Longer Infusion Gives Bivalirudin the Upper Hand in PCI

Continued bivalirudin (Angiomax) infusion after primary percutaneous coronary intervention (PCI) may overcome its disadvantage in acute stent thrombosis rates compared with heparin while keeping the lower bleeding risk, according to a meta-analysis.

Bivalirudin use during PCI was tied to a doubling of acute stent thrombosis cases compared with heparin (risk ratio [RR] 2.36, 95% CI 1.46-3.02), found Rahman Shah, MD, of the University of Tennessee School of Medicine in Memphis, and colleagues.

 However, continuing with a full bivalirudin dose for 3 to 4 hours after PCI negated this effect (RR 0.90, 95% CI 0.32-2.54), the investigators reported online in JACC: Cardiovascular Interventions. There was no difference in acute stent thrombosis rates between patients who got heparin and full-dose bivalirudin in mixed-treatment models (odds ratio 0.97, 95% CI 0.36-2.21).

Post-procedural infusion of a low dose of bivalirudin failed to ameliorate the stent thrombosis disadvantage of the antithrombotic (RR 3.61, 95% CI 1.17-11.13).

At 30 days post-PCI, bivalirudin recipients had 47% lower odds of major bleedingcompared with their heparin counterparts. Those who got full-dose bivalirudin infusions were also less likely to have major bleeding (RR 0.29, 95% CI 0.16-0.53).

“While bivalirudin is associated with a greater risk of acute stent thrombosis than heparin post-primary PCI, this limitation may be mitigated by continuing full-dose bivalirudin (not reduced-dose bivalirudin) 3 to 4 hours postoperatively. The decrease in bleeding risk with bivalirudin compared to heparin is not compromised by this strategy,” Shah’s group concluded.

Marco Valgimigli, MD, PhD, and Giuseppe Gargiulo, MD, both of Bern University Hospital in Switzerland, called the results “potentially practice changing” and consistent with recommendations for bivalirudin in the U.S.

In an accompanying editorial, they recommended caution when interpreting the findings, however, due to the meta-analysis’ nonrandomized and unadjusted nature.

Shah’s investigation included five randomized controlled trials and 16,294 patients withacute coronary syndrome who underwent primary PCI.

BRIGHT in Print: Bivalirudin Bests Heparin for Fewer Bleeding Events During PCI, but Dose Matters

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[1].

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[1], 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.

 The investigators write of the HEAT-PPCI trial that “caveats of single-center trials are well-known.” On the other hand, they note that BRIGHT is the first multicenter trial to make direct comparison of these three regimens in patients undergoing PCI for acute MI.

“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.

Bivalirudin Started during Emergency Transport for Primary PCI.


Bivalirudin, as compared with heparin and glycoprotein IIb/IIIa inhibitors, has been shown to reduce rates of bleeding and death in patients undergoing primary percutaneous coronary intervention (PCI). Whether these benefits persist in contemporary practice characterized by prehospital initiation of treatment, optional use of glycoprotein IIb/IIIa inhibitors and novel P2Y12 inhibitors, and radial-artery PCI access use is unknown.


We randomly assigned 2218 patients with ST-segment elevation myocardial infarction (STEMI) who were being transported for primary PCI to receive either bivalirudin or unfractionated or low-molecular-weight heparin with optional glycoprotein IIb/IIIa inhibitors (control group). The primary outcome at 30 days was a composite of death or major bleeding not associated with coronary-artery bypass grafting (CABG), and the principal secondary outcome was a composite of death, reinfarction, or non-CABG major bleeding.


Bivalirudin, as compared with the control intervention, reduced the risk of the primary outcome (5.1% vs. 8.5%; relative risk, 0.60; 95% confidence interval [CI], 0.43 to 0.82; P=0.001) and the principal secondary outcome (6.6% vs. 9.2%; relative risk, 0.72; 95% CI, 0.54 to 0.96; P=0.02). Bivalirudin also reduced the risk of major bleeding (2.6% vs. 6.0%; relative risk, 0.43; 95% CI, 0.28 to 0.66; P<0.001). The risk of acute stent thrombosis was higher with bivalirudin (1.1% vs. 0.2%; relative risk, 6.11; 95% CI, 1.37 to 27.24; P=0.007). There was no significant difference in rates of death (2.9% vs. 3.1%) or reinfarction (1.7% vs. 0.9%). Results were consistent across subgroups of patients.


Bivalirudin, started during transport for primary PCI, improved 30-day clinical outcomes with a reduction in major bleeding but with an increase in acute stent thrombosis.

Source: NEJM


Major Bleed Risk Falls with Bivalirudin vs Heparin en Route to PCI for STEMI: EUROMAX.

The 30-day risk of death or major bleeding fell significantly in ST-elevation MI (STEMI) patients treated with bivalirudin (Angiomax, the Medicines Company) compared with heparin-based management, both initiated prior to arrival at a hospital for primary PCI, in a large randomized but open-label study[1].

The bivalirudin benefit for that composite end point in the European Ambulance Acute Coronary Syndrome Angiography(EUROMAX) trial was driven by a significant drop in major bleeding, the definition of which excluded bleeding related to CABG surgery.

The heparin-based strategy consisted of either unfractionated heparin (UFH) or the low-molecular-weight heparin enoxaparin(Lovenox, Sanofi). Both groups could receive a GP IIb/IIIa inhibitor provisionally.

EUROMAX was published today in the New England Journal of Medicine with lead author Dr Philippe Gabriel Steg (Hôpital Bichat, Paris, France) to coincide with his presentation of the trial here at TCT 2013 .


Dr Philippe Gabriel Steg

Bivalirudin’s 40% primary-end-point relative risk reduction included a >50% drop in risk for non-CABG major bleeding. On the other hand, the relative risk of stent thrombosis with bivalirudin was nearly threefold what was seen in the heparin group, although absolute rates were very low.

At a media briefing on the trial, Steg said the excess stent thromboses with bivalirudin were driven by events in the acute phase, within 24 hours of PCI. And, he observed, they didn’t translate into more reinfarctions or ischemia-driven revascularization.

Still, “acute stent thrombosis . . . while rarely fatal and not outweighing the advantages of bivalirudin, is the only troubling issue with bivalirudin in STEMI, and we do need strategies to reduce this complication,” according to Dr Gregg W Stone (New York-Presbyterian Hospital/Columbia University Medical Center New York, NY), the assigned discussant following Steg’s formal presentation of EUROMAX.


The trial’s findings are reminiscent of the HORIZONS AMI trial 30-day outcomes reported about six years ago and covered then by heartwire . That trial, Steg et al observe, preceded some important changes in STEMI management and PCI technique that likely affected bleeding risk, changes that were a part of EUROMAX. These included the expansion of radial-artery PCI access, newer antiplatelet agents, reduced GP-IIb/IIIa-inhibitor use, and progressively earlier initiation of IV anticoagulants.

In the >3600-patient HORIZONS AMI, anticoagulation wasn’t started early during transport. But both it and EUROMAX with its nearly 2200 patients saw a decreased bleeding risk and increased stent-thrombosis risk with bivalirudin compared with heparin. But in contrast to EUROMAX, the earlier trial also showed a reduced risk of cardiac death in bivalirudin patients.

The two studies taken together have more to say than either alone. “I think the results of EUROMAX will heavily impact clinical use of bivalirudin in Europe,” Steg said to heartwire . “The results are very consistent wih HORIZONS AMI, even to the point of the stent-thrombosis signal” and are “reassuring enough to embrace [bivalirudin] in the prehospital setting.” That is, he added, “If you want to. [The EUROMAX results] are not mind-blowing because we don’t see a mortality reduction. But they suggest that the benefits seen in HORIZONS AMI can be extended to the contemporary prehospital setting. “

At the media briefing, Dr Bernard Gersh (Mayo Clinic, Rochester, MN), who wasn’t involved in the trial, said, “It’s not that often that you see trials that really will change clinical practice, and I think this will.”

The Role of Prehospital Diagnosis and Treatment

Gersh also said, “I’ve never seen really anything that suggests that prehospital administration [of anticoagulants] and [STEMI] diagnosis is not beneficial.”

But whether they are achievable in the field varies by country, even within Europe. Interviewed, Steg pointed out that at most participating centers, there were no physicians in the ambulances. It does take some expertise to interpret the ECGs, unless the tracings can be transmitted to a center for remote reading. But, he said, “It’s been shown in other trials if you have good trained paramedics, they do just as well if not better than physicians.”

Also speaking at the briefing as a EUROMAX observer, Dr Philippe Généreux (NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY) said prehospital STEMI diagnosis and treatment initiation could make the most difference in countries like Canada, “where there aren’t cath labs on every corner” and it might take 45 to 60 minutes for an ambulance to reach a PCI center.

Prospects for prehospital management in the US seem more remote, observers agreed. Dr James B Hermiller, Jr (St Vincent Hospital/The Heart Center of Indiana, Indianapolis,) said at the briefing, “The barrier to this in the US is very great. It’s difficult just to  get ECGs in the field, let alone administer anticoagulants, but we need to get there because this is very important.”

The Open-Label Randomization

EUROMAX randomized patients at centers in nine European countries presenting within 12 hours of onset of symptoms from electrocardiographically defined STEMI, on an open-label basis, to the bivalirudin or heparin strategies. Treatment was initiated in the ambulance or at a non-PCI hospital with subsequent transport to a PCI center.

For the 1089 patients who received bivalirudin, the drug was started as a 0.75-mg/kg bolus followed by an infusion of 1.75 mg/kg/h continued for at least four hours after PCI. The 1109 control patients received UFH at either 100 IU/g or 60 IU/kg with a GP IIb/IIIa inhibitor or were allowed to have enoxaparin at 0.5 mg/kg. Adjuvant GP IIb/IIIa inhibitors were allowed at physicians’ discretion. All patients received aspirin plus a P2Y12 inhibitor.

Relative Risk (95% CI) for Outcomes, Bivalirudin vs Heparin Strategies for STEMI Initiated During Emergency Transport to Primary PCI

End points

RR (95% CI)


30-day death from any cause or non-CABG major bleedinga

0.60 (0.43–0.82)


30-day death from any cause, reinfarction, or non-CABG major bleeding

0.72 (0.54–0.96)


Non-CABG major bleeding

0.43 (0.28–0.66)


Major bleeding (TIMI definition)

0.62 (0.32–1.20)


Severe or life-threatening bleeding (GUSTO definition)

0.61 (0.22–1.68)


Definite stent thrombosisb

2.89 (1.14–7.29)


a. Primary end point 
b. Academic Research Consortium criteria

No significant differences were seen at 30 days for the composite of death, reinfarction, ischemia-driven revascularization, or stroke, or for any stroke or ischemic stroke. A committee blinded to treatment assignment adjudicated bleeding episodes and clinical events.

As discussant, Stone pointed out that PCI via the radial artery, rather than the femoral artery, was done in only 6% of cases in HORIZONS AMI but in 47% of EUROMAX patients. Some predicted that the greater proportion of radial procedures would lead to a much lower major bleeding rate and make it hard for bivalirudin to show an effect. A EUROMAX subgroup analysis found, however, that the benefits of bivalirudin over the heparin-based strategy were consistent for different kinds of patients, including whether their PCI was by the radial or femoral routes.

“Therefore, bivalirudin is beneficial regardless of the access site, and this is because most bleeding in the STEMI and ACS setting is not access-site related,” he said. It’s the non–access-site bleeds to pose the greater threat to later outcomes. So, he said, “the advantages of bivalirudin are present in patients undergoing radial as well as femoral intervention, and radialists should pay attention to this.”

Stone said EUROMAX raises the question of whether using cangrelor (the Medicines Company) as part of the accompanying antiplatelet therapy might help prevent stent thrombosis with bivalirudin, and that’s being addressed in HORIZONS-AMI-2, which is starting soon.

Bivalirudin During Transport for PCI in STEMI Lowers Bleeding, But Increases Stent Thrombi.

The direct thrombin inhibitor bivalirudin — when given to patients with ST-segment elevation myocardial infarction (STEMI) during transport for percutaneous coronary intervention (PCI) — is associated with lower rates of major bleeding after PCI. However, risks for early stent thrombosis are increased sixfold, according to a New England Journal of Medicine study. The drug’s maker participated in the study.

 Some 2200 patients with STEMI being transported to facilities for PCI were randomized en route to begin antithrombotic treatment with either bivalirudin or with heparin and optional glycoprotein inhibitors. By 30 days, the composite outcome of death or major bleeding was lower with bivalirudin (5.1% vs. 8.5%). However, the risk for stent thrombosis within 24 hours was higher with bivalirudin (1.1% vs. 0.2%).

An editorialist observes that the “clearest findings” after two bivalirudin trials are that the drug increases stent thrombosis while reducing bleeding complications. He writes that it’s “critical that clinicians weigh the relative importance of these events before selecting an antithrombotic strategy for their patients.”

Source: NEJM