Apixaban Surpasses Warfarin At All Risk Levels in A-Fib Patients

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Apixaban reliably benefits patients with atrial fibrillation (A-fib) irrespective of their predicted bleeding or stroke risk and regardless of the risk score used. The findings, from a secondary analysis of the ARISTOTLE trial published online October 1, 2012, ahead of print in the Lancet, suggest that commonly used approaches to risk stratification may be unnecessary when considering the new oral anticoagulants.

ARISTOTLE, published last September in the New England Journal of Medicine, showed that the novel anticoagulant provides superior protection against stroke and systemic embolism while decreasing mortality and bleeding risk. More than 18,000 A-fib patients with at least 1 additional risk factor for stroke were randomized in the double-blind trial to apixaban 5 mg twice daily or warfarin titrated to a target INR range of 2.0 to 3.0.

Net Clinical Benefit Obtained

For the current analysis, researchers led by Renato D. Lopes, MD, PhD, of Duke University Medical Center (Durham, NC), calculated each patient’s baseline bleeding and stroke risk according to 3 scoring systems—CHADS_2, CHA₂DS₂VASc, and HAS-BLED.

Median scores were well distributed between the 2 treatment groups. Patients with higher risk scores were older, had more comorbidities, and were more likely to have persistent or permanent A-fib than their lower-risk counterparts.

The overall advantage for apixaban over warfarin for the primary endpoint of stroke or systemic embolism was evident in patients that fell into CHADS₂ categories 1, 2, or 3 and above. While the differences did not always reach significance within individual categories, the trend toward benefit was consistent across groups and net clinical events (composite of stroke, systemic embolism, all-cause death, and ISTH major bleeding) favored apixaban (table 1).

Table 1. Outcomes by CHADS₂ Score: Percent per Person-Year

In addition, both all-cause mortality and major bleeding were reduced for apixaban in all CHADS₂ risk categories.

Similar patterns were seen when outcomes were analyzed according to CHA₂DS₂VASc and HAS-BLED scores. In particular, intracranial bleeding was reduced by a greater degree among patients with HAS-BLED scores of 3 or higher (HR 0.22; 95% CI 0.10-0.48) than among those with scores of 0 to 1 (HR 0.66; 95% CI 0.39-1.12), though the difference between the 2 levels of risk was not significant.

Scores Do Not Speak to Risk vs. Benefit

Dr. Lopes told TCTMD in a telephone interview that the take-home message from these findings is not that existing scores are inadequate. Rather, risk scores may not be necessary in the context of A-fib.

According to Dr. Lopes, clinical risk scores serve 2 general purposes—predicting the likelihood of events and guiding therapy. The scores relevant to A-fib are “pretty good” at the former but less suited for the latter because the same patients likely to experience ischemic events are those who tend to experience bleeding events. “So it does not give me the threshold or final [answer] for whether it is worth giving an anticoagulant or not,” in part because the clinical impact of such events is not necessarily equal, he added.

An alternative way “to overcome this problem is to have a drug that can work across the board and work better than the ones that we have nowadays, regardless of the ischemic risk and the bleeding risk of the patient,” Dr. Lopes said.

One of the “most striking findings,” he continued, is the fact that even in patients at high bleeding risk “the magnitude of benefit of apixaban compared to warfarin was even greater than in patients at low risk for bleeding.”

Based on the “good news” from this study and others, physicians may no longer need to calculate scores when using apixaban and the other emerging alternatives to warfarin, Dr. Lopes concluded. “The new [oral anticoagulants] that work across the board facilitate physicians’ lives and therefore will likely improve patient care.”

Cost-Effectiveness a Consideration

In an editorial accompanying the paper, Vassilis S. Vassiliou, MBBS, of Papworth Hospital and Paul D. Flynn, PhD, of Addenbrooke’s Hospital (both Cambridge, United Kingdom), ask whether the time has come for apixaban to replace warfarin as the treatment of choice in A-fib patients.

“The answer,” they say, “is probably not, at least not yet.” It is unclear how much of an edge apixaban will hold in patients at lower risk than those enrolled in ARISTOTLE, Drs. Vassiliou and Flynn comment, and it is unwise to rely on subgroup analyses of a trial not powered to detect differences among the various risk categories. Moreover, they suggest that warfarin therapy in ARISTOTLE may have been suboptimal, with patients showing a mean time in therapeutic range of only 62%.

Cost could also be an obstacle for apixaban. “At least in the [United Kingdom], new treatments not only need to confer a clinical advantage over existing therapy, but also need to be cost-effective,” the physicians write, estimating that the number needed to treat (NNT) per year to prevent 1 thromboembolic or bleeding event or death is about 100. That number, however, varies widely by risk score; for example, the NNT is roughly 120 for patients with CHADS₂ scores of 1 and 60 for those with CHADS₂ scores of 3 or higher.

Study Details

CHADS₂ takes into account baseline congestive heart failure, hypertension, age 75 years or older, diabetes, and previous stroke, TIA, or systemic embolism. CHA₂DS₂VASc considers the above factors plus female sex, age 65 to 75 years, vascular disease, diabetes, and LV dysfunction. HAS-BLED estimates bleeding risk based on hypertension, abnormal renal or liver function, history of stroke or bleeding, labile INR on warfarin, age greater than 65 years, drug or alcohol abuse, and use of antiplatelets, NSAIDS, or anti-inflammatory drugs.

 

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Sources:
1. Lopes RD, Al-Khatib SM, Wallentin L, et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: A secondary analysis of a randomised controlled trial. Lancet. 2012;Epub ahead of print.

2. Vassiliou VS, Flynn PD. Apixaban in atrial fibrillation: Does predicted risk matter? Lancet. 2012;Epub ahead of print.

 

 

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