The Very Old in Randomized Surgical Intracerebral Hemorrhage Trails . Limitations Induced by Upper Age Limits

Spontaneous intracerebral hemorrhage (ICH) is one of the leading causes of death worldwide. In randomized trials on surgical therapy inclusion of the very old was limited by the recruitment process. This study was performed to evaluate the age limits in published surgical trials on ICH, and to determine how upper age limits effect the inclusion of men and women in these and future trials on the basis of a large cohort of ICH patients in central Europe. The Hessian stroke registry, a state-wide prospective stroke databank, was used to analyze upper age limits and sex differences for patients with the diagnosis of ICH (ICD-10: I61.0 to I61.9) who were admitted between January 2010 and December 2012. Sex differences were calculated at different age cutoffs, and the proportions of potentially excluded sex-specific patients from surgical trials on ICH were calculated. Overall, 5184 patients with the diagnosis of spontaneous ICH were identified. A total of 2457 (47.4%) patients were female and 2727 (52.6%) patients were male. Mean age was 72.3 ± 13.6 years. Female patients were significantly older compared to male patients (74.9 ± 13.5 years vs. 69.9 ± 13.2 years; p<0.001). With an upper age limit of 70, 75, and 80 years, 3437 patients (66.3%), 2664 patients (51.4%), and 1765 patients (34.0%) were excluded, respectively. Upper age limits in surgical trials on ICH could lead to the exclusion of a significant portion of patients from studies. This should be noted when transferring conclusions from these trials into clinical practice. DOI : 10.14302/issn.2470-5020.jnrt-16-980 Corresponding Author: Dr. Marco Stein, Department of Neurosurgery, Justus Liebig University Giessen, Klinikstrasse 33, 35392 Giessen, Germany. Phone: +4964198557160, Email: Marco.Stein@neuro.med.uni-giessen.de Running title: The very old in surgical intracerebral hemorrhage trails.


Introduction:
Spontaneous intracerebral hemorrhage (ICH) accounts for 11-22% of all strokes worldwide. 1The early case fatality rate was 25-35% in the first month.
Incidence of ICH increases with advanced age. 2 Over the coming decades, the aging of the population will force a major shift in clinical care of patients with ICH, and the group of patients older than 80 years will increase by the factor 2.5 from 2009 to 2050 in middle Europe. 3fferences of life expectancy between males and females lead to a higher proportion of females in the very old.This results in a higher rate of females in older patients with ICH.
In stroke trials, upper age limits were used to exclude patients from these studies for different reasons. 4For older individuals, higher rates of inhospital mortality and higher rates of moderate or severe neurological deficits were noted. 5However, the aging of the population worldwide will create a serious challenge in the treatment of ICH in the coming decades.If current treatment concepts in the very old continue and incidence rates of ICH remain stable in this patient group, the demographical changes will lead to higher in-hospital mortality rates and higher rates of patients with severe disabilities.
Since the first published randomized surgical trial on ICH by McKissock et al. 6 in 1961, several randomized surgical trials on ICH have been published.
To date, no randomized surgical trial on open hematoma evacuation by craniotomy after ICH has been able to show that this procedure is superior to conservative treatment.Some randomized trials that include minimally invasive surgical concept at least in one arm of the study show a benefit of these procedures in special circumstances 7 , or a slightly improved functional outcome. 8,9  study was conducted to evaluate the upper age limits in published randomized surgical trials on ICH, and to calculate the proportions of potentially excluded patients for different upper age limits in a large representative cohort of patients with spontaneous ICH in central Europe.

Methods:
We performed a systematic literature search on (17.3%), and 259 (5.0%) will be excluded, respectively (Figure 2).In the very old, the cohort of patients with ICH was not gender neutral.With an age limit of 80 years, 1086 female patients (44.2% of all female patients), but only 679 male patients (24.9% of all male patients), were excluded (P<0.001).

Summary of Findings
Upper age limits in RCT on surgical therapy of ICH leads to an exclusion of a considerable number of patients with ICH.The majority of published surgical trials on ICH defined age limitations in the inclusion criteria.Despite that no upper age limit was part of the inclusion criteria in 7 of the 17 evaluated RCT, 6,[11][12][13][14][15][16] only   Concerning the second point: a significant gender mismatch exists in the very old with spontaneous ICH.With an age of 80 years or older the proportion of female patients is significantly higher through the differences in life expectancy between males and females (Table 2).The only published surgical trial on ICH with a balanced gender distribution is also the oldest trial. 6In all other included trials a strong domination of male patients in the study population exists (Table 1).When compared to our data, it appears that surgical therapies for ICH were evaluated with a disproportionately higher proportion of male patients; but this does not reflect the sex distribution in the very old.

Several surgical RCTs on open hematoma
[15][16][17][18][19] In our study, 9 of 17 trials evaluated the impact of open hematoma evacuation by craniotomy versus conservative therapy.However, 8 trials out of 17 had at least one minimally invasive arm.
The prior experience of most clinicians suggested that very old individuals with spontaneous ICH will not tolerate an open hematoma evacuation operative procedure well.One theory for this hypothesis is that the procedure related injury to the normal brain and the length of anesthesia in the very old could mask the effect of the hematoma evacuation.However, an increase of RCTs on minimally invasive surgery can be observed in recent decades.Some positive effects were observed in these studies.Auer et al. 7

Freely 5 Figure 1 :
Figure 1: Age distribution of 5184 patients with spontaneous intracerebral hemorrhage who were admitted to an acute care hospital in the State of Hesse, Germany, between January 2010 and December 2012.With an age of ≥80 years a significant increase in the proportion of female patients compared with an age <80 years exists (61.5% versus 40.1%;P<0.001).

were Freely Available Online www.openaccesspub.org | JNRT CC-license DOI : 10.14302/issn.2470-5020.jnrt-16-980 Vol
-1 Issue 3 Pg.no.-3 calculated from the published manuscripts and were rounded to one decimal figure.We calculate the proportions of men and woman who will not be included in randomized surgical trials on ICH when different age limits are set (70, 75, and 80 years).Results:Randomized Surgical Trials on ICHSeventeen published randomized surgical trials on ICH with a total of 3472 patients met the inclusion criteria of this study (Table1).In 11 (68.8%)trials an age limit was part of the inclusion criteria.Mean or median age was reported in 15 (88.2%) trials.Mean age ranges from 51.7 years 11 to 68.0 years 12 .An upper age range of included patients was noted in 11 (64.7%)Data from the Acute Stroke Care Project, State of Hesse, Germany Between January 2010 and December 2012, 5184 patients with the diagnosis of spontaneous ICH (ICD-10: I61) were admitted to an acute care hospital in the state of Hesse, Germany.Main characteristics of the cohort are shown in Table 2.The median age in this cohort was 75 years with an interquartile range of 65

Table 1 .
Age and gender distributions in published randomized surgical trials on intracerebral hemorrhage.

Table 2 .
Main characteristics of 5184 patients with spontaneous intracerebral hemorrhage by age.
An inclusion of patients in a surgical RCT on ICH depends on several variables, not only age.Some prognostic factors, like the volume of the intracerebral hematomas, are not available in our data.However, this variable is not essential for an analysis of upper age limits.The rate of patients with disabilities is significantly higher in the very old compared to younger patients; this is an exclusion criterion in several surgical trials on ICH.In this case we have overestimated the amount of excluded patients in our analysis.Patients with spontaneous ICH outside surgicalRCT on ICH in central Europe are older compared to the published study populations.Currently, no specific surgical trial for the very old with spontaneous ICH exists, and it is questionable whether that would occur.This should be noted if results from surgical RCTs for spontaneous ICH are transferred to clinical practice among the very old.
However, with the exception of the trial by Teernstra et al.,12the very old were not represented in these trials.the question is not only which method of surgical therapy is best, but also when it should be performed, and which therapy would benefit the very old best.Freely Available Online www.openaccesspub.org| JNRT CC-license DOI : 10.14302/issn.2470-5020.jnrt-16-980Vol-1 Issue 3 Pg.no.-7