Reversible Anticoagulation Shows Promise for ACS Patients Undergoing Catheterization

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At least 50% anticoagulation reversal is required to allow for safe early sheath removal after cardiac catheterization in patients with acute coronary syndromes (ACS), according to a study published online August 2, 2012, ahead of print in the European Heart Journal. The authors suggest that a novel system pairing an anticoagulant and its fast-acting antidote is a safe and effective strategy for managing patients who require short-term high-intensity anticoagulation.

For the phase II RADAR trial, John H. Alexander, MD, MHS, of Duke University Medical Center (Durham, NC), and colleagues assessed the REG1 anticoagulation system in 640 non-ST-segment elevation ACS patients with planned early catheterization via femoral access at 67 centers in North America and Europe.

REG1 (Regado Biosciences, Basking Ridge, NJ) consists of pegnivacogin, a selective factor IXa inhibitor, and its controlling agent, anivamersen. Pegnivacogin is an aptamer, an RNA oligonucleotide that in this case binds to factor IXa; anivamersen is a complementary RNA molecule that neutralizes the aptamer, thereby reversing factor IXa inhibition and restoring coagulation. Patients were randomized in a 2:1:1:2:2 fashion to pegnivacogin with 25%, 50%, 75%, or 100% anivamersen reversal or heparin.

Similar Bleeding, Ischemic Event Rates

Enrollment in the 25% reversal arm was stopped after 41 patients when excess bleeding was observed. Overall, enrollment was stopped after 3 patients experienced allergic-like reactions to treatment.

At 30 days, rates of total ACUITY bleeding, the primary endpoint, were similar for all but the group receiving 25% reversal of REG1. Major bleeding decreased as the degree of reversal increased (P = 0.01 for trend). There was also a lower rate of bleeding with 100% reversal compared with 25% reversal of REG1 (P < 0.0001; table 1).

Table 1. Thirty-Day Bleeding Rates

 

Total ACUITY Bleeding

Major Bleeding

REG1 25%

65.0%

20.0%

REG1 50%

33.6%

10.6%

REG1 75%

34.5%

8.4%

REG1 100%

30.4%

7.3%

Heparin

31.3%

10.1%


The incidence of the composite ischemic endpoint (death, nonfatal MI, urgent TVR, or recurrent ischemia in the target vessel) was numerically lower in patients assigned to REG1 than heparin (3.0% vs. 5.7%; P = 0.1), but ischemic events were rare overall and evenly distributed among the various reversal arms.

The rate of adverse events was similar between the REG1 (16%) and heparin (11%) treated patients. Of the 3 patients who experienced allergic-like reactions within 24 hours of drug administration, 2 were deemed serious.

All Signs Point to Phase III

“RADAR met its primary objectives, defining that at least 50% pegnivacogin reversal is required to allow early sheath removal after cardiac catheterization via a femoral approach and suggesting that near complete inhibition of factor IXa with pegnivacogin, followed by anivamersen-mediated reversal, may provide a strategy that permits effective periprocedural anticoagulation without increased bleeding despite immediate postprocedure sheath removal,” the authors write.

Several questions remain about the safety of this new approach, however. “A theoretical concern is that immediate, complete reversal of anticoagulation might result in an increased risk of acute thrombotic complications,” Dr. Alexander and colleagues write, although they add that they did not observe any increase in acute or short-term thrombotic events with higher levels of reversal.

In addition, Dr. Alexander told TCTMD in a telephone interview that the allergic-like reactions observed over the course of the study were not expected and further research will be required to prevent them from happening in other patients.

“We’ve done additional investigation and [the reactions appear] to be due to some preexisting antibodies that these patients had and we’re a little bit unclear as to the significance of these allergic reactions in terms of the overall program going forward,” he explained, adding that it can be difficult to “tease apart” to what extent the severe reactions were due to treatments administered rather than an actual allergic reaction.

“We’ve done all the investigation we can in animals and from the patients involved in this phase II study to understand these allergic reactions and understanding them further will require exposure of more patients,” he continued. “That’s a key part of what we’ve planned into a phase III program.”

Dr. Alexander said he was excited to start on the next phase of REG1 trials, especially because of the surprising “efficacy signals” observed in the current study. “It’s a little bit unusual to see that in phase II and it makes me hopeful about further development,” he said. “But one obviously needs to be cautious about not over interpreting those findings in a small study.”

Note: Coauthor Roxana Mehran, MD, is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

Source:

Povsic TJ, Vavalle JP, Aberle LH, et al. A phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: Results of the RADAR trial. Eur Heart J. 2012:Epub ahead of print.

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Reversible Anticoagulation Shows Promise for ACS Patients Undergoing Catheterization

At least 50% anticoagulation reversal is required to allow for safe early sheath removal after cardiac catheterization in patients with acute coronary syndromes (ACS), according to a study published online August 2, 2012, ahead of print in the European Heart
Disclosures
  • The RADAR trial was funded by Regado Biosciences.
  • Dr. Alexander reports receiving research salary support through Duke Clinical Research Institute from Regado Biosciences and serving on the medical advisory board for Regado.

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