Meta-Analysis: Worse Clinical Outcomes But Less Bleeding With Bivalirudin in PCI

Download this article's Factoid (PDF & PPT for Gold Subscribers)

Bivalirudin increases adverse events and stent thrombosis but lowers major bleeding compared with heparin in patients scheduled for percutaneous coronary intervention (PCI), according to a meta-analysis published in the August 16, 2014, issue of the Lancet. However, the difference in bleeding was mitigated in trials that included comparable use of glycoprotein IIb/IIIa inhibitors (GPIs) in both groups.   

“I believe these results will cause cardiologists who use predominantly bivalirudin when performing PCI to reevaluate if this approach is truly the most appropriate strategy given the increase in ischemic events,” study author Matthew A. Cavender, MD, of Brigham and Women’s Hospital (Boston, MA), told TCTMD in an email. With GPIs now less common in PCI patients—and the strategy of heparin plus provisional GPI use gaining traction—the earlier advantage seen for bivalirudin has been attenuated, he added.

Worse Clinical Outcomes, Less Bleeding with Bivalirudin

Through 30 days of follow-up, 2,422 patients had a MACE (primary efficacy endpoint) and 1,406 had a major bleed (primary safety endpoint).

The MACE rate was higher overall with bivalirudin compared with heparin (8% vs 7%) and across patient subsets and approaches to GPI use. This difference was driven by increased risks of MI and ischemia-driven revascularization with bivalirudin. Mortality did not differ between the groups, but bivalirudin was associated with an elevated risk of stent thrombosis primarily due to more acute cases in STEMI patients (RR 4.27; 95% CI 2.28-8.00; table 1).

Table 1. Thirty-Day Clinical Outcomes: Bivalirudin vs Heparin

Overall, bivalirudin was associated with a lower risk of major bleeding (RR 0.62; 95% CI 0.49-0.78), although the relationship varied based on how GPIs were used in the trials. The risk of major bleeding was only lower when the add-on agents were used predominantly in the heparin arm alone (table 2).

Table 2. Major Bleeding Risk by GPI Strategy: Bivalirudin vs Heparin

Declining Use of GPIs  

Drs. Cavender and Sabatine point out that recent studies have shown routine use of GPIs to be not “as beneficial as it was previously thought to be, and thus has become less common.”  

In an accompanying editorial, A. Michael Lincoff, MD, of the Cleveland Clinic (Cleveland, OH), raises the question of whether GPIs are still needed with heparin given the availability of newer, more potent antiplatelets.  

“Although no trial has explicitly tested whether these drugs remove the need for use of a GPI with heparin, GPI use has nonetheless decreased,” he writes. Moreover, increased use of radial access and the availability of newer stents lower the risks of PCI bleeding complications and stent thrombosis, respectively.  

“With changing interventional treatments, recent trials have re-examined bivalirudin compared with heparin-based regimens,” Dr. Lincoff notes, pointing to HEAT-PPCI in particular.  

“Findings from this meta-analysis suggest that routine use of bivalirudin offers little advantage over heparin among patients undergoing PCI, at least in settings in which ticagrelor or prasugrel are frequently used and vascular access is primarily through the radial artery,” he writes, adding that a more definitive answer will come when the results of the 6,800-patient MATRIX trial are reported.   

“Unless new trial data to the contrary with bivalirudin become available, the findings of this meta-analysis provide a rationale to consider heparin monotherapy as the preferred anticoagulant regimen for contemporary PCI,” Dr. Lincoff concludes.   

Don’t Count Out Bivalirudin Yet

But Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), told TCTMD in a telephone interview that Dr. Lincoff’s conclusions go too far.

“It’s too simplistic a view of a very complicated field, and it ignores basically the history of the last 20 years of how we’ve gotten to where we are,” he said. “I understand the desire to want to use a simple, time-tested, inexpensive anticoagulant, but I think we owe it to our patients to make a more nuanced and considered interpretation.”

Dr. Stone, who was the principal investigator for the ACUITY and HORIZONS-AMI trials, said that nuance can be lost in a meta-analysis such as this one, and that the literature as a whole provides clear evidence that bivalirudin reduces major bleeding with a similar rate of ischemic complications compared with heparin with or without GPIs in patients with NSTE-ACS or stable CAD.

But the evidence is “much more complicated” for STEMI, he said. The risk of acute stent thrombosis is higher with bivalirudin when the drug is stopped at the end of the procedure, though, Dr. Stone noted, emerging data suggest continuing bivalirudin for 2 to 4 hours after PCI might mitigate the risk.

“The one thing that everybody can agree on is that bivalirudin is the agent that has the lowest rate of major bleeding and thrombocytopenia compared to any alternative, and to me it’s the agent of choice in stable CAD and [NSTE-ACS] and, if used appropriately, in [STEMI],” Dr. Stone said. “So the results of this meta-analysis really don’t change my opinion from a careful look at the data.”

Sources: 
1. Cavender MA, Sabatine MS. Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomized controlled trials. Lancet. 2014;384:599-606.

2. Lincoff AM. Heparin monotherapy for percutaneous coronary intervention [editorial]? Lancet. 2014;384:564-566.

Disclosures:

• Dr. Sabatine reports relationships with numerous pharmaceutical companies.
• Dr. Lincoff reports receiving grants from AstraZeneca, CSL, Genentech, Lilly, Pfizer, Regado, Roche, Takeda, and Vivus.
• Drs. Cavender and Stone report no relevant conflicts of interest.

Related Stories:

• HEAT PPCI Published: Discrepant Finding of Heparin’s Superiority over Bivalirudin in Primary PCI Still Puzzles
• EUROMAX: Bivalirudin May Hold Key to Solving Problem of Early ST After Primary PCI
• Bivalirudin Safer Than Heparin Alone in ‘Real-World’ PCI Patients Without STEMI