BRIGHT-4: Large, ‘Clean’ Trial Clarifies Bivalirudin Benefits in STEMI

CHICAGO, IL—(UPDATED) Most cath labs have abandoned bivalirudin during primary PCI in the wake of multiple trials showing no advantages over heparin, but investigators for the BRIGHT-4 study say that should change.

BRIGHT-4, a 6,000-patient trial conducted in China, rigorously stripped away all the practical and procedural quibbles that led to bivalirudin’s retirement.

In STEMI patients undergoing primary PCI, predominantly via radial access, a bivalirudin bolus followed by a 2- to 4-hour infusion, reduced rates of all-cause mortality and major bleeding at 30 days compared with heparin monotherapy, a relative risk reduction of 25% and an absolute reduction in risk of 1.33%.

Whether that’s enough to sway interventionalists who’ve been using unfractionated heparin in primary PCI for the better part of two decades is anyone’s guess.

“We believe that bivalirudin should have an important place in most cath labs around the world,” primary investigator Yaling Han, MD (General Hospital of Northern Theater Command, Shenyang, China), told TCTMD in an email. Han and colleagues, including co-principal investigator Gregg Stone, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who presented the findings here at the American Heart Association 2022 Scientific Sessions, simultaneously reported the full BRIGHT-4 results in the Lancet.

“Prior studies mixed patients with NSTEMI with STEMI, bivalirudin with no infusion or with a low-dose or high-dose infusion, heparin with or without routine glycoprotein IIb/IIIa inhibitor use, radial versus femoral access, and previous use of anticoagulants in both arms before randomization,” Han explained. “Therefore, these trials were unable to sort out the relative risks and benefits of the two regimens that have emerged as the safest and most effective in patients undergoing primary PCI in STEMI with radial access.”

BRIGHT-4, she continued, was “carefully designed . . . to allow these two anticoagulant regimens to be fairly and directly compared by removing all the extraneous factors.”

Blast From the Past

Bivalirudin made inroads as an acute MI anticoagulant in early trials, such as HORIZONS-AMI and EUROMAX, showing that it reduced bleeding with no price tag in ischemic events when compared with heparin plus a glycoprotein IIb/IIIa inhibitor (GPI). A range of subsequent trials, most notably HEAT-PPCI and VALIDATE-SWEDEHEART, clarified that that when GPI use was not mandated, and particularly when radial access was used, the agents were comparable. Heparin easily won out as the cheaper, more straightforward strategy.

Contacted by TCTMD, HEAT-PPCI principal investigator Rod Stables, MD (Liverpool Heart and Chest Hospital, England), said he could find no fault with BRIGHT-4. “I like the study,” he said. “I cannot find anything to criticize in the study whatsoever, and I believe the results are also credible and biologically plausible.”

Likewise, EUROMAX principal investigator Philippe Gabriel Steg, MD (Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, France), who was also the discussant following Stone's presentation, also praised the clean, clear, "unambiguous" results, calling the data “as good as they can be.”

But both Steg and Stables predicted these results are unlikely to change practice.

“It’s too late,” Steg said. “I think it's a win, as clear a win as it could be, but I'm not sure it's going to convince people, because people have already moved away from bivalirudin. It's an old story. They've moved away 5 to 7 years ago and even though the data are as good as they can be, bivalirudin remains more complex, more expensive, more difficult to implement,” he told TCTMD. “It’s a hassle, and interventionalists like things that are simple.”

It’s a hassle, and interventionalists like things that are simple. Philippe Gabriel Steg

Stable had a similar take. “For me personally, I'd have to balance this against what I would call the realities or the practicalities,” he said. “Managing infusions during the time of your primary PCI and in the period afterwards, it's not difficult, it's well within the capabilities of any modern healthcare system. It's not a big ask, but it's a little ask. It’s another thing which creates a little bit of a kind of additional care burden on the medical and nursing teams and on the patient themselves.”

But Han disagreed, saying that if operators are familiar with the process, the infusion “does not obviously increase the complexity. Furthermore, considering the benefits of bivalirudin in reducing major bleeding, death, and stent thrombosis, we think this additional complexity . . . is worthwhile and insignificant.”

Celina Yong, MD (Stanford University), one of the moderators during today’s late-breaker, told TCTMD that the results have given her something to think about, since her cath lab exclusively uses heparin. “For STEMI patients, I think it’s worth reconsidering,” she said. “For me, in my practice, I’ll think about it—again.”

BRIGHT-4 Details

BRIGHT-4 was investigator-initiated, open-label, and conducted at 63 cities in China where 6,016 STEMI patients undergoing radial PCI for STEMI with no prior lytics, anticoagulants, or GPI use were randomized to either bivalirudin bolus plus high-dose infusion for a median of 3 hours, or heparin monotherapy. GPI use was reserved for periprocedural thrombotic complications, regardless of randomization group. In all, more than 93% of patients were treated with a radial approach.

At 30 days, 132 deaths or BARC 3-5 bleeds had occurred in the heparin-treated patients as compared with 92 such events in the bivalirudin group, a difference of 1.33% (HR 0.69; 95% CI 0.53-0.91). All-cause deaths within 30 days also favored bivalirudin over heparin at 89 versus 118 (HR 0.75; 95% CI 0.57-0.99), as did BARC 3-5 bleeds at five versus 24 (HR 0.21; 95% CI 0.08-0.54).

Stent thrombosis in this 1-month window was seen in 11 bivalirudin patients and 22 heparin-treated patients (P = 0.0015).

“These improvements in clinical outcomes are substantial, and were generated from a high-quality, very large randomized trial which enrolled a broad spectrum of STEMI patients designed to mitigate most of the heterogeneity and limitations of previous trials,” Han said.

Speaking with TCTMD, Stone insisted that bivalirudin “should” be back on cath lab shelves, noting that it is now a generic, costing approximately $150 dollars as compared with “a few dollars” for heparin. “The difference in prices is really trivial, so that should no longer be an issue,” he said.

Any qualms about the trial being conducted solely in China also don’t hold water, he said. All treatment processes in China mirror those in the US or Europe, including the use of radial artery access, selective use of thrombectomy, and rapid door-to-balloon times. Moreover, all prior Chinese STEMI studies have been consistent with Western population studies, there are no known genetic polymorphisms relative to anticoagulation that could pose differences geographically, and lastly, these results were “predicable” from analyses of earlier trials that singled out this specific patient group—namely, STEMI-treated patients who got a high-dose post-PCI bivalirudin infusion, Stone said.

Stone and others who spoke with TCTMD referenced the patient-level meta-analysis that all of the major trial investigators were involved with, presented by Stone at TCT 2020. He said a manuscript is now being reviewed for possible publication. In that analysis, combining ACUITY, HORIZONS-AMI, ISAR-REACT 4, EUROMAX, BRIGHT, HEAT-PPCI, MATRIX, and VALIDATE-SWEDEHEART, STEMI patients who received a post-PCI bivalirudin infusion had a lower risk of mortality similar to that seen here.

Prying the Nail Out of the Coffin?

Whether that mortality reduction—0.9%—is persuasive enough to change practice remains open to interpretation. Stone says it should be, noting that it is the same mortality difference demonstrated in the early STEMI trials between TPA and streptokinase, and not too different from the mortality difference later seen between TPA and primary PCI.

“It's a substantial difference in mortality, and the number needed to treat was only 76 patients to prevent one major event,” said Stone. “And given the fact that you're only using this for a few hours in the cath lab, it should be a very, easy decision. It's much less expensive and much more effective than many of the other, more expensive technologies that we use.”

Steg, likewise, said he himself would consider a return to bivalirudin, noting that his early interest in the drug was spurred by the data suggesting a reduction in mortality, which was unequivocally confirmed here.

“Can you afford not to give a drug that reduces mortality by 0.9% and in relative terms by 25%?” asked Steg. “A quarter of all deaths may be avoided by choosing bivalirudin over heparin—that's pretty impressive.”

Stables, on the other hand, called the difference “very, very modest.”

“When the evidence changes, I'm always happy to follow and accept high-quality science, and I take my hat off to the guys who did this,” Stables said. “We'll have to see if the clinical community felt that the magnitude of gain was good enough to make the switch back, if there are penalties with cost or manpower, time, or practicality.”

In an editorial accompanying the Lancet paper, J.J. Coughlan, MD, and Adnan Kastrati, MD (both Deutsches Herzzentrum, Munich, Germany), note that bivalirudin was downgraded in the last European guidelines, with heparin given a class I recommendation for STEMI patients undergoing primary PCI.

“The results of BRIGHT-4 might not be strong enough to change future guideline recommendations,” they write.

But the editorialists then follow that with a statement no one could have predicted seeing, just a few years ago: “However, at the very least, these findings set the stage for further randomized trials that mandate the use of a full dose post PCI bivalirudin infusion in order to determine whether bivalirudin should become the first choice anticoagulant during primary PCI in all patients with STEMI worldwide.”