Endovascular Treatment Effect Diminishes With Increasing Thrombus Perviousness

Supplemental Digital Content is available in the text.


Contents
: Effects of acquisition details on TAI 12 Supplemental Tables  13  Supplemental Table I Figure

Statistical Analysis Plan
Thrombus perviousness and effect of endovascular treatment in acute ischemic stroke: analysis of the HERMES collaboration data. We aim to determine the effect of thrombus perviousness on functional outcome in acute ischemic stroke and its modification on the effect of endovascular treatment (EVT). Thrombus perviousness is represented by thrombus attenuation increase (TAI) in Hounsfield Units (HU).
I. Primary study objectives a. Determine the association between TAI and functional outcome. b. Determine the modification of endovascular treatment effect by TAI with ordinal mRS as outcome measure.
II. Secondary objectives a. Determine the association between TAI and dichotomized functional outcome (mRS 0-2 vs. 3-6; 0-4 vs. 5-6; 0-5 vs. 6). b. Determine the modification of EVT effect by TAI, with dichotomized functional outcome as outcome measure. c. Determine the association between TAI and post-EVT reperfusion (eTICI 2B-3). Reporting of baseline and follow-up characteristics Medians and Interquartile Ranges (IQR) will be reported for all continuous variables. Numbers and percentages (n(%)) will be reported for all categorical and dichotomous variables. All baseline characteristics will be shown for the overall patient group with TAI measurements available, and per quartile of TAI, and compared to the overall HERMES patient cohort; see Manuscript Table 1 and Supplementary Table 1 II. Analysis of primary and secondary study objectives For all primary and secondary study objectives, regression analyses will be performed. TAI grouped per 5 HU is used as the independent variable. The primary/secondary outcome of interest is used as the dependent variable.
Regression analyses/mixed effects models For every objective, four regression analyses will be performed: adjusted and unadjusted, with and without interaction term. In the 'b' models, we include an interaction term of TAI*treatment allocation (EVT) for all Study Objectives except for Secondary Objective d. For Secondary Objectives d, the tested interaction is between TAI and IV rtPA treatment, for all outcome measures. The analyses will be adjusted for the following pre-specified variables: treatment allocation, IVT yes/no, age, occlusion site, atrial fibrillation, diabetes, and time from stroke onset to IVT, NCCT-CTA slice thickness difference. Random effects will be included for study in Model 1a and 1b, and study and scanner brand in Model 2a and 2b.

Model
Unadjusted odds ratios (uOR; Model 1a and 1b) and adjusted odds ratios (aOR; Model 2a and 2b) with confidence intervals and corresponding p-values for interaction terms will be presented in Manuscript Table 2 and Supplementary Table 2

and 3.
In case of a significant interaction term, subgroup analyses will be performed to acquire separate uORs and aORs for the intervention group and control group patients, also to be presented in Manuscript Table 2  Secondary study objectives: For dichotomized mRS 0-2 vs. 3-6 and mRS 0-4 vs. 5-6, boxplots will be shown for TAI versus outcome, for treatment and control arm patients separately. In addition, probability of the outcome variable, calculated from the ORs will be plotted: TAI on the x-axis and probability of the outcome of interest on the y-axis. This will be done for adjusted/unadjusted results, and treatment subgroups. Confidence intervals will be plotted around the probability lines. For post-EVT reperfusion, boxplots will be shown for TAI versus reperfusion, for IV rtPA treatment yes and no separately. For final infarct volume, the linear regression results will be shown in a scatter plot with TAI on the x-axis and final infarct volume on the y-axis, for adjusted/unadjusted results, and treatment subgroups.

Rationale 3
Describe the rationale for the review in the context of what is already known.

3
Objectives 4 Provide an explicit statement of the questions being addressed with reference, as applicable, to participants, interventions, comparisons, outcomes and study design (PICOS). Include any hypotheses that relate to particular types of participantlevel subgroups.

Protocol and registration 5
Indicate if a protocol exists and where it can be accessed. If available, provide registration information including registration number and registry name. Provide publication details, if applicable.

4
Eligibility criteria 6 Specify inclusion and exclusion criteria including those relating to participants, interventions, comparisons, outcomes, study design and characteristics (e.g. years when conducted, required minimum follow-up). Note whether these were applied at the study or individual level i.e. whether eligible participants were included (and ineligible participants excluded) 6 from a study that included a wider population than specified by the review inclusion criteria. The rationale for criteria should be stated. Identifying studies -search 8 Present the full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

N/A
Study selection processes 9 State the process for determining which studies were eligible for inclusion.

4
Data collection processes 10 Describe how IPD were requested, collected and managed, including any processes for querying and confirming data with investigators. If IPD were not sought from any eligible study, the reason for this should be stated (for each such study).

4, HERMES original pooling report 1
If applicable, describe how any studies for which IPD were not available were dealt with. This should include whether, how and what aggregate data were sought or extracted from study reports and publications (such as extracting data independently in duplicate) and any processes for obtaining and confirming these data with investigators.

Data items 11
Describe how the information and variables to be collected were chosen. List and define all study level and participant level data that were sought, including baseline and follow-up information. If applicable, describe methods of standardising or translating variables within the IPD datasets to ensure common scales or measurements across studies.

IPD integrity A1
Describe what aspects of IPD were subject to data checking (such as sequence generation, data consistency and completeness, baseline imbalance) and how this was done.

4, HERMES original pooling report 1
Risk of bias assessment in individual studies.

12
Describe methods used to assess risk of bias in the individual studies and whether this was applied separately for each outcome. If applicable, describe how findings of IPD checking were used to inform the assessment. Report if and how risk of bias assessment was used in any data synthesis.

Specification of outcomes and effect measures
13 State all treatment comparisons of interests. State all outcomes addressed and define them in detail. State whether they were pre-specified for the review and, if applicable, whether they were primary/main or secondary/additional outcomes. Give the principal measures of effect (such as risk ratio, hazard ratio, difference in means) used for each outcome.

5
Synthesis methods

14
Describe the meta-analysis methods used to synthesise IPD. Specify any statistical methods and models used. Issues should include (but are not restricted to): • Use of a one-stage or two-stage approach.

4-7
• How effect estimates were generated separately within each study and combined across studies (where applicable).
• Specification of one-stage models (where applicable) including how clustering of patients within studies was accounted for. • Use of fixed or random effects models and any other model assumptions, such as proportional hazards.
• Methods for quantifying statistical heterogeneity (such as I 2 and t 2 ).
• How studies providing IPD and not providing IPD were analysed together (where applicable).
• How missing data within the IPD were dealt with (where applicable).

Exploration of variation in effects A2
If applicable, describe any methods used to explore variation in effects by study or participant level characteristics (such as estimation of interactions between effect and covariates). State all participant-level characteristics that were analysed as potential effect modifiers, and whether these were pre-specified. applicable, the number of events), effect estimates and confidence intervals. These may be tabulated or included on a forest plot.
Individual reporting of substudy results per trial is not possible under the HERMES pooling agreements.

Results of syntheses 21
Present summary effects for each meta-analysis undertaken, including confidence intervals and measures of statistical heterogeneity. State whether the analysis was pre-specified, and report the numbers of studies and participants and, where applicable, the number of events on which it is based.
7-10 10 7-12 When exploring variation in effects due to patient or study characteristics, present summary interaction estimates for each characteristic examined, including confidence intervals and measures of statistical heterogeneity. State whether the analysis was pre-specified. State whether any interaction is consistent across trials.
Provide a description of the direction and size of effect in terms meaningful to those who would put findings into practice.

Risk of bias across studies 22
Present results of any assessment of risk of bias relating to the accumulated body of evidence, including any pertaining to the availability and representativeness of available studies, outcomes or other variables.

Additional analyses 23
Give results of any additional analyses (e.g. sensitivity analyses). If applicable, this should also include any analyses that incorporate aggregate data for studies that do not have IPD. If applicable, summarise the main meta-analysis results following the inclusion or exclusion of studies for which IPD were not available.

Summary of evidence 24
Summarise the main findings, including the strength of evidence for each main outcome.

12-13
Strengths and limitations 25 Discuss any important strengths and limitations of the evidence including the benefits of access to IPD and any limitations arising from IPD that were not available.
14 Conclusions 26 Provide a general interpretation of the findings in the context of other evidence.

13-14
Implications A4 Consider relevance to key groups (such as policy makers, service providers and service users). Consider implications for future research.

Funding 27
Describe sources of funding and other support (such as supply of IPD), and the role in the systematic review of those providing such support. Reasons; also see manuscript Figure 1: -Thin-slice scans unavailable: n=1076 -Different scanners: n=11 ->30 minutes between scans: n=40 -Insufficient quality/incomplete scan: n=106 -Registration errors: n=76 -Other (see Figure 1): n=14 Participants for whom no data were provided: n=0 Analysed data Obtaining data

Aggregate data (report for each main outcome)
Not applicable, data provided for all eligible studies, for all eligible patients.
The PRISMA IPD flow diagram © Reproduced with permission of the PRISMA IPD Group, which encourages sharing and reuse for non commercial purposes
Effect of scan acquisition characteristics on thrombus perviousness Slice thickness difference between NCCT and CTA varied significantly between TAI quartiles (p<0.01; Supplemental Results Figure A). Larger slice thickness difference (larger NCCT slices versus thinner CTA slices) corresponded to larger TAI. TAI values and thrombus density on NCCT differed significantly between scanner brands (p<0.01; Supplemental Results Figure C and F). Thrombus density on NCCT decreased with increasing NCCT slice thickness (τ=-0.08, p=0.02; Supplemental Results Figure D). No significant effect of slice thickness or scanner brand on clot length was observed (p=0.73, p=0.41 respectively). No effect of peak kilovoltage (kVp) on TAI or NCCT thrombus density was observed (Supplemental Results Figure B and E).