Apixaban Superior to Warfarin Regardless of A-fib Type, Duration

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In patients with nonvalvular atrial fibrillation (A-fib), the novel anticoagulant apixaban shows the same efficacy and safety advantages over warfarin regardless of the duration or type of the condition. However, absolute stroke risk is higher in patients with persistent or permanent compared with paroxysmal A-fib.

The findings, from a prespecified analysis of the ARISTOTLE trial, were published online April 17, 2013, ahead of print in the European Heart Journal.

The main trial randomized 18,201 patients with A-fib and at least 1 stroke risk factor to dose-adjusted warfarin plus placebo (n = 9,081) or apixaban (5 mg [2.5 mg for those at high bleeding risk] twice daily) plus placebo (n = 9,120). Apixaban proved superior to warfarin for preventing stroke or systemic embolism, the primary endpoint (1.27% vs. 1.60% per year; P for superiority = 0.01). The new agent also resulted in lower rates of major bleeding (P < 0.001) and all-cause death (P = 0.047). The results were published in the New England Journal of Medicine in September 2011.

Subanalysis Drills Down to A-fib Type, Duration

For the current substudy, investigators led by Sana M. Al-Khatib, MD, MHS, of the Duke Clinical Research Institute (Durham, NC), stratified patients according to the type of A-fib:

  • Paroxysmal (n = 2,786; 15.3%)
  • Persistent or permanent (n = 15,412)

as well as the duration of A-fib:

  • Median 489 days for paroxysmal patients
  • Median 914 days for persistent/permanent patients

Apixaban showed a consistent advantage over warfarin with regard to stroke or systemic embolism, all-cause mortality, major bleeding, and net benefit (composite of the preceding endpoints) for both types of A-fib (table 1).

Table 1. Annual Outcomes by A-fib Type and Treatment

 

Apixaban

Warfarin

P for Interaction

Stroke or Systemic Embolism
Paroxysmal
Persistent/Permanent

 
0.82%
1.35%

 
1.14%
1.69%

 
0.71

Major Bleeding
Paroxysmal
Persistent/Permanent

 
1.88%
2.18%

 
2.56%
3.19%

 
0.75

All-Cause Mortality
Paroxysmal
Persistent/Permanent

 
2.79%
3.65%

 
2.82%
4.15%

 
0.50

Net Benefit
Paroxysmal
Persistent/Permanent

 
5.02%
6.33%

 
5.58%
7.51%

 
0.62

 
The duration of A-fib at study entry did not affect the advantage of apixaban for any endpoint (P > 0.13 for all interactions).

After adjustment for potential confounders, the overall risk of stroke or systemic embolism was lower in patients with paroxysmal A-fib compared with those with persistent/permanent A-fib.  The paroxysmal group also showed a trend toward lower rates of all-cause mortality and net benefit. The risk of major bleeding was similar between the 2 types (table 2).

Table 2. Adjusted Risk of Events: Paroxysmal vs. Persistent/Permanent A-fib

 

Adjusted HR

95% CI

P Value

Stroke or Systemic Embolism

0.70

0.51-0.93

0.015

All-Cause Mortality

0.85

0.71-1.01

0.068

Major Bleeding

0.93

0.75-1.15

0.487

Net Benefit

0.881

0.772-1.0

0.0614

 
According to the authors, the finding of generally lower event rates in patients with paroxysmal A-fib contrasts with the results of previous clinical trials of warfarin and other anticoagulants that showed no difference. But they note that those studies were smaller and included fewer patients with persistent or permanent A-fib. Dr. Al-Khatib and colleagues also speculate that the discrepancy “may relate to differences in patient characteristics, definitions of types of [A-fib], and outcomes or overall management of patients.”

In addition, the authors say the current results should be interpreted with caution because classification of A-fib into types is challenging, especially given that patients may transition from 1 type to another at various time points. The investigators also note that they were unable to analyze persistent A-fib and permanent A-fib separately, and “because patients with these types of A-fib may be inherently different, combining them may have introduced some bias.”

‘A Consistent Story’

In a telephone interview with TCTMD, Michael D. Ezekowitz, MD, PhD, of Thomas Jefferson Medical College (Philadelphia, PA), said the finding that A-fib type does not affect the relative efficacy of apixaban was not surprising “because its effect has been remarkably consistent among the various subgroups that have been evaluated thus far. And in RE-LY, the results for paroxysmal and persistent/permanent A-fib were identical with the 150 mg dose of [the direct thrombin inhibitor] dabigatran. So this seems to be a very consistent story.”

As for whether rivaroxaban, the other approved factor Xa inhibitor, is likely to show the same pattern, Dr. Ezekowitz cautioned against jumping to conclusions because the patient population in the ROCKET-AF trial was higher-risk, with an average CHADS2 score of 5.5. “But I think it is important that such subanalyses be done for all the [new anticoagulant] trials because they’re changing the practice of medicine,” he commented.

Dr. Ezekowitz said the lower stroke rate seen for paroxysmal A-fib is explained by the fact that these patients generally have a lower CHADS2 score and are in an earlier stage of atrial disease. By contrast, patients with persistent or permanent A-fib not only tend to have more comorbidities, but their disease has progressed to the stage of atrial remodeling and enlargement, putting them at higher risk.

All the new anticoagulants were developed to simplify management of all A-fib patients, Dr. Ezekowitz concluded, and the current ARISTOTLE subanalysis supports that goal. 

Study Details 

Compared with patients with paroxysmal A-fib, those with the persistent or permanent version were older and more often men with a history of heart failure and a higher CHADS2 score. Paroxysmal patients showed a trend toward a higher rate of prior stroke, TIA, or systemic embolism and more commonly had histories of prior MI, hypertension, and vascular disease.

The majority of patients had data entered on 2 or fewer ECGs during follow-up (69.4% of the persistent or permanent group and 67.4% in the paroxysmal group). At study entry, 30.9% of the paroxysmal group had A-fib on their last trial ECG, while 87.3% of the persistent/permanent group had A-fib on their last ECG.

 


Source:Al-Khatib SM, Thomas L, Wallentin L, et al. Outcomes of apixaban vs. warfarin by type and duration of atrial fibrillation: Results from the ARISTOTLE trial. Eur Heart J. 2013;Epub ahead of print.

Related Stories:

Apixaban Superior to Warfarin Regardless of A-fib Type, Duration

In patients with nonvalvular atrial fibrillation (A-fib), the novel anticoagulant apixaban shows the same efficacy and safety advantages over warfarin regardless of the duration or type of the condition. However, absolute stroke risk is higher in patients with persistent or permanent compared with paroxysmal A-fib.
Disclosures
  • The study was supported by Bristol-Myers Squibb and Pfizer.
  • Dr. Al-Khatib reports serving on the steering committee for the trial.
  • Dr. Ezekowitz reports serving as co-principal investigator for the RE-LY and X-ERT trials and receiving consulting fees, lecture fees, and grant support from Aryx Therapeutics and Boehringer-Ingelheim, consulting fees from Sanofi-Aventis, and lecture fees and grant support from Portola Pharmaceuticals.

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