LANCELOT: Antiplatelet Agent Shows Positive Signs in Patients With ACS, Stable CAD

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Two new parallel studies show that the novel antiplatelet drug atopaxar, an oral reversible inhibitor of the PAR-1 receptor, improves signs of ischemia without significantly increasing major bleeding in patients with acute coronary syndromes (ACS) as well as more stable coronary artery disease (CAD). Results from the 2 phase II studies, published online April 18, 2011, ahead of print in Circulation, were initially presented in September 2010 at the annual Transcatheter Cardiovascular Therapeutics symposium in Washington, DC.

For the LANCELOT-ACS (Lessons from ANtagonizing the CELlular effects Of Thrombin-ACS) trial, researchers led by Michelle L. O’Donoghue, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), enrolled 603 patients with NSTE ACS at 187 sites in 22 countries. Patients were assigned to placebo (n = 142) or 1 of 3 daily doses of atopaxar: 50 mg (n = 156), 100 mg (n = 157) or 200 mg (n = 148). All patients who received atopaxar, which interferes with thrombin-mediated platelet effects, received a 400-mg loading dose. About 43% of all patients underwent PCI.

Over 12 weeks of treatment, the incidence of CURE major or minor bleeding (primary endpoint) was similar between the placebo and combined atopaxar groups, with no dose-related trend (P = 0.80). CURE major bleeding was numerically higher with atopaxar, but the difference did not reach statistical significance. There was also no difference between the combined atopaxar group and the placebo group in TIMI bleeding, or any of the individual components of TIMI bleeding, with no dose-dependent trend in this type of bleeding either (P = 0.63)

Table 1. Bleeding Outcomes: LANCELOT-ACS

In terms of clinical outcomes, the composite endpoint of CV death, MI, stroke, or recurrent ischemia was similar between the combined atopaxar group and the placebo group (8.0% vs. 7.8%; P = 0.93), with no dose-dependent trend (P = 0.26). When the composite was limited to CV death, MI, and stroke, there was a numerical advantage seen in the combined atopaxar group, but the difference did not reach statistical significance (3.3% vs. 5.6%; P = 0.20).

Interestingly, continuous ECG monitoring showed a 34% reduction in Holter-detected ischemia in the combined atopaxar group (RR 0.67; 95% CI 0.48-0.94; P = 0.02) during the first 48 hours after the loading dose. Transient dose-dependent transaminase elevation and relative QTc prolongation were observed with the highest doses of atopaxar.

“In patients after ACS, atopaxar significantly reduced early ischemia on Holter monitoring without a significant increase in major or minor bleeding,” Dr. O’Donoghue and colleagues conclude. “Larger trials are required to fully establish the efficacy and safety of atopaxar.”

More Minor Bleeding in Stable Patients

For the phase II LANCELOT-CAD (Lessons from ANtagonizing the CELlular effects Of Thrombin-CAD) trial, researchers led by Stephen D. Wiviott, MD, of Brigham and Women’s Hospital (Boston, MA), randomized 720 patients with high-risk, stable CAD to placebo or 1 of the same 3 doses of atopaxar for 24 weeks.

The primary endpoint of overall CURE bleeding, driven mainly by CURE minor bleeding, was higher in the combined atopaxar group (RR 6.82; 95% CI 1.17-94.0), with higher doses associated with increased bleeding (P = 0.01). The combined atopaxar group also showed a trend for more TIMI bleeding, with a dose-dependency that just missed statistical significance (P = 0.07; table 2).

Table 2. Bleeding Outcomes: LANCELOT-CAD

  
The combined MACE endpoint (composite of CV death, MI, stroke, or refractory ischemia) was low and similar between the combined atopaxar group and the placebo group (2.6% vs. 4.6%; P = 0.2), although each atopaxar arm had numerically fewer MACE events than the placebo group. There was no dose-dependent relationship linking higher doses with increased efficacy, though. On the contrary, the most effective MACE reduction occurred with the lowest dose (50 mg).

All atopaxar regimens achieved high levels of platelet inhibition. As in LANCELOT-ACS, patients receiving atopaxar in LANCELOT-CAD experienced transient elevations in liver transaminase levels and QTc prolongation. These did not translate to any clinical complications.

“In this dose-ranging study of patients with CAD, treatment with atopaxar resulted in platelet inhibition, more minor bleeding, and numerically but not statistically fewer ischemic events,” the researchers conclude. “Larger-scale trials are needed to determine whether these patterns translate into clinically meaningful effects.”

In an editorial accompanying the 2 reports, Frans Van de Werf, MD, PhD, of the University of Leuven (Leuven, Belgium), agreed that the combined results of the 2 trials could be sufficient to warrant a phase-III trial program with atopaxar. However, “the numerically higher incidence of major bleeding complications, the . . . liver dysfunction and relative QTc prolongation, and the lack of a convincing dose-related trend for bleeding risk and efficacy are somewhat troublesome,” he writes.

New Agents May Not Be PAR-1 for the Course

As it happens, 2 large phase III trials are ongoing with another PAR-1 inhibitor, vorapaxar. However, the Data Safety Monitoring Board (DSMB) for the TRA2P (Thrombin Receptor Antagonist in Secondary Prevention of atherothrombotic ischemic events) trial has recommended to stop 1 of the study’s 3 arms because of an excess of intracranial bleeding in patients with a history of ischemic stroke randomized to vorapaxar.

Meanwhile, in the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in ACS) trial, the entire study was halted early after the DSMB determined that “a sufficient number of events were collected to test the primary hypothesis of the study.”

According to Dr. Van de Werf, “the future of the PAR-1 receptor antagonists will depend on the final results of the 2 phase-III studies with vorapaxar.”

In any event, even if agents such as vorapaxar and atopaxar are able to reduce ischemic events to a level that makes any bleeding risk acceptable, “for reasons of compliance and cost it is doubtful that many patients would be willing to take 2 or 3 antiplatelet agents or 2 antiplatelet agents and an anticoagulant (on top of other medication like statins and antihypertensive agents) for a long period of time,” he writes.

Dr. Van de Werf urged the development of more simple antithrombotic regimens, both with new PAR-1 antagonists and other promising drugs such as dabigatran and anti-Xa agents currently being tested.

 

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Sources:
1. O’Donoghue ML, Bhatt DL, Wiviott SD, et al. Safety and tolerability of atopaxar in the treatment of patients with acute coronary syndromes: The lessons from antagonizing the cellular effects of thrombin-acute coronary syndromes trial. Circulation. 2011;Epub ahead of print.

2. Wiviott SD, Flather MD, O’Donoghue ML, et al. Randomized trial of atopaxar in the treatment of patients with coronary artery disease: The lessons from antagonizing the cellular effects of thrombin-coronary artery disease trial. Circulation. 2011;Epub ahead of print.

3. Van de Werf F. Inhibitors of the platelet thrombin receptor: Will they live up to their promises? Circulation. 2011;Epub ahead of print.

 

Disclosures:

• The LANCELOT-ACS and LANCELOT-CAD trials were funded by Eisai.
• Dr. O’Donoghue reports receiving research grants from Eisai and GlaxoSmithKline and receiving honoraria from Daiichi Sankyo and Eli Lilly.
• Dr. Wiviott reports receiving research funding from Daiichi Sankyo, Eli Lilly, and Schering Plough; consulting fees from Arena, AstraZeneca, Bristol-Myers Squibb,  Medco, and Sanofi-Aventis; and independent CME speaking fees from Daiichi Sankyo, Eli Lilly, and Schering Plough.
• Dr. Van de Werf reports serving as an executive committee member of the TRACER trial and as a steering committee member of the TRA2P trial.

 

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