RESEARCHERS FOCUS ON TREATMENT OPTIONS

Historically, treatment options for intracerebral hemorrhage (ICH) have been few and have been based on limited anecdotal evidence. Over the last few years, however, this situation has radically changed. An evolving understanding of the mechanisms of brain injury following ICH, coupled with the completion of a number of well-designed controlled trials of medical and surgical therapies for ICH, have signaled a new era in the approach to this disease. Broadly speaking, therapeutic efforts can be divided into those that directly reduce brain injury from hemorrhage, either by halting hemorrhage expansion or removing blood products, and those that indirectly reduce brain injury by modulating secondary mechanisms of neuronal injury.

STOP THE BLEEDING

Most patients with ICH who present within the first few hours of symptom onset have active ongoing cerebral bleeding. Serial CT studies of such patients show that 72% of patients have some degree of hematoma expansion over the first 24 hours after symptom onset.¹ Dramatic hemorrhage expansion (defined as hemorrhage expansion by >1/3 of its original size) occurs in 38% of such patients in the first 24 hours after presentation. Most of this expansion occurs within the first few hours after onset.² Not surprisingly, hemorrhage expansion is associated with clinical deterioration and poor outcome. 

Treatment with recombinant activated factor VII

While it is widely accepted that patients with anticoagulant-related ICH require emergent correction of their coagulopathy, recent data suggest a role for procoagulant therapy in patients with ICH with normal coagulation parameters. Two small pilot studies using recombinant activated factor VII (rFVIIa) in acute ICH showed treatment was feasible and without major safety concern.^3,4

Another recent large phase IIb trial of rFVIIa in these patients also has been completed.⁵ This trial randomized patients to placebo or 40, 80, or 160 µg/kg of body weight doses of rFVIIa. The drug was given as a one-time rapid injection. Three hundred and ninety-nine patients were enrolled, and study treatment had to be started within 4 hours of symptom onset. The study’s primary outcome measure was hemorrhage expansion on CT scan at 24 hours compared to baseline. The mean percent increase in hemorrhage volume at 24 hours was 29% in the placebo arm, 16% in the 40 µg/kg arm, 14% in the 80 µg/kg arm, and 11% in the 160 µg/kg arm (P = .01 for combined rFVIIa groups vs placebo group). Further, this decrease in hemorrhage growth was associated with improved outcome. The absolute reduction in mortality was 11% (relative reduction, 38%) in the 3 treatment groups combined compared to the placebo group. Death or severe disability occurred in 69% of the patients in the placebo arm, 55% in the 40 µg/kg arm, 49% in the 80 µg/kg arm, and 54% in the 160 µg/kg arm (P = .004 for combined rFVIIa groups vs placebo group). Interestingly, a significant effect of time to treatment on hematoma growth was observed. When medication was given within 3 hours after symptom onset, the mean increase in ICH volume was 34% for the placebo group compared to 13% for the treated patients (P = .004). In contrast, no treatment effect was observed when medication was given 3-4 hours after symptom onset (P = .86). Serious thromboembolic events occurred in 7% of the patients treated with rFVIIa compared to 2% of the patients treated with placebo (P = .12). While the difference between fatal or disabling thromboembolic events did not differ between the study groups, these safety findings certainly bear close observation.

A larger, phase III trial of rFVIIa, called rFVIIa in Acute Hemorrhage Stroke Treatment (FAST), has recently been completed. This trial compared doses of 20 µg/kg and 80 µg/kg of rFVIIa to placebo and had a design similar to the phase IIb trial described above. Preliminary and limited results of this trial were recently made available. While rFVIIa did significantly reduce intracerebral bleeding and improve neurological outcome compared to placebo at day 15, no difference between rFVIIa and placebo was seen on the primary study end point of mortality or severe disability at 90-day follow-up. Detailed results are to be presented at the 59th annual meeting of the American Academy of Neurology, which will be held in Boston from April 28 to May 5, 2007, and at the European Stroke Congress, which will be held in Glasgow from May 29 to June 1, 2007.

Lowering blood pressure

Lowering of blood pressure (BP) is another intervention widely used in patients with ICH in an effort to stop ongoing bleeding. The rationale extends from experience in surgical settings, where aggressive BP-lowering (and even induced hypotension) is known to reduce bleeding in the operative field. Unfortunately, very limited data exist regarding the efficacy of such an approach in acute ICH. Although several small retrospective studies found that higher BPs are correlated with worse outcome,^6-8 whether acute treatment of hypertension improves outcome remains uncertain.

A widely raised concern about BP-lowering relates to the theoretical risk of causing cerebral ischemia in penumbral tissue surrounding the ICH. To date, however, most evidence suggests that no significant perihematomal ischemic penumbra exist and that aggressive BP-lowering can be performed without adversely impacting global or regional cerebral blood flow.^9,10 Two clinical trials are underway to evaluate the safety and efficacy of lowering BP acutely. One, the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT), is a randomized open-label study with 2 different BP targets that allows individual investigator selection of the BP-lowering agent. The other, the Antihypertensive Treatment of Acute Cerebral Haemorrhage (ATACH) trial, is a randomized trial of intravenous nicardipine with 3 different BP targets. The results of these trials should provide important information about the safety and efficacy of BP-lowering.

REMOVE THE BLOOD

The role of surgical evacuation of the hematoma has been, and continues to be, a subject of much debate. The International Surgical Trial for Intracerebral Hemorrhage (I-STICH),¹¹ by far the largest trial to ever address this issue, enrolled over 1,000 patients from 27 different countries. Patients with acute ICH in whom the treating surgeon was uncertain about the benefits of evacuation were randomized to early surgery or initial conservative treatment. Surgery was performed at a median of 30 hours after onset. A 25% crossover rate from the medical to surgical arm was present in patients who deteriorated clinically. Overall, the trial showed no benefit to surgical treatment. Of patients allocated to early surgery, 26% had a favorable outcome compared with 24% of patients allocated to initial conservative treatment (odds ratio, 0.89; P = .414). A possible trend was observed, however, toward benefit of surgery in patients with superficial cortical hemorrhage.

Numerous limitations of I-STICH have been pointed out. First, patient selection was based on the surgeon’s uncertainty regarding treatment. Thus, patients most likely to benefit from surgery may have been systematically excluded. Second, more than a quarter of the patients randomized to medical therapy eventually crossed over to surgery, further complicating interpretation of the study. Finally, some authors have raised concern that evacuation at 30 hours after onset is too late to substantially improve outcome. On the other hand, ultra-early evacuation (<4 hours after onset) is associated with a high rate of rebleeding and resultant poor outcome.¹² Combining procoagulant therapy with early evacuation may mitigate this problem and is an area for further study.

The observation that patients with superficial cortical hemorrhage trended toward benefit in the I-STICH trial, along with the aforementioned limitations of the trial, prompted initiation of a second study, the STICH II trial, by the same group. STICH II focuses on the subgroup of patients with spontaneous, superficial (within 1 cm of the cortical surface), nonaneurysmal, lobar ICH. The STICH-II trial has just begun. The patients in the trial will be assigned to either early (within 48 h of ictus) surgery with craniotomy or observation with initial conservative treatment. A target of 600 patients is estimated necessary to achieve power to show a 10% benefit in this subgroup of patients with ICH.¹³

Removing hemorrhage in the ventricular system using thrombolytic agents is another novel therapeutic approach under investigation. The Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR IVH) dose-finding study tested low-dose tissue plasminogen activator (tPA) instilled through an intraventricular catheter to treat intraventricular hemorrhage (IVH).¹⁴ Low-dose tPA produced good clearance of IVH with no significant bleeding complications. A phase III study using low-dose tPA infused through an intraventricular catheter to treat IVH is anticipated.

NEUTRALIZE THE SECONDARY EFFECTS OF THE BLOOD

After ICH occurs, a cascade of events leads to secondary neuronal injury. Therapies aimed at reducing this injury are an important area of translational research and may be of clinical use in the years ahead. Edema develops around the site of hemorrhage over hours to days because of clot retraction¹⁵ followed by opening of the blood-brain barrier.^16,17 Infiltration of leukocytes occurs, as well as activation of resident microglia; this results in the release of cytokines^18,19 and matrix metalloproteinases.^20,21 These substances contribute directly to neuronal injury and sustain a robust inflammatory response. 

The triggers and mechanisms of injury have not yet been fully elucidated. Although thrombin is important in achieving hemostasis, it is also likely to be a key early mediator of damage.^22,23 Argatroban, a direct thrombin inhibitor, has been shown to reduce edema in animal models of ICH²⁴ without causing bleeding when given 6 hours after hemorrhage induction.

Lysis of red blood cells occurs over several days after ICH onset and results in the release of hemoglobin, which is then metabolized by heme oxygenase. The result is the formation of heme, carbon monoxide, and biliverdin. These hemoglobin degradation products have been shown to cause oxidative brain injury in rat models of ICH.^25-27 In rats, inhibition of heme oxygenase by zinc protoporphyrin reduces edema and atrophy and improves functional outcome,²⁸ and chelation of iron by deferoxamine attenuates hemoglobin-induced edema.²⁵

Oxidative stress is a potential mechanism of injury after hemorrhage. A pilot trial in humans (Cerebral Hemorrhagic And NXY-059 Treatment [CHANT]) that evaluates the safety of a free radical–trapping agent (NXY-059) thought to prevent mitochondrial dysfunction has been completed. In a preliminary report, this trial showed no difference in outcome between treated and untreated patients, although the study was powered for safety, not efficacy.²⁹  

HMG-CoA reductase inhibitors (statins) have pleiotropic effects beyond the lowering of cholesterol levels. These include upregulation of nitric oxide synthase, decreased leukocyte recruitment, and promotion of neurogenesis.^30-32 Statin therapy with atorvastatin reduced perihematomal cell death and improved functional outcome in 2 rat models of ICH.^33,34

CONCLUSION

Although no specific proven treatments for ICH are currently available, research is ongoing and accelerating, and several promising therapeutic candidates are on the near horizon. Early rapid use of procoagulant therapy to stop hemorrhage expansion may provide a treatment analogous to tPA for ischemic stroke. Further understanding of surgical interventions may allow targeted treatment of patients who are likely to benefit from surgery. Agents designed to prevent secondary neuronal injury likely have a longer time window and are under active study. Physicians treating patients with ICH in the future may well have an arsenal of therapies proven to reduce disability and death.

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