Safety and Efficacy of Remote Ischemic Preconditioning in Patients With Severe Carotid Artery Stenosis Before Carotid Artery Stenting: A Proof-of-Concept, Randomized Controlled Trial.
BACKGROUND
Remote ischemic preconditioning (RIPC) can inhibit recurrent ischemic events effectively in patients with acute or chronic cerebral ischemia. However, it is still unclear whether RIPC can impede ischemic injury after carotid artery stenting (CAS) in patients with severe carotid artery stenosis.


METHODS
Subjects with severe carotid artery stenosis were recruited in this randomized controlled study, and assigned to RIPC, sham, and no intervention (control) groups. All subjects received standard medical therapy. Subjects in the RIPC and sham groups underwent RIPC and sham RIPC twice daily, respectively, for 2 weeks before CAS. Plasma neuron-specific enolase and S-100B were used to evaluate safety, hypersensitive C-reactive protein, and new ischemic diffusion-weighted imaging lesions were used to determine treatment efficacy. The primary outcomes were the presence of ≥1 newly ischemic brain lesions on diffusion-weighted imaging within 48 hours after stenting and clinical events within 6 months after stenting.


RESULTS
We randomly assigned 189 subjects in this study (63 subjects in each group). Both RIPC and sham RIPC procedures were well tolerated and completed with high compliance (98.41% and 95.24%, respectively). Neither plasma neuron-specific enolase levels nor S-100B levels changed significantly before and after treatment. No severe adverse event was attributed to RIPC and sham RIPC procedures. The incidence of new diffusion-weighted imaging lesions in the RIPC group (15.87%) was significantly lower than in the sham group (36.51%; relative risk, 0.44; 96% confidence interval, 0.20-0.91;P<0.01) and the control group (41.27%; relative risk, 0.39; 96% confidence interval, 0.21-0.82;P<0.01). The volumes of lesions were smaller in the RIPC group than in the control and sham groups (P<0.01 each). Ischemic events that occurred after CAS were 1 transient ischemic attack in the RIPC group, 2 strokes in the control group, and 2 strokes and 1 transient ischemic attack in the sham group, but these results were not significantly different among the 3 groups (P=0.597).


CONCLUSIONS
RIPC is safe in patients undergoing CAS, which may be able to decrease ischemic brain injury secondary to CAS. However, the mechanisms and effects of RIPC on clinical outcomes in this cohort of patients need further investigation.


BACKGROUND
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01654666.
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Wenbo
W
Zhao
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Ran
R
Meng
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Chun
C
Ma
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Baojun
B
Hou
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Liqun
L
Jiao
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Fengshui
F
Zhu
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Weijuan
W
Wu
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Jingfei
J
Shi
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Yunxia
Y
Duan
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Renling
R
Zhang
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Jing
J
Zhang
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Yongxin
Y
Sun
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Hongqi
H
Zhang
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Feng
F
Ling
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Yuping
Y
Wang
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Wuwei
W
Feng
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Yuchuan
Y
Ding
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.).
Bruce
B
Ovbiagele
From Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China (W.Z., R.M., W.W., J.Z., Y.S., Y.W.); Department of Surgical Intensive Care Unit, Beijing Anzhen Hospital, Capital Medical University, China (C.M.); Department of Intensive Care Unit, Shanxian Central Hospital, Heze, China (B.H.); Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China (L.J., F.Z., H.Z., F.L., X.J.); China-America Joint Institution of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China (J.S., Y.D.); Department of Nuclear Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China (R.Z.); Department of Neurology, Medical University of South Carolina, Charleston (W.F., B.O.); and Department of Neurosurgery, Wayne State University, Detroit, MI (Y.D.). jixm@ccmu.edu.cn.
Xunming
X
Ji
D000368:Aged; D016893:Carotid Stenosis / Q000150:complications*; D005260:Female; D006801:Humans; D019194:Ischemic Preconditioning / Q000379:methods; D008297:Male; D012307:Risk Factors; D015607:Stents / Q000706:statistics & numerical data*; D016896:Treatment Outcome
carotid stenosis; cerebral embolism; ischemic preconditioning; stents