August 24th, 2011

ARISTOTLE at ESC: What to Look for When the Data Are Unveiled

At 11:54 a.m. on August 28 in Paris (5:54 a.m. U.S. east coast time), I can almost imagine a huge drop in cell phone call volume as the ARISTOTLE presentation begins at ESC. The ESC exposition site is right next to Charles de Gaulle airport. Will a temporary “no fly zone” be declared? We know from a terse press release this past June that the factor Xa inhibitor apixaban, at 5 mg twice daily, prevented more strokes than warfarin and was associated with less major bleeding than warfarin in this megatrial of about 18,000 patients at more than 1000 study locations in over 3 dozen countries.

Atrial fibrillation is the most preventable cause of thromboembolic stroke. Warfarin for stroke prevention has a narrow therapeutic window, with an optimal dose yielding an International Normalized Ratio between 2.0 and 3.0. The higher the INR, the more likely a hemorrhagic catastrophe such as massive gastrointestinal or intracranial bleed is to occur; the lower the INR, the more likely it is that the patient will have a thrombotic stroke.

The promise of novel oral anticoagulants such as apixaban is that they are administered in a fixed dose, without the need for any routine laboratory coagulation monitoring or dose adjustment. However, the premise remains that the more intensive the anticoagulation, the more likely hemorrhage is to ensue. The apt expression: “You can’t get something for nothing.”

Yet apixaban had previously hinted that it might break this longstanding rule. In the AVERROES trial (N Engl J Med 2011; 364:806), involving 5599 patients with nonvalvular atrial fibrillation, apixaban cut the risk for stroke in half over aspirin. The trial had to be stopped after only half the subjects were enrolled because continuing treatment was considered unethical. Yet major bleeding with apixaban occurred no more often than with aspirin.

 As we anticipate the oral presentation of ARISTOTLE at ESC, I’ve listed 10 items to ponder:

1. What is the magnitude of stroke reduction with apixaban versus that with warfarin?

2. What is the magnitude of reduction in major hemorrhage?

3. Will any plausible mechanism be presented to explain the simultaneous finding of less thrombosis and less hemorrhage with apixaban?

4. Was apixaban a winner in all countries or, as in some other recent drug megatrials, were results in North America either better or worse than the overall results?

5. What was the time within the therapeutic range (TTR) among patients randomized to warfarin?

6. How good was the double-blinding?

7. What proportion of patients in both groups continued to comply with medication from enrollment until study termination?

8. What were the average and median CHADS and CHADS-VASC scores among patients enrolled in ARISTOTLE?

9. Even though the “punch line” was announced in a press release in June, will the “awe factor” overwhelm the packed crowd at the auditorium when ARISTOTLE is presented?

10. How will apixaban compare with dabigatran and rivaroxaban, even though there are no head-to-head studies?

Stay tuned!

4 Responses to “ARISTOTLE at ESC: What to Look for When the Data Are Unveiled”

  1. David Powell , MD, FACC says:

    The preannouncement was that the trial met its primary endpoint of NONINFERIORITY re time to first stroke or embolism. They go on to claim superiority for combined hemorrhage and embolic events: the SECONDARY endpoint. The statistical relevance of these “details” may be important when attempting to compare agents.
    I am also interested on the effect of CKD on dosing and outcomes.

    Competing interests pertaining specifically to this post, comment, or both:
    speaker for BI.

  2. I also wonder about the median CHADS-VASC scores among the patients enrolled, and about the statistical relevance of the details that Dr. Powell mentioned.

  3. Apixaban would add to the arsenal of drugs in afib patients. I would be interested to know about three more issues:

    1)What was the risk in those missing a dose? Contrary to warfarin, apixaban is taken bid and has a short half life.

    2)Will the data on all-cause mortality and vascular mortality be reported?

    3)How rapidly could the anticoagulant effects of apixaban be reverted if necessary? What was the outcome of patients undergoing unforeseen surgery in either group? For warfarin we have vitamin K and FFP.

    Competing interests pertaining specifically to this post, comment, or both:

  4. Edgar Abovich, MD says:

    More questions from real life experiences:
    1.Will the data be presented for older patients let say over 75?
    2.What about the affects of patients size?
    3.What are the consequences of falls and injuries? And what did they do about it? It seems that it never happens in the trials.IS a balance check part of entry criteria???
    4.Alcohol Intake?
    5. ASA and NSAIDs?

    Competing interests pertaining specifically to this post, comment, or both: