Dataset Information

High-dose lovastatin for acute ischemic stroke: results of the phase I dose escalation neuroprotection with statin therapy for acute recovery trial (NeuSTART).

ABSTRACT:

Background

Hydroxymethylglutaryl coenzyme A reductase inhibitors ('statins') reduce the neuronal injury in dose-dependent fashion in rodent stroke models. We sought to determine whether lovastatin at doses above those currently approved can be administered safely within 24 h after an acute ischemic stroke.

Methods

We conducted a phase 1B dose-finding study using an adaptive design novel to stroke trials, the continual reassessment method, to find the highest tolerated dose of lovastatin. Planned doses were 1, 3, 6, 8 and 10 mg/kg/day for 3 days. The primary safety outcomes were myotoxicity and hepatotoxicity. The model was calibrated to select a dose causing 7-13% toxicity.

Results

We enrolled 33 patients (16 men/17 women, age range 23-82 years). Three patients were treated at 1 mg/kg, 10 at 3 mg/kg, 12 at 6 mg/kg, and 8 at 8 mg/kg. Thirty of the 33 patients (90.9%) completed at least 11 of 12 doses. Two patients at the 6-mg/kg dose level experienced transient mild elevations in transaminases without clinical sequelae. After an initial dose reduction, the dose was re-escalated to 8 mg/kg, and no further patients reached safety outcomes. No clinical liver disease, myopathy, or creatine phosphokinase elevations occurred. The final model-based toxicity at 8 mg/kg was 13%; no patient was treated at 10 mg/kg.

Conclusions

Lovastatin at doses above those currently approved by the Food and Drug Administration is feasible for 3 days after an acute ischemic stroke and the maximum tolerated dose is estimated to be 8 mg/kg/day. Further randomized studies are warranted to confirm its safety and to demonstrate its efficacy in improving functional outcomes after stroke.

SUBMITTER: Elkind MS

PROVIDER: S-EPMC2814015 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Publications

High-dose lovastatin for acute ischemic stroke: results of the phase I dose escalation neuroprotection with statin therapy for acute recovery trial (NeuSTART).

Elkind Mitchell S V MS Sacco Ralph L RL Macarthur Robert B RB Peerschke Ellinor E Neils Greg G Andrews Howard H Stillman Joshua J Corporan Tania T Leifer Dana D Liu Rui R Cheung Ken K

Cerebrovascular diseases (Basel, Switzerland) 20090716 3

<h4>Background</h4>Hydroxymethylglutaryl coenzyme A reductase inhibitors ('statins') reduce the neuronal injury in dose-dependent fashion in rodent stroke models. We sought to determine whether lovastatin at doses above those currently approved can be administered safely within 24 h after an acute ischemic stroke.<h4>Methods</h4>We conducted a phase 1B dose-finding study using an adaptive design novel to stroke trials, the continual reassessment method, to find the highest tolerated dose of lova ...[more]

PMID: 19609078

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Project description:Background: Low lipid level is associated with better cardiovascular outcome. However, lipid paradox indicating low lipid level having worse outcomes could be seen under acute injury in some diseases. The present study was designed to clarify the prognostic significance of acute-phase lipid levels within 1 day after admission for stroke on mortality in first-ever statin-naïve acute ischemic stroke (IS) and hemorrhagic stroke (HS). Methods: This observational study was conducted using the data collected from Stroke Registry In Chang-Gung Healthcare System (SRICHS) between 2009 and 2012. Patients with recurrent stroke, onset of symptoms >1 day, and history of the use of lipid-lowering agents prior to index stroke were excluded. Stroke was classified into IS and hypertension-related HS. The primary outcomes were 30-day and 1-year mortality identified by linkage to national death registry for date and cause of death. Receiver operating characteristic (ROC) curve analysis and multivariate Cox proportional hazard models were used to examine the association of lipid profiles on admission with mortality. Results: Among the 18,268 admitted stroke patients, 3,746 IS and 465 HS patients were eligible for analysis. In IS, total cholesterol (TC) <163.5 mg/dL, triglyceride (TG) <94.5 mg/dL, low-density lipoprotein (LDL) <100 mg/dL, non-high-density lipoprotein cholesterol (non-HDL-C) <130.5 mg/dL, and TC/HDL ratio <4.06 had significantly higher risk for 30-day/1-year mortality with hazard ratio (HR) of 2.05/1.37, 1.65/1.31, 1.68/1.38, 1.80/1.41, and 1.58/1.38, respectively, compared with high TC, TG, LDL, non-HDL-C, and TC/HDL ratio (p < 0.01 in all cases). In HS, lipid profiles were not associated with mortality, except HDL for 30-day mortality (p = 0.025) and high uric acid (UA) concentrations for 30-day and 1-year mortality (p = 0.002 and 0.012, respectively). High fasting glucose and high National Institute of Health Stroke Scale (NIHSS) score at admission were associated with higher 30-day and 1-year mortality in both IS and HS and low blood pressure only in IS (p < 0.05). Synergic effects on mortality were found when low lipids were incorporated with high fasting glucose, low blood pressure, and high NIHSS score in IS (p < 0.05). Conclusions: Lipid paradox showing low acute-phase lipid levels with high mortality could be seen in statin-naïve acute IS but not in HS. The mortality in IS was increased when low lipids were incorporated with high fasting glucose, low blood pressure, and high NIHSS score.

Project description:BackgroundPrevious experimental studies have found that ischemic post-conditioning exhibits neuroprotective effects by alleviating ischemia-reperfusion injury in an acute ischemic stroke model, and its efficacy is thought to be related to the duration of ischemic post-conditioning. However, ischemic post-conditioning has not been used in patients with acute ischemic stroke. This study aims to determine the safety, tolerability, and maximum tolerable duration of ischemic post-conditioning in patients with acute ischemic stroke receiving mechanical thrombectomy.MethodsPatients with acute ischemic stroke with unilateral middle cerebral artery M1 segment occlusion eligible for mechanical thrombectomy will be enrolled. We adopt a 3 + 3 dose-escalation design with a duration escalation schedule of 0, 1, 2, 3, 4, and 5 min × 4 cycles for the ischemic post-conditioning study. After successful reperfusion following mechanical thrombectomy, the balloon for ischemic post-conditioning will be inflated at the site proximal to the culprit lesion four times for 0-5 min with low-pressure (3-4 atmospheres) inflations, each separated by 0-5 min of reflow. We pre-defined the major responses (vessel perforation or rupture, reocclusion of the culprit vessel after ischemic post-conditioning, vessel dissection, severe vasospasm, ischemic post-conditioning related thrombotic events, and rupture of the balloon used for ischemic post-conditioning) as the stopping rules. Each patient will undergo a rigorous evaluation to determine the safety, tolerability, and maximum tolerable duration of ischemic post-conditioning.DiscussionThis will be the first clinical study to ascertain the safety and tolerability of ischemic post-conditioning in patients with acute ischemic stroke receiving mechanical thrombectomy. The maximum tolerable duration obtained in this study will also serve as a starting point for future studies on the efficacy of ischemic post-conditioning.Clinical trial registration[https://clinicaltrials.gov], identifier [NCT05153655].

Dataset Information

High-dose lovastatin for acute ischemic stroke: results of the phase I dose escalation neuroprotection with statin therapy for acute recovery trial (NeuSTART).

Background

Methods

Results

Conclusions

Publications

High-dose lovastatin for acute ischemic stroke: results of the phase I dose escalation neuroprotection with statin therapy for acute recovery trial (NeuSTART).

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