Neuroprotective Strategies for Intracerebral Hemorrhage
Trials and Translation
Intracerebral hemorrhage is a devastating neurological illness with few treatment options. In the past 10 years, 6 clinical trials have been completed examining the potential role that putative neuroprotective agents might play in improving outcome. Although each of these trials failed to show a benefit, animal research continues to supply the translational pipeline and 5 clinical trials evaluating neuroprotective agents in intracerebral hemorrhage are currently ongoing. Despite initial failures, neuroprotective agents continue to show promise in the treatment of intracerebral hemorrhage, but improvements in clinical trial design and more accurate predictive outcome models are necessary.
Despite extensive research efforts in basic and clinical studies, intracerebral hemorrhage (ICH) accounts for 15% of all strokes in the United States and remains the most deadly form of stroke. In the same way that ischemic stroke has eluded successful intervention, evidence-based therapy for ICH continues to be supportive. A number of clinical trials have examined interventions designed to improve ICH outcome through secondary neuroprotection. These methods include controlling blood pressure (Antihypertensive Treatment of Acute Cerebral Hemorrhage [ATACH], The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial [ICH ADAPT], Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage [INTERACT] trials) and preventing hematoma expansion (Factor Seven for Acute Hemorrhagic Stroke [FAST] I/II, Platelet Transfusion in Cerebral Hemorrhage [PATCH]). There have also been several efforts to study primary neuroprotection by targeting such processes as excitotoxicity, oxidant stress, and inflammation, yet none of these has proven unequivocally positive.
The Translational Pipeline
Neuroprotection after ICH is a complex undertaking, because ICH is thought to trigger a multitude of deleterious cascades in both white and gray matter. An eruption of blood into the parenchyma generates direct tissue destruction and culminates in hematoma expansion with a subsequent mass effect on adjacent tissues. Inflammatory pathways are activated and lead to tissue necrosis, cellular apoptosis, and edema, resulting in further increases in intracranial pressure. A harmful positive feedback loop ensues with increased intracranial pressure and edema leading to penumbral hypoperfusion, which in turn causes further cell death, inflammation, and edema.
Work with animal models of ICH within the last 5 years has suggested many potential neuroprotective agents for translation into clinical studies. These interventions have explored dozens of pathophysiological avenues, including iron chelation, heme oxygenase inhibition, neurogenesis, blockade of inflammatory pathways, toxic neurotransmitter inhibition, antioxidants, matrix metalloproteinase inhibition, and antiapoptosis (Table 1).1–5
Completed Clinical Trials of Neuroprotective Agents in ICH
Based on a search of clinicaltrials.gov and the Washington University Internet Stroke Trials database, 1773 patients have been enrolled in neuroprotective ICH trials. These trials include the: (1) Glycine Antagonist In Neuroprotection (GAIN) ICH trial; (2) NXY-059 Cerebral Hematoma And NXY Treatment (CHANT) trial; (3) Mannitol in ICH trial; (4) Glycerol in ICH trial; (5) Citicoline in ICH trial; and (6) Rosuvastatin in ICH trial (Table 2). Each is discussed in detail subsequently, but only the rosuvastatin trial showed a clear benefit for the primary end point and this trial was nonrandomized and consisted of only 18 treated patients.
GAIN ICH Trial
GAIN is a set of 2 studies, 1 conducted in the Americas6,7 and 1 conducted internationally,8 which examined the neuroprotective effect of gavestinel, an N-methyl-d-aspartate receptor blocker, in both ischemic stroke and ICH. In total, 3450 patients were randomized in GAIN International (N=1804) and GAIN Americas (N=1646). Of these, 571 were identified as having spontaneous ICH. The difference in distribution of trichotomized Barthel Index scores (95 to 100 [independent], 60 to 90 [assisted independence], and 0 to 55 [dependent] or dead) at 3 months between gavestinel and placebo was not statistically significant (P=0.09). That said, there was a trend in improved outcome with the drug (18% relative improvement in good outcome and 10% relative reduction in poor outcome) and serious adverse events were similar in the 2 treatment groups.9
Cerebral Hemorrhage and NXY-059 Treatment
The CHANT trial enrolled 607 patients in a randomized, double-blind, placebo-controlled, multicenter Phase IIb trial.10 There was a mortality rate of 20% in both those treated within 6 hours with 2270 mg NXY-059 followed by 960 mg/hour for 72 hours and the placebo groups and no difference in functional outcome when evaluated by modified Rankin Scale (OR, 1.01; 95% CI, 0.75 to 1.35).
Citicoline ICH Trial
Based on both animal studies and an early double-blind, randomized clinical trial displaying improvements in muscular function post-ICH,11 the cell membrane component citicoline (cytidine-5-diphosphocholine) has been implicated as a neuroprotective agent with therapeutic potential. A trial of 182 patients treated with 4 g/day showed an increase in the percentage of patients with a favorable Barthel Index (BI), but there was no effect on modified Rankin Scale (mRS) or National Institutes of Health Stroke Scale (NIHSS) at Day 90 (presented at the 27th International Stroke Conference in February 2002). A 38-person pilot randomized controlled trial was designed to test the safety and use of citicoline; this demonstrated both safety and a positive trend regarding efficacy.12
Rosuvastatin is a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase13 and was recently examined as a neuroprotective agent in a prospective, nonrandomized study of 18 patients receiving 20 mg rosuvastatin daily and 57 control subjects. Treated patients had an OR of 0.04 (95% CI, 0.003 to 0.93) for a NIHSS score of ≥15 at discharge and 0.20 (95% CI, 0.02 to 1.67) for mortality. Given the nonrandomized study design, the results must be interpreted with caution and more studies are necessary to provide reasonable evidence that statins improve outcome after ICH.14
Mannitol in ICH Trial
In a randomized controlled trial, 100 mL of 20% mannitol given every 4 hours for 5 days to 64 patients with ICH followed by a 48-hour taper did not seem to be beneficial when compared with 64 control subjects. At 1 month, 16 patients died in each group. In the study group, 23 patients had poor, 18 partial, and 8 complete recovery, whereas in the control group, 18 had poor, 20 partial, and 9 had complete recovery.15
Glycerol in ICH Trial
In a randomized controlled trial of 216 patients, 500 mL of 10% glycerol in saline by intravenous infusion over 4 hours for 6 consecutive days did not result in any improvement in any of the primary outcome measures, which included Scandinavian Stroke Scale, Glasgow Coma Scale, and BI at 5 months.16
Ongoing Clinical Trials of Neuroprotective Agents in ICH
Currently there are 5 ongoing trials of ICH neuroprotection: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition, iron chelation, cyclo-oxygenase-2 inhibition, peroxisome proliferator-activated receptor-γ agonism, and antiapoptotic strategies (Table 3).
Simvastatin in ICH Trial
Building on the results with rosuvastatin, a Phase II randomized controlled trial is testing 14-day administration of 80 mg simvastatin as a potential therapy for ICH. Perihematomal edema is the primary outcome and BI and mRS at 30 and 90 days is the secondary outcome.
Another area of intense research has focused on the use of the iron chelator deferoxamine mesylate in the treatment of ICH.17,18 A Phase I trial involves intravenously infusing deferoxamine in varying dose regimens (from 7 to 125 mg/kg) for 3 consecutive days. The study is very close to Phase II status with 23 patients enrolled in 5 dosage schedules, and preliminary data show alterations in serum markers of oxidative stress.18 Studies have shown that erythrocyte breakdown and subsequent release of hemoglobin contribute to iron-mediated neurotoxicity post-ICH.
The selective cyclo-oxygenase-2 inhibitor celecoxib has been investigated in ICH therapy due to its anti-inflammatory properties. Phase II trials are being conducted in the Angiotensin-Converting Enzyme–ICH study in South Korea, administering 400 mg celecoxib twice daily for 2 weeks post-ICH. This work is based on prior studies that demonstrated the efficacy of celecoxib in reducing edema and inflammation and improving functional recovery in a rat ICH model.19,20
The perixosome proliferator-activated receptor-γ agonist pioglitazone is thought to act in ICH through interruption of matrix metalloproteinase activation,21 microglial activation,22 and resulting inflammation. The Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC) trial is a randomized controlled trial parallel-assignment study aiming to gauge the effect of escalating doses for 3 days followed by 30 mg daily until 75% of the hematoma is gone on imaging. Eighty patients will be enrolled within 24 hours of ICH, primarily assessing mortality at 14 days.
Intravenous Tauroursodeoxycholic Acid
Aiming to counteract the plethora of apoptotic pathways stimulated post-ICH, the compound tauroursodeoxycholic acid has been investigated in clinical treatments. This component of traditional Chinese medicine is thought to act through the Bcl-2 antiapoptotic pathway in hemorrhagic settings.23 A small (n=30) Phase I pilot trial is investigating the safety and tolerability of doses varying from 10 to 200 mg/kg begun within 5 hours of ICH. Although primarily a safety study, the investigators will also track efficacy using the mRS, BI, and NIHSS at 90 days.
If present and future efforts are to be effective in establishing neuroprotection in ICH as a reality, investigators must learn from the failure of drug development for ischemic stroke. Elements of the Stroke Therapy Academic Industry Roundtable (STAIR) criteria for ischemic stroke remain relevant in hemorrhagic stroke. Investigators must take special care to plan trials that make full use of the preclinical data and take into account issues of timing and heterogeneity among study subjects.
That said, developing neuroprotective drugs for ICH may prove more fruitful than attempts in ischemic stroke because the clinical outcome may be more homogenous, the biological response easier to assay, and the therapeutic window may prove more generous. In addition, significant work has been done to identify neuroprotective agents in ischemic stroke and those drugs may provide a template in ICH as many of the pathophysioloigcal cascades are shared. Nonetheless, it will be important to avoid high-profile, expensive failures to maintain the interest of the public and industry. The best way to do this is to avoid moving forward with agents in which the data are anything less than compelling.
Sources of Funding
E.S.C. is supported by the following grants: NS 40409, FD 3728, NS 56146, AG 17604, S 39512, and NS 42167.
- Received August 10, 2010.
Karki K, Knight RA, Han Y, Yang D, Zhang J, Ledbetter KA, Chopp M, Seyfried DM. Simvastatin and atorvastatin improve neurological outcome after experimental intracerebral hemorrhage. Stroke. 2009; 40: 3384–3389.
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Rodrigues CM, Sola S, Nan Z, Castro RE, Ribeiro PS, Low WC, Steer CJ. Tauroursodeoxycholic acid reduces apoptosis and protects against neurological injury after acute hemorrhagic stroke in rats. Proc Natl Acad Sci U S A. 2003; 100: 6087–6092.