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Strategy of Potent Anticoagulation with Rapid Post-PCI Reversal Appears Safe, Effective

By L.A. McKeown

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A novel anticoagulation system consisting of a factor IXa inhibitor and its reversal agent appears to be safe and feasible, effectively suppressing ischemic events during percutaneous coronary intervention (PCI) while also showing a favorable bleeding profile, according to a study published online June 16, 2014, ahead of print in EuroIntervention.

The REG1 anticoagulation system (Regado Biosciences; Basking Ridge, NJ) is a 2-component system consisting of pegnivacogin, a selective factor IXa inhibitor, and its controlling agent, anivamersen. Pegnivacogin is an aptamer, an RNA oligonucleotide that binds to factor IXa; anivamersen is a complementary RNA molecule that neutralizes the aptamer, thereby reversing factor IXa inhibition and restoring coagulation.

Methods
The phase II RADAR trial, published in August 2012 in the European Heart Journal, assessed REG1 in NSTE-ACS patients undergoing planned early catheterization via femoral access at 67 centers in North America and Europe. Among the 640 patients randomized to pegnivacogin (1 mg/kg) with 25%, 50%, 75%, or 100% anivamersen reversal or unfractionated heparin, 388 (61%) underwent PCI.
For the RADAR-PCI study, Thomas J. Povsic, MD, PhD, of Duke University Medical Center (Durham, NC), and colleagues looked at ischemic events and 30-day bleeding. PCI was performed a median of 10.1 and 9.8 hours after randomization in REG1 and heparin patients, respectively.
Thienopyridine use was high but similar in both the REG1 and heparin arms (72.6% vs 66.7%; P = .25), with the exception of prasugrel, which was used more frequently in the heparin group.

Thrombotic Complications Similar to Heparin

The incidence of angiographic complications, including mechanical and thrombotic issues, also was similar in REG1- and hepa­rin-treated patients (11.2% vs 10.8%; P = .9). Periprocedural thrombus formation on guidewires or catheters was not observed in any patients, and none of the REG1 patients required transition to heparin.

Occurrence of ischemic events at 30 days was similar in both treatment arms. Incidence of the composite ischemic endpoint of 30-day death, nonfatal MI, urgent TVR, or recurrent ischemia in the target vessel distribution was lower in the REG1 vs heparin group, but the difference was not statistically significant (4.4% vs 7.3%; P = .3).

In the REG1 patients with at least 50% reversal, ACUITY-defined 30-day total and major bleeding rates were similar to heparin (table 1). Patients in the 25% reversal group (n = 22) had the highest rates of bleeding overall.

Table 1. ACUITY-Defined Total, Major Bleeding at 30 Days

 

50% Reversal

(n = 68)

75% Reversal

(n = 71)

100% Reversal

(n = 116)

Heparin

(n = 111)

Total Bleeding

   30 Days

   Through Discharge

 

38.8%

38.2%

 

35.2%

32.4%

 

34.2%

26.7%

 

37.8%

36.9%

Major Bleeding

   30 Days

   Through Discharge

 

11.9%

11.8%

 

8.5%

8.5%

 

7.0%

5.2%

 

10.9%

10.8%

 

Although the study was not powered to compare bleeding rates statistically, there was a lower rate of total bleed­ing at 30 days with REG1 and 100% reversal compared with REG1 and 25% reversal (P = .003). The use of glycoprotein IIb/IIIa inhibitors increased bleeding to a similar degree in all groups.

Stepwise Bleeding Advantage

The study authors say the stepwise relationship between degree of anivamersen reversal and total and major bleeding is consistent with prior observations showing a clear relationship between degree of anticoagulation and bleeding after PCI. “RADAR-PCI suggests that REG1-mediated near complete factor IXa inhibition coupled with > 50% reversal results in no increase in bleeding,” they add.

Dr. Povsic and colleagues say the REG1 research is part of a new approach to the development of better anticoagulants that favorably affect both ischemic and bleeding events.

On the anti-ischemic side, these strategies “include targeting novel steps in the coagulation process or use of high-potency therapeutics with short half-lives.” Furthermore, they contend that factor IXa “is a more important determinant of thrombin generation than factor Xa or thrombin, plays a vital role in both initiation and propagation of coagulation, and is present at lower and more stable levels than other downstream targets.” Since factor IXa is directly acti­vated in response to contact with foreign surfaces, its inhibition may play a role in suppressing catheter-related ischemic complications, the authors add.

On the bleeding side of the equation, they say, “REG1 for the first time allows precise and immediate partial or complete post-procedural reversal of anticoagulation, perhaps mitigating the risk of high-level (> 99%) intraprocedural factor inhibition through the use of a controlling strategy to titrate actively the level of anticoagulation to which the patient is exposed.”

In March, Regado announced that the US Food and Drug Administration had designated REG1 as a Fast Track development program for the lead indication of PCI. The ongoing phase III REGULATE-PCI study is the next step the investigators hope will demonstrate a clinically meaningful advantage of REG1 vs currently available therapies.

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

Source:
Povsic TJ, Vavalle JP, Alexander JH, et al. Use of the REG1 anticoagulation system in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the phase II RADAR-PCI study. Eurointervention. 2014;Epub ahead of print.

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Disclosures
  • The RADAR-PCI trial was funded by Regado Biosciences.
  • Dr. Povsic reports being an employee of the Duke Clinical Research Institute, which receives research support from Regado.

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