ORIGINAL ARTICLE

Ischemic Conditioning Is Safe and Effective for Octo-and Nonagenarians in Stroke Prevention and Treatment

Ran Meng1 & Yuchuan Ding2 & Karam Asmaro2 & David Brogan2 & Lu Meng3 &Meng Sui4 & Jingfei Shi1 & Yunxia Duan1 & Zhishan Sun1 & Yang Yu1,5 & Jianping Jia1 &Xunming Ji1

Published online: 9 May 2015# The American Society for Experimental NeuroTherapeutics, Inc. 2015

Abstract Symptomatic intracranial arterial stenosis (SIAS) isvery common in octo- and nonagenarians, especially in theChinese population, and is likely the most common cause ofstroke recurrence worldwide. Clinical trials demonstrate thatendovascular treatment, such as stenting, may not be suitablefor octogenarians with systemic diseases. Hence, less invasivemethods for the octogenarian patients are urgently needed.Our previous study (unique identifier: NCT01321749)showed that repetitive bilateral arm ischemic preconditioning(BAIPC) reduced the incidence of stroke recurrence by im-proving cerebral perfusion (confirmed by single photon emis-sion computed tomography and transcranial Doppler sonog-raphy) in patients younger than 80 years of age; however, thesafety and effectiveness of BAIPC on stroke prevention inocto- and nonagenarians with SIAS are still unclear. The

objective of this study was to evaluate the safety and effec-tiveness of BAIPC in reducing stroke recurrence in octo- andnonagenarian patients with SIAS. Fifty-eight patients withSIAS were enrolled in this randomized controlled prospectivestudy for 180 consecutive days. All patients enrolled in thestudy received standard medical management. Patients in theBAIPC group (n=30) underwent 5 cycles consisting of bilat-eral arm ischemia followed by reperfusion for 5 min eachtwice daily. Those in the control group (n=28) underwentsham-BAIPC twice daily. Blood pressure, heart rate, localskin status, plasma myoglobin, and plasma levels of throm-botic and inflammatory markers were documented in bothgroups before beginning the study and for the first 30 days.Finally, the incidences of stroke recurrence and magnetic res-onance imaging during the 180 days of treatment were com-pared. Compared with the control, BAIPC had no adverseeffects on blood pressure, heart rate, local skin integrity, orplasma myoglobin, and did not induce cerebral hemorrhagein the studied cohort. BAIPC reduced plasma high sensitiveC-reactive protein, interleukin-6, plasminogen activator inhib-itor-1, leukocyte count, and platelet aggregation rate and ele-vated plasma tissue plasminogen activator (all p

Introduction

Symptomatic intracranial atherosclerotic stenosis (IAS) is oneof the leading causes of ischemic stroke in China [1], and isassociated with a high risk of stroke recurrence secondary toartery-to-artery embolism, hemodynamic failure, or occlusionof the involved vasculature [1, 2]. The risk of stroke recur-rence depends on the severity of the IAS. Patients with≥70 %luminal narrowing have a 35% risk of stroke recurrence in thefirst year; this risk decreases to 18 % with antithrombotictherapy [3]. Current therapy available to patients with symp-tomatic IAS includes medication with or withoutendovascular intervention [4]. However, recent findings fromthe SAMMPRIS (Stenting and Aggressive MedicalManagement for Preventing Recurrent Stroke in IntracranialStenosis) clinical trial showed a higher risk of early strokerecurrence after stenting compared with aggressive medicalmanagement (14.7 % vs 5.8 %) [5]. Although effective, ag-gressive medical management does not completely preventstroke recurrence [6]. In the WASID (Warfarin-AspirinSymptomatic Intracranial Disease) trial, Kasner et al. [6] re-ported that 19 % of patients presented with recurrent stroke inthe same cerebral hemisphere; additionally, most presentedwithin the first year. Furthermore, the efficacy of stenting forsymptomatic IAS remains to be fully evaluated, especially inocto- and nonagenarians, as clinical trials demonstrate thatoctogenarians may have a greater number of periproceduralevents than nonoctogenarians. One study utilizing follow-upangiography suggested that, with≥50 % stenosis, octogenar-ians assume a 3-fold higher risk of periprocedural death and/orstroke recurrence compared with non-octogenarians [7].Hence, more suitable, less invasive treatment methods forthe octogenarian patient population are urgently needed.

In the early 1990s, Przyklenk et al. [8] proposed the con-cept of remote ischemic preconditioning. In their study, briefischemia of the remote circumflex artery provided protectionto ischemic myocardium from subsequent sustained left ante-rior descending artery occlusion. Emerging clinical trials havecorroborated the previous research, suggesting that remotepreconditioning may indeed protect the heart [9–11]. In addi-tion, recent findings in experimental animal models and clin-ical studies suggest that remote ischemic preconditioning mayalso be beneficial to the brain without exacerbating intracere-bral hemorrhage [12–19].

Our previous study (unique identifier: NCT01321749)showed that repetitive bilateral arm ischemic precondi-tioning (BAIPC) reduced the incidence of stroke recur-rence by improving cerebral perfusion (confirmed by sin-gle photon emission computed tomography and transcra-nial Doppler sonography) [18]. We demonstrated a signif-icant reduction in the incidence of recurrent strokes atboth 90 days (5 % vs 23.3 %) and 300 days (7.9 % vs26.7 %) in the BAIPC group when compared with the

control. However, our cohort was limited to a patientpopulation younger than 81 years of age. In this study,we test the safety and efficacy of BAIPC in octo- andnonagenarians with symptomatic IAS.

Materials and Methods

Patient Selection and Study Design

Patients that presented within 7 days of an ischemic stroke ortransient ischemic attack (TIA) were enrolled and randomizedif their neurologic symptoms and signs corresponded with theterritory of the diseased vessel shown by magnetic resonanceimaging (MRI), diffusion weighted imaging (DWI), magneticresonance angiography (MRA), or computed tomographic an-giography (CTA) [19, 20].

The criterion for IAS is similar to that of carotid arterystenosis, and is detailed as intracranial arterial stenosis ofat least 70 % by MRA or CTA [21]. The degree of arterialstenosis was based on the MRA or CTA imaging [22, 23]and calculated as 1 (the inside diameter of the blood ves-sel at the point of greatest stenosis/inside diameter of thenormal blood vessel at the distal end). Additional inclu-sion criteria included 1) age 80–95 years; 2) TOAST(Trial of Org 10172 in Acute Stroke Treatment) subtype1 of stroke (a stroke caused by IAS) [24, 25]; 3) NationalInstitutes of Health Stroke Scale (NIHSS) score of 0–15,and modified Rankin Scale (mRS) score of 2–4; 4)ABCD2 score of 6–7 [20]; 5) stable vital signs, and nor-mal hepatic and renal function; 6) no hemorrhagictendency.

Exclusion criteria included 1) extracranial arterial stenosisor extracranial in combination with intracranial arterial steno-sis; 2) recent (within 72 h) intra-arterial or intravenous throm-bolysis; 3) intracranial hemorrhage; 4) any soft tissue, ortho-pedic, or vascular injury, and any disease of the extremitiesthat may contraindicate remote preconditioning; 5) acutemyocardial infarction; 6) systolic blood pressure >200 mmHg with medication; 7) hematologic disease; 8) se-vere hepatic or renal dysfunction; 9) mRS score of 0–1; 10)severe or unstable concomitant diseases; 11) no informed con-sent; 12) failure to complete the entire treatment regimen.

The study design is summarized in Fig. 1.

Approvals and Patient Consent

All study protocols were approved by the local research ethicscommittee at the Capital Medical University. All participants(or their guardians) signed informed consent prior toenrollment.

668 Meng et al.

Registrations

This study was registered with the Clinical Trial Registration(http://www.clinicaltrials.gov) in 2012 (unique identifier:NCT01570231). The study was conducted from 2008 to2010 at Xuanwu Hospital.

Procedures

All patients received standard medical care (including eitherclopidogrel 75 mg/day in combination with atorvastatin20 mg/day or aspirin 100 mg/day and clopidogrel 75 mg/dayin combination with atorvastatin 20 mg/day). In addition, pa-tients in the BAIPC group (n=30) underwent BAIPC treat-ment twice daily for 180 consecutive days. The BAIPC pro-cedures were initiated after excluding the presence of unstableplaques and intravascular thrombosis in the upper extremitiesusing a vascular ultrasound. The BAIPC treatment consistedof 5 cycles of simultaneous bilateral upper arm ischemia for5 min followed by reperfusion for another 5 min, performedtwice daily for 180 consecutive days. The BAIPC procedurewas performed using an electric autocontrol device with cuffsthat inflated to a pressure of 200 mmHg during the ischemicperiod (patent number ZL200820123637.X, China) [18, 26].At the end of the BAIPC treatment, all devices were donatedto the patients enrolled. The process was performed with thehelp of a nurse in the hospital or a family member at home.The device recorded and documented each BAIPC cycle, aswell as the patient’s heart rate and blood pressure in real time.The BAIPC process could also be stopped at any time if thepatient experienced discomfort. Control participants (n=28)underwent a sham BAIPC procedure during which bilateralupper arm cuffs were inflated to a pressure of 30 mmHg for5 min, followed by 5 min of relaxation of the cuffs, for a total

of 5 cycles twice daily for 180 consecutive days [18, 26].Aside from the preset cuff pressure during ischemia, theBAIPC and shamBAIPC devices were similar in both appear-ance and function. The heart rate and blood pressure of eachpatient before and after BAIPC or sham BAIPC were com-pared daily for the first 30 days of treatment.

Blood samples were collected before the treatment began(day 0) to establish a baseline, and 1 h after the second BAIPCor sham BAIPC treatment on days 1, 15, and 30. The sampleswere analyzed using the immunoturbidimetry assay in a co-agulation autoanalyzer (ACL2000; InstrumentationLaboratory, Milan, Italy). Those who examined the sampleswere blinded to the sample group. Plasma levels of highlysensitive C-reactive protein (hsCRP), leukocyte count, fibrin-ogen, D-dimer, plasminogen activator inhibitor (PAI)-1, tissueplasminogen activator (TPA), and platelet aggregation rateswere assayed and compared between both groups.

Randomization and Masking

We used a computer-generated blocked randomization tech-nique; the allocation sequence was computer generated andsubsequently concealed in consecutively numbered, opaque,sealed envelopes. The trial coordinator randomized the partic-ipants to treatment groups after assessment; a total of 58 octo-and nonagenarians with symptomatic IAS were randomizedinto 2 groups in a 1:1 ratio.

While there was a profound difference between the pres-sure point used in the BAIPC group and that used in controlgroup (200 vs 30 mmHg), patients were not made aware ofeither the exact values or what it took to obtain an optimalischemic event. However, owing to the nature of ischemicpreconditioning, it was not possible to completely blind thepatients by providing the same pressures between bothgroups. The research assistants responsible for local skin sta-tus evaluations, blood pressure measurements, heart rate mea-surements, plasma sample assays, and neuroradiology inter-pretation were blinded to the treatment groups.

Patient Compliance Assurance

All patients who underwent BAIPC and sham BAIPC treat-ment demonstrated compliance during their hospital stay.Compliance following hospital discharge was confirmed bythe automated real-time recording of the BAIPC device.Patients were required to show the recorded list (print out fromthe device) at the time of follow-up.

Safety Monitoring End Points

The following were defined as primary safety end points [26]:1) Objective signs of tissue or neurovascular injury resultingfrom BAIPC treatment—inspection by observers blinded to

Fig. 1 Schematic diagram of the clinical trial profile. BAIPC=bilateralarm ischemic preconditioning

Ischemic Conditioning is Safe and Effective in Stroke Treatment 669

http://www.clinicaltrials.gov/

the study protocol included palpation of distal radial pulses,visual inspection for local edema, erythema, and/or skin le-sions, and palpation for tenderness; 2) development of symp-tomatic or asymptomatic upper extremity deep vein thrombo-sis as detected by a vascular ultrasound; 3) elevation of plasmamyoglobin levels beyond normal limits after BAIPC treat-ment; 4) symptomatic hemorrhagic transformation after cere-bral infarction; 5) patients not tolerating BAIPC treatment.Any suspicious BAIPC or sham BAIPC treatment relatedevents were to be reported to the investigators by the observerswho were blinded to the study protocol.

Clinical Outcome Evaluation End Points

Stroke and TIA recurrence during the 180 consecutive days oftreatment were defined as primary outcome end points. Strokerecurrence was defined as sudden functional deterioration inneurologic status with a decrease of 4 or more in the NIHSS,or a new stroke lesion on MRI/DWI located at the territory ofthe affected intracranial arteries [27]. Local symptoms andsigns corresponding with the territory of the affected intracra-nial arteries that reappeared and lasted

Table 1 Patient characteristicsVariable BAIPC (n=30) Control (n=28)

Age (mean±SD) 83.5±2.3 84.2±1.6

Sex (male/female) 18/12 17/11

Nationality 27 Han/3 Hui 24 Han/4 Hui

Time from stroke onset to day of enrollment (day±SD) 4.5+1.5 4.7±1.2

Diabetes 13 (43.3) 11 (39.2)

Hypertension 20 (66.7) 18 (64.3)

Smoking 2 (6.7) 3 (10.7)

Hyperlipidemia 22 (73.3) 20 (71.4)

Stenosis+TIA 10 (33.3) 9 (32.1)

Stenosis+stroke 11 (36.7) 10 (35.7)

Stenosis+stroke+TIA 5 (16.7) 6 (21.4)

Intracranial stenosis (%) 71.7±4.8 70.3±5.9

Abnormally elevated cholesterol 23 (76.7) 22 (78.6)

Abnormally elevated TRIG 21 (70.0) 20 (71.4)

Abnormally elevated LDL 26 (86.7) 24 (85.7)

Abnormally elevated fibrinogen 24 (80.0) 22 (78.6)

Abnormally elevated D-dimer 4 (13.3) 3 (10.7)

Abnormally elevated hsCRP 11 (36.7) 9 (32.1)

NIHSS (score±SD) 11.3±2.3 11.1±2.6

mRS (score±SD) 3.4±0.6 3.5±0.5

Locations of stenosis

Right ICA 6 (20.0) 5 (17.9)

Left ICA 4 (13.3) 5 (17.9)

Right MCA 5 (16.7) 5 (17.9)

Left MCA 5 (16.7) 4 (14.3)

BA 2 (6.7) 2 (7.1)

Multifocal stenosis 8 (26.6) 7 (25.0)

ACE inhibitors 2 (6.7) 3 (10.7)

ARBs 3 (10.0) 2 (7.1)

ARBs+CCBs 11 (36.7) 10 (35.7)

CCBs 4 (13.3) 3 (10.7)

Antidiabetic oral therapy 9 (30.0) 8 (28.6)

Antidiabetic insulin therapy 4 (13.3) 3 (10.7)

Anticoagulation and statin therapy before enrollment

Aspirin 11 (36.7) 12 (42.9)

Clopidogrel 1 (3.3) 2 (7.1)

Aspirin+clopidogrel 0 0

Warfarin 1 (3.3) 1 (3.6)

Statins 2 (6.7) 3 (10.7)

Anticoagulation and statin therapy after enrollment

Clopidogrel 75 mg/d+statin 20 mg/d 27 (90.0) 24 (85.7)

Aspirin 100 mg+clopidogrel 75 mg/d+statin 20 mg/d 3 (10) 4 (14.3)

Warfarin 0 0

Values are given as n (%) unless otherwise indicated. There were no significant differences between the bilateralarm ischemic preconditioning (BAIPC) and control (sham BAIPC) groups (all p >0.05). TIA=transient ischemicattack; TRIG=trigylcerides; LDL=low-density lipoprotein; hsCRP=highly sensitive C-reactive protein; NIHSS=National Institutes of Health Stroke Scale; mRS=modified Rankin Scale; ICA=internal cervical artery (in-tracranial section); MCA=middle cerebral artery; BA=basilar artery; ACE=angiotensin-converting enzyme;ARB=angiotensin receptor blocker; CCBs=calcium channel blocker

Ischemic Conditioning is Safe and Effective in Stroke Treatment 671

Safety Monitoring Results

Blood Pressure and Heart Rate

To assess the effects of BAIPC on the cardiovascular system,blood pressure and heart rate were measured immediately be-fore and 1 h after BAIPC and sham BAIPC treatment for thefirst 30 days of the study. No statistical differences in bloodpressure or heart rate were observed between the BAIPC andthe control sham BAIPC group before or after treatment(Fig. 2A–D). Furthermore, no statistical difference was ob-served before or after treatment between the individual groups(BAIPC or the control).

Local Skin and Muscle

As the BAIPC method involved repeated episodes of brieflimb ischemia, potential adverse effects on local skin andmuscle integrity were assessed. Transient sporadic petechiaeswere observed in 3 cases during the first 30 days of the study,but disappeared soon after without discontinuing BAIPCtreatment. No ecchymosis, tenderness to palpation, edema,skin breakage, or other skin lesions were observed. No deepvein thromboses were detected by vascular sonography duringor at the end of the 180 days of BAIPC. The average plasma

level of myoglobin was 70.2±6.5 μg/l at baseline, 69.3±5.5 μg/l on day 1, 70.4±4.1 μg/l on day 15, and 69.9±5.7 μg/l on day 30 of BAIPC (F=0.147, p=0.93).

Clinical Outcome Evaluation

Inflammation

Plasma levels of hsCRP, interleukin (IL)-6, leukocyte count,and platelet aggregation rates were quantified at baseline andat days 1, 15, and 30 following the daily treatment in bothBAIPC and control groups (Fig. 3A, B).

Plasma levels of hsCRP and IL-6, as well as plateletaggregation rates, improved significantly at days 15 and30 in both the BAIPC and sham BAIPC groups whencompared with day 0 (1-way ANOVA test, p

30; p

Coagulation and Fibrinolysis

Plasma levels of fibrinogen, D-dimer, TPA, and PAI-1 werequantified and monitored at days 0, 1, 15, and 30. We ob-served statistically significant differences in the levels of fi-brinogen and PAI-1 after 15 and 30 days of treatment in theBAIPC group (one-way ANOVA test, p

Ischemic Conditioning is Safe and Effective in Stroke Treatment 675

octo- and nonagenarians with symptomatic IAS remained un-clear. This study attempted to assess the BAIPC therapeuticapproach amongst an older patient population.

Our preliminary findings in octo- and nonagenarians withsymptomatic IAS undergoing BAIPC treatment are promising.There were no adverse effects of BAIPC on heart rate, bloodpressure, or local tissue during the study. Meanwhile, BAIPCtreatment improved clinical outcomes by decreasing the inci-dences of stroke and TIA recurrence. Our plasma biomarkersresults further suggest that the underlying mechanisms ofBAIPC may involve the amelioration of inflammatory path-ways, increasing endogenous fibrinolytic activity, and reducingendogenous coagulation activity and platelet aggregation.

However, perhaps most promising is that the IAS can bedetected by MRA/CTA and transcranial Doppler vascular ul-trasound at a common physical examination before strokeonset. Therefore, BAIPC has great potential in clinical appli-cation not only to treat, but also to prevent stroke occurrenceor recurrence in a cohort of elderly patients with IAS.

Despite the several points mentioned alluding to the safety,efficacy, and potential of BAIPC in octo- and nonagenarianswith symptomatic IAS, several points require further study.First, we do not know whether the timing and dosing of ourBAIPC therapy are truly optimal. Previous studies suggestthat preconditioning yields two protective windows: an acutewindow that is induced within hours, and a delayed windowthat may last from 1 to 7 days following treatment [32, 37, 38].The duration of our BAIPC treatments span a much longerperiod. Our prolonged approach may be consistent with stud-ies suggesting that long-term (weeks or years) protection maybe achieved by repeated doses of preconditioning [11, 39, 40].Future studies should examine different protocols to find theoptimal treatment timing and doses. Another potential limita-tion involves the exact mechanism of protection. Consistentwith data from experimental models, we were able to detectbeneficial effects in terms of inflammatory and coagulationbiomarkers. However, we recognize that our measurementsare only correlational, as our study was not designed to provecausality. Finally, our case numbers are modest in this prelim-inary study. More powerful studies with larger patient num-bers will be required to confirm and validate our BAIPC ther-apeutic approach fully.

The beneficial effects of BAIPC on the brain have mostlybeen studied in animal models [34, 41–43]. To our knowl-edge, this is the first translational study that attempts to applyexperimental data to the clinical setting in a cohort of octo-and nonagenarians with symptomatic IAS who are not candi-dates for other therapies. In conclusion, this study suggeststhat remote ischemic preconditioning may be a simple, non-invasive, and well-tolerated method not only to treat, but alsoto prevent stroke occurrence and recurrence in elderly patientswith symptomatic IAS. Further investigations to develop thispromising stroke therapy are ongoing.

Acknowledgments We thank Professor Xiaoying Wang for helpingrevise the manuscript.

Required Author Forms Disclosure forms provided by the authors areavailable with the online version of this article.

Conflict of Interest RM, YD, KA, DB, LM, JS, YD, ZS, BW, and JJreport no disclosures or conflict of interest. XJ is one of the inventors ofthe electric auto-control device which has been is patented in china(ZL200820123637.X).

Funding Sources This study was sponsored by the National NaturalScience Foundation (81371289), China, The Foundation of the BeijingHigh Level Health Systems (Talented Technical Personnel Program2009-03-02), China; and The National Key Department of Neurologyfunded by Chinese Health and Family Planning Committee

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Ischemic Conditioning is Safe and Effective in Stroke Treatment 677

Ischemic Conditioning Is Safe and Effective for Octo- and Nonagenarians in Stroke Prevention and TreatmentAbstractIntroductionMaterials and MethodsPatient Selection and Study DesignApprovals and Patient ConsentRegistrationsProceduresRandomization and MaskingPatient Compliance AssuranceSafety Monitoring End PointsClinical Outcome Evaluation End PointsBlood Evaluation End PointsStatistics

ResultsPatient CharacteristicsPatient Compliance with the Study ProtocolSafety Monitoring ResultsBlood Pressure and Heart RateLocal Skin and Muscle

Clinical Outcome EvaluationInflammationCoagulation and FibrinolysisClinical Outcome

DiscussionReferences