Light From BRIGHT: More Fuel for Bivalirudin-Heparin Debate

Shelley Wood

September 15, 2014

WASHINGTON, DC — US cardiologists attending TCT 2014 finally got a first-hand look at the Chinese BRIGHT trial, heralded as the first randomized trial to compare bivalirudin, unfractionated heparin (UFH) alone, and heparin plus a GP IIb/IIIa inhibitor (tirofiban).

As previously reported by heartwire , the primary results from BRIGHT were first released at the China Interventional Therapeutics meeting in Shanghai last March and showed that net adverse clinical events (NACE, a combination of bleeding plus major adverse cardiac events) were significantly reduced in the bivalirudin vs UFH/tirofiban arms and skirted statistical significance in the bivalirudin vs UFH-monotherapy arms.

Dr Yaling Han

A similar pattern was seen for all bleeding events, with 50% to 60% reductions in the bivalirudin-treated patients vs the heparin-monotherapy and heparin/GP-IIb/IIIa-inhibitor groups (p=0.041 and 0.001, respectively).

The numbers Dr Yaling Han (General Hospital of Shenyang Military Region) presented at TCT were nearly identical to those presented in China (according to slides obtained by heartwire ), although she did not provide separate p values for the different heparin-vs-bivalirudin arms. She also had new data, not previously released, on stent thrombosis, showing no significant differences between the three groups.

Stent Thrombosis at 30 Days

Event Bivalirudin (n=735), n (%)
Heparin (n=729), n (%) Heparin + tirofiban, n (%)
p
All definite/probable stent thrombosis 4 (0.6) 6 (0.9) 5 (0.7) 0.77
Acute (<24 h) 2 (0.3) 2 (0.3) 2 (0.3) 1.00
Subacute (1–30 d) 2 (0.3) 4 (0.6) 3 (0.4) 0.66

Han also presented one year outcomes showing that for major adverse cardiac and cerebrovascular events (MACCE), there were no difference between groups, but for NACE, the highest rate of events at one year was in the heparin-monotherapy arm at 20.5%, followed by heparin/tirofiban at 16.5%, and bivalirudin at 12.8%, with the bivalirudin results being statistically superior to the other strategies.

During a morning press conference, moderator Dr Roxana Mehran (Mount Sinai Medical School, New York) took a stab at summarizing those NACE results, saying: "All of the benefit is in the bleeding; there was no difference in the major adverse ischemic outcomes."

Higher Heparin Dose

The BRIGHT findings are in keeping with some of the early major bivalirudin trials that used heparin plus a GP IIb/IIIa inhibitor as a comparator. But they are at odds with HEAT-PPCI , the single-center study led by Dr Rod Stables (Liverpool Heart and Chest Hospital, UK) that first kicked over the hornets' nest back at ACC 2014 and prompted international interest in this Chinese trial.

Experts discussing BRIGHT during its late-breaking presentation and in the press conference had a number of hypotheses as to why BRIGHT produced results different from HEAT-PPCI.

For one, Chinese investigators used a higher dose in the heparin-monotherapy arm than was used in HEAT-PPCI: 100 U/kg as opposed to 70 U/kg in HEAT-PPCI.

Dr Gabriel Steg

"One wonders whether the bleeding effect is related to the heparin arm getting too high a dose, but I would point out, these are the exact guideline-recommended doses," said Dr Gabriel Steg (Institut National de la Santé et de la Recherche Médicale, Paris, France), who led another recent bivalirudin-vs-heparin trial, EuroMAX . The 100-U/kg dose is "exactly what the guidelines state, and had the authors given another dose they would have been criticized for not following the guidelines. Maybe the guidelines need to be revised, but the data to support lower doses of heparin are not there, it's [based] purely [on] practice, but not data."

Prolonged Bivalirudin Infusion

Another key difference in BRIGHT: investigators used a prolonged bivalirudin infusion, lasting between three to four hours post-PCI, consistent with what Stables characterized as "running down the bag."

This strategy, and the lack of stent thrombosis seen, is consistent with what was seen in a subset of patients in EuroMAX, Steg noted, and suggests that in the setting of STEMI, "It would be good to consider a prolonged infusion for a couple of hours."

This is a concept that has been raised before over the past few months and one that Stables has rejected on the grounds of cost.

Dr Rod Stables

Today, Stables was more conciliatory. "I'm pretty sure that it would be easy to develop a strategy where you could use bivalirudin and abolish the stent-thrombosis hazard. I use bivalirudin every single week in the context of clinical trials and feel confident to do so without putting patients at threat. I'm really impressed with the emerging data on the prolonged infusion, which I think would solve the problem really quite well as suggested in this trial. . . . This is good evidence that provides guidance to people for more effective and safe use of the drug, and I'm very grateful to the investigators for doing that."

Yesterday, however, in a debate on the topic, Stables noted that depending on the duration and dose of the continued infusion, in addition to other factors, the cost of bivalirudin could be as much as 1400-times higher than UFH.

Asked by heartwire about the cost differential in China, Han agreed that the cost of a bivalirudin strategy would be "much more" than a heparin-monotherapy strategy, but would not be as expensive as it is in countries where bivalirudin is sold as Angiomax (the Medicines Company). In China, bivalirudin is sold by Salubris, which was also a cosponsor of the trial.

Populations, Antiplatelets, and Primary PCI

Dr Stephan Windecker

Dr Stephan Windecker (University Hospital Inselspital, Bern, Switzerland), also in today's press conference, raised another question about the trial, noting that studies of dual antiplatelet therapy have shown much lower rates of stent thrombosis in Asian patients. The lack of a difference in stent-thrombosis rates in BRIGHT may have had to do with the lower incidence of this hazard in Chinese subjects, he suggested.

Stables pointed to another issue: the fact that STEMI patients, who made up 89% of patients in BRIGHT, were defined as all patients with ST-elevation MI treated within 12 hours. That's different from patients in HEAT-PPCI, who typically had door-to-balloon times in the range of of half an hour.

"It would be good to know what proportion constituted emergency revascularization in the context of primary PCI, because it is a very, very different scenario, not only in terms of the the hazard experience by patients during that phase of the natural history of the condition, but also because of its implications for the duration of oral antiplatelet therapy," he told heartwire .

Asked if the BRIGHT results will change their practice, Stables responded with an emphatic "No."

Steg observed that "the driving force for adopting bivalirudin was the mortality reduction as was seen in HORIZONS —that is what drives adoption of therapy in STEMI." No mortality reduction was seen in BRIGHT, he noted, but it also wasn't powered to show a difference. "If we are going to look at mortality, we really need to pool the trials."

In the meantime, he said, the practice in his cath lab "is to use bivalirudin for STEMI patients with a prolonged infusion, and we have further evidence to support that today."

Windecker, citing the constraints of the economic environment in which he practices, said he won't be changing his practice.

The BRIGHT trial was supported by a research grant from Salubris and by nonprofit grants from National Key R&D projects for 12th five-year plan. Han and coauthors had no conflicts of interest. Mehran disclosed grant support/research contracts from regado biosciences, Daiichi-Sankyo/Eli Lilly, and The Medicines Company, and consultant fees/honoraria from Abbott Vascular, Boston Scientific, Covidien, Merck/Schering Ploug, Sanofi Aventis, Osprey, AstraZeneca, Janssen/J&J. Stables disclosed grant support/research contracts from AstraZeneca, Cook Medical, the Medicines Company, and consultant fees/honoraria from AstraZeneca, Boston Scientific, Abbott Vascular, and Cook Medical. Steg disclosed consultant fees/honoraria from Merck/Schering Plough, the Medicines Company, GlaxoSmithKline, Pfizer, Novartis, and AstraZeneca. Windecker disclosed research grants from Biotronik and St Jude Medical.

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