Rivaroxaban STEMI study hits print as FDA delivers setback: ATLAS ACS 2-TIMI 51

March 05, 2013

Boston, MA (updated) - The rate of recurrent CV events over two years following an acute ST-segment-elevation MI (STEMI) fell with twice-daily rivaroxaban (Xarelto, Bayer/Janssen) therapy in the placebo-controlled ATLAS ACS 2-TIMI 51 trial, whose prespecified STEMI subgroup analysis is now published in the Journal of the American College of Cardiology[1].

Compared with placebo, the factor Xa inhibitor cut the risk of cardiovascular death, MI, or stroke—the primary end point—by 19% (p=0.019) vs placebo in the analysis of about 7800 STEMI patients, nearly all of whom were also on dual antiplatelet therapy. The benefit reached significance after as little as 30 days.

Importantly, rivaroxaban overall was associated with significantly more instances of TIMI major bleeding unrelated to CABG as well as intracranial hemorrhage, although not fatal bleeding.

But with the drug given at two twice-daily dosages, 2.5 mg or 5 mg, "the lower-dose regimen resulted in a more favorable safety profile and might explain, in part, the better survival results with the very low dose of rivaroxaban," write the authors of the STEMI report, led by Dr Jessica L Mega (Brigham and Women's Hospital, Boston, MA). She had presented, and heartwire covered, the trial's STEMI analysis at the August European Society of Cardiology 2012 Congress .

"In this study, the benefits of treatment with rivaroxaban began to emerge early, at a time when STEMI patients are at particularly high risk of recurrent events," and then "persisted during continued treatment with background antiplatelet therapies," Mega told heart wire in an email. Taken together, the findings show that "the addition of rivaroxaban 2.5 mg twice daily offered an effective strategy to reduce cardiovascular events in patients following a STEMI."

Despite those results, the efficacy of the lower rivaroxaban dosage was only modestly significant. But Mega et al are reporting a subgroup analysis; the primary study was designed for a larger, broader ACS population, in whom "the trial met its primary end point," she explained. "Because [that] test was significant, the individual doses were then evaluated. By testing two doses, the trial provided additional information on the dose that best balanced efficacy and safety."

A rocky regulatory road

In June 2012, the US Food and Drug Administration declined rivaroxaban's application for approval in ACS pending submission of further safety data, as heart wire reported. And yesterday, Janssen Research & Development, which is codeveloping the agent with Bayer, announced the agency delivered a second "complete response letter," a sign that it is once again holding its decision until it can review further data.

The FDA's Cardiovascular and Renal Drugs Advisory Committee in May 2012 had voted not to recommend a rivaroxaban approval in ACS by a narrow margin, based largely on concerns over missing follow-up safety data and methodological issues with ATLAS ACS 2-TIMI 51.

The trial randomized its 7817 STEMI patients to the low- (n=2601) or high-dose (n=2584) rivaroxaban regimen or to placebo (n=2632) after they had been stabilized, at a median of 4.7 days after the acute event.

Outcomes for rivaroxaban (both dosages) vs placebo in STEMI, intention-to-treat analysis

End point s HR (95% CI)
Primary end point (CV death/MI/stroke) at 2 y 0.81 (0.67-0.97)
CV death (including fatal bleeding) 0.76 (0.57-1.02)
MI 0.78 (0.62-0.98)
Stroke 1.42 (0.81-2.46)
Primary end point on background DAP T 0.78 (0.64-0.94)
Primary end point at 30 d 0.71 (0.51-0.99)

STEMI=ST-segment-elevation myocardial infarction
DAPT=dual agent antiplatelet therapy

The two rivaroxaban groups combined showed a significant reduction vs placebo in the trial's primary efficacy end point of cardiovascular death, MI, or stroke (p=0.019) over two years. The advantage for rivaroxaban emerged as significant in the first 30 days of follow-up (p=0.042). It also remained significant over two years in an analysis that included only events that occurred while patients were actually receiving dual antiplatelet therapy (p=0.010).

Rivaroxaban dose levels in STEMI

Much of the benefit from rivaroxaban was concentrated among patients who received the drug at 2.5 mg twice daily, who showed strongly significant reductions in CV death (p=0.006) and all-cause mortality (p=0.008), while those end points were not significantly affected in the high-dose group.

Hazard ratios (95% CI) for two-year outcomes, rivaroxaban vs placebo by dosage

End point s Rivaroxaban 2.5 mg Rivaroxaban 5 mg
Primary end point (CV death/MI/stroke) 0.81 (0.65-1.00) 0.81 (0.66-1.00)
CV death 0.60 (0.42-0.87) 0.92 (0.67-1.28)
Death by any cause 0.63 (0.45-0.89) 0.99 (0.73-1.35)

In the combined-dosage group, the rate of intracranial hemorrhage went up significantly (HR 8.14, 95% CI 1.08-61.37; p=0.015). A more modestly increased risk was only marginally significant (p=0.031) in the low-dose group, but the risk went up more steeply (p=0.008) in the high-dose group.

Regardless of dosage, rivaroxaban pushed up the rate of non-CABG-related TIMI major bleeding significantly compared with placebo.

Hazard ratio (95% CI) for non-CABG-related TIMI major bleeding, rivaroxaban vs placebo, by dosage

Comparator vs placebo HR (95% CI)*
Rivaroxaban (both dosages) 4.52 (2.27-9.01)
Rivaroxaban ( 2.5 mg) 3.63 (1.73-7.61)
Rivaroxaban ( 5 mg) 5.47 (2.68-11.17)

*All p<0.001

An apparent increase in fatal bleeding risk in the two dosage groups combined wasn't significant (HR 1.54, 95% CI 0.42-5.70; p=0.51). Nor was there a significant difference at either of the two separate dosages.

The authors caution that "the trial was designed to exclude individuals with an increased risk of bleeding and thus would not apply to these patients" and that the analysis didn't account for any antiplatelet or anticoagulant agents used during the acute phase of STEMI.

The trial was supported by research grants from Johnson & Johnson Pharmaceutical Research and Development and Bayer Healthcare. Mega discloses receiving research support from Johnson & Johnson, Bayer Healthcare, Bristol-Myers Squibb/Sanofi, Daiichi Sankyo, and Eli Lilly; research supplies from Accumetrics and Nanosphere; and honoraria from Merck for consulting. Disclosures for the coauthors are listed in the paper.




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