Among patients with acute STEMI undergoing primary PCI, is anticoagulation with bivalirudin alone superior to treatment with unfractionated heparin plus glycoprotein IIb/IIIa inhibitors?
Among patients presenting with acute STEMI and undergoing PCI, treatment with bivalirudin alone leads to lower rates of adverse clinical events and major bleeding when compared to treatment with unfractionated heparin plus GPIIb/IIIa.
In patients presenting with STEMI, primary PCI restores blood flow in the culprit coronary artery(s) in more than 95% of patients . A potential complication with PCI is distal embolization as a result of mechanical intervention. Consequently, antithrombotic and antiplatelet therapies are often employed prior to PCI to reduce the risk of thrombotic complications. Prior to the publication of this trial, most patients in the United States were administered unfractionated heparin (UFH) and a glycoprotein IIb/IIIa inhibitor prior to PCI. Results from the 2007 ACUITY trial suggest that bivalirudin, a short-acting direct thrombin inhibitor, improves clinical outcomes in patients undergoing PCI for stable/unstable angina and NSTEMI by reducing bleeding complications. Given the lack of data for bivalirudin in STEMI patients, the HORIZON-AMI trial was conducted to see if ACUITY findings could be replicated in STEMI patients.
Published in 2008, the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZON-AMI) trial randomized 3,602 patients with STEMI undergoing PCI to receive bivalirudin alone or UFH plus a GPIIb/IIIa inhibitor. The 30-day rate of net clinical and major bleeding events were significantly lower in the bilvalirudin group vs. the UFH plus GPIIb/IIIa group (net clinical events: 9.2% vs. 12.1%, P=0.005 [CI 0.63-0.92]) (major bleeding: 4.9% vs. 8.3%, P<0.001 [CI 0.46-0.77]). Additionally, treatment with bivalirudin alone led to significantly lower 30-day rates of cardiac death and all cause death (cardiac death: 1.8% vs. 2.9%, P=0.03 [CI 0.40-0.95]) (Death from all causes: 2.1% vs. 3.1%, P=0.047 [CI, 0.44 to 1.00]). Of some concern was an increase in the risk of acute stent thrombosis within 24 hours in the bivalirudin group, however, this risk was not present by 30 days. Of note, most patients in the bivalirudin group received heparin in the emergency room prior to randomization which may potentially weaken the findings. A criticism of both the ACUITY and HORIZON-AMI trials is that both were conducted in an open-label manner which may have influenced study findings.
Follow-up of the HORIZON-AMI patients at 3 years showed that patients in the bivalirudin group had significantly lower rates of all-cause mortality, cardiac mortality, reinfarction, and major bleeding . Given the total findings of this trial, STEMI guidelines were updated to include the recommendation of using bivalirudin as an anticoagulant prior to PCI in STEMI patients.
ACCF/AHA STEMI Guidelines (2013, adapted)
- For patients with STEMI undergoing primary PCI, the following supportive anticoagulant regimens are recommended:
- a) UFH, with additional boluses administered as needed to maintain therapeutic activated clotting time levels, taking into account whether a GP IIb/IIIa receptor antagonist has been administered (Class I, level C); or
- b) Bivalirudin with or without prior treatment with UFH (Class I, level B)
- Multinational, multicenter, open-label randomized controlled trial
- N = 3,602 patients with STEMI undergoing primary PCI
- Setting: 123 centers in 11 countries
- Enrollment: March 2005 - May 2007
- Follow-up: 30-days, 6 months, 1 year, yearly for 5 years.
- Analysis: Intention to treat
- Primary outcomes: Major bleeding and combined adverse clinical events within 30 days (combination of major bleeding or major adverse CV events including death, reinfarction, target-vessel revascularization for ischemia, and stoke)
- Age >18y
- Chest pain >20 min but <12h in duration before randomization consistent with STEMI
- ST-segment elevation >1mm in >2 contiguous leads, or new LBBB, or true posterior MI with ST depression of >1mm in >2 contiguous anterior leads
- Provide written informed consent
- Contraindications to the study medications
- Prior administration of thrombolytic agents, bivalirudin, glycoprotein IIb/ IIIa inhibitors, low-molecular-weight heparin, or fondaparinux for the present admission (although prior unfractionated heparin was allowed)
- Current use of warfarin; history of bleeding diathesis, coagulopathy, heparin-induced thrombocytopenia, intracerebral mass, aneurysm, arteriovenous malformation, or hemorrhagic stroke
- Stroke or transient ischemic attack within the previous 6 months or any permanent neurologic deficit
- Refusal to receive blood transfusions
- Gastrointestinal or genitourinary bleeding within the previous 2 months
- Major surgery within the previous 6 weeks
- A known platelet count of less than 100,000 cells per cubic millimeter or a hemoglobin level of less than 10 g per deciliter, a planned elective surgical procedure that would necessitate an interruption in treatment with thienopyridines during the first 6 months after enrollment
- Coronary stent implantation within the previous 30 days
- Noncardiac coexisting conditions that could limit life expectancy to less than 1 year or that might interfere with compliance with the protocol
From the Bivalirudin group’’
- Demographics: Age 59.8 years, male 77.1%
- PMH: Diabetes 15.6%, HTN 51.8%, HLD 43.4%, Current smoker 47.2%, Renal insufficiency: 15.8%, Anemia: 10.3%, Thrombocytopenia 3.7%
- Cardiac hx: Prior MI 10.4%, prior PCI 10.5%, prior CABG 3.3%
- Weight 80kg
- Interval from symptom onset to hospital arrival: 2.2 hrs
- Killip class II, III, or IV: 8.5%
- LVEF 50%
- Randomization to bivalirudin alone or to UFH plus GP IIb/IIIa inhibitor therapy group
- All patients received aspirin in the ED, and a loading dose of clopidogrel or ticlopidine prior to catheterization
- All patients continued clopidogrel therapy for at least 6 months
Comparisons are Bivalirudin alone vs. UFH plus GP IIb/IIIa inhibitor
- Major bleeding endpoint
- 4.9% vs. 8.3% (RR 0.60, 95% CI 0.46-0.77 P<0.001)
- Combined adverse clinical events
- 9.2% vs. 12.1% (RR 0.76, 95% CI 0.63-0.92 P=0.005)
- Bleeding adverse events in bivalirudin group: blood transfusion 3.5%, TIMI major, minor and combined: 5.0%, 4.6%, 9.6%, GUSTO severe, moderated and combined bleeding: 0.6%, 5.0%, 5.6%, Moderate, severe and profound thrombocytopenia: 2.9%, 0.9%, 0.4%
- Major adverse CV events in bivalirudin group: death 3.1%, reinfarction 1.8%, revascularization of target vessel for ischemia 1.9%, Stroke 0.6%
- Trial was conducted in an open label fashion
- 66% of patients in the bivalirudin group received heparin in the ED
- Funded by the Cardiovascular Research Foundation, a nonprofit foundation affiliated with Columbia University (receiving funding from several commercial entities)
- Morrow D.A. “Antithrombotic therapy to support primary PCI.” NEJM. 2008 May 22;358(21):2280-2.
- Stone G.W. et al. “Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): Final 3-year results from a multicentre, randomised controlled trial” Lancet. 2011 Jun 25;377(9784):2193-204.
- O'Gara PT et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013. 127:e362-425.