

5357

0.4 (0.3-0.7)

5400

0.3 (0.2-0.4)

2.6-3.0

2388

0.9 (0.6-1.4)

2409

0.5 (0.3-0.9)

3.1-3.5

834

0.7 (0.3-1.6)

843

0.6 (0.3-1.4)

3.6-3.9

243

0.4 (.01-2.9)

247

0.4 (0.1-2.9)

4.0-4.5

144

1.4 (0.4-5.5)

147

2.7 (1.0-7.3)

>4.5

115

2.6 (0.8-8.1)

118

9.4 (5.2-16.9


* Difference in the numbers of person-years between stroke and intracranial hemorrhage reflects differences in the time at which data were censored.

A risk factor-based approach for patients with nonvalvular AF can be expressed as an acronym, CHA2DS2-VASc.  This scheme is based on a point system in which 2 points are assigned for a history of stroke or TIA, or age ≥75; and 1 point each is assigned for age 65 to 74 years, a history of hypertension, diabetes, recent cardiac failure, vascular disease (myocardial infarction, complex aortic plaque, and PAD, including prior revascularization, amputation due to PAD, or angiographic evidence of PAD, etc), and female sex. Thus, this acronym extends the original CHADS2 scheme by considering additional stroke risk factors that may influence a decision whether or not to anticoagulate.
 
Table 4: CHADS2 and CHA2DS2-VASc Risk Scoring Systems for Assessing Stroke Risk in AF Patients 9,10
 

 

Risk Factor

Points

 C 

Congestive heart failure

1

 H

Hypertension: blood pressure consistently above 140/90 mmHg (or treated hypertension on medication)

1

 A

Age >75 years

1

 D

Diabetes Mellitus

1

 S2

Prior Stroke or TIA

2

Maximum Score

6

 

Risk Factor

Points

 C 

Congestive heart failure/ LV dysfunction

1

 H

Hypertension: blood pressure consistently above 140/90 mmHg (or treated hypertension on medication)

1

 A2

Age >75 years

2

 D

Diabetes Mellitus

1

 S2

Prior Stroke/TIA/Embolism

2

V

Vascular disease

1

A

Age 65-74

1

Sc

Sex category (Female)

1

Maximum Score

9

CHA2DS2-VASc Score

Stroke (% / yr)

1

0%

2

1.3%

3

2.2%

4

4.0%

5

6.7%

6

9.8%

7

9.6%

8

6.7%

9

15.2%


The European Society of Cardiology (ESC) has developed and published guidelines for stroke prevention using antiplatelet and anticoagulant therapy based on the patient’s CHA2DS2-VASc scores, delineated in Table 5.3  To maximize the effectiveness of warfarin and minimize the risk of hemorrhagic stroke, a target INR range of 2.0-3.0 is recommended.
 
Table 5: ESC 2012 AF Guidelines for the Use of Antiplatelet and Anticoagulant Therapies for the Prevention of Stroke in AF Patients 10

Risk Profile

Class/Level

CHA2DS2-VASc = 0

No antithrombotic therapy

IB

CHA2DS2-VASc = 1

VKA (INR 2-3)

OR

dabigatran/rivaroxaban/apixaban

IIa A (favored)

CHA2DS2-VASc ³ 2

VKA (INR 2-3)

OR

dabigatran/rivaroxaban/apixaban

I A (favored)

When prescribing an anticoagulant to prevent ischemic stroke, it is important to consider the risk of bleeding. Using a ‘real-world’ cohort of 3978 European patients with AF from the EuroHeart Survey, a new simple bleeding risk score, HAS-BLED, has been derived (Table 6). In individuals with a high HAS-BLED score (>3) careful review of the patient's risk factors and medications should be performed to help minimize the risk of bleeding with anticoagulant therapy. In most patients, the risk of ischemic stroke is greater than the risk of serious bleeding so a high HAS-BLED score should generally not be used to withhold anticoagulation.


Table 6: HAS-BLED Scoring System for the Assessment of Bleeding Risk in Patients with Atrial Fibrillation10 11

 

Clinical Characteristic

Points

H

Hypertension

1

A

Abnormal liver or renal function

1 or 2

S

Stroke

1

B

Bleeding

1

L

Labile INR

1

E

Elderly (age > 65)

1

D

Drugs or alcohol

1 or 2

 

Maximum Score

9


 Table6
The challenges of maintaining patients on warfarin within the narrow therapeutic INR range are significant.  As a result, a number of pharmaceutical companies have developed or are in the process of developing and testing the effectiveness and safety of several novel oral anticoagulants, also known as direct oral anticoagulants (DOACs).  These novel oral anticoagulantsfall into one of two classes: anti-Xa or direct thrombin inhibitors. 

Several of these agents are available for clinical use and have been proven to be as effective, or more efffective, than warfarin in preventing stroke and much safer with respect to serious and life-threatening bleeding. Questions remain as to how clinicians will use these drugs and what kind of impact their introduction to the marketplace will have in overcoming the reluctance of physicians and patients to use anticoagulation for stroke prevention.


Gaps and Barriers to Optimal Care

Underutilization of anticoagulant therapy for AF patients is widely reported, despite published guidelines recommending anticoagulation for stroke prevention.6  40% of AF patients at high risk for stroke are not being anticoagulated, even though they should be. Among patients who are anticoagulated with warfarin, only 60% are effectively managed with the INR within the recommended range of 2.0 to 3.0.  Even when properly prescribed, patients with AF may not adhere to their anticoagulation regimen.
 
Embolic strokes from AF are more devastating than ischemic strokes. A review of 2,135 patients registered in the Canadian Stroke Network demonstrates that 28% of patients who suffered their first ischemic stroke had been diagnosed with atrial fibrillation. 20% of the strokes in AF patients were fatal and another 60% were disabling.16  Underutilization of warfarin is particularly prevalent among elderly patients due to fear of excessive bleeding, especially when the patient has an increased risk of falling.  Additional barriers to warfarin use include:

    •    Delayed onset/offset
    •    Unpredictable dose response
    •    Narrow therapeutic index
    •    Drug-drug, drug-food interactions
    •    Problematic and inconvenient monitoring
    •    Perceived bleeding risk
    •    Genetic variation in metabolism
 
INR testing, as an obstacle to anticoagulation, has been addressed through the introduction of patient self-monitoring (point-of-care testing, POC).  However, POC is not feasible for all warfarin-treated patients, and low CMS reimbursement rates have contributed to its limited utilization.
 
Since 2010, apixaban, dabigatran, edoxaban, and rivaroxaban have been approved for stroke prevention in patients with atrial fibrillation.
 
Table 6:  Comparison of the pharmacological features of dabigatran, rivaroxaban, and apixaban17

Feature

Dabigatran

Rivaroxaban

Apixaban

Edoxaban

Target

Thrombin

Factor Xa

Factor Xa

Factor Xa

Pro-drug

Yes

No

No

No

Dosing

Fixed, twice daily

Fixed, once daily

Fixed, twice daily

Fixed, once daily

Bioavailability (%)

7

80

66

>45

Transporters

P-gp

P-gp/BCRP

P-gp

P-gp

Protein binding (%)

35

>90

87

55

Coagulation Monitoring

No

No

No

No

Half-life (h)

12-14

5-13

8-15

8-10

Clearance mechanism

Renal

Renal

Hepatic

Hepatic and Fecal

Renal clearance (%)

80

66*

25

35

Linear PK

Yes

No

Yes

Yes

Interactions

P-gp Inhibitors**

Combined P-gp and CYP3A4 Inhibitors***

Potent CYP3A4 Inhibitors***

Combined P-gp and CYP3A4 Inhibitors***

Trial

RELY18

ARISTOTLE19

AVERROES20

ROCKET-AF21

ENGAGE AF-TIMI 48

Status

Approved

Approved

Approved

Approved****


* Half of the 66% is excreted unchanged in the urine.
** P-glycoprotein (P-gp) inhibitors include: verapamil, clarithromycin, and quinidine. Quinidine is contraindicated in patients receiving dabigatrin etexilate.
*** Cytochrome P450 (CYP) 3A4 inhibitors include: ketoconazole, macrolide antibiotics (e.g., clarithromycin), and protease inhibitors (e.g., atanazavir).
**** Not recommended in patients with CrCL >95 mL/min

The introduction and potential addition of these new drugs to the arsenal of anticoagulant therapies raise new questions for clinicians and insurance providers:

    •    Do these drugs represent a significant improvement for patients who have been taking warfarin with consistently therapeutic INR values for months/years?
    •    What is the optimum approach to transitioning between anticoagulant therapies?
    •    What will be the impact of missed doses?
    •    Will adverse side effects lead to non-compliance or discontinuation?
    •    Will the elimination of regular INR measurement reduce or improve medication adherence?
    •    How will patients react to the lack of data providing reassurance that they are within range?
    •    What is the consequence of a lack of a reversal agent?
    •    How should drug dosing be modified for patients with significantly impaired renal or hepatic function?
    •    How does a clinician prepare a patient for elective surgery?
    •    How will the cost of novel agents compare to warfarin costs (including INR monitoring, dose adjustments, etc.)?
    •    Will there be an overall savings in health costs based on improved patient outcomes?

 
References

1. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, Seward JB, Tsang TS. Secular trends in incidence of atrial fibrillation in olmsted county, minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114:119-125

2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The framingham study. Stroke. 1991;22:983-988

3. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S. Acc/aha/esc 2006 guidelines for the management of patients with atrial fibrillation-executive summary: 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). Eur Heart J. 2006;27:1979-2030

4. Waktare JE. Cardiology patient page. Atrial fibrillation. Circulation. 2002;106:14-16

5. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention: The anticoagulation and risk factors in atrial fibrillation (atria) study. Jama. 2001;285:2370-2375

6. Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL, Lip GY, Manning WJ. Antithrombotic therapy in atrial fibrillation: American college of chest physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133:546S-592S

7. Connolly SJ, Crijns HJ, Torp-Pedersen C, van Eickels M, Gaudin C, Page RL, Hohnloser SH. Analysis of stroke in athena: A placebo-controlled, double-blind, parallel-arm trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter. Circulation. 2009;120:1174-1180

8. Benjamin EJ, Wolf PA, D'Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: The framingham heart study. Circulation. 1998;98:946-952

9. Gage BF, van Walraven C, Pearce L, Hart RG, Koudstaal PJ, Boode BS, Petersen P. Selecting patients with atrial fibrillation for anticoagulation: Stroke risk stratification in patients taking aspirin. Circulation. 2004;110:2287-2292

10. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. 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;31:2369-2429

11. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (has-bled) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The euro heart survey. Chest. 2010;138:1093-1100

12. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O'Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364:806-817

13. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151

14. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992

15. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891

16. Gladstone DJ, Bui E, Fang J, Laupacis A, Lindsay MP, Tu JV, Silver FL, Kapral MK. Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke. 2009;40:235-240

17. Lopes RD, Piccini JP, Hylek EM, Granger CB, Alexander JH. Antithrombotic therapy in atrial fibrillation: Guidelines translated for the clinician. J Thromb Thrombolysis. 2008;26:167-174

18. Eriksson BI, Dahl OE, Buller HR, Hettiarachchi R, Rosencher N, Bravo ML, Ahnfelt L, Piovella F, Stangier J, Kalebo P, Reilly P. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: The bistro ii randomized trial. J Thromb Haemost. 2005;3:103-111

19. Kubitza D, Haas S. Novel factor xa inhibitors for prevention and treatment of thromboembolic diseases. Expert Opin Investig Drugs. 2006;15:843-855

20. Lassen MR, Davidson BL, Gallus A, Pineo G, Ansell J, Deitchman D. The efficacy and safety of apixaban, an oral, direct factor xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost. 2007;5:2368-2375

21. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: Clinical outcomes in the international cooperative pulmonary embolism registry (icoper). Lancet. 1999;353:1386-1389

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