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Platelet transfusion in brain haemorrhage


- candidate number3250
- NTR NumberNTR1303
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR29-apr-2008
- Secondary IDsNL16450.018.08 METC van het AMC
- Public TitlePlatelet transfusion in brain haemorrhage
- Scientific TitlePlatelet transfusion in cerebral haemorrhage
- ACRONYMPATCH
- hypothesisPlatelet transfusion limits haematoma growth and thus improves outcome in patients with intracerebral haemorrhage using anti-platelet therapy.
- Healt Condition(s) or Problem(s) studiedStroke, Intracerebral haemorrhage, Stroke, Platelet therapy
- Inclusion criteria1. Age > 18 years
2. Non-traumatic, primary, supratentorial ICH
3. Haematoma volume > 150 cc
4. GCS score 8-15
5. Anti-platelet therapy for at least the previous 7 days
6. Transfusion can be started < 6 hrs after onset
7. Transfusion can be started < 1,5 hrs after CT
8. mRankin scale score before ICH 0 or 1
9. Informed consent obtained
- Exclusion criteria1. Bleeding pattern on CT suggestive of AVM or aneurysm
2. Haematoma evacuation planned < 24 hrs
3. Intraventricular haemorrhage (sedimentation in posterior horns is allowed)
4. Previous adverse reaction to platelet transfusion
5. Known use of vitamine K antagonists
6. Known thrombocytopenia < 100 x 109/l
7. History of coagulopathy
8. Previously legally incompetent adults prior to stroke
9. Death appears imminent
- mec approval receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingSingle
- controlActive
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-jun-2008
- planned closingdate1-jun-2010
- Target number of participants190
- Interventions- 95 patients receive platelet transfusion as soon as possible within 6 hours after onset
- 95 patients receive standard care

Platelet transfusion consists of a single gift of 5 or 10 donor units depending on type of anti-platelet medication (only patients using clopidogrel receive 10 units).
- Primary outcomePoor outcome defined as a modified Rankin Scale (mRS) score 4-6 after 3 months.
- Secondary outcome- Haematoma growth on CT in the first 24 hours
- Complications of platelet transfusion
- Whether the CTA "spot sign" can predict primary outcome
- Whether the CTA "spot sign" can predict haematoma enlargement on CT
- Survival rate and level of physical disability at three months
- Functional health at three months using the full ordinal scoring range of the mRS
- Costs
- TimepointsPrimary outcome will be determined after 3 months.
- Trial web siteN/A
- statusstopped: trial finished
- CONTACT FOR PUBLIC QUERIES Irem Baharoglu
- CONTACT for SCIENTIFIC QUERIES Irem Baharoglu
- Sponsor/Initiator Academic Medical Center (AMC), Amsterdam
- Funding
(Source(s) of Monetary or Material Support)
ZON-MW, The Netherlands Organization for Health Research and Development, Sanquin Blood Supply
- PublicationsN/A
- Brief summaryPlatelet Transfusion in Cerebral Haemorrhage (PATCH)
Background
Stroke is a major cause of acquired disability in the Netherlands. After the care for children born with a handicap, the care for stroke patients consumes the largest portion of the total health care budget.
In recent years acute treatment in ischemic stroke improved significantly. Thrombolysis within 3 hours was shown to improve clinical outcome. However, for haemorrhagic stroke or intracerebral haemorrhage (ICH), which accounts for 15% of all stroke patients, no acute treatment option currently exists. Haematoma volume is one of the most important outcome predictors in ICH. Because several studies have shown that haematoma volume increases during the first 6 hours after onset of ICH, reduction of this haematoma growth provides a promising target to improve outcome. Patients using platelet aggregation inhibitors (PAI) are especially at risk for haematoma growth and therefore platelet transfusion (PT) is an acute treatment option which should be investigated.

Objective
The objective of our study is to investigate whether platelet transfusion within 6 hours after onset of ICH can improve functional outcome by limiting haematoma growth in patients using PAI.

Study Design
Probe: Prospective, randomised, open treatment, blind end-point evaluation

Study Population
Patients with spontaneous ICH who were using PAI at least during the 7 days preceding haemorrhage.

Intervention
Patients are randomised to receive a single gift of platelets (5 or 10 donor units) within 6 hours after start of symptoms or standard care without platelet transfusion

Outcome
The primary endpoint is poor functional outcome as recorded on the modified Rankin Scale (mRS) at three months follow-up (mRS 4-6).
Secondary endpoints are complications of PT, haematoma enlargement on CT-scan, survival at three months, changes in outcome at three months (analysis of the mRS score as an ordinal scale ), poor outcome defined as mRS 3-6, disability assessed with the ALDS scale, cause of poor outcome, costs and predictive value of the CTA 'spot sign' and different laboratory measurements.

Sample Size
Poor outcome occurs in at least 70% of these patients. To detect a reduction of poor outcome from 70% to 50% with a two group Chi-square test with a 0.05 two-sided significance level and 80% power, 95 patients are needed in each group (190 patients in total).
Thirty centers are willing to participate in our study. If each center can randomize 3 to 4 patients each year, patient inclusion will be completed in 21 months. The last patient will then be assessed 2 years after the onset of the study.

- Main changes (audit trail)30-03-2016
STATISTICAL ANALYSIS PLAN PATCH 14 March 2016

Overall principles
The data analysis will start after the 3-month follow-up data of the last included patient has been obtained, and after the clinical trial module of the study database has been cleaned and locked. The analyses will be done by a co-investigator (M Irem Baharoglu) supervised by the principal investigator (Yvo B Roos) and an independent epidemiologist/statistician of the AMC Clinical Research Unit. The statistical programming and analysis to produce all summary tables and figures will use the statistical package IBM SPSS statistics version 22. In general, variables will be summarized using simple descriptive statistics such as means with standard deviation for continuous symmetric variables, medians and interquartile ranges for continuous skewed variables, and frequencies with percentages for categorical variables. All analyses will be done according to the intention-to-treat principle, by analysing patients in the groups to which they were allocated by randomisation. The analyses will first be performed blind to treatment allocation, to allow for checking of the data and the proposed summaries/analyses. After the investigation and correction of any isolated or systematic data errors, treatment allocation will be unmasked. The primary outcome will be analysed in the pre-specified subgroups below, irrespective of the presence of statistical significance in the overall analysis. Safety outcomes will be additionally analysed in the as-treated (not per- protocol) population.

Overall level of statistical significance
According to Haybittle-Peto's stopping rule used in the interim analysis, no adjustment of the p-value will be used for the final analysis [1]. A two-sided p-value < 0.05 will be considered statistically significant. Statistical uncertainty will be expressed in a two-sided 95% CI.

Handling of missing data
Missing baseline and outcome data will not be imputed. We will state which data are missing and calculate frequencies using the total number of patients with available data. When a patient is lost to follow-up or has withdrawn consent, we will use all available data up until withdrawal of consent or loss to follow-up. A specific section in the paper will report on missing data.

Definition of populations for analysis
The unit of analysis will be the patient.

Intention-to-treat population
All randomised patients will be analysed in the treatment group to which they were originally allocated irrespective of non-adherence or deviations from protocol. Occasionally, investigators randomised the same patient twice in the web-based randomisation system because they were not aware of the treatment allocation from the first randomisation; in these cases, the treatment allocation of the second randomisation was used in practice, and will be used in the final analyses, and the first unused randomisation record was removed from the trial database.

As-treated population
Patients will be analysed in groups according to treatment received irrespective of allocated treatment at randomization, thus creating a group that did not receive platelet transfusion (control) and a group that received any platelet transfusion (intervention). The patients will still be included in the as-treated analysis if there was a protocol violation (e.g. not receiving treatment within the described time-frame, not receiving the correct number of units of platelets, or not meeting inclusion or exclusion criteria).

List of analyses
Recruitment and retention
The trial profile and inclusion will be shown in a CONSORT flow diagram, including the total number of randomised patients and then showing per treatment group the numbers receiving allocated treatment, withdrawing consent, and lost to follow up.

Baseline characteristics
The baseline characteristics of all participants in each treatment group will be outlined in a table, but no formal statistical testing will be performed. The table will describe the following variables: age, sex, vascular co-morbidities, history of coagulopathy, type of antiplatelet therapy (as used for stratification), use of a statin, Glasgow Coma Scale score, NIHSS score, platelet count, ICH location and volume on baseline imaging, presence/extent of intraventricular blood on baseline imaging, and the ICH score [2].

Protocol deviations and violations
All substantial protocol violations will be listed.

Adherence to allocated treatment
Adherence will be reported descriptively.

Primary outcome
We have chosen to quantify the effect of platelet transfusion on the primary outcome of the mRS at three months with the common OR and 95%CI from an ordinal logistic regression analysis of the shift of all categories of the mRS [3], rather than using the pre-specified fixed dichotomous approach. First a crude OR with 95% CI will be calculated after which multivariable regression analysis will be used to adjust for the following:
X Type of antiplatelet therapy used (stratification variable: cyclooxygenase inhibitor only vs. ADP receptor inhibitor only vs. cyclooxygenase inhibitor in combination with an adenosine reuptake inhibitor vs. cyclooxygenase inhibitor in combination with ADP receptor inhibitor).
X ICH severity, quantified by the ICH score [2]
X Any large, chance imbalances at baseline between intervention and control groups in covariates that might have a major influence on the primary outcome.
We will not correct for the number of centres that recruited patients, although this was a stratification variable. This because many centres included only a small number of patients and adjusting for all centres might lead to unreliable estimates of the treatment effect. We will perform a separate sensitivity analysis to evaluate modification of treatment effect by centre, as described below.

Secondary outcomes
Survival of patients and the proportion of patients with poor outcome according to the different fixed dichotomous analyses of the mRS (score 4V6 or 3V6), at three months will be expressed as proportions for each treatment group and the difference will be tested using the chi-square test and quantified using OR with 95%CI. ICH volume will be expressed in absolute mL and the difference in this volume (i.e. growth) between imaging at baseline and after 24 hours will be calculated in mL, where a positive figure will represent growth and a negative value will represent shrinkage of ICH. The median difference in ICH growth will be compared between treatment groups using the Mann Whitney U test. The ordinal distribution of the mRs will be shown for patients that received platelet transfusion within 3 hours and between 3 and 6 hours of symptoms separately.

Safety outcomes
Safety outcomes will be reported in the intention-to treat and as-treated populations. Proportions will be tested for between-group differences using the chi-square test and expressed in OR with 95% CI. For all continuous variables either means with standard deviation or medians with interquartile range will be calculated where appropriate and testing for difference will be performed with either the two-group T-test or Mann Whitney U test where appropriate.

Subgroup analyses
We will test for modification of the effect of platelet transfusion on the primary outcome using ordinal regression analyses for the following sub-groups:
X Pre-ICH antiplatelet therapy used: single vs. dual therapy X ICH volume at baseline, trichotomised according to the distribution of ICH volume on the baseline diagnostic scan X country of randomisation (The Netherlands vs. Scotland vs. France)

Sensitivity analyses
Using ordinal regression we will test for heterogeneity in the effect of platelet transfusion on the primary outcome in the centres that randomised at least five patients (eight in The Netherlands, three in Scotland, and three in France), representing 66% of all patients included. Inclusion of at least five patients was chosen so that it was likely that there would be at least one outcome in each treatment arm of the trial in each centre.

REFERENCES
1 Schulz KF, Grimes DA. Multiplicity in randomised trials II: subgroup and interim analyses. Lancet 2005;365(9471):1657-1661
2 Hemphill JC 3rd, Bonovich DC, Besmertis L et al.; The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32(4):891-7
3 Bath PM, Lees KR, Schellinger PD et al.; European Stroke Organisation Outcomes Working Group. Statistical analysis of the primary outcome in acute stroke trials. Stroke 2012;43(4):1171-8
- RECORD29-apr-2008 - 30-mrt-2016


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