Prolonged Full-Dose Bivalirudin May Preserve Bleeding Benefit Without Upping Thrombotic Events After STEMI, Meta-Analysis Suggests


Despite its ability to curb bleeding, bivalirudin use in STEMI patients has been controversial due to the drug carrying a higher risk of acute stent thrombosis and higher cost compared with heparin. But a new meta-analysis—which the authors believe is the first of its kind—suggests that prolonging bivalirudin treatment for up to 4 hours after PCI at the full-dose ameliorates any thrombotic risk without compromising bleeding prevention.

Another View. Prolonged Full-Dose Bivalirudin May Preserve Bleeding Benefit Without Upping Thrombotic Events After STEMI, Meta-Analysis Suggests

Several large trials have compared bivalirudin (Angiomax; The Medicines Company) with its long-established predecessor heparin after primary PCI, but following a 2015 pooled analysis of the HORIZONS-AMI and EUROMAX trials, the US Food and Drug Administration (FDA) in March announced a change to the package label on bivalirudin to note the added risk of acute stent thrombosis and suggested continuing therapy for up to 4 hours at the full dose (1.75 mg/kg/h).

The new meta-analysis, led by Rahman Shah, MD (University of Tennessee, Memphis), and published online June 15, 2016, ahead of print in JACC: Cardiovascular Interventions, includes the two aforementioned trials as well as BRIGHT, HEAT-PPCI, and MATRIX for a total of 16,294 patients who were treated with either heparin or one of three bivalirudin regimens: only during PCI or for up to 4 hours after at either the full dose or a low (0.25 mg/kg/h) dose.

Comparing among patients of all five trials, the researchers confirmed an increased risk of acute stent thrombosis with bivalirudin versus heparin, but this effect was not seen in patients who received the full bivalirudin dose after primary PCI. Overall, regardless of the regimen, major bleeding rates at 30 days were lower for the bivalirudin-treated patients than for those who received heparin. Importantly, this benefit was maintained in the full-dose bivalirudin group. A mixed treatment analysis confirmed these results.

 Table. Prolonged Full-Dose Bivalirudin May Preserve Bleeding Benefit Without Upping Thrombotic Events After STEMI, Meta-Analysis Suggests

‘Potentially Practice Changing’

“These results are potentially practice changing and largely consistent with the updated recommendations for use of bivalirudin in [the United States],” write Marco Valgimigli, MD, PhD, and Giuseppe Gargiulo, MD (Bern University Hospital, Switzerland), in an accompanying editorial.

Gregg W. Stone, MD (Columbia University Medical Center, New York, NY), told TCTMD that prior studies have hinted at the need for prolonged bivalirudin, but “this is the first time that it’s all collectively being put into one place in a meta-analysis, and I think that it will bring attention to this issue.”

However, the study has several limitations that should “raise caution,” according to Valgimigli and Gargiulo. Namely, each of the included trials used a slightly different antithrombin regimen and only MATRIX randomized patients to post-PCI infusion or no infusion of bivalirudin. “Even more worrisome is the comparison between low versus full post-PCI regimen,” they write, since this choice was often left to the treating physicians who may have chosen the lower dose for patients at higher bleeding risk and the full dose for those at increased risk of acute stent thrombosis.

Since the FDA changed bivalirudin’s label, Shah said he has observed a more active conversation about its use among his peers, but much variability in practice still remains. Stone believes continued bivalirudin therapy is “a more common practice outside the United States.” This could be because “the data is not well appreciated yet, and it always takes years to translate new information into day-to-day practice,” he said.

Bivalirudin in Today’s Clinical Practice

For now, Cindy Grines, MD (Detroit Medical Center, MI), advises using bivalirudin in patients at high bleeding risk (eg, femoral access, women, elderly, those with baseline anemia), and giving a “potent oral anticoagulant (prasugrel or ticagrelor) that is chewed to achieve earlier antiplatelet effect. Alternatively one could give cangrelor IV.

“Early antiplatelet effect is very important since an analysis of HORIZONS and EUROMAX data show most [stent thrombosis] occurred in the first 4 hours,” she told TCTMD in an email.

Ron Waksman, MD (MedStar Heart and Vascular Institute, Washington, DC), told TCTMD he also uses bivalirudin with prolonged infusion for all STEMI patients. But he admitted that it might make economic sense to use unfractionated heparin instead, particularly if performing PCI transradially since radial access is associated with less bleeding than femoral.

Acknowledging that many physicians returned to using heparin after the issue with stent thrombosis was initially identified with bivalirudin, Waksman characterized that shift as an “overreaction.” Now, with the prolonged infusion, there is a “solution,” he said.

Among STEMI patients, Waksman said he does not typically differentiate between those who are and aren’t at high risk, because “there’s no time to do the scoring” when trying to achieve a 90-minute door-to-balloon time. Therefore, he treats all patients with bivalirudin because “it’s still going to [result in] less bleeding compared to any regimen of heparin,” he reported.

But Rod Stables, MD (Liverpool Heart and Chest Hospital, England), countered: “Bivalirudin use persists based on the belief that [it] reduces bleeding risk—a fallacy in my opinion.”

Explaining his thoughts to TCTMD via email, he said, that “robust evidence” backs the idea that bivalirudin and heparin are associated with comparable bleeding risk if  accompanied by glycoprotein IIb/IIIa inhibitors, “ideally a low-use, true bail-out approach,” and when the “heparin dose reflects modern practice (avoiding overdose by using 60-70 u/kg as the initial bolus).” 

Beyond specific allergy or heparin-induced thrombocytopenia cases, “there is no need to use bivalirudin at all,” Stables added. “We can enjoy improved ischemic outcomes with comparable bleeding risk at much reduced cost using a more convenient administration regime.”

Cost-Effectiveness Unanswered

Ongoing studies like the SWEDEHEART trial, which is mandating full-dose bivalirudin post-PCI in patients with STEMI and NSTEMI, may help shed light on the current uncertainty, Shah said. Of course without comparison between the full and low doses of the drug, unanswered questions will still remain, Valgimigli and Gargiulo contend.

Additionally, Stone said the HORIZONS-ABSORB AMI study—still in the planning phase—will randomize approximately 7,000 STEMI patients treated with intravenous cangrelor (Kengreal; The Medicines Company) to either heparin alone, full-dose bivalirudin with a short post-PCI infusion, or full-dose bivalirudin with an extended post-PCI infusion. Cangrelor should enable all patients to have immediate platelet inhibition, so “it’s possible that . . . the extended bivalirudin may no longer be necessary,” he noted, predicting that the results, though years away could change the conversation all over again.

Then there’s the question of price. Bivalirudin has been frequently lambasted for costing as much as 150 times that of heparin, and many argue whether its benefits are worth the added expense.

“Bivalirudin is expensive,” Stables said, adding that “attempts to mitigate the stent thrombosis threat seem to involve the inconvenience and expense of a continued infusion.”

“Cost is an issue with bivalirudin,” Shah acknowledged, noting that the FDA approved a generic form last summer, which man “help.” Even so, he continued, “higher acquisition costs for bivalirudin are offset” by a decrease in bleeding and subsequently shorter hospitalizations as well as quality of life benefits.

The question is remains if bivalirudin will still be cost-effective after a prolonged full dose. “I argue it will,” Shah said. “However, a definite conclusion can only be done by a proper cost-effective analysis.” Grines agreed that future studies should include cost-effective components.

Meanwhile, “we have to give patients the best treatment available,” Waksman said. “And if it costs more? Then it costs more.” Naysayers, he said, are “just angry [with] everything that is expensive.”

Waksman concluded: “I don’t think that should be a consideration right now, not for this specific population.”

 


 

 

 

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Sources
  • Shah R, Rogers KC, Ahmed AJ, et al. Effect of post-primary percutaneous coronary intervention bivalirudin infusion on acute stent thrombosis: meta-analysis of randomized controlled trials. J Am Coll Cardiol Intv. 2016;Epub ahead of print.

  • Valgimigli M, Gargiulo G. Bivalirudin in current practice: melius abundare quam deficere? J Am Coll Cardiol Intv. 2016;Epub ahead of print.

Disclosures
  • Shah, Stables, Stone, Grines, Waksman, and Gargiulo report no relevant conflicts of interest.
  • Valgimigli reports receiving institutional grants from Terumo and the Medicines Company for the conduct of the Matrix trial.

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