Bivalirudin’s Bleeding Benefits Dampened by PCI Advances, Analysis Shows

Use of transradial access and of more potent P2Y12 inhibitors than clopidogrel appear to mitigate the advantage bivalirudin has over heparin in terms of reducing major bleeding after PCI, a new meta-analysis shows. Also, use of the newer antiplatelets does not seem to eliminate the greater risk of stent thrombosis seen with bivalirudin.

This is the most comprehensive analysis comparing bivalirudin and heparin thus far, and it suggests that the risk-benefit calculation might be changing, according to study author John Bittl, MD, of Munroe Regional Medical Center (Ocala, FL).

“As newer approaches, such as transradial access and use of the more potent P2Y12 agents increases in clinical practice, the usefulness of bivalirudin to reduce bleeding may diminish,” Bittl told TCTMD. “On the other hand, for patients who are being treated with more traditional oral agents such as clopidogrel or undergoing transfemoral access, bivalirudin still has a bleeding advantage over heparin.”

Risks of bleeding and stent thrombosis also should be considered, he said. Patients with a higher risk for bleeding should be treated with bivalirudin, he said, whereas patients at increased risk for stent thrombosis should probably be managed with an antithrombotic approach that is not based on bivalirudin.

Commenting to TCTMD in an email, Sunil V. Rao, MD, of Duke University Medical Center (Durham, NC), said “the study suggests that both strategies are pretty equivalent with respect to bleeding if one uses a radial approach and prasugrel or ticagrelor. The issue then comes down to ease of use, cost, and the risk for stent thrombosis, which is also dependent on specific coronary anatomical characteristics.”

The study was published online last week in Circulation: Cardiovascular Interventions.

Factors Influence Bivalirudin vs Heparin Comparison

Numerous PCI trials have pitted bivalirudin vs heparin, with most showing a lower risk of major hemorrhage with bivalirudin and some demonstrating a greater risk of stent thrombosis with the drug.

However, certain variables—such as choice of vascular access site and use of adjunctive glycoprotein IIb/IIIa inhibitors (GPIs) and the new oral P2Y12 inhibitors ticagrelor (Brilinta; AstraZeneca) and prasugrel (Effient; Eli Lilly)—can influence bleeding and stent thrombosis risks.

“One of the challenges with medical evidence is that the field moves forward so quickly that trial findings are sometimes out of date by the time they get into the public domain,” Rao said. “For the bivalirudin studies, for example, the increased use of radial access and the increasing use of ticagrelor and prasugrel may not have been fully accounted for in the trials.”

To explore the impact of those other factors, Bittl and colleagues modeled the risks of bleeding and ischemic outcomes in the 30 days after PCI by randomized treatment assignment and use of adjunctive therapies in 18 RCTs with a total of 41,871 patients. Results of the trials were published between 2002 and 2015.

Overall, using a Bayesian hierarchical statistical approach, bivalirudin treatment was associated with a reduction in major bleeding, higher odds of definite stent thrombosis, and what the researchers describe as a “borderline” increase in MI risk at 30 days compared with heparin, with no difference in all-cause mortality.

The findings were similar when using traditional meta-analytic techniques.

In a risk-benefit analysis, bivalirudin was associated with 19 fewer bleeds, 5 more cases of stent thrombosis, and 6 more MIs (the latter with marginal significance) for every 1,000 patients treated with that drug instead of heparin.

The investigators then examined how various factors aside from treatment assignment affected the relationships.

In 2 trials that used transradial access in the majority of patients—BRIGHT and HEAT PPCI—major bleeding was no longer reduced with bivalirudin vs heparin (OR 0.89; 95% CI 0.57-1.41). Similarly, bleeding risk did not differ between groups in 5 trials in which GPI use was planned in the bivalirudin arm (OR 1.07; 95% CI 0.87-1.31) or in 3 trials in which most patients received prasugrel or ticagrelor rather than clopidogrel (OR 0.80; 95% CI 0.63-1.03).

On the other hand, bivalirudin maintained its bleeding advantage relative to either heparin plus provisional GPIs or low-bolus heparin (≤ 65 U/kg). 

In terms of stent thrombosis, risk was still higher with bivalirudin in trials using ticagrelor or prasugrel in the majority of patients and in trials confined to STEMI patients.

PCI Advances Come Into Play

“Several pharmacological and technical advances have improved the safety and success of PCI,” the authors note. “After reports linked post-PCI bleeding with an unfavorable prognosis and supported the hemostatic advantage of bivalirudin over heparin, interventional practice gradually substituted oral P2Y12 inhibitors for intravenous GPIs, introduced transradial access, and developed biocompatible stent designs. The implementation of these advances has altered the bleeding-thrombosis calculus and should impact the selection of an anticoagulant during PCI.”When transradial access is chosen, ticagrelor or prasugrel are used instead of clopidogrel, or GPIs are planned with bivalirudin, “it seems reasonable in the absence of an increased bleeding risk in current practice to use heparin in place of bivalirudin to reduce the risk of stent thrombosis,” they state.

They point out that fewer than 20% of patients in the most recent RCTs of bivalirudin vs heparin received newer-generation DES, which carry a lower risk of stent thrombosis compared with older devices. Future studies are needed to determine whether the trade-off between the bleeding reduction and increase in stent thrombosis seen with bivalirudin is different with newer stents, Bittl said.

“It’s always good to have more data, as long as the studies are well designed and incorporate other standard-of-care strategies,” Rao said, noting that “the SCAAR [Swedish Coronary Angiography and Angioplasty Registry] group is doing a large registry-based trial comparing bivalirudin and heparin, which will be very interesting.”

Source: 
Bittl JA, He Y, Lang CD, et al. Factors affecting bleeding and stent thrombosis in clinical trials comparing bivalirudin with heparin during percutaneous coronary intervention. Circ Cardiovasc Interv. 2015;8:e002789.

Disclosures:

• Bittl reports no relevant conflicts of interest.
• Rao reports serving as a consultant to Medtronic and Terumo.

Related Stories:

• Transradial PCI May Attenuate Bivalirudin Benefits
• HEAT-PPCI Published: Discrepant Finding of Heparin’s Superiority over Bivalirudin in Primary PCI Still Puzzles
• MATRIX Provides Support for Radial Access, Mixed Results for Bivalirudin