Reasons for non-recruitment of eligible patients to a randomised controlled trial of secondary prevention after intracerebral haemorrhage: observational study
Abstract:BackgroundRecruitment to randomised prevention trials is challenging, not least for intracerebral haemorrhage (ICH) associated with antithrombotic drug use. We investigated reasons for not recruiting apparently eligible patients at hospital sites that keep screening logs in the ongoing REstart or STop Antithrombotics Randomised Trial (RESTART), which seeks to determine whether to start antiplatelet drugs after ICH.MethodBy the end of May 2015, 158 participants had been recruited at 108 active sites in RESTART.… Show more
“…20 participants also enrolled in RESTART after they enrolled in the Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2) trial. Although the planned period of recruitment was extended by 1 year (until May 31, 2018), we did not achieve the planned sample size after a time-limited extension agreed by the funder, because only one in 12 eligible patients was recruited; 25 therefore, we increased the duration of follow-up by 1 year to accrue the planned numbers of person-years of follow-up and primary outcome events.Figure 1Trial profile…”
Summary
Background
Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.
Methods
The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).
Findings
Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92).
Interpretation
These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention.
Funding
British Heart Foundation.
“…20 participants also enrolled in RESTART after they enrolled in the Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2) trial. Although the planned period of recruitment was extended by 1 year (until May 31, 2018), we did not achieve the planned sample size after a time-limited extension agreed by the funder, because only one in 12 eligible patients was recruited; 25 therefore, we increased the duration of follow-up by 1 year to accrue the planned numbers of person-years of follow-up and primary outcome events.Figure 1Trial profile…”
Summary
Background
Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.
Methods
The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).
Findings
Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92).
Interpretation
These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention.
Funding
British Heart Foundation.
“…Since RESTART began in 2013, recruitment has been challenging. We have learned that one in 12 eligible patients is actually randomised, mostly because morbidity and mortality after ICH and physician certainty are impediments to recruitment [ 10 ]. We have tried to boost recruitment with a variety of promotional activities, including: patient-orientated information on our website ( http://www.restarttrial.org/patient.html ), monthly collaborator newsletters, annual collaborator meetings, a complex recruitment intervention which has been rolled out to all sites after the PRIME SWAT was completed [ 11 ], and one-to-one engagement with site investigators by the chief investigator by telephone and in person.…”
Section: Discussionmentioning
confidence: 99%
“…At the time of writing, RESTART collaborators are based at 122 hospital sites in the National Health Service in the United Kingdom (see the ‘Acknowledgements’ section below for a list of these sites and collaborators). In view of slow recruitment [ 10 ], we conducted the Promoting Recruitment using Information Management Efficiently (PRIME) stepped-wedge, cluster randomised study within a trial (SWAT) at 72 sites to determine whether a complex intervention could boost recruitment [ 11 , 12 ]. One hundred and four sites are recruiting participants to the sub-study, which involves the conduct of brain magnetic resonance imaging (MRI) before randomisation according to the MRI sequences and parameters specified by an imaging protocol ( www.restarttrial.org/documents/RESTART_MRI_protocol.pdf ).…”
BackgroundFor adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs results in an increase in the risk of recurrent ICH or a beneficial net reduction of all serious vascular events compared to avoiding antiplatelet drugs.Methods/designThe REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, randomised, open, assessor-blind, parallel-group, randomised trial comparing starting versus avoiding antiplatelet drugs for adults surviving antithrombotic-associated ICH at 122 hospital sites in the United Kingdom. RESTART uses a central, web-based randomisation system using a minimisation algorithm, with 1:1 treatment allocation to which central research staff are masked. Central follow-up includes annual postal or telephone questionnaires to participants and their general (family) practitioners, with local provision of information about adverse events and outcome events. The primary outcome is recurrent symptomatic ICH. The secondary outcomes are: symptomatic haemorrhagic events; symptomatic vaso-occlusive events; symptomatic stroke of uncertain type; other fatal events; modified Rankin Scale score; adherence to antiplatelet drug(s). The magnetic resonance imaging (MRI) sub-study involves the conduct of brain MRI according to a standardised imaging protocol before randomisation to investigate heterogeneity of treatment effect according to the presence of brain microbleeds. Recruitment began on 22 May 2013. The target sample size is at least 720 participants in the main trial (at least 550 in the MRI sub-study).DiscussionFinal results of RESTART will be analysed and disseminated in 2019.Trial registrationISRCTN71907627 (www.isrctn.com/ISRCTN71907627). Prospectively registered on 25 April 2013.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2542-6) contains supplementary material, which is available to authorized users.
“…We did not ask collaborators at participating sites to record every patient they screened for eligibility, although some sites' standard practice was to do this anyway, which enabled us to investigate reasons for non-recruitment of eligible patients at these sites [22]. We asked collaborators to report and record every patient for whom written informed consent was obtained, so we will report the numbers of patients with consent who were either randomised or not randomised (with reasons).…”
Background: For adults surviving stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) who had taken an antithrombotic (i.e. anticoagulant or antiplatelet) drug for the prevention of vaso-occlusive disease before the ICH, it is unclear whether starting antiplatelet drugs modifies the risks of recurrent ICH, haemorrhagic events, vaso-occlusive events, or a composite of all serious vascular events compared to avoiding antiplatelet drugs.
Methods/design: The REstart or STop Antithrombotics Randomised Trial (RESTART) is an investigator-led, parallel group, open, assessor-blind, randomised trial comparing starting versus avoiding antiplatelet drugs for adults surviving antithrombotic-associated ICH. Recruitment began on 22 May 2013 and ended on 31 May 2018. Follow-up ended on 30 November 2018. This update to the protocol describes the statistical analysis plan (version 1.7, finalised on 25 January 2019). Database lock and un-blinding occured on 29 January 2019, after which the un-blinded trial statistician conducted the final analyses according to this statistical analysis plan.
Discussion: Final results of RESTART will be analysed and disseminated in May 2019.
Trial registration: ISRCTN registry 71907627. Prospectively registered on 25 April 2013.
The trial is funded by a British Heart Foundation special project grant (SP/12/2/29422) and a travel fellowship (FS/13/72/30531). The trial sponsor is the Academic and Clinical Central Office for Research and Development (ACCORD), which is a partnership between the University of Edinburgh and NHS Lothian Health Board.
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