Bivalirudin Safer Than Heparin Alone in ‘Real-World’ PCI Patients Without STEMI

This story was originally published on April 22, 2014. It has been updated with an interview with Dr. William O'Neill (audio).
 

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In patients undergoing percutaneous coronary intervention (PCI) for either non-ST-segment elevation acute coronary syndromes (NSTE-ACS) or stable ischemic heart disease, bivalirudin is associated with less bleeding compared with unfractionated heparin monotherapy, according to an observational study published online April 15, 2014, ahead of print in Circulation: Cardiovascular Interventions. Additionally, the newer antithrombotic did not increase ischemic outcomes including stent thrombosis.

Sripal Bangalore, MD, MHA, of New York University School of Medicine (New York, NY), and colleagues looked at patients with NSTE-ACS (n = 1,480) or stable ischemic heart disease (n = 3,517) enrolled in the EVENT (Evaluation of Drug-Eluting Stents and Ischemic Events) registry between July 2004 and June 2007. All patients underwent PCI with either bivalirudin or unfractionated heparin monotherapy at the discretion of the operating physician.

Of the patients with NSTE-ACS, 48% received heparin, 52% received an adequate clopidogrel loading dose before PCI, and most received DES (86.1%).

Propensity matching of 518 patient pairs from the 2 treatment arms demonstrated no difference in death or MI (primary ischemic endpoint) or stent thrombosis in the NSTE-ACS population. Bivalirudin was associated with 36% less in-hospital composite bleeding (clinically important access site bleeding, TIMI major or minor bleeding, or transfusion) compared with heparin monotherapy with a number needed to treat of 30 to prevent 1 bleeding event. The drug also had a lower rate of access site complications and showed a trend toward a shorter hospital stay (table 1).

Table 1. In-hospital Outcomes: Propensity-Matched NSTE-ACS Cohort

 

Heparin
(n = 518)

Bivalirudin
(n = 518)

P Value

Death or MI

5.6%

6.8%

0.45

Composite Bleeding

6.0%

2.7%

0.01

Transfusion

2.9%

2.1%

0.43

Access Site Complications

4.1%

0.6%

0.002

Stent Thrombosis

0.4%

0

0.47

Postprocedure Length of Stay, days

1.8 ± 2.4

1.5 ± 4.2

0.05


In the stable disease cohort, 32% received heparin, 50% received an adequate clopidogrel load pre-PCI, and most received DES (88%).

Propensity matching resulted in 1,031 patient pairs and once again demonstrated no difference in death or MI or stent thrombosis between bivalirudin and heparin. Bivalirudin also maintained its bleeding benefit, yielding a 50% reduction in composite bleeding compared with heparin with a number needed to treat of 53, as well as an advantage with regard to access-site complications (table 2).

Table 2. In-hospital Outcomes: Propensity-Matched Stable Ischemic Heart Disease Cohort

 

Heparin
(n = 1,031)

Bivalirudin
(n = 1,031)

P Value

Death or MI

4.9%

5.3%

0.70

Composite Bleeding

3.8%

1.9%

0.01

Transfusion

1.5%

1.1%

0.43

Access Site Complications

2.7%

1.0%

0.005

Stent Thrombosis

0

0.3%

0.38


Moreover, there were no differences in the individual outcomes of death, MI, or stent thrombosis at 1 year between the 2 treatment groups in either disease cohort.

Bivalirudin Bleeding Advantage ‘Preserved’

“Our study thus extends the observation from [the ACUITY and PROTECT-TIMI 30] randomized trials to a cohort of patients treated with heparin monotherapy and shows that the bleeding advantage of bivalirudin is preserved even when compared with heparin monotherapy,” Dr. Bangalore and colleagues write.

But the “efficacy and safety of bivalirudin during PCI in patients without acute coronary syndromes is less well defined—particularly when compared with [unfractionated heparin] alone,” they add.

Since the current study was not powered to show a mortality difference, the authors note, “larger studies are needed to test these associations. In addition, although there was no statistically significant difference between bivalirudin and [unfractionated heparin] monotherapy for ischemic outcomes, the upper limit of the 95% CI does not rule out a clinically meaningful increase in either the primary ischemic outcome… or the secondary ischemic outcome… with bivalirudin.”

Consistent Findings

In a telephone interview with TCTMD, Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), said the findings are consistent with prior research, although a majority of trials have compared bivalirudin with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor.

“There have been other registries, which have looked at the outcomes of bivalirudin compared with heparin alone, which in general have shown reduced bleeding, and many of them also show lower mortality with bivalirudin,” he said. “But I think this is an important study because it’s contemporary, it’s in patients who received drug-eluting stents, and it was a prospective study with careful collection of endpoints, at least as careful as can be within the registry framework.”

Interestingly, Dr. Stone continued, “the mortality rates in the propensity-adjusted analysis, while not statistically different, tended to be a little bit less with bivalirudin, questioning what would have happened in a randomized trial. Although with stable ischemic heart disease, mortality is extremely low and with [NSTE-ACS] it’s somewhat higher but still not that high. So it would require very large clinical trials to see if there were any differences between the 2 therapies in terms of mortality.”

In contrast, he said, “in the randomized HORIZONS-AMI trial in STEMI, the highest risk situation where mortality is substantially higher, we did see a difference in mortality with bivalirudin compared to heparin and glycoprotein IIb/IIIa inhibitors.”

Bivalirudin the Preferred Regimen

Given the growing body of evidence, Dr. Stone said that “bivalirudin is the best option to minimize [major and minor] bleeding, and all prior studies have shown lower rates of thrombocytopenia with bivalirudin compared to heparin alone or heparin with glycoprotein IIb/IIIa inhibitors.”

Still, “it’s much less certain whether there’s any mortality difference,” he added. “[Moreover,] some of that difference in bleeding would be mitigated by a radial approach. But we know that after PCI at least half of the bleeding events are nonaccess-site related, and actually it’s the nonaccess-site-related bleeds that are more prognostically important. I think it’s worth preventing those episodes as well with bivalirudin even with radial artery intervention.”

William W. O’Neill, MD, of Henry Ford Hospital (Detroit, MI), called the study “well done,” but in a telephone interview with TCTMD, noted that “if you take a closer [look at the] analysis, the whole thing was driven by access site complications.”

Dr. O’Neill also noted that femoral access was used for a full 98.9% of procedures in bivalirudin patients compared with 94.0% of heparin patients.

 “The thing to me that was striking in this modern era,’ he said, “is the only 2% rate of radial intervention, which seems pretty appalling. The message that I get from this is there’s probably a more potent way of decreasing vascular complications and that’s by doing more procedures from a radial approach. It’s quite interesting that there’s a little bit of a lethargy in the United States to switch from transfemoral to transradial approaches.”

One downside to bivalirudin might be the higher cost, Dr. Stone observed. “For healthcare systems that can afford the best care,… bivalirudin would be the preferred regimen. However, I think in stable ischemic heart disease, if cost is a major issue, that heparin remains an acceptable alternative…. In patients with [NSTE-ACS who are troponin positive], then heparin alone is an inferior regimen.”

Given the constantly changing clinical picture, Dr. Stone said he would most like to see a large-scale randomized trial comparing bivalirudin with heparin alone in stable ischemic heart disease.

Dr. O’Neill did not think the EVENT registry results should provide any reassurance to clinicians concerned by HEAT PPCI, claiming the disparate findings encountered in the 2 trials make it “really an apples and oranges” comparison. “We need a well done transradial trial to compare heparin to bivalirudin, and my suspicion is that there’s not going to be very much difference [between them] when you do transradial PCI,” he concluded.

 

 


Source:
Bangalore S, Pencina MJ, Kleiman NS, et al. Heparin monotherapy or bivalirudin during percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes or stable ischemic heart disease: results from the Evaluation of Drug-Eluting Stents and Ischemic Events registry. Circ Cardiovasc Interv. 2014;Epub ahead of print.

 

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Disclosures
  • The EVENT registry was funded by Merck-Schering Plough and Millennium Pharmaceuticals.
  • Dr. Bangalore reports receiving research grant support from Abbott Vascular and the National Heart, Lung, and Blood Institute and serving as a consultant to Abbott, Abbott Vascular, Boehringer Ingelheim, Daiichi-Sankyo, Gilead, and Pfizer.
  • Dr. Stone reports serving as a consultant to Boston Scientific.
  • Dr. O’Neill reports no relevant conflicts of interest.

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