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When to Anticoagulate?

ABSTRACT Atrial fibrillation (AF) is the most common cardiac arrhythmia disorder in the United States. It is a major independent risk factor for stroke and thromboembolism that is influenced by multiple factors and comorbidities. Oral anticoagulant treatments with aspirin and warfarin have been shown to reduce the risk of stroke in AF patients, but warfarin treatment is associated with significant risks for major bleeding.  Thus it is important to identify those patients with significant risk for stroke warranting the use of anticoagulant treatment. This review evaluates the most recent risk stratification schemes, new alternatives to warfarin, and how they might affect decision-making for thromboprophylaxis in atrial fibrillation. INTRODUCTION

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia disorder. The absence of a strong contraction of the left atrium during atrial fibrillation increases the risk of blood clot formation, quadrupling the risk for stroke and making AF a major independent risk factor for stroke and thromboembolism.1Thromboprophylaxis in AF patients has been a difficult challenge over past decades, mainly due to the high risk of bleeding associated with oral anticoagulation therapy. In addition, the risk of stroke and bleeding varies in each AF patient and that risk is influenced by multiple factors and comorbidities. In the last five years, researchers have validated new risk stratification schemas for predicting stroke and bleeding, and developed new oral anticoagulant alternatives to warfarin. These recent findings have led to a paradigm shift in how to identify patients who need anticoagulation therapy and how to choose which treatment options are most appropriate.

RISK ASSESSMENT FOR STROKE CHADS2 Risk Assessment

In the past twenty years, nine different risk stratification schemas for assessing risk for stroke in atrial fibrillation patients have been proposed. The most commonly used risk schemata in clinical practice for the past decade is the CHADS2 scoring system, proposed by Gage et al in2001 and validated by several retrospective cohorts in the years thereafter.2, 3, 4 Because of its simplicity, the rubric has been widely endorsed by the National Collaborating Centre for Chronic Conditions, The American College of Cardiology, American Heart Association, and the European Society of Cardiology.5, 6, 7 The schema identifies five different significant risk factors, assigns a score to each factor, and then categorizes the need for oral anticoagulation treatment based on the total score (Table 1).

According to the CHADS2 strata, one point is assigned if the patient has had: 1) recent clinical heart failure or impaired left ventricular systolic function, 2) history of hypertension, 3) older than 75 years, or 4) history of diabetes mellitus. Two points are assigned for patients with a history of stroke or transient ischemic attack. Patients with a history of stroke or transient ischemic attack, or have at least two of the other risk factors are categorized as being “high risk” for stroke.

“High risk” patients are recommended for oral anticoagulation therapy. Patients with none of those five defined factors are considered “low risk” and do not need oral anticoagulation therapy. Patients who do not have a history of stroke but have another risk factor are categorized into an “intermediate risk” group. The treatment plan for this group is based on the individual patient’s treatment preference, and the physician’s assessment of the patient’s characteristics. This is because the “intermediate risk” group has an increased risk of thromboembolism, but not all patients in this group have elevated enough risk to mandate oral anticoagulation. Thus in these cases, many physicians will choose to use aspirin, or a combination of aspirin and clopidogrel, as a safe but less effective alternative to oral anticoagulation.8, 9

Table 1: CHADS2 Scoring Rubric

Risk Factor Score
Recent clinical heart failure or impaired left ventricular systolic function 1
History of hypertension 1
Age greater than 75 1
History of diabetes mellitus 1
History of stroke or transient ischemic attack 2
ScoreRange: 0-60 = low risk →  no anticoagulation needed1 = intermediate risk → treatment with aspirin or oral anticoagulation therapy ≥2 = high risk → oral anticoagulation therapy necessary

The simplicity of the CHADS2 scoring system has been the most appealing justification for its clinical use. However, the 2009 European Heart Survey on Atrial Fibrillation study argues that the CHADS2 scheme classifies too large of a proportion of patients into the “intermediate” risk category, where the decision of how to treat for stroke prevention is most unclear.8 In addition, some patients classified as “low risk” and thus not using anticoagulation therapy still experience stroke rates of 1.4%.8 Further studies in the past three years have now shown that women have been underrepresented in clinical trials and that their risk increases linearly with age starting from 65 years old.9, 10

CHA2DS2-VASc Risk Assessment

In light of the limitations of the early CHADS2 guidelines, a new rubric has been proposed in the Birmingham Study in 2008 and validated by the European Heart Survey on Atrial Fibrillation study in 2009.8, 9 The stratification scheme is now called the CHA2DS2-VASc score, which modifies the original CHADS2 system by adding three additional risk factors, and assigning two points to the category, “Age ≥75″ (Table 2).

In the CHA2DS2-VASc scoring system, one point is assigned to the following risk factors: history of heart failure, history of hypertension, history of diabetes mellitus, history of vascular disease, female sex, and age between 65-74 years. In the newer scoring rubric, age greater than 75 years and history of stroke or transient ischemic attack are identified as “definitive risk factors,” for which 2 points are assigned. Any patient with a “definitive risk factor” is immediately recommended for oral anticoagulation treatment. As before, patients with none of the identified risk factors are not recommended for oral anticoagulation therapy.

Table 2: CHA2DS2-VASc Scoring Rubric

Risk Factor Score
Heart Failure 1
History of hypertension 1
Age greater than 75 2
History of diabetes mellitus 1
History of stroke or transient ischemic attack 2
Vascular Disease 1
Age 65-74 1
Female Sex 1
ScoreRange: 0-90 = low risk → no anticoagulation needed1 = intermediate risk → treatment with aspirin or oral anticoagulation therapy ≥2 = high risk → oral anticoagulation therapy is necessary

Thus with more refined CHA2DS2-VASc system, physicians can clearly identify a “truly low risk” category of patients who have a score of 0, compared to the CHADS2 schemata.

Since the initial validation the European Heart Survey, several additional validation studies have been conducted in the past three years comparing the CHA2DS2-VASc with CHADS2, showing an improved predictive ability for CHA2DS2-VASc.12, 13, 14 In a 2011cohort study of 73,538 patients, Olesen et al compares the accuracy of predicting stroke risk for both schemes by calculating the “c-statistic value.” The c-statistic value determines how well the risk scheme predicted future events of stroke in atrial fibrillation patients. C-value = 0.50 means that the predictive value of the rubric is the same as a coin toss. C-value lower than 0.50 meant the rubric is worse than a guess, and inaccurately identifies risk factors. C-value greater than 0.50 means the rubric is able to predict with some accuracy which patient will have higher risk for stroke; the higher the number, the better the accuracy.

The study results show that the stroke predictability in patients is the same for both rubrics when looking at each individual score (c>0.6), but when categorizing patients into “low,” “intermediate,” and “high” groups, CHA2DS2-VASc has a significantly higher predictability score for assessing risk of stroke (c>0.8.) in the 1 yr, 5 yr, and 10 yr follow up (Table 3).

Table 3: C-statistic (95% CI) based on the Cox regression models

 Risk Stratefication

1 yr follow up

5 yr follow up

10 yr follow up

CHADS2 score 0-6

0.66

0.762

0.781

CHADS2 3 groups

0.722

0.796

0.812

CHA2DS2VASc score 0-9

0.661

0.758

0.777

CHA2DS2VASc 3 groups

0.850

0.880

0.888

Based on the results of this study, the CHADS2 risk stratification accurately identifies that history of clinical heart failure or impaired left ventricular systolic function, history of hypertension, age older than 75 years, and history of diabetes mellitus are stroke risk factors in atrial fibrillation patients. However, when looking at which rubric is better at categorizing “low risk,” “intermediate risk,” and “high risk” groups, CHADS2 has a lower c-value than CHA2DS2VASc (c = 0.722 vs c=0.850). This indicates that there are more risk factors for stroke that are unaccounted for by the CHADS2 scoring system. CHADS2 inaccurately groups more patients into the low risk and intermediate risk categories, when they may in fact be of higher risk. For example, a female patient between the ages of 65-74 will be considered to have no risk for thromboembolism by the CHADS2 rubric, but by the CHA2DS2VASc rubric, she will actually be considered to have high risk, and will be recommended for oral anticoagulation therapy. In summary, the CHA2DS2-VASc is a more specific yet simple guideline for assessing the risk factors for stroke in atrial fibrillation patients.

RISK ASSESSMENT FOR BLEEDING

Thrombophylaxis with oral anticoagulation is shown to be most effective in reducing stroke, compared with antiplatelet therapy, but the associated risk for major bleeding while on oral anticoagulation therapy has led to multiple assessment guidelines for identifying which patients are at too high risk of bleeding for anticoagulation to be effective. In the past decade, five major risk stratifications have been proposed and validated in large cohort studies.16, 17, 18, 19, 20 Like the risk stratifications for stroke, a specific number is assigned to a clinically significant risk, and the sum of the numerical scores are separated into “low,” “intermediate,” and “high” risk categories. However each schema identifies different factors as indicators for high risk of bleeding while using anticoagulants. In addition, many systems use a complex scoring system for calculating “low,” “intermediate,” or “high” risk for having a major bleeding event while being treated with oral anticoagulation therapy. Appendix A shows a summary of the different bleeding scoring systems.

The risk schemas HEMORR2HAGES and the HAS-BLED are most commonly used because of their simplicity. In these rubrics, a major bleeding event is defined as fatal or clinically overt bleeding associated with either transfusion of ≥ 2 U of blood or ≥20 g/l decrease in hemoglobin or bleeding involving a critical anatomic site other than brain parenchyma.21 HEMORR2HAGES assigns 2 points to history of bleeding, and 1 point to liver/renal disease, alcohol abuse, cancer, age >75 years, low platelet count or function, anemia, genetic factor (CYP2C9), and risk of falling or stroke. In contrast, the HAS-BLED schema is even simpler, assigning one point to hypertension, renal/liver disease, history of stroke, history or predisposition for bleeding, labile INR, age >75, and concomitant drug/alcohol use. Tables 4 and 5 are a summary of these two stratification schemes.

Table 4: HEMORR2HAGES Scoring Rubric

Risk Factor Score
Previous bleeding 2
Liver/Renal disease 1
Alcohol Abuse 1
Malignancy/cancer 1
Old Age < 75 years 1
Low platelet count or function 1
Hypertension, uncontrolled 1
Anemia 1
Genetic Factor (CYP9) 1
Stroke or falling risk 1
ScoreRange: 0-110-1 = low risk → safe to use oral anticoagulant therapy2-3 = intermediate risk → aspirin or oral anticoagulant therapy ≥4 = high risk → aspirin preferred
Table 5: HASBLED Scoring Rubric

Risk Factor Score
Hypertension 1
Abornmal Renal/Liver Function 1
Stroke history 1
History of Predisposition for Bleeding 1
Labile INR 1
Age older than 75 1
Drug/Alcohol, concomitant use 1
ScoreRange: 0-70 = low risk → safe to use oral anticoagulation therapy1-2 = intermediate risk → treatment with aspirin or oral anticoagulation therapy ≥3 = high risk → aspirin is preferred

An extensive cohort study with 7,329 subjects for validating all five bleeding risk stratifications has been conducted in 2010. The predictive capability of each rubric is determined by a c-statistic value. The higher the c-statistic is, the greater the ability to accurately predict the event of major bleeding occurring in patients taking oral anticoagulants. The results of this study for HAS-BLED and HEMORR2HAGES are summarized in Table 6.

Table 6: Predictive value of contemporary bleeding risk schemas in patients with atrial fibrillation taking oral anticoagulation: C-statistic (95% CI)

Study All Patients Warfarin-Naïve Patients Patients taking Warfarin + Aspirin Overall results
Pisters et al, 2010HAS-BLED .65HAS-BLED predicted 65% of bleeding events in all patients in the study trial .66HAS-BLED predicted 66% of bleeding events in warfarin-naive patients in the study trial .60HAS-BLED predicted 60% of bleeding events for patients taking both warfarin and aspirin HAS-BLED is better at predicting whether or not certain patients have a higher risk for major bleeding when taking oral anticoagulants
Gage et al, 2006HEMORR2HAGES .62HEMORR2HAGES predicted 62% of bleeding events in all patients in the study trial .62HEMORR2HAGES predicted 62% of bleeding events in warfarin-naive patients in the study trial .58HEMORR2HAGES predicted 58% of bleeding events for patients taking both warfarin and aspirin

Based on the results of the 2010 study, HAS-BLED is able to accurately predict whether a patient will have major bleeding about 65% of the time, while HEMORR2HAGES predicts 62% of the major bleeding events. The difference is significant, and HAS-BLED is considered the more accurate scoring system for predicting risk of bleeding.

COMBINING STROKE RISK ASSESSMENT WITH BLEEDING RISK ASSESSMENT

In the past, CHADS2 and HEMORR2AGES have been combined to assess which patients are at high risk for stroke and yet low risk for bleeding, thus warranting oral anticoagulation therapy. However, Somme et al, in 2009 has now shown that both schemes use almost the same categories for identifying patients, and places too many patients into the “intermediate risk” categories where decision for treatment is most vague. Thus the clinical utility for using both CHADS2 and HEMORRHAGES is not perfect.23

The validation study for HAS-BLED shows significantly higher c-statistics than HEMORR2HAGES, suggesting that combining HAS-BLED and CHA2DS2VASc schemas may be more effective in balancing the risks for taking oral anticoagulants.23

Recent studies suggest that CHA2DS2VASc is a more refined and accurate predictor for assessing risk of stroke, while HAS-BLED schema has been validated as an effective assessment for risk of bleeding while taking oral anticoagulation. Because these results are recent, there are no published studies validating the clinical usage of combining CHA2DS2VASc and HAS-BLED to enable physicians make the decision. A key step in trying this new combination has been taken by Ortuno et al in 2011.24 Ortuno et al apply a decision tree model to the two risk schema, with the options for treatment as: 1) “no treatment,” 2) “advise aspirin,” and 3) “risks justify warfarin.” Risk for stroke and bleeding are adjusted for by taking the annual rates of stroke and bleeding found by Lip et al, 2009, 2010 (Table 7).

Table 7: Summary of results of decision tree: CHA2DS2VASc vs HAS-BLED

5+  –  –  –  –  –  O  O  O  O O
4  –  –  –  –  –  O  O  O  O  O
3  –  –  –  –  –  x  x  x  x  x
2  –  –  –  –  x  x  x  x  x  x
1  –  –  x  x  x  x  x  x  x  x
0  –  x  x  x  x  x  x  x  x
0 1 2 3 4 5 6 7 8 9

x-axis = CHA2DS2VASc y-axis = HAS-BLED (-) = no treatment recommended (O) = aspirin recommended (x) = risks of stroke justifies use of warfarin and outweighs risk of bleeding

In accordance with the suggested risk strata and treatment recommendations mentioned earlier, any patient with CHA2DS2VASc score of 1 or lower does not need anticoagulation. Any patient with a CHA2DS2VASc score of 2 or high is recommended for anticoagulation therapy. However, HAS-BLED risk stratification shows that if a patient’s risk for bleeding is above three, the high risk for bleeding complications will outweigh the decision to treat with anticoagulants, and aspirin will be considered a safer option.

TREATMENT OPTIONS FOR PATIENTS WITH ATRIAL FIBRILATION: PAST AND PRESENT Warfarin

In the past 60 years, vitamin K antagonists (VKAs) have been the only available anticoagulant.25 Warfarin is the most commonly used VKA in North America, while acenocoumarol, phenprocoumon, and fluindione are most popular in Europe. Warfarin significantly reduces the risk of stroke by 64%, but its unpredictable effects and associations with major bleeding complications have made it a non-ideal course of treatment.26Physicians who treat patients with warfarin must monitor the therapy closely with routine changes in dosage to adjust for bleeding risks and multiple drug and food interactions. Despite close monitoring, major bleeding still occurs in 1-3% of patients per year, and for patients over 65 years old, warfarin complications account for one-third of emergency hospitalizations due to drug side-effects.27

Aspirin

The alternative to warfarin is aspirin or other antiplatelet drugs, but clinical trials have showed that it only reduced the risk of stroke by 22%.26 Even when combining aspirin with clopidogrel (Plavix), the risk of stroke is only reduced by 28%, less than half of the efficacy of warfarin. In addition, the risk for bleeding is the same as warfarin for patients older than 75 years.28, 29 Thus, aspirin or aspirin/clopidogrel combination has been preferred for patients with low risk scores for stroke (CHADS2 < 2) and who were younger.

New Oral Anticoagulants

New oral anticoagulants have aimed to be an alternative to warfarin and aspirin, maintaining or improving safety and efficacy. The three most prominent in the US currently are dabigatran and rivaroxaban, which are FDA approved, and apixaban which is anticipating FDA approval in late 2012.30, 31, 32 Dabigatran etexilate is an oral pro-drug that is rapidly converted by a serum esterase to dabigatran, where it directly competes as an inhibitor with thrombin, an enzyme that facilitates blood clotting.30 Apixaban and rivaroxaban are direct competitive inhibitors of Factor Xa, a serine endopeptidase in the coagulation cascade.31, 32 The rapid peak levels and shorter half-life time of all three new anticoagulants make dosage monitoring no longer necessary for physicians prescribing the treatment. In addition, by directly inhibiting specific enzymes in the coagulation cascade instead of broad targeting Vitamin K, negative food/drug interactions are significantly decreased. Table 8 lists a summary of characteristics of these novel oral anticoagulants.33

Table 8: Summary of Pharmacological Characteristics of Novel Anticoagulants for Stroke Prevention in Nonvalvular Atrial Fibrillation (adapted from Lip et al, 2012).

Dabigatran (Pradaxa) Apixaban (Eliquis) Rivaroxaban (Xarelto)
Mechanism of Action Oral direct thrombin inhibitor Oral direct factor Xa inhibitor Oral direct factor Xa inhibitor
Bioavailability* 6% 60-80% 50%
Time it takes to reach peak levels 3 hours 3 hours 3 hours
Half-life 12-17 hours 5-9 hours 9-14 hours
Method of excretion 80% renal 2/3 liver, 1/3 renal 25% renal, 75% fecal
Available dosages 150 mg BID110 mg BID 5 mg BID2.5 mg BID 20 mg Qday15 mg Qday

* Bioavailability = fraction of administered dose that remains unchanged when it reaches the systemic circulation

Unlike VKAs, direct thrombin inhibitors and direct factor Xa inhibitors are processed in the liver, and have the potential to accumulate in patients with renal impairment. In the study trials for these new anticoagulants, lower dosages of each treatment are given to patients with renal dysfunction. While the anticoagulant effect of VKAs can be readily measured using INR, accurate laboratory methods of monitoring the new oral anticoagulants are less widely available. In addition, because of the much shorter half-life, missing even one dose of the new oral anticoagulants may lead to loss of efficacy. Currently, no antidotes are readily available for emergency situations (eg. bleeding and urgent surgery), but Octaplex (warfarin antidote) and prothrombin complex concentrate (PCC) are currently under investigation as potential antidotes for rivaroxaban and dabigatran.34, 35

CLINICAL TRIALS FOR NEW ORAL ANTICOAGULANTS

The efficacy and safety of dabigatran, apixaban, and rivaroxaban have been initially evaluated in four randomized clinical trials: RE-LY, AVERROES, ARISTOTLE, and ROCKET-AF. These studies compare each new anticoagulant to warfarin, as well as apixaban to aspirin treatment. The characteristics of each trial are shown in Table 9.

Table 9: Study Characteristics of Clinical Trials for Novel Anticoagulant Therapy

RE-LY (Dabigatran) ARISTOTLE (Apixaban) AVERROES (Apixaban) ROCKET-AF (Rivaroxaban)
Dose Tested Dabigatran 150mg BIDDabigatran 110 mg BIDDose adjusted Warfarin Apixaban 5mg BIDDose adjusted Warfarin Apixaban 5mg BIDAspirin 81-324 mg per day Rivaroxaban 20mg per dayRivaroxaban 15mg per day for pts with renal dysfunctionDose adjusted Warfarin
Study Design Randomized open label, noninferiority trial Randomized control, double-blind, parallel arm,  noninferiority trial Double-blind, superiority Trial Multicenter, randomized, double-blind, double-dummy, noninferiority trial
Number of Patients 18,113 18,201 5599 14,264
Follow-up period 2 years (median) 1.8 years (median) 1.1 years (mean) 2.1 days (median)
Year of endpoint 2009 2011 2011 2011
Full Name Randomized Evaluation of Long-Term Anticoagulation Therapy Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation Apixaban Versus ASA to Reduce the risk of Strokes Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation

Dabigatran Extelate

Dabigatran extelate (Pradaxa) is an oral direct thrombin inhibitor with a half-life of 12-17 hours, and a bioavailability of 6%. 80% of the given dosage is excreted by the kidneys. Currently, the FDA has approved two doses, 150mg and 110mg. The initial clinical trial for its efficacy and safety was conducted in the RE-LY study in 2009.

How Effective is Dabigatran Extelate? (See Table 10)

Dabigatran 150mg reduces the risk of stroke or systemic embolism by 35%, compared to warfarin (p<0.001).36 Dabigatran 110mg is noninferior to warfarin for general stroke or systemic embolism prevention, but is not significantly superior to warfarin (p=0.34).36 A devastating complication of warfarin therapy is intracranial hemorrhage and stroke, and both doses of dabigatran significantly reduced the rate of hemorrhagic stroke by more than 67%, compared to warfarin (p<0.001).36 The death rate from cardiovascular disease is also lower for patients taking either doses of dabigatran. The benefit of dabigatran may be due in part to the twice-daily dosing treatment regimen and the specificity of the drug’s target for inhibition. Since the elimination half-life of dabigatran is 12-17 hours and the drug is taken twice a day, the variability in anticoagulation effect is greatly reduced.36

There was, however, a higher rate of myocardial infarction occurring with both dabigatran therapies than with warfarin.36 Warfarin is known to reduce the risk of myocardial infarction, suggesting a superior cardioprotective role of warfarin rather than an adverse effect of dabigatran.36, 37 However, the exact cause is still unclear.

Subgroup analysis shows that the benefits of dabigatran for stroke prevention are consistent in patients either experienced or naive to warfarin therapy, in patients with or without a history of stroke, and in different regions of the world.36In addition, dabigatran has been validated as an alternative to warfarin in patients requiring cardioversion.36

Table 10: RE-LY (2009) STUDY RESULTS: Rate of Stroke or Cardiovascular Event Occurring While Taking Dabigatran 150mg, Dabigatran 110mg, or Warfarin

TREATMENT OPTION

EVENT RATE  PER YEAR WHILE TAKING EACH DRUG*

Stroke or systemic embolism Ischemic Stroke or Unspecified Stroke Hemorrhagic Stroke Myocardial Infarction Death from vascular cause
Dabigatran 150 mg 1.11% per year 0.92% per year 0.10% per year 0.74% per year 2.28%per year
Dabigratran 110 mg 1.53% per year 1.34% per year 0.12%per year 0.72% per year 2.43% per year
Warfarin 1.69% per year 1.20% per year 0.38% per year 0.53% per year 2.69% per year
WHICH IS BETTER?*Based on Study Results Dabigratan 150mgis the better option for reducing the risk of all types of stroke in AF patients Dabigatran 150mgis the better option for reducing the risk of  ischemic stroke in AF patients Dabigatran 150mgis the better option for reducing the risk of hemorrhagic stroke in AF patients Warfarinis the better option for reducing the risk of myocardial infarction in AF patients Dabigatran 150mgis the better option for reducing the risk of death from vascular cause in AF patients

*Higher event rate = the drug was less effective in preventing stroke or cardiovascular event

Is Dabigatran Extelate Safer than Warfarin?(See Table 11)

Patients experience 20% less of major bleeding events overall while taking Dabigatran 110mg, compared to warfarin therapy.36 The superior safety of dabigatran may be explained by the specificity of the drug’s target. By selectively inhibiting only thrombin, dabigatran preserves some other hemostatic mechanism in the coagulation system, and thus potentially limiting the risk of bleeding.36

For gastrointestinal bleeding, dabigatran 110mg does not show a significant difference compared to warfarin (p=0.43), but the higher dose of dabigatran 150mg had a higher gastrointestinal bleeding rate.36 This may be partly explained by the tartaric acid core of dabigatran capsules, which is used to enhance the absorption of dabigatran.36

For extracranial bleeding, a subgroup analysis shows that there is an interaction between age and treatment for.36 Both doses of dabigatran lower the rate of extracranial bleeding in patients under 75 years, but dabigatran 150mg show a higher rate of extracranial bleeding compared to warfarin in patients older than 75 years.36

Apixaban

Apixaban is a direct oral factor Xa inhibitor, with a peak time of 2 hours and a half-life of 12 hours. Its bioavailability is 50%, and 25% of the given dosage is excreted by the kidneys. The major clinical trial study assessing the efficacy and safety of apixaban is ARISTOTLE in 2011, which compares apixaban 5mg to dose-adjusted warfarin in atrial fibrillation patients with at least one risk factor for stroke.

Table 11: RE-LY (2009) STUDY RESULTS: How Often Bleeding Occurs While Taking Dabigatran 150mg, Dabigatran 110mg, or Warfarin

TREATMENT OPTION

EVENT RATE PER YEAR WHILE TAKING EACH DRUG*

Major Bleeding Intracranial Bleeding Extracranial Bleeding Gastrointestinal Bleeding
Dabigatran 150 mg 3.32% per year 0.33% per year 2.84% per year 1.51% per year
Dabigratran 110 mg 2.87% per year 0.23% per year 2.51%per year 1.12% per year
Warfarin 3.75% per year 0.74 % per year 2.67% per year 1.02% per year
WHICH IS SAFER?Based on Study Results Dabigratran 110 mgis the safer option with the least amount of major bleeding in AF patients Dabigratran 110 mgis the safer option with the least amount of intracranial bleeding in AF patients Dabigratran 110 mgis the safer option with the least amount of extracranial bleeding in AF patients Warfarinis the safer option with the least amount of gastrointestinal bleeding in AF patients

*Higher event rate = the drug is not as safe because it was correlated with more bleeding events

Is Apixaban More Effective than Warfarin? (See Table 12)

The use of apixaban, compared to warfarin, significantly reduces the risk of stroke or systemic embolism in atrial fibrillation patients by 21%.38 The risk for hemorrhagic stroke is reduced by 49%, compared to warfarin, while the risk for ischemic stroke is reduced by 8%.38 The rate of cardiovascular death is lower by 11% in patients receiving apixaban therapy, and there is no significant difference in the rate of myocardial infarction.38

Within the subgroup analysis, the results were consistent across all predefined groups, such as geographic region, experience with warfarin treatment, age, sex, level of renal impairment, and presence of various risk factors for stroke.38 The rate of discontinuation of apixaban was also lower than seen with warfarin.38

Table 12: ARISTOTLE (2011) STUDY RESULTS: Rate of Stroke or Cardiovascular Event Occurring While Taking Apixaban 5mg or Warfarin

TREATMENT OPTION

EVENT RATE  PER YEAR WHILE TAKING EACH DRUG*

Stroke or systemic embolism Ischemic Stroke or Unspecified Stroke Hemorrhagic Stroke Myocardial Infarction Death from vascular cause
Apixaban 5mg 1.27% per year 0.97% per year 0.24% per year 0.53% per year 1.80% per year
Warfarin 1.60% per year 1.05% per year 0.47% per year 0.61% per year 2.02% per year
WHICH IS BETTER?Based on Study Results Apixaban 5mgis a the better option for reducing the risk of all types of stroke in AF patients Apixaban 5mgis the better option for reducing the risk of ischemic stroke in AF patients Apixaban 5mgis almost 2x better for reducing the risk of hemorrhagic stroke in AF patients Apixaban 5mgis the better option for reducing the risk of myocardial infarction in AF patients Apixaban 5mgis the better option for reducing the risk of death from vascular cause in AF patients

*Higher event rate = the drug was less effective in preventing stroke or cardiovascular event

Is Apixaban Safer than Warfarin? (See Table 13)

The risk for major bleeding is 31% lower in patients treated with apixaban compared to patients using warfarin (p<0.001).38 Across all bleeding subcategories, apixaban is substantially safer than warfarin, including the rate of gastrointestinal bleeding.38 These results are consistent within all subgroup characteristics such as age, sex, level of renal impairment, stroke risk factors, geographic location, and experience with warfarin.

There is no different adverse events compared with warfarin, and no significantly different effects for patients with renal or liver impairment.38

In summary, apixaban is superior to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation, safer in lowering the risk for major bleeding, and more convenient in not requiring the need for constant monitoring.

Table 13: ARISTOTLE (2011) STUDY RESULTS: How Often Bleeding Occurred While Taking Apixaban 5mg or Warfarin

TREATMENT OPTION

EVENT RATE  PER YEAR WHILE TAKING EACH DRUG*

Major Bleeding Intracranial Bleeding Extracranial Bleeding Gastrointestinal Bleeding
Apixaban 5mg 2.13% per year 0.33% per year 1.79% per year 0.76% per year
Warfarin 3.09% per year 0.80% per year 2.27% per year 0.86% per year
WHICH IS SAFER?Based on Study Results Apixaban 5mgis the safer option with the least amount of major bleeding in AF patients Apixaban 5mgis the safer option with the least amount of intracranial bleeding in AF patients Apixaban 5mgis the safer option with the least amount of extracranial bleeding in AF patients Apixaban 5mgis the safer option with the least amount of gastrointestinal bleeding in AF patients

*Higher event rate = the drug is not as safe because it was correlated with more bleeding events

How Does Apixaban 5mg Compare to Aspirin?(See Table 14)

The AVERROES study investigates the effects of Apixaban 5mg and aspirin for patients with atrial fibrillation deemed unsuitable for vitamin K antagonist therapy. These patients include those who refuse VKA treatment, who are classified as “low” risk for stroke by the CHADS2 (score = 1), who are at high risk for major bleeding, or who cannot maintain regular monitoring of VKA treatment.

In the trial study, apixaban 5mg is so clearly and overwhelmingly superior to aspirin that the trial is stopped early.  Apixaban 5mg is associated with 50% less events of stroke and systemic embolism compared to aspirin, with apixaban superior by 4 SDs (p<0.001).39 For ischemic stroke, apixaban is associated with 1/3 less events than aspirin. Death by vascular disease occurs 13% less in apaixaban treatment than with aspirin, and there is no significant difference between rates of myocardial infarction (p=0.59) and hemorrhagic stroke (p=0.45).38

The risk for permanent discontinuation of treatment is 12% lower for apixaban 5mg, with a discontinuation rate of 17.9% for apixaban 5mg and 20.5% for aspirin (p< 0.001).39There are no adverse events from apixaban 5mg that were significantly different from aspirin. All results were consistent across all subgroup categories such as VKA experienced or naive, and gender.

Table 14: AVERROES (2011) STUDY RESULTS: Rate of Stroke or Cardiovascular Event Occurring While Taking Apixaban 5mg or Aspirin

TREATMENT OPTION

EVENT RATE  PER YEAR WHILE TAKING EACH DRUG*

Stroke or systemic embolism Ischemic Stroke or Unspecified Stroke Hemorrhagic Stroke Myocardial Infarction Death from vascular cause
Apixaban 5mg 1.6% per year 1.1% per year 0.2% per year 0.8% per year 2.7% per year
Aspirin 3.7% per year 3.0% per year 0.3% per year 0.9% per year 3.1% per year
WHICH IS BETTER?Based on Study Results Apixaban 5mgis more than 2x better for reducing the risk of preventing all types of stroke in AF patients Apixaban 5mgis almost 3x better for reducing the risk of preventing ischemic stroke in AF patients No significant differencefor reducing the risk of hemorrhagic stroke in AF patients No significant differencefor reducing the risk of myocardial infarction in AF patients Apixaban 5mgis the better option for reducing the risk of death from vascular cause in AF patients

*Higher event rate = the drug was less effective in preventing stroke or cardiovascular event

Is Apixaban 5mg as Safe as Aspirin? (See Table 15)

There are no significant differences in major bleeding events and all subcategories studied between apixaban 5mg and aspirin. In fact, there is a significant decrease of adverse event rates (22% vs 27%, p<0.001), due to fewer events related to vascular disorders of the central nervous system among patients taking apixaban 5mg.39 With the new oral anticoagulants that are processed in the kidney, there may be high risk for patients with renal impairment. However, the AVERROES study shows no significant difference in safety between apixaban 5mg and aspirin. Overall, apixaban is as safe as aspirin while still significantly decreasing the risk of stroke.

Table 15: AVERROES (2011) STUDY RESULTS: How Often Bleeding Occurred While Taking Apixaban 5mg or Aspirin

TREATMENT OPTION

EVENT RATE  PER YEAR WHILE TAKING EACH DRUG*

Major Bleeding Intracranial Bleeding Extracranial Bleeding Gastrointestinal Bleeding
Apixaban 5mg 1.4% per year 0.4% per year 0.9% per year 0.4 % per year
Aspirin 1.2% per year 0.4% per year 1.1% per year 0.4 % per year
WHICH IS SAFER?Based on Study Results No significant differencefor major bleeding in AF patients No significant differencefor intracranial bleeding in AF patients No significant differencefor extracranial bleeding in AF patients No significant differencefor gastrointestinal bleeding in AF patients

*Higher event rate = the drug is not as safe because it was correlated with more bleeding events

Rivaroxaban

Rivaroxaban is a direct oral factor Xa inhibitor. It has a bioavailability of 50% and a half-life of 9-14 hours. 25% of the given dosage is excreted by the kidneys. It is available in two doses, 20mg and 15mg, and is currently pending FDA approval.

Is Rivaroxaban More Effective than Warfarin?(See Table 16)

The answer is no. Rivaroxaban 20mg is noninferior to warfarin (p<0.001), but not significantly superior (p=0.121) for reducing the risk of stroke or systemic embolism in patients with atrial fibrillation.40 Rivaroxaban 20mg is correlated with 37% less hemorrhagic stroke events than warfarin (p=0.024), although there is significant difference in myocardial infarction events (p=0.121).40 In the subgroup analysis, patients with moderate renal impairment are given a lower dose of rivaroxaban (15mg) during the study tiral, but both warfarin and rivaroxaban 15mg groups show higher stroke events than patients without renal impairment.41Thus, rivaroxaban is a noninferior alternative to warfarin, with a greatly decreased risk for hemorrhagic stroke.

Table 16: ROCKET-AF (2011) STUDY RESULTS: Rate of Stroke or Cardiovascular Event Occurring While Taking Rivaroxaban 20mg or Warfarin

TREATMENT OPTION

EVENT RATE  PER YEAR WHILE TAKING EACH DRUG*

Stroke or systemic embolism Ischemic Stroke or Unspecified Stroke Hemorrhagic Stroke Myocardial Infarction Death from vascular cause
Rivaroxaban 20mg 2.1% per year 2.1% per year 0.44% per year 1.43% per year Not part of study
Warfarin 2.4% per year 2.3% per year 0.71% per year 1.78% per year Not part of study
WHICH IS BETTER?Based on Study Results No significant differencefor reducing the risk of all types of stroke in AF patients No significant differencefor reducing the risk of ischemic stroke in AF patients Rivaroxaban 20mgis the better option for reducing the risk of ischemic stroke in AF patients No significant differencefor reducing the risk of ischemic stroke in AF patients Not part of study

*Higher event rate = the drug was less effective in preventing stroke or cardiovascular event

Is Rivaroxaban Safer than Warfarin? (See Table 17)

The ROCKET-AF study finds no significant difference in the rate of major bleeding events between rivaroxaban 20mg and warfarin.40 There is a 33% reduction of intracranial bleeding in the rivaroxaban 20mg group (p=0.02), but there is a 31% increase in gastrointestinal bleeding in the rivaroxaban 20mg group.40 The results are consistent for patients with renal impairment, and across all other subgroup categories such as ethnicity, sex, and age.

Overall, rivaroxaban is noninferior to warfarin for effectiveness and safety, and the results can be preserved in for patients with moderate renal impairment by prescribing them a lower dosage.

Table 17: ROCKET-AF (2011) STUDY RESULTS: How Often Bleeding Occurred While Taking Rivaroxaban 20mg or Warfarin

TREATMENT OPTION

EVENT RATE  PER YEAR WHILE TAKING EACH DRUG*

Major Bleeding Intracranial Bleeding Extracranial Bleeding Gastrointestinal Bleeding
Rivaroxaban 20mg 5.6% per year 0.8% per year Not part of study 3.2% per year
Warfarin 5.4% per year 1.2% per year Not part of study 2.2% per year
WHICH IS SAFER?Based on Study Results No significant differenceof major bleeding in AF patients Rivaroxaban 20mgis the safer option with the least amount of intracranial bleeding in AF patients Not part of study Warfarinis the safer option with the least amount of gastrointestinal bleeding in AF patients

*Higher event rate = the drug is not as safe because it was correlated with more bleeding events

How do the new oral anticoagulants compare with each other?

Based on the results of RE-LY, ARISTOTLE, and ROCKET-AF, as well as the results from an indirect comparison conducted by Lip et al, 2011, we ranked the new oral anticoagulants and warfarin in order of highest efficacy and safety based on their event rates.33 Tables 18 and 19 shows those rankings.

Efficacy (see Table 9)

Dabigatran 150mg is significantly superior to rivaroxaban 20mg and dabigatran 110mg in preventing stroke or systemic embolism. Dabigatran 150mg is also associated with more reduction of stroke events than apixaban 5mg, but the results were not statistically significant. However, apixaban 20mg has been found to be superior to the lower dose of dabigatran 110mg, and rivaroxaban.

Dabigatran 150mg shows the highest reduction in hemorrhagic stroke, and is significantly superior to rivaroxaban 20mg and dabigatran 5mg. Apixaban is also significantly superior to rivaroxaban and dabigatran 110mg, but show no significant difference with dabigatran 150mg.

In reducing the risk of ischemic stroke or death by vascular causes, there are no significant differences between each new oral anticoagulant, although all are significantly superior to warfarin.

For reducing the risk of myocardial infarction, warfarin is still superior to all the new oral anticoagulants, and there was no significant difference between each new oral anticoagulant.

Safety (see Table 10)

Apixaban 5mg is associated with much lower major bleeding rates than dabigatran 150mg and rivaroxaban 20mg, but has a nonsignificant difference with dabigatran 110mg. Apixaban is superior to all the other new oral anticoagulants in reducing the risk for gastrointestinal bleeding and extracranial bleeding. For intracranial bleeding, dabigatran 110 is associated with the lowest risk.

Overall, dabigatran 150mg and apixaban 5mg have the highest reduction of stroke or systemic embolism, while apixaban 5mg and dabigatran 110mg are the safest for showing the lowest events of major bleeding.33

Table 18:INDIRECT COMPARISON of Effectiveness for All Available Oral Anticoagulants

 

RELATIVE RISK (RR) FOR EVENTS COMPARED TO WARFARIN

Ranked from lowest risk (1) to highest risk (5)

  Ranking                                               Relative Risk (95% CI­­) WHICH IS THE BEST OPTION?
Stroke or systemic embolism 1. Dabigatran 150mg                         RR = 0.66 (0.53-82)2. Apixaban 5mg                               RR = 0.79 (0.66-0.95)3. Rivaroxaban 20mg                         RR = 0.88 (0.75-1.03) 4. Dabigatran 110mg                          RR = 0.91 (0.74-1.11) 5. Warfarin                                        RR = 1.00 Dabigatran 150mgis the most effective for reducing the risk of stroke or systemic embolism
Ischemic or uncertain type of stroke 1. Dabigatran 150mg                         RR = 0.76 (0.60-0.98)2. Apixaban 5mg                               RR = 0.92 (0.74-1.13)3. Rivaroxaban 20mg                         RR = 0.94 (0.87-1.03) 4. Warfarin                                        RR = 1.00 5. Dabigatran 110mg                          RR = 1.11 (0.89-1.40) Dabigatran 150mgis most effective for reducing the risk of ischemic stroke
Hemorrhagic stroke 1. Dabigatran 150mg                         RR = 0.26 (0.14-0.49)2. Dabigatran 110mg                         RR = 0.31 (0.17-0.56)3. Apixaban 5mg                               RR = 0.51 (0.35-0.75) 4. Rivaroxaban 20mg                         RR = 0.59 (0.51-0.70) 5. Warfarin                                        RR = 1.00 Dabigatran 150mgis most effective for reducing the risk of hemorrhagic stroke
Nondisabling stroke 1. Dabigatran 150mg                          RR = 0.62 (0.43-0.91)2. Dabigatran 110mg                          RR = 0.86 (0.61-1.22)3. Warfarin                                        RR = 1.00 4. Rivaroxaban 20mg                         RR = 1.03 (0.92-1.15) no data for Apx Dabigatran 150mgis most effective for reducing the risk of nondisabling stroke
Death from vascular causes 1. Dabigatran 110mg                          RR = 0.85 (0.72-0.99)2. Rivaroxaban 20mg                         RR = 0.89 (0.80-0.97)3. Apixaban 5mg                               RR = 0.89 (0.76-1.04) 4. Dabigatran 150mg                         RR = 0.90 (0.77-1.06) 5. Warfarin                                       RR = 1.00 Dabigatran 110mgis most effective for reducing the risk of death from vascular causes
Myocardial infarction 1. Rivaroxaban 20mg                         RR = 0.85 (0.79-0.92)2. Apixaban 5mg                               RR = 0.88 (0.66-1.17)3. Warfarin                                       RR = 1.00 4. Dabigatran 110mg                         RR = 1.35 (0.98-1.87) 5. Dabigatran 150mg                         RR = 1.38 (1.00-1.91) Warfarinis most effective for reducing the risk of myocardial infarction

Table 19: INDIRECT COMPARISON of Safety for All Available Oral Anticoagulants

Factors

RELATIVE RISK (RR) FOR EVENTS COMPARED TO WARFARIN

Ranked from lowest risk (1) to highest risk (5)

Major bleeding
  1. Apixaban 5mg                           RR = 0.71 (0.68-0.75)
  2. Dabigatran 110mg                     RR = 0.80 (0.69-0.93)
  3. Dabigatran 150mg                     RR = 0.93 (0.81-1.07)
  4. Warfarin                                   RR = 1.00
  5. Rivaroxaban 20mg                    RR = 1.04 (.96-1.13)
Safest Option by indirect comparison:Apixaban 5mg
Major or clinically relevant non-major bleeding
  1. Apixaban 5mg                           RR = 0.68 (0.61-0.75)
  2. Dabigatran 110mg                     RR = 0.78 (0.74-0.83)
  3. Dabigatran 150mg                     RR = 0.91 (0.86-0.97)
  4. Warfarin                                   RR = 1.00
  5. Rivaroxaban 20mg                    RR = 1.04 (.96-1.13)
Safest Option by indirect comparison:Apixaban 5mg
Intracranial bleeding
  1. Dabigatran 110mg                     RR = 0.31(0.20-0.47)
  2. Dabigatran 150mg                     RR = 0.40 (0.27-0.60)
  3. Apixaban 5mg                           RR = 0.42 (0.30-0.58)
  4. Rivaroxaban 20mg                     RR = 0.67 (0.47-0.93)
  5. Warfarin                                    RR = 1.00
Safest Option by indirect comparison:Dabigatran 110mg
Gastrointestinal bleeding
  1. Apixaban 5mg                           RR = 0.89 (0.70-1.15)
  2. Warfarin                                   RR = 1.00
  3. Dabigatran 110mg                     RR = 1.10 (0.86-1.41)
  4. Rivaroxaban 20mg                    RR = 1.45 (1.23-1.60)
  5. Dabigatran 150mg                     RR = 1.50 (1.19-1.89)
Safest Option by indirect comparison:Apixaban 5mg
Extracranial or unclassified bleeding
  1. Apixaban 5mg                           RR = 0.79 (0.68-0.93)
  2. Dabigatran 110mg                     RR = 0.94 (0.80-1.10)
  3. Warfarin                                   RR = 1.00
  4. Dabigatran 150mg                     RR = 1.07 (0.92-1.25)

no data for Riv

Safest Option by indirect comparison:Apixaban 5mg

Summary of the Pros and Cons of New Oral Anticoagulant Alternatives to Warfarin

Pros:

  1. All the new alternates to warfarin are associated with a lower risk for stroke or systemic embolism.
  2. All the new alternatives to warfarin are associated with fewer deaths from cardiovascular causes.
  3. All the new alternatives to warfarin are associated with lower rates of discontinuation.
  4. None of the new alternatives to warfarin require dosage monitoring.
  5. The drug effects of all the new alternatives are more predictable and can be generalized across all patient populations.
  6. The two most effective alternatives to warfarin, dabigatran and apixaban, are substantially safer than warfarin.

Cons:

  1. The effectiveness of the new oral anticoagulants decreases even if one dose is missed.
  2. Information on the effects during pregnancy or in patients with extreme body weights is still unknown.
  3. There is no approved antibody for the new oral anticoagulants yet.
  4. Dabigatran is associated with dyspepsia as an adverse event.
  5. Warfarin is still superior in reducing the risk for myocardial infarction, although none of the new oral anticoagulants increase the risk.
  6. Warfarin is associated with less gastrointestinal bleeding.
  7. Only dabigatran has been FDA-approved in the United States.

CONCLUSION

Patients diagnosed with atrial fibrillation are at a significantly higher risk for stroke. To assess whether these patients are suitable for oral anticoagulation therapy and the associated bleeding risks, physicians can categorize patients with the CHA2DS2VASc stroke risk rubric, and pair it with the HAS-BLED bleeding risk rubric. Patients with a CHA2DS2VASc score >1 are recommended for anticoagulation therapy. Patients with a HAS-BLED score >3 even with a CHA2DS2VASc score >1, are at too high risk for oral anticoagulation therapy, and can be treated with aspirin instead. The new available anticoagulants, dabigatran, apixaban, and rivaroxaban, are now shown to be better alternatives to warfarin for first-line therapy. As the efficacy and safety of each oral anticoagulant also depends on age and renal function, the choice of anticoagulant will depend on the individual characteristics of each patient.


Appendix A: Contemporary Bleeding Risk Stratification Schemas

Study Low Intermediate High Calculation of Bleeding Point System
Beyth et al, 1998 0 1-3 >3 1.6 for age ≥60 years1.3 for female sex2.2 for cancer malignancy
Kuijer et al, 1999 0 1-2 >3 1 point for:Age ≥65GI bleeding in the past 2 weeks Previous history of stroke Recent MI, Hct <30&, diabetes, creatinine>1.5 ml/l)
Gage et al, 2006HEMORR2HAGES 0-1 2-3 > 4 2 points for previous bleeding1 point for:Liver/Renal disease Alcohol abuse Cancer/malignancy Age
Shireman et al,2006 ≤ 1.07 > 1.07-<2.19 >2.19 .49 for Age > 70 years0.32 for Female sex0.58 for Remote bleeding 0.62 for Recent bleeding 0.71 for Alcohol/Drug abuse 0.27 for History of Diabetes 0.86 for Anemia 0.32 for Concomitant antiplatelet drug use
Pisters et al, 2010HAS-BLED 0 1-2 ≥3 1 point for:HypertensionAbnormal Renal/Liver Function History of stroke History of predisposition for bleeding Labile INR Age older than 75 Concomitant Drug/Alcohol use

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