A Bivalirudin Rebuttal: ‘Some Issues’ to Discuss With BRIGHT-4

A letter in the Lancet last week is posing some questions to the BRIGHT-4 trialists, suggesting that certain trial findings need a tad more explanation.

As previously reported by TCTMD, BRIGHT-4 was the 6,000-patient trial in China that rigorously stripped away all the practical and procedural quibbles with the key trials that had led cath labs around the world to drop or radically curtail their use of bivalirudin. Led by Yaling Han, MD (General Hospital of Northern Theater Command, Shenyang, China), the trial was published in the Lancet last November showing that, 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. The absolute reduction in risk was 1.33%.

At the time, observers seemed to agree that the trial was unequivocally positive, but too little, too late: the world has already reverted back to cheaper, familiar, and easier to use heparin as the anticoagulant of choice in primary PCI for STEMI.

Now, writing in the Lancet online April 8, 2023, Pierre-Guillaume Piriou, MD (Nantes Université, CHU de Nantes, France), and colleagues raise several issues with the trial findings that they believe warrant clarification.

They note that the use of  glycoprotein IIb/IIIa inhibitors (GPIs)was higher in the heparin group than the bivalirudin group, potentially explaining the increased bleeds in the former. “Moreover, bleeding complications remained less than 1% in both groups, limiting the clinical relevance, Piriou et al say.

On the other hand, while stent thrombosis rates were reported to be higher in the heparin-treated patients, “these outcomes are difficult to link with initial anticoagulation since most of them occurred beyond the first day,” they write, and in some cases may have been related to a mechanical problem such as strut malposition, not anticoagulation regimen.

Lastly, they suggest, some unique characteristics of the study population—very few patients were already taking chronic oral anticoagulants in both arms (~2%), one-third were treated with clopidogrel rather than a more potent P2Y12 inhibitor, and certain subgroups (those with pulmonary edema, cardiogenic shock, high body mass index [BMI], or high CRUSADE bleeding risk scores) did not demonstrate the same benefits from bivalirudin seen in the overall trial.

For all these reasons, the letter’s authors say, there are “some issues that should be discussed” about the BRIGHT-4 trial.

BRIGHT-4 Response

In a published response, BRIGHT-4 investigators, including Han as well as Gregg Stone, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who presented the original findings at the American Heart Association Scientific Sessions last year, clarify that GPIs were only used for therapeutic complications and point out that while major bleeding was infrequent, roughly 41% of patients with major bleeds died within 30 days in both groups.

To the stent thrombosis point, they note that the link between stent malposition and thrombosis is contentious; in this case, the fact that 50% of the reduction in stent thrombosis in the bivalirudin arm occurred within 24 hours suggests that it was likely due to the direct effects of anticoagulation.

Lastly, as to the generalizability of the results, the BRIGHT-4 investigators caution against making too much of underpowered subgroups, but contend that the findings, being very consistent with the European MATRIX trial, are “generalizable to most patients with STEMI.” The relative treatment benefits of bivalirudin versus heparin were similar, they add, in patients treated with ticagrelor compared with clopidogrel.

“Regular use of [bivalirudin] rather than heparin in patients with ST-segment elevation myocardial infarctions having primary percutaneous coronary intervention offers the potential to prevent major bleeding and save tens of thousands of lives annually,” they write.

Tempering Conclusions

Asked whether the response from the BRIGHT-4 investigators sufficiently addressed their concerns, Piriou told TCTMD that the authors’ reply “answers some of our questions with correct arguments.”

However, it’s unlikely that many operators will “return to bivalirudin” as a result of BRIGHT-4, he said in an email. 

“As we mentioned in our letter, bleeding complications remained less than 1% in both groups, limiting the clinical relevance. The primary endpoint is certainly significant—but not in important subgroups, [those with] BMI > 25 in particular,” said Piriou.

The lack of a difference for the primary endpoint in women also is notable, he continued, although lack of power might explain this. Still, the heterogeneity seen between different subgroups makes it difficult to know how to extend these results to clinical practice, he said.

“Despite the enthusiasm of the authors, their conclusions must be tempered by remembering that previous studies have not shown such miraculous results in favor of bivalirudin [and] it has been downgraded from [a class] I to IIb [recommendation] in the guidelines,” Piriou stressed. “It remains an effective drug that can be considered as an alternative to unfractionated heparin in certain cases.”

In conclusion, Piriou continued, “to say that ‘bivalirudin has the potential to save tens of thousands of lives each year’ seems a bit optimistic.”