NPC Archive Item: One-year follow up data for bivalirudin▼ in patients with high-risk STEMI

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25 February 2010

The HORIZONS-AMI trial assessed high-risk patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). One year follow-up data to this study suggest that bivalirudin150mg reduced bleeding complications, and early and late cardiac and all-cause mortality compared to unfractionated heparin given with glycoprotein IIb/IIIa inhibitors (GLPI).

Level of evidence:
Level 1 (good quality patient-orientated evidence) according to the SORT criteria.

The results from this study suggest bivalirudin can be used as sole therapy in patients with STEMI undergoing primary PCI, as it is associated with significant less major bleeding than heparin plus GLP inhibitors. This may be an option for patients with the highest bleeding risk, but might be less appropriate for those with acute stent thrombosis.  However, the authors of the paper note that long-term follow-up is necessary to confirm the findings. Follow-up for a total of five years is planned.

A NICE clinical guideline on acute coronary syndrome (ACS) is due to be published in March 2010 and includes advice on the use of bivalirudin in unstable angina and NSTEMI.

What is the background to this?
Although GLP inhibitors are commonly employed in patients undergoing primary PCI, they have been associated with an increased risk of bleeding complications and thrombocytopenia which may result in premature death. Bivalirudin is a direct thrombin inhibitor which is licensed for patients undergoing PCI, including patients with STEMI undergoing primary PCI. It is also indicated for the treatment of patients with unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI) planned for urgent or early intervention.

In the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial, 3,602 patients with high-risk STEMI undergoing primary PCI were randomly assigned to receive bivalirudin alone or heparin plus a GLPI. When the results were analysed at 30 days, those receiving bivalirudin had reduced rates of major bleeding and thrombocytopenia and improved survival compared to heparin plus GLPI. Net adverse clinical events (major bleeding or major cardiovascular events such as death, reinfarction or stroke) were seen in 9.2% of bivalirudin patients compared to 12.1% of control patients, relative risk [RR] 0.76, 95% confidence interval[CI] 0.63 to 0.92, P=0.005, mainly due to a decrease in the risk of major bleeding.

There was an increased risk of stent thrombosis within 24 hours in the bivalirudin group, but no significant increase was present by 30 days.

Treatment with bivalirudin, as compared with heparin plus GLPI, resulted in lower 30-day rates of death from cardiac causes (1.8% vs. 2.9%; RR 0.62, 95%CI 0.40 to 0.95, P=0.03).  All cause mortality was 2.1% versus 3.1%, RR 0.66, 95% CI 0.44 to 1.00, P=0.047.

This blog discusses the results from a prespecified analysis of 1-year outcomes designed to ascertain whether the beneficial effects seen at 30 days were still present one year later.

What does the one year follow-up to this study claim?
After one year’s follow-up, major bleeding not related to coronary artery by-pass grafting (CABG) was lower in the bivalirudin patients compared to heparin plus GLPI: 5.8% versus 9.2%, hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.48 to 0.78, P<0.0001.

Net adverse clinical events were seen in 15.6% of bivalirudin patients and 18.3% of control patients, HR 0.83, 95% CI 0.71 to 0.97, P=0.022. This outcome was mainly driven by less major bleeding in the bivalirudin group.

The 1-year rates of cardiac mortality (2.1% vs. 3.8%, HR 0.57, 95% CI 0.38 to 0.84, P=0.005) and all-cause mortality (3.5%vs. 4.8%, HR 0.71 95%CI 0.51 to 0.98, P=0.037) were lower in the bivalirudin group than in the control group. Hence the number needed to treat (NNT) to prevent one cardiac death and one all-cause death is approximately 59 and 77 patients, respectively.

How does this relate to other studies?
Bivalirudin has also been assessed in unstable angina and NSTEMI (ACUITY trial) and in stable and unstable ischaemic syndromes (REPLACE-2).  The authors of this Lancet article state that in an unpublished meta-analysis (n=18,819) incorporating data from the above trials and HORIZONS-AMI there was a non-significant 9% decrease in 30-day mortality but a significant 15% decrease at one year. The trials suggest that preventing early bleeding complications reduces the risk of premature death.

Follow-up of HORIZON-AMI participants is planned for a total of five years.  Other trials are on-going, including one of bivalirudin in combination with prasugrel, which may provide information on the risk of stent thrombosis.

So what?
The data reported here confirm that the early reduction in bleeding as well as in cardiac and all-cause mortality observed in the initial HORIZON-AMI study in patients given bivalirudin were maintained at 1-year follow-up. The increase in stent thrombosis observed with bivalirudin at 30 days did not translate to worse outcomes at 1 year.

The management of patients with the highest risk of bleeding, for example those with chronic kidney disease and the elderly, has not been clarified by HORIZONS-AMI as outcome data were not stratified according to estimates of bleeding risk, and patients at risk of bleeding were excluded. It might be expected that these patients would have the most to gain from an intervention which reduces the risk of bleeding.

This is one of the largest completed prospective, randomised trials in patients with STEMI undergoing primary PCI, but it has limitations. The logistics of the study meant that an open-label design was employed. Bias was minimised by masking laboratory technicians and adjudication committees to the treatment allocation.  The reduction in rates of death and re-infarction is encouraging, but longer-term follow-up is needed to ascertain the robustness of the findings, as well as providing a thorough assessment of the safety profile of this agent.

A NICE clinical guideline on acute coronary syndrome (ACS) is due to be published in March 2010 and includes advice on the use of bivalirudin in unstable angina and NSTEMI.  The use of glycoprotein IIb/IIIa (GLP) inhibitors in the management of ACS and early thrombolysis in acute myocardial infarction are reviewed in NICE appraisals. Further information on ACS can be found on the cardiovascular section of NPC.

Study details
Mehran R, Lansky AJ, Witzenbichler B et al for the HORIZONS-AMI Trial Investigators. Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. Lancet 2009; 374:1149-59

Design: Randomised open-label trial, although laboratory staff and the clinical events committee (who adjudicated the primary and stent thrombosis events) were blind to antithrombotic treatment and stent allocation. The trial was designed to show non-inferiority, but it is accepted practice that if non-inferiority is proven then the results can be re-evaluated for superiority. Allocation was concealed.

Patients: Patients were included if they presented within 12 hours after onset of symptoms and had ST-segment elevation, new left bundle-branch block, or true posterior MI. Exclusions included conditions that increase risk of bleeding. Over 75% of participants were male, median age 60.2 years.

Intervention and comparison: Patients were randomised to bivalirudin (n=1,800) or unfractionated heparin plus GLPI (abciximab or eptifibatide; n=1,802). Bivalirudin was given as an IV bolus dose of 0.75mg/kg followed by an infusion of 1.75mg/kg/hour. Heparin was titrated to a target activated clotting time of 200 to 250 seconds. All were stopped at completion of PCI or angiography, unless the clinician deemed continued low doses were necessary. Bivalirudin patients could be given a GLPI if there was no re-flow or giant thrombus after PCI (less than 10% of patients received one). Aspirin was administered in the emergency department, during hospital stay and on discharge. A loading dose of clopidogrel (either 300mg or 600mg), or ticlopidine, was followed by oral clopidogrel 75mg for at least six months.

Following emergency coronary angiography, patients could receive medical management, CABG or PCI (this procedure was done in 93% of patients). The latter were randomised to bare-metal or paclitaxel-eluting stents.

Outcomes and results: The primary endpoints were major bleeding not related to CABG and net adverse clinical events (including death, re-infarction, stroke, major bleeding). Secondary outcomes assessed the effect of the different types of stents.

Intention-to-treat analysis after one year’s follow-up found that net adverse clinical events were seen in 15.6% of bivalirudin patients and 18.3% of control patients, HR 0.83, 95% CI 0.71 to 0.97, P=0.022. This was mainly driven by less major bleeding in the bivalirudin group (5.8% versus 9.2%, HR 0.61, 95% CI 0.48 to 0.78, P<0.0001). All-cause mortality at 3.5% vs. 4.8% (HR 0.71, 95% CI 0.51 to 0.98, P=0.037) and cardiac mortality at 2.1% vs. 3.8% (HR 0.57, 95% CI 0.38 to 0.84, P=0.005) was less with bivalirudin than the control group.

The rate of stent thrombosis was not different between the groups. The type of stent the patient received did not make any difference to outcomes. Patients who suffered from major bleeding (n=268) had significantly higher morbidity and mortality. For example, one-year death rates were 16.6% versus 3.1%, P<0.0001. The incidence of thrombocytopenia was not reported at one year.

Sponsorship: Cardiovascular Research Foundation with unrestricted grants from Boston Scientific Corporation and The Medicines Company

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