Glycoprotein IIb/IIIa Inhibitors in Prevention and Rescue Treatment of Thromboembolic Complications During Endovascular Embolization of Intracranial Aneurysms

Glycoprotein IIb/IIIa Inhibitors in Prevention and Rescue Treatment of Thromboembolic... Abstract Thromboembolic complications remain a major risk of endovascular neurosurgery during the treatment of intracranial aneurysms, despite the use of therapeutic heparinization and oral antiplatelet therapy when indicated. Glycoprotein (GP) IIb/IIIa inhibitors target a nonredundant pathway of platelet aggregation following adhesion and activation. Initially established and implemented in the cardiovascular arena, this drug class has provided a new tool in the neurovascular armamentarium as well. Numerous case reports, case series, and retrospective reviews have evaluated the safety and efficacy of abciximab, eptifibatide, and tirofiban in the treatment of acute thromboembolic complications during the endovascular treatment of intracranial aneurysms. The use of this drug class has also been found to be beneficial as a prophylactic agent, providing ischemia protection during the placement of intracranial stents, flow diverters, and thrombogenic coils in the setting of subarachnoid hemorrhage and during elective aneurysmal embolization. While the current published literature clearly establishes efficacy and safety of GP IIb/IIIa inhibitors in the prevention of thromboembolic complications, there does not yet exist an established protocol for their administration in endovascular neurosurgery. This review provides a comprehensive evaluation of the current published literature pertaining to the use of all available GP IIb/IIIa inhibitors for thromboembolic complications, providing recommendations for dosing and administration of abciximab, eptifibatide, and tirofiban based on previously published rates of efficacy and intracranial hemorrhage. Intracranial aneurysm, Antiplatelet drugs, Cerebral embolism and thrombosis, Glycoproteins IIb-IIIa, GPIIb-IIIa receptors ABBREVIATIONS ABBREVIATIONS ADP adenosine diphosphate EPIC Evaluation of 7E3 for the Prevention of Ischemic Complication GP glycoprotein ICH intracranial hemorrhage The growth of endovascular neurosurgery for the treatment of intracranial aneurysms and arteriovenous malformations has greatly shifted the landscape of vascular neurosurgery. Despite its many advantages, endovascular treatment generates a significant rate of thromboembolic complications, ranging from 2% to 15%,1 associated with a 3.8% risk of permanent morbidity and mortality.2 The rates of clinically silent microembolic events are likely much higher given previous studies evaluating diffusion-weighted magnetic resonance imaging following aneurysmal coil embolization.3 Increased utilization of carotid, intracranial, and flow diverting stents provides a thrombogenic platform, worsening the risk of ischemic complications. While heparin and oral antiplatelet drugs remain a mainstay of treatment, rapid and efficacious intravenous antiplatelet medications are often needed in the setting of acute stent placement or acute thrombus formation during endovascular procedures. Such rescue therapy has been observed in 5% to 10% of cases during the treatment of intracranial aneurysms.1 Inhibitors of the platelet integrin complex, glycoprotein IIb/IIIa (GP IIb/IIIa), are often utilized in either rescue therapy for thrombotic complications or in a prophylactic manner when the preoperative risk is significant. Despite their increasing use, optimal clinical protocols to prevent thromboembolic complications have not yet been established. Here, we provide a comprehensive review of the literature pertaining to the use of GP IIb/IIIa inhibitors in the setting of endovascular neurosurgical procedures, presenting the best practices for each GP IIb/IIIa inhibitor in current clinical practice. GLYCOPROTEIN IIB/IIIA INHIBITORS GP IIb/IIIa Receptor Through blockade of the GP IIb/IIIa receptor, GP IIb/IIIa inhibitors are platelet-specific drugs (Figure). Platelet activation by thrombin generates a conformational change in the platelet, ultimately triggering an increase in intracellular calcium and resulting in the calcium-dependent upregulation of GP IIb/IIIa to the platelet surface. GP IIb/IIIa then serves as a receptor for fibrinogen and von Willebrand factor, and fibrinogen acts to bind platelets to one another, generating thrombus formation as the essential, nonredundant step in platelet aggregation. Clot stabilization occurs secondarily through the coagulation cascade as thrombin converts fibrinogen to insoluble fibrin strands, which are then cross-linked by factor XIII, resulting in a stable thrombus. Hyperacute thrombus formation during an endovascular procedure is primarily composed of activated platelets; therefore, GP IIb/IIIa inhibitors play an important role in inhibiting platelet plug formation.4 This would be particularly useful in the setting of a ruptured cerebral aneurysm as the GP IIb/IIIa inhibitor would not be expected to disrupt the subacute fibrin-stabilized thrombus at the site of aneurysmal rupture, while actively preventing platelet aggregation and hyperacute thrombus formation during attempted endovascular treatments. FIGURE. View largeDownload slide The mechanism of action of current therapeutics for platelet inhibition. Inhibitors of the P2Y12 receptor (clopidogrel, ticagrelor, prasugrel) effectively inhibit the ability of adenosine diphosphate (ADP) to initiate platelet activation. The inhibitory effect of aspirin on cyclooxygenase (COX)-1 decreases thromboxane A2 (TXA2) production from arachidonic acid (AA), limiting its ability to activate platelets via its receptor (TPαR). The current glycoprotein (GP) IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) block the ability of platelet-platelet interactions with fibrinogen. The key initial step of platelet adhesion to the endothelial surface occurs via the interaction of GP IbIXV and von Willebrand Factor (vWF). FIGURE. View largeDownload slide The mechanism of action of current therapeutics for platelet inhibition. Inhibitors of the P2Y12 receptor (clopidogrel, ticagrelor, prasugrel) effectively inhibit the ability of adenosine diphosphate (ADP) to initiate platelet activation. The inhibitory effect of aspirin on cyclooxygenase (COX)-1 decreases thromboxane A2 (TXA2) production from arachidonic acid (AA), limiting its ability to activate platelets via its receptor (TPαR). The current glycoprotein (GP) IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) block the ability of platelet-platelet interactions with fibrinogen. The key initial step of platelet adhesion to the endothelial surface occurs via the interaction of GP IbIXV and von Willebrand Factor (vWF). Abciximab, Eptifibatide, and Tirofiban The 3 currently available GP IIb/IIIa inhibitors include abciximab, eptifibatide, and tirofiban, all of which are able to disrupt acute platelet-mediated thrombosis. Abciximab is a humanized monoclonal antibody with essentially irreversible activity on the GP IIb/IIIa receptor due to its high affinity and slow off-rate, whereas eptifibatide and tirofiban are small molecules with faster on-off pharmacokinetics, making the duration of their effect much shorter.5 Intravenous administration ranges from 0.15 to 0.3 mg/kg, providing irreversible dose-dependent platelet inhibition,6 and a single loading dose is sufficient to provide greater than 80% receptor blockade.4 While the plasma half-life is relatively short (10-30 min), abciximab will remain in circulation in its platelet-bound state for ≥10 d.6 Sustained inhibition of newly formed platelets can be achieved through continuous infusion, while platelet aggregation returns to 50% of baseline within 24 h of drug cessation.6 Despite this modest improvement, platelet aggregation does not return to normal function for 48 to 72 h.4,7 Given this profound, sustained antiplatelet effect, concerns have been raised regarding its safety. Several studies have found abciximab to be associated with a high risk of intracranial hemorrhage (ICH) and early rehemorrhage in the setting of ruptured aneurysms, incurring significant mortality.8,9 While no reversal agent exists for abciximab, platelet administration and drug cessation are the mainstays of treatment in the setting of intracranial or severe systemic hemorrhagic complications.10 Due to the short plasma half-life, the addition of new platelets redistributes the bound drug across a greater number of receptors, diluting its antiplatelet effect. Eptifibatide is a selective, competitive inhibitor of the GP IIb/IIIa receptor.11 It is a cyclic heptapeptide derived from barbourin in the venom of southeastern pigmy rattlesnakes with a rapid onset of action, short half-life (10-15 min) and quick reversal of its antiplatelet effects.6 Platelet function returns to 50% of baseline within 4 h of drug cessation, allowing invasive procedures when necessary.6 Tirofiban is a nonpeptide competitive inhibitor of the GP IIb/IIIa receptor. A derivative of tyrosine, tirofiban mimics the morphology of the arginine-glycine-aspartic acid sequence of fibrinogen.6 Similar to eptifibatide, tirofiban has a rapid onset of action and is rapidly reversible on the molecular level. The antiplatelet effect is directly proportional to its plasma concentration with a half-life of 2 to 4 h, while platelet function returns to normal within 4 to 8 h of drug cessation.6,7 Compared to abciximab, the shorter half-life and diminished receptor affinity seen with eptifibatide and tirofiban prove advantageous when a surgical procedure may be required during the immediate postoperative period. Abciximab effectively provides a therapeutic antiplatelet response for 48 h following a loading dose, whereas the therapeutic window of eptifibatide and tirofiban is limited to 4 to 8 h. Despite the short half-life of these small molecule inhibitors, no reversal agents have yet been developed, and platelet administration has limited utility in eptifibatide or tirofiban-related hemorrhage as new platelets are simply inhibited by circulating drug. While no reversal protocol has been agreed upon in the setting of systemic or intracranial hemorrhage, use of desmopressin (0.3 μg/kg),12 cryoprecipitate,13 and platelet transfusion has been utilized with some success. Initial Drug Development The clinical benefit of GP IIb/IIIa inhibitors was first demonstrated in patients with cardiovascular disease, particularly those undergoing percutaneous coronary intervention. While percutaneous coronary angioplasty improves symptoms of ischemia and quality of life, significant drawbacks arose secondary to a 4% to 9% risk of acute thrombotic complications, yielding a 10-fold increase in mortality.14 Abciximab was studied in a large randomized controlled trial of patients undergoing coronary angioplasty or atherectomy through the Evaluation of 7E3 for the Prevention of Ischemic Complication (EPIC) trial.14 The EPIC trial demonstrated that abciximab use decreased ischemic complications, which was most profound when administered as a loading dose followed by an infusion.14 Furthermore, patients with the highest risk for ischemic complications, such as presence of an acute or recent myocardial infarction or unstable angina, had a substantial treatment benefit.15 While hemorrhage risk was significantly increased following abciximab, 71% of these complications occurred at the site of vascular access and rarely were life threatening.15 Comparing hemorrhagic stroke, no difference was found between the placebo and treatment groups.15 Overall, use of abciximab during and after percutaneous coronary intervention generated a 35% to 50% decrease in adverse clinical events and improved 30-d mortality.14-16 These findings were corroborated for coronary stenting procedures in the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting trial, which also demonstrated decreased mortality and ischemic complications following abciximab with no increase in major bleeding complications.17 Following the efficacy established in these trials, use of GP IIb/IIIa inhibitors in neurointerventional surgery has increased significantly for thromboembolic complications associated with endovascular treatments. GLYCOPROTEIN IIB/IIIA INHIBITORS AND FIBRINOLYTICS In addition to GP IIb/IIIa inhibitors, fibrinolytics have been used for rescue therapy in the setting of thromboembolic complications during endovascular treatment of intracranial aneurysms. Utilizing a separate mechanism, fibrinolytics, such as tissue plasminogen activator, catalyze the conversion of plasminogen to plasmin, a major enzyme involved in thrombolysis. While angioplasty and fibrinolytics have shown a 44% to 75% recanalization rate, re-occlusion is a major limitation to successful treatment.18 A meta-analysis found GP IIb/IIIa inhibitors to be superior to fibrinolytics for rescue therapy of thromboembolic complications during intracranial aneurysm intervention, resulting in decreased perioperative morbidity from ischemia and hemorrhage with decreased long-term morbidity.1 While GP IIb/IIIa inhibitors demonstrated a trend toward improved recanalization rates compared to fibrinolytics, this was not found to be statistically significant.1 Past studies have also found the use of fibrinolytics in rescue therapy to be associated with increased risk of ICH compared to GP IIb/IIIa inhibitors.19 While fibrinolytics may still have a role, the use of GP IIb/IIIa inhibitors for acute thrombus development during neurointerventional procedures has become a mainstay of treatment. THROMBOEMBOLIC RESCUE Abciximab Thromboembolic events are the most frequent complication following endovascular treatment of intracranial aneurysms, occurring in approximately 3% of patients.20 The routine use of intraoperative heparin and the preoperative administration of aspirin and clopidogrel in select cases have ameliorated some of this risk. Given the validity established through the EPIC trial, abciximab has been the most commonly utilized GP IIb/IIIa inhibitor in the neurovascular literature. Despite the uniform dosage protocols in the cardiovascular literature, consisting of a 0.25 mg/kg bolus prior to intervention and an infusion of 0.125 μg/kg/min for 12 h following the procedure,14,17 reported utilization of abciximab in the neurointerventional literature has been quite variable. Many of the early reported cases utilizing abciximab for intraoperative thromboembolic complications during embolization of aneurysms utilized a single bolus dose immediately following clot formation, initially used only after failure of angioplasty and fibrinolytics.4,21 With increasing evidence of its superiority to fibrinolytics,1 abciximab emerged as the treatment of choice for the rescue of acute thrombus formation during endovascular procedures. A great deal of variability in dosing methods still exist,14 ranging from a single or multiple boluses at the time of thrombus formation4,22-30 to simple infusion following the procedure4 or an intraoperative bolus with a postoperative infusion.4,21,31-33 The dosage among given methods is also quite variable, with weight-based dosing of 0.25 mg/kg being used in a few reports.4,23,28 The majority of abciximab dosing has involved standardized aliquots of either intraarterial (2-5 mg)4,24,25,30 or intravenous (5-20 mg) administration,22,25,26 usually with a maximum dose of 20 mg or 0.25 mg/kg. Utilization of a continuous infusion following an intraoperative bolus has also gained traction, following the dosage protocols in the EPIC trial with an initial bolus of 0.25 mg/kg at the time of thrombus formation and a continuous infusion of 0.125 μg/kg/min for 12 h.4,21,31-33 A slightly different protocol, starting with 5 mg aliquots for the initial bolus with additional aliquots as needed up to a maximum dose of 0.25 mg/kg, has been reported as well.33 Despite a great degree of variability in the administration of a simple bolus and bolus dosing followed by continuous infusion, the rates of recanalization remain similar at 72.7% to 100%4,21,23-25,27-30 and 69.6% to 100%,4,21,31-33 respectively. Rates of ICH reported in these studies were between 2% and 3%, with a tendency for increased rates of hemorrhage in patients having previously suffered an ischemic insult. In addition to administering intraoperative abciximab immediately following identification of a thromboembolic event, a second protocol was also evaluated, in which abciximab was administered in the postoperative setting for symptoms of ischemia.27 This protocol was ultimately abandoned due to a higher rate of ICH, likely secondary to preexisting cerebral infarcts.27 The use of abciximab for thromboembolic complications in the setting of subarachnoid hemorrhage has also been shown to be reasonably safe and effective as numerous studies revealed similar efficacy and safety profiles in the treatment of ruptured and unruptured aneurysms.4,21-25,29,30,33 Based on the EPIC trial and these reports in the neurovascular literature, the use of a bolus dose of 0.25 mg/kg given either intraarterially or intravenously, followed by a continuous infusion of 0.125 μg/kg/min for 12 h, appears to be both relatively safe and effective. While other protocols have demonstrated efficacy as well, this protocol has an established safety profile in a large cardiovascular cohort and has been further validated as safe and highly efficacious in numerous patients in the neurovascular literature. Additionally, weight-based dosing provides a standardized and individualized dose for optimal platelet inhibition. Eptifibatide Given its short half-life, eptifibatide allows for platelet function to return to 50% of baseline within 4 h of cessation. Theoretically reducing the risk of ICH, the role of eptifibatide in thromboembolic rescue has been evaluated in 2 studies (Table 1).5,34 Using a single intraarterial bolus of 0.2 mg/kg of eptifibatide at the time of the thromboembolic event in both ruptured and unruptured aneurysms, eptifibatide was found to be highly efficacious with a complete or partial recanalization rate of 91% and no hemorrhagic complications.5 Interestingly, all patients suffering from thrombus formation at the junction of the coil and parent artery experienced complete revascularization.5 In contrast, eptifibatide performed poorly in cases involving peripheral emboli, with a complete revascularization rate of 37.5%.5 TABLE 1. Glycoprotein IIb/IIIa Inhibitor Utilization for Thromboembolic Complications Authors  Patients  Disease  Route  Bolus  Infusion/duration  Recanalization  Intracranial hemorrhage  Abciximab  273               Ng et al 200122  1  Aneurysm  IV  20 mg  None  Complete  None   Alexander et al 200223  1  Aneurysm  IV  20 mg (0.25 mg/kg)  None  Complete  None   Mounayer et al 200324  13  Aneurysm  IA  4-10 mg  None  92% C, 8% P  None   Bendok et al 200431  1  Aneurysm  IV  0.25 mg/kg  0.125 μg/kg/min (12 h)  Complete  None   Fiorella et al 20044  5  Aneurysm/AVM  IA  2-5 mg aliquots (max: 10 mg)  None  60% C, 40% P  None    2  Aneurysm/AVM  IV  0.25 mg/kg  None  100% C  None    5  Aneurysm  IV  0.25 mg/kg  0.125 μg/kg/min (12 h)  20% C, 80% P  None    1  Aneurysm  IV  None  0.125 μg/kg/min (12 h)  Complete  None   Song et al 200425  4  Aneurysm  IA  5 mg  None  50% C, 25% P, 25% N  50%    1  Aneurysm  IA+IV  5 mg IA; 17 mg IV  None  Complete  None    1  Aneurysm  IA  2 mg  None  Complete  None    1  Aneurysm  IA+IV  2 mg IA; 3 mg IV  None  Complete  None   Aviv et al 200526  6  Aneurysm  IV  5 mg  None  83.3% C, 16.7% P  16.7%    1  Aneurysm  IV  7.5 mg  None  Complete  None    4  Aneurysm  IV  10 mg  None  50% C, 50% P  None    1  Aneurysm  IV  20 mg  None  Partial  100%   Velat et al 200632  26  Aneurysm  IA/IVa  0.25 mg/kg  0.125 μg/kg/min (12 h)  69.2% C, 23.1% P, 7.7% N  11.5%    1  WADA  IA/IVa  0.25 mg/kg  0.125 μg/kg/min (12 h)  N/A  None    2  Carotid stenosis  IA/IVa  0.25 mg/kg  0.125 μg/kg/min (12 h)  50% C, 50% P  None   Gralla et al 200827  27  Aneurysm  IA  13.5 mg ± 13.5 mg, intraoperativeb  None  68.3% C, 19.5% P, 12.2% Nb  2.4%b    12  Aneurysm  IV  13.5 mg ± 13.5 mg, intraoperativeb  None  68.3% C, 19.5% P, 12.2% Nb  2.4%b    2  Aneurysm  IA+IV  13.5 mg ± 13.5 mg, intraoperativeb  None  68.3% C, 19.5% P, 12.2% Nb  2.4%b    22  Aneurysm  IV  11.3 mg ± 3.6 mg, postproceduralb  None  N/A  4.5%   Jones et al 200821  23  Aneurysm  IV  0.25 mg/kg  0.125 μg/kg/min (12 h)  26.1% C, 43.5% P, 30.4% N  None    15  Aneurysm  IA  0.25 mg/kg  0.125 μg/kg/min (12 h)  40% C, 46.7% P, 13.3% N  None   Ries et al 200928  3  Aneurysm  IA  0.25 mg/kg  None  14.3% C, 59.5% P, 26.2% Ne  None    39  Aneurysm  IV  0.25 mg/kg  None  14.3% C, 59.5% P, 26.2% Ne  None   Aggour et al 201033  23  Aneurysm  IA  Initial dose: 5 mg; more as needed; max: 0.25 mg/kg  0.125 μg/kg/min (12 h)  56.5% C, 34.8% P, 8.7% N  None   Linfante et al 201029  19  Aneurysm  IA  10.5 mg ± 4.2 mg  None  N/A  None   Jeong et al 201330  11  Aneurysm  IA  12.3 mg ± 4.1 mg; 2 mg aliquots (max: 20 mg)  None  9.1% C, 63.6% P, 27.3% N  None  Eptifibatide  65               Ramakrishnan et al 201334  20  Aneurysm  IA  2.2512 mg (<90 μg/kg); initial dose: 25% of 90 μg/kg  0.5 μg/kg/min (2-48 h)(n = 20); none (n = 20)  77.5% C, 20% P, 2.5% N  Nonef   Sedat et al 20145  45  Aneurysm  IA  0.2 mg/kg  None  62.2% C, 28.8% P, 9% N  None  Tirofiban  93               Kang et al 200837  25  Aneurysm  IA  0.64 mg ± 0.25 mg; Initial 0.2-0.5 mg, then 0.1 mg aliquots q2-3 min  None (n = 23); IV infusionc (0.1 μg/ kg/min, 6 h) (n = 2)  16% C, 80% P, 4% N  None   Chalouhi et al 201238  5  Aneurysm  IV  0.4 μg/kg/min (30 min)  0.1 μg/kg/min (12 h)  80% C, 20% P  None    4  Aneurysm  IV  None  0.1 μg/kg/min (12 h)  75% C, 25% P  1.9%g   Cho et al 201236  39  Aneurysm  IA  0.71 mg ± 0.26 mg; 4 μg/kg aliquots (max: 25 μg/kg)  0.1 μg/kg/min IV (12 h)(n = 14)d; none (n = 25)  87.2% C, 7.7% P, 5.1% N  5.1%   Jeon et al 201235  9  Aneurysm  IA  0.3 mg aliquots (max: 1.2 mg)  None (n = 9); IV infusion (dose unknown)(n = 1)  80% C, 10% P, 10% N  None   Jeong et al 201330  11  Aneurysm  IA  0.47 mg ± 0.29 mg; 50 μg aliquots (max: 1000 μg)  None  36.4% C, 54.5% P, 9.1% N  None  Authors  Patients  Disease  Route  Bolus  Infusion/duration  Recanalization  Intracranial hemorrhage  Abciximab  273               Ng et al 200122  1  Aneurysm  IV  20 mg  None  Complete  None   Alexander et al 200223  1  Aneurysm  IV  20 mg (0.25 mg/kg)  None  Complete  None   Mounayer et al 200324  13  Aneurysm  IA  4-10 mg  None  92% C, 8% P  None   Bendok et al 200431  1  Aneurysm  IV  0.25 mg/kg  0.125 μg/kg/min (12 h)  Complete  None   Fiorella et al 20044  5  Aneurysm/AVM  IA  2-5 mg aliquots (max: 10 mg)  None  60% C, 40% P  None    2  Aneurysm/AVM  IV  0.25 mg/kg  None  100% C  None    5  Aneurysm  IV  0.25 mg/kg  0.125 μg/kg/min (12 h)  20% C, 80% P  None    1  Aneurysm  IV  None  0.125 μg/kg/min (12 h)  Complete  None   Song et al 200425  4  Aneurysm  IA  5 mg  None  50% C, 25% P, 25% N  50%    1  Aneurysm  IA+IV  5 mg IA; 17 mg IV  None  Complete  None    1  Aneurysm  IA  2 mg  None  Complete  None    1  Aneurysm  IA+IV  2 mg IA; 3 mg IV  None  Complete  None   Aviv et al 200526  6  Aneurysm  IV  5 mg  None  83.3% C, 16.7% P  16.7%    1  Aneurysm  IV  7.5 mg  None  Complete  None    4  Aneurysm  IV  10 mg  None  50% C, 50% P  None    1  Aneurysm  IV  20 mg  None  Partial  100%   Velat et al 200632  26  Aneurysm  IA/IVa  0.25 mg/kg  0.125 μg/kg/min (12 h)  69.2% C, 23.1% P, 7.7% N  11.5%    1  WADA  IA/IVa  0.25 mg/kg  0.125 μg/kg/min (12 h)  N/A  None    2  Carotid stenosis  IA/IVa  0.25 mg/kg  0.125 μg/kg/min (12 h)  50% C, 50% P  None   Gralla et al 200827  27  Aneurysm  IA  13.5 mg ± 13.5 mg, intraoperativeb  None  68.3% C, 19.5% P, 12.2% Nb  2.4%b    12  Aneurysm  IV  13.5 mg ± 13.5 mg, intraoperativeb  None  68.3% C, 19.5% P, 12.2% Nb  2.4%b    2  Aneurysm  IA+IV  13.5 mg ± 13.5 mg, intraoperativeb  None  68.3% C, 19.5% P, 12.2% Nb  2.4%b    22  Aneurysm  IV  11.3 mg ± 3.6 mg, postproceduralb  None  N/A  4.5%   Jones et al 200821  23  Aneurysm  IV  0.25 mg/kg  0.125 μg/kg/min (12 h)  26.1% C, 43.5% P, 30.4% N  None    15  Aneurysm  IA  0.25 mg/kg  0.125 μg/kg/min (12 h)  40% C, 46.7% P, 13.3% N  None   Ries et al 200928  3  Aneurysm  IA  0.25 mg/kg  None  14.3% C, 59.5% P, 26.2% Ne  None    39  Aneurysm  IV  0.25 mg/kg  None  14.3% C, 59.5% P, 26.2% Ne  None   Aggour et al 201033  23  Aneurysm  IA  Initial dose: 5 mg; more as needed; max: 0.25 mg/kg  0.125 μg/kg/min (12 h)  56.5% C, 34.8% P, 8.7% N  None   Linfante et al 201029  19  Aneurysm  IA  10.5 mg ± 4.2 mg  None  N/A  None   Jeong et al 201330  11  Aneurysm  IA  12.3 mg ± 4.1 mg; 2 mg aliquots (max: 20 mg)  None  9.1% C, 63.6% P, 27.3% N  None  Eptifibatide  65               Ramakrishnan et al 201334  20  Aneurysm  IA  2.2512 mg (<90 μg/kg); initial dose: 25% of 90 μg/kg  0.5 μg/kg/min (2-48 h)(n = 20); none (n = 20)  77.5% C, 20% P, 2.5% N  Nonef   Sedat et al 20145  45  Aneurysm  IA  0.2 mg/kg  None  62.2% C, 28.8% P, 9% N  None  Tirofiban  93               Kang et al 200837  25  Aneurysm  IA  0.64 mg ± 0.25 mg; Initial 0.2-0.5 mg, then 0.1 mg aliquots q2-3 min  None (n = 23); IV infusionc (0.1 μg/ kg/min, 6 h) (n = 2)  16% C, 80% P, 4% N  None   Chalouhi et al 201238  5  Aneurysm  IV  0.4 μg/kg/min (30 min)  0.1 μg/kg/min (12 h)  80% C, 20% P  None    4  Aneurysm  IV  None  0.1 μg/kg/min (12 h)  75% C, 25% P  1.9%g   Cho et al 201236  39  Aneurysm  IA  0.71 mg ± 0.26 mg; 4 μg/kg aliquots (max: 25 μg/kg)  0.1 μg/kg/min IV (12 h)(n = 14)d; none (n = 25)  87.2% C, 7.7% P, 5.1% N  5.1%   Jeon et al 201235  9  Aneurysm  IA  0.3 mg aliquots (max: 1.2 mg)  None (n = 9); IV infusion (dose unknown)(n = 1)  80% C, 10% P, 10% N  None   Jeong et al 201330  11  Aneurysm  IA  0.47 mg ± 0.29 mg; 50 μg aliquots (max: 1000 μg)  None  36.4% C, 54.5% P, 9.1% N  None  IA, intraarterial, IV, intravenous; C, complete; P, partial; N, none. aIA only given if microcatheter already in location of thrombus, otherwise administered IV. bPatients who underwent intraoperative administration were evaluated as a single cohort; post-procedural administration was based on stroke-like symptoms in absence of ICH. cIV infusion used with persistent thrombus at aneurysm neck. dIV infusion used with persistent thrombus or extruded coils. eAll patients (IA or IV) were evaluated in a single cohort. fNo hemorrhagic complications when eptifibatide used alone, 15% rate of ICH when used in combination with fibrinolytics or high-dose anticoagulation. gChalouhi et al 201238 did not specify whether hemorrhagic complication in their revised protocol occurred in a patient receiving rescue treatment of prophylactic tirofiban. View Large A second protocol administered intraoperative aliquots up to a maximum loading dose of 90 μg/kg (starting with 25% of the dose limit), followed by a continuous maintenance infusion of 0.5 μg/kg/min for 2 to 48 h in half of their cohort.34 This was found to be efficacious for the treatment of thromboembolic events in unruptured aneurysms, subarachnoid hemorrhage, and during treatment of vasospasm with an overall recanalization rate of 97.5%.34 With the addition of the postoperative continuous infusion, no cases of ICH were observed when only eptifibatide and therapeutic heparinization were used, and they noted no increase in systemic hemorrhagic complications. ICH during this study only occurred when eptifibatide was used in combination with fibrinolytics or high-dose anticoagulation.34 Intraarterial bolus dosing of eptifibatide with a continuous intravenous infusion is highly efficacious without evidence of ICH when used in the absence of fibrinolytics or anticoagulation, providing a therapeutic strategy when surgery or placement of an external ventricular drain is imminent. If anticoagulation or fibrinolytics have been given, this method of thromboembolic rescue therapy should be avoided given the significant ICH risk of 15%.34 Tirofiban Similar to eptifibatide, tirofiban has a very short half-life, providing normalization of platelet function within 4 h of discontinuation. Past reports (Table 1) of tirofiban use have been quite variable, including bolus dosing,30,35-37 postoperative infusion alone,38 and an intraoperative bolus followed by continuous infusion.35-38 All treatment modalities have been efficacious, ranging from 90% to 100% revascularization. While the majority of studies reported no ICH despite treatment in both ruptured and unruptured aneurysms, one group reported 2 hemorrhagic complications, both asymptomatic in nature.36 Most authors utilizing a bolus followed by a continuous infusion only administered the infusion if thrombus was still present on delayed angiography or when delayed thrombus formation was expected, typically in cases with protruding coils.36,37 One group reported their experience using a protocol including an intraoperative bolus and continuous maintenance infusion for all patients and found an alarmingly high rate of symptomatic ICH and mortality, prompting a new protocol in which a postoperative continuous infusion alone was used.38 While a continuous postoperative infusion should not be used in all cases, it can provide an additional measure of safety when a partial thrombus or thrombogenic material remains within the artery lumen. Among patients treated with tirofiban requiring either ventriculostomy or decompressive hemicraniectomy shortly after the coiling procedure, none suffered from hemorrhagic complications given that they were performed at least 2 h following discontinuation.36 Few studies have compared the safety and efficacy of the 3 GP IIb/IIIa inhibitors. Despite the drawbacks of its long-term potency, abciximab has been used with the greatest frequency. In a head-to-head comparison between abciximab and tirofiban for thromboembolic complications during treatment of ruptured and unruptured aneurysms, there was no statistically significant difference with respect to recanalization or hemorrhagic complications.30 Interestingly, a meta-analysis found lower rates of recanalization in patients treated with abciximab compared to those treated with eptifibatide and tirofiban, although no difference in clinical outcome was found.1 At this juncture, it is difficult to definitively compare the 3 GP IIb/IIIa inhibitors, although eptifibatide and tirofiban offer a distinct advantage at times when urgent surgical intervention may be required. THROMBOEMBOLIC PREVENTION Abciximab The prophylactic use of GP IIb/IIIa inhibitors during or prior to placement of thrombogenic stents or coils during neuroendovascular procedures has only been utilized relatively recently. In the placement of intracranial stents and flow diverters, patients are typically placed on dual antiplatelet medication preoperatively, although the decision to utilize a stent may be made intraprocedurally. Levitt et al39 evaluated patients given a bolus of 0.125 mg/kg of abciximab intraoperatively during or immediately after stent deployment to patients pretreated with dual antiplatelet medication (Table 2). In a patient population that included multiple stents and flow diverters, there was no significant difference in diffusion restriction imaging postoperatively and no evidence of ICH in either treatment arm. This provides an excellent antiplatelet treatment method in cases where a stent is placed in an emergent fashion and potentially avoids the use of preoperative dual antiplatelet therapy in cases where its use may not be required. TABLE 2. Glycoprotein IIb/IIIa Inhibitor Utilization for Thromboembolic Prophylaxis Authors  Patient (n)  Disease  Route  Bolus  Infusion/duration  Thromboembolic complications  Intracranial hemorrhage  Abciximab  48               Aviv et al 200526  1  Aneurysm  IV  5 mg  None  None  None   Levitt et al 201539  47  Aneurysm  IV  0.125 mg/kg  None  10.6%  None  Eptifibatide  177               Yi et al 200640  77  Aneurysm  IV  180 μg/kg  None  1.3%  2.6%   Sedat et al 201511  100  Aneurysm  IA  200 μg/kg  None  7%  4%  Tirofiban  104               Chalouhi et al 201238  11  Aneurysm  IV  0.4 μg/kg/min (30 min)  0.1 μg/kg/min (12 h)  None  27.3%    47  Aneurysm  IV  None  0.1 μg/kg/min (12 h)  None  1.9%a   Chalouhi et al 20167  46  Aneurysm  IV  None  0.1 μg/kg/min (intraop, continue for 2 h after)  2.2%  2.2%  Authors  Patient (n)  Disease  Route  Bolus  Infusion/duration  Thromboembolic complications  Intracranial hemorrhage  Abciximab  48               Aviv et al 200526  1  Aneurysm  IV  5 mg  None  None  None   Levitt et al 201539  47  Aneurysm  IV  0.125 mg/kg  None  10.6%  None  Eptifibatide  177               Yi et al 200640  77  Aneurysm  IV  180 μg/kg  None  1.3%  2.6%   Sedat et al 201511  100  Aneurysm  IA  200 μg/kg  None  7%  4%  Tirofiban  104               Chalouhi et al 201238  11  Aneurysm  IV  0.4 μg/kg/min (30 min)  0.1 μg/kg/min (12 h)  None  27.3%    47  Aneurysm  IV  None  0.1 μg/kg/min (12 h)  None  1.9%a   Chalouhi et al 20167  46  Aneurysm  IV  None  0.1 μg/kg/min (intraop, continue for 2 h after)  2.2%  2.2%  IA, intraarterial; IV, intravenous. aChalouhi et al (2012)38 did not specify whether hemorrhagic complication in their revised protocol occurred in a patient receiving rescue treatment of prophylactic tirofiban. View Large Eptifibatide Eptifibatide has also been used in a preventative manner in the endovascular treatment of both ruptured and unruptured aneurysms (Table 2). The first established protocol for the use of eptifibatide as a prophylactic measure utilized a single bolus of 180 μg/kg during the coiling procedure.40 In this study, stents were placed in approximately one-quarter of the patient population with a remarkably low rate of thromboembolic complications in 1.3%.40 In addition, only 2.6% of their patient population suffered from ICH, one secondary to intraoperative rupture and the second due to hemorrhagic conversion of a prior infarct.40 A more recent study evaluated the prophylactic use of eptifibatide compared to a retrospective cohort of patients who had not received the GP IIb/IIIa inhibitor.11 Using a single intraarterial bolus of 200 μg/kg at the beginning of the procedure, they found thromboembolic complications to be significantly lower in the eptifibatide-treated group (7%) compared to control (20%) with a statistically equal risk of ICH (4%).11 The success of these 2 studies reveals eptifibatide to be a safe and efficacious means of preventing thromboembolic complications. While the retrospective nature of these studies imposes inherent bias, the improved efficacy seen in the eptifibatide-treated patients provides a platform for further studies to confirm these outcomes and potentially develop a new standard of treatment. Tirofiban Tirofiban provides distinct advantages given its short half-life and rapid clearance. Several studies have evaluated its prophylactic use in the setting of endovascular treatment in both ruptured and unruptured aneurysms with intracranial stents (Table 2).7,38 Due to a high risk of fatal ICH, Chalouhi et al38 abandoned their initial protocol, consisting of an intraoperative bolus followed by a continuous infusion, and began utilizing a continuous infusion alone of 0.1 μg/kg/min for 12 h starting immediately after deployment of the first stent or coil. Under the revised protocol, there were no patients with thromboembolic complications and only a 1.9% rate of ICH.38 While this initial study evaluated stent-assisted coiling, a follow-up study evaluated the use of tirofiban prophylaxis for flow diversion treatment of both ruptured and unruptured intracranial aneurysms, using a continuous infusion of 0.1 μg/kg/min starting immediately after flow diverter deployment.7 Treatment with this protocol had a low risk of thromboembolic complications at 2.2% and only a 2.2% rate of ICH.7 These 2 studies reveal tirofiban to be a safe treatment in the setting of subarachnoid hemorrhage and provide an effective and immediate means of antiplatelet therapy when needed for intracranial stents and flow diversion in the treatment of intracranial aneurysms. CONCLUSION GP IIb/IIIa is a receptor for fibrinogen and von Willebrand factor, resulting in platelet activation and aggregation in thrombus formation. Drugs targeting this receptor inhibit acute clot formation, making them well suited for thromboembolic complications during neuroendovascular procedures. In the setting of subarachnoid hemorrhage, thrombus formation at the aneurysm dome would be stabilized by cross-linked fibrin and should remain unaffected by GP IIb/IIIa inhibitors—a theoretical advantage to provide thrombosis prevention without precipitating aneurysmal re-rupture. Early studies evaluating GP IIb/IIIa inhibitors as a treatment of thromboembolic complications during the treatment of intracranial aneurysms have found them to be both safe and effective. According to the cardiovascular literature, GP IIb/IIIa inhibitors are generally administered as a bolus, followed by a continuous maintenance infusion while current neurointerventional literature has varied greatly in dosing and administration methods. The use of a bolus and continuous infusion allows continued protection from further thromboembolic events originating from thrombogenic stents and coils, lending an advantage to this method when hemorrhagic complications appear no more frequently. While the initial bolus eliminates acute platelet activation, aggregation, and thrombus formation, continued platelet inhibition eliminates the potential for new thrombus formation as the patient is bridged to an oral antiplatelet regimen. Likewise, there is no consensus on intraarterial or intravenous delivery as both have proven to be efficacious. Given this, intraarterial administration may be slightly advantageous for acute thrombus formation given its direct delivery to the occluded artery. Intravenous bolus infusion may be best utilized after placement of a thrombogenic device in the vessel lumen in the absence of thrombosis, providing time while oral antiplatelet medications are started. If the patient develops new or worsening signs or symptoms of intracranial pathology following GP IIb/IIIa inhibitor administration, intracranial imaging with a non-contrast computed tomography of the head would certainly be warranted, although in the absence of such symptoms, imaging is probably of limited clinical utility. The prophylactic use of GP IIb/IIIa inhibitors to prevent thromboembolic complications has only recently been evaluated. In cases where the patient cannot receive preoperative dual antiplatelet therapy due to subarachnoid hemorrhage or in situations where an intracranial stent was unexpected preoperatively, these inhibitors provide a relatively safe and immediate antiplatelet strategy to avoid ischemic complications prior to being converted to an oral antiplatelet regimen. In various clinical scenarios, including simple coiling, stent-assisted coiling, and flow diversion, this preventative strategy has been proven to be both safe and effective. When used as a bridging agent to oral antiplatelet therapy, exposure to tirofiban and eptifibatide within 48 h or abciximab within 10 d of cessation will affect baseline ARU and PRU values in the VerifyNow assay, making them an unreliable test of platelet inhibition by aspirin or clopidogrel, respectively. While GP IIb/IIIa inhibitors have been present in cardiovascular surgery for quite some time, their utility in neurovascular surgery remains in its infancy, and the dosage and administration methods of GP IIb/IIIa inhibitor protocols vary significantly. Based on the reported risk of hemorrhage and efficacy in thromboembolic rescue or prevention, recommendations for abciximab, eptifibatide, and tirofiban are provided (Table 3). While randomized, prospective studies are needed and will further establish ideal protocols for GP IIb/IIIa inhibitors in the setting of neuroendovascular thromboembolic complications and prophylaxis, the best practices highlighted in the current studies demonstrate efficacy of this drug class with a minimal risk of ICH. TABLE 3. Protocol Recommendations for Glycoprotein IIb/IIIa Inhibitors in Thromboembolic Rescue and Prevention During Intracranial Endovascular Treatment Drug  Indication  Bolus  Infusion  Abciximab      Rescue  0.25 mg/kg (IA or IV)  0.125 μg/kg/min (12 h)    Prophylaxis  0.125 mg/kg (IV)  None  Eptifibatide      Rescue  90 μg/kg (IA)  0.5 μg/kg/min (12 h)    Prophylaxis  180 μg/kg  None  Tirofiban      Rescue  4 μg/kg aliquots (IA)  0.1 μg/kg/min (12 h)a      (Max: 25 μg/kg)      Prophylaxis  None  0.1 μg/kg/min (12 h)b        0.1 μg/kg/min (2 h)b  Drug  Indication  Bolus  Infusion  Abciximab      Rescue  0.25 mg/kg (IA or IV)  0.125 μg/kg/min (12 h)    Prophylaxis  0.125 mg/kg (IV)  None  Eptifibatide      Rescue  90 μg/kg (IA)  0.5 μg/kg/min (12 h)    Prophylaxis  180 μg/kg  None  Tirofiban      Rescue  4 μg/kg aliquots (IA)  0.1 μg/kg/min (12 h)a      (Max: 25 μg/kg)      Prophylaxis  None  0.1 μg/kg/min (12 h)b        0.1 μg/kg/min (2 h)b  IA, intraarterial; IV, intravenous. aContinuous infusion only when thrombus still present following bolus dosing or for coil protrusion. bInfusion for 12 h in setting of stent-assisted coiling; 2 h with use of a flow diverting stent to be started immediately after stent placement. View Large Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Brinjikji W, Morales-Valero SF, Murad MH, Cloft HJ, Kallmes DF. Rescue treatment of thromboembolic complications during endovascular treatment of cerebral aneurysms: a meta-analysis. AJNR Am J Neuroradiol.  2015; 36( 1): 121- 125. Google Scholar CrossRef Search ADS PubMed  2. Pierot L, Cognard C, Anxionnat R, Ricolfi F. Ruptured intracranial aneurysms: factors affecting the rate and outcome of endovascular treatment complications in a series of 782 patients (CLARITY study). Radiology . 2010; 256( 3): 916- 923. Google Scholar CrossRef Search ADS PubMed  3. Rordorf G, Bellon RJ, Budzik RE Jr et al.   Silent thromboembolic events associated with the treatment of unruptured cerebral aneurysms by use of Guglielmi detachable coils: prospective study applying diffusion-weighted imaging. 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Google Scholar CrossRef Search ADS PubMed  20. Vinuela F, Duckwiler G, Mawad M. Guglielmi detachable coil embolization of acute intracranial aneurysm: perioperative anatomical and clinical outcome in 403 patients. J Neurosurg . 1997; 86( 3): 475- 482. Google Scholar CrossRef Search ADS PubMed  21. Jones RG, Davagnanam I, Colley S, West RJ, Yates DA. Abciximab for treatment of thromboembolic complications during endovascular coiling of intracranial aneurysms. AJNR Am J Neuroradiol.  2008; 29( 10): 1925- 1929. Google Scholar CrossRef Search ADS PubMed  22. Ng PP, Phatouros CC, Khangure MS. Use of glycoprotein IIb-IIIa inhibitor for a thromboembolic complication during Guglielmi detachable coil treatment of an acutely ruptured aneurysm. AJNR Am J Neuroradiol.  2001; 22( 9): 1761- 1763. Google Scholar PubMed  23. Alexander MJ, Duckwiler GR, Gobin YP, Vinuela F. Management of intraprocedural arterial thrombus in cerebral aneurysm embolization with abciximab: technical case report. Neurosurgery . 2002; 50( 4): 899- 901; discussion 901-902. Google Scholar CrossRef Search ADS PubMed  24. Mounayer C, Piotin M, Baldi S, Spelle L, Moret J. Intraarterial administration of Abciximab for thromboembolic events occurring during aneurysm coil placement. AJNR Am J Neuroradiol.  2003; 24( 10): 2039- 2043. Google Scholar PubMed  25. Song JK, Niimi Y, Fernandez PM et al.   Thrombus formation during intracranial aneurysm coil placement: treatment with intra-arterial abciximab. AJNR Am J Neuroradiol.  2004; 25( 7): 1147- 1153. Google Scholar PubMed  26. Aviv RI, O’Neill R, Patel MC, Colquhoun IR. Abciximab in patients with ruptured intracranial aneurysms. AJNR Am J Neuroradiol.  2005; 26( 7): 1744- 1750. Google Scholar PubMed  27. Gralla J, Rennie AT, Corkill RA et al.   Abciximab for thrombolysis during intracranial aneurysm coiling. Neuroradiology . 2008; 50( 12): 1041- 1047. Google Scholar CrossRef Search ADS PubMed  28. Ries T, Siemonsen S, Grzyska U, Zeumer H, Fiehler J. Abciximab is a safe rescue therapy in thromboembolic events complicating cerebral aneurysm coil embolization: single center experience in 42 cases and review of the literature. Stroke . 2009; 40( 5): 1750- 1757. Google Scholar CrossRef Search ADS PubMed  29. Linfante I, Etezadi V, Andreone V et al.   Intra-arterial abciximab for the treatment of thrombus formation during coil embolization of intracranial aneurysms. J Neurointervent Surg . 2010; 2( 2): 135- 138. Google Scholar CrossRef Search ADS   30. Jeong HW, Jin SC. Intra-arterial infusion of a glycoprotein IIb/IIIa antagonist for the treatment of thromboembolism during coil embolization of intracranial aneurysm: a comparison of abciximab and tirofiban. AJNR Am J Neuroradiol.  2013; 34( 8): 1621- 1625. Google Scholar CrossRef Search ADS PubMed  31. Bendok BR, Padalino DJ, Levy EI, Qureshi AI, Guterman LR, Hopkins LN. Intravenous abciximab for parent vessel thrombus during basilar apex aneurysm coil embolization: case report and literature review. Surg Neurol . 2004; 62( 4): 304- 311. Google Scholar CrossRef Search ADS PubMed  32. Velat GJ, Burry MV, Eskioglu E, Dettorre RR, Firment CS, Mericle RA. The use of abciximab in the treatment of acute cerebral thromboembolic events during neuroendovascular procedures. Surg Neurol . 2006; 65( 4): 352- 358, discussion 358-359. Google Scholar CrossRef Search ADS PubMed  33. Aggour M, Pierot L, Kadziolka K, Gomis P, Graftieaux JP. Abciximab treatment modalities for thromboembolic events related to aneurysm coiling. Neurosurgery . 2010; 67( 2 Suppl Operative): 503- 508. Google Scholar PubMed  34. Ramakrishnan P, Yoo AJ, Rabinov JD, Ogilvy CS, Hirsch JA, Nogueira RG. Intra-arterial eptifibatide in the management of thromboembolism during endovascular treatment of intracranial aneurysms: case series and a review of the literature. Intervent Neurol . 2013; 2( 1): 19- 29. Google Scholar CrossRef Search ADS   35. Jeon JS, Sheen SH, Hwang G, Kang SH, Heo DH, Cho YJ. Intraarterial tirofiban thrombolysis for thromboembolisms during coil embolization for ruptured intracranial aneurysms. J Cerebrovasc Endovasc Neurosurg . 2012; 14( 1): 5- 10. Google Scholar CrossRef Search ADS PubMed  36. Cho YD, Lee JY, Seo JH et al.   Intra-arterial tirofiban infusion for thromboembolic complication during coil embolization of ruptured intracranial aneurysms. Eur J Radiol . 2012; 81( 10): 2833- 2838. Google Scholar CrossRef Search ADS PubMed  37. Kang HS, Kwon BJ, Roh HG et al.   Intra-arterial tirofiban infusion for thromboembolism during endovascular treatment of intracranial aneurysms. Neurosurgery . 2008; 63( 2): 230- 237; discussion 237-238. Google Scholar CrossRef Search ADS PubMed  38. Chalouhi N, Jabbour P, Kung D, Hasan D. Safety and efficacy of tirofiban in stent-assisted coil embolization of intracranial aneurysms. Neurosurgery . 2012; 71( 3): 710- 714; discussion 714. Google Scholar CrossRef Search ADS PubMed  39. Levitt MR, Moon K, Albuquerque FC, Mulholland CB, Kalani MY, McDougall CG. Intraprocedural abciximab bolus versus pretreatment oral dual antiplatelet medication for endovascular stenting of unruptured intracranial aneurysms. J Neurointervent Surg . 2015; 8( 9): 909- 912. Google Scholar CrossRef Search ADS   40. Yi HJ, Gupta R, Jovin TG et al.   Initial experience with the use of intravenous eptifibatide bolus during endovascular treatment of intracranial aneurysms. AJNR Am J Neuroradiol.  2006; 27( 9): 1856- 1860. Google Scholar PubMed  COMMENT The authors review the role of IIb/IIIa inhibitors for prevention and rescue therapy of thrombotic complications during endovascular treatment of aneurysms. Depending on the definition and imaging modalities used, the reported frequency of thrombotic events during aneurysm embolization varies greatly. Such events correlate with poor clinical outcomes. Standardized protocols on the use of IIb/IIIa agents are currently lacking. This review summarizes clinically relevant data on the use of IIb/IIIa inhibitors for neurointerventional procedures, and provides clear and concise recommendations on its dose and administration regimen. Maxim Mokin Tampa, Florida Copyright © 2017 by the Congress of Neurological Surgeons http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Glycoprotein IIb/IIIa Inhibitors in Prevention and Rescue Treatment of Thromboembolic Complications During Endovascular Embolization of Intracranial Aneurysms

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Congress of Neurological Surgeons
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Copyright © 2017 by the Congress of Neurological Surgeons
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0148-396X
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1524-4040
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10.1093/neuros/nyx170
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Abstract

Abstract Thromboembolic complications remain a major risk of endovascular neurosurgery during the treatment of intracranial aneurysms, despite the use of therapeutic heparinization and oral antiplatelet therapy when indicated. Glycoprotein (GP) IIb/IIIa inhibitors target a nonredundant pathway of platelet aggregation following adhesion and activation. Initially established and implemented in the cardiovascular arena, this drug class has provided a new tool in the neurovascular armamentarium as well. Numerous case reports, case series, and retrospective reviews have evaluated the safety and efficacy of abciximab, eptifibatide, and tirofiban in the treatment of acute thromboembolic complications during the endovascular treatment of intracranial aneurysms. The use of this drug class has also been found to be beneficial as a prophylactic agent, providing ischemia protection during the placement of intracranial stents, flow diverters, and thrombogenic coils in the setting of subarachnoid hemorrhage and during elective aneurysmal embolization. While the current published literature clearly establishes efficacy and safety of GP IIb/IIIa inhibitors in the prevention of thromboembolic complications, there does not yet exist an established protocol for their administration in endovascular neurosurgery. This review provides a comprehensive evaluation of the current published literature pertaining to the use of all available GP IIb/IIIa inhibitors for thromboembolic complications, providing recommendations for dosing and administration of abciximab, eptifibatide, and tirofiban based on previously published rates of efficacy and intracranial hemorrhage. Intracranial aneurysm, Antiplatelet drugs, Cerebral embolism and thrombosis, Glycoproteins IIb-IIIa, GPIIb-IIIa receptors ABBREVIATIONS ABBREVIATIONS ADP adenosine diphosphate EPIC Evaluation of 7E3 for the Prevention of Ischemic Complication GP glycoprotein ICH intracranial hemorrhage The growth of endovascular neurosurgery for the treatment of intracranial aneurysms and arteriovenous malformations has greatly shifted the landscape of vascular neurosurgery. Despite its many advantages, endovascular treatment generates a significant rate of thromboembolic complications, ranging from 2% to 15%,1 associated with a 3.8% risk of permanent morbidity and mortality.2 The rates of clinically silent microembolic events are likely much higher given previous studies evaluating diffusion-weighted magnetic resonance imaging following aneurysmal coil embolization.3 Increased utilization of carotid, intracranial, and flow diverting stents provides a thrombogenic platform, worsening the risk of ischemic complications. While heparin and oral antiplatelet drugs remain a mainstay of treatment, rapid and efficacious intravenous antiplatelet medications are often needed in the setting of acute stent placement or acute thrombus formation during endovascular procedures. Such rescue therapy has been observed in 5% to 10% of cases during the treatment of intracranial aneurysms.1 Inhibitors of the platelet integrin complex, glycoprotein IIb/IIIa (GP IIb/IIIa), are often utilized in either rescue therapy for thrombotic complications or in a prophylactic manner when the preoperative risk is significant. Despite their increasing use, optimal clinical protocols to prevent thromboembolic complications have not yet been established. Here, we provide a comprehensive review of the literature pertaining to the use of GP IIb/IIIa inhibitors in the setting of endovascular neurosurgical procedures, presenting the best practices for each GP IIb/IIIa inhibitor in current clinical practice. GLYCOPROTEIN IIB/IIIA INHIBITORS GP IIb/IIIa Receptor Through blockade of the GP IIb/IIIa receptor, GP IIb/IIIa inhibitors are platelet-specific drugs (Figure). Platelet activation by thrombin generates a conformational change in the platelet, ultimately triggering an increase in intracellular calcium and resulting in the calcium-dependent upregulation of GP IIb/IIIa to the platelet surface. GP IIb/IIIa then serves as a receptor for fibrinogen and von Willebrand factor, and fibrinogen acts to bind platelets to one another, generating thrombus formation as the essential, nonredundant step in platelet aggregation. Clot stabilization occurs secondarily through the coagulation cascade as thrombin converts fibrinogen to insoluble fibrin strands, which are then cross-linked by factor XIII, resulting in a stable thrombus. Hyperacute thrombus formation during an endovascular procedure is primarily composed of activated platelets; therefore, GP IIb/IIIa inhibitors play an important role in inhibiting platelet plug formation.4 This would be particularly useful in the setting of a ruptured cerebral aneurysm as the GP IIb/IIIa inhibitor would not be expected to disrupt the subacute fibrin-stabilized thrombus at the site of aneurysmal rupture, while actively preventing platelet aggregation and hyperacute thrombus formation during attempted endovascular treatments. FIGURE. View largeDownload slide The mechanism of action of current therapeutics for platelet inhibition. Inhibitors of the P2Y12 receptor (clopidogrel, ticagrelor, prasugrel) effectively inhibit the ability of adenosine diphosphate (ADP) to initiate platelet activation. The inhibitory effect of aspirin on cyclooxygenase (COX)-1 decreases thromboxane A2 (TXA2) production from arachidonic acid (AA), limiting its ability to activate platelets via its receptor (TPαR). The current glycoprotein (GP) IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) block the ability of platelet-platelet interactions with fibrinogen. The key initial step of platelet adhesion to the endothelial surface occurs via the interaction of GP IbIXV and von Willebrand Factor (vWF). FIGURE. View largeDownload slide The mechanism of action of current therapeutics for platelet inhibition. Inhibitors of the P2Y12 receptor (clopidogrel, ticagrelor, prasugrel) effectively inhibit the ability of adenosine diphosphate (ADP) to initiate platelet activation. The inhibitory effect of aspirin on cyclooxygenase (COX)-1 decreases thromboxane A2 (TXA2) production from arachidonic acid (AA), limiting its ability to activate platelets via its receptor (TPαR). The current glycoprotein (GP) IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) block the ability of platelet-platelet interactions with fibrinogen. The key initial step of platelet adhesion to the endothelial surface occurs via the interaction of GP IbIXV and von Willebrand Factor (vWF). Abciximab, Eptifibatide, and Tirofiban The 3 currently available GP IIb/IIIa inhibitors include abciximab, eptifibatide, and tirofiban, all of which are able to disrupt acute platelet-mediated thrombosis. Abciximab is a humanized monoclonal antibody with essentially irreversible activity on the GP IIb/IIIa receptor due to its high affinity and slow off-rate, whereas eptifibatide and tirofiban are small molecules with faster on-off pharmacokinetics, making the duration of their effect much shorter.5 Intravenous administration ranges from 0.15 to 0.3 mg/kg, providing irreversible dose-dependent platelet inhibition,6 and a single loading dose is sufficient to provide greater than 80% receptor blockade.4 While the plasma half-life is relatively short (10-30 min), abciximab will remain in circulation in its platelet-bound state for ≥10 d.6 Sustained inhibition of newly formed platelets can be achieved through continuous infusion, while platelet aggregation returns to 50% of baseline within 24 h of drug cessation.6 Despite this modest improvement, platelet aggregation does not return to normal function for 48 to 72 h.4,7 Given this profound, sustained antiplatelet effect, concerns have been raised regarding its safety. Several studies have found abciximab to be associated with a high risk of intracranial hemorrhage (ICH) and early rehemorrhage in the setting of ruptured aneurysms, incurring significant mortality.8,9 While no reversal agent exists for abciximab, platelet administration and drug cessation are the mainstays of treatment in the setting of intracranial or severe systemic hemorrhagic complications.10 Due to the short plasma half-life, the addition of new platelets redistributes the bound drug across a greater number of receptors, diluting its antiplatelet effect. Eptifibatide is a selective, competitive inhibitor of the GP IIb/IIIa receptor.11 It is a cyclic heptapeptide derived from barbourin in the venom of southeastern pigmy rattlesnakes with a rapid onset of action, short half-life (10-15 min) and quick reversal of its antiplatelet effects.6 Platelet function returns to 50% of baseline within 4 h of drug cessation, allowing invasive procedures when necessary.6 Tirofiban is a nonpeptide competitive inhibitor of the GP IIb/IIIa receptor. A derivative of tyrosine, tirofiban mimics the morphology of the arginine-glycine-aspartic acid sequence of fibrinogen.6 Similar to eptifibatide, tirofiban has a rapid onset of action and is rapidly reversible on the molecular level. The antiplatelet effect is directly proportional to its plasma concentration with a half-life of 2 to 4 h, while platelet function returns to normal within 4 to 8 h of drug cessation.6,7 Compared to abciximab, the shorter half-life and diminished receptor affinity seen with eptifibatide and tirofiban prove advantageous when a surgical procedure may be required during the immediate postoperative period. Abciximab effectively provides a therapeutic antiplatelet response for 48 h following a loading dose, whereas the therapeutic window of eptifibatide and tirofiban is limited to 4 to 8 h. Despite the short half-life of these small molecule inhibitors, no reversal agents have yet been developed, and platelet administration has limited utility in eptifibatide or tirofiban-related hemorrhage as new platelets are simply inhibited by circulating drug. While no reversal protocol has been agreed upon in the setting of systemic or intracranial hemorrhage, use of desmopressin (0.3 μg/kg),12 cryoprecipitate,13 and platelet transfusion has been utilized with some success. Initial Drug Development The clinical benefit of GP IIb/IIIa inhibitors was first demonstrated in patients with cardiovascular disease, particularly those undergoing percutaneous coronary intervention. While percutaneous coronary angioplasty improves symptoms of ischemia and quality of life, significant drawbacks arose secondary to a 4% to 9% risk of acute thrombotic complications, yielding a 10-fold increase in mortality.14 Abciximab was studied in a large randomized controlled trial of patients undergoing coronary angioplasty or atherectomy through the Evaluation of 7E3 for the Prevention of Ischemic Complication (EPIC) trial.14 The EPIC trial demonstrated that abciximab use decreased ischemic complications, which was most profound when administered as a loading dose followed by an infusion.14 Furthermore, patients with the highest risk for ischemic complications, such as presence of an acute or recent myocardial infarction or unstable angina, had a substantial treatment benefit.15 While hemorrhage risk was significantly increased following abciximab, 71% of these complications occurred at the site of vascular access and rarely were life threatening.15 Comparing hemorrhagic stroke, no difference was found between the placebo and treatment groups.15 Overall, use of abciximab during and after percutaneous coronary intervention generated a 35% to 50% decrease in adverse clinical events and improved 30-d mortality.14-16 These findings were corroborated for coronary stenting procedures in the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting trial, which also demonstrated decreased mortality and ischemic complications following abciximab with no increase in major bleeding complications.17 Following the efficacy established in these trials, use of GP IIb/IIIa inhibitors in neurointerventional surgery has increased significantly for thromboembolic complications associated with endovascular treatments. GLYCOPROTEIN IIB/IIIA INHIBITORS AND FIBRINOLYTICS In addition to GP IIb/IIIa inhibitors, fibrinolytics have been used for rescue therapy in the setting of thromboembolic complications during endovascular treatment of intracranial aneurysms. Utilizing a separate mechanism, fibrinolytics, such as tissue plasminogen activator, catalyze the conversion of plasminogen to plasmin, a major enzyme involved in thrombolysis. While angioplasty and fibrinolytics have shown a 44% to 75% recanalization rate, re-occlusion is a major limitation to successful treatment.18 A meta-analysis found GP IIb/IIIa inhibitors to be superior to fibrinolytics for rescue therapy of thromboembolic complications during intracranial aneurysm intervention, resulting in decreased perioperative morbidity from ischemia and hemorrhage with decreased long-term morbidity.1 While GP IIb/IIIa inhibitors demonstrated a trend toward improved recanalization rates compared to fibrinolytics, this was not found to be statistically significant.1 Past studies have also found the use of fibrinolytics in rescue therapy to be associated with increased risk of ICH compared to GP IIb/IIIa inhibitors.19 While fibrinolytics may still have a role, the use of GP IIb/IIIa inhibitors for acute thrombus development during neurointerventional procedures has become a mainstay of treatment. THROMBOEMBOLIC RESCUE Abciximab Thromboembolic events are the most frequent complication following endovascular treatment of intracranial aneurysms, occurring in approximately 3% of patients.20 The routine use of intraoperative heparin and the preoperative administration of aspirin and clopidogrel in select cases have ameliorated some of this risk. Given the validity established through the EPIC trial, abciximab has been the most commonly utilized GP IIb/IIIa inhibitor in the neurovascular literature. Despite the uniform dosage protocols in the cardiovascular literature, consisting of a 0.25 mg/kg bolus prior to intervention and an infusion of 0.125 μg/kg/min for 12 h following the procedure,14,17 reported utilization of abciximab in the neurointerventional literature has been quite variable. Many of the early reported cases utilizing abciximab for intraoperative thromboembolic complications during embolization of aneurysms utilized a single bolus dose immediately following clot formation, initially used only after failure of angioplasty and fibrinolytics.4,21 With increasing evidence of its superiority to fibrinolytics,1 abciximab emerged as the treatment of choice for the rescue of acute thrombus formation during endovascular procedures. A great deal of variability in dosing methods still exist,14 ranging from a single or multiple boluses at the time of thrombus formation4,22-30 to simple infusion following the procedure4 or an intraoperative bolus with a postoperative infusion.4,21,31-33 The dosage among given methods is also quite variable, with weight-based dosing of 0.25 mg/kg being used in a few reports.4,23,28 The majority of abciximab dosing has involved standardized aliquots of either intraarterial (2-5 mg)4,24,25,30 or intravenous (5-20 mg) administration,22,25,26 usually with a maximum dose of 20 mg or 0.25 mg/kg. Utilization of a continuous infusion following an intraoperative bolus has also gained traction, following the dosage protocols in the EPIC trial with an initial bolus of 0.25 mg/kg at the time of thrombus formation and a continuous infusion of 0.125 μg/kg/min for 12 h.4,21,31-33 A slightly different protocol, starting with 5 mg aliquots for the initial bolus with additional aliquots as needed up to a maximum dose of 0.25 mg/kg, has been reported as well.33 Despite a great degree of variability in the administration of a simple bolus and bolus dosing followed by continuous infusion, the rates of recanalization remain similar at 72.7% to 100%4,21,23-25,27-30 and 69.6% to 100%,4,21,31-33 respectively. Rates of ICH reported in these studies were between 2% and 3%, with a tendency for increased rates of hemorrhage in patients having previously suffered an ischemic insult. In addition to administering intraoperative abciximab immediately following identification of a thromboembolic event, a second protocol was also evaluated, in which abciximab was administered in the postoperative setting for symptoms of ischemia.27 This protocol was ultimately abandoned due to a higher rate of ICH, likely secondary to preexisting cerebral infarcts.27 The use of abciximab for thromboembolic complications in the setting of subarachnoid hemorrhage has also been shown to be reasonably safe and effective as numerous studies revealed similar efficacy and safety profiles in the treatment of ruptured and unruptured aneurysms.4,21-25,29,30,33 Based on the EPIC trial and these reports in the neurovascular literature, the use of a bolus dose of 0.25 mg/kg given either intraarterially or intravenously, followed by a continuous infusion of 0.125 μg/kg/min for 12 h, appears to be both relatively safe and effective. While other protocols have demonstrated efficacy as well, this protocol has an established safety profile in a large cardiovascular cohort and has been further validated as safe and highly efficacious in numerous patients in the neurovascular literature. Additionally, weight-based dosing provides a standardized and individualized dose for optimal platelet inhibition. Eptifibatide Given its short half-life, eptifibatide allows for platelet function to return to 50% of baseline within 4 h of cessation. Theoretically reducing the risk of ICH, the role of eptifibatide in thromboembolic rescue has been evaluated in 2 studies (Table 1).5,34 Using a single intraarterial bolus of 0.2 mg/kg of eptifibatide at the time of the thromboembolic event in both ruptured and unruptured aneurysms, eptifibatide was found to be highly efficacious with a complete or partial recanalization rate of 91% and no hemorrhagic complications.5 Interestingly, all patients suffering from thrombus formation at the junction of the coil and parent artery experienced complete revascularization.5 In contrast, eptifibatide performed poorly in cases involving peripheral emboli, with a complete revascularization rate of 37.5%.5 TABLE 1. Glycoprotein IIb/IIIa Inhibitor Utilization for Thromboembolic Complications Authors  Patients  Disease  Route  Bolus  Infusion/duration  Recanalization  Intracranial hemorrhage  Abciximab  273               Ng et al 200122  1  Aneurysm  IV  20 mg  None  Complete  None   Alexander et al 200223  1  Aneurysm  IV  20 mg (0.25 mg/kg)  None  Complete  None   Mounayer et al 200324  13  Aneurysm  IA  4-10 mg  None  92% C, 8% P  None   Bendok et al 200431  1  Aneurysm  IV  0.25 mg/kg  0.125 μg/kg/min (12 h)  Complete  None   Fiorella et al 20044  5  Aneurysm/AVM  IA  2-5 mg aliquots (max: 10 mg)  None  60% C, 40% P  None    2  Aneurysm/AVM  IV  0.25 mg/kg  None  100% C  None    5  Aneurysm  IV  0.25 mg/kg  0.125 μg/kg/min (12 h)  20% C, 80% P  None    1  Aneurysm  IV  None  0.125 μg/kg/min (12 h)  Complete  None   Song et al 200425  4  Aneurysm  IA  5 mg  None  50% C, 25% P, 25% N  50%    1  Aneurysm  IA+IV  5 mg IA; 17 mg IV  None  Complete  None    1  Aneurysm  IA  2 mg  None  Complete  None    1  Aneurysm  IA+IV  2 mg IA; 3 mg IV  None  Complete  None   Aviv et al 200526  6  Aneurysm  IV  5 mg  None  83.3% C, 16.7% P  16.7%    1  Aneurysm  IV  7.5 mg  None  Complete  None    4  Aneurysm  IV  10 mg  None  50% C, 50% P  None    1  Aneurysm  IV  20 mg  None  Partial  100%   Velat et al 200632  26  Aneurysm  IA/IVa  0.25 mg/kg  0.125 μg/kg/min (12 h)  69.2% C, 23.1% P, 7.7% N  11.5%    1  WADA  IA/IVa  0.25 mg/kg  0.125 μg/kg/min (12 h)  N/A  None    2  Carotid stenosis  IA/IVa  0.25 mg/kg  0.125 μg/kg/min (12 h)  50% C, 50% P  None   Gralla et al 200827  27  Aneurysm  IA  13.5 mg ± 13.5 mg, intraoperativeb  None  68.3% C, 19.5% P, 12.2% Nb  2.4%b    12  Aneurysm  IV  13.5 mg ± 13.5 mg, intraoperativeb  None  68.3% C, 19.5% P, 12.2% Nb  2.4%b    2  Aneurysm  IA+IV  13.5 mg ± 13.5 mg, intraoperativeb  None  68.3% C, 19.5% P, 12.2% Nb  2.4%b    22  Aneurysm  IV  11.3 mg ± 3.6 mg, postproceduralb  None  N/A  4.5%   Jones et al 200821  23  Aneurysm  IV  0.25 mg/kg  0.125 μg/kg/min (12 h)  26.1% C, 43.5% P, 30.4% N  None    15  Aneurysm  IA  0.25 mg/kg  0.125 μg/kg/min (12 h)  40% C, 46.7% P, 13.3% N  None   Ries et al 200928  3  Aneurysm  IA  0.25 mg/kg  None  14.3% C, 59.5% P, 26.2% Ne  None    39  Aneurysm  IV  0.25 mg/kg  None  14.3% C, 59.5% P, 26.2% Ne  None   Aggour et al 201033  23  Aneurysm  IA  Initial dose: 5 mg; more as needed; max: 0.25 mg/kg  0.125 μg/kg/min (12 h)  56.5% C, 34.8% P, 8.7% N  None   Linfante et al 201029  19  Aneurysm  IA  10.5 mg ± 4.2 mg  None  N/A  None   Jeong et al 201330  11  Aneurysm  IA  12.3 mg ± 4.1 mg; 2 mg aliquots (max: 20 mg)  None  9.1% C, 63.6% P, 27.3% N  None  Eptifibatide  65               Ramakrishnan et al 201334  20  Aneurysm  IA  2.2512 mg (<90 μg/kg); initial dose: 25% of 90 μg/kg  0.5 μg/kg/min (2-48 h)(n = 20); none (n = 20)  77.5% C, 20% P, 2.5% N  Nonef   Sedat et al 20145  45  Aneurysm  IA  0.2 mg/kg  None  62.2% C, 28.8% P, 9% N  None  Tirofiban  93               Kang et al 200837  25  Aneurysm  IA  0.64 mg ± 0.25 mg; Initial 0.2-0.5 mg, then 0.1 mg aliquots q2-3 min  None (n = 23); IV infusionc (0.1 μg/ kg/min, 6 h) (n = 2)  16% C, 80% P, 4% N  None   Chalouhi et al 201238  5  Aneurysm  IV  0.4 μg/kg/min (30 min)  0.1 μg/kg/min (12 h)  80% C, 20% P  None    4  Aneurysm  IV  None  0.1 μg/kg/min (12 h)  75% C, 25% P  1.9%g   Cho et al 201236  39  Aneurysm  IA  0.71 mg ± 0.26 mg; 4 μg/kg aliquots (max: 25 μg/kg)  0.1 μg/kg/min IV (12 h)(n = 14)d; none (n = 25)  87.2% C, 7.7% P, 5.1% N  5.1%   Jeon et al 201235  9  Aneurysm  IA  0.3 mg aliquots (max: 1.2 mg)  None (n = 9); IV infusion (dose unknown)(n = 1)  80% C, 10% P, 10% N  None   Jeong et al 201330  11  Aneurysm  IA  0.47 mg ± 0.29 mg; 50 μg aliquots (max: 1000 μg)  None  36.4% C, 54.5% P, 9.1% N  None  Authors  Patients  Disease  Route  Bolus  Infusion/duration  Recanalization  Intracranial hemorrhage  Abciximab  273               Ng et al 200122  1  Aneurysm  IV  20 mg  None  Complete  None   Alexander et al 200223  1  Aneurysm  IV  20 mg (0.25 mg/kg)  None  Complete  None   Mounayer et al 200324  13  Aneurysm  IA  4-10 mg  None  92% C, 8% P  None   Bendok et al 200431  1  Aneurysm  IV  0.25 mg/kg  0.125 μg/kg/min (12 h)  Complete  None   Fiorella et al 20044  5  Aneurysm/AVM  IA  2-5 mg aliquots (max: 10 mg)  None  60% C, 40% P  None    2  Aneurysm/AVM  IV  0.25 mg/kg  None  100% C  None    5  Aneurysm  IV  0.25 mg/kg  0.125 μg/kg/min (12 h)  20% C, 80% P  None    1  Aneurysm  IV  None  0.125 μg/kg/min (12 h)  Complete  None   Song et al 200425  4  Aneurysm  IA  5 mg  None  50% C, 25% P, 25% N  50%    1  Aneurysm  IA+IV  5 mg IA; 17 mg IV  None  Complete  None    1  Aneurysm  IA  2 mg  None  Complete  None    1  Aneurysm  IA+IV  2 mg IA; 3 mg IV  None  Complete  None   Aviv et al 200526  6  Aneurysm  IV  5 mg  None  83.3% C, 16.7% P  16.7%    1  Aneurysm  IV  7.5 mg  None  Complete  None    4  Aneurysm  IV  10 mg  None  50% C, 50% P  None    1  Aneurysm  IV  20 mg  None  Partial  100%   Velat et al 200632  26  Aneurysm  IA/IVa  0.25 mg/kg  0.125 μg/kg/min (12 h)  69.2% C, 23.1% P, 7.7% N  11.5%    1  WADA  IA/IVa  0.25 mg/kg  0.125 μg/kg/min (12 h)  N/A  None    2  Carotid stenosis  IA/IVa  0.25 mg/kg  0.125 μg/kg/min (12 h)  50% C, 50% P  None   Gralla et al 200827  27  Aneurysm  IA  13.5 mg ± 13.5 mg, intraoperativeb  None  68.3% C, 19.5% P, 12.2% Nb  2.4%b    12  Aneurysm  IV  13.5 mg ± 13.5 mg, intraoperativeb  None  68.3% C, 19.5% P, 12.2% Nb  2.4%b    2  Aneurysm  IA+IV  13.5 mg ± 13.5 mg, intraoperativeb  None  68.3% C, 19.5% P, 12.2% Nb  2.4%b    22  Aneurysm  IV  11.3 mg ± 3.6 mg, postproceduralb  None  N/A  4.5%   Jones et al 200821  23  Aneurysm  IV  0.25 mg/kg  0.125 μg/kg/min (12 h)  26.1% C, 43.5% P, 30.4% N  None    15  Aneurysm  IA  0.25 mg/kg  0.125 μg/kg/min (12 h)  40% C, 46.7% P, 13.3% N  None   Ries et al 200928  3  Aneurysm  IA  0.25 mg/kg  None  14.3% C, 59.5% P, 26.2% Ne  None    39  Aneurysm  IV  0.25 mg/kg  None  14.3% C, 59.5% P, 26.2% Ne  None   Aggour et al 201033  23  Aneurysm  IA  Initial dose: 5 mg; more as needed; max: 0.25 mg/kg  0.125 μg/kg/min (12 h)  56.5% C, 34.8% P, 8.7% N  None   Linfante et al 201029  19  Aneurysm  IA  10.5 mg ± 4.2 mg  None  N/A  None   Jeong et al 201330  11  Aneurysm  IA  12.3 mg ± 4.1 mg; 2 mg aliquots (max: 20 mg)  None  9.1% C, 63.6% P, 27.3% N  None  Eptifibatide  65               Ramakrishnan et al 201334  20  Aneurysm  IA  2.2512 mg (<90 μg/kg); initial dose: 25% of 90 μg/kg  0.5 μg/kg/min (2-48 h)(n = 20); none (n = 20)  77.5% C, 20% P, 2.5% N  Nonef   Sedat et al 20145  45  Aneurysm  IA  0.2 mg/kg  None  62.2% C, 28.8% P, 9% N  None  Tirofiban  93               Kang et al 200837  25  Aneurysm  IA  0.64 mg ± 0.25 mg; Initial 0.2-0.5 mg, then 0.1 mg aliquots q2-3 min  None (n = 23); IV infusionc (0.1 μg/ kg/min, 6 h) (n = 2)  16% C, 80% P, 4% N  None   Chalouhi et al 201238  5  Aneurysm  IV  0.4 μg/kg/min (30 min)  0.1 μg/kg/min (12 h)  80% C, 20% P  None    4  Aneurysm  IV  None  0.1 μg/kg/min (12 h)  75% C, 25% P  1.9%g   Cho et al 201236  39  Aneurysm  IA  0.71 mg ± 0.26 mg; 4 μg/kg aliquots (max: 25 μg/kg)  0.1 μg/kg/min IV (12 h)(n = 14)d; none (n = 25)  87.2% C, 7.7% P, 5.1% N  5.1%   Jeon et al 201235  9  Aneurysm  IA  0.3 mg aliquots (max: 1.2 mg)  None (n = 9); IV infusion (dose unknown)(n = 1)  80% C, 10% P, 10% N  None   Jeong et al 201330  11  Aneurysm  IA  0.47 mg ± 0.29 mg; 50 μg aliquots (max: 1000 μg)  None  36.4% C, 54.5% P, 9.1% N  None  IA, intraarterial, IV, intravenous; C, complete; P, partial; N, none. aIA only given if microcatheter already in location of thrombus, otherwise administered IV. bPatients who underwent intraoperative administration were evaluated as a single cohort; post-procedural administration was based on stroke-like symptoms in absence of ICH. cIV infusion used with persistent thrombus at aneurysm neck. dIV infusion used with persistent thrombus or extruded coils. eAll patients (IA or IV) were evaluated in a single cohort. fNo hemorrhagic complications when eptifibatide used alone, 15% rate of ICH when used in combination with fibrinolytics or high-dose anticoagulation. gChalouhi et al 201238 did not specify whether hemorrhagic complication in their revised protocol occurred in a patient receiving rescue treatment of prophylactic tirofiban. View Large A second protocol administered intraoperative aliquots up to a maximum loading dose of 90 μg/kg (starting with 25% of the dose limit), followed by a continuous maintenance infusion of 0.5 μg/kg/min for 2 to 48 h in half of their cohort.34 This was found to be efficacious for the treatment of thromboembolic events in unruptured aneurysms, subarachnoid hemorrhage, and during treatment of vasospasm with an overall recanalization rate of 97.5%.34 With the addition of the postoperative continuous infusion, no cases of ICH were observed when only eptifibatide and therapeutic heparinization were used, and they noted no increase in systemic hemorrhagic complications. ICH during this study only occurred when eptifibatide was used in combination with fibrinolytics or high-dose anticoagulation.34 Intraarterial bolus dosing of eptifibatide with a continuous intravenous infusion is highly efficacious without evidence of ICH when used in the absence of fibrinolytics or anticoagulation, providing a therapeutic strategy when surgery or placement of an external ventricular drain is imminent. If anticoagulation or fibrinolytics have been given, this method of thromboembolic rescue therapy should be avoided given the significant ICH risk of 15%.34 Tirofiban Similar to eptifibatide, tirofiban has a very short half-life, providing normalization of platelet function within 4 h of discontinuation. Past reports (Table 1) of tirofiban use have been quite variable, including bolus dosing,30,35-37 postoperative infusion alone,38 and an intraoperative bolus followed by continuous infusion.35-38 All treatment modalities have been efficacious, ranging from 90% to 100% revascularization. While the majority of studies reported no ICH despite treatment in both ruptured and unruptured aneurysms, one group reported 2 hemorrhagic complications, both asymptomatic in nature.36 Most authors utilizing a bolus followed by a continuous infusion only administered the infusion if thrombus was still present on delayed angiography or when delayed thrombus formation was expected, typically in cases with protruding coils.36,37 One group reported their experience using a protocol including an intraoperative bolus and continuous maintenance infusion for all patients and found an alarmingly high rate of symptomatic ICH and mortality, prompting a new protocol in which a postoperative continuous infusion alone was used.38 While a continuous postoperative infusion should not be used in all cases, it can provide an additional measure of safety when a partial thrombus or thrombogenic material remains within the artery lumen. Among patients treated with tirofiban requiring either ventriculostomy or decompressive hemicraniectomy shortly after the coiling procedure, none suffered from hemorrhagic complications given that they were performed at least 2 h following discontinuation.36 Few studies have compared the safety and efficacy of the 3 GP IIb/IIIa inhibitors. Despite the drawbacks of its long-term potency, abciximab has been used with the greatest frequency. In a head-to-head comparison between abciximab and tirofiban for thromboembolic complications during treatment of ruptured and unruptured aneurysms, there was no statistically significant difference with respect to recanalization or hemorrhagic complications.30 Interestingly, a meta-analysis found lower rates of recanalization in patients treated with abciximab compared to those treated with eptifibatide and tirofiban, although no difference in clinical outcome was found.1 At this juncture, it is difficult to definitively compare the 3 GP IIb/IIIa inhibitors, although eptifibatide and tirofiban offer a distinct advantage at times when urgent surgical intervention may be required. THROMBOEMBOLIC PREVENTION Abciximab The prophylactic use of GP IIb/IIIa inhibitors during or prior to placement of thrombogenic stents or coils during neuroendovascular procedures has only been utilized relatively recently. In the placement of intracranial stents and flow diverters, patients are typically placed on dual antiplatelet medication preoperatively, although the decision to utilize a stent may be made intraprocedurally. Levitt et al39 evaluated patients given a bolus of 0.125 mg/kg of abciximab intraoperatively during or immediately after stent deployment to patients pretreated with dual antiplatelet medication (Table 2). In a patient population that included multiple stents and flow diverters, there was no significant difference in diffusion restriction imaging postoperatively and no evidence of ICH in either treatment arm. This provides an excellent antiplatelet treatment method in cases where a stent is placed in an emergent fashion and potentially avoids the use of preoperative dual antiplatelet therapy in cases where its use may not be required. TABLE 2. Glycoprotein IIb/IIIa Inhibitor Utilization for Thromboembolic Prophylaxis Authors  Patient (n)  Disease  Route  Bolus  Infusion/duration  Thromboembolic complications  Intracranial hemorrhage  Abciximab  48               Aviv et al 200526  1  Aneurysm  IV  5 mg  None  None  None   Levitt et al 201539  47  Aneurysm  IV  0.125 mg/kg  None  10.6%  None  Eptifibatide  177               Yi et al 200640  77  Aneurysm  IV  180 μg/kg  None  1.3%  2.6%   Sedat et al 201511  100  Aneurysm  IA  200 μg/kg  None  7%  4%  Tirofiban  104               Chalouhi et al 201238  11  Aneurysm  IV  0.4 μg/kg/min (30 min)  0.1 μg/kg/min (12 h)  None  27.3%    47  Aneurysm  IV  None  0.1 μg/kg/min (12 h)  None  1.9%a   Chalouhi et al 20167  46  Aneurysm  IV  None  0.1 μg/kg/min (intraop, continue for 2 h after)  2.2%  2.2%  Authors  Patient (n)  Disease  Route  Bolus  Infusion/duration  Thromboembolic complications  Intracranial hemorrhage  Abciximab  48               Aviv et al 200526  1  Aneurysm  IV  5 mg  None  None  None   Levitt et al 201539  47  Aneurysm  IV  0.125 mg/kg  None  10.6%  None  Eptifibatide  177               Yi et al 200640  77  Aneurysm  IV  180 μg/kg  None  1.3%  2.6%   Sedat et al 201511  100  Aneurysm  IA  200 μg/kg  None  7%  4%  Tirofiban  104               Chalouhi et al 201238  11  Aneurysm  IV  0.4 μg/kg/min (30 min)  0.1 μg/kg/min (12 h)  None  27.3%    47  Aneurysm  IV  None  0.1 μg/kg/min (12 h)  None  1.9%a   Chalouhi et al 20167  46  Aneurysm  IV  None  0.1 μg/kg/min (intraop, continue for 2 h after)  2.2%  2.2%  IA, intraarterial; IV, intravenous. aChalouhi et al (2012)38 did not specify whether hemorrhagic complication in their revised protocol occurred in a patient receiving rescue treatment of prophylactic tirofiban. View Large Eptifibatide Eptifibatide has also been used in a preventative manner in the endovascular treatment of both ruptured and unruptured aneurysms (Table 2). The first established protocol for the use of eptifibatide as a prophylactic measure utilized a single bolus of 180 μg/kg during the coiling procedure.40 In this study, stents were placed in approximately one-quarter of the patient population with a remarkably low rate of thromboembolic complications in 1.3%.40 In addition, only 2.6% of their patient population suffered from ICH, one secondary to intraoperative rupture and the second due to hemorrhagic conversion of a prior infarct.40 A more recent study evaluated the prophylactic use of eptifibatide compared to a retrospective cohort of patients who had not received the GP IIb/IIIa inhibitor.11 Using a single intraarterial bolus of 200 μg/kg at the beginning of the procedure, they found thromboembolic complications to be significantly lower in the eptifibatide-treated group (7%) compared to control (20%) with a statistically equal risk of ICH (4%).11 The success of these 2 studies reveals eptifibatide to be a safe and efficacious means of preventing thromboembolic complications. While the retrospective nature of these studies imposes inherent bias, the improved efficacy seen in the eptifibatide-treated patients provides a platform for further studies to confirm these outcomes and potentially develop a new standard of treatment. Tirofiban Tirofiban provides distinct advantages given its short half-life and rapid clearance. Several studies have evaluated its prophylactic use in the setting of endovascular treatment in both ruptured and unruptured aneurysms with intracranial stents (Table 2).7,38 Due to a high risk of fatal ICH, Chalouhi et al38 abandoned their initial protocol, consisting of an intraoperative bolus followed by a continuous infusion, and began utilizing a continuous infusion alone of 0.1 μg/kg/min for 12 h starting immediately after deployment of the first stent or coil. Under the revised protocol, there were no patients with thromboembolic complications and only a 1.9% rate of ICH.38 While this initial study evaluated stent-assisted coiling, a follow-up study evaluated the use of tirofiban prophylaxis for flow diversion treatment of both ruptured and unruptured intracranial aneurysms, using a continuous infusion of 0.1 μg/kg/min starting immediately after flow diverter deployment.7 Treatment with this protocol had a low risk of thromboembolic complications at 2.2% and only a 2.2% rate of ICH.7 These 2 studies reveal tirofiban to be a safe treatment in the setting of subarachnoid hemorrhage and provide an effective and immediate means of antiplatelet therapy when needed for intracranial stents and flow diversion in the treatment of intracranial aneurysms. CONCLUSION GP IIb/IIIa is a receptor for fibrinogen and von Willebrand factor, resulting in platelet activation and aggregation in thrombus formation. Drugs targeting this receptor inhibit acute clot formation, making them well suited for thromboembolic complications during neuroendovascular procedures. In the setting of subarachnoid hemorrhage, thrombus formation at the aneurysm dome would be stabilized by cross-linked fibrin and should remain unaffected by GP IIb/IIIa inhibitors—a theoretical advantage to provide thrombosis prevention without precipitating aneurysmal re-rupture. Early studies evaluating GP IIb/IIIa inhibitors as a treatment of thromboembolic complications during the treatment of intracranial aneurysms have found them to be both safe and effective. According to the cardiovascular literature, GP IIb/IIIa inhibitors are generally administered as a bolus, followed by a continuous maintenance infusion while current neurointerventional literature has varied greatly in dosing and administration methods. The use of a bolus and continuous infusion allows continued protection from further thromboembolic events originating from thrombogenic stents and coils, lending an advantage to this method when hemorrhagic complications appear no more frequently. While the initial bolus eliminates acute platelet activation, aggregation, and thrombus formation, continued platelet inhibition eliminates the potential for new thrombus formation as the patient is bridged to an oral antiplatelet regimen. Likewise, there is no consensus on intraarterial or intravenous delivery as both have proven to be efficacious. Given this, intraarterial administration may be slightly advantageous for acute thrombus formation given its direct delivery to the occluded artery. Intravenous bolus infusion may be best utilized after placement of a thrombogenic device in the vessel lumen in the absence of thrombosis, providing time while oral antiplatelet medications are started. If the patient develops new or worsening signs or symptoms of intracranial pathology following GP IIb/IIIa inhibitor administration, intracranial imaging with a non-contrast computed tomography of the head would certainly be warranted, although in the absence of such symptoms, imaging is probably of limited clinical utility. The prophylactic use of GP IIb/IIIa inhibitors to prevent thromboembolic complications has only recently been evaluated. In cases where the patient cannot receive preoperative dual antiplatelet therapy due to subarachnoid hemorrhage or in situations where an intracranial stent was unexpected preoperatively, these inhibitors provide a relatively safe and immediate antiplatelet strategy to avoid ischemic complications prior to being converted to an oral antiplatelet regimen. In various clinical scenarios, including simple coiling, stent-assisted coiling, and flow diversion, this preventative strategy has been proven to be both safe and effective. When used as a bridging agent to oral antiplatelet therapy, exposure to tirofiban and eptifibatide within 48 h or abciximab within 10 d of cessation will affect baseline ARU and PRU values in the VerifyNow assay, making them an unreliable test of platelet inhibition by aspirin or clopidogrel, respectively. While GP IIb/IIIa inhibitors have been present in cardiovascular surgery for quite some time, their utility in neurovascular surgery remains in its infancy, and the dosage and administration methods of GP IIb/IIIa inhibitor protocols vary significantly. Based on the reported risk of hemorrhage and efficacy in thromboembolic rescue or prevention, recommendations for abciximab, eptifibatide, and tirofiban are provided (Table 3). While randomized, prospective studies are needed and will further establish ideal protocols for GP IIb/IIIa inhibitors in the setting of neuroendovascular thromboembolic complications and prophylaxis, the best practices highlighted in the current studies demonstrate efficacy of this drug class with a minimal risk of ICH. TABLE 3. Protocol Recommendations for Glycoprotein IIb/IIIa Inhibitors in Thromboembolic Rescue and Prevention During Intracranial Endovascular Treatment Drug  Indication  Bolus  Infusion  Abciximab      Rescue  0.25 mg/kg (IA or IV)  0.125 μg/kg/min (12 h)    Prophylaxis  0.125 mg/kg (IV)  None  Eptifibatide      Rescue  90 μg/kg (IA)  0.5 μg/kg/min (12 h)    Prophylaxis  180 μg/kg  None  Tirofiban      Rescue  4 μg/kg aliquots (IA)  0.1 μg/kg/min (12 h)a      (Max: 25 μg/kg)      Prophylaxis  None  0.1 μg/kg/min (12 h)b        0.1 μg/kg/min (2 h)b  Drug  Indication  Bolus  Infusion  Abciximab      Rescue  0.25 mg/kg (IA or IV)  0.125 μg/kg/min (12 h)    Prophylaxis  0.125 mg/kg (IV)  None  Eptifibatide      Rescue  90 μg/kg (IA)  0.5 μg/kg/min (12 h)    Prophylaxis  180 μg/kg  None  Tirofiban      Rescue  4 μg/kg aliquots (IA)  0.1 μg/kg/min (12 h)a      (Max: 25 μg/kg)      Prophylaxis  None  0.1 μg/kg/min (12 h)b        0.1 μg/kg/min (2 h)b  IA, intraarterial; IV, intravenous. aContinuous infusion only when thrombus still present following bolus dosing or for coil protrusion. bInfusion for 12 h in setting of stent-assisted coiling; 2 h with use of a flow diverting stent to be started immediately after stent placement. 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Intervent Neurol . 2013; 2( 1): 19- 29. Google Scholar CrossRef Search ADS   35. Jeon JS, Sheen SH, Hwang G, Kang SH, Heo DH, Cho YJ. Intraarterial tirofiban thrombolysis for thromboembolisms during coil embolization for ruptured intracranial aneurysms. J Cerebrovasc Endovasc Neurosurg . 2012; 14( 1): 5- 10. Google Scholar CrossRef Search ADS PubMed  36. Cho YD, Lee JY, Seo JH et al.   Intra-arterial tirofiban infusion for thromboembolic complication during coil embolization of ruptured intracranial aneurysms. Eur J Radiol . 2012; 81( 10): 2833- 2838. Google Scholar CrossRef Search ADS PubMed  37. Kang HS, Kwon BJ, Roh HG et al.   Intra-arterial tirofiban infusion for thromboembolism during endovascular treatment of intracranial aneurysms. Neurosurgery . 2008; 63( 2): 230- 237; discussion 237-238. Google Scholar CrossRef Search ADS PubMed  38. Chalouhi N, Jabbour P, Kung D, Hasan D. Safety and efficacy of tirofiban in stent-assisted coil embolization of intracranial aneurysms. Neurosurgery . 2012; 71( 3): 710- 714; discussion 714. Google Scholar CrossRef Search ADS PubMed  39. Levitt MR, Moon K, Albuquerque FC, Mulholland CB, Kalani MY, McDougall CG. Intraprocedural abciximab bolus versus pretreatment oral dual antiplatelet medication for endovascular stenting of unruptured intracranial aneurysms. J Neurointervent Surg . 2015; 8( 9): 909- 912. Google Scholar CrossRef Search ADS   40. Yi HJ, Gupta R, Jovin TG et al.   Initial experience with the use of intravenous eptifibatide bolus during endovascular treatment of intracranial aneurysms. AJNR Am J Neuroradiol.  2006; 27( 9): 1856- 1860. Google Scholar PubMed  COMMENT The authors review the role of IIb/IIIa inhibitors for prevention and rescue therapy of thrombotic complications during endovascular treatment of aneurysms. Depending on the definition and imaging modalities used, the reported frequency of thrombotic events during aneurysm embolization varies greatly. Such events correlate with poor clinical outcomes. Standardized protocols on the use of IIb/IIIa agents are currently lacking. This review summarizes clinically relevant data on the use of IIb/IIIa inhibitors for neurointerventional procedures, and provides clear and concise recommendations on its dose and administration regimen. Maxim Mokin Tampa, Florida Copyright © 2017 by the Congress of Neurological Surgeons

Journal

NeurosurgeryOxford University Press

Published: Mar 1, 2018

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