Efficacy of NeuroFlo Device in Treatment of Patients with Atrial Fibrillation

Efficacy of NeuroFlo Device in Treatment of Patients with Atrial Fibrillation Gary L. Bernardini, MD, PhD,* Peter D. Schellinger, MD, PhD,† Alex Abou-Chebl, MD,‡ Kevin Cockroft, MD,x Ashfaq Shuaib, MD,k Rishi Sheorajpanday, MD, MSc, PhD,{ Souvik Sen, MD,** Hans-Christoph Diener, MD, PhD,†† Ronen R. Leker, MD,‡‡ and Natan M. Bornstein, MDxx

Atrial fibrillation (AF) is a well-established independent risk factor for stroke. We examined cerebral blood flow augmentation in the treatment of acute ischemic stroke (AIS) in patients with AF by performing secondary analysis of data from the Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke (SENTIS) trial, a randomized controlled trial evaluating NeuroFlo treatment in stroke patients within 14 hours of symptom onset. We report subgroup analyses of outcomes in SENTIS patients with a history or new diagnosis of AF. Among patients with AF, those treated with NeuroFlo demonstrated significant improvement over those not treated for multiple end points: global efficacy end point (P 5 .030), modified Rankin Scale (mRS) score 0-2 versus 3-6 (P 5 .029), and stroke-related mortality (P 5 .015). There was a significant improvement in global end point for those aged 60 years or older (P 5.042) and 80 years or older (P 5.017), with a trend toward improvement for age 70 years or older (P 5 .055), and significant improvement in those who achieved good outcomes (mRS score 0-2 versus 3-6) at age 60 years or older (P 5 .038), 70 years or older (P 5 .022), and 80 years or older (P 5 .008). NeuroFlo treatment in stroke patients with AF resulted in significantly better outcomes compared with nontreated patients with AF. Collateral flow recruitment, maintenance of cerebral blood flow around stroke core, and improvement of penumbral blood flow are potential mechanisms for these improved outcomes. NeuroFlo may represent a valid therapeutic option for patients with AF and AIS, and therefore, future trials of the device are warranted. Key Words: Aortic occlusion— NeuroFlo—brain perfusion augmentation—clinical trials—ischemic stroke—atrial fibrillation. Ó 2013 by National Stroke Association

From the *Department of Neurology, Albany Medical College, Albany, New York; †Department of Neurology, Johannes Wesling Klinikum Minden, Minden, Germany; ‡Department of Neurology, University of Louisville, Louisville, Kentucky; xDepartments of Neurosurgery and Radiology and Public Health Sciences, Penn State Hershey Medical Center, Hershey, Pennsylvania; kDepartment of Medicine, University of Alberta, Edmonton, Canada; {Laboratory for Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; **Department of Neurology, University of South Carolina School of Medicine, Columbia, South Carolina; ††Department of Neurology, University Hospital Essen, University Duisburg-Essen, Essen, Germany; ‡‡Department of Neurosurgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and xxDepartment of Neurology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Received September 3, 2013; revision received November 20, 2013; accepted December 4, 2013. Disclosures: The SENTIS trial was sponsored by CoAxia, Inc., Maple Grove, MN. All participating sites received clinical study payments based on the number of patients enrolled in the SENTIS trial. G.L.B., R.R.L., A.A., K.C., A.S., R.S., and H.C.D. have no disclosures. S.S. received consulting fees from CoAxia, Inc. P.D.S. received consulting fees/honorarium from CoAxia, Inc. N.M.B. received consultation fees from CoAxia, Inc. Address correspondence to Gary L. Bernardini, MD, PhD, Department of Neurology, Albany Medical Center, 47 New Scotland Avenue, MC-70, Albany, NY 12208. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.006

Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2013: pp 1-5

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Introduction Atrial fibrillation (AF) affects over 2.3 million people in the United States and is an independent risk factor for ischemic stroke.1 Furthermore, it is associated with hypertension, older age, and more severe strokes.2,3 Patients with acute ischemic stroke (AIS) because of AF have poorer prognosis, increased in-hospital medical and neurologic complications, and higher rates of mortality (particularly in those older than 75 years) than patients without AF.2 Unfortunately, acute stroke treatment is limited in AF patients on anticoagulation therapy because of contraindication for thrombolytic therapy; even in those who receive intravenous thrombolytic therapy, outcomes are worse.4 The recently published Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke (SENTIS) trial5 evaluated cerebral blood flow augmentation using the NeuroFlo catheter (CoAxia, Maple Grove, MN) in the treatment of AIS. We performed post hoc analysis on acute treatment effects of NeuroFlo in a subset of SENTIS patients with AF to determine whether outcomes were significantly improved compared with nontreated patients with AF.

Materials and Methods The SENTIS trial5 was an international, prospective, randomized controlled trial. The objective of the trial was to determine the safety and efficacy of NeuroFlo treatment in improving neurologic outcome in AIS. The trial was approved by the Institutional Review Board or Ethics Committee at each participating center. Written informed consent was obtained for all patients. See the previously published report on SENTIS study design and enrollment.5 The primary efficacy end point in SENTIS was the National Institute of Neurological Disorders and Stroke (NINDS) Global score, comprising the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Barthel Index, and Glasgow Outcome Scale scores. A history of AF was documented for 115 (22%) of the total 515 patients in SENTIS. In addition, a number of study patients (n 5 28) had a new diagnosis of AF within 30 days of trial enrollment. The majority (23 of 28) of these patients had diagnosis of AF within 4 days of admission. This resulted in a total cohort of 143 AF patients (Table 1).

Statistical Analysis Baseline and medical history data were summarized for NeuroFlo-treated and nontreated subjects within the AF group. Categorical variables were summarized using counts and percentages. Statistical comparisons of baseline demographics between groups were made using 2sample Wilcoxon tests (continuous variables) and Fisher exact tests (categorical variables). For the AF subgroup in SENTIS, we evaluated differences in efficacy and safety end points between NeuroFlo-treated patients with AF

and nontreated patients with AF. The global efficacy end point, described in SENTIS,5 was compared within the AF subgroup using repeated measures logistic regression. Dichotomized mRS (score 0-2 versus 3-6) and strokerelated mortality were evaluated using logistic regression measuring the odds of a better outcome. Logistic regression models were fit with covariate adjustment for age and stroke severity (NIHSS). The global end point was also assessed by a model with covariate adjustment for age, stroke severity, glucose at stroke presentation, history of hypertension, and gender. Dichotomized mRS was also assessed by models with covariate adjustments for age, baseline NIHSS, gender, time from symptom onset, and smoking status. The proportion of subjects experiencing serious adverse events was compared using a Cochran– Mantel–Haenszel test, stratified by baseline stroke severity (NIHSS) and age. In addition, among the patients with AF, the global efficacy end point and mRS score 0-2 end point were compared between treatment groups for varying age categorizations ($60, $70, and $80 years). Formal clinical evaluations were timed from pretreatment NIHSS examinations during hospitalization up to 90 days follow-up in final blinded assessment.

Results In this analysis from SENTIS trial, 56 treated and 87 nontreated patients had AF. Demographics, baseline characteristics, and medical history are listed in Table 1. There were no significant differences in demographic or baseline characteristics nor serious adverse events between groups. NeuroFlo-treated patients with AF had significant improvement in global efficacy end point (odds ratio [OR], 2.48; confidence interval [CI], 1.09-5.62; P 5 .030), good functional outcome with mRS dichotomized score 02 versus 3-6 (OR, 2.93; CI, 1.12-7.67; P 5 .029), and strokerelated mortality (OR, 3.80; CI 1.29-11.20; P 5 .015) compared with nontreated patients with AF. Results of logistic regression models are shown in Table 2. There was also significant improvement in outcomes by age in NeuroFlo-treated (versus nontreated) AF patients with AIS: global end point for age 60 years or older (total group n 5 132; 52 treated; 80 nontreated; OR, 2.31; CI, 1.03-5.18; P 5 .042) and 80 years or older (total group n 5 59; 28 treated; 31 nontreated; OR, 4.73; CI, 1.3216.91, P 5 .017), with a trend toward improvement for age 70 years or older (total group n 5 113; 48 treated; 65 nontreated; OR, 2.46; CI, .98-6.19; P 5 .055), and good outcome of mRS score 0-2 (versus 3-6) for age 60 years or older (OR, 2.95; CI, 1.06-8.19, P 5.038), 70 years or older (OR, 3.84; CI, 1.22-12.15; P 5 .022), and 80 years or older (OR, 14.51; CI, 1.98-106.15; P 5 .008) compared with nontreated patients with AF. There was significant reduction in stroke-related mortality for age 60 years or older (OR, 5.04; CI, 1.55-16.40; P 5 .007), 70 years or older (OR,

EFFICACY OF NEUROFLO IN AF PATIENTS

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Table 1. Demographics and baseline characteristics History or new diagnosis of AF

Demographics Age (y) Mean 6 SD Median Range Gender, male % (n) Stroke symptoms Time from symptom onset to randomization (h) Mean 6 SD Median Range Baseline NIHSS Mean 6 SD Median Range Glucose (mg/dL) Mean 6 SD Median Range General medical history Diabetes mellitus, % (n) Hypertension, % (n) Hyperlipidemia, % (n) Current smoker, % (n) Neurologic history Cerebral ischemic infarct (stroke), % (n) TIA, % (n) Cardiovascular history CABG, % (n) MI, % (n)

Treated (n 5 56)

Nontreated (n 5 87)

P value

77.5 6 9.2 80.0 48.7-93.4

75.7 6 9.4 77.6 47.6-92.9

.1576

32.1% (18)

40.2% (35)

.3774

7.5 6 2.8 7.2 2.5-13.7

8.0 6 2.8 7.6 3.3-15.6

12.3 6 4.1 13.0 5.0-19.0

11.4 6 4.6 12.0 3.0-20.0

.2602

136.2 6 56.6 120.0 82.0-426.0

130.5 6 41.6 121.0 79.0-370.0

.9600

26.8% (15) 85.7% (48) 57.1% (32) 8.9% (5)

25.3% (22) 83.9% (73) 54.0% (47) 12.6% (11)

.8473 .8170 .7337 .5930

14.3% (8) 10.7% (6)

19.5% (17) 13.8% (12)

.5023 .7969

14.3% (8) 14.3% (8)

9.2% (8) 17.2% (15)

.4181 .8161

.3358

Abbreviations: AF, atrial fibrillation; CABG, coronary artery bypass graft; MI, myocardial infarction; NIHSS, National Institutes of Health Stroke Scale; TIA, transient ischemic attack.

4.83; CI, 1.48-15.76:P 5 .009), and 80 years or older (OR, 5.97; CI, 1.36-26.21; P 5 .018) in treated patients. Baseline median NIHSS scores for AF versus non-AF patients in SENTIS reflected an increase in severity of stroke (NIHSS: 12.0 6 4.4 versus 10.0 6 4.2, respectively; P 5 .006). Stroke patients with AF in SENTIS were greater in age compared with patients without AF (mean age: 76.3 6 9.4 [SD] versus 64.6 6 14.3 years, respectively; P , .0001).

Discussion The SENTIS trial is the first randomized trial evaluating an interventional device to treat ischemic stroke with longterm neurologic end points.5 Patients with a history or new diagnosis of AF treated with NeuroFlo in SENTIS had significant improvement in the primary end point of global outcome and in the secondary end points of good outcome

of mRS (score 0-2 versus 3-6) and stroke-related mortality compared with nontreated patients with AF. There was significant improvement in stroke-related mortality and those achieving mRS score 0-2 (versus 3-6) in treated patients with AF age 60 years or older, 70 years or older, and 80 years or older. There were no significant differences in serious adverse events between the groups. Strokes from AF are embolic and tend to involve large vessels, resulting in higher initial NIHSS scores, larger infarct volumes, double mortality rates, and increased disability compared with strokes in patients without AF.2,3,6,7 The baseline median NIHSS scores in the SENTIS trial reflected this increase in severity for AF versus non-AF patients. Stroke patients with AF in SENTIS were older than patients without AF, consistent with increased prevalence of AF with advancing age.7 The mainstay of AIS treatment remains intravenous recombinant tissue plasminogen activator given up to

G.L. BERNARDINI ET AL.

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Table 2. Efficacy results History or new diagnosis of AF

Global end point mRS score 0-2 Stroke-related mortality

Base model OR (95% CI),* P value

Multivariate analysis OR (95% CI)yz P value

2.48 (1.09-5.62), P 5 .030 2.93 (1.12-7.67), P 5 .029 3.80 (1.29-11.20), P 5 .015

2.26 (1.03-4.93) P 5 .037 3.03 (1.11-8.31) P 5 .031 N/A

Abbreviations: AF, atrial fibrillation; CI, confidence interval; mRS, modified Rankin Scale; N/A, not applicable; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio (for treated versus nontreated). *Logistic regression models adjusted by age and baseline NIHSS. yRepeated logistic regression model for global endpoint adjusted by age, baseline NIHSS, glucose, history of hypertension, and gender. zLogistic regression model for mRS score 0-2 adjusted by age, baseline NIHSS, gender, time from symptom onset, and smoking status.

4.5 hours after symptom onset in those who qualify.8 Treatment may be limited in AF stroke patients because of concomitant anticoagulation therapy. In addition, stroke patients with AF may have poorer outcomes even after thrombolysis compared with treated patients without AF because of increased risk of symptomatic intracerebral hemorrhage or failure to recanalize after intravenous recombinant tissue plasminogen activator.4 In contrast, stroke patients with AF treated with NeuroFlo had significant improvement in global outcomes, dichotomized mRS, and mortality compared with those without treatment. Even patients in older age groups with AIS and AF who were treated with NeuroFlo had significantly higher chances for survival and obtaining independent functional state (mRS score 0-2). This finding parallels that seen in the SENTIS-treated cohort of older patients.9 The presence of leptomeningeal collaterals on neuroimaging may be a strong predictor of long-term functional outcome with large vessel intracranial occlusion10 and can significantly reduce infarct size and improve clinical outcomes.11 The mechanism of action of NeuroFlo is not entirely understood. Aortic balloon deployment results in immediate blood volume increases distal to occlusion, increases in cerebral blood flow and volume, and persistent effects after treatment.12,13 We postulate that the observed good outcomes with NeuroFlo in stroke patients with AF may be due in part to collateral recruitment. The presence of collaterals, particularly in a setting of adequate cerebral perfusion pressure and intact circle of Willis, increases the potential for good outcome after AIS.14 The benefit seen in older patients may be because of recruitment and support of already existing collaterals that might not ordinarily be recruited without the help of this device. This study has limitations. It is a post hoc analysis without prespecified end points, and numbers of patients in each group are relatively small. Also, the different age groups overlap, with subgroups becoming successively smaller and, thus, are not independent samples. Nevertheless, the data were gathered prospectively in a

randomized fashion and, therefore, should serve as hypothesis generating for future trials.

Conclusions The current analysis of data from the SENTIS trial shows that therapy with the NeuroFlo device may lower stroke burden in patients with AF who are otherwise more likely to have poorer outcomes and higher mortality rates. For many anticoagulated patients with AF and AIS, NeuroFlo may represent a valid therapeutic option. These observations should be confirmed in future trials with the device.

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EFFICACY OF NEUROFLO IN AF PATIENTS 8. Hacke W, Kaste M, Bluhmki E, et al, for ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-1329. 9. Leker RR, Molina C, Cockroft K, et al. Effects of age on outcome in the SENTIS trial: better outcomes in elderly patients. Cerebrovasc Dis 2012;34:263-271. 10. Lima FO, Furie KL, Silva GS, et al. The pattern of leptomeningeal collaterals on CT angiography is a strong predictor of long-term functional outcome in stroke patients with large vessel intracranial occlusion. Stroke 2010; 41:2316-2322. 11. Ringelstein EB, Biniek R, Weiller C, et al. Type and extent of hemispheric brain infarctions and clinical outcome in

5 early and delayed middle cerebral artery recanalization. Neurology 1992;42:289-298. 12. Hammer M, Jovin T, Wahr JA, et al. Partial occlusion of the descending aorta increases cerebral blood flow in a nonstroke porcine model. Cerebrovasc Dis 2009;28:406-410. 13. Nussbaum ES, Sebring LA, Ganz WF, et al. Intra-aortic balloon counterpulsation augments cerebral blood flow in the patient with cerebral vasospasm: a xenonenhanced computerized tomographic study. Neurosurgery 1998;42:206-214. 14. Liebeskind DS. Reperfusion for acute ischemic stroke: arterial revascularization and collateral therapeutics. Curr Opin Neurol 2010;23:36-45.