Antithrombotic Therapy in Atrial Fibrillation

Transcription

1 Clin Geriatr Med 22 (2006) Antithrombotic Therapy in Atrial Fibrillation David A. Garcia, MD a, T, Elaine M. Hylek, MD, MPH b a Department of Internal Medicine, University of New Mexico, MSC , Albuquerque, NM 87131, USA b Department of Medicine, General Internal Medicine Research Unit, Boston University School of Medicine, 91 East Concord Street, Suite 200, Boston, MA 02118, USA Atrial fibrillation (AF) is a common dysrhythmia and its prevalence, especially among the elderly, is expected to increase significantly in the coming decades [1]. For men and women 40 years of age and older, the lifetime risk of developing AF is one in four [2]. Because disorganized electromechanical activity can lead to thrombosis within the left atrium, patients with AF at any age have a fivefold increased risk for stroke. An estimated 15% of all strokes occur in individuals with AF [3]. Cerebrovascular accidents related to AF have 25% 30-day mortality and are more likely to result in significant disability than are noncardioembolic strokes [4 6]. Warfarin has been shown to reduce the risk of stroke for patients with AF. Despite its proved efficacy, warfarin continues to be underused particularly among elderly patients who are at the highest risk of stroke. Weighing the benefits of anticoagulation against the risks is more difficult among patients 80 years of age and older because few octogenarians have been enrolled in clinical trials. Efficacy of warfarin During the late 1980s and early 1990s, five primary prevention trials and one secondary prevention study yielded consistent results supporting the hypothesis that warfarin can reduce the risk of stroke among patients with AF [7 12]. In a meta-analysis of these studies, Hart and colleagues [13] determined that, compared with placebo, anticoagulation with a vitamin K antagonist, such as T Corresponding author. address: davgarcia@salud.unm.edu (D.A. Garcia) /06/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi: /j.cger geriatric.theclinics.com

2 156 garcia & hylek warfarin, can effect a 62% reduction in the relative risk for stroke among patients with AF. A significant proportion of the strokes reported among the patients assigned to receive warfarin in these trials occurred among patients whose anticoagulation was subtherapeutic. Because trial results are derived from intentionto-treat analyses, it is likely that the relative risk reduction calculated by Hart and colleagues [13] underestimates the power of warfarin to protect AF patients from stroke. Safety of warfarin Pooled analysis of the primary stroke prevention trials demonstrates that the annual rate of major hemorrhage among AF patients treated with warfarin is 2.3% (annual rate of intracranial hemorrhage, 0.3%) [14]. Major hemorrhage was defined slightly differently in these trials and could be represented by a bleeding event that required a blood transfusion or an emergency procedure, led to admission, involved the central nervous system, or resulted in prominent residual impairment. Intracranial hemorrhage, because it produces sequelae that are often at least as devastating as ischemic stroke, may be a more important clinical end point. A meta-analysis of six randomized clinical trials indicates that compared with placebo, oral anticoagulation is associated with an absolute risk increase of 0.2% per year for intracranial hemorrhage [13]. This is consistent with the report from a large observational cohort study that the rate of intracranial hemorrhage (per 100 person-years) increased from 0.23 among patients not taking warfarin to 0.46 among patients who were taking warfarin [15]. These findings (ie, that 1 year of warfarin therapy produces an estimated one to two additional intracranial hemorrhages per 1000 patients) have strongly supported the hypothesis that, for most patients with AF, the benefits of warfarin substantially outweigh the risks. Translating the results of randomized trials into clinical practice Despite the proved benefit of warfarin and low rates of major hemorrhage, warfarin therapy remains underused in clinical practice [16 22]. The authors of a study assessing the quality of care received by Medicare beneficiaries during the period 1998 to 1999 reported that warfarin was prescribed at hospital discharge to only 42% to 65% of patients with documented AF [23]. There may be several reasons that high-quality evidence of the efficacy of warfarin has not produced more widespread clinical practice change; concerns have been raised about whether the findings of randomized controlled trials (that enrolled highly selected patients who were closely monitored) can be generalized. Indeed, the relatively low enrollment rate among patients screened for the landmark primary prevention studies raises concerns about the external validity of the results of such trials (Table 1). The paucity of elderly participants included in placebo-controlled studies of vitamin K antagonists (see Table 1) is also important because older age has

3 antithrombotic therapy in atrial fibrillation 157 Table 1 Randomized controlled trials evaluating primary stroke prevention in atrial fibrillation a Randomized / Study Design screened Age comment AFASAK warfarin versus ASA versus placebo 1007 / 2546 Median age = 74.2 BAATAF warfarin versus no warfarin NR 32 / 420 pts. N80 (ASA permitted) CAFA warfarin versus placebo NR Median age = 68 (warfarin), 67.4 (placebo) SPAF Group 1: warfarin versus ASA 1330 / / 1330 pts. N75 versus placebo Group 2: ASA versus placebo SPINAF Warfarin versus placebo 538 / / 538 pts. N75 SPORTIF III Warfarin versus ximelagatran 3410 / / 3410 pts. 75 (open-label) SPORTIF V Warfarin versus ximelagatran (double-blind) 3922 / / 3922 pts. 75 Abbreviations: ASA, acetylsalicylic acid; NR, not reported; pts, patients. a The five primary prevention studies (no shading) that established the efficacy and safety of warfarin and two recent noninferiority studies (shaded) comparing warfarin with ximelagatran are shown. repeatedly been shown to be an independent risk factor for major bleeding on warfarin [14,24 29]. Some reassurance is provided by the low rates of hemorrhagic stroke (0.1% and 0.4%, respectively) reported among the patients assigned to receive warfarin in two recently published large clinical trials designed to evaluate ximelagatran, Stroke Prevention using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF V and SPORTIF III) [30,31]. In SPORTIF V, 42% (N = 820) of patients randomized to warfarin were age 75 or greater and 33% (N = 565) were in this age range in SPORTIF III. It is important to note, however, that for SPORTIF V and III, 84% and 74% of patients, respectively, had been taking an oral vitamin K antagonist at the time of randomization. Thus most patients included in these trials were already proved to be at lower risk of hemorrhage. Like the randomized controlled trials, many observational studies of AF populations have included relatively few patients over the age of 80. A notable exception is the Anticoagulation and Risk Factors In Atrial Fibrillation study, an observational cohort study involving over 11,500 adults with nonvalvular AF. The mean age of enrolled patients was 71 years and 2211 patients taking warfarin were age 75 years or greater. Treatment with warfarin was associated with a 51% lower risk of thromboembolism compared with no warfarin therapy (either no antithrombotic therapy or aspirin) and the rate of intracranial hemorrhage was 0.46% [15]. Although reassuring, studies of prevalent warfarin use may underestimate the rate of major hemorrhage because the early phase of therapy, which is reported to convey the highest risk, is often not included. Observational studies are also subject to selection bias resulting from the physician s initial assessment of an individual s candidacy for long-term anticoagulation. More data are needed to elucidate better the risks and benefits of anticoagulation therapy among patients over age 80 in real-world practice.

4 158 garcia & hylek Antiplatelet agents Aspirin is an inexpensive, widely available, and relatively safe medication that has several advantages over warfarin: substantially less potential for drug-drug or drug-diet interactions, wider therapeutic index, and no need for coagulation monitoring. Although a meta-analysis of six randomized controlled trials suggests that aspirin therapy does reduce the risk for ischemic stroke among patients with AF, the protective effect associated with aspirin use is substantially less powerful than that observed with full-intensity warfarin therapy (pooled relative risk reductions compared with placebo are 22% and 62%, respectively) [13]. All six of the individual trials included in the meta-analysis demonstrated a trend favoring aspirin over placebo but only one of these studies (the SPAF study) [9] reported a statistically significant difference. It is noteworthy that in the SPAF study, 52% of the strokes were nondisabling. When only the 12 patients who suffered more severe stroke are considered, the difference between aspirin and placebo in the SPAF study is not statistically significant. Aspirin therapy probably does reduce the risk of stroke in patients with AF but the evidence to support this conclusion is weaker than the evidence for warfarin. Whether a thienopyridine derivative, such as clopidogrel (either added to or prescribed instead of aspirin), might reduce the risk of stroke for patients with AF is unknown. This class of medications inhibits platelet function by a mechanism different from that of aspirin, and the combination of clopidogrel with aspirin has been shown to be of significant benefit for patients with ischemic heart disease [32]. A large, randomized clinical trial (the ACTIVE study) designed to evaluate the role of clopidogrel for stroke prevention in AF is underway. Restoring sinus rhythm Several nonpharmacologic strategies to prevent stroke in AF patients have been proposed; a comprehensive discussion of these is beyond the scope of this article, but important results from trials that examined the use of a strategy to restore and maintain sinus rhythm in AF patients are worthy of mention. Cardioversion for AF patients has several theoretical benefits, including the possibility that if normal atrial electromechanical activity can be re-established, the risk of cardioembolism might be eliminated and antithrombotic therapy would be unnecessary. The strategy of rhythm-control has now been directly compared with rate-control in several randomized, clinical trials that enrolled AF patients at risk for stroke [33 37]. In a pooled analysis that included three of these trials, the frequency of ischemic stroke in patients assigned to rate-control versus the frequency among patients assigned to rhythm-control was comparable (3.5% versus 3.9%, respectively; odds ratio, 0.50; 95% confidence interval, ; P =.30) [38]. Based on these results, the hope that restoring sinus rhythm might obviate the need to anticoagulate AF patients has greatly diminished.

5 antithrombotic therapy in atrial fibrillation 159 Optimal target international normalized ratio range The currently recommended anticoagulation intensity for stroke prevention in AF is an international normalized ratio (INR) of 2 to 3 [39]. Numerous studies have documented an increased risk of bleeding with an INR of 4 or greater (Fig. 1) [5,40]. Compared with patients whose INR is N2, AF patients whose INR value is b2 are at increased risk to suffer a stroke; furthermore, the strokes Fig. 1. (A) Relationship of odds ratio for ischemic stroke versus International Normalized Ratio (INR) value at, or closest to, the time of the event. Reference value is INR of 2.0. Dashed line corresponds to an odds ratio of 1.0. All cases and control had atrial fibrillation and were treated with warfarin. (From Haylek EM, Skates SJ, Sheehan MA, et al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996;335:540 6; with permission.) (B) Relationship of odds ratio for intracranial hemorrhage versus prothrombin time ratio (PTR) value at, or closest to, the time of the event. In this display the PTR values for the data points are the median values for the following intervals: , , , , , and The reference interval is (PTR 1.4 median). All cases and controls were taking warfarin. INR equivalent can be roughly approximated as the square of the PTR value. (From Haylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994;120: ; with permission.)

6 160 garcia & hylek Fig. 2. Kaplan-Meier estimate of survival among nonvalvular AF patients during the 30 days after an ischemic stroke. The patient groups are separated according to medication status at the time of admission. INR, international normalized ratio. (From Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349: ; with permission. Copyright 2003 Massachusetts Medical Society. All rights reserved.) experienced by AF patients with INR values b2 are more likely to result in death or disability (Fig. 2) [5]. Stroke risk assessment for individual patients Several factors should be considered when determining whether a particular patient with AF should receive warfarin therapy to prevent stroke: their baseline risk for stroke, their risk of bleeding on warfarin therapy, the overall burden of their INR monitoring, and their personal preferences. A number of models and risk classification schemes are now available to assist clinicians in estimating an individual patient s annual risk of stroke [41 45]. Although these models were derived or validated in different populations, they have consistently identified important risk factors that, for patients with AF, are independently associated with an increased risk of stroke. Advancing age, prior stroke, hypertension, heart failure, diabetes, and female sex are examples of such risk factors. A useful resource for estimating an individual patient s risk of stroke was derived by Wang and coworkers from the Framingham Heart Study [45]. The tool is easy to use and can be found at stroke.htm. An adapted point-based risk estimate for the 5-year risk of stroke is reproduced in Fig. 3. Using this model, an 84-year-old woman with a history of diabetes and prior ischemic stroke has an estimated 5-year risk of stroke of 48%. In contrast, a 70-year-old man with well-controlled hypertension has a 5-year stroke risk closer to 7%.

7 antithrombotic therapy in atrial fibrillation 161 Age,y >93 Sex Men Women Step 2 Step 3 Systolic Blood Pressure, mm Hg < >179 Step 1 Step 4 Points Diabetes 0 No 1 Yes 2 3 Step Prior Stroke or TIA 6 No 7 Yes 8 9 Step 6 10 Points 0 6 Points Predicted 5-year Risk of Stroke Points Total Points 5- Year Risk, % Points 0 6 Add Up Points From Steps 1 Through 5 Look Up Predicted 5-Year Risk of Stroke in Table Fig. 3. This point-based scoring system approximates the predicted 5-year risk of stroke for an individual with nonvalvular AF. A more precise risk function is available at about/framingham/stroke.htm. TIA, transient ischemic attack. (From Wang TJ, Massaro JM, Levy D, et al. A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study. JAMA 2003;290: ; with permission.) Another recently published risk classification scheme, CHADS 2, estimates an AF patient s annual risk of stroke based on the presence or absence of five risk factors (Table 2) [42]. The external validity of the CHADS 2 scheme is good because the scoring system was derived from a cohort of 1733 Medicare patients with AF. Although the simplicity of the mnemonic makes it easy to remember, the CHADS 2 scoring system may provide less precise risk estimates than the Framingham Model because CHADS 2 treats age and blood pressure as dichotomous variables. Improving the safety margin of anticoagulant therapy in the elderly population Older age is associated with lower maintenance doses of warfarin. Large initiating doses of warfarin should be avoided in older patients. The warfarin dose schedule should be kept as consistent as possible to minimize dosing confusion. Clinicians should warn patients about (and remain vigilant for) medications known to interact with warfarin, especially amiodarone. A consistent amount of foods rich in vitamin K should be consumed because this may reduce

8 162 garcia & hylek Table 2 Risk of stroke in National Registry of Atrial Fibrillation participants, stratified by CHADS 2 Score a CHADS 2 score No. of patients (N = 1733) No. of strokes (N = 94) NRAF crude stroke rate per 100 patient-years NRAF adjusted stroke rate, (95% CI) b (1.2 3) (2 3.8) ( ) ( ) ( ) ( ) ( ) Abbreviations: CI, confidence interval; NRAF, National Registry of Atrial Fibrillation. a CHADS 2 score is calculated by adding 1 point for recent congestive heart failure, hypertension, age at least 75 years, or diabetes mellitus, and adding 2 points for having had a prior stroke or transient ischemic attack. b The adjusted stroke rate is the expected stroke per 100 patient-years from the exponential survival model, assuring that aspirin was not taken. 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. JAMA 2001;285: INR variability. Circumstantial evidence suggests that, for patients treated with warfarin who must take concomitant aspirin, doses 100 mg may have the most acceptable bleeding risk [46]. Anticoagulated patients who require analgesia should be counseled about the risks of combining certain pain-relieving medications with warfarin. Nonsteroidal anti-inflammatory medications, regardless of their selectivity for cyclooxygenase inhibition, seem to increase the risk of hemorrhage among warfarin users. This association is probably related to some combination of these drugs effects on both the gastric mucosa and platelet function [47,48]. In the case of acetaminophen, augmentation of warfarin s anticoagulant effect through interference with the enzymes of the vitamin K cycle has been reported [49,50]. Finally, it is important to warn patients about the risk of falling while taking warfarin; measures to optimize a patient s balance should be considered. Newer antithrombotic strategies Because warfarin has many negative attributes (narrow therapeutic window, drug-diet interactions, the need for INR monitoring), several clinical trials examining alternative pharmacologic agents have been undertaken in recent years. Ximelagatran, an oral anticoagulant (direct thrombin inhibitor) that does not require coagulation monitoring, has been compared with warfarin therapy (target INR range 2 3) for the prevention of stroke in patients with AF. Although no statistically significant difference in the rate of stroke or major bleeding was observed, ximelagatran is not currently available on the United States market because of other safety concerns that are being addressed (Food and Drug Administration decision letter released October 2004).

9 antithrombotic therapy in atrial fibrillation 163 Idraparinux, an injectable inhibitor of factor Xa, is another anticoagulant under study among patients with AF. Because it has a prolonged half-life, this agent needs to be administered only once per week. Because its bioavailability is highly predictable, it is believed that coagulation monitoring will be unnecessary in patients using idraparinux. A large phase III study Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients with Atrial Fibrillation (AMADEUS) comparing this drug with warfarin has recently been stopped. Finally, clopidogrel in combination with aspirin is being studied headto-head with warfarin Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) for the prevention of ischemic stroke in patients with AF. Nonpharmacologic approaches Other, nonpharmacologic strategies for protecting AF patients from stroke (eg, pulmonary vein isolation, occlusion or removal of the left atrial appendage, and deployment of a polytetrafluoroethylene membrane) are being studied and have been described elsewhere [51 55]. To the authors knowledge, there is no published high-quality evidence demonstrating that any of these approaches reduces the risk of stroke in an unselected population with AF. Summary Warfarin is highly effective at reducing the risk of stroke in AF. The benefit of oral anticoagulant therapy strongly outweighs the risk in most patients with AF. More data are needed to define better the overall risk-to-benefit ratio for patients age 80 years and greater. Because a significant proportion of elderly individuals may not be optimal candidates for anticoagulant therapy, clinicians must continue to evaluate alternative stroke prevention strategies while redoubling efforts to understand the mechanisms underlying AF and thrombogenesis. References [1] Go AS, Hylek EM, Phillips KA, et al. 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: [2] Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004;110: [3] Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22: [4] Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation: the Framingham Study. Stroke 1996;27: [5] Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:

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