Still No Edge for Bivalirudin in VALIDATE-SWEDEHEART’s STEMI Patients

A fresh look at the VALIDATE-SWEDEHEART trial focused exclusively on STEMI patients has once again confirmed that bivalirudin is no better than heparin monotherapy for cutting death, MI, or major bleeding in modern-day practice, which includes radial access and potent P2Y12 inhibitors.

The STEMI analysis, published online in Circulation: Cardiovascular Interventions last week, closely mirrors the main study findings, which also included NSTEMI patients, first presented at the European Society of Cardiology Congress 2017, as reported by TCTMD. At the time, the findings were widely hailed as “definitive,” confirming the earlier HEAT-PPCI trial and cementing the role of what had long been the cheaper, more-established strategy over the newer, more-expensive agent, although it has since come off patent.

Since then, however, a large, patient-level meta-analysis restricted to STEMI patients from eight trials led some, including Gregg Stone, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who presented the results at TCT Connect last year, to insist that bivalirudin should still play a role. Others, however, pointed out at the time that the meta-analysis included trials designed to include disproportionate use of glycoprotein IIb/IIIa inhibitors (GPIs) in the heparin arm, thereby biasing bleeding outcomes in favor of bivalirudin, and were done before radial access and stronger pre-PCI antiplatelet drugs were widely in use.

Speaking with TCTMD, lead author on the new analysis, Stefan James, MD (Uppsala University Hospital, Sweden), noted that the original trial was powered to look at the STEMI and NSTEMI patients separately. The STEMI paper was delayed in part while they waited to see whether the meta-analysis ultimately showed something different, said James, who was a co-author with Stone.

“The meta-analysis will be published eventually, I hope, because it’s been [presented], but not published as a whole,” said James. “But I don't really see how bivalirudin can come back after this. It’s not inferior, it just seems not to provide any significant or clinically valuable benefits as compared to simple, inexpensive heparin.”

The STEMI Cohort

In VALIDATE-SWEDEHEART, 3,005 STEMI patients were randomized equally to bivalirudin or heparin. Radial access was used in 90% of patients, and 87% were treated with a potent P2Y12 inhibitor prior to angioplasty (an oral bolus dose of ticagrelor or prasugrel or parenteral cangrelor); 4.9% and 3.4% of patients in the heparin and bivalirudin arms, respectively, received a bailout GPI.

I don't really see how bivalirudin can come back after this. Stefan James

Rates of a composite of death, MI, or major bleeding were no different between groups. Looking at the individual components, rates of death were identical, and rates of MI and of major bleeding were similar. Definite stent thrombosis was infrequent—0.5% in the bivalirudin arm as compared with 1.3% in the heparin arm—a statistically significant difference. But all of these individual endpoint analyses were underpowered “and the clinical significance of these findings should be interpreted carefully,” the authors write.

Of note, a signal of benefit with bivalirudin over heparin in women that was seen in the main trial results was not replicated in the STEMI cohort, and analyses based on lower versus higher body weight or femoral versus radial access also showed no benefit with the newer agent.

In fact, said James, for these latter two groups, you might expect to see a signal of benefit for bivalirudin, but in fact the numbers go in the opposite direction.

‘Pretty Much Settled’

Some still argue that there are benefits to bivalirudin in terms of ease of use, requiring less need for activated clotting time (ACT) monitoring, but James stressed that heparin is such a “familiar” agent that any advantages in this regard would be negligible.

“Perhaps a lower bleeding risk could be anticipated in some risk groups but the difference is really not large and there's no benefit on any other aspects, so I think it's pretty much settled. The meta-analysis may have a greater power to look at some subgroups, but I don't think it will show any clinically important difference that would make it worthwhile to change strategies for really any subgroups of patients.”

James said he does not keep bivalirudin in stock at his hospital. “Theoretically that could be done for high-bleeding-risk patients, but we don’t really know which patients those would be. Of course there are very good predictors of high bleeding risk, but we haven’t really shown that [bivalirudin] provides any more value in really high-risk patients.”