Hemorrhagic stroke
ORIGINAL RESEARCH
Tailoring platelet inhibition according to multiple electrode aggregometry decreases the rate of thrombotic complications after intracranial flow-diverting stent implantation Ismail Oran,1 Celal Cinar,1 Halil Bozkaya,1 Mehmet Korkmaz2 1
Department of Radiology, Ege University Medical School, Izmir, Turkey 2 Department of Radiology, Dumlupinar University Medical School, Kutahya, Turkey Correspondence to Professor Ismail Oran, Department of Radiology, Ege University Hospital, Izmir 35100, Turkey; [email protected] Received 29 October 2013 Revised 10 March 2014 Accepted 16 March 2014 Published Online First 10 April 2014
To cite: Oran I, Cinar C, Bozkaya H, et al. J NeuroIntervent Surg 2015;7:357–362.
ABSTRACT Background and purpose Pretreatment with dual antiaggregant drugs is accepted as a standard step in intracranial stent implantation. The aim of this study was to determine whether tailored antiaggregant medication based on platelet reactivity testing with multiple electrode aggregometry (Multiplate) yields superior outcomes after intracranial flow-diverting stent (FDS) implantation compared with standard clopidogrel treatment. Methods We retrospectively analyzed the following data from 100 consecutive patients: endovascular procedure characteristics, antiaggregant medications, procedural variables, and perioperative complications after FDS implantation for intracranial aneurysm. Patients were divided into two groups: uniform treatment with clopidogrel (untailored, early phase) and tailored treatment based on the results of aggregometry (late phase). Statistical comparisons included the Fisher exact test to compare categorical variables between the standard and aggregometry groups and the Mann– Whitney U test to compare ADP test values within the aggregometry group between groups receiving tailored or untailored treatment. Results In the aggregometry group (68 patients, 71 procedures) there were 17 (25%) clopidogrel-resistant patients, according to a cut-off value of 468 area under the aggregation curve; 12 underwent FDS implantation under tailored antiaggregant medication. In the standard treatment group (32 patients, 33 procedures) there were 3 (9.1%) spontaneous thrombotic events and 1 (3.3%) technical hemorrhagic complication. In the aggregometry group there were 2 (2.8%) spontaneous hemorrhagic events and 1 (1.4%) technical ischemic complication. In the aggregometry group, thrombotic complications and morbidity were lower than in the standard (no test) group ( p468 AUC (47 U) following clopidogrel pretreatment (normal range in the absence of antiaggregants is 569–1130 AUC as reported by the manufacturer) was considered indicative of clopidogrel non-response or hyporesponse (resistance).11 Aspirin nonresponsiveness or hyporesponsiveness was defined as aggregation >500 AUC (50 U) (normal range in the absence of aspirin is 706–1148 AUC). In the standard group, FDS implantation followed the standard protocol. In the aggregometry group, however, according to the test results, the following procedures and loading doses were changed: in some clopidogrel-resistant patients, following ingestion of the alternative P2Y12 receptor antagonist ticlopidine at a loading dose of 1 g (reloading), the embolization procedure was postponed for at least 4 h. Other clopidogrel-resistant patients underwent the same scheduled embolization after 1 g of ticlopidine via nasogastric tubing under the protection of bridging intravenous tirofiban (a short half-life platelet glycoprotein IIb–IIIa receptor inhibitor) in a dose of 0.25–1 mg (aggressive loading). For the remaining hyporesponding patients, the heparin intravenous dose was increased during and after the procedure without a change in the antiaggregant medication (unchanged loading). In general, very high ADP values in patients with a stable aneurysm led to postponed procedures, high ADP values in patients with an aneurysm with a 358
history of SAH or a recently symptomatic aneurysm led to modified loading, and limited hyporesponse to clopidogrel (ADP test values near the upper level of therapeutic window, 468 AUC) and a full response to aspirin were considered compatible with the standard procedure. The reloading and aggressive loading groups together constituted the ‘antiaggregant tailored’ group. After intravenous tirofiban bridging loading accompanied by peroral ticlopidine loading via a nasogastric tube, the ADP test was repeated 30 min and 4 h later. Following stent implantation, all patients were prescribed dual antiplatelet treatment with 100– 300 mg aspirin (for 6 months) and 75 mg clopidogrel (or 2×250 mg ticlopidine) daily (for 3 months). If MRI detected an objective mass effect such as perianeurysmal edema and/or neurological examination revealed cranial nerve palsy due to aneurysm compression, patients immediately received an intravenous steroid at the beginning of the procedure (methylprednisolone 80–250 mg) and were thereafter prescribed a peroral steroid ( prednisolone) starting at 1–2 mg/kg and gradually decreasing the dose within 1 month.
Endovascular procedure The parent artery was catheterized telescopically with a 6 Fr long sheath (Shuttle; Cook Medical, Bloomington, Indiana, USA or Destination; Terumo, Japan) and 6 Fr distal access guide catheter (Fargo/FargoMax, Balt Extrusion, Montmorency, France). All patients were implanted with Pipeline FDS (Covidien/ev3, Irvine, California, USA). During implantation, care was taken to obtain full expansion of the stent. In case of insufficient expansion, an intracranial balloon (Hyperglide, Covidien/ev3) was used to dilate the stent. Some procedures necessitated wire exchange maneuvers.
Statistical analysis Statistical analysis was performed using the SPSS V.15.0 software. The Fisher exact test was used to analyze categorical variables in the standard and aggregometry groups. Within the aggregometry group, the Mann–Whitney U test was used to compare the ADP values in the tailored and untailored groups. A p value of < 0.05 was taken to indicate statistical significance.
RESULTS Between January 2010 and June 2013, 100 consecutive patients with intracranial aneurysm undergoing FDS implantation in the interventional radiology department were enrolled into this retrospective study; the first 32 were allocated to the standard group (no platelet function test) while clopidogrel and aspirin response was tested by multiple electrode aggregometry in the remaining 68. There were 33 loadings in the standard group (one patient had bilateral aneurysms treated in a separate elective session) and 71 loadings in the aggregometry group (three patients had bilateral aneurysms treated separately). All 33 procedures in the standard group and 70 of 71 in the aggregometry group were performed after loading with clopidogrel; the remaining patient was loaded with ticlopidine. Baseline anatomical, clinical, and procedural characteristics were well balanced between the standard and aggregometry groups (table 1). In the aggregometry group, 17 of 68 patients (25%) were considered clopidogrel non-responsive/hyporesponsive based on the cut-off value (>468 AUC). This predetermined cut-off value thus defined the upper quartile of platelet activity in our patient population. Five of these 17 patients were responsive to aspirin and had only limited clopidogrel resistance (ie, ADP test values were very close to the cut-off value of 468 AUC); their endovascular procedures proceeded without changes in the antiplatelet
Oran I, et al. J NeuroIntervent Surg 2015;7:357–362. doi:10.1136/neurintsurg-2013-011023
Hemorrhagic stroke Table 1 Initial comparison of the two study groups
Basic characteristics Age in years (mean) Male gender (n, %) Hypertension (n, %) Smoking (n, %) Thrombocyte count (mean) Presentation Recent (
ORIGINAL RESEARCH
Tailoring platelet inhibition according to multiple electrode aggregometry decreases the rate of thrombotic complications after intracranial flow-diverting stent implantation Ismail Oran,1 Celal Cinar,1 Halil Bozkaya,1 Mehmet Korkmaz2 1
Department of Radiology, Ege University Medical School, Izmir, Turkey 2 Department of Radiology, Dumlupinar University Medical School, Kutahya, Turkey Correspondence to Professor Ismail Oran, Department of Radiology, Ege University Hospital, Izmir 35100, Turkey; [email protected] Received 29 October 2013 Revised 10 March 2014 Accepted 16 March 2014 Published Online First 10 April 2014
To cite: Oran I, Cinar C, Bozkaya H, et al. J NeuroIntervent Surg 2015;7:357–362.
ABSTRACT Background and purpose Pretreatment with dual antiaggregant drugs is accepted as a standard step in intracranial stent implantation. The aim of this study was to determine whether tailored antiaggregant medication based on platelet reactivity testing with multiple electrode aggregometry (Multiplate) yields superior outcomes after intracranial flow-diverting stent (FDS) implantation compared with standard clopidogrel treatment. Methods We retrospectively analyzed the following data from 100 consecutive patients: endovascular procedure characteristics, antiaggregant medications, procedural variables, and perioperative complications after FDS implantation for intracranial aneurysm. Patients were divided into two groups: uniform treatment with clopidogrel (untailored, early phase) and tailored treatment based on the results of aggregometry (late phase). Statistical comparisons included the Fisher exact test to compare categorical variables between the standard and aggregometry groups and the Mann– Whitney U test to compare ADP test values within the aggregometry group between groups receiving tailored or untailored treatment. Results In the aggregometry group (68 patients, 71 procedures) there were 17 (25%) clopidogrel-resistant patients, according to a cut-off value of 468 area under the aggregation curve; 12 underwent FDS implantation under tailored antiaggregant medication. In the standard treatment group (32 patients, 33 procedures) there were 3 (9.1%) spontaneous thrombotic events and 1 (3.3%) technical hemorrhagic complication. In the aggregometry group there were 2 (2.8%) spontaneous hemorrhagic events and 1 (1.4%) technical ischemic complication. In the aggregometry group, thrombotic complications and morbidity were lower than in the standard (no test) group ( p468 AUC (47 U) following clopidogrel pretreatment (normal range in the absence of antiaggregants is 569–1130 AUC as reported by the manufacturer) was considered indicative of clopidogrel non-response or hyporesponse (resistance).11 Aspirin nonresponsiveness or hyporesponsiveness was defined as aggregation >500 AUC (50 U) (normal range in the absence of aspirin is 706–1148 AUC). In the standard group, FDS implantation followed the standard protocol. In the aggregometry group, however, according to the test results, the following procedures and loading doses were changed: in some clopidogrel-resistant patients, following ingestion of the alternative P2Y12 receptor antagonist ticlopidine at a loading dose of 1 g (reloading), the embolization procedure was postponed for at least 4 h. Other clopidogrel-resistant patients underwent the same scheduled embolization after 1 g of ticlopidine via nasogastric tubing under the protection of bridging intravenous tirofiban (a short half-life platelet glycoprotein IIb–IIIa receptor inhibitor) in a dose of 0.25–1 mg (aggressive loading). For the remaining hyporesponding patients, the heparin intravenous dose was increased during and after the procedure without a change in the antiaggregant medication (unchanged loading). In general, very high ADP values in patients with a stable aneurysm led to postponed procedures, high ADP values in patients with an aneurysm with a 358
history of SAH or a recently symptomatic aneurysm led to modified loading, and limited hyporesponse to clopidogrel (ADP test values near the upper level of therapeutic window, 468 AUC) and a full response to aspirin were considered compatible with the standard procedure. The reloading and aggressive loading groups together constituted the ‘antiaggregant tailored’ group. After intravenous tirofiban bridging loading accompanied by peroral ticlopidine loading via a nasogastric tube, the ADP test was repeated 30 min and 4 h later. Following stent implantation, all patients were prescribed dual antiplatelet treatment with 100– 300 mg aspirin (for 6 months) and 75 mg clopidogrel (or 2×250 mg ticlopidine) daily (for 3 months). If MRI detected an objective mass effect such as perianeurysmal edema and/or neurological examination revealed cranial nerve palsy due to aneurysm compression, patients immediately received an intravenous steroid at the beginning of the procedure (methylprednisolone 80–250 mg) and were thereafter prescribed a peroral steroid ( prednisolone) starting at 1–2 mg/kg and gradually decreasing the dose within 1 month.
Endovascular procedure The parent artery was catheterized telescopically with a 6 Fr long sheath (Shuttle; Cook Medical, Bloomington, Indiana, USA or Destination; Terumo, Japan) and 6 Fr distal access guide catheter (Fargo/FargoMax, Balt Extrusion, Montmorency, France). All patients were implanted with Pipeline FDS (Covidien/ev3, Irvine, California, USA). During implantation, care was taken to obtain full expansion of the stent. In case of insufficient expansion, an intracranial balloon (Hyperglide, Covidien/ev3) was used to dilate the stent. Some procedures necessitated wire exchange maneuvers.
Statistical analysis Statistical analysis was performed using the SPSS V.15.0 software. The Fisher exact test was used to analyze categorical variables in the standard and aggregometry groups. Within the aggregometry group, the Mann–Whitney U test was used to compare the ADP values in the tailored and untailored groups. A p value of < 0.05 was taken to indicate statistical significance.
RESULTS Between January 2010 and June 2013, 100 consecutive patients with intracranial aneurysm undergoing FDS implantation in the interventional radiology department were enrolled into this retrospective study; the first 32 were allocated to the standard group (no platelet function test) while clopidogrel and aspirin response was tested by multiple electrode aggregometry in the remaining 68. There were 33 loadings in the standard group (one patient had bilateral aneurysms treated in a separate elective session) and 71 loadings in the aggregometry group (three patients had bilateral aneurysms treated separately). All 33 procedures in the standard group and 70 of 71 in the aggregometry group were performed after loading with clopidogrel; the remaining patient was loaded with ticlopidine. Baseline anatomical, clinical, and procedural characteristics were well balanced between the standard and aggregometry groups (table 1). In the aggregometry group, 17 of 68 patients (25%) were considered clopidogrel non-responsive/hyporesponsive based on the cut-off value (>468 AUC). This predetermined cut-off value thus defined the upper quartile of platelet activity in our patient population. Five of these 17 patients were responsive to aspirin and had only limited clopidogrel resistance (ie, ADP test values were very close to the cut-off value of 468 AUC); their endovascular procedures proceeded without changes in the antiplatelet
Oran I, et al. J NeuroIntervent Surg 2015;7:357–362. doi:10.1136/neurintsurg-2013-011023
Hemorrhagic stroke Table 1 Initial comparison of the two study groups
Basic characteristics Age in years (mean) Male gender (n, %) Hypertension (n, %) Smoking (n, %) Thrombocyte count (mean) Presentation Recent (
