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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.
Circulation 2017; 135(14):1325-1335Circ

Abstract

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.

CLINICAL TRIAL REGISTRATION

URL: http://www.clinicaltrials.gov. Unique identifier: NCT01654666.

Authors+Show Affiliations

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.).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.).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.).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.).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.).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.).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.).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.).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.).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.).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.).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.).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.).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.).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.).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.).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.).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.).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.

Pub Type(s)

Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

28174194

Citation

Zhao, Wenbo, et al. "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." Circulation, vol. 135, no. 14, 2017, pp. 1325-1335.
Zhao W, Meng R, Ma C, et al. 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. Circulation. 2017;135(14):1325-1335.
Zhao, W., Meng, R., Ma, C., Hou, B., Jiao, L., Zhu, F., ... Ji, X. (2017). 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. Circulation, 135(14), pp. 1325-1335. doi:10.1161/CIRCULATIONAHA.116.024807.
Zhao W, et al. 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. Circulation. 2017 Apr 4;135(14):1325-1335. PubMed PMID: 28174194.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Zhao,Wenbo, AU - Meng,Ran, AU - Ma,Chun, AU - Hou,Baojun, AU - Jiao,Liqun, AU - Zhu,Fengshui, AU - Wu,Weijuan, AU - Shi,Jingfei, AU - Duan,Yunxia, AU - Zhang,Renling, AU - Zhang,Jing, AU - Sun,Yongxin, AU - Zhang,Hongqi, AU - Ling,Feng, AU - Wang,Yuping, AU - Feng,Wuwei, AU - Ding,Yuchuan, AU - Ovbiagele,Bruce, AU - Ji,Xunming, Y1 - 2017/02/07/ PY - 2016/08/06/received PY - 2017/01/26/accepted PY - 2017/2/9/pubmed PY - 2017/5/2/medline PY - 2017/2/9/entrez KW - carotid stenosis KW - cerebral embolism KW - ischemic preconditioning KW - stents SP - 1325 EP - 1335 JF - Circulation JO - Circulation VL - 135 IS - 14 N2 - 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. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01654666. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/28174194/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_ DB - PRIME DP - Unbound Medicine ER -