Treating Intracerebral Hemorrhage: Where Does the Blade Fade Away and the Neuro-Intensivist Move In?
Abstracts & Commentary
Commentary by Alan Z. Segal, MD, Assistant Professor, Department of Neurology, Weill-Cornell Medical College, Attending Neurologist, New York Presbyterian Hospital, and Assistant Editor, Neurology Alert.
Synopsis: Surgical treatment was associated with a cost savings due to shorter hospital stays and the use of fewer services upon discharge into the community.
Sources: Mendelow AD, et al. Early Surgery vs Initial Conservative Treatment in Patients with Spontaneous Supratentorial Intracerebral Haematomas in the International Surgical Trial in Intracerebral Hemorrhage (STICH): A Randomized Trial. Lancet. 2005;365:387-397; Mayer SA, et al. Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage. N Engl J Med. 2005;352:777-785.
Intracerebral hemorrhage (ICH) is an often devastating disorder for which there is little treatment beyond supportive care. The mortality associated with large hematomas may approach 90% or more in patients who present in coma. Surgical evacuation may be beneficial in selected patients, but randomized data and meta-analyses have yet to provide evidence for a clear surgical benefit. The ideal timing for surgical intervention also remains unclear. Optimal management of blood pressure is an additional controversy, as excessively aggressive attempts to lower blood pressure may put tissue at risk in the peri-hematoma penumbra. Higher blood pressures may promote hematoma extension or re-bleeding. Early hematoma growth has been identified as a key factor in neurological prognosis, following an ICH. These reports by Mayer, Mendelow, and colleagues represents both the medical and surgical approaches to this disease and shed important light on these issues.
Recombinant activated factor VII (rFVIIa; known as Novo-7) is an agent approved for the treatment of bleeding in patients with hemophilia, and may also reduce bleeding in patients without coagulopathy. Mayer et al studied 399 patients with ICH diagnosed by CT scanning within 3 hours of symptom onset. There were 96 patients in the placebo group, with the remainder receiving 40mg, 80mg or 160mg of rFVIIa (n = 96, 108 and 103 for each of these groups, respectively). Of note, 160mg is nearly double the dose indicated to treat hemophiliacs. The primary outcome measure of the study was growth of hematoma volume at 24 hours, which was significantly reduced in the rFVIIa groups. The mean increase in hematoma volume was 29% for placebo and 16%, 14%, and 11% for the 160?g, 80?g and 40?g groups, respectively. Compared with placebo, hematoma volume was reduced by approximately 4-5 ml in the treated groups, with a clear dose effect throughout the range tested. Mortality was 29% in the placebo group, compared with 18% in the rFVIIa groups combined (P = 0.02).
There was an increase in thromboembolic events in the rFVIIa treated patients, clearly a concern for an agent that promotes clotting. Such events occurred in 7% of the rFVIIa patients, compared with 2% in the placebo group, but this did not reach statistical significance (P = 0.12). There were 7 myocardial infarctions, including only one that was clinically significant, and there were 9 ischemic strokes, with 2 of these being massive and fatal.
In contrast to rFVIIa, which is a novel agent produced by recombinant genetic technology, the surgical option for ICH management has been available for decades. While surgical technique has advanced, with the addition of stereotactic and endoscopic approaches, standard craniotomy still remains the procedure of choice in the hands of most neurosurgeons. The STICH trial enrolled 1033 patients, ultimately randomizing 503 to early surgery and 530 to initial conservative treatment. The primary outcome of the study was that 112 (26%) surgical patients had a favorable outcome, compared to 118 (24%) of those treated conservatively. Patients could be randomized within 3 days of their ICH, and required an operation within 24 hours following that. Among the patients randomized to surgery, 6% ultimately did not have surgery and an additional 6% were delayed beyond 24 hours. In the medical group, 140 patients (26%) ultimately required surgery, primarily due to continued clinical deterioration. A good outcome was not defined by a single absolute value, but rather was correlated with the patient’s initial clinical grade.
Multiple subgroup analyses have been or will be done with the STICH data. Roughly 20% of STICH patients had a Glasgow coma score (GCS) of 5-8, while the remaining 80% were split between GCS categories 9-12 and 13-15. Results were not significantly impacted by the side of the hematoma, the site of the hematoma (lobar or basal ganglia), or by the hematoma volume (greater or less than 50mL). There was a trend towards a benefit for surgery among patients with hematomas < 1cm deep to the cortical surface in contrast to patients with clots that were > 1cm deep. Since the vast majority of patients underwent craniotomy rather than a stereotactic approach, Mendolow et al note that surgery may have done damage to those patients with deep bleeds. Patients who presented with GCS scores of < 8 did uniformly poorly, with surgery raising the relative risk of a poor outcome by 8%. The study did not account for withdrawals of care, which may have skewed the results for this group. Of note, surgical treatment was associated with a cost savings due to shorter hospital stays and the use of fewer services upon discharge into the community.
Commentary
The Novo-7 and STICH trials raise perhaps as many or more questions than they answer. Novo-7 is a highly expensive agent, which has already come into sporadic use, but certainly requires further study before it will become standard of care. Of utmost importance will be defining the optimal dose of this drug, balancing benefit for ICH with a clearly significant risk of thromboembolic complications. Given the sobering results of the STICH trial, the role for Novo-7 in the management of ICH becomes that much more magnified. Despite the results of STICH, however, the surgical option for ICH management is not entirely dead. STICH provides excellent randomized data across a broad range of ICH patients. It was an extremely difficult undertaking to complete, taking over 8 years, with multiple sites, to recruit 1000 patients. Nevertheless, STICH has definite methodological limitations. Most importantly, patients were operated on 3-4 days after their ICH, a time point after which neurological damage, not only at the site of the clot, but also in the perihematoma region, was likely irreversible. In addition, a study such as STICH cannot substitute for clinical judgment applied to an individual patient. There are patients who are clearly not surgical candidates, such as those in very poor or very good clinical grade, those with deep, inaccessible hematomas, or those with a static natural history. There are others, however, in an intermediate clinical grade, with an evolving (worsening) exam, for whom surgery may be beneficial. In fact, the subgroup in STICH with a GCS of 9-12, had a favorable odds ratio for surgery (OR = 0.72) with the 95% CI only slightly overlapping 1.0. Finally, it should be noted that surgery did surprisingly save money and moved patients out of the hospital more quickly, a benefit that cannot be ignored in our current cost containment climate. — Alan Z. Segal
Surgical treatment was associated with a cost savings due to shorter hospital stays and the use of fewer services upon discharge into the community.
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