A Randomized Clinical Trial and Meta-analysis of Early Surgery vs Initial Conservative Treatment in Patients With Spontaneous Lobar Intracerebral Hemorrhage

Starke, Robert M.; Komotar, Ricardo J.; Connolly, E. Sander

doi: 10.1227/01.neu.0000442974.53712.26
Science Times

Spontaneous supratentorial intracerebral hemorrhage (ICH) affects 4 million patients worldwide each year.1,2 Although this is a heterogeneous disorder with a wide range of outcomes, overall mortality at 1 month is approximately 40%, and only 25% of patients have a favorable outcome.1,2 Early surgery may reduce the volume of ICH, local mass effect, herniation, and secondary injury due to ischemia.3,4 Nonetheless, the optimal patient selection and timing of surgery remain unclear.

Meta-analysis of the 10 trials that have previously assessed the effects of surgery plus routine medical management, compared with routine medical management alone, in patients with primary supratentorial ICH have included 2059 patients.5 Results demonstrate a statistically significant benefit in both overall functionally outcome and decreased death in those that received surgical intervention. Despite these promising results, in the initial early surgery vs initial conservative treatment in patients with spontaneous supratentorial ICH (STICH) randomized clinical trial, surgery was not found to be beneficial.6 There was no significant difference in overall favorable outcome in the 503 patients randomized to early surgery (26%) as compared to the 530 patients randomized to conservative treatment (24%). Subgroup analysis demonstrated an improved outcome in those receiving surgery if the hematoma was within 1 cm of the cortical surface and if the hematoma was evacuated with a craniotomy.

Critics noted a failure of benefit in the STICH trial may have been attributed to heterogeneity in ICHs along with unrefined patient selection criteria. Patients with a small ICH without mass effect or a large ICH in the basal ganglia might all be unlikely to benefit from surgery. Additionally, presence of hydrocephalus, intraventricular hemorrhage, advanced age, or eloquent location might be predictors of poor outcome following surgery.

Based on findings in the STICH trial, a follow-up trial was designed to determine whether surgery improves outcomes compared with initial conservative treatment in patients with superficial lobar supratentorial ICH without intraventricular hemorrhage (STICH II).7 The hypothesis was that early surgery could improve outcome in conscious patients in whom there is a superficial ICH age of 10 to 100 mL. In this international trial involving 78 centers in 27 countries, patients were randomized to early surgical hematoma evacuation within 12 h of randomization plus medical treatment vs initial medical treatment alone. Later evacuation was allowed if deemed necessary, and intention to treat analysis was carried out to determine if there was a difference in overall functional outcome at 6 months between cohorts. Patients were stratified by country group and planned operation (craniotomy or other), and within these strata they were allocated according to a minimization algorithm based on age (<60 years, 60-69 years, or ≥70 years) and neurological deficit in the worst affected arm or leg (normal, weak, or paralyzed).

Randomization to early surgery occurred in 307 of 601 patients, and 294 were randomized to initial conservative therapy. The 2 cohorts were similar in terms of both patient and ICH characteristics. The median age of patients was 65 years (range, 17-94) and 57% were males. Half of the patients in the early surgery group and 49% in the initial conservative treatment group had a Glasgow Coma Scale score (GCS) of 14 or 15 at randomization. The median volume of the ICH was 36 mL (range, 23-55) and the median depth from the cortex surface was 1 mm (range, 0-2). The planned method of evacuation in 98% of all cases was craniotomy. Patients were randomly assigned within 48 hours of ictus and a quarter of patients in both cohorts were assigned within 12 hours. Of the 301 assessable patients in the early surgery group, 96% had surgery and 4% did not have surgery because their families refused or they had other medical or logistical problems. Of 291 assessable patients in the initial conservative treatment group, 62 (21%) had surgery, of which decline in GCS, increased edema, rebleeding, and increased intracranial pressure were the most common (n = 58) reasons for surgery.

Post-randomization adverse events reported during the hospital stay before the 2-week point were similar in the 2 groups. Although patients receiving surgery had better discharge outcomes, there was no significant difference in the incidence of unfavorable 6-month outcome among those patients randomized to early surgery (59%) vs those randomized to initial conservative treatment (62%). Adjustment for the covariates age, GCS, hemorrhage volume, and neurological deficit made little difference. There was a trend toward decreased mortality in the surgical cohort at 6 months (18%) vs the initial conservative treatment group (24%), and the actual survival advantage during the first 6 months demonstrated a similar trend.

As with many surgical trials, overall interpretation is somewhat limited due to cross over. Patients initially assigned to medical therapy with delayed deterioration that ultimately underwent surgery may have been saved from a fatal course, thus inflating the overall outcomes in the conservative cohort by intention to treat analysis.

A further limitation is that a majority of patients in the trial were fully conscious or just confused. These patients may be optimally managed with conservative therapy with delayed surgery carried out only if they were to deteriorate. Thus, the trial did not directly determine the role of early surgery in patients with increased intracranial pressure, who are most likely to benefit from surgery. Additionally, when stratifying the patients into a good and bad prognosis cohort based on GCS and ICH size, those deemed to have a poor prognosis had a significantly better overall outcome in subgroup analysis. The average time from presentation to surgery was 26.7 hours, which may be too long to reverse permanent neurological damage and toxic ICH products. A trial may be necessary to demonstrate the potential benefits of surgery in close proximity to clinical decline.

STICH II is the 15th randomized trial to assess the role of surgery in ICH as compared with medical therapy.7 Addition of STICH II to the 14 prior trials gives an overall sample size of 3,366 patients. Overall analysis demonstrates a beneficial role of surgery (OR = 0.74; 95% CI, 0.64-0.86, P < .0001), but with significant heterogeneity due to differences in patient, ICH, and surgical characteristics. Cumulative assessment STICH II along with prior trials concerning of lobar ICH without intraventricular hemorrhage (n = 923) demonstrates a trend toward a benefit of surgery (OR = 0.78; 95% CI, 0.59-1.02, P =.07), but without significant heterogeneity.

STICH II provides further evidence that certain patients with ICH may benefit from surgical therapy. Other less invasive surgical techniques may be more beneficial, including endoscopic-assisted ICH evacuation. Trials that employ stereotactic delivery of tissue plasminogen activator (tPA) to dissolve clots and tPA to dissolve intraventricular hemorrhages are currently underway.8-10 These minimal access techniques might be more beneficial for deep clots, intraventricular hemorrhage, and specific subsets of patients with superficial ICH.

Back to Top | Article Outline


1. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9(2):167–176.
2. Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol. 2003;2(1):43–53.
3. Siddique MS, Fernandes HM, Arene NU, Wooldridge TD, Fenwick JD, Mendelow AD. Changes in cerebral blood flow as measured by HMPAO SPECT in patients following spontaneous intracerebral haemorrhage. Acta Neurochir Suppl. 2000;76:517–520.
4. Mendelow AD. Mechanisms of ischemic brain damage with intracerebral hemorrhage. Stroke. 1993;24(suppl 12):I115–I117; discussion I8-I9.
5. Prasad K, Mendelow AD, Gregson B. Surgery for primary supratentorial intracerebral haemorrhage. Cochrane Database Syst Rev. 2008;(4):CD000200.
6. Mendelow AD, Gregson BA, Fernandes HM, et al.. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005;365(9457):387–397.
7. Mendelow AD, Gregson BA, Rowan EN, Murray GD, Gholkar A, Mitchell PM. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet. 2013;382(9890):397–408.
8. Hanley DF. Minimally Invasive Surgery plus rTPA for ICH Evacuation Phase III. 2013. Available at: http://braininjuryoutcomes.com/mistie-iii-about. Accessed November 11, 2013.
9. Naff N, Williams MA, Keyl PM, et al.. Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: the intraventricular hemorrhage thrombolysis trial. Stroke. 2011;42(11):3009–3016.
10. Hanley DF. CLEAR-III clot lysis: evaluating accelerated resolution of intraventricular hemorrhage Phase III. 2013. Available at: http://braininjuryoutcomes.com/clear-about. Accessed November 11, 2013.
Copyright © by the Congress of Neurological Surgeons