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Apixaban▼ versus warfarin in atrial fibrillation: the ARISTOTLE study in context

On The Horizon Rapid Review NPC Logo

23 November 2011

The ARISTOTLE study found that apixaban 5 mg twice a day reduced the risk of the composite outcome of ischaemic or haemorrhagic stroke or systemic embolism compared to adjusted-dose warfarin in patients with atrial fibrillation (AF). Apixaban also reduced the risks of (separately) all-cause death, major bleeding, and non-major bleeding; the risk of the composite of stroke, systemic embolism, major bleeding or death from any cause; and the risk of the composite of stroke, systemic embolism, myocardial infarction (MI) or death from any cause.

Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.

Action
Apixaban is licensed for prevention of venous thromboembolism (VTE) in adult patients who have undergone elective hip or knee replacement surgery. Commissioners should include in their planning the possibility that it may also be marketed in the future for the prevention of stroke in AF. They should note that a NICE technology appraisal relating to its use in VTE is in progress, and one has been proposed for its use in AF. Commissioners will need to consider this information alongside their planning for the use of dabigatran▼ and rivaroxaban▼by people with AF. Dabigatran is licensed and marketed for the prevention of stroke and systemic embolism in people with AF who have certain risk factors. Rivaroxaban has also received a positive opinion from the European Medicines Agency (EMA) for this indication (with slight differences in the specified risk factors). NICE is developing technology appraisals relating to the use of dabigatran and rivaroxaban for prevention of stroke in AF.

This study represents the best available evidence relating to apixaban in this indication. These data, together with their limitations, should be taken into account by local decision-makers when planning for the entry of this new medicine and the commissioning of appropriate services. Local decision-makers may need to consider additional published data about this product as they emerge.

What is the background to this?
Three novel oral anticoagulant drugs are now on the market. Dabigatran is a direct thrombin inhibitor, whereas apixaban and rivaroxaban are direct Factor Xa inhibitors.

Use in prevention and treatment of VTE
All three novel oral anticoagulants are currently licensed and marketed for prevention of VTE in patients undergoing elective hip or knee replacement surgery. Dabigatran and rivaroxaban are both recommended in NICE technology appraisals as options for this indication (TA157 and TA170 respectively). A NICE technology appraisal on apixaban for this indication is in progress and expected in April 2012.

Rivaroxaban has recently (22 September 2011) received positive opinions for treatment of deep vein thrombosis (DVT) and prevention of recurrent DVT and pulmonary embolism following an acute DVT in adults. NICE technology appraisals are in progress relating to rivaroxaban for use in the treatment and secondary prevention of VTE (expected July 2012) and prevention of VTE in people hospitalised for acute medical conditions.

Use in prevention of stroke and systemic embolism in AF
Dabigatran is the only one of the novel oral anticoagulants which is currently licensed and marketed for the prevention of stroke and systemic embolism in patients with AF who have certain risk factors. A NICE technology appraisal relating to the use of dabigatran for this indication is being developed (expected December 2011). Rivaroxaban also recently (22 September 2011) received a positive opinion for this indication (with slight differences in the specified risk factors). A NICE technology appraisal relating to rivaroxaban for this indication is in progress (expected May 2012).

Apixaban has previously been studied for the prevention of stroke or systemic embolism in people with AF. The AVERROES study, discussed further below, compared apixaban with aspirin in patients with AF who were not suitable for warfarin. A NICE technology appraisal for its use to prevent stroke or systemic embolism in people with AF has been proposed.

What did this study set out to do?
The ARISTOTLE double blind, double dummy randomised controlled trial (RCT) also examined the effects of apixaban on the risk of stroke or systemic embolism in patients with AF. It compared apixaban 5 mg twice a day with adjusted-dose warfarin (target INR 2.0 to 3.0) in 18,201 patients with AF and at least one additional risk factor for stroke (mean CHADS2 score 2.1), over a median follow-up of 1.8 years. The trial was designed to test for non-inferiority, but demonstrated the superiority of apixaban (a pre-specified analysis).

What does this study claim?
The rate of the primary outcome (ischaemic or haemorrhagic stroke or systemic embolism) was 1.27% per year in the apixaban group compared with 1.60% per year in the warfarin group (hazard ratio [HR] with apixaban 0.79, 95% confidence interval [CI] 0.66 to 0.95, p<0.001 for non-inferiority; p=0.01 for superiority, number needed to treat [NNT] over 1.8 years 168, 95%CI 95 to 773).

The rate of major bleeding was 2.13% per year in the apixaban group and 3.09% per year in the warfarin group (HR 0.69, 95%CI 0.60 to 0.80 p<0.001, NNT over 1.8 years 66, 95%CI 48 to 110), and the rates of death from any cause were 3.52% and 3.94%, respectively (HR 0.89, 95%CI 0.80 to 0.998, p=0.047, NNT over 1.8 years 132, 95%CI 67 to 6951).

The risk of the composite outcome of stroke, systemic embolism, MI or death from any cause was reduced in the apixaban group: HR 0.88 (95%CI 0.80 to 0.97, p=0.01, NNT over 1.8 years 91, 95%CI 51 to 406). The risk of the net clinical outcome of stroke, systemic embolism, major bleeding or death from any cause was also reduced in the apixaban group: HR 0.85 (95%CI 0.78 to 0.92, p<0.001, NNT over 1.8 years 56, 95%CI 36 to 117). Further information on adverse events is given in the supplementary appendix. Statistical analysis is not presented, but the adverse event rates appear similar in both study groups, including the rates for disturbances of liver function tests. Fewer patients in the apixaban group discontinued the study drug before the end of the study: 25.3% (3.6% due to death) versus 27.5% (3.8% due to death) in the warfarin group, p=0.001.

How does this relate to other key studies?
The RE-LY study found that dabigatran at 150 mg twice daily was statistically significantly more effective than warfarin (relative risk [RR] 0.66; 95%CI 0.53 to 0.82; P<0.001). However, more patients randomised to dabigatran discontinued treatment during the study than patients randomised to warfarin, and there was a higher incidence of discontinuations that were a result of serious side effects in the dabigatran group. The rate of MI was significantly higher in the dabigatran 150 mg group (0.74% per year) than in the warfarin group (0.53% per year) (RR 1.38, 95% CI, 1.00 to 1.91; P=0.048)*. As an editorial in the BMJ pointed out, the RE-LY trial was conducted in a select group of patients and the outcomes may be difficult to extrapolate to everyday clinical practice. The clinical benefits have to be balanced against an excess of dyspepsia, gastrointestinal bleeding, MI and the potential for the drug to accumulate in patients suffering from renal dysfunction. The mean baseline CHADS2 score in RE-LY was 2.1, the same as in ARISTOTLE.

In the ROCKET AF double blind RCT (median follow up 1.9 years), rivaroxaban was shown to be non-inferior to adjusted-dose warfarin for prevention of stroke or systemic embolism, but not statistically significantly superior to it. The risk of fatal bleeding was lower in the rivaroxaban group (0.2% vs. 0.5%, p=0.003), but there was no significant difference in the risk of major and non-major clinically relevant bleeding (14.9% for rivaroxaban and 14.5% per year for warfarin, HR 1.03, 95%CI 0.96 to 1.11, p=0.44). The mean baseline CHADS2 score in ROCKET AF was 3.5. ROCKET AF was reviewed in more depth in On The Horizon Rapid Review 4580.

The AVERROES study of apixaban versus aspirin was terminated early after a mean of 1.1 years because of a clear benefit in favour of apixaban. The rate of the primary outcome of stroke or systemic embolism was 1.6% per year among patients assigned to apixaban and 3.7% per year among those assigned to aspirin (HR 0.45, 95%CI 0.32 to 0.62, p<0.001). The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (HR 0.79, 95% CI 0.62 to 1.02, p=0.07). The rates of major bleeding were 1.4% per year in the apixaban group and 1.2% per year in the aspirin group (HR 1.13, 95%CI 0.74 to 1.75, p=0.57). These observed differences in bleeding rates were not statistically significant but this is difficult to interpret because the trial was terminated early: it may have been underpowered to detect a true difference in bleeding risk. The CHADS2 score at baseline in AVERROES was 2.0 in the apixaban group and 2.1 in the aspirin group: similar to that in RE-LY and ARISTOTLE but lower than in ROCKET AF.

So what
Differences among study populations, study designs, and times within target INR range (for patients randomised to warfarin) limit the comparisons which can be drawn between apixaban, dabigatran and rivaroxaban. For example, patients in ROCKET AF (rivaroxaban) had a higher risk of stroke at baseline than those in other studies. As an editorial accompanying ARISTOTLE points out, in all the studies the reductions in the primary efficacy end point — which included haemorrhagic as well as ischaemic stroke — were greatly influenced by a marked reduction in the risk of haemorrhagic stroke. Of the three drugs, only dabigatran at a dose of 150 mg also significantly reduced the risk of ischaemic stroke compared with warfarin. Point estimates for reduction in risk of stroke and reduction in all-cause mortality were similar in all studies. However, only apixaban has so far been shown to exhibit the combination of being significantly superior to warfarin in terms of stroke reduction; all-cause mortality; and fatal, major, and non-major bleeding; with no statistically significant increase in risk of MI.

Probably the biggest gap in the evidence relating to all these drugs, including apixaban, is the limited long term safety and efficacy data. The long term effects of dabigatran are being evaluated in an ongoing follow-up study (RELY-ABLE) of patients enrolled in RE-LY. Long term effects of apixaban are similarly being investigated in the Long Term Open label extension of AVERROES.

The place of these drugs in therapy and the impact for local services is not altogether clear. The cost per daily dose of these drugs is higher than that for warfarin, but they do not need regular anticoagulant monitoring, and there might be an opportunity to reduce some costs associated with anticoagulation services and reduce the impact of the monitoring component on patients’ lives. On the other hand, commissioners may wish to include in their planning that many of the costs associated with current warfarin services will be fixed, because of the need to maintain the existing infrastructure for long-standing patients while the place in therapy of these newer antithrombotics is established.

The licence relating to apixaban for VTE prophylaxis relates to a 2.5 mg dose tablet. This reflects the dose used twice-daily in the ADVANCE studies, but it is half the 5 mg twice-daily dose used in ARISTOTLE. At present no information on the likely costs of apixaban compared to dabigatran for use in AF is available.

Study details
Granger CB et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 10.1056/NEJMoa1107039, published online 28 August 2011

Design Double blind, double dummy randomised controlled trial

Patients 18,201 patients with atrial fibrillation or flutter. In addition, at least one of the following risk factors for stroke was required: an age of at least 75 years; previous stroke, transient ischaemic attack, or systemic embolism; symptomatic heart failure within the previous three months or left ventricular ejection fraction of no more than 40%; diabetes mellitus; or hypertension requiring pharmacologic treatment. Key exclusion criteria included AF due to a reversible cause; stroke within the previous seven days; mitral stenosis; another indication for warfarin, aspirin >165 mg/day or aspirin plus clopidogrel (31% of patients were taking aspirin at baseline, and 2% were taking clopidogrel); and severe renal insufficiency (serum creatinine level of >221 micromol/L or calculated creatinine clearance of <25 ml per minute). Patients were classified as not having received warfarin previously if they had used warfarin or another vitamin K antagonist for no more than 30 consecutive days. The CHADS2 score at baseline was 2.1.

Intervention and comparison 9120 participants received apixaban (almost all at a dose of 5 mg twice daily. 428 patients received 2.5 mg twice daily, these people had two or more of the following criteria: an age of at least 80 years, a body weight of no more than 60 kg, or a serum creatinine level of 133 micromol/L or more). 9081 patients received warfarin adjusted to achieve an INR of 2.0 to 3.0. Patients in this group had an INR in this range for a median of 66.0% of the time and a mean of 62.2% of the time, after the exclusion of INR values during the first 7 days after randomization and during study-drug interruptions. Mean duration of follow up was 1.8 years.

Outcomes and results

Outcome

Event rate per year (%)

Hazard ratio (95%CI)

p value

NNT over 1.8 years (95%CI)

Apixaban

Warfarin

Stroke or systemic embolism1

1.27

1.60

0.79

(0.66 to 0.95)

0.01

168

(95 to 773)

Ischaemic or uncertain type of stroke

0.97

1.05

0.92

(0.74 to 1.13)

0.42

Haemorrhagic stroke

0.24

0.47

0.51

(0.35 to 0.75)

<0.001

238

(153 to 535)

Death from any cause

3.52

3.94

0.89

(0.80 to 0.998)

0.047

132

(67 to 6951)

Myocardial infarction (MI)

0.53

0.61

0.88

(0.66 to 1.17)

0.37

ISTH major bleeding2

2.13

3.09

0.69

(0.60 to 0.80)

<0.001

66

(48 to 110)

Major or clinically relevant non-major bleeding3

4.07

6.01

0.68

(0.61 to 0.75)

<0.001

34

(27 to 47)

Any bleeding

18.1

25.8

0.71

(0.68 to 0.75)

<0.001

13

(11 to 15)

Stroke, systemic embolism, major bleeding or death from any cause

6.13

7.20

0.85

(0.78 to 0.92)

<0.001

56

(36 to 117)

Stroke, systemic embolism, MI or death from any cause

4.85

5.49

0.88

(0.80 to 0.97)

0.01

91

(51 to 406)

  1. Primary efficacy outcome
  2. Primary safety outcome, defined as “clinically overt bleeding accompanied by a decrease in the haemoglobin level of at least 2 g per decilitre or transfusion of at least 2 units of packed red cells, occurring at a critical site, or resulting in death”.
  3. A composite of major bleeding and clinically relevant non-major bleeding, which was defined as clinically overt bleeding that did not satisfy the criteria for major bleeding and that led to hospital admission, physician-guided medical or surgical treatment, or a change in antithrombotic therapy.

Further information on adverse events is given in the supplementary appendix. Statistical analysis is not presented, but the rates appear similar in both study groups. For example, the outcome of ALT or AST >3 times upper limit of normal (ULN) and total bilirubin >2 times ULN and alkaline phosphatase <2 times ULN occurred in 0.2% of patients in each group.

Study sponsorship: Supported by Bristol-Myers Squibb and Pfizer

Further information on atrial fibrillation can be found on NHS Evidence and in the e-learning section of the NPC website

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*Amendment 14th December 2011.

The authors of the RE-LY study updated their article after identifying several additional primary efficacy and safety outcomes. This included an additional 4 cases of clinical myocardial infarction (MI) and 28 cases of silent MI. Silent MI is included in the RE-LY definition for cases of myocardial infarction.

When these cases were taken into account the rate of MI was numerically higher, but not statistically significantly higher, in the dabigatran 150 mg group (0.81% per year) than in the warfarin group (0.64% per year) (RR 1.27, 95% CI, 0.94-1.71; P=0.12).

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