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Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2012. | This topic last updated: Jan 6, 2012.

INTRODUCTION — Embolization of atrial thrombi can occur with any form (ie, paroxysmal, persistent, or permanent) of atrial fibrillation (AF) (see "Paroxysmal atrial fibrillation"). Ischemic stroke is the most frequent clinical manifestation of embolization associated with AF. It can occur at any point during the clinical course of AF (see "Stroke in patients with atrial fibrillation"). Systemic and pulmonary thromboembolism also occur, but are less commonly recognized.

As a result, chronic antithrombotic therapy with either oral anticoagulation (ie, a vitamin K antagonist, direct thrombin inhibitor, or factor Xa inhibitor) or antiplatelet therapy is considered for most of these patients. Both therapies are effective in preventing clinical systemic embolization, although anticoagulant therapy is far more effective and preferred in all but the lowest-risk patients. As antithrombotic therapy is associated with an increased risk of bleeding, its use must take both benefit and risk into account [1].

Antithrombotic therapy for the prevention of embolic events in patients with nonvalvular AF will be reviewed here. The role of anticoagulation in relation to restoration of sinus rhythm and the treatment of patients with AF who have suffered a stroke are discussed separately. (See "Anticoagulation prior to and after restoration of sinus rhythm in atrial fibrillation" and "Stroke in patients with atrial fibrillation".)

PATIENTS WITH VALVULAR HEART DISEASE — The major clinical trials of antithrombotic therapy and subsequent meta-analyses have largely been restricted to patients with nonvalvular or nonrheumatic AF [2-11].

Issues related to anticoagulation for AF in patients with valvular heart disease are discussed elsewhere in the appropriate topic reviews:

MECHANISM OF THROMBOEMBOLISM — The mechanisms leading to an increased risk of thrombus, embolism, and stroke in AF are multiple and closely interact with each other. Blood stasis, especially in the left atrial appendage (LAA), and activation of the hemostatic system are thought to play primary roles in patients with nonvalvular AF. Coexistent aortic atherosclerosis may also play a role. These topics are discussed in detail separately. (See "Mechanisms of thrombogenesis in atrial fibrillation" and "Echocardiographic evaluation of the atria and appendages" and "Role of echocardiography in atrial fibrillation".)

RISK STRATIFICATION TO GUIDE THERAPY — Many studies have evaluated risk factors for embolization in nonvalvular AF, and multivariate risk models have been constructed [12]. The CHADS2 risk score is the most popular and has been best validated in different patient populations (calculator 1). The main advantage of the CHADS2 score compared to other risk models is its simplicity [13,14]. A detailed discussion of risk stratification is found elsewhere. (See "Risk of embolization in atrial fibrillation".)

Some of our authors and reviewers support the use of the CHA2DS2-VASc model, which emphasizes the importance of age over 74 years and includes female sex, age 65 to 74 years, and the presence of atherosclerotic cardiovascular disease as risk factors and improves risk stratification among patients with CHADS2 scores of 0 and 1. (See "Risk of embolization in atrial fibrillation", section on 'CHA2DS2-VASc score'.)

Despite limitations of all current models, including CHADS2 [15], we recommend risk stratification in all patients as part of the process of choosing therapy. Consideration needs to be made for patient factors, such as stroke risk versus bleeding complication, as well as patient compliance and comorbidities.

ANTITHROMBOTIC PREVENTION — Many antithrombotic (anticoagulant and antiplatelet) strategies to decrease the risk of clinical embolic events in AF have been evaluated in randomized trials. These trials [2-8] and meta-analyses [9-11] have demonstrated that among patients with nonvalvular AF at high risk of thromboembolic events, warfarin, compared to placebo, significantly reduces the incidence of clinical stroke. The evidence that aspirin is better than placebo is less robust. Warfarin is approximately three times as effective as aspirin [16].

The use of warfarin is made difficult by the need for monitoring using the International Normalized Ratio (INR). The newer oral anticoagulants dabigatran, rivaroxaban, and apixaban, which have comparable efficacy and safety to warfarin in randomized trials, do not require monitoring with laboratory testing [17-19]. (See 'Studies of anticoagulant monotherapy' below.)

If the use of antithrombotic therapy carried no risk or cost, virtually all patients with AF would receive such preventative therapy. However, patients need to have their risk (of embolization) assessed to make sure that the benefit from therapy exceeds its risk. We suggest using the CHADS2 (or CHAS2DS2-VAS) score for evaluating risk of stroke an arterial embolization. Recommendations are then made based on patient risk.

Prevention approach by CHADS2 score — Long-term antithrombotic therapy, usually with anticoagulant therapy, is recommended for most patients with chronic nonvalvular AF who have risk factors for stroke. While all current risk stratification schemes, which include the individual risk factors, provide only modest capacity to predict stroke risk, the CHADS2 score (table 1) is simple and well validated. As a result, our recommendations for antithrombotic therapy depend on the CHADS2 scheme [13,14]. (See "Risk of embolization in atrial fibrillation".)

We suggest the following approach to antithrombotic therapy, which is based on evidence provided by the many studies of antithrombotic therapy discussed below (see 'Studies of anticoagulant monotherapy' below and 'Alternatives to anticoagulant monotherapy' below):

  • Patients with a CHADS2 score of 0 who receive no antithrombotic therapy are at low risk of stroke (rate of 0.5 to 1.7 percent per), and a benefit from aspirin has not been conclusively shown in these patients. Thus, we suggest no antithrombotic therapy, as the risks likely outweigh the benefits.

    For these patients who have one risk factor included in the CHA2DS2-VASc model (age 65-74 years, atherosclerotic cardiovascular disease, or female sex), some of our authors and reviewers believe it is reasonable to consider antithrombotic therapy.

Patients with a CHADS2 score of 1 are at intermediate risk of stroke (2 percent per year, or perhaps somewhat less) and should be treated with oral anticoagulant therapy or aspirin (75 to 325 mg daily). Based on the studies discussed below, which show that anticoagulant is more effective than aspirin, we prefer anticoagulant therapy to aspirin in most CHADS2 patients with a score of 1.

The choice between anticoagulation and aspirin will depend upon many factors, including the clinician's assessment of risk, the ability to provide high-quality monitoring of the intensity of oral anticoagulation (if warfarin is chosen as the anticoagulant), the patient's risk of bleeding with oral anticoagulation, and patient preference. Patient preference is an important issue, since the absolute reduction in stroke risk is likely to be small, but stroke remains a feared outcome. Better patient education can improve understanding of the benefits and risks of anticoagulant therapy [20].

The role of dual antiplatelet therapy with aspirin plus clopidogrel remains unclear in patients with a CHADS2 score of 1 who do not wish to take anticoagulant therapy, for reasons such as the inconvenience of INR monitoring or cost of the newer agents. Dual antiplatelet therapy and oral anticoagulation have similar bleeding risks, as shown in the ACTIVE W trial. Such an approach may be reasonable for patients who require dual antiplatelet therapy for other reasons, such as those with coronary stent placement or acute coronary syndrome. (See 'Aspirin plus clopidogrel' below.)

As antiplatelet therapy is inferior to anticoagulant therapy with regard to efficacy, patients should be fully informed of this fact before a decision is made to choose antiplatelet therapy. If the reason for not choosing anticoagulant therapy is concern about bleeding, aspirin plus clopidogrel is NOT an option as the combination produces a similar risk of bleeding to that seen with warfarin.

  • Patients with a CHADS2 score of at least 2 are at high risk of stroke (4 percent per year and higher). Oral anticoagulant therapy is strongly recommended for most patients with a CHADS2 score of 2 or higher [21].
  • The RE-LY, ROCKET-AF, and ARISTOTLE trials (table 2), using dabigatran, rivaroxaban, and apixaban, respectively, came to similar conclusions regarding the efficacy and safety of these newer agents compared to warfarin. We prefer dabigatran, rivaroxaban, or apixaban to warfarin in most cases in which oral anticoagulant therapy is chosen. Among the newer agents, we prefer dabigatran for reasons of cost and availability and pending reviews of non-public (not published) data by the United States Food and Drug Administration and the European Medicines Agency. Recommendations may need to change should these agencies detect adverse outcomes not currently reported.

    The following are situations in which it is reasonable to prefer warfarin instead of these newer anticoagulants:

CHA2DS2-VASc — Some of our authors and reviewers, who support the use of the CHA2DS2-VASc score, consider it reasonable to choose antithrombotic therapy for patients with one following risk factors: age 65-74 years, female sex, and evidence of atherosclerotic cardiovascular disease. Benefit from therapy in such patients has not been established. These authors and reviewers agree with the 2010 European Society of Cardiology guidelines for the management of AF, which recommend either warfarin or aspirin for these patients, with a preference for the former [22]. (See 'Risk stratification to guide therapy' above and "Risk of embolization in atrial fibrillation".)

Studies of anticoagulant monotherapy — The efficacy and safety of warfarin, dabigatran, rivaroxaban, and apixaban have been evaluated in large randomized trials. These studies form the basis of our recommendations discussed above.

Warfarin

Efficacy — Warfarin was studied in numerous trials, including SPAF- I, SPAF- II, and SPAF- III trials, and AFASAK, BAATAF, SPINAF, and CAFA [2-7]. Together, these trials randomly assigned more than 4000 patients with nonvalvular or nonrheumatic AF to aspirin, warfarin, or placebo, and demonstrated that anticoagulation with adjusted-dose warfarin [equivalent to INR 2-3] significantly reduced clinical stroke risk in patients with AF when compared with aspirin [3-5] or placebo (figure 1) [2,3,5-7]. Overall, adjusted-dose warfarin reduces the risk of stroke by two-thirds compared to no antithrombotic therapy, with the expected degree of absolute benefit dependent on baseline risk (table 3) [8,9,23]. The relative risk reduction compared to aspirin is about 50 percent. Warfarin is effective in both men and women and in all age groups, including those over the age of 75 years (figure 2) [8,24-26]. In addition, mortality was significantly reduced by warfarin compared to no antithrombotic therapy [9].

In addition, warfarin provides benefit in patients who have already had a stroke. (See "Stroke in patients with atrial fibrillation".)

These trials were conducted more than 15 years ago, and the following concerns have been raised about whether the findings can be applied to current practice [27]:

  • While more recent studies continue to support the efficacy of warfarin, lower absolute levels of stroke risk have been observed, resulting in a smaller absolute benefit of anticoagulant therapy [14,28].
  • The real-world benefit may be lower than that demonstrated in clinical trials, since the patients are less likely to have a therapeutic international normalized ratio (INR). (See 'Underutilization and discontinuation' below.)

Bleeding risk — The major safety concern with the use of warfarin (and all oral anticoagulants) is the risk of major bleeding. Major bleeding includes bleeding that requires hospitalization, transfusion, or surgery, or involves particularly sensitive anatomic locations. Intracranial bleeding is the most serious bleeding complication with warfarin, since the likelihood of mortality or subsequent disability is substantially higher than bleeding at other sites [29].

Overanticoagulation (as defined as a supratherapeutic INR), prior stroke, and increasing patient age are three of the most important predictors of major bleeding, which includes intracranial hemorrhage (ICH) [21,27,30,31]. In an attempt to estimate the probability of major bleeding in patients on chronic warfarin therapy, a number of risk models have been developed (table 4 and table 5). The risk factors and risk models are discussed in depth separately. (See "Therapeutic use of warfarin", section on 'Bleeding' and "Risk of intracerebral hemorrhage in patients treated with warfarin".)

The increased risk of major bleeding (with or without aspirin) is particularly relevant to older adults in whom varying combinations of frailty, poor mobility, poor compliance, the use of concomitant medications that can result in drug interactions, and frequent falls are common. Issues related to anticoagulation in older adults are discussed separately. (See "Anticoagulation in older adults".)

The risk of major bleeding appears to be significantly higher with adjusted-dose warfarin compared with aspirin. In the individual patient meta-analysis of six prevention trials cited above, the absolute rate increase of major bleeding with warfarin compared with aspirin was 0.9 events per 100 patient-years (2.2 versus 1.3 events per 100 patient-years) [10]. The risk of ICH is extremely high at an INR above 5.0 (figure 3) [32].

Many patients on warfarin also require aspirin for another indication, such as intracoronary stent placement or acute coronary syndrome. The combination of warfarin and aspirin increases the risk of bleeding. In the study of Medicare recipients discussed above, the rate of major bleeding was 2.8 percent in those treated with warfarin plus aspirin. Combination therapy was associated with a threefold increase in the risk of ICH (0.9 versus 0.3 percent, odds ratio 2.95). In another meta-analysis, combination therapy was associated with a significant increase in the risk of ICH (relative risk 2.4, 95% CI 1.2-4.8) [33]. (See 'Aspirin' below.)

The rates of major bleeding in patients taking the newer oral anticoagulants (ie dabigatran, rivaroxaban, and apixaban) are presented below and are similar to or less than the rate in patients taking warfarin (table 2). (See 'Dabigatran' below and 'Rivaroxaban' below and 'Apixaban' below.)

The management of anticoagulant therapy in patients who are bleeding is discussed elsewhere. (See "Correcting excess anticoagulation after warfarin", section on 'Treatment' and "Anticoagulants other than heparin and warfarin", section on 'Dosing and safety issues' and "Anticoagulants other than heparin and warfarin", section on 'Reversal of dabigatran activity'.)

Net clinical benefit — The decision to use antithrombotic therapy to prevent clinical embolization in patients with nonvalvular AF is based upon an assessment of the absolute benefits and risks of such therapy. For most patients, the benefit will outweigh the (bleeding) risks and thus a formal assessment of bleeding risk using one of the available risk models is not necessary (See "Therapeutic use of warfarin", section on 'Bleeding'.)

Combining ischemic events with major bleeding together to yield net clinical benefit attempts to balance benefits and risks. The ATRIA study evaluated the net clinical benefit (NCB) of warfarin in 13,559 patients with nonvalvular AF who were identified in an outpatient database in 1996 and 1997 [27]. NCB was defined as the difference between annualized rate of thromboembolic events prevented by warfarin, minus the annualized rate of ICH induced by warfarin, multiplied by a weighting factor. In the model, ICH was weighted as 1.5 times the impact of ischemic stroke. A strength of this analysis is that extracranial bleeds, which have less long-term impact compared with strokes, were excluded.

Outcomes were evaluated in the warfarin and no-warfarin groups (approximately 50 percent of the latter were on aspirin) over a median follow-up of six years. The NCB became statistically significant at a CHADS2 score of 2 (1 event prevented per 100 patient-years) and progressively increased at higher CHADS2 scores (2.2 events prevented per 100 patient-years at a CHADS2 score of 4 to 6). This relationship reflects the much greater reduction in embolic risk compared to increase in ICH risk with higher CHADS2 scores.

The ATRIA study supports the benefits of warfarin therapy in patients with a CHADS2 score of 2 or higher. The NCB with warfarin in patients with a CHADS2 score of 1 was small, and the confidence intervals around the NCB included the possibility of harm.

A larger analysis, which evaluated the net clinical benefit in 132,372 patients in the Danish National Patient Registry whose risk of stroke or embolization was assessed using the CHADS2 score, came to similar conclusions [34]. Of note, this study also evaluated net clinical benefit using the CHA2DS2-VASc score, which includes age 65-74, female sex, and atherosclerotic cardiovascular disease as risk factors (in addition to those in the CHADS2 model) (see 'CHA2DS2-VASc' above). In patients with a CHA2DS2-VASc score of 1 (n=86,370), there was a trend toward net clinical benefit, particularly in patients at higher risk of bleeding.

Thus, for patients with CHADS2 scores of 0 or >1, formal assessment of bleeding risk is not necessary. Patients with a CHADS2 score of 1 who are at high risk of bleeding, particularly ICH (table 4 and table 5), may reasonably choose aspirin instead of an anticoagulant. While most patients with risk factors for bleeding have a CHADS2 score greater than 1, some risk factors for bleeding such as history of gastrointestinal bleeding , abnormal renal or hepatic function, drugs or alcohol, or high risk for falls are not included in the CHADS2 model. These are the patients for whom a decision to choose aspirin rather than anticoagulant may be reasonable.

Initiation of therapy — The choice of whether to start warfarin alone or in combination with unfractionated heparin or low-molecular-weight heparin (ie, bridging) is based upon an assessment of the risk of a thrombus developing within the next several days versus the risk of bleeding complications.

In most patients with nonvalvular AF, the risk of stroke during the several days typically required to reach a therapeutic INR is very low. Thus, it is reasonable to administer warfarin as an outpatient without bridging. For patients with nonvalvular AF deemed to be at high risk of thromboembolism (eg, remote cerebrovascular event/TIA or intracardiac thrombus) and low risk of ICH, initiation of warfarin with a heparin bridging regimen is reasonable. This approach is in general agreement with the 2008 ACCP guidelines [35]. However, there are no data from randomized trials addressing such patients, and expert opinion is divided as to the benefit of heparin bridging in certain situations.

Patients with nonvalvular AF who present with acute stroke have a relatively high risk of recurrent embolism and/or progressive ischemia (approximately 5 percent during the first two weeks) [36,37]. Although early use of heparin reduced the rate of recurrent embolism and/or progressive ischemia in some trials, this was balanced by an increased incidence of ICH, especially in patients with large strokes. The conclusion from these data is that there is no overall benefit to early heparin therapy [36,37], and we do not recommend heparin bridging in patients with acute stroke.

Other issues surrounding the initiation of warfarin are found elsewhere. (See "Therapeutic use of warfarin", section on 'Loading doses'.)

INR monitoring and goal — An INR between 2.0 and 3.0 has been generally recommended for most patients with nonvalvular AF who receive warfarin [35,38]. This is based upon the increased risk of stroke observed with INR values significantly below 2.0 (four- to sixfold at an INR of 1.3 compared with an INR of 2.0 or above) and the increased risk of bleeding associated with higher intensities of anticoagulation (figure 3) [35,39-42]. The severity of stroke and the mortality rate in patients with nonvalvular AF are also increased when the INR is below 2.0 [40]. (See 'Bleeding risk' above.)

Advanced age (over 74 years) is an independent risk factor for bleeding during anticoagulation, and some experts argue that a lower INR target (1.8 to 2.5) is a reasonable compromise between toxicity and efficacy for some patients in this age group [21] since patients with an INR of 1.8 are afforded considerable protection from stroke [27,43,44]. However, the BAFTA trial, in which the mean age of participants was 81 years, found that warfarin (target INR 2.0 to 3.0) was superior to aspirin (75 mg/day) for stroke prevention, with no difference in major bleeding between the two treatment arms [26]. The benefits of warfarin were independent of age (75 to 79, 80 to 84, or 85+ years). Furthermore, aiming for an INR range of 1.8 to 2.5 will likely lead to a substantial number of patients whose INRs are below 1.8, which carries an attendant increased risk of stroke but does not significantly reduce the risk of intracranial hemorrhage [27]. Therefore, aiming for an INR of 2.0 to 3.0 provides the best target range for guarding against the sequelae of under- and over-anticoagulation. (See "Anticoagulation in older adults".)

Some have suggested that target INR values higher than 2.0 to 3.0 be used for patients at particularly high risk, such as those with prior thromboembolism [21,41] or TEE documented atrial thrombi. Evidence from the ATRIA study makes it clear that the there is no benefit in targeting INR levels higher than the standard range of INR 2.0 to 3.0 (figure 4) [42].

Maintenance of the INR between 2.0 and 3.0 is often not achieved, and the failure to maintain a therapeutic INR is associated with worse outcomes [45-48]. The following observations illustrate the range of findings:

  • In the SPAF-III trial, only 61 percent of INR values were between 2.0 and 3.0, and 25 percent were less than 2.0, despite the use of a warfarin nomogram and nursing assistance with INR monitoring and warfarin dose adjusting [45].
  • Similar findings were noted in a systematic review of four studies in which the INR was less than 2.0 on 26 percent of measurements [46]. An INR at this level was associated with a fivefold increase in ischemic events compared to values in the therapeutic range.
  • In a retrospective analysis of the SPORTIF III and V trials, patients assigned to warfarin therapy were categorized as having poor, moderate, or good control of anticoagulation (therapeutic INRs less than 60 percent, 60 to 75 percent, or greater than 75 percent of the time, respectively) [47]. Patients with poor control had, when compared to those with moderate or good control, significantly higher annual rates of mortality (4.2 versus 1.8 and 1.7 percent), and major bleeding (3.9 versus 2.0 and 1.6 percent). In addition, patients with poor control had a significantly higher annual rate of stroke or systemic embolization than those with good control (2.1 versus 1.1 percent).

The importance of time in therapeutic range (TTR) was further emphasized in a secondary analysis from the ACTIVE-W trial of clopidogrel plus aspirin versus vitamin K antagonists (VKA) [48]. A wide variation in TTR achieved across participating centers and countries was observed, and the relative benefit of vitamin K antagonists for patients with AF was strongly associated with average TTR. For example, in the analysis by participating country, an average TTR of 50 percent was needed to demonstrate any benefit of anticoagulant therapy versus clopidogrel plus aspirin. This benefit increased with higher levels of average TTR, while at lower TTR levels anticoagulant therapy was the inferior therapy [49].

Our authors and reviewers believe that the benefit from warfarin is greatest when the TTR is at least 60 percent and that the higher the TTR the greater the anticipated benefit. For patients whose TTR is less than this goal, physicians should review with the patient possible causes of poor INR control, such as inconsistent adherence, dietary changes, or interference from concomitant medications. If poor INR control cannot be remedied, then consideration should be given to switching. However, the benefit from such a practice has not been evaluated.

The frequency of INR monitoring soon after initiation of warfarin therapy is determined by how quickly the patient can get to the INR target consistently. The initial three months of adjusted-dose warfarin are a particularly high-risk period for bleeding; as a result, especially close anticoagulation monitoring is warranted during this period [50].

After stabilization at a therapeutic level of warfarin, the INR should be monitored monthly, and more frequently if there has been a change in medication or diet as these may alter the effect of warfarin. The method of follow-up will vary from patient to patient and practice to practice. Less frequent (every three months) monitoring may be reasonable for patients who have been maintained on a stable dose of warfarin with therapeutic INR [51]. (See "Therapeutic use of warfarin", section on 'Laboratory monitoring'.)

Temporary cessation of anticoagulation — Patients on long-term warfarin therapy may occasionally require cessation of warfarin anticoagulation to prevent bleeding in the periprocedural or perisurgical period or to avoid teratogenesis during pregnancy. Less often, reversal of anticoagulation may be required for emergent surgery or other urgent indications. These issues are discussed in detail elsewhere. (See "Management of anticoagulation before and after elective surgery" and "Management of anticoagulants in patients undergoing endoscopic procedures" and "Anticoagulation during pregnancy" and "Correcting excess anticoagulation after warfarin", section on 'Temporary reversal of warfarin'.)

The discussion of the management of anticoagulant therapy in the patient undergoing percutaneous coronary intervention is found elsewhere [52,53]. (See "Antithrombotic therapy for intracoronary stent implantation: General use", section on 'Patients who require warfarin'.)

Underutilization and discontinuation — Despite the compelling evidence that warfarin reduces the risk of stroke in most patients with AF, such therapy continues to be underutilized [11,54-60]. In a study of over 3600 patients with AF or atrial flutter in a community database (2000-2007), antithrombotic treatment was given in accordance with guideline recommendations in only 53 percent of patients, with 31 percent classified as undertreated [61]. Patients were less likely to be treated if they had paroxysmal AF or atrial flutter. The lack of warfarin use in those with paroxysmal atrial fibrillation may be related to the misconception regarding thromboembolic risk and rhythm.

Even when anticoagulation is appropriately initiated, it is often discontinued, or the target international normalized ratio (INR) is not achieved. Discontinuation rates between 26 and 34 percent at one year have been reported [57,62]. The risks of termination of warfarin therapy, even in patients in whom sinus rhythm has been restored, were highlighted in the AFFIRM and RACE trials. Seventy to eighty percent of ischemic strokes occurred either after discontinuation of warfarin or when the INR was subtherapeutic [59,60].

Thromboembolism in anticoagulated patients — Thromboembolic events occur despite adequate anticoagulation in patients with AF. Predictors of these events include (see "Antithrombotic treatment of acute ischemic stroke", section on 'Atrial fibrillation and cardioembolic stroke'):

  • TEE evidence of dense spontaneous echo contrast and low left atrial appendage velocity [63]. The international normalized ratio is often subtherapeutic [46]. (See "Echocardiographic evaluation of the atria and appendages" and 'Underutilization and discontinuation' above.)
  • TEE evidence of complex aortic plaque [63]. TEE detected thrombi can be related to clinical risk factors [64].
  • Elevated D-dimer levels. In a single center, prospective, observational study of 269 patients, D-dimer levels were elevated (≥0.5 mcg/mL) in 23 percent and elevated levels were significantly associated with a higher rate of thromboembolism (hazard ratio 15.8, 95% CI 3.33 to 75.5) [65], similar for von Willebrand factor [66]. However, we do not recommend D-dimer or von Willebrand factor testing, as it has not been shown that changing the antithrombotic regimen alters outcome in this setting.
  • While most ischemic stroke in AF patients is due to embolism of left atrial thrombi, other stroke mechanisms should be considered. (See "Pathophysiology of ischemic stroke", section on 'Stroke subtypes'.)

Direct thrombin and factor Xa inhibitors — Dabigatran, a direct thrombin inhibitor, and rivaroxaban and apixaban, both factor Xa inhibitors, have been compared to adjusted-dose warfarin (INR of 2.0 to 3.0) in large randomized trials of patients at moderate to high risk of stroke. Aspirin use was allowed in the trials.

These trials, discussed below, demonstrate equal or better efficacy and safety of these newer anticoagulants compared to warfarin. These drugs do not require monitoring of their anticoagulant effect and have minimal food and drug interactions, making them preferable to warfarin for many patients.

Dabigatran — The RE-LY trial (table 2) evaluated the efficacy and safety of dabigatran (at two doses) compared to warfarin [17].

In RE-LY, 18,113 patients with nonvalvular AF were randomly assigned to receive oral dabigatran at one of two doses (110 or 150 mg) twice daily, or warfarin (INR 2.0-3.0). Exclusion criteria included important valvular heart disease, conditions associated with a high risk of bleeding (eg, recent or planned surgery, bleeding diathesis, or gastrointestinal hemorrhage within the past year), active liver disease, pregnant women or those who might become pregnant during the study, or a creatinine clearance of less than 30 mL/min.

After a median follow-up of two years, the following findings were noted (the event rates and their associated risk ratios, with the exception of hemorrhagic stroke, reflect those reported in an updated analysis of RE-LY [67], except as noted):

  • The rate of the primary efficacy outcome of stroke (including hemorrhagic stroke) or systemic embolism was 1.54, 1.11, and 1.71 percent per year in the dabigatran 110 mg, dabigatran 150 mg, and warfarin groups, respectively. The differences in rates were driven principally by reductions in ischemic stroke. Dabigatran 110 mg met the criteria for non-inferiority compared to adjusted dose warfarin (relative risk 0.90, 95% CI 0.74-1.10), while dabigatran 150 mg was significantly more effective than warfarin (relative risk [RR] 0.65, 95% CI 0.52-0.81) or dabigatran 110 mg (RR 0.73, 95% CI 0.58-0.91).
  • The rate of major bleeding (defined as a reduction in the hemoglobin concentration of at least 2.0 g per deciliter, transfusion of at least two units of blood, or symptomatic bleeding in a critical area or organ [including hemorrhagic stroke]) was 2.9, 3.3, and 3.6 percent per year in dabigatran 110 mg, dabigatran 150 mg, and warfarin groups, respectively. The risk of major bleeding was significantly less with dabigatran 110 mg than warfarin, and dabigatran 150 mg was of equal safety to warfarin (RR 0.80, 95% CI 0.70-0.93 and 0.93, 95% CI 0.81-1.07 respectively).

    The rates of hemorrhagic stroke were significantly lower in the dabigatran 110 and 150 mg groups compared to warfarin (0.12, 0.10, and 0.38 percent per year, respectively; RR 0.31, 95% CI 0.17-0.56 and 0.26, 95% CI 0.14-0.49, respectively).
  • The benefit from dabigatran at both doses was similar in patients with and without prior warfarin exposure [68].
  • There was a trend toward a higher rate of bleeding with dabigatran 150 mg in patients aged ≥75 years (5.10 versus 4.37 percent per year; p=0.07) [69]. This finding was evident for extracranial but not ICH.

Advantages to dabigatran include no requirement for monitoring of the INR, less susceptibility to dietary and drug interactions, and absence of warfarin’s narrow therapeutic window [70]. Disadvantages include twice-daily dosing, higher pharmaceutical cost, lack of an antidote/reversing agent, the potential need for dose adjustment in patients with chronic kidney disease of mild to moderate severity, and lack of long-term safety and “real world” data.

We prefer the 150 mg twice daily dose for patients not a high risk of bleeding. For those patients at high risk of bleeding (such as those above age 75 years) or those patients who are particularly concerned about bleeding complications while on anticoagulant therapy, the 110 mg twice daily dose is reasonable (but not available in the United States). A 75 mg twice daily dose is available in the USA and is approved for patients with creatinine clearances of 15 to 30 ml/min based on pharmacokinetic modeling. However, we do not recommend use of the 75 mg twice daily dose, as it has not been tested in clinical trials.

Drug stability — Due to the potential for product breakdown from moisture and loss of potency, dabigatran capsules should only be dispensed and stored in the original bottle (with desiccant) or blister package. Patients should not store or place this agent in any other container, such as pill boxes or pill organizers. Once the bottle is opened, the pills inside must be used within four months [71].

The management of patients on dabigatran who require invasive procedures or surgery is discussed elsewhere. (See "Anticoagulants other than heparin and warfarin", section on 'Dabigatran'.)

Rivaroxaban — Rivaroxaban has been approved for use in the United States, Canada, and the European Union for the prevention of thromboembolism in nonvalvular AF as well as for prophylaxis of venous thromboembolism in some postoperative orthopedic patients. (See "Prevention of venous thromboembolic disease in surgical patients", section on 'Rivaroxaban'.)

In the ROCKET AF trial (table 2), 14,264 AF patients at moderate to high risk of stroke (table 1) were randomly assigned to either rivaroxaban (20 mg daily or 15 mg daily in patients with a creatinine clearance of 30-49 ml/min) or warfarin (target INR 2.0-3.0) [18].

With regard to the rate of the primary efficacy end point (composite of stroke and systemic embolism), rivaroxaban was noninferior to warfarin (1.7 versus 2.2 percent per year; hazard ratio [HR] 0.79, 95% CI 0.66-0.96) in the per-protocol as-treated analysis. In the intention to treat analysis, the rate of primary end point was 2.1 and 2.4 percent per year respectively (HR 0.99, 95% CI 0.74-1.03). There was no significant difference between rivaroxaban and warfarin in the primary safety end point of major and non-major clinically relevant bleeding (14.9 versus 14.5 percent per year, respectively). In addition, the rates of ICH and fatal bleeding, each a component of the safety outcome, occurred significantly less often in the rivaroxaban group (0.5 versus 0.7 and 0.2 versus 0.5 events per 100 patient-years, respectively).

Apixaban — Apixaban has been approved in Europe for the prevention of venous thromboembolism in postoperative patients (see "Anticoagulants other than heparin and warfarin", section on 'Apixaban').

In the ARISTOTLE trial (table 2), 18,201 AF patients were randomly assigned to either apixaban (5 mg twice daily) or warfarin (target INR 2.0-3.0) [72]. The primary composite end point of stroke and systemic embolism was significantly reduced in the apixaban group (1.27 versus 1.60 percent per year; hazard ratio 0.79, 95% CI 0.66-0.95), meeting criteria for non-inferiority (and superiority in a similar prespecified secondary end point). The rate of major bleeding, the primary safety end point, was significantly lower in the apixaban group (2.13 versus 3.09 percent per year), including a significant reduction in the rate of hemorrhagic stroke (0.24 versus 0.47 percent per year). In addition ARISTOTLE is the first study to show a significant reduction in the rate of all-cause death compared to warfarin (3.52 versus 3.94 percent per year).

Reversal of anticoagulant effect — An important concern, about the use of direct thrombin and factor Xa inhibitors, is that no antidote has been shown, in studies of patients taking these drugs, to cause immediate reversal of their anticoagulant effect. In one promising study in 12 healthy volunteers, the infusion of prothrombin complex concentrate led immediate and complete reversal of the anticoagulant effect of rivaroxaban; this effect was not seen with dabigatran [73]. This issue is discussed separately. (See "Anticoagulants other than heparin and warfarin", section on 'Dosing and safety issues' and "Anticoagulants other than heparin and warfarin", section on 'Reversal of dabigatran activity'.)

Alternatives to anticoagulant monotherapy — Prior to the randomized trials of factor Xa and direct thrombin inhibitors (discussed above), alternatives to warfarin with antiplatelet therapy were studied, including aspirin, low-dose warfarin plus aspirin, and aspirin plus clopidogrel. Warfarin is superior to these alternatives in patients at high risk of stroke, while aspirin therapy is considered a reasonable option in patients at low thromboembolic risk. (See "Risk of embolization in atrial fibrillation".)

Aspirin — Aspirin has been compared to either warfarin or placebo and been shown to be less effective than the former and not clearly superior to the latter.

Randomized trials have shown that aspirin is consistently and substantially less effective than warfarin in all AF patients with a CHADS2 score above 0 (table 3) [4,9,10]. The magnitude of the difference was illustrated in an individual patient meta-analysis of six prevention trials (AFASAK 1, EAFT, PATAF, SPAF-II, AFASAK 2, SPAF-III) in patients with nonvalvular AF (76 percent primary prevention) [10]. Patients treated with warfarin were significantly less likely to experience an ischemic stroke (2.0 versus 4.3 per 100 patient-years, hazard ratio 0.55, 95% CI 0.45-0.71); the benefit was similar in patients with chronic and paroxysmal AF. It was concluded that treating 100 patients with warfarin rather than aspirin for one year would prevent 2.3 ischemic strokes.

The issue of whether aspirin could be a reasonable choice in very low risk patients (CHADS2=0) has not been well addressed. The individual trials that compared aspirin to placebo enrolled very few such patients. Two meta-analyses performed in 2006 and 2007 found that the risk of stroke was reduced by about 20 percent, but that the confidence intervals included the potential for harm [9,11].

Thus, for patients with no identified risk factors for stroke, defined as a CHADS2 score of 0, aspirin is of uncertain benefit (or anticoagulant). This is consistent with the 2010 European Society of Cardiology guidelines for the management of AF, which concluded that the available evidence does not support the use of aspirin in most patients who are defined as a CHA2DS2-VASc of 0, as the risk of bleeding may exceed the small benefit [22].

For those patients with CHADS2 score of 0 who are willing to accept the risks of aspirin therapy in exchange for a likely small decrease in the risk of stroke, aspirin may be a reasonable choice. With regard to efficacy, there is no solid evidence favoring one dose of aspirin over another, although several trials have used 325 mg daily. No significant difference in bleeding risk has been found between doses of aspirin above 162 to 325 mg/day compared to 75 to 162 mg/day. While some of our authors and reviewers are comfortable with an aspirin dose within the 75 to 325 mg daily range, most prefer a dose of 75 or 81 mg daily. (See "Benefits and risks of aspirin in secondary and primary prevention of cardiovascular disease", section on 'Dosing and bleeding risk'.)

The use of aspirin for secondary prevention of cardiovascular disease in patients treated with warfarin for AF is discussed below. (See 'Patients with cardiovascular disease' below.)

Aspirin plus clopidogrel — Two large randomized trials have investigated the safety and efficacy of dual antiplatelet therapy in patients with AF. ACTIVE W compared clopidogrel plus aspirin to warfarin and ACTIVE A compared clopidogrel plus aspirin to aspirin alone in patients who were not candidates for anticoagulation with a vitamin K antagonist. All of the patients in the two trials had AF and one or more risk factors for stroke (table 1). The primary end point in both trials was a composite outcome (the first occurrence of stroke, systemic [non-central nervous system] embolization, MI, or vascular death).

The ACTIVE W trial included 6706 patients who were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to 100 mg/day) or to oral anticoagulation with a vitamin K antagonist (target INR 2.0 to 3.0) [74]. The trial was stopped at an interim analysis after a median follow-up of 1.3 years because warfarin anticoagulation significantly lowered the annual rate of the primary end point compared to combined antiplatelet therapy (3.9 versus 5.6 percent, relative risk 0.69, 95% CI 0.57-0.85). Although the overall rate of bleeding was significantly increased in the dual antiplatelet group (15.4 versus 13.2 percent per year), there was no significant difference in major bleeding (2.4 versus 2.2 percent per year). There were numerically more myocardial infarction events in dual antiplatelet therapy treated patients, compared to warfarin. Thus, in AF patients who are candidates for oral anticoagulation, dual antiplatelet therapy should NOT be considered an alternative.

The ACTIVE A trial included 7554 patients with AF who were not candidates for anticoagulation and were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to 100 mg/day) or to aspirin alone at the same dose [75]. The reasons that patients were not considered candidates for anticoagulation included the physician's judgment that such treatment was inappropriate (50 percent), a specific risk for bleeding (23 percent), and strong patient preference (26 percent). Patients were excluded from participation in ACTIVE A if they had documented peptic ulcer disease in the previous six months, significant thrombocytopenia, prior ICH, or ongoing alcohol abuse. The primary end point, as in ACTIVE W, was the first occurrence of stroke, systemic (non-central nervous system) embolization, MI, or vascular death.

After a median follow-up period of 3.6 years, patients treated with clopidogrel plus aspirin had a significantly lower annual rate of the primary combined end point (6.8 versus 7.8 percent, relative risk [RR] 0.89, 95% CI 0.81-0.98), which was primarily driven by a reduction in stroke (2.4 versus 3.3 percent, RR 0.72, 95% CI 0.62-0.83). On the other hand, dual antiplatelet therapy had a significantly increased incidence of major bleeding (2.0 versus 1.3 percent per year, RR 1.57, 95% CI 1.29-1.92).

The net clinical benefit of adding clopidogrel to aspirin (compared to aspirin monotherapy) was assessed in an analysis of data from the two ACTIVE trials, using methodology similar to that discussed above (see 'Net clinical benefit' above) [76]. There was a small non-significant benefit, defined as ischemic stroke equivalents prevented, to combination therapy (0.57 events per 100 patient-years of treatment; 95% CI -0.12-1.24).

Dual antiplatelet therapy may be a reasonable alternative to therapy with aspirin alone in the occasional high-risk patient with AF who CANNOT be treated with anticoagulation. With the availability of newer oral anticoagulants, this situation should be extremely uncommon. It should be kept in mind that as dual antiplatelet therapy and oral anticoagulation have similar bleeding risks, a patient who would not be a candidate for oral anticoagulation because of bleeding risk is also not a candidate for dual antiplatelet therapy.

Aspirin plus low-dose warfarin — In contrast to adjusted-dose warfarin, low-dose warfarin (1.25 mg/day or target INR between 1.2 and 1.5) in combination with aspirin (300 to 325 mg/day) should not be used to reduce stroke risk in patients with AF [23,45,77]. In the SPAF-III trial of 1044 patients with AF who were at high risk for embolism, low-dose warfarin plus aspirin had a much higher rate of morbidity and mortality than full anticoagulation/adjusted-dose warfarin (figure 5 and figure 6) [45].

Aspirin plus full dose warfarin — The antithrombotic strategies listed directly above address concerns about the INR monitoring, dietary and medication interactions, and the risk of major bleeding. The issue of whether combination of aspirin plus full dose warfarin might have greater efficacy than warfarin alone has not been well studied. In a post-hoc analysis of the SPORTIF trials, which included a high percentage of patients with cardiovascular disease or at high risk, combination therapy with warfarin (or ximelagatran) plus aspirin, in comparison to anticoagulant alone, did not reduce the rate of stroke or systemic embolism [78].

However, patients may require aspirin (or other antiplatelet agent) for reasons such as the primary or secondary prevention of coronary artery disease, treatment of acute coronary syndrome, or after placement of an intracoronary stent. This issue is discussed below. (See 'Patients with cardiovascular disease' below.)

Nonpharmacologic alternatives — Interventional techniques to prevent thrombus formation in the LAA have been attempted. The data evaluating the efficacy of these procedures are presented separately. (See "Nonpharmacologic therapy to prevent embolization in patients with atrial fibrillation".)

Nonpharmacologic strategies to prevent recurrent AF might reduce the risk of embolic stroke. Approaches that may be considered include the surgical atrial isolation/maze procedure in patients undergoing cardiac surgery for some other reason and pulmonary vein isolation by radiofrequency catheter ablation. However, there are only limited data confirming a reduction in embolic risk with these procedures, and their use should be considered only in selected patients and only by experienced operators. (See "Radiofrequency catheter ablation to prevent recurrent atrial fibrillation" and "The role of pacemakers in the prevention of atrial fibrillation" and "Surgical approaches to prevent recurrent atrial fibrillation".)

Specific patient groups

Patients with acute stroke — Recommendations for the prevention of secondary embolism in AF patients with an acute stroke and for the antithrombotic management of patients with an acute embolic stroke are presented separately. (See "Stroke in patients with atrial fibrillation".)

Patients treated with rhythm control — Patients treated with pharmacologic rhythm control have rates of thromboembolic events similar to those with rate control, as was shown in the RACE and AFFIRM trials. (See "Rhythm control versus rate control in atrial fibrillation", section on 'Clinical trials'.)

This observation likely occurs for two reasons: recurrent episodes of AF are common and asymptomatic in up to 90 percent [79,80], and some patients have other reasons for thromboembolic risk, such as aortic plaque or left ventricular systolic dysfunction. (See "Indications for anticoagulation in heart failure" and "Embolism from aortic plaque: Thromboembolism".)

Based upon these findings, most patients with AF, regardless of whether a rate-control or rhythm-control strategy is chosen, should receive antithrombotic therapy.

Patients with hyperthyroidism — The role of anticoagulant therapy is less well defined in patients in whom the underlying disease associated with AF can be corrected, as in hyperthyroidism. (See "Epidemiology of and risk factors for atrial fibrillation" and "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.)

The 2006 ACC/AHA/ESC guidelines recommended warfarin anticoagulation in these patients [21]. This recommendation was made even without firm evidence that AF in hyperthyroidism is associated with increased thromboembolic risk. Once the patient is euthyroid, the recommendations for antithrombotic prophylaxis if AF persists are similar to those in patients without hyperthyroidism (see 'Prevention approach by CHADS2 score' above). The 2008 American College of Chest Physicians guidelines on antithrombotic therapy in atrial fibrillation did not make a separate recommendation for patients with hyperthyroidism [1].

Lower-than-normal warfarin doses are usually required, since hyperthyroidism is associated with increased clearance of vitamin K-dependent clotting factors [81].

Patients undergoing cardiac surgery — The approach to patient at risk of AF after cardiac surgery is discussed separately. (See "Arrhythmias after cardiac surgery: Atrial fibrillation and atrial flutter".)

Patients with cardiovascular disease — The role of aspirin in the prevention of stroke or systemic embolization in patients with AF is discussed above. (See 'Alternatives to anticoagulant monotherapy' above.)

A separate issue is whether aspirin is necessary for secondary prevention of cardiovascular disease in patients treated with anticoagulant for AF. This issue is discussed in detail elsewhere. (See "Secondary prevention of cardiovascular disease" and "Supraventricular arrhythmias after myocardial infarction", section on 'Anticoagulation'.)

Combined therapy with aspirin and an anticoagulant may be reasonable in selected patients with coronary artery disease, such as those with acute coronary syndromes or those who receive coronary stents, for whom the potential benefits may outweigh the increased risk of hemorrhage [82-84]. (See "Chronic anticoagulation after acute coronary syndromes" and "Antithrombotic therapy for intracoronary stent implantation: General use", section on 'Patients who require warfarin'.)

Patients with chronic kidney disease — The approach to antithrombotic therapy in patients with chronic kidney disease is presented separately. (See "Management of thromboembolic risk in patients with atrial fibrillation and chronic kidney disease".)

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SUMMARY AND RECOMMENDATIONS

Indications for and choice of therapy — Antithrombotic therapy with either anticoagulant or antiplatelet therapy is effective in reducing the risk of systemic embolization in patients with nonvalvular atrial fibrillation (AF). Anticoagulation, with warfarin, dabigatran, apixaban, or rivaroxaban reduces this risk by almost 70 percent, and should be considered for most of these patients. Aspirin reduces the risk by a much smaller amount. Combination antiplatelet therapy with clopidogrel plus aspirin is superior to aspirin and inferior to warfarin in terms of efficacy, but is associated with a higher rate of bleeding than aspirin alone (see 'Alternatives to anticoagulant monotherapy' above). Risk (of arterial embolization) stratification should be performed in all patients as part of the process of choosing therapy, and we prefer the CHADS2 score (table 1) (calculator 1) for this purpose (see 'Risk stratification to guide therapy' above).

The use of antithrombotic therapy is also associated with an increased risk of major bleeding. Prior to recommending its use, patients should be informed of this risk. However, most patients do not need a formal assessment of bleeding, as the benefit from therapy will outweigh the risks in most patients. (See 'Net clinical benefit' above.)

Our recommendations for antithrombotic therapy in patients with nonvalvular AF are based on the CHADS2 score (see 'Prevention approach by CHADS2 score' above):

  • For patients with a CHADS2 score of 0, we suggest no antithrombotic therapy rather than aspirin (Grade 2B). For those patients who are willing to accept the increased risk of bleeding with aspirin in exchange for a likely small decrease in the risk of stroke, aspirin may be a reasonable choice. (See 'Aspirin' above.)

    For these patients, who have one risk factor included in the CHA2DS2-VASc model (age 65-74 years, atherosclerotic cardiovascular disease, or female sex), our authors and reviewers have differing approaches, with most recommending no antithrombotic therapy and some recommending either warfarin or aspirin. (See 'CHA2DS2-VASc' above.)
  • For patients with a CHADS2 score greater than 0, we recommend chronic antithrombotic therapy (Grade 1A).
  • For patients with a CHADS2 score of 1, we suggest anticoagulant therapy in preference to aspirin (Grade 2A). In deciding between the two, it is particularly important to be sure patients are well informed about the benefits and risks of therapy, and that patient preferences are part of the decision. For patients at high risk of major bleeding (table 4 and table 5), aspirin is a reasonable choice. (See 'Bleeding risk' above and 'Net clinical benefit' above.)
  • For patients with CHADS2 score of 2 or greater, we recommend anticoagulant rather than antiplatelet therapy (Grade 1A). For the uncommon patient who cannot take anticoagulant therapy for reasons other than bleeding risk, we suggest aspirin 75-100 mg daily plus clopidogrel 75 mg daily, rather than aspirin alone (Grade 2A). (See 'Alternatives to anticoagulant monotherapy' above.)
  • In patients with AF for whom anticoagulant therapy is chosen, we recommend a oral direct thrombin inhibitor or a factor Xa inhibitor rather than warfarin (Grade 1B). Although three randomized trials with the newer anticoagulants (dabigatran, rivaroxaban, or apixaban) have found similar or superior efficacy compared to warfarin, we currently prefer dabigatran (compared to either rivaroxaban or apixaban) based on uncertainties around reimbursement and pending review of non-published data by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

    Warfarin is a reasonable choice in the following circumstances:

Dosing issues

  • For patients prescribed warfarin, we recommend a target INR between 2.0 and 3.0, as opposed to values below or above this range (Grade 1B). The efficacy and safety of warfarin therapy decreases the more time the patient spends outside this INR range. For patients whose time in therapeutic range cannot be increased above 60 percent, consideration should be given to using another anticoagulant. Patients whose time in therapeutic range is persistently below 50 percent may be getting little to no benefit from warfarin therapy. (See 'INR monitoring and goal' above.)
  • For patients prescribed dabigatran, we suggest the 150 mg twice daily dose, as opposed to the 110 mg dose, for most patients (Grade 2B). The 110 mg twice daily dose may be preferred in those who are particularly concerned about the risk of bleeding while on anticoagulant therapy or in those assessed to be at increased risk of bleeding, such as patients older than 75 years. (See 'Dabigatran' above and 'Bleeding risk' above.)

    In the United States, the 110 mg capsule is not available, and a 75 mg capsule has been marketed. We suggest not using the 75 mg twice daily dose (Grade 2C) (see 'Dabigatran' above). The use of dabigatran in patients with chronic kidney disease is discussed elsewhere. (See "Management of thromboembolic risk in patients with atrial fibrillation and chronic kidney disease", section on 'Summary and recommendations'.)
  • Rivaroxaban should be prescribed at a dose of 20 mg daily or 15 mg daily in patients with a creatinine clearance of 30-49 ml/min).
  • Apixaban should be prescribed at a dose of 5 mg twice daily.
  • For the rare patient in whom aspirin is chosen as antithrombotic monotherapy, doses that have shown benefit range between 75 and 325 mg daily. Most, but not all, of our authors and reviewers prefer dosing at the lower end of the range. (See 'Aspirin' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate, Inc. would like to acknowledge Dr. Robert Hart, who contributed to earlier versions of this topic review.

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