Publication of the multicenter Chinese BRIGHT study has reopened the bivalirudin-heparin debate on treatment for patients undergoing PCI. The randomized trial showed that patients who received bivalirudin after an acute MI had significantly fewer net adverse clinical events (NACE) and bleeding events at 30 days and 1 year than those receiving heparin plus the GP IIb/IIIa inhibitor tirofiban and those receiving heparin alone.
There were no between-group differences in major cardiac events or stroke, in rates of stent thrombosis or acute stent thrombosis, or acquired thrombocytopenia.
The results, which were previously reported in part at the 2014 China Interventional Therapeutics meeting and the 2014 Transcatheter Cardiovascular Therapeutics (TCT) meeting, are published in the April 7, 2015 issue of the Journal of the American Medical Association.
They also contradict results from the controversial single-center HEAT-PPCI trial, which showed significantly fewer major adverse cardiac events in patients treated with heparin vs those treated with bivalirudin and no differences in bleeding complications.
In an accompanying editorial, Drs Mathew A Cavendar and David P Faxon (Brigham and Women’s Hospital, Boston, MA) note that the differences between the two trials could be due to differing patient populations and treatment doses.
“The BRIGHT trial . . . is an important contribution that raises questions including what is the optimal dose of heparin,” they write.
Single Center vs Multicenter?
The BRIGHT investigators, led by Dr Yaling Han (General Hospital of Shenyang Military Region, Liaoning Province, China), note that they wanted to conduct this trial because previous research had shown “disparate results” in the safety and efficacy of bivalirudin during PCI, “especially compared with heparin alone.”
A total of 2194 adult patients with acute MI were enrolled between August 2012 and June 2013 at 82 centers in China. All were randomly assigned to one of three treatment arms upon arrival in the cath lab for emergency PCI: bivalirudin (n=735; 82.7% men; mean age 57.3 years), heparin (n=729; 81.6% men; mean age 58.1 years), or heparin/tirofiban (n=730; 82.1% men; mean age 58.2 years).
“Bivalirudin . . . was given as a bolus of 0.75 mg/kg followed by infusion of 1.75 mg/kg/h during the PCI procedure and for at least 30 minutes but no more than 4 hours afterward,” report the investigators. The heparin-only group received a dose of 100 U/kg; the combination group received heparin 60 U/kg and tirofiban 10 µg/kg followed by postprocedure infusions of tirofiban at 0.15 µg/kg/min for 18 to 36 hours.
NACE at 30 days’ postprocedure, the primary end point, were reported for 8.8% of the bivalirudin group vs 17% of the heparin/tirofiban group (relative risk [RR] 0.52; 95% CI 0.39–0.69; P<0.001). NACE also occurred in 13.2% of the heparin-only group (RR 0.67; 95% CI 0.50–0.90; P=0.008).
The 30-day bleeding rate occurred in 4.1% of the patients receiving bivalirudin vs 12.3% of those receiving heparin/tirofiban vs 7.5% of those receiving heparin alone.
One-year follow-up results were similar. At that time, NACE occurred in 12.8% of the bivalirudin group vs 20.5% of the heparin/tirofiban group (P <0.001) vs 16.5% of the heparin-only group (P=0.05). Bleeding rates at 1 year were 6.3% vs 14.2% and 9.9%, respectively.
“Individualized Treatment” Needed
The editorialists add that examining the two trials’ different methodologies and procedures may also shed some light on the differing results “without challenging validity of either trial.”
Whereas BRIGHT included patients with both STEMI and NSTE-ACS who were undergoing emergency PCI, HEAT-PPCI included only patents with STEMI. In addition, anticoagulants were given before arrival at the cath lab in HEAT-PPCI vs upon arrival in BRIGHT, and the novel platelet P2Y12 inhibitors were available only in HEAT-PPCI.
“Despite longstanding use, the best dose and degree of anticoagulation during PCI remains unclear,” write the editorialists, adding that current guidelines support starting heparin at doses between 70 and 100 U/kg — which were the doses used by HEAT-PPCI and BRIGHT, respectively.
They add that the BRIGHT patients were supposed to receive bivalirudin infusions for 30 minutes after PCI but many received longer sessions, based on the treating physician. Interestingly, this did not result in increases in either bleeding or stent thrombosis. On the other hand, the anticoagulant was cut off right after PCI in the HEAT-PPCI patients and there was increased stent thrombosis vs the patients receiving heparin.
“Even though BRIGHT did not specifically test the hypothesis that prolonged infusion . . . reduces ischemic events and stent thrombosis, the study does provide some evidence that [it] is safe and could be an effective strategy to reduce the risk of stent thrombosis seen with bivalirudin in other trials,” write Cavendar and Faxon.
They note, though, that the biggest push for using bivalirudin in patients with STEMI has been the suggestion that it can reduce mortality, as shown in the HORIZONS-AMI trial. However, the mortality rate was not significantly reduced for the bivalirudin group vs the heparin/tirofiban group in BRIGHT.
“Furthermore, when all of the trials in which bivalirudin has been compared with heparin are pooled (including BRIGHT), there was no relationship between the reduction in bleeding and death,” report the editorialists.
They add that two recent meta-analyses, which included BRIGHT data, showed reduced risk of bleeding in patients treated with bivalirudin, especially when compared with heparin plus a GP IIb/IIIa inhibitor, but an increased risk of ischemic events.
Because of all this, an individualized treatment approach should be offered to patients undergoing PCI based on whether they’re at high risk for bleeding or for thrombosis, they note.
“Understanding how to optimize outcomes for each individual patient remains the ultimate goal — a goal that is only achieved with the help of more studies like BRIGHT,” the editorialists conclude.