RUBY-1: Yet Another Novel Anticoagulant Tested in ACS Patients on Antiplatelets

PARIS, France—Darexaban, a novel oral factor Xa inhibitor, was associated with a twofold to fourfold increased risk of major bleeding when added to aspirin and/or clopidogrel in patients with acute coronary syndromes (ACS), according to results of a dose ranging trial presented Tuesday, August 30, at the European Society of Cardiology Congress 2011.

Unfortunately, the new anticoagulant also failed to achieve any decrease in ischemic events, though the study was not powered for efficacy, noted lead researcher Philippe Gabriel Steg, MD, of Hôpital Bichat (Paris, France). The results were simultaneously published online ahead of print in the European Heart Journal.

For the multicenter international RUBY-1 trial, researchers randomized 1,258 patients with recent high-risk non-ST-segment or ST-segment elevation ACS to placebo or cumulative daily doses of 10, 30, or 60 mg darexaban (given as once or twice daily formulations) on top of standard therapy. Almost three-fourths of each group underwent PCI for the index event, and over 97% of patients in each group were on dual antiplatelet therapy. Other baseline characteristics were similar between groups, with the exception of a higher prevalence of diabetes in the darexaban group (23.5% vs. 18.8%).

At 6 months, patients in the placebo group showed a 3.1% rate of major and clinically relevant non-major bleeding events (primary safety endpoint). There was a dose-response relationship for increased bleeding with progressively higher doses of darexaban (YM150, Astellas, Leiderdorp, The Netherlands), with cumulative bleeding rates of 6.2%, 6.5%, and 9.3% for each of the total daily doses, respectively (P = 0.009 for trend). The increase was statistically significant at the 30 mg twice daily dose (P = 0.002).

Kaplan-Meier analysis showed a similar elevation in risk with increasing dosage (table 1).

Table 1. Risk of Primary Safety Endpoint at 6 Months

Dosage Formulation

Rate

HR (95% CI)

P Value

10 mg
Once Daily
5 mg Twice Daily

5.6%
6.8%

1.775 (0.68-4.60)
2.045 (0.81-5.15)

0.238
0.129

30 mg
Once Daily
15 mg Twice Daily

5.6%
7.5%

1.831 (0.71-4.75)
2.269 (0.92-5.59)

0.213
0.075

60 mg
Once Daily
30 mg Twice Daily

 
7.3%
11.3%


2.425 (0.98-5.97)
3.796 (1.66-8.68)


0.054
0.002


Overall, the primary safety endpoint was more frequent with darexaban than placebo (HR 2.275; 95% CI 1.13-4.60; P = 0.022). The overall rate of any bleeding event ranged from 9.2% in patients receiving placebo to 23.1% in patients receiving 30 mg darexaban twice daily.

No fatal bleeds or intracranial hemorrhages occurred in any group, while the overall number of adverse events was similar across the darexaban groups and slightly lower in the placebo group.

Adverse events leading to discontinuation of the study drug were more frequent in the groups receiving high-dose darexaban regimens (about 65% vs. 57% with placebo). For other safety outcomes, darexaban showed good tolerability, with no increase in major adverse effects or liver toxicity.

Patients receiving darexaban showed no significant difference in the main efficacy composite of all-cause death, nonfatal MI, nonfatal stroke, or severe recurrent ischemia (5.6% for all doses combined vs. 4.4% with placebo), although the trial was not powered to determine efficacy outcomes.

More of the Same, or Hope for the Future?

The study marks yet another trial in which adding a novel anticoagulant on top of antiplatelet therapy resulted in excess bleeding rates with no improvement in efficacy in ACS patients. Previous examples include APPRAISE with apixaban and ATLAS with rivaroxaban. Nevertheless, Dr. Steg was not discouraged by the results of RUBY-1.

“Rates of TIMI major bleeds were exceedingly low in all arms, but there was a similar pattern to the primary endpoint,” Dr. Steg said. “If you look at trends in novel anticoagulants in patients with ACS, it’s probably too early to forego the idea of adding anticoagulants to antiplatelet therapy. The results of RUBY-1 suggest using a low-dose, possibly a lower dose than what is used acutely,” he added at a press conference.

But discussant Steen D. Kristensen, MD, DMSc, of Aarhus University Hospital (Skejby, Denmark), was more cautious. “There was quite a substantial difference in doses to try to find the right dose,” he said. “Newer and more effective drugs also cause more bleeding. There might be a benefit, but I’m sure there will be a price to pay. [However,] in the first 3 months, the increase in bleeds is not that big [with darexaban].”

Dr. Kristensen also wrote an editorial accompanying the EHJ paper. “Clearly, the concern is that a reduction in ischemic events with the addition of oral factor Xa inhibition to dual antiplatelet therapy might be outbalanced by an increase in bleeding,” he notes in the article. “Hopefully, future studies will enable the identification of the right combinations of drugs for the right patients in order to improve clinical outcomes further in the setting of ACS.”



Sources:
1. Steg PG, Mehta SR, Jukema JW, et al. RUBY-1: A randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur Heart J. 2011;Epub ahead of print.

2. Kristensen SD. On the cutting edge of acute coronary syndromes: adding oral factor Xa-inhibition with darexaban to dual antiplatelet therapy: The RUBY-1 trial. Eur Heart J. 2011;Epub ahead of print.

 

 

Related Stories:

RUBY-1: Yet Another Novel Anticoagulant Tested in ACS Patients on Antiplatelets

PARIS, France—Darexaban, a novel oral factor Xa inhibitor, was associated with a twofold to fourfold increased risk of major bleeding when added to aspirin and or clopidogrel in patients with acute coronary syndromes (ACS), according to results of a dose
Disclosures
  • The RUBY-1 trial was supported and funded by Astellas Pharma.
  • Dr. Steg reports receiving research grants from Servier and fees for speaking, consulting, or developing educational programs from Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo/Eli Lilly, Glaxo SmithKline, Medtronic, Merck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, and The Medicines Company as well as owning stock in Aterovax.
  • Dr. Kristensen reports receiving lecture fees from AstraZeneca, Eli Lilly, Merck, and The Medicines Company.

Comments