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Published on 13 July 2009

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Bivalirudin in coronary angioplasty procedures

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Bivalirudin in PCI is an attractive alternative to unfractionated heparin as it maintains effectiveness against ischaemia while reducing bleeding and in primary angioplasty compared with unfractionated heparin and IIb/IIIa antagonists reduces mortality

Cheuk-Kit Wong
MD FCSANZ

Cardiology
Dunedin School of
Medicine
Otago University

Harvey D White
DSc FCSANZ

Director of
Cardiovascular Research
Greenlane Cardiovascular
Service
Auckland City Hospital

New Zealand

The binding of bivalirudin to thrombin is not only noncompetitive but also reversible, as thrombin after binding cleaves an Arg3-Pro4 bond in bivalirudin that re-exposes the thrombin catalytic site. Bivalirudin has a short half-life (~25 minutes) and an almost linear dose-response characteristic. All these factors explain the intense antithrombin action for efficacy, while the controlled short duration of action reduces bleeding risks.

Elimination of bivalirudin is by both proteolytic clearance and renal excretion. In dialysis-dependent patients the clearance is reduced by 80% and the elimination half-life is 3.5 hours. In patients with a creatinine clearance of 10-29 ml/min, clearance is reduced by 20% and the elimination half-life is 34-57 minutes. Like unfractionated heparin, bivalirudin prolongs the activated clotting time (ACT) and the activated partial thromboplastin time (APTT) in a dose-dependent manner. However, monitoring is unnecessary providing that correct dosage is followed.

Bivalirudin was approved by the FDA for clinical use in December 2000 as an alternative to unfractionated heparin for patients with unstable angina during percutaneous coronary intervention (PCI), based primarily on the randomised Bivalirudin Angioplasty Study performed in 4,312 patients in the early 1990s.[1] However, contemporary PCI involves the widespread use of coronary stents, smaller guiding catheters through either a femoral or radial arterial puncture entry site, upstream or in-laboratory use of glycoprotein IIb/IIIa inhibitors and the routine use of thienopyridines poststenting.

In the randomised evaluation of PCI Linking Angiomax to reduced Clinical Events (REPLACE) 2 study,[2,3 6,10] patients undergoing elective or urgent PCI between October 2001 and August 2002 were randomised to bivalirudin (0.75 mg/kg and 1.75 mg/kg/h IV) and provisional abciximab or eptifibatide versus the planned use of these agents and unfractionated
heparin (65 mg/kg IV) in a double-blind, double-dummy manner. This study used a non-inferiority trial design for the “triple ischaemic endpoint” of death, myocardial infarction or urgent revascularisation by 30 days and the “quadruple endpoint” of ischaemia and bleeding. Bivalirudin with provisional glycoprotein IIb/IIIa blockade was statistically non-inferior to unfractionated heparin + planned glycoprotein IIb/IIIa blockade with regard to suppression of acute ischaemic endpoints and was associated with a 41% reduction in major bleeding (in-hospital major bleeding 2.4% vs 4.1%, p < 0.001).[2]

In REPLACE-2, multivessel intervention was undertaken in ~15% of cases and saphenous vein graft intervention in 6% of patients. Provisional use of a glycoprotein IIb/IIIa inhibitor for patients randomised to bivalirudin (or placebo for patients randomised to unfractionated heparin + planned glycoprotein IIb/IIIa blockade) was permitted for a wide range of indications, and this occurred in 7.5% of bivalirudintreated patients and 5.2% of unfractionated heparin/ glycoprotein IIb/IIIa inhibition patients.

Bivalirudin treatment was associated with a similar rate of ischaemic events (7.6% vs 7.9%, OR 1.09, 95% CI 0.90-1.32, p = 0.40). There was a trend for a small nonsignificant excess in CKMB elevations 5—10 times the upper limit of normal. There was no increase in Q-wave MI or myocardial infarctions with CKMB elevations >10 times; however, bleeding events were significantly reduced. While not designed to evaluate mortality at 12 months, there was a lower point estimate for mortality in favour of the bivalirudin arm (1.6% vs 2.5%, p = 0.16).3 In June 2005, the FDA approved the new labelling for the use of bivalirudin in PCI based on the results of REPLACE-2. Data from REPLACE-2 also indicated that the use of bivalirudin was costeffective with a net cost saving of US$375-400 per patient, with US$159 attributed to reduced bleeding.4

The more recent Acute Catheterisation and Urgent Intervention Triage strategy (ACUITY) trial studied moderate and high-risk patients (n = 13,819) with non-ST elevation acute coronary syndromes undergoing an invasive strategy.[5] Patients were randomised to three open-labelled arms (unfractionated heparin or LMWH + glycoprotein IIb/IIIa inhibitors, bivalirudin + glycoprotein IIb/IIIa inhibitors, and bivalirudin alone). There was a second randomisation to the timing of administration of the glycoprotein IIb/IIIa inhibitors (upstream or in the catheterisation laboratory). Three 30-day primary endpoints were prespecified: composite ischaemia (death, MI, unplanned revascularisation for ischaemia), major bleeding not related to CABG, and net adverse clinical events (NACE) (composite ischaemia or major bleeding). The median time from drug administration to angiogram was 5.3 hours, and all underwent angiography within 72 hours. Fifty-six percent of patients underwent PCI, 32% had medical therapy and 12% had surgery.

At 30 days, bivalirudin + GPIIb/IIIa inhibitor, compared with unfractionated heparin + GPIIb/IIIa inhibitor, was associated with non-inferior rates of composite ischaemia (7.7% and 7.3%), major bleeding (5.3% and 5.7%) and net adverse clinical events (11.8% and 11.7%). However, the bivalirudin monotherapy group (with 9% provisional use of glycoprotein IIb/IIIa inhibitors), as compared with unfractionated heparin + GPIIb/IIIa inhibitor, was associated with a non-inferior rate of composite ischaemia (7.8% and 7.3%), and significantly reduced major bleeding (3.0% vs 5.7%, RR 0.53, 95% CI 0.43-0.65, p < 0.001) and NACE (10.1% vs 11.7%, RR 0.86, 95% CI 0.77—0.97, p = 0.02). Results were similar when evaluated in the subgroup that underwent PCI. One-year mortality was similar in the bivalirudin monotherapy group (3.7%), in the bivalirudin + GP IIb/IIIa inhibitor group (3.8%) and in the unfractionated heparin + GP IIb/IIIa inhibitor group (3.9%).

There was a nonsignificant (p = 0.054) interaction with ischaemic outcomes in patients with and patients without prior use of clopidogrel. In patients with thienopyridine use before angiography or PCI, ischaemic events occurred in 7.0% bivalirudin vs 7.3% unfractionated heparin + IIb/IIIa antagonists (RR 0.97, 95% CI 0.80-1.17), whereas in patients with no thienopyridine use before angiography or PCI ischaemic events occurred in 9.1% bivalirudin vs 7.1% unfractionated heparin + IIb/IIIa antagonists (RR 1.29, 95% CI 1.03-1.63). At 12-month follow-up there was no difference in mortality between patients who had or had not received clopidogrel loading prior to angiography or PCI.

Among 7,851 US patients in ACUITY, hospital costs were lower with bivalirudin (mean difference range $184 to $1,081, p < 0.001) and at 30 days (mean difference range $123 to $938, p = 0.005), as compared with unfractionated heparin + IIb/IIIa antagonists, despite higher drug costs.[6] Savings were largely due to less major ($8,658 per event) and less minor bleeding with bivalirudin ($2,282 per event), as well as shorter length of stay with bivalirudin (p = 0.02).

Thus the simpler regimen of bivalirudin alone, using glycoprotein IIb/IIIa inhibitors only for bail-out situations during PCI (in 9% of ACUITY patients), resulted in significantly greater net clinical benefit and an almost 50% reduction in major bleeding.

The recent Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 3) trial included 4,570 stable patients (none had troponin elevations) undergoing PCI with 600 mg of clopidogrel loading at least two hours before PCI.[7] Bivalirudin did not reduce the incidence of the composite endpoint of death, myocardial infarction, urgent target-vessel revascularisation and major bleeding as compared with unfractionated heparin dosed at 140 units/kg, but it did significantly reduce the incidence of major bleeding by 33%.

The Harmonising Outcomes with RevascularIsation and Stents in Acute Myocardial Infarction (HORIZONSAMI) trial randomised 3,602 patients with STEMI undergoing primary PCI (all receiving aspirin and thienopyridine), then to unfractionated heparin plus the routine use of GP IIb/IIIa inhibitors or bivalirudin with provisional use of GP IIb/IIIa inhibitors.8

Bivalirudin monotherapy (with 7.2% provisional inlaboratory use of IIb/IIIa inhibitors), compared with unfractionated heparin + GP IIb/IIIa inhibitors, resulted in a significant reduction in the 30-day primary endpoint of death, reinfarction, ischaemic target vessel revascularisation, or stroke or major bleeding (9.2% vs 12.1%, p = 0.006). Major bleeding was reduced by 40%. Major bleeding was defined as intracranial or intraocular haemorrhage; bleeding at the access site, with a haematoma that was 5 cm or larger that required intervention; a decrease in the haemoglobin level of 4 g per decilitre or more without an overt bleeding source or 3 g per decilitre or more with an overt bleeding source; reoperation for bleeding; or blood transfusion (4.9% vs 8.3%, p < 0.001). There were similar rates of major adverse cardiovascular events (5.4% vs 5.5%, p = 1.0).

Rates of cardiac-related mortality at 30 days were significantly reduced among bivalirudin-treated patients (1.8% vs 2.9%, p = 0.03), as was total mortality (2.1% vs 3.1%, p = 0.047). Stent thrombosis was increased in the first 24 hours (1.3% vs 0.3%), p < 0.001), but not at 30 days (2.5% vs 1.9%). At 12-month follow-up the mortality differences increased: cardiac mortality 2.1% vs 3.8% (p = 0.025), total mortality 3.4% vs 4.8% (p = 0.029). The European guidelines give bivalirudin a class IIa recommendation (weight of evidence/opinion is in favour of usefulness/efficacy) for primary PCI given as an IV bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/h not titrated to ACT and usually terminated at the end of the procedure.[9]

Conclusion
The role of bivalirudin in PCI is established as it reduces post-PCI bleeding, a complication that causes patient discomfort, prolongs hospitalisation, increases costs and is prognostically relevant. In primary PCI bivalirudin is a particularly attractive alternative to the standard of care of unfractionated heparin as it reduces 30-day and one-year mortality.

References
1. Bittl JA, et al. N Engl J Med 1995;333:764-9.
2. Lincoff AM, et al. JAMA 2003;289:853-63.
3. Lincoff AM, et al. JAMA 2004;292:696-703.
4. Cohen DJ, et al. J Am Coll Cardiol 2004;44:1792-800.
5. Stone GW, et al. N Engl J Med 2006;355:2203-16.
6. Pinto DS, et al. J Am Coll Cardiol 2008;52:1758-68.
7. Kastrati A, et al. N Engl J Med 2008;359:688-96.
8. Stone GW, et al. N Engl J Med 2008;358:2218-30.
9. Van de Werf F, et al. Eur Heart J 2008; 29: 2909-45.



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