Limits...
Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease.

Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL, J-LANCELOT (Japanese-Lesson from Antagonizing the Cellular Effect of Thrombin) Investigato - Eur. Heart J. (2010)

Bottom Line: E5555 (50, 100, and 200 mg) did not increase clinically significant bleeding, although there was a higher rate of any TIMI bleeding with the highest two doses.All doses tested achieved a significant level of platelet inhibition.There was a significant dose-dependent increase in liver function abnormalities and QTcF.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan. shinichi@is.icc.u-tokai.ac.jp

ABSTRACT

Aims: Two multicentre, randomized, double-blind, placebo-controlled Phase II studies assessed the safety and efficacy of the oral protease-activated receptor 1 (PAR-1) antagonist E5555 in addition to standard therapy in Japanese patients with acute coronary syndrome (ACS) or high-risk coronary artery disease (CAD).

Methods and results: Patients with ACS (n = 241) or high-risk CAD (n = 263) received E5555 (50, 100, or 200 mg) or placebo once daily for 12 (ACS patients) or 24 weeks (CAD patients). The incidence of TIMI major, minor, and minimal bleeds requiring medical attention was similar in the placebo and combined E5555 (atopaxar) groups (ACS: 6.6% placebo vs. 5.0% E5555; CAD: 1.5% placebo vs. 1.5% E5555). There were no TIMI major bleeds and three CURE major bleeds (two with placebo; one with 100 mg E5555). There was a numerical increase in 'any' TIMI bleeding with the E5555 200 mg dose (ACS: 16.4% placebo vs. 23.0% E5555, P = 0.398; CAD: 4.5% placebo vs. 13.2% E5555, P = 0.081). The rate of major cardiovascular adverse events in the combined E5555 group was not different from placebo (ACS: 6.6% placebo vs. 5.0% E5555, P = 0.73; CAD: 4.5% placebo vs. 1.0% E5555, P = 0.066). There was a statistically significant dose-dependent increase in liver function abnormalities and QTcF with E5555. At trough dosing levels in both populations, mean inhibition of platelet aggregation was > 90% with 100 and 200 mg E5555, and 20-60% with 50 mg E5555.

Conclusion: E5555 (50, 100, and 200 mg) did not increase clinically significant bleeding, although there was a higher rate of any TIMI bleeding with the highest two doses. All doses tested achieved a significant level of platelet inhibition. There was a significant dose-dependent increase in liver function abnormalities and QTcF. Although further study is needed, PAR-1 antagonism may have the potential to be a novel pathway for platelet inhibition to add on to the current standard of care therapy.

Show MeSH

Related in: MedlinePlus

CEC-adjudicated TIMI bleeding by category. CEC-adjudicated TIMI bleeding in placebo, E5555 pooled, and each dose tested of E5555, as shown. Any TIMI bleeding, including minimal bleeding not requiring medical attention, occurred more in patients treated by E5555. However, TIMI bleeding requiring medical attention or more severe bleeding did not increase even when patients were treated by E5555. Details are described in the Results section.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2966970&req=5

EHQ320F3: CEC-adjudicated TIMI bleeding by category. CEC-adjudicated TIMI bleeding in placebo, E5555 pooled, and each dose tested of E5555, as shown. Any TIMI bleeding, including minimal bleeding not requiring medical attention, occurred more in patients treated by E5555. However, TIMI bleeding requiring medical attention or more severe bleeding did not increase even when patients were treated by E5555. Details are described in the Results section.

Mentions: There were 45 and 22 patients who experienced any TIMI bleeding (i.e. in any category including TIMI minimal bleeding) in the ACS and CAD studies, respectively (Table 3). TIMI bleeds due to invasive procedures were 26 of 45 in ACS and 0 of 22 in CAD patients, thus occurring in early phase (most of the events occurred within 15 days). There was a numerical increase in ‘any’ TIMI bleeding with the E5555 200 mg dose (ACS: 16.4% placebo vs. 23.0% E5555, P = 0.398; CAD: 4.5% placebo vs. 13.2% E5555, P = 0.081) as shown in Figure 3.Table 3


Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease.

Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL, J-LANCELOT (Japanese-Lesson from Antagonizing the Cellular Effect of Thrombin) Investigato - Eur. Heart J. (2010)

CEC-adjudicated TIMI bleeding by category. CEC-adjudicated TIMI bleeding in placebo, E5555 pooled, and each dose tested of E5555, as shown. Any TIMI bleeding, including minimal bleeding not requiring medical attention, occurred more in patients treated by E5555. However, TIMI bleeding requiring medical attention or more severe bleeding did not increase even when patients were treated by E5555. Details are described in the Results section.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2966970&req=5

EHQ320F3: CEC-adjudicated TIMI bleeding by category. CEC-adjudicated TIMI bleeding in placebo, E5555 pooled, and each dose tested of E5555, as shown. Any TIMI bleeding, including minimal bleeding not requiring medical attention, occurred more in patients treated by E5555. However, TIMI bleeding requiring medical attention or more severe bleeding did not increase even when patients were treated by E5555. Details are described in the Results section.
Mentions: There were 45 and 22 patients who experienced any TIMI bleeding (i.e. in any category including TIMI minimal bleeding) in the ACS and CAD studies, respectively (Table 3). TIMI bleeds due to invasive procedures were 26 of 45 in ACS and 0 of 22 in CAD patients, thus occurring in early phase (most of the events occurred within 15 days). There was a numerical increase in ‘any’ TIMI bleeding with the E5555 200 mg dose (ACS: 16.4% placebo vs. 23.0% E5555, P = 0.398; CAD: 4.5% placebo vs. 13.2% E5555, P = 0.081) as shown in Figure 3.Table 3

Bottom Line: E5555 (50, 100, and 200 mg) did not increase clinically significant bleeding, although there was a higher rate of any TIMI bleeding with the highest two doses.All doses tested achieved a significant level of platelet inhibition.There was a significant dose-dependent increase in liver function abnormalities and QTcF.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan. shinichi@is.icc.u-tokai.ac.jp

ABSTRACT

Aims: Two multicentre, randomized, double-blind, placebo-controlled Phase II studies assessed the safety and efficacy of the oral protease-activated receptor 1 (PAR-1) antagonist E5555 in addition to standard therapy in Japanese patients with acute coronary syndrome (ACS) or high-risk coronary artery disease (CAD).

Methods and results: Patients with ACS (n = 241) or high-risk CAD (n = 263) received E5555 (50, 100, or 200 mg) or placebo once daily for 12 (ACS patients) or 24 weeks (CAD patients). The incidence of TIMI major, minor, and minimal bleeds requiring medical attention was similar in the placebo and combined E5555 (atopaxar) groups (ACS: 6.6% placebo vs. 5.0% E5555; CAD: 1.5% placebo vs. 1.5% E5555). There were no TIMI major bleeds and three CURE major bleeds (two with placebo; one with 100 mg E5555). There was a numerical increase in 'any' TIMI bleeding with the E5555 200 mg dose (ACS: 16.4% placebo vs. 23.0% E5555, P = 0.398; CAD: 4.5% placebo vs. 13.2% E5555, P = 0.081). The rate of major cardiovascular adverse events in the combined E5555 group was not different from placebo (ACS: 6.6% placebo vs. 5.0% E5555, P = 0.73; CAD: 4.5% placebo vs. 1.0% E5555, P = 0.066). There was a statistically significant dose-dependent increase in liver function abnormalities and QTcF with E5555. At trough dosing levels in both populations, mean inhibition of platelet aggregation was > 90% with 100 and 200 mg E5555, and 20-60% with 50 mg E5555.

Conclusion: E5555 (50, 100, and 200 mg) did not increase clinically significant bleeding, although there was a higher rate of any TIMI bleeding with the highest two doses. All doses tested achieved a significant level of platelet inhibition. There was a significant dose-dependent increase in liver function abnormalities and QTcF. Although further study is needed, PAR-1 antagonism may have the potential to be a novel pathway for platelet inhibition to add on to the current standard of care therapy.

Show MeSH
Related in: MedlinePlus