BRIGHT Published: Prolonged Bivalirudin Reduces Bleeding, Tames Early Stent Thrombosis in Primary PCI

In acute MI patients undergoing primary PCI, bivalirudin reduces bleeding but does not increase ischemic events compared with heparin with or without tirofiban, according to a large randomized trial published online March 16, 2015, ahead of print in the Journal of the American Medical Association. Importantly, use of the direct thrombin inhibitor, which was continued for several hours after the procedure, was not associated with a higher rate of acute stent thrombosis.Take Home: BRIGHT Published: Prolonged Bivalirudin Reduces Bleeding, Tames Early Stent Thrombosis in Primary PCI

Findings from the BRIGHT study were originally presented at the Transcatheter Cardiovascular Therapeutics scientific symposium in September 2014.

Investigators led by Yaling Han, MD, PhD, of the General Hospital of the Shenyang Military Region (Shenyang, China), looked at 2,194 acute MI patients (most with STEMI) undergoing primary PCI at 82 Chinese hospitals between August 22, 2012, and June 25, 2013. Patients were randomized to:

  • Bivalirudin (Shenzhen Salubris Pharmaceuticals; Guangdong, China) with a postprocedural infusion (n = 735)
  • Heparin bolus alone (n = 729)
  • Or heparin plus tirofiban with a post-PCI infusion of tirofiban (n = 730)

Study drugs were administered in the cath lab before angiography. Bivalirudin was given as a bolus of 0.75 mg/kg followed by infusion of 1.75 mg/kg/h for a median of 3 hours; 15.6% of patients thereafter received a reduced-dose infusion (0.2 mg/kg/h) for a median of 400 minutes at the physician’s discretion. In the heparin-only group, a bolus dose of 100 U/kg was administered according to guidelines. For the heparin plus tirofiban group, heparin 60-U/kg and tirofiban 10-µg/kg boluses were given followed by a 0.15 µg/kg/min tirofiban infusion for 18 to 36 hours.

Additional heparin was administered if the postbolus activated clotting time was less than 200 seconds. Bailout tirofiban, allowed for no reflow or other thrombotic complications, was used in 4.4% of the bivalirudin group and 5.6% of the heparin-only group.

Baseline characteristics were well matched among the groups (mean age about 58 years; about 82% men), as were treatments and procedures. Radial access was used in 78.5% of patients, and PCI was performed in 98.6%, with the vast majority receiving DES.

Bleeding Reduction Makes the Difference

The primary endpoint was 30-day net adverse clinical events (NACE; defined as MACCE [all-cause death, reinfarction, ischemia-driven TVR, or stroke] or any BARC bleeding).

At 30 days, the NACE risk was lower in the bivalirudin group compared with both the heparin-alone group (RR 0.67; 95% CI 0.50-0.90) and the heparin-plus-tirofiban group (RR 0.52; 95% CI 0.39-0.69). There were no differences among the groups for MACCE or its individual components. Importantly, among the approximately 96% of patients who received stents, both acute and 30-day stent thrombosis were similar across the 3 groups.

Compared with heparin with or without tirofiban, bivalirudin reduced all bleeding (P < .001) as well as major bleeding and bleeding requiring medical intervention. It also showed a trend toward less acquired thrombocytopenia (P = .07; table 1).

 Table 1. Thirty-Day Outcomes 

The reduction in NACE was consistent across multiple prespecified subgroups, but bivalirudin’s effect on event-free survival was more pronounced in women, patients with creatinine clearance ≤ 60 mL/min, and those at high bleeding risk (CRUSADE score > 30).

At 1 year, bivalirudin maintained its NACE advantage over heparin with or without tirofiban due to lower rates of bleeding, while rates of MACCE and stent thrombosis were similar among the treatment groups.

The findings were consistent in the STEMI subgroup. Overall, there was no interaction between acute MI type (STEMI vs NSTEMI) and the relative benefit of bivalirudin for rates of 30-day NACE, MACCE, and bleeding.

Turning on the HEAT

The recent HEAT-PPCI trial, which found no advantage of bivalirudin over heparin, stirred considerable controversy in the interventional community, observed Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), in a telephone interview with TCTMD. “In that context, the BRIGHT trial—with its core finding of a reduction in bleeding—is very useful,” he said.

Importantly, BRIGHT addressed a concern raised by earlier studies over excess acute stent thrombosis with bivalirudin after primary PCI, Dr. Bhatt said. That increased risk was eliminated, apparently due to protection from the postprocedural infusion.

In an email with TCTMD, BRIGHT coauthor Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), noted that suppression of stent thrombosis with a 3-4 hour infusion has now been seen in both BRIGHT and EUROMAX. Although the strategy has not been tested in a randomized fashion, “given that bleeding was still markedly reduced with this regimen compared to both heparin and heparin plus a glycoprotein IIb/IIIa inhibitor in both trials, I do believe this should be the new standard of care.”

Cost Potential Barrier

Nonetheless, the incremental cost of prolonged infusion is an important issue, Dr. Bhatt said, suggesting that its cost-effectiveness needs to be analyzed in the context of the US healthcare system—especially because heparin is cheap and the price of tirofiban has declined substantially. However, he added, cost becomes less relevant if a mortality benefit is pinned down.

Dr. Stone suggested that “stent thrombosis is such a devastating complication that most practitioners will find this benefit worth the cost. Moreover, because stent thrombosis is an expensive event, some of the costs will be recaptured.”

In an accompanying editorial, Matthew A. Cavender, MD, MPH, and David P. Faxon, MD, both of Brigham and Women’s Hospital, note that the “strongest evidence” supporting use of bivalirudin in STEMI patients has been the mortality reduction seen in the HORIZONS-AMI trial, yet “when all of the trials in which bivalirudin has been compared with heparin are pooled (including BRIGHT), there was no relationship between the reduction in bleeding and death.”

Agreeing that “mortality trumps all,” Dr. Stone countered that a survival benefit has been seen in the largest trials, HORIZONS-AMI and now MATRIX—“the only ones with [a] chance of observing this real difference.” In the antithrombin portion of the latter trial, presented at the American College of Cardiology/i2 Scientific Session on March 16, 2015, bivalirudin reduced bleeding and mortality, including cardiovascular death, compared with heparin, though rates of NACE and MACE were comparable.

In addition, almost all of the smaller trials found numerically lower cardiac mortality with bivalirudin in ACS, Dr. Stone noted.

Will MATRIX Overcome Doubts About Bivalirudin?

Despite being a single-center study, HEAT-PPCI has had an impact on practice, Dr. Bhatt said, in large part because it supports a more economical approach to anticoagulation. Heparin use is especially attractive to radial operators, who typically give the drug at a low dose for angiography and then may simply continue it for PCI, he noted.

Given the trade-off between bleeding and ischemic benefits seen in 2 recent meta-analyses, Drs. Cavender and Faxon suggest that the choice of anticoagulant regimen should be tailored to a patient’s individual risk profile.

In the end, Dr. Bhatt said, if cost were not a factor, then the message of MATRIX would be clear: there is no reason to not use bivalirudin routinely. But, he added, the healthcare system’s tolerance for the increased cost of a postprocedural infusion remains a key unknown.

“If the cost is very high, then the drug will have to be used more selectively in patients with clear bleeding risk—for example, an older woman with a low BMI and renal dysfunction,” Dr. Bhatt said. “But if it is priced competitively—especially compared with glycoprotein IIb/IIIa inhibitors—then I think its use in the US will be high.”

Dr. Stone was more optimistic about bivalirudin’s prospects. “As soon as the MATRIX and BRIGHT data are widely disseminated, bivalirudin should emerge as the clear standard of care for STEMI, as well as NSTEMI, even in geographies that are cost conscious,” he asserted. “But this therapy might be reserved outside of the US for higher-bleeding-risk patients.”

Note: Dr. Stone is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 


Sources:
1. Han Y, Guo J, Zheng Y, et al. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA. 2015;Epub ahead of print.
2. Cavender MA, Faxon DP. Can BRIGHT restore the glow of bivalirudin [editorial]? JAMA. 2015;Epub ahead of print.

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Disclosures
  • The study was supported by a general research fund from the General Hospital of Shenyang Military Region, profit grants from the Chinese government, and a research grant from Salubris Pharmaceutical.
  • Drs. Han and Faxon report no relevant conflicts of interest.
  • Dr. Stone reports serving as a consultant to multiple pharmaceutical and device companies and holding equity in the Biostar family of funds, Caliber, Embrella, Guided Delivery Systems, the MedFocus family of funds, Micardia, and VNT.
  • Dr. Cavender reports receiving consulting fees from AstraZeneca and Merck.
  • Dr. Bhatt reports receiving research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-Aventis, and The Medicines Company.

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