Applicability of Clinical Trials in an Unselected Cohort of Patients With Intracerebral Hemorrhage
Background and Purpose—Patient selection in clinical trials on intracerebral hemorrhage (ICH) affects overall applicability of results. We estimated eligibility for completed, ongoing, and planned clinical trials in an unselected cohort of patients with ICH.
Methods—Large clinical ICH trials were identified using trial registration databases. Each trial’s inclusion criteria were applied to a consecutive group of patients with ICH from the prospective hospital-based Lund Stroke Register. Survival status was obtained from the National Census Office and 90-day poor functional outcome (modified Rankin Scale ≥4) from the Swedish Stroke Register or medical files.
Results—Among 253 patients with ICH, estimated eligibility proportions ranged between 2% and 36% for the 11 identified clinical trials. Patients not eligible for any trial (n=96) had more intraventricular hemorrhage, lower baseline level of consciousness, higher rates of cerebellar ICH, and lower rates of lobar ICH (P≤0.001). Thirty-day case fatality for noneligible patients was 54% versus 18% among patients eligible in ≥1 trial (95% confidence interval, 44%–64% versus 13%–25%; P<0.001). Noneligible ICH patients more frequently had poor functional outcome (75% versus 48%; 95% confidence interval, 65%–83% versus 40%–56%; P<0.001).
Conclusions—There is large variation in proportions of patients with ICH eligible for inclusion in clinical trials and over a third of patients with ICH are not eligible for any trial.
Clinical treatment trials in intracerebral hemorrhage (ICH) often use several selection criteria to ensure patient safety and detect possible therapeutic benefits. This selection may reduce the trials’ overall external validity (generalizability) in a general population of patients with ICH, which is of significance as treatment trials constitute an important basis for clinical guidelines and decision making. It is, therefore, important for clinicians to understand trials’ applicability and what characterizes included and nonincluded patients. Previous eligibility estimates for ICH trials have been low,1–3 and Fonville et al1 reported that 17% to 32% of patients with ICH were not eligible for any of the 17 trials they studied.
However, eligibility for several large completed and ongoing ICH trials have not previously been estimated and an update on the subject is needed. We, therefore, assessed the (1) eligibility proportions for large surgical or medical clinical ICH trials and (2) overall characteristics and outcomes for eligible and noneligible patients, in a large consecutive and well-categorized ICH patient cohort.
We identified randomized controlled trials on ICH using 3 online clinical trial registration databases: ClinicalTrials.gov (http://www.ClinicalTrials.gov), ISRCTN registry (http://www.isrctn.com), and the Stroke Trials Registry (http://www.strokecenter.org). We included large (≥300 patients with ICH) completed, ongoing, and planned phase II–IV interventional trials (Figure I in the online-only Data Supplement). Patients with missing data (other than time from ictus to computed tomography) were considered eligible. All eligible patients were assumed to consent to inclusion.
Consecutive first-ever stroke patients with ICH were prospectively included in the Lund Stroke Register in 2001 to 2007. Registration of patients, baseline variables, and outcome follow-up has been previously described.4 The study was approved by the Regional Ethical Review Board.
The Lund Stroke Register patients’ eligibility status for each identified trial was determined on information from prospectively registered data, medical files, and baseline computed tomography scan, as described in the online-only Data Supplement. Survival status was obtained in 2011 from the National Census Office. Functional outcome (modified Rankin scale [mRS]) was obtained from the Swedish Stroke Register or review of medical records.4 Poor outcome was defined as mRS score of ≥4 at 90 days (range 50–150 days) or death <150 days after ICH, choosing the outcome closest to 90 days.
Mann–Whitney U test and Pearson χ2 test were used for descriptive statistics. Confidence intervals (CIs) for sample proportions were calculated with Wilson method. Kaplan–Meier plots were used for 30- and 365-day survival analysis. IBM SPSS statistics version 22.0 was used for statistical analyses and P values <0.05 were considered significant.
Trial Identification and Patient Selection
Of 59 unique interventional ICH trials identified, 11 matched our selection criteria (Table); exclusion causes were phase 0/I trial (n=6) or phase II trial succeeded by a phase III trial (n=5), trial inactive/suspended (n=13), <300 patients with ICH (n=23), and unclear inclusion criteria (n=1). For eligibility estimation, we included 253 Lund Stroke Register patients with spontaneous ICH (Figure II in the online-only Data Supplement). Survival status was available for all patients; functional outcome (functional status for survivors or death) was obtainable for 224 patients (89%; 139 eligible for ≥1 trial), with a median follow-up time of 94 days (interquartile range, 90–115) for patients who survived ≥150 days.
Eligibility proportions ranged from 2% to 36% between included trials, and 96 (38%) patients with ICH were ineligible for all of the included trials. Individual trial characteristics are shown in Figure and Table.
Baseline Characteristics Eligible Versus Noneligible ICH Patients
Compared with patients with ICH not eligible for any trial, patients eligible for ≥1 trial had higher admission level of consciousness (using Glasgow Coma Scale, P<0.001), less severe intraventricular hemorrhage (using modified Graeb Scale, P=0.001), and more often lobar and less often cerebellar ICH (P<0.001), see Table I in the online-only Data Supplement. No differences in age, sex, or ICH volume were observed (P>0.05).
Outcome Eligible Versus Noneligible ICH Patients
Eligible patients had 30- and 365-day case fatality rates of 18% (n=29) and 28% (n=44) (95% CI, 13%–25% and 22%–36%), whereas corresponding rates among noneligible patients were 54% (n=52) and 59% (n=57; 95% CI, 44%–64% and 49%–69%). Survival plots illustrate these differences (Figure III in the online-only Data Supplement; P<0.001 for both end points). The eligible ICH patients less frequently had poor functional outcome compared with the noneligible ICH patients (n=67/139=48% versus 64/85=75%; 95% CI, 40%–56% versus 65%–83%; P<0.001).
Eligibility for clinical trials on ICH differ greatly, and even in trials with the broadest inclusion criteria, a minority was estimated to be eligible. Compared with an unselected cohort, clinical trials generally include ICH patients with less severe baseline characteristics and better outcomes that should be considered when translating trial results into clinical practice and guidelines. However, many noneligible patients would likely also be ineligible for future trials because of serious prognosis with nonsurvivable hemorrhages or hematomas requiring life-saving surgery.
We present novel eligibility and survival estimates for 7 trials, of which 4 are ongoing and 2 are recently completed. Eligibility proportions ranged from 2% to 36% with current surgical trials being the least inclusive, possibly because of negative results from the previous, more inclusive, surgical trials The International Surgical Trial in ICH (STICH-I) and Surgical Trial in Lobar ICH (STICH-II).9,10 In our cohort, 9% (95% CI, 6%–13%) of patients with ICH were potentially eligible for STICH-II, which is higher than reported in a previous study (4%)1 but in line with another (8%).2 Our eligibility estimate for the Recombinant Factor VIIa in Acute ICH trial (FAST; 17%; 95% CI, 13%–23%) was similar to an eligibility study on recombinant factor VIIa-therapy (13%–18%)3 but higher than an all-inclusive population-based study (7%)1 with somewhat different design compared with Lund Stroke Register. The latter study had a lower eligibility estimate for The Second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT-2; 7% versus 16%; 95% CI, 12%–21%) but a similar estimate for STICH-I (40% versus 35%; 95% CI, 30%–41%) compared with our study.1 Our eligibility proportions were higher than the screening to enrollment ratios for FAST (9%)7 and INTERACT-2 (10%)8 but similar to screening results from STICH-II (8%),10 Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III trial (CLEAR-III; 5%, online-only Data Supplement), and Antihypertensive Treatment of Acute Cerebral Hemorrhage trial (ATACH-II; 12%).11
Our well-categorized consecutive hospital-based ICH patient cohort from a setting with high hospitalization and CT rates for patients with stroke4 provides validity to our findings. Eligibility might have been overestimated because patients with missing data were included, and consent from all patients was assumed.
Our study highlights the importance of understanding how eligibility criteria affect patient selection in trial design and clinical implementation of trial results.
Dr Hanley is a principal investigator for the trials Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III (CLEAR-III; National Institute of Neurological Disorders and Stroke grant U01NS062851) and Minimally Invasive Surgery Plus rt-PA for ICH Evacuation Phase III (MISTIE-III; National Institute of Neurological Disorders and Stroke grant U01NS080824). Dr Lindgren reports honoraria from Bristol-Myers Squibb for seminar presentations, and Boehringer Ingelheim, Bayer, and Astra Zeneca for medical advisory board participation. The other authors report no conflicts.
Guest Editor for this article was Giuseppe Lanzino, MD.
The abstract was published at the International Stroke Conference, Los Angeles, CA, February 17–19, 2016 (Stroke. 2016;47:AWP356).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.014203/-/DC1.
- Received June 21, 2016.
- Revision received August 1, 2016.
- Accepted August 9, 2016.
- © 2016 American Heart Association, Inc.
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