High-dose lovastatin for acute ischemic stroke: results of the phase I dose escalation neuroprotection with statin therapy for acute recovery trial (NeuSTART).
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.
Elkind
Mitchell S V
MS
Department of Neurology, College of Physicians and Surgeons, New York, N.Y., USA. mse13@columbia.edu
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
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D023381:Endpoint Determination; D005006:Ethnicity; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008111:Liver Function Tests; D008148:Lovastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents; D010974:Platelet Aggregation / Q000187:drug effects; D010979:Platelet Function Tests; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D020127:Recovery of Function; D020521:Stroke / Q000145:classification / Q000188:drug therapy* / Q000209:etiology*; D055815:Young Adult
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018696:Neuroprotective Agents; D047888:Receptors, Tumor Necrosis Factor, Type I; D008148:Lovastatin