Anticoagulation in atrial fibrillation

Stroke risk scores

The most widely used algorithm for estimation of stroke risk in patients with non-valvular atrial fibrillation has been the CHADS₂ score.23 It assigns 1 point to each of congestive heart failure, hypertension, age over 75 years, and diabetes mellitus; and 2 points for a history of stroke or transient ischemic attack. The score was developed from risk factors identified in clinical trials and was subsequently measured and validated in 1733 patients in the national registry of atrial fibrillation, a combined dataset of Medicare patients participating in a quality improvement initiative. The score robustly identifies patients at significantly increased risk of stroke and has been validated repeatedly in other cohorts.24

However, in an effort to improve risk stratification in seemingly low risk patients, the CHADS₂ score was expanded to incorporate additional risk factors.25 The CHA₂DS₂-VASc score further stratified age (1 point for age 65-74 years, 2 points for age ≥75 years) and added 1 point each for female sex and the presence of vascular disease (coronary, peripheral, or aortic plaque on imaging). The CHA₂DS₂-VASc score was tested and validated in 1084 Euro Heart Survey patients with non-valvular atrial fibrillation who were not taking oral anticoagulation. It showed improved resolution of patients at the lowest scores—no patients with a CHA₂DS₂-VASc score of 0 had events during follow-up and the adjusted rate of stroke was 0.7% for patients with a score of 1 (fig 1⇓).

Fig 1 Event rates, according to scores on the various risk stratification algorithms, for (A) stroke and (B) bleeding23 25 26 27

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However, the CHADS₂ and CHA₂DS₂-VASc scores have limitations. Although they have been validated across many different cohorts of thousands of patients, the discriminatory power of the scores is limited (c statistics range 0.5-0.6). This may be partly because of the relatively narrow cohorts from which they were derived.24 28 In addition, although the CHA₂DS₂-VASc score improved discrimination at the lower end of the risk spectrum, stratification remains challenging—confidence intervals for the rate of stroke in patients with a CHA₂DS₂-VASc score of 1 range from 0% to 3.4%.25 Thus, guidelines committees have modified the CHA₂DS₂-VASc score further, downplaying the risk conveyed by a CHA₂DS₂-VASc score of only 1 when the single point comes from female sex.29 This is because studies have yielded conflicting estimates on the risk conveyed by female sex. In summary, risk factors can vary in the severity of risk they convey; and the same risk factor may not be equivalent across populations.24 28 30

Bleeding scores

Because the risk of stroke needs to be balanced against the risk of bleeding, several scoring algorithms have been developed to identify patients at highest risk of bleeding in the setting of oral anticoagulation. The most commonly cited algorithms are the ATRIA, HAS-BLED, and HEMORR₂HAGES scores.26 27 31 Each combines several potential markers for future bleeding and has performed relatively well in large derivation and validation cohorts.

However, in clinical practice not all data points from these scores are readily available or calculable, and no robust prospective studies have shown any benefit for withholding anticoagulation on the basis of a high bleeding score. Furthermore, large observational datasets have failed to identify a group of patients whose risk of intracranial hemorrhage from anticoagulation outweighs the risk of stroke from withholding anticoagulation.32

Thus, it is difficult to identify patients with atrial fibrillation whose bleeding risk represents a true contraindication to antithrombotic therapy, and the decision is largely up to the subjective judgment of the individual provider (see box). Guidelines cite bleeding scores as potential tools to reduce the subjectivity involved in the decision but emphasize that these scores should not be the sole basis for a patient being excluded from treatment.33 Although stroke and bleeding risk factors overlap (for example, advanced age), current evidence suggests net clinical benefit for all but those with the highest risk of bleeding.32

Warfarin

Vitamin K antagonists have been the mainstay of oral anticoagulation for nearly half a century, particularly for patients with atrial fibrillation. Several randomized clinical trials showed that warfarin was significantly better than placebo and antiplatelet agents (aspirin) for the prevention of stroke in patients with atrial fibrillation. The most important of these were the SPAF-I, SPAF-II, SPINAF, and AFASAK trials.34 35 36 37 In a meta-analysis of these and other randomized trials, warfarin reduced stroke in untreated patients at intermediate risk from 4.3% to 1.1% (1.4% for aspirin), and in high risk patients from 12% to 4% (10% for aspirin).38 An updated meta-analysis of 29 trials across comparators confirmed these findings; dose adjusted warfarin was associated with a 64% (95% confidence interval 49% to 74%) relative risk reduction for stroke compared with placebo and a 39% (22% to 52%) relative risk reduction compared with antiplatelet drugs.10

Warfarin was also compared with newer antiplatelet regimens, including the combination of aspirin and clopidogrel in the ACTIVE W trial.39 Warfarin was significantly better than dual antiplatelet therapy for the prevention of stroke, without a significant increased risk of bleeding. In fact, in patients who had previously taken warfarin, the risk of bleeding was numerically higher in the dual antiplatelet group. Therefore, despite the development of highly potent oral antiplatelet agents, warfarin remained the standard for stroke prevention in patients with atrial fibrillation through the turn of the century.

Subsequent analyses of the bleeding risk associated with warfarin have shown minimal additional risk in patients treated in the community, outside the setting of well conducted clinical trials. An observational study of 11 526 outpatients with non-valvular atrial fibrillation found a significant benefit of warfarin for the prevention of stroke or systemic embolism (51% reduction compared with no treatment or aspirin, 95% confidence interval 39% to 60%).9 Furthermore, although warfarin use was associated with a small but significant increased risk of intracranial hemorrhage (0.46 v 0.23 events/100 person years; adjusted hazard 1.97, 1.24 to 3.13), it was associated with lower all cause mortality (0.69, 0.61 to 0.77).

Dabigatran

In 2010, the direct thrombin inhibitor dabigatran etexilate became the first alternative to vitamin K antagonism approved for the prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation. The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, a prospective open label randomized trial compared dose adjusted warfarin to dabigatran at 150 mg twice daily or 110 mg twice daily in 18 113 patients with non-valvular atrial fibrillation.40 The primary endpoint of stroke or systemic embolism was similar between warfarin and dabigatran 110 mg (relative risk 0.91 for dabigatran 110 mg; P<0.001 for non-inferiority) and lower in patients receiving dabigatran 150 mg (0.66; P<0.001). Rates of major bleeding were lowest in the 110 mg dabigatran group (2.71%) and equivalent between warfarin (3.36%) and dabigatran 150 mg (3.11%; P=0.31 for warfarin v dabigatran 150 mg), whereas intracranial hemorrhage was highest in the warfarin group (0.31 for dabigatran 110 mg, 0.4 for dabigatran 150 mg; P<0.001 for both comparisons with warfarin). Risk of gastrointestinal bleeding was significantly higher in patients receiving both doses of dabigatran compared with warfarin (1.50 for dabigatran 150 mg, 1.36 for dabigatran 110 mg; P<0.001 and P=0.007, respectively). Largely on the basis of this trial, dabigatran was approved in the US at doses of 150 mg and 75 mg (for patients with creatinine clearance 15-30 mL/min/1.73 m²) and in the European Union at doses of 110 and 150 mg (dose based on clinical judgment).41 42

Several additional analyses have provided further data on the use of dabigatran. Firstly, the efficacy of the 150 mg dose and the safety of the 110 mg dose were both consistent with the overall trial across the spectrum of warfarin management quality (as assessed by time in therapeutic range).43 An in-depth review of intracerebral haemorrhage events in the RE-LY trial found a similar spectrum of severity of bleeding between warfarin and dabigatran.44 Patients in this trial who needed an invasive procedure had equivalent rates of periprocedural bleeding events (after carefully scripted discontinuation and restart of their anticoagulant),45 although this has not been a consistent finding across procedures and anticoagulation indications.46

In an observational extension of the RE-LY trial, the RELY-ABLE (Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation) trial demonstrated efficacy of dabigatran up to 28 months beyond the original RE-LY follow-up period, with a consistent lower risk of bleeding in patients taking 110 mg (v 150 mg).47

Of note, the primary results of the RE-LY trial suggested a potential signal for increased risk of myocardial ischemic events. A subsequent meta-analysis of dabigatran trials across disease states confirmed such an association,48 although a mechanism has yet to be confirmed. To date, observational “real world” cohort studies of dabigatran users have demonstrated safety and effectiveness consistent with the RE-LY trial, without a signal for increased risk of myocardial events or higher than expected bleeding.49 50 51 Further investigation of this potential signal for myocardial events is warranted.

Rivaroxaban

In 2011, rivaroxaban became the first oral factor Xa inhibitor approved for the prevention of stroke in patients with non-valvular atrial fibrillation. The ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism) trial is a double blind double dummy trial, which randomized 14 246 patients with non-valvular atrial fibrillation to dose adjusted warfarin (international normalized ratio (INR) 2-3) or rivaroxaban, 20 mg daily (15 mg for creatinine clearance 30-49 mL/min/1.73 m²).52 This trial enrolled a population with a moderate to high risk of stroke (mean CHADS₂ score 3.5; 55% had previous stroke or transient ischemic attack). In the intention to treat analysis, rivaroxaban was non-inferior to warfarin for the endpoint of stroke or systemic embolism (1.7% for rivaroxaban v 2.2% for warfarin; P<0.001 for non-inferiority).53 Overall major and clinically relevant non-major bleeding was similar between rivaroxaban and warfarin (14.9 v 14.5 events/100 patient years; P=0.44), although rates of intracerebral hemorrhage were significantly lower with rivaroxaban (hazard ratio 0.67; P=0.02). In contrast, gastrointestinal bleeding was significantly more common in the rivaroxaban group (3.15% v 2.16%; P<0.001). The treatment effects were consistent in patients with renal impairment treated with the 15 mg dose.54

When interpreting the ROCKET AF data, it should be noted that the time in therapeutic range (a well known marker of anticoagulation quality55 56 57) in those randomized to warfarin was lower than in other randomized trials of anticoagulation therapy (mean 55% of the time). However, the treatment effects of rivaroxaban were consistent over the spectrum of low and high time in therapeutic range.58 Secondly, the number of strokes in the rivaroxaban group increased after mandatory discontinuation of rivaroxaban at the end of the trial. This increase in stroke events was attributed to the delayed therapeutic effect of transitioning to open label warfarin (median 13 days to therapeutic INR when transitioning from rivaroxaban v 3 days in the warfarin arm).59 60 On the basis of these and other data, careful attention to the transition from a short acting anticoagulant to warfarin is warranted, regardless of the agent(s) used.61

An additional randomized trial of rivaroxaban was performed separately in Japan, the J-ROCKET AF trial.62 This was done for two reasons—firstly, pharmacokinetic data suggested that Japanese patients required lower dosing to achieve target drug concentrations; and, secondly, anticoagulation goals are generally lower in Japanese practice. The investigators randomized 1280 patients to rivaroxaban 15 mg daily or dose adjusted warfarin (INR goals 2-3 for patients <70 years, 1.6-2.6 for age >70 years). Rivaroxaban was non-inferior for the efficacy endpoint of stroke or systemic embolism (hazard ratio 0.49 for rivaroxaban, 0.24 to 1.00), and the safety endpoint of major bleeding or non-major clinically relevant bleeding (1.11 for rivaroxaban; P<0.001 for non-inferiority). Finally, rivaroxaban is the only once daily dosed novel anticoagulant available for stroke prevention in patients with atrial fibrillation.63

Apixaban

In 2012, apixaban became the second factor Xa inhibitor to be approved for patients with non-valvular atrial fibrillation. It was shown to be safe and effective in two large phase III trials of patients with non-valvular atrial fibrillation: the AVERROES (Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) trial and the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial.

In the AVERROES trial, 5599 patients with non-valvular atrial fibrillation, who were deemed by their physician not to be candidates for warfarin (40% had previously taken warfarin), were blindly randomized to daily aspirin or twice daily apixaban (5 mg).64 Reasons for not using warfarin included: difficulty with performing INR testing (43%); inability to maintain appropriate INR therapeutic range (42%); only moderate risk for stroke (CHADS₂ score 1, 21%); and refusal to take warfarin (37%; sole reason in 15%). The trial was stopped prematurely, and at one year follow-up the primary outcome of stroke or systemic embolism significantly favored apixaban (1.6% v 3.7%; P<0.001). Rates of bleeding were low, but statistically equivalent between the two groups (hazard ratio for apixaban 1.13, 0.74 to 1.75; P=0.57), including gastrointestinal bleeding (0.86, 0.40 to 1.86; P=0.71).

In the ARISTOTLE trial, 18 201 patients with non-valvular atrial fibrillation were blindly randomized to dose adjusted warfarin (INR 2-3) or apixaban 5 mg twice daily.65 Patients with at least two of three select risk factors (age ≥80 years, weight ≤60 kg, and serum creatinine ≥1.5 mg/dL; 1 mg/dL=88.4 µmol/L) received 2.5 mg twice daily. After a median follow-up of 1.8 years, apixaban was superior for the reduction of stroke or systemic embolism (hazard ratio for apixaban 0.79; P=0.01 for superiority). Major bleeding occurred in 2.13% of patients taking apixaban each year versus 3.09% in those taking warfarin (P<0.001); gastrointestinal bleeding was equivalent between the groups (0.89, 0.70 to 1.15; P=0.37). Furthermore, the ARISTOTLE trial was the only study of an approved novel anticoagulant to show significantly lower rates of all cause mortality in the novel anticoagulant group (3.52% v 3.94%; P=0.047); however, a non-significant trend has been consistent in trials of other novel agents. Additional analyses of ARISTOTLE have shown consistently positive results across different types of atrial fibrillation (paroxysmal v persistent),66 degrees of warfarin anticoagulation control (time in therapeutic range),67 and stroke and bleeding risk score groups.68

Emerging treatments

In addition to the approved agents above, several anticoagulants are at various stages of development. The most advanced is edoxaban, another oral factor Xa inhibitor. The ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction) trial is a randomized double blind double dummy trial that compared two different once daily doses (30 mg and 60 mg) to dose adjusted warfarin.69 A total of 21 105 patients with moderate to high risk non-valvular atrial fibrillation were randomized, and the trial mandated a dose reduction (by half) for patients with any of the following: creatinine clearance 30-50 mL/min; weight ≤60 kg; or concomitant use of verapamil, quinidine, or dronedarone. Rates of stroke or systemic embolism were similar to those of warfarin for edoxaban 30 mg (hazard ratio 1.07; P=0.005 for non-inferiority) and 60 mg (0.79; P<0.001 for non-inferiority), with an increased risk of ischemic stroke in the low dose edoxaban group compared with warfarin (1.77; P<0.001). Compared with warfarin, rates of major bleeding were lower for both doses (30 mg edoxaban 0.47, 60 mg edoxaban 0.80; P<0.001 for both), and mortality was lower for low dose edoxaban (0.87; P=0.006), with a similar trend for high dose edoxaban (0.92; P=0.08).

Other novel oral anticoagulants are at earlier stages of development, including the factor Xa inhibitors betrixaban and darexaban,70 71 and the direct thrombin inhibitor AZD0837.72 Interventional treatments for stroke prevention are also emerging, including left atrial appendage closure devices.73 74 75 76 77

Competing risks

All anticoagulants increase the risk of bleeding. However, apixaban is the only agent to demonstrate safety and efficacy in a randomized trial of patients thought to be suboptimal candidates for warfarin (the AVERROES trial).64 In these patients, apixaban showed greater efficacy and equivalent safety compared with aspirin. Furthermore, the ARISTOTLE trial showed similar results with a reduced dosing regimen of apixaban in patients at particular risk of bleeding (based on age, weight, and serum creatinine, as noted above).65 Thus, in patients considered at higher risk of bleeding and those who are not candidates for vitamin K antagonism, apixaban may have several advantages, particularly with respect to bleeding.

By contrast, for patients at particular risk of ischemic stroke, dabigatran may be the most suitable novel anticoagulant. Although apixaban and rivaroxaban prevented more strokes than warfarin through a reduction in the number of hemorrhagic events, dabigatran was the only one of the three drugs that also significantly reduced non-hemorrhagic stroke events (as seen in the RE-LY trial).40 However, patients at high risk of non-hemorrhagic stroke may also be at high risk of acute coronary syndromes, and these risks must be balanced. Because of the observed association between dabigatran and increased risk of myocardial infarction, some investigators advocate that dabigatran should be avoided in patients with, or at risk of, coronary artery disease.48 It is important to note though, that the association between dabigatran and acute coronary events stems from retrospective analyses of randomized trials, and subsequent observational data have been conflicting.49 50 51

Other populations

Patients with chronic kidney disease represent a challenging population for the prescription and management of anticoagulation. Chronic kidney disease increases the risks of both stroke and bleeding,27 88 and patients with advanced disease are often under-represented in clinical trials. Each of the novel anticoagulant trials excluded patients with the most severe renal dysfunction, although both the ROCKET AF and ARISTOTLE trials tested reduced dosing of the drugs that they were testing.

In the ROCKET AF trial, the dose of rivaroxaban was reduced to 15 mg daily in patients with creatinine clearance of 30-49 mL/min/1.73 m² (and received regulatory approval down to 15 mL/min/1.73 m²).53 63 In the ARISTOTLE trial, the dose of apixaban was reduced to 2.5 mg twice daily for patients with two or more of the following: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥133 µmol/L.65 Although the use of serum creatinine as a measure of renal function has limitations, it does provide supporting data for the use of apixaban in such patients.

For dabigatran, pharmacokinetic studies were used to identify the preferred, renally adjusted dose in the US (75 mg), as is common practice for the Food and Drug Administration.89 Thus, although some dose adjustment for renal impairment is available for each of the novel anticoagulants, the evidence base for such recommendations varies, and this should be taken into account for patients with marginal kidney function.

Although as a group novel agents have fewer drug-drug and food-drug interactions than warfarin, there are specific, major interactions to be aware of. Antifungal agents almost all have major interactions with novel anticoagulants, as do HIV protease inhibitors and rifampin (US) and rifampicin (UK) (although fewer data are available). In addition, both rivaroxaban and apixaban interact with drugs that are strong inhibitors or inducers of cytochrome P450 3A4. More specific interactions include those between dabigatran and verapamil, quinidine, amiodarone, and dronedarone. However, data on interactions with rivaroxaban or apixaban are more limited,81 and many drugs have yet to be rigorously tested for interactions with these newer anticoagulants. The requirement for long term concomitant treatment with an interacting agent may guide the choice of anticoagulant in certain patients (table 1).

Additional considerations

Overall, the novel oral anticoagulants are well tolerated with few common side effects; however, dyspepsia is a problem in about 10% of patients receiving dabigatran and is relieved by a change of drug.40 Thus, it may be best to avoid dabigatran in patients with known dyspepsia, reflux, or gastrointestinal motility disease. Apixaban is the only approved novel anticoagulant that is not associated with an increased risk of gastrointestinal bleeding. Adherence can be a challenge for patients managing anticoagulation. In those patients who find it difficult to manage multiple daily dosages or monitoring, rivaroxaban is the only once daily alternative to warfarin currently available. Lastly, in regions lacking a single payer healthcare system, cost may influence the decision of which, if any, novel anticoagulant to use. To date, cost effectiveness data have favored novel anticoagulants (mostly because they do not need to be monitored),90 and as more become available they may become more affordable.

Patients stable on warfarin

The management of patients who are stable on warfarin is a challenge for clinicians. The decision to switch a stable patient (with adequate time in therapeutic range) to a new drug should be individually tailored; however, there are several considerations. Most importantly, clinical data to date show that novel oral anticoagulants are more efficacious and safe than dose adjusted warfarin (fig 2⇓). Furthermore, stability on warfarin is highly variable—many patients may tolerate the drug but their time in therapeutic range is insufficient to confer a clinical benefit.43 55 58 67

Fig 2 Evidence from major randomized comparisons of anticoagulants for stroke prevention in patients with atrial fibrillation.10 40 53 64 65 69 The efficacy endpoint includes stroke or systemic embolism (except warfarin v aspirin, stroke only). Safety includes major bleeding, as defined by the trial (except warfarin v aspirin, extracranial bleeding only). Estimates for warfarin versus aspirin are approximate conversions from risk reduction to relative risk (hazard). ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism trial) efficacy includes intention to treat analysis; safety and mortality include the on treatment population. ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 trial) efficacy includes intention to treat analysis. CI=confidence interval

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Providers should consider exactly how well controlled the INR is in these patients because novel drugs may be more beneficial in patients with poor control on warfarin.55

Nevertheless, switching has additional implications for the individual patient, who may be accustomed to warfarin and reluctant to fix “what isn’t broke.” For some, an agent that does not require repeated blood draws or dietary restrictions will be appealing. However, all patients should be advised about the availability of these new drugs, their risks, and their benefits and should be offered these alternatives where clinically appropriate. Patients’ engagement and subsequent adherence are paramount to the effective implementation of these newer treatments.