Safety and Tolerability of High-Intensity Anticoagulation with Bivalirudin During Neuroendovascular Procedures
Bivalirudin (Angiomax) is a direct thrombin inhibitor used in interventional cardiology due to its several distinct advantages over heparin, most notably a shorter half-life and a potentially superior safety profile. Bivalirudin is also safe to use in patients with active or remote heparin-induced thrombocytopenia. Our objective was to evaluate the safety and tolerability of high-intensity anticoagulation using bivalirudin during neuroendovascular procedures.
The bivalirudin dosing regimens reported in the cardiac literature were modified empirically for two different activated clotting time (ACT) target ranges. The low-dose protocol (ACT of 250 to 300 s) was used for embolization procedures and the high-dose protocol (ACT of 300–350) was employed for angioplasty and stent placement. The bivalirudin treated patients were matched for age, gender, and type of procedure with a random sample of patients who underwent neuroendovascular procedures with the standardized heparin protocol. The thromboembolic and hemorrhagic complications were compared between the two groups and bleeding complications were categorized as major (hemorrhage that was intra-cerebral or resulted in Hb decrease ≥ 5 g/dl), minor, or insignificant.
Bivalirudin was used in 30 patients with high-dose and low-dose bivalirudin protocols used in 26 and 4 patients, respectively. These were compared to the 60 control patients who received heparin. There were no bleeding or thromboembolic complications in the bivalirudin treated patients; however one patient reported a transient headache. In patients treated with heparin, one bleeding complication of a groin hematoma was reported. Also one patient was found to have left-arm weakness following the procedure which was attributed to a new small middle cerebral artery ischemic event.
Our data supports that bivalirudin usage is likely a safe alternative to heparin for high-intensity anticoagulation in neuroendovascular procedures. Further studies are required for more definitive comparisons for efficacy and cost-effectiveness between the two agents.
KeywordsBivalirudin Angiomax Anticoagulation Heparin Neuroendovascular procedures Stent
Unfractionated heparin and low-molecular-weight heparin are used for high-dose anticoagulation during cardiac catheterization and neuroendovascular procedures to prevent procedural thrombotic complications. More recently, direct thrombin inhibitors (DTIs) have been extensively evaluated as anticoagulants during percutaneous coronary interventions (PCIs) to reduce the rate of peri-procedural clinical events including ischemia, bleeding, and mortality associated with use of heparin and its derivatives. Bivalirudin (Angiomax®, The Medicines Company, NJ) (previously known as Hirulog®), is a DTI that has been shown to have (1) a shorter half-life and a better safety profile , (2) ability to inhibit free- and clot-bound thrombin , (3) wihtout platelet activation , (4) avoidance of heparin-induced thrombocytopenia (HIT) , and (5) a significant reduction of bleeding without an increase in thrombotic or ischemic outcomes as compared to heparin use during PCIs [5, 6]. Due to the above advantages, bivalirudin is replacing heparin as the anticoagulant of choice in patients presenting with acute coronary syndromes (ACSs). In PCIs, however, target ACT values are usually higher, and precise ACT control is not as critical as in neuroendovascular procedures . This mandates a more careful assessment of bivalirudin in neuroendovascular procedures prior to its widespread application. We evaluated the safety and tolerability of bivalirudin in neuroendovascular procedures by first studying its effect on ACT values using different dosing regimens and then comparing the clinical outcomes with patients receiving heparin in a matched controlled study.
The dosing protocol employed for endovascular procedures was empirically modified from studies performed in patients undergoing PCIs. The initial experience of using different dosing protocols in neuroendovascular procedures has already been reported by our group . Briefly, three different dosing protocols were initially used in four consecutive patients with normal renal function undergoing neuroendovascular procedures. The bivalirudin dosing regimens empirically targeted two different activated clotting time (ACT) ranges. The low-dose protocol (target ACT of 250 to 300 s) was used for embolization procedures and the high-dose protocol (target ACT of 300–350) was employed for angioplasty and stent placement. An initial bolus of 0.60 mg/kg of bivalirudin was administered intravenously at the time of guide-catheter placement and the infusion was continued at a rate of 1.25 mg/kg/h. ACT was measured at 5 min after the initial dose and after other dose adjustments. Once target ACT range was achieved, ACT monitoring was done at 15 min intervals until the guide-catheter was removed and bivalirudin infusion discontinued.
Patient Selection and Outcome Measures
Information about all patients who underwent neuroendovascular procedures was kept in prospectively collected databases at three university hospitals from January 2008 to December 2009. From this database, patients who received bivalirudin were identified. Data regarding the demographics, clinical indications, type of procedures, and clinical outcomes was also noted.
Clinical outcomes of patients treated with bivalirudin were compared to a random sample of patients treated with a standardized heparin protocol for anticoagulation (control group) selected from the same database. Two control subjects per treatment subject were randomly selected using a computer generated program and matched by age (within 5 years), gender and type of procedure. Patients with coagulopathies and platelet count <100,000 were excluded from the analysis.
The outcome measures were thromboembolic events and hemorrhagic complications within 24 h of the procedure. Hemorrhagic complications were classified as major, minor, or insignificant according to criteria used by the Thrombolysis in Myocardial Infarction trial group. Major bleeding was defined as any intracranial hemorrhage or a decrease in hemoglobin level of >5 g/dl. Minor bleeding was defined as any decrease in hemoglobin level of 3 to 5 g/dl. Other bleeding complications were classified as insignificant. Thromboembolic complications were classified as major or minor ischemic stroke. Minor (non-disabling) stroke was defined by a modified Rankin scale score of 2 or less, and major (disabling) stroke was defined by a modified Rankin scale score of greater than 2 within 48 h of the procedure.
Our database did not have the information about baseline hemoglobin, platelets PTT/INR of all the patients who underwent neuroendovascular procedures; however we did perform a subset analysis comparing these values between 15 bivalirudin and 30 heparin treated patients in whom this information was available. Fisher exact test was selected to detect statistical significance among the outcome variables; however, due to a zero frequency of events, they are not reported.
At our institutions, a single bolus dose of heparin (50 units/kg) was used to achieve an activated coagulation time (ACT) of 250–300 s for low-dose anticoagulation procedures. For high-dose anticoagulation, we administered 70 units/kg bolus of heparin to achieve target ACT of 300–350 s. During the initial dosing and after any dose adjustment, ACT was measured after 5–15 min. Once target ACT range was achieved, the ACT was monitored in 1 h intervals until the guide-catheter was removed at which point heparin infusion was discontinued.
Characteristics of patients that received bivalirudin or heparin for high-intensity anticoagulation during neuroendovascular procedures
Bivalirudin treated (n = 30)
Heparin treated (n = 60)
Coronary artery disease
Median hemoglobin (units) [range]
Platelet (units) [range]
PTT (units) [range]
Femoral closure device used
ICU days (median ± SD)
1 (2%) (groin hematoma)
None of the patients who received bivalirudin had any hemorrhagic complication. However, one patient in the heparin treated group developed a groin hematoma. Groin hematoma in the patient mentioned was not severe and was managed conservatively. Similarly no thromboembolic complication was noted in patients administered bivalirudin compared to one patient who developed minor ischemic stroke in the heparin treated group. This was a 67 year old man with hypertension and coronary artery disease who underwent carotid angioplasty and stent placement for symptomatic severe right extracranial carotid artery stenosis. The patient was neurologically intact during the procedure but was found to have left-arm weakness immediately following the procedure and was diagnosed with a new minor ischemic stroke referable to the middle cerebral artery distribution. One patient that received bivalirudin complained of headache after the procedure which subsided shortly. No allergic or other adverse drug effects were seen in patients given bivalirudin or heparin during these procedures.
The DTI bivalirudin has been studied extensively in patients undergoing PCI, and has replaced heparin as the most widely used anticoagulant for PCI . Although it is not being widely used for neuroendovascular procedures, there might be a great advantage to its use.
Although therapeutic ACT values are typically reached in less than 5 min with either agent  bivalirudin compared with heparin has a shorter half-life (25 vs. 90 min) allowing a higher level of titration. Therefore, spontaneous return to normal coagulation parameters and early removal of the femoral sheath is possible. The shorter half-life may be beneficial in events of peri-procedural intracranial hemorrhages observed in up to 4% of patients undergoing carotid or intracranial endovascular revascularizations .
The target ACT for high-intensity anticoagulation for both treatment paradigms was similar. The optimal ACT value for neuroendovascular procedures is still a subject of debate. In procedures such as angioplasty and stent placement with a higher risk of intimal injury and higher risk of thromboembolic complications, we use a target ACT of 300–350 s . A lower ACT range of 250–300 s is used in some studies . A disadvantage of bivalirudin use despite its short half-life is it cannot be reversed like heparin using protamine. This should be kept in mind during clinical situations with anticipated increased risk of bleeding. Also, it is important to reduce dose of bivalirudin in patients with impaired renal function by titration in accordance with the creatinine clearance. Patients with moderate renal impairment (creatinine clearance of 30–59 ml/min) should receive a lower dose of 1.75 mg/kg/h. If the creatinine clearance is less than 30 ml/min, the infusion rate should be reduced to 1.0 mg/kg/h. No reduction is however required in the bolus dose .
Recent literature has confirmed improved short term (30-day) survival rates with bivalirudin use when compared to heparin. This is a result of significant reduction in major bleeding and subsequent adverse events in patients with ACS [14, 15]. There have been several studies that have reported an independent association between major bleeding (with or without transfusions) and subsequent mortality in patients undergoing PCI [16, 17, 18]. A meta-analysis of the REPLACE-2 , ACUITY , and HORIZONS-AMI  trials compared the outcomes between bivalirudin and heparin in combination with a platelet GP IIB/IIIA inhibitor in patients with myocardial infarction and ACSs with PCI . Bivalirudin was associated with a non-significant 9% reduction in 30-day mortality, and a significant 15% reduction in 1-year mortality in PCI patients. Also initial results from carotid artery interventions are encouraging. Bush et al.  reported neither any major neurological sequelae nor hemorrhagic complications necessitating transfusion or operative intervention with adjuvant use of bivalirudin in over 150 patients who underwent carotid stent placement. Similarly, Schneider et al.  reported their 3 year experience of using bivalirudin during carotid stent placement in 514 patients. In their series, major stroke and death occurred in 6 (1.1%) of patients within 30 days of procedure. Both investigators concluded that use of bivalirudin is safe in patients undergoing carotid stent placement.
A potential drawback to the use of bivalirudin is the higher cost of the agent. In studies conducted in patients undergoing PCI, the higher cost is offset by the lower risk of bleeding complications and associated cost compared with the combination of GPIIB/IIIA inhibitors and heparin . Although we were able to show the safety and tolerability of bivalirudin in neuroendovascular procedures, our study has several limitations. Our sample of patients was small; therefore it was difficult to establish the efficacy and complication rates associated with this drug. Also, the biological activity of bivalirudin does not correlate well with ACT measurements and ideally thrombin time should be used. Our protocol was derived from the cardiology literature, which used ACT to monitor intensity of anticoagulation. Moreover, the time duration patients were within the target range is unavailable. Further, the procedures were quite heterogeneous which we tried to address by including the procedure type in the matching process. Furthermore, we cannot rule out a confounding bias due to a imbalance in cardiovascular risk factors between the two groups. We have reported only the safety outcomes that are unlikely to be associated with patient risk factors.
Our data supports that the use of bivalirudin is likely to be a safe alternative to heparin for high-intensity anticoagulation in neuroendovascular procedures. Further studies are required for more definitive comparisons for efficacy and cost-effectiveness between the two agents.
- 7.Georgiadis AL SQ, Suri MFK, Qureshi AI. Adjunct bivalirudin dosing protocol for neuro-endovascular procedures. J Vasc Intervent Neurol. 2008;1(2):50–3.Google Scholar
- 8.Cohen DJ, Lincoff AM, Lavelle TA, et al. Economic evaluation of bivalirudin with provisional glycoprotein IIB/IIIA inhibition versus heparin with routine glycoprotein IIB/IIIA inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial. J Am Coll Cardiol. 2004;44(9):1792–800.PubMedGoogle Scholar
- 13.Brunton LL, Lazo JS, Parker KL, editors. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York: Mc-Graw-Hill Companies; 2006.Google Scholar
- 21.Mehran R, Pocock SJ, Stone GW, et al. Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial. Eur Heart J. 2009;30(12):1457–66.PubMedCrossRefGoogle Scholar