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Indian Heart J. 2015 Jul-Aug; 67(4): 293–294.
Published online 2015 June 22. doi:  10.1016/j.ihj.2015.05.008
PMCID: PMC4561783

BRIGHT HORIZONS for Bivalirudin? EUROMAXimizing benefits of bleeding risk but catching a MATRIX of HEAT for stent thrombosis[star]

In this issue, Kaul et al describe their single center experience in 1453 patients using bivalirudin or heparin ± glycoprotein IIb/IIIa inhibitors (GPI) for percutaneous coronary intervention (PCI). Though limited by its design, this “real world” observational study from an underrepresented patient population reports a lower rate of bleeding, possible mortality benefit, and neutral stent thrombosis with the use of bivalirudin. These data add to a mixed body of evidence supporting the safe, effective use of bivalirudin for PCI and its particular advantages in properly selected patients.

Bivalirudin is a synthetic polypeptide direct thrombin inhibitor given by intravenous infusion. Its pharmacokinetics allow for rapid onset/offset of the medication, permitting tight control of the timing of anticoagulation. Peak plasma concentrations occur within 2 min, are maintained with minimal interpatient variability, and combined renal and proteolytic clearance lead to an elimination half-life of 25–30 min in patients with normal kidney function.1

There are now a wealth of clinical data on the use of this agent. It has been studied in over 24,000 patients, including at least 13 large randomized trials of patients with acute coronary syndromes.2 One of the largest of these trials, the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, provided an initial glimpse of the impact of bivalirudin's rapid clearance.3 The trial randomized 3602 patients with ST-segment elevation myocardial infarction (STEMI) to bivalirudin or heparin + GPI. The use of bivalirudin improved thirty-day major bleeding (4.9% vs. 8.3%, p < 0.001) and overall mortality rates (2.1% vs. 3.1%, p = 0.047). However, there was an increased risk of acute stent thrombosis within 24 h, though differences in stent thrombosis rates equilibrated by 30 days—suggesting the presence of a vulnerable period between the elimination of bivalirudin and effect of oral antiplatelet therapy.

At least two other large trials—How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention (HEAT-PPCI) and European Ambulance Acute Coronary Syndrome Angiography (EUROMAX)— and a recent meta-analysis have echoed these outcomes: lower bleeding and higher acute (<24 h) but not subacute (24 h-30days) stent thrombosis.2,4,5 By limiting the use of GPI, these two trials also raised questions about bivalirudin's superiority (there was no mortality benefit) to heparin alone.

But a more recent trial has provided some insight into the increased stent thrombosis rates and a path towards preventing it. The Bivalirudin in Acute Myocardial Infarction vs. Heparin and GPI Plus Heparin Trial (BRIGHT) randomized 2194 patients with ACS to bivalirudin, heparin, or heparin + GPI in 1:1:1 fashion.6 As part of the study protocol, bivalirudin infusion was continued post-PCI for a minimum of 30 min and maximum of 4 h at a rate of 1.75 mg/kg/h, with a discretionary extension at low dose (0.2 mg/kg/h) up to 20 h. With a median 3 h of post-infusion, BRIGHT revealed no numerical or statistical increase in stent thrombosis rates but continued reduction in bleeding with bivalirudin compared to either heparin alone or heparin + GPI. Subgroup analysis of those patients who received a prolonged infusion of high-dose bivalirudin in the EUROMAX trial also revealed similar stent thrombosis and reduced bleeding rates compared with heparin alone; of note, there was no improvement in stent thrombosis rates with prolonged infusion of low-dose bivalirudin.7 The present study by Kaul et al followed a recommendation that bivalirudin be continued post procedure, although the protocol of “letting the bag run out” provides variable treatment durations and it is unclear how this impacted their outcomes.

More recently, the Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) demonstrated a reduction in secondary endpoints of bleeding and all-cause mortality with bivalirudin vs. heparin alone, but similar outcomes in primary combined endpoints.8 The largest of any of the trials covered thus far, MATRIX randomized 7213 patients to bivalirudin vs. heparin—both with equal use of bailout GPI—and to radial vs. femoral access with downstream randomization of bivalirudin to prolonged (>4 h) versus immediately terminated post-procedure infusion. This trial again revealed a slight increase in stent thrombosis rates (1.0% vs. 0.6%; RR 1.71; 95% CI 1.00–2.93). The study has not been published and the full analysis is not available, thus the final word on whether or not a prolonged infusion strategy works will have to wait.

But while the exact timing has not been elucidated in randomized fashion, the currently available literature suggests that if bivalirudin is selected, a high-dose infusion should be considered for a minimum of 3 h post-procedure in acute coronary syndromes. Though the cost effectiveness of prolonged infusion has not been studied, this paper and others suggest that bivalirudin treatment is associated with net economic benefits.9 Despite higher up-front costs, this strategy may help ensure that those patients with the most to gain from bivalirudin may avoid its risks as well.

Footnotes

[star]This editorial is pertaining to the article: Comparison of Anti-Thrombotic Strategies using Bivalirudin, Heparin plus GPI and UFH for Patients Undergoing PCI in a real world setting.

References

1. Gladwell T.D. Bivalirudin: a direct thrombin inhibitor. Clin Ther. Jan 2002;24:38–58. [PubMed]
2. Navarese E.P., Schulze V., Andreotti F. Comprehensive meta-analysis of safety and efficacy of bivalirudin versus heparin with or without routine glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndrome. JACC Cardiovasc Interv. Jan 2015;8(1 Pt B):201–213. [PubMed]
3. Stone G.W., Witzenbichler B., Guagliumi G. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. May 22 2008;358:2218–2230. [PubMed]
4. Steg P.G., van 't Hof A., Hamm C.W. Bivalirudin started during emergency transport for primary PCI. N Engl J Med. Dec 5 2013;369:2207–2217. [PubMed]
5. Shahzad A., Kemp I., Mars C. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet. Nov 22 2014;384:1849–1858. [PubMed]
6. Han Y., Guo J., Zheng Y. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA. Apr 7 2015;313:1336–1346. [PubMed]
7. Clemmensen P., Wiberg S., Van't Hof A. Acute stent thrombosis after primary percutaneous coronary intervention: insights from the EUROMAX trial (European Ambulance Acute Coronary Syndrome Angiography) JACC Cardiovasc Interv. Jan 2015;8(1 Pt B):214–220. [PubMed]
8. Valgimigli M. 2015. Bivalirudin Infusion Compared to Unfractionated Heparin in Patients with Acute Coronary Syndromes Undergoing Invasive Management: Results from the Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (MATRIX) Antithrombin Program. American College of Cardiology/i2 Scientific Session; March 16, 2015. San Diego, CA.
9. Schwenkglenks M., Toward T.J., Plent S., Szucs T.D., Blackman D.J., Baumbach A. Cost-effectiveness of bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitor in the treatment of acute ST-segment elevation myocardial infarction. Heart. Apr 2012;98:544–551. [PubMed]

Articles from Indian Heart Journal are provided here courtesy of Elsevier