HF Worsens Outcomes Following ACS, With No Benefit From Apixaban

Among high-risk patients treated shortly after an ACS event, prior or acute heart failure (HF) is associated with worse clinical outcomes and increased bleeding during recovery, according to a prespecified subgroup analysis of the APPRAISE-2 trial published online January 7, 2015, ahead of print in the American Heart Journal. As in the entire trial population, apixaban did not mitigate those risks vs placebo in patients with HF. 

Take Home: HF Worsens Outcomes Following ACS, With No Benefit From Apixaban

The APPRAISE-2 trial included 7,392 high-risk ACS patients who were stable and receiving standard single or dual antiplatelet therapy. They were randomized to apixaban (Eliquis; Bristol-Myers Squibb) 5 mg (or a half dose for patients with an estimated creatinine clearance less than 40 mL/min) or to placebo twice daily. The trial was stopped early because of excess bleeding in the apixaban arm without a corresponding reduction in ischemic events through a median follow-up of 8 months.

In this subanalysis, originally presented as an abstract at the European Society of Cardiology Congress in 2012, Jan H. Cornel, MD, PhD, of Medisch Centrum Alkmaar (Alkmaar, the Netherlands), and colleagues examined the impact of HF on the results. Overall, 41% of patients (n = 2,995) had HF, including 28% with prior HF and 27% with acute HF complicating the ACS. HF patients were more likely than others to be managed medically before randomization.

Worse Outcomes With HF

When the apixaban and placebo groups were combined, HF—whether prior or acute—was associated with higher rates of the primary endpoint (CV death, MI, or ischemic stroke), CV death, MI, and stent thrombosis (table 1).

 Table 1. Clinical Outcomes: HF vs No HF

HF also corresponded with a higher risk of TIMI major bleeding, although the relationship only reached significance for acute HF (adjusted HR 1.78; 95% CI 1.03-3.08) and not for prior HF (adjusted HR 1.22; 95% CI 0.65-2.27).

Still No Apixaban Effect

Consistent with the main trial results, apixaban was associated with a higher risk of bleeding without ischemic benefit in patients with HF. There was a trend toward a lower risk of the primary endpoint in the apixaban arm for patients with acute HF (HR 0.76; 95% CI 0.57-1.01), but the interaction was not significant (P = .13).

“Acute HF complicating an ACS event, compared with prior HF, is more likely to be related to acute coronary thrombosis,” the authors note.

But Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), does not read too much into the hint of benefit from apixaban. “These results raise the question of whether anticoagulation may have a particular role in heart failure patients, specifically those with ACS,” he told TCTMD in an email. “Ongoing prospective trials will need to answer that before [we act] on these results.”

The findings of APPRAISE-2 and this prespecified subgroup analysis appear to conflict with those of the ATLAS ACS 2-TIMI 51 trial, which evaluated the addition of another oral factor Xa inhibitor, rivaroxaban (Xarelto; Janssen Pharmaceuticals), to antiplatelet therapy. Rivaroxaban, administered at a dose 2- to 4-fold lower than that used in A-fib trials such as ROCKET AF, reduced the rate of CV death, MI, or stroke in the overall study population, with a greater benefit seen in patients with HF, according to an unpublished analysis presented to an FDA advisory panel.

“These results have not been published in the peer-reviewed literature, and it is unknown how HF was diagnosed or defined in [ATLAS ACS 2-TIMI 51],” the authors write. “Nevertheless, different, lower dosing of these oral anticoagulants could open new avenues to reduce thrombotic events for patients with ACS and HF.”

Dr. Bhatt agreed that dosing, rather than differences between the drugs themselves, likely explains the discrepant results of the 2 trials. Apixaban was administered at similar doses in APPRAISE-2 and A-fib trials such as ARISTOTLE.

“Full-dose anticoagulation added to a background of (largely) dual antiplatelet therapy is a recipe for bleeding, and that likely outweighs any potential benefit in ACS,” he said. “A very low dose, as [was] used in [ATLAS ACS 2-TIMI 51], seems to strike the right balance.”


Cornel JH, Lopes RD, James S, et al. Anticoagulant therapy and outcomes in patients with prior or acute heart failure and acute coronary syndromes: insights from the APixaban for PRevention of Acute ISchemic Events 2 (APPRAISE-2) trial. Am Heart J. 2015;Epub ahead of print.


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Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • APPRAISE-2 was funded by Bristol-Myers Squibb and Pfizer.
  • The paper contains no statement regarding conflicts of interest for Dr. Cornel.
  • Dr. Bhatt reports relationships with multiple pharmaceutical and device companies and serving on the steering committee and as the US national coordinator for APPRAISE-2.