Guidelines for Anticoagulation of Atrial Fibrillation: Is It Time for an Update?

for an Update?

A.L. W

Introduction

Atrial fibrillation is the most common arrhythmia in the Western world. In the United States, it currently affects about 2.4 million people, and by the year 2050 the number will be about 5.6 million [1]. Two principal clinical problems are associated with atrial fibrillation [2]. One is that if the ventric- ular response rate is not adequately controlled, patients may develop a tachy- cardia-mediated cardiomyopathy. The other problem is the risk of stroke.

Patients with atrial fibrillation have a five-fold increased risk of stroke com- pared to those in sinus rhythm [3]. And, as patients get older, the prevalence of atrial fibrillation increases, roughly doubling with each decade beginning with the seventh; so that 2–3% of people in their 60s, 5–6% of people in their 70s, and 8–10% of people in their 80s have atrial fibrillation [1, 3, 4].

Moreover, the population-attributable risk also increases with age, as almost one-third of patients in their 80s who present with a stroke have atrial fibril- lation [3]. There is also a 14.7–58% incidence of so-called silent strokes, i.e., strokes in which there are no manifestations of motor or sensory deficit, in patients with atrial fibrillation who are at risk for stroke but untreated with warfarin [5–8]. Such strokes are associated w ith senile dementia or Alzheimer’s disease. Clearly, prevention of stroke in patients with atrial fib- rillation is a key management goal.

Currently, the principal method of preventing strokes in patients with atrial fibrillation at risk of stroke is the use of oral anticoagulants, i.e., vita- min K antagonists. Over the years, guidelines have been proposed to guide physicians in the use of oral anticoagulants for the treatment of atrial fibril-

Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH, USA

lation. This chapter will deal with the recommendations of the two main sets of guidelines for the use of oral anticoagulation to prevent stroke in patients with atrial fibrillation, and will offer suggestions regarding some of the guidelines’ recommendations which need updating. The two main sets of guidelines are those of the American College of Chest Physicians (ACCP), published in October of 2004 [9]; and the American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC) guidelines, published in September of 2001 [10] and cur- rently undergoing revision. These guidelines are generally quite compatible with each other, but there are some significant differences. Moreover, there are some sections of the guidelines which should be considered for an update.

Comparisons of the ACCP And ACC/AHA/ESC Guidelines

Both sets of guidelines generally indicate that if patients have risk factors for stroke [9, 10] (prior ischaemic stroke, transient ischaemic attack, or systemic embolism; age above 75 years; moderately or severely impaired left ventricu- lar systolic function and/or congestive heart failure; history of hypertension;

or diabetes mellitus), anticoagulation with an oral vitamin K antagonist, such as warfarin, is recommended. There is virtually universal acceptance of such recommendations. However, the ACC/AHA/ESC guidelines differ from the ACCP guidelines in several respects. First, the ACC/AHA/ESC guidelines use the age of 60 years as a cut-off for some considerations, whereas the ACCP uses the age of 65 years as a cut-off. If one is under the age of 60 years and has no heart disease, the ACC/AHA/ESC guidelines recommend aspirin (325 mg/day) or no therapy, and if one is under age 60 years of age with heart disease but no risk factors for stroke, they recommend aspirin (325 mg/day). The ACCP uses the same recommendation, but for age less than 65 years. It is not clear why the ACC/AHA/ESC guidelines chose age 60 as the cut-off, as the data regarding age per se as a risk factor for stroke start at age 65 [11].

Then, from age 60 to 75 years and with no risk factors, the ACC/AHA/ESC

recommend aspirin (325 mg/day), but for the same age group when diabetes

or coronar y ar ter y disease is present they recommend warfar in

(International Normalised Ratio [INR] 2–3) with additional aspirin (81–162

mg) optional . It is clear that age is one of the risk factors for stroke. The new

ACCP guidelines state that in patients with persistent atrial fibrillation or

paroxysmal atrial fibrillation, aged 65–75 years, and with no other risk fac-

tors, they recommend anti-thrombotic therapy with either an oral vitamin K

antagonist or aspirin (325 mg/day) in this group of patients who are at

intermediate risk of stroke. We suggest that because the data indicate that beginning at age 65 there is 1.4 relative risk for stroke, and that this increases by 1.4 per decade, aspirin only may not be an appropriate recommendation for patients between 65–74 years of age without other risk factors for stroke.

Over age 75, both guidelines agree that age per se is enough reason to recom- mend a vitamin K antagonist.

Is Aspirin Ever Sufficiently Effective as Prophylaxis Against Stroke in the Presence of Any Risk Factors?

This gets us to the question of whether aspirin is really ever sufficiently effi-

cacious to use it in patients who are at any significant risk of stroke. As indi-

cated in the most recent ACCP report [10], the evidence supporting the effi-

cacy of aspirin is substantially weaker than the evidence supporting the effi-

cacy of warfarin. Among the several studies that have compared aspirin with

warfarin, it is clear that warfarin is far superior to aspirin in diminishing the

risk of stroke [10, 12]. Moreover, of the several studies that have compared

aspirin with placebo, only the Stroke Prevention in Atrial Fibrillation (SPAF)

I trial demonstrated a relative risk reduction in stroke with aspirin [13]. Not

only is that study an outlier, driving the meta-analysis of the several trials

comparing aspirin with placebo, but also the data from the SPAF I trial

demonstrate an internal inconsistency between patients in group I (patients

eligible for warfarin) and patients in group II (patients with a relative or

absolute contraindication to warfarin), both of which compared aspirin with

placebo (Fig. 1). The analysis of these data throws yet more doubt on the

efficacy of aspirin as an effective treatment for prevention of stroke in

patients with atrial fibrillation [14]. For the most part, this is reflected in the

guidelines regarding the type of anticoagulation therapy that is recommend-

ed for patients with atrial fibrillation who are at risk of stroke. Additionally,

not only do we know that aspirin is a poor second best to warfarin in pre-

venting stroke in patients with atrial fibrillation at risk of stroke, but also,

should a stroke occur on aspirin, it is usually more severe, and is associated

with significantly higher in-hospital mortality and 30-day mortality com-

pared with warfarin therapy that maintains an INR in the therapeutic range

[15]. In short, the data clearly indicate that aspirin not only is insufficiently

effective in preventing stroke compared with warfarin, but also, should a

stroke occur, the consequences are likely to be far more severe. Thus, the rec-

ommendations for the use of aspirin really need to be reconsidered or at

least more seriously tested. A reasonable interpretation of the aspirin data is

that they are consistent with the notion that, if one needs protection against

stroke in the presence of atrial fibrillation, one needs a vitamin K antagonist.

The question of whether a combination of aspirin and clopidogrel – two antiplatelet agents – will be effective as prophylaxis against stroke in patients with atrial fibrillation remains to be demonstrated. We await the results of the ACTIVE trials to give us clinical trial data in this regard.

Concerns About Intracerebral Bleeding Risk in Patients Taking Vitamin K Antagonists

The appropriate level of warfarin anticoagulation in elderly patients with atrial fibrillation has been debated because of an age-associated increase in intracerebral haemorrhage. The ACC/AHA/ESC guidelines, but not the ACCP guidelines, have suggested that if one is concerned about the risk of bleeding in patients over the age of 75 who have had no prior stroke, one can lower the target INR to 2.0 with a ‘therapeutic range’ of 1.6–2.5. It is unclear on

Aspirin Eligible AF Patients

Warfarin Aspirin (n=206) 1 event

Anticoagulation Eligible Group I

Anticoagulation Ineligible Group II

Placebo (n=211) 18 events

Aspirin (n=346) 25 events

Group II

Placebo (n=357) 26 events Group I

Risk reduction 94%

p < 0.001

Risk reduction 8%

p = 0.75 SPAF I Analysis

Risk reduction 42%

p = 0.02

Fig. 1. Aspirin-eligible patients with atrial fibrillation: outcome of patients randomised to

receive aspirin vs placebo in group I of the SPAF I trial. In group I, there was only one event

(stroke) in patients receiving aspirin vs 18 events in the placebo group. This was a statis-

tically highly significant difference. However, in group II, there were 25 events in patients

receiving aspirin vs 26 events in patients receiving placebo. This difference was not sta-

tistically significant. Thus, there was internal inconsistency.When the data from both groups

were combined, the data were significant, but this was driven by what appears to be the

outlier data from group I. See text for discussion (modified from [14])

what data that recommendation is based. It seems to have been based on a concern that there is an increased risk for intracranial haemorrhage in the elderly.

Although the relative risk of ischaemic stroke increases by 1.4 per decade beginning at the age of 65 years, so does the relative risk of intracranial bleeding while taking warfarin [16]. This seems to have led to the above rec- ommendation for the primary prevention of ischaemic stroke and systemic embolism in patients older than 75 years who are considered at increased risk of bleeding complications, but have no frank contraindications to oral anticoagulant therapy (a class II recommendation). However, it is important to emphasise that because the base rate of ischaemic stroke is considerably greater than the risk of intracranial bleeding, the risk of ischaemic stroke in the absence of warfarin therapy is considerably greater that the risk of intracranial bleeding while receiving warfarin [16]. An additional perspec- tive is that, although there is no increased therapeutic benefit associated with an INR greater than 3, an increased risk of bleeding does not occur until the INR reaches 3.9–4.0 [15, 16]. The most recent study [17] demon- strated that although intracerebral haemorrhage was associated with increasing age (especially > 85 years) and increasing INR (especially > 3.5), the incidence of intracerebral haemorrhage was not statistically different in patients with INRs below 2 and those with INRs between 2 and 3. This was true even among those older than 75 years of age. Thus, the risk of intracere- bral haemorrhage is not diminished in elderly patients with atrial fibrillation when anticoagulation is maintained with an INR below 2.0. Therefore, there really seems no basis to support the idea that a target of 2.0 with a range of 1.6–2.5 of the INR is desirable in this patient age group.

Optimal Management of Interruption of Oral Anticoagulation

At present, there is a consensus that one can interrupt oral anticoagulation

for 5–7 days if need be (e.g., for major or minor surgery) in patients with

atrial fibrillation at risk of stroke. It is recognised that there is a small risk,

but since the risk of stroke has been calculated on a yearly basis, it is thought

that the risk of stroke with cessation of oral anticoagulation for 1 week is

acceptable. But one wonders, particularly in the era of the ready accessibility

and effectiveness of low-molecular-weight heparins, whether one should

simply terminate warfarin treatment without providing a bridge during ces-

sation of warfarin therapy to cessation by giving low-molecular-weight

heparin until all anticoagulation must stop (e.g., for surgery), and a bridge to

reinitiation of warfarin therapy by giving low-molecular-weight heparins

after the need to withhold warfarin therapy is past.

Cessation of Oral Anticoagulation After Apparent Complete Suppression of Atrial Fibrillation with Drug Therapy or Cure with Radiofrequency Ablation or a Maze Surgical Procedure

One of the putative advantages of pursuing a rhythm control strategy (i.e., attempting to maintain sinus rhythm) in patients with atrial fibrillation at risk of stroke is that, with the absence of atrial fibrillation, the cause of clot formation in the left atrium is eliminated. For this reason, it has been a clini- cal assumption that there is no longer any need for oral anticoagulation with warfarin. Several factors have clearly affected this assumption. First are the data from the Atrial Fibrillation Follow-up Investigation of Rhy thm Management (AFFIRM) trial examining the relationship of ischaemic stroke to INR and the presence of atrial fibrillation [18]. It is noteworthy that there was no significant difference in the incidence of stroke in the rate control versus the rhythm control arms. However, of the strokes that occurred in the rhythm control arm, 57% occurred in patients not taking warfarin, and 22%

occurred in patients whose INR was less than 2. It is probable that these data are in part explained by a significant incidence of so-called silent or asymp- tomatic atrial fibrillation [19–22]. There is now a large body of evidence indicating a significant incidence of asymptomatic atrial fibrillation in patients with a history of atrial fibrillation who were thought to be in sinus rhythm. For instance, in a recent study in patients with a history of atrial fib- rillation in whom atrial fibrillation recurred, in more than one-third (38%) the atrial fibrillation was both asymptomatic and of greater than 48 h dura- tion [22]. Moreover, 16% of the patients developed asymptomatic atrial fib- rillation of greater than 48 h duration, even after documented freedom from atrial fibrillation for 3 months. Data such as those from the AFFIRM trial and from the several trials demonstrating asymptomatic atrial fibrillation have led to the widely accepted conclusion that patients with atrial fibrilla- tion and risk factors for stroke should receive anticoagulation indefinitely, even when sinus rhythm appears to be restored and maintained [18]. The point is that success rates of maintaining continuous sinus rhythm in patients with a history of atrial fibrillation are often grossly overestimated, with potentially serious consequences for the patient.

So the question then extends to patients who are ostensibly cured of atri-

al fibrillation with radiofrequency catheter ablation or a surgical maze pro-

cedure. Can we ever stop anticoagulation in those patients? At present, the

patient follow-up is probably not long enough to make definitive declara-

tions about the incidence of late recurrence of atrial fibrillation in these

patients. The survey data recently published [23] indicate a late recurrence

rate in patients months after undergoing radiofrequency catheter ablation. It

is not clear whether those data are applicable to results from using current

ablation techniques. Nor is the incidence of recurrence clear. However, a community standard seems to be developing in which many patients who are thought to be cured of atrial fibrillation are being advised to terminate oral anticoagulation therapy 3–6 months following apparent successful cure.

Whether this turns out to be good medicine or not is yet to be determined.

There are no good data relating to surgical ablation of which we are aware. A consensus regarding these issues ought to be updated in the guidelines. The most conservative approach for now would seem to be that there are no data yet available to support the safe cessation of oral anticoagulation in these patients.

Conclusions

Several areas regarding use of oral anticoagulation have been identified which are in need of updating or reconsideration. Recommendations are always best when data-driven. For some of these areas, the data are lacking, weak, or controversial. For others, the data seem clear. Because these several areas are important, we hope they will gain the attention they deserve from the ACC/AHA/ESC and ACCP guideline committees.

References

1. Go AS, Hylek EM, Phillips KA et al for the AnTicoagulation and Risk factors In Atrial Fibrillation (ATRIA) Study (2001) Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention.

JAMA 285:2370–2375

2. Waldo AL (2003) Stroke prevention in atrial fibrillation. JAMA 209:1093–1095 3. Wolf PA, Abbott RD, Kannel WB (1987) Atrial fibrillation: a major contributor to

stroke in the elderly. The Framingham Study. Arch Intern Med 147:1561–1564 4. Feinberg WM, Blackshear JL, Laupacis A et al (1995) Prevalence, age distribution,

and gender of patients with atrial fibrillation: analysis and implications. Arch Intern Med 155:469–473

5. Petersen P, Madsen EB, Brun B et al (1987) Silent cerebral infarction in chronic atrial fibrillation. Stroke 18:1098–1100 (abs)

6. Guidotti M, Tadeo G, Zanasi S et al (1990) Silent cerebral ischemia in patients with chronic atrial fibrillation: a case-control study. Irish J Med Sci 159:96–97

7. Feinberg WM, Seeger JF, Carmody RF et al (1990) Epidemiologic features of asymptomatic cerebral infarction in patients with nonvalvular atrial fibrillation.

Arch Intern Med 150:2340–2344 (abs)

8. Ezekowitz MD, James KE, Nazarian SM et al for the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators (1995) Silent cerebral infarction in patients w ith nonrheumatic atrial fibrillation. Circulation 92:2178–2182

9. Singer DE, Albers GW, Dalen JE et al (2004) Antithrombotic therapy in atrial fibril-

lation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126:429S–456S

10. Fuster V, Ryden LE, Asinger RW et al (2002) ACC/AHA/ESC 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 and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation): developed in collaboration with the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol 38:1231–1266

11. Ezekowitz MD, Levine JA (1999) Preventing stroke in patients with atrial fibrilla- tion. JAMA 281:1830–1835

12. van Walraven C, Hart RG, Singer DE et al (2002) Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. JAMA 288:2441–2448

13. Hart RG, Benavente O, McBride R, Pearce LA (1999) Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 131:492–501

14. Anonymous (1993) A differential effect of aspirin in prevention of stroke on atrial fibrillation. Stroke Prevention in Atrial Fibrillation Investigators. J Stroke Cerebrovasc Dis 3:181–188

15. Hylek EM, Go AS, Chang Y et al (2003) Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 349:1019–1026 16. Hylek EM, Singer DE (1994) Risk factors for intracranial hemorrhage in outpa-

tients taking warfarin. Ann Intern Med 120:897–902

17. Fang MC, Chang Y, Hylek EM et al (2004) Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 141:745–752

18. Wyse DG, Waldo AL, DiMarco JP et al (2002) A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 34:1825–1833

19. Bhandari AK, Anderson JL, Gilbert M et al; Flecainide Supraventricular Tachycardia Study Group (1992) Correlation of symptoms with occurrence of paroxysmal supraventricular tachycardia or atrial fibrillation: a transtelephonic monitoring study. Am Heart J 124:381–386

20. Page RL, Wilkerson WE, Clark WK et al (1994) Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supra- ventricular tachycardia. Circulation 89:224–227

21. Savelieva I, Camm AJ (2000) Clinical relevance of silent atrial fibrillation: prevalen- ce, prognosis, quality of life, and management. J Intervent Cardiac Electrophysiol 4:369–382

22. Israel C, Ehrlich JR, Gronefeld G et al (2004) Long-term risk of recurrent atrial fibrillation as documented by an implantable monitoring device: implications for optional patient care. J Am Coll Cardiol 43:47–52

23. Cappato R, Calkins H, Chen SA et al (2005) Worldwide survey on the methods, effi-

cacy and safety of catheter ablation for human atrial fibrillation. Circulation

111:1100–1105