Remote Ischemic Conditioning After Stroke Trial 2: A Phase IIb Randomized Controlled Trial in Hyperacute Stroke

Abstract

Background Repeated episodes of limb ischemia and reperfusion (remote ischemic conditioning [RIC]) may protect the brain from ischemic reperfusion injury. Methods and Results We performed a phase IIb blinded dose-escalation sham-controlled trial in patients with hyperacute stroke, randomized 1:1 to receive RIC (four 5-minute cycles) or sham to the nonparetic upper limb, in 3 blocks of increasing dose, starting within 6 hours of ictus. The primary outcome was trial feasibility (recruitment, attrition). Secondary outcomes included adherence, tolerability, safety (serious adverse events), plasma biomarkers at days 1 and 4 (S100-ß protein, matrix metalloproteinase-9, and neuron-specific enolase), and functional outcome. Sixty participants were recruited from 2 centers (3 per month) with no loss to follow-up: time to randomization 4 hours 5 minutes (SD 72 minutes), age 72 years (12), men 60%, blood pressure 154/80 mm Hg (25/12), National Institutes of Health Stroke Scale 8.4 (6.9), and 55% thrombolyzed. RIC was well tolerated with adherence not differing between RIC and sham, falling in both groups on day 3 (P=0.001, repeated measures ANOVA) because of discharge or transfer. S100ß increased in the sham group (mean rise 111 pg/mL [302], P=0.041, repeated measures ANCOVA) but not the RIC group. There were no differences in matrix metalloproteinase-9, neuron-specific enolase, number with serious adverse events (RIC 10 versus sham 10, P=0.81), deaths (2 versus 4, P=0.36), or modified Rankin Scale score (2 [interquartile range 1-4], 2 [interquartile range, 1-3]; P=0.85). Conclusions RIC in hyperacute stroke is feasible when given twice daily for 2 days and appears safe in a small population with hyperacute stroke. A larger phase III trial is warranted. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02779712.

Keywords: feasibility; randomized controlled trial; remote ischemic conditioning; stroke.

Figures

Figure 1

Trial flow. RIC indicates remote ischemic conditioning.

Figure 2

Adherence to remote ischemic conditioning (RIC) or sham by dose number and mean total duration of limb ischemia (seconds±SD). Maximum length of cuff inflation is 300 seconds per dose (4× 5 minutes per cycle). Compared with dose 1, there is a significant fall in adherence over time from day 3 (*P=0.001, **P<0.001 repeated measures ANOVA), with no between‐group differences (P=0.64). “n” sham/RIC=dose 1: 29/31; dose 2: 19/21; and doses 3 to 8: 10/10.

Figure 3

Plasma S100ß (A), matrix metalloproteinase‐9 (MMP‐9, B), and neuron‐specific enolase (NSE, C) on days 1 and 4 by treatment group. S100ß levels increase by day 4 in the sham group from 34.5 pg/mL (SD 37.8) to 145.6 pg/mL (309.1), mean difference 111 pg/mL (95% CI, 5.6–216; P=0.041*). There were no significant between‐group differences at day 4. Analysis by repeated measures ANCOVA, Sidak correction for multiple comparisons, and adjusted for baseline stroke severity. RIC indicates remote ischemic conditioning.

Figure 4

Day 90 modified Rankin Scale (mRS) score by treatment group. Unadjusted common odds ratios (cORs) and 95% CIs comparing groups are analyzed by ordinal logistic regression. There was no significant interaction when treatment*thrombolysis was introduced into the model. The line demarcates dichotomy at functional independence, an mRS of ≤2. RIC indicates remote ischemic conditioning.

Figure 5

Recurrent vascular events (nonfatal and fatal stroke, nonfatal and fatal myocardial infarction) in randomized controlled trials assessing remote ischemic conditioning (RIC) in stroke. RECAST indicates Remote Ischemic Conditioning After Stroke Trial; Ref, reference number.