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

Abstract

Symptomatic intracranial arterial stenosis (SIAS) is very common in octo- and nonagenarians, especially in the Chinese population, and is likely the most common cause of stroke recurrence worldwide. Clinical trials demonstrate that endovascular treatment, such as stenting, may not be suitable for octogenarians with systemic diseases. Hence, less invasive methods 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 improving cerebral perfusion (confirmed by single photon emission computed tomography and transcranial Doppler sonography) in patients younger than 80 years of age; however, the safety and effectiveness of BAIPC on stroke prevention in octo- and nonagenarians with SIAS are still unclear. The objective of this study was to evaluate the safety and effectiveness of BAIPC in reducing stroke recurrence in octo- and nonagenarian patients with SIAS. Fifty-eight patients with SIAS were enrolled in this randomized controlled prospective study for 180 consecutive days. All patients enrolled in the study received standard medical management. Patients in the BAIPC group (n = 30) underwent 5 cycles consisting of bilateral arm ischemia followed by reperfusion for 5 min each twice daily. Those in the control group (n = 28) underwent sham-BAIPC twice daily. Blood pressure, heart rate, local skin status, plasma myoglobin, and plasma levels of thrombotic and inflammatory markers were documented in both groups before beginning the study and for the first 30 days. Finally, the incidences of stroke recurrence and magnetic resonance imaging during the 180 days of treatment were compared. Compared with the control, BAIPC had no adverse effects on blood pressure, heart rate, local skin integrity, or plasma myoglobin, and did not induce cerebral hemorrhage in the studied cohort. BAIPC reduced plasma high sensitive C-reactive protein, interleukin-6, plasminogen activator inhibitor-1, leukocyte count, and platelet aggregation rate and elevated plasma tissue plasminogen activator (all p < 0.01). In 180 days, 2 infarctions and 7 transient ischemic attacks were observed in the BAIPC group compared with 8 infarctions and 11 transient ischemic attacks in the sham BAIPC group (p < 0.05). BAIPC may safely inhibit stroke recurrence, protect against brain ischemia, and ameliorate plasma biomarkers of inflammation and coagulation in octo- and nonagenarians with SIAS. A multicenter trial is ongoing.

Clinical trial registration: www.clinicaltrials.gov, unique identifier: NCT01570231.

Figures

Fig. 1

Schematic diagram of the clinical trial profile. BAIPC = bilateral arm ischemic preconditioning

Fig. 2

Cardiovascular parameters during 30 days of bilateral arm ischemic preconditioning (BAIPC) (n = 30) and sham BAIPC (n = 28) treatment. (A, C) The black curve represents blood pressure immediately before BAIPC/sham BAIPC, and the red curve represents the blood pressure at 1 h after BAIPC/sham-BAIPC. (B, D) The black curve represents the heart rate immediately before BAIPC/sham BAIPC and the red curve represents the heart rate at 1 h after BAIPC/sham BAIPC. There were no significant effects on the systolic and diastolic blood pressures and heart rates in the BAIPC group (log-rank test: blood pressure and heart rate, before vs after BAIPC, p = 0.063 and p = 0.191, respectively; blood pressure and heart rate in the BAIPC vs sham-BAIPC, p = 0.189 and p = 0.693, respectively)

Fig. 3

Plasma inflammatory biomarkers. (A) High sensitive C-reactive protein (CRP) and interleukin (IL)-6 levels; (B) leukocyte count and platelet aggregation rates; (C) fibrinogen and D-dimer levels; (D) plasminogen activator inhibitor (PAI)-1 and tissue plasminogen activator (TPA) levels. Blood samples were collected before treatment and on days 1, 15, and 30 of sham bilateral arm ischemic preconditioning (BAIPC) (n = 28) or BAIPC (n = 30) treatment (*p <0.05, **p < 0.01). Black bars represent sham BAIPC (control group); gray bars represent BAIPC. WBC = white blood cell

Fig. 4

Kaplan–Meier curves for primary and secondary end points, log-rank test. Bilateral arm ischemic preconditioning (BAIPC) group (n = 30) and control group (n = 28). (A) Primary end point: stroke and transient ischemic attack (TIA) recurrence. (B) Secondary end point: National Institutes of Health Stroke Scel (NIHSS) score improvement. (C) Secondary end point: modified Rankin Scale (mRS) scores of 0–1. The green line represents the controls; the blue line represents the BAIPC group. The NIHSS and mRS scores were computed on a near daily basis ± 1 day. Twenty-six of the 30 patients in the BAIPC group and 25 of the 28 patients in the control group had a brain magnetic resonance at day 30; 4 of the 30 patients in the BAIPC group and 3 of the 28 patients in the control group had brain computed tomography at day 30; no symptomatic hemorrhages were observed in either group, indicating that BAIPC does not promote acute cerebral hemorrhage