Prolonged Reversible Ischemic Neurological Deficit Research Articles

Incidence of Thromboembolic Events Across Eltrombopag Clinical Trials In Chronic Immune Thrombocytopenia (ITP)

AbstractAbstract 70 Introduction:Chronic ITP is characterized by decreased platelet counts resulting from autoantibody-mediated peripheral platelet destruction and suboptimal platelet production. Eltrombopag is an oral, thrombopoietin receptor agonist approved for the treatment of ITP in the USA and elsewhere. Thromboembolic events (TEEs) can occur in patients with ITP; it has been speculated that ITP has prothrombotic characteristics and that low platelet counts may prevent a higher incidence of TEEs (Sarpatwari, 2010; Aledort, 2004; Zelcer, 2003). In the UK General Practice Research Database, incidence rates for TEEs were 1.35/100 patient years (PYs) (95% CI [0.99, 1.79]) for patients with ITP vs 1.16/100 PYs (95% CI [0.99, 1.35]) in patients without ITP (Sarpatwari, 2010). Similar results were found in a US claims database study (Bennett, 2008) and in romiplostim studies (Bussel, 2009). In this study we evaluated the incidence of TEEs in patients with chronic ITP treated with eltrombopag. Methods:Data from 446 patients with chronic ITP exposed to eltrombopag were analyzed from 5 eltrombopag clinical trials: two 6-week, randomized, double-blind, phase 2 and 3 studies, with patients on eltrombopag (n=164) or placebo (n=67) (Bussel, 2007; Bussel, 2009); RAISE, a 6-month, randomized, double-blind, phase 3 study, with 135 patients on eltrombopag and 62 on placebo (Cheng, 2010); REPEAT, a phase 2 study with 66 patients on eltrombopag for 3 cycles of 6 weeks on-therapy followed by up to 4 weeks off therapy (Psaila, 2008); and EXTEND, an ongoing extension study with 299 of the same patients on eltrombopag for at least 2 years (Cheng, 2008). The first occurrence of a TEE was used in the calculation of the incidence rates across the ITP program. Confirmed or suspected cases of TEEs were either reported by investigators or identified after sponsor evaluation based on symptoms reported as adverse events (AEs) that were potentially compatible with a TEE. In an additional analysis, the odds ratio for a TEE at different platelet thresholds was investigated to assess if a direct relationship could be established. Results:Across the ITP program, 20 patients (4.5%, 20/446) exposed to eltrombopag have experienced 27 TEEs. The TEEs were DVT (12), pulmonary embolism (6), MI (4), ischemic stroke (3), suspected prolonged reversible ischemic neurologic deficit (1), and transient ischemic attack (1). No placebo-treated patient experienced a TEE. The PYs of exposure to study medication was approximately 17 times greater than PYs of exposure to placebo (eltrombopag 584.4 PYs; placebo 35.4 PYs). Despite the increased exposure to eltrombopag in the EXTEND study, the incidence of TEEs (3.14/100 PYs, 95% CI [1.92, 4.85]) decreased compared to previously reported data (4.04/100 PYs, 95% CI [2.35, 6.46], Bussel, 2009). There was no clear pattern observed with regard to time to TEE onset; events were reported as early as day 1 and up to day 981 (median time to onset 229 days). The platelet counts most proximal to the events ranged between 14,000/μ L and 482,000/μ L (median 143,000/μ L). The majority of patients (55%, 11) had platelet counts below the normal range at the time of the TEE (<150,000/μ L). 4/20 patients experienced the TEE closest to their maximum platelet count achieved on study, whereas the majority (80%, 16/20) experienced the TEE at a lower platelet count than their maximum platelet count during treatment with eltrombopag. As seen in the Table, no changes in the odds ratio for a TEE at different platelet thresholds were observed. All patients experiencing a TEE had at least one risk factor for TEE; analysis did not reveal any one risk factor that was associated with the majority of cases. Two of 15 patients with TEEs tested had positive results for heterozygous Factor V Leiden mutation. Conclusions:There is no increase in the incidence rate of TEEs across the ITP program despite longer duration of eltrombopag treatment. The data presented here confirm previous observations that there is no evidence of a correlation between platelet count increases and the occurrence of TEEs in patients with chronic ITP on eltrombopag.TableOdds Ratio of Experiencing a TEE Based on Maximum Platelet Count Across the Eltrombopag ITP TrialsPlatelet CountOR (95% CI)P value≥100 Gi/L vs <100 Gi/L0.464 (0.18, 1.18)0.108≥150 Gi/L vs <150 Gi/L0.432 (0.17, 1.10)0.078≥200 Gi/L vs <200 Gi/L0.526 (0.20, 1.36)0.185 Disclosures:Bussel:GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cheng:GlaxoSmithKline: Consultancy, Honoraria, Speakers Bureau. Saleh:GlaxoSmithKline, Novartis, Imcoline, Celgene: Honoraria, Speakers Bureau. Mayer:GlaxoSmithKline: Employment, Equity Ownership. Vasey:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment.

Contralateral Internal Carotid Artery Occlusion Impairs Early But Not 30-Day Stroke Rate Following Carotid Endarterectomy

Neurological complications and mortality within 30 days following carotid endarterectomy (CEA) alone or with concomitant cardiac surgery/cardiopulmonary bypass (CPB) were assessed in patients with or without contralateral occlusion of the internal carotid artery (CO-ICA).Of 335 patients undergoing CEA, 173 underwent concomitant cardiac surgery with CPB. Group A consisted of 260 patients without CO-ICA and group B of 75 patients with CO-ICA. The neurological complications (peripheral nerve damage, transient ischemic attack [TIA], prolonged reversible ischemic neurological deficit [PRIND], and stroke) and the Rankin index within 24 hours and 30 days postoperatively were compared. Strokes within 24 hours were significantly increased (P = .006) in group B (11%) compared with A (3.1%); TIA and PRIND did not differ (P = .33). The overall neurological complications and in particular for peripheral neurological damage, TIA/PRIND, and stroke did not differ within the 30-day-period postsurgery. A significantly higher stroke rate within 24 hours postsurgery occurred in patients with CO-ICA.

Does the use of carbon dioxide field flooding during heart valve surgery prevent postoperative cerebrovascular complications?

A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was whether there is any benefit with the use of carbon dioxide (CO(2)) field flooding techniques in heart valve surgery, in order to reduce postoperative neurological complications. Altogether 202 articles were found using the reported search, and six of them were used to answer the clinical question. All but one trial, were prospective, randomised. Four studies reported a significantly lower intracardiac bubble count in the CO(2) group. A significant reduction of p300 peak latencies in the CO(2) group was observed in one study. Otherwise, neurocognitive test batteries did not reveal any advantages of CO(2) field flooding in two studies. Three studies reported on postoperative cerebrovascular complications and the overall rate of stroke, transient ischemic attack (TIA) or prolonged reversible ischemic neurological deficit was 1.2% in the CO(2) group and 2.5% in the control group (P=ns). Although the use of CO(2) field flooding has been observed to be associated with a significantly lower count of intracardiac air bubbles, and improved survival in two small studies, so far there is no evidence of a sustained reduction of cerebrovascular complications with the use of this method.

Simultaneous carotid endarterectomy and cardiac surgery--additional risk factor or safety procedure?

The occurrence of severe carotid artery disease in more than 12 % of patients requiring CABG results in a discrepancy concerning the best treatment for both diseases. We reviewed the early outcome of patients with CABG and/or valve replacement and simultaneous carotid endarterectomy (CEA). We evaluated retrospectively 244 patients operated simultaneously between 7/94 and 10/2001. 209 patients received CABG; 35 patients CABG and/or valve replacement. Mean age was 68 years. 188 patients were male. We analyzed risk factors, morbidity, incidence of neurological complications and 30 day mortality. Perioperative stroke with hemiplegia occurred in 3.3 % (8 patients). 4 of these patients showed contralateral carotid artery occlusion, 2 contralateral severe stenosis. 2 patients (0.8 %) experienced prolonged reversible ischemic neurological deficit (PRIND), 4 patients (1.6 %) transient ischemic attack (TIA). 30-day lethality was 4.5 %. 3 patients died due to low cardiac output, 6 patients due to extracardial reasons, 2 patients (0.8 %) developed a cerebral death. Simultaneous CEA and cardiac surgery can be performed with an acceptable risk for neurological complications and mortality. Occlusion of contralateral carotid artery could be identified as an evident predictor for increased neurological complications. Compared to two-stage procedures, combined operations yield a reduction of hospital costs.

Stroke after cardiac surgery: a risk factor analysis of 16,184 consecutive adult patients

Background Stroke remains a devastating complication after cardiac surgical procedures despite advances in perioperative monitoring and management. The purpose of this study was to determine the predictors of stroke in a large, contemporary cardiac surgery population. Methods Prospective data on 16,184 consecutive patients undergoing cardiac surgery (coronary artery bypass grafting [CABG], n = 8,917; beating heart CABG, n = 1,842; aortic valve surgery, n = 1,830; mitral valve surgery, n = 708; double or triple valve surgery, n = 381; CABG and valve surgery, n = 2,506) between April 1996 and August 2001 were subjected to univariate and multivariate analysis. Stroke was defined as any new permanent (manifest stroke) or temporary neurologic deficit or deterioration (transient ischemic attack or prolonged reversible ischemic neurologic deficit) and was confirmed by computed tomography or magnetic resonance imaging whenever possible. Results Overall incidence of stroke was 4.6% and varied between surgical procedures (CABG 3.8%; beating-heart CABG 1.9%; aortic valve surgery 4.8%; mitral valve surgery 8.8%; double or triple valve surgery 9.7%; CABG and valve surgery 7.4%). Of 63 patient-specific and treatment variables, 54 were found to have a significant univariate association with postoperative stroke. Multivariable analysis revealed 10 variables that were independent predictors of stroke: history of cerebrovascular disease, peripheral vascular disease, diabetes, hypertension, previous cardiac surgery, preoperative infection, urgent operation, CPB time more than 2 hours, need for intraoperative hemofiltration, and high transfusion requirement. Beating heart CABG was associated with a lower incidence of stroke in this multivariable analysis. Conclusions Identification of predictors for stroke is important for understanding the pathogenesis of this devastating complication as well as for developing preventative strategies. Although retrospective analyses can be subject to selection bias we believe beating heart CABG is associated with a lower incidence of stroke and may therefore improve patient outcomes.

Catheter closure of the persistent foramen ovale: mid-term results in 162 patients.

Four different types of occluder systems were used to close a persistent foramen ovale (PFO) in 162 patients with paradoxical embolic events. Ninety-eight patients had ischemic stroke, 60 transient ischemic attacks (TIA) or prolonged reversible ischemic neurological deficit (PRIND), and 4 had peripheral arterial embolism. The age of the patients was 40.2 +/- 11.9 years and the ischemic event had happened 7 +/- 10 months before device closure. CardioSeal and Amplatzer occluders were the most commonly used devices (73 and 77 cases, respectively). Implantations were successful in all patients. Serious catheter-related complications included two device embolizations and two venous bleedings. Six patients had documented supraventricular arrhythmias within the first month after implantation, which disappeared spontaneously within some weeks without therapy in three patients; the other three patients with atrial fibrillation needed conversion to sinus rhythm. Residual leaks were found in 5 out of 116 patients who had been followed by transesophageal echocardiography (TEE) and one leak was closed by a second device. During a follow-up period of 19.4 +/- 16.2 months per patient, TIA and PRIND occurred in 3 of 116 patients. Interventional closure of PFO is a simple, effective and quick method that is superior to surgery and avoids the problems of life-long anticoagulation.

Early Carotid Surgery for Recent Neurologic Deficit

Early carotid endarterectomy after recent neurologic deficit is controversial. Traditionally, an interval of at least 4 to 6 weeks has been recommended based on poor historical results of early surgical intervention after recent strokes and fear of hemorrhagic transformation of the infarct. On the other hand, recurrent strokes have been observed in up to 9.5% of patients while awaiting carotid repair. Since 1996 we have adopted a more aggressive approach to a highly selected group of patients with fresh ischemic deficits, prolonged reversible ischemic neurologic deficit (PRIND), or crescendo transient ischemic attacks (TIAs). Of 2824 patients who underwent carotid endarterectomy between August 1996 and December 1998, 112 patients (3.9%) underwent 123 carotid operations within less than 30 days (median interval: 8 days) after a nondisabling stroke, PRIND, or TIA. Postoperatively five patients (4.4%) suffered a stroke, one patient a transient worsening of his preoperative deficit, and one patient a TIA. Six...

Early Carotid Surgery for Recent Neurologic Deficit

Early carotid endarterectomy after recent neurologic deficit is controversial. Traditionally, an interval of at least 4 to 6 weeks has been recommended based on poor historical results of early surgical intervention after recent strokes and fear of hemorrhagic transformation of the infarct. On the other hand, recurrent strokes have been observed in up to 9.5% of patients while awaiting carotid repair. Since 1996 we have adopted a more aggressive approach to a highly selected group of patients with fresh ischemic deficits, prolonged reversible ischemic neurologic deficit (PRIND), or crescendo transient ischemic attacks (TIAs). Of 2824 patients who underwent carotid endarterectomy between August 1996 and December 1998, 112 patients (3.9%) underwent 123 carotid operations within less than 30 days (median interval: 8 days) after a nondisabling stroke, PRIND, or TIA. Postoperatively five patients (4.4%) suffered a stroke, one patient a transient worsening of his preoperative deficit, and one patient a TIA. Six patients died, three of which were due to their stroke (mortality 5.3%). One of these fatal strokes was due to an intracerebral hemorrhage in a patient with normal preoperative computed tomography. The combined 30-day permanent neurologic stroke and death rate was 7.1%. Functional neurologic outcome was excellent with 74.1% of patients suffering no or minimal deficit (Rankin scale 0-1). Patients with unstable or progressing neurologic deficit were found to have a significantly increased postoperative stroke rate (25%). Early carotid endarterectomy after nondisabling neurologic deficit may be performed with acceptable risk in carefully selected patients. The benefit of early versus delayed surgery, however, can only be determined in a prospective randomized study.

Differentiation between transient ischemic attack and ischemic stroke within the first six hours after onset of symptoms by using 99mTc-ECD-SPECT.

The aim of this study was to define the accuracy of 99mTc-ethyl cysteinate dimer-single photon emission computed tomography (99mTc-ECD-SPECT) in distinguishing transient ischemic attack from completed ischemic stroke at early stages after the onset of symptoms. In a prospective study we examined 82 patients within 6 hours after the onset of symptoms (neurologic deficit caused by middle cerebral artery ischemia) using both 99mTc-ECD-SPECT and computed tomography (CT). The follow-up was based on Scandinavian Stroke Scale (SSS) 24 hours and 5-7 days, as well as on CT 7 days, after the event. SPECT evaluation was performed both visually and using semiquantitative region-of-interest (ROI) analysis. According to visual SPECT analysis, on admission 59 of 82 patients had activity deficits in the symptomatic hemisphere. After 7 days, all these patients had neurologic symptoms (SSS 28 +/- 12 points), caused by a cerebral infarction as evidenced with CT. Twenty-three of 82 patients displayed no early activity deficit despite clinical symptoms. None of these patients had neurologic symptoms after 7 days (indicating transient ischemic attack or prolonged reversible ischemic neurologic deficit). In the semiquantitative SPECT analysis, all patients had abnormal count densities in the respective ROI (activity < 90% compared with the contralateral side). All patients with transient ischemia (n = 23) had count rate densities more than 70% of the respective contralateral ROI, whereas all patients with subsequent infarction (n = 59) had values < 70%. Use of 99mTc-ECD-SPECT allows transient ischemia to be distinguished from ischemic infarction using relative regional activity thresholds within the first 6 hours after onset of symptoms.

Zerebrale manifestationen bei angioneurotischem Ödem

Cerebral manifestations in angioneurotic edema Two patients with hereditary angioneurotic edema are described. A female patient, born in 1929, showed an infarction in the area of the right posterior cerebral artery, verified by computer tomography. The son of this patient, aged 20 years, suffered from a transitory ischemic attack and a prolonged reversible ischemic neurological deficit, both in the territory of the left middle cerebral artery. Etiology, symptomatology, therapy, and differential diagnosis of cerebral manifestations in angioneurotic edema are discussed in view of previously described cases.

Sensitivity of Computed Tomography and Serial Scintigraphy in Cerebrovascular Disease

Computed tomography and serial scintigraphy with 99mTc-pertechnetate (radionuclide angiography and early and late static imaging) were compared in 214 patients with cerebrovascular disease. CT correctly identified 151 (95.0%) of 159 patients with completed ischemic stroke but was positive in only 11 (25%) of 44 patients with asymptomatic stenosis, transient ischemic attacks (TIA), or prolonged reversible ischemic neurological deficit (PRIND). Scintigraphy was positive in 93.1% of patients with completed stroke. CT detected 175 territories of vascular supply involved, scintigraphy 164. In patients with asymptomatic stenosis, TIA, or PRIND, scintigraphy was correct in 77.3% of cases. The combined evaluation offered a sensitivity of 97.5% in patients with completed stroke and 86.4% in those with asymptomatic stenosis, TIA, or PRIND. The rate of true-positive scintigraphic findings in patients with completed stroke did not change as the interval between ictus and study increased. In patients with intracerebral hematoma, CT was far more specific than scintigraphy. If cerebrovascular disease is suspected, radionuclide angiography should be performed first.