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Tolerability, Safety and Intermediary Pharmacological Effects of Cilostazol and Isosorbide Mononitrate, Alone and Combined, in Patients with Lacunar Ischaemic Stroke: The LACunar Intervention-1 (LACI-1) Trial

118 Pages Posted: 18 Oct 2018

See all articles by Gordon W. Blair

Gordon W. Blair

University of Edinburgh - Centre for Clinical Brain Sciences; UK Dementia Research Institute - Edinburgh Dementia Research Centre; University of Edinburgh - Edinburgh Imaging

Jason P Appleton

University of Nottingham

Katie Flaherty

University of Nottingham - Stroke Trials Unit

Fergus Doubal

University of Edinburgh - Centre for Clinical Brain Sciences; UK Dementia Research Institute - Edinburgh Dementia Research Centre; University of Edinburgh - Edinburgh Imaging

Nikola Sprigg

University of Nottingham

Richard Dooley

University of Nottingham - Stroke Trials Unit

Carla Richardson

University of Nottingham - Stroke Trials Unit

Iona Hamilton

University of Edinburgh - Centre for Clinical Brain Sciences; UK Dementia Research Institute - Edinburgh Dementia Research Centre; University of Edinburgh - Edinburgh Imaging

Zhe Kang Law

University of Nottingham - Stroke Trials Unit; National University of Malaysia (UKM) - Medical Centre

Yulu Shi

University of Edinburgh - Centre for Clinical Brain Sciences; UK Dementia Research Institute - Edinburgh Dementia Research Centre; University of Edinburgh - Edinburgh Imaging

Michael S. Stringer

University of Edinburgh - Centre for Clinical Brain Sciences; UK Dementia Research Institute - Edinburgh Dementia Research Centre; University of Edinburgh - Edinburgh Imaging

Michael J. Thrippleton

University of Edinburgh - Centre for Clinical Brain Sciences; UK Dementia Research Institute - Edinburgh Dementia Research Centre; University of Edinburgh - Edinburgh Imaging

Julia Boyd

University of Edinburgh

Kirsten Shuler

Pennsylvania State University - Milton S. Hershey Medical Center

Philip M. Bath

University of Nottingham - Stroke Trials Unit

Joanna Wardlaw

University of Edinburgh - Centre for Clinical Brain Sciences; UK Dementia Research Institute - Edinburgh Dementia Research Centre; University of Edinburgh - Edinburgh Imaging

More...

Abstract

Background  Lacunar stroke, a form of small vessel disease (SVD), differs pathologically from other ischaemic stroke subtypes and has no specific long-term secondary prevention. Licenced drugs, isosorbide mononitrate (ISMN) and cilostazol, have relevant actions to prevent SVD progression.    

Methods  We recruited independent patients with clinically confirmed lacunar ischaemic stroke without cognitive impairment to a prospective randomised clinical trial, LACunar Intervention-1 (LACI-1). We randomised patients using a central web-based system, 1:1:1:1 with minimisation, to masked ISMN 25mg bd, cilostazol 100md bd, both ISMN and cilostazol started immediately, or both with start delayed. We escalated doses to target over two weeks, sustained for eight weeks. Primary outcome was the proportion achieving target dose. Secondary outcomes included symptoms, safety (haemorrhage, recurrent vascular events), cognition, haematology and vascular function. LACI-1 was powered (80%, alpha 0·05) to detect 35% (90% versus 55%) difference between the proportion reaching target dose on one versus both drugs at 55 patients. Registration ISRCTN12580546.    

Findings   LACI-1 enrolled 57 participants between March 2016 and August 2017: 18 (32%) female, mean age 66 (SD 11, range 40-85) years, onset-randomisation 203 (range 6-920) days. Most achieved full (64%) or over half (87%) dose, with no difference between cilostazol vs ISMN, single vs dual drugs. Headache and palpitations increased initially then declined similarly with dual versus single drugs. There was no between-group difference in BP, pulse-wave velocity, haemoglobin or platelet function, but pulse rate was higher (mean difference, MD, 6·4, 95%CI 1·2-11·7, p=0·02), platelet count higher (MD 35·7, 95%CI 2·8, 68·7, p=0·03) and white matter hyperintensities reduced more (p=0·007) with cilostazol versus no cilostazol.    

Interpretation  Cilostazol and ISMN are well tolerated when the dose is escalated, without safety concerns, in patients with lacunar stroke. Larger trials with longer term follow-up are justified.      

Trial Registration Number: ISRCTN12580546

Funding: Alzheimer's Society (AS-PG-14-033)

Declaration of Interest: JMW, PB, NS, FD, GB, KF, RD, MJT, IG received funding from the Alzheimer’s Society (ASPG-14-033); FD, PB, NS, JMW report funding from the UK Stroke Association; FD also reports funding from NHS Research Scotland; GB also received funding from Edinburgh and Lothians Health Foundation and the Stroke Association Princess Margaret Research Development Fellowship scheme; YS received funding from the China Scholarships Council; MJT also received funding from NHS Lothian Research and Development Office; JMW also received funding from the Scottish Funding Council; JMW, FD, MJT, MS and GB also received funding from European Union Horizon 2020 (666881, ‘SVDs@Target’) and the Fondation Leducq (16 CVD 05). NS, PB, JMW, JPA also received funding from the British Heart Foundation; PB, NS, JPA, also received funding from the National Institutes of Health Research (NIHR) HTA Programme; PB, NS, CR also received funding from the NIHR Clinical Research network (CRN) East Midlands PB is a NIHR Senior Investigator.

Ethical Approval: The trial was approval by the Scotland A Research Ethics Committee (Ref 15/SS/0154), the Medicines and Healthcare Regulatory Agency (Ref 01384/0244/001-0001) and NHS R D (Ref 2015/0354/TMF) and all participants gave written informed consent.

Keywords: lacunar stroke, small vessel disease, randomised controlled trial, cilostazol, isosorbide mononitrate, endothelium, white matter hyperintensities, blood-brain barrier, cerebrovascular reactivity

Suggested Citation

Blair, Gordon W. and Appleton, Jason P and Flaherty, Katie and Doubal, Fergus and Sprigg, Nikola and Dooley, Richard and Richardson, Carla and Hamilton, Iona and Law, Zhe Kang and Shi, Yulu and Stringer, Michael S. and Thrippleton, Michael J. and Boyd, Julia and Shuler, Kirsten and Bath, Philip M. and Wardlaw, Joanna, Tolerability, Safety and Intermediary Pharmacological Effects of Cilostazol and Isosorbide Mononitrate, Alone and Combined, in Patients with Lacunar Ischaemic Stroke: The LACunar Intervention-1 (LACI-1) Trial (October 14, 2018). Available at SSRN: https://ssrn.com/abstract=3266989 or http://dx.doi.org/10.2139/ssrn.3266989

Gordon W. Blair

University of Edinburgh - Centre for Clinical Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

UK Dementia Research Institute - Edinburgh Dementia Research Centre

United Kingdom

University of Edinburgh - Edinburgh Imaging

Edinburgh
United Kingdom

Jason P Appleton

University of Nottingham

University Park
Nottingham, NG8 1BB
United Kingdom

Katie Flaherty

University of Nottingham - Stroke Trials Unit

Nottingham, NG5 1PB
United Kingdom

Fergus Doubal

University of Edinburgh - Centre for Clinical Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

UK Dementia Research Institute - Edinburgh Dementia Research Centre

United Kingdom

University of Edinburgh - Edinburgh Imaging

Edinburgh
United Kingdom

Nikola Sprigg

University of Nottingham

University Park
Nottingham, NG8 1BB
United Kingdom

Richard Dooley

University of Nottingham - Stroke Trials Unit

Nottingham, NG5 1PB
United Kingdom

Carla Richardson

University of Nottingham - Stroke Trials Unit

Nottingham, NG5 1PB
United Kingdom

Iona Hamilton

University of Edinburgh - Centre for Clinical Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

UK Dementia Research Institute - Edinburgh Dementia Research Centre

United Kingdom

University of Edinburgh - Edinburgh Imaging

Edinburgh
United Kingdom

Zhe Kang Law

University of Nottingham - Stroke Trials Unit

Nottingham, NG5 1PB
United Kingdom

National University of Malaysia (UKM) - Medical Centre

Kuala Lumpur
Malaysia

Yulu Shi

University of Edinburgh - Centre for Clinical Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

UK Dementia Research Institute - Edinburgh Dementia Research Centre

United Kingdom

University of Edinburgh - Edinburgh Imaging

Edinburgh
United Kingdom

Michael S. Stringer

University of Edinburgh - Centre for Clinical Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

UK Dementia Research Institute - Edinburgh Dementia Research Centre

United Kingdom

University of Edinburgh - Edinburgh Imaging

Edinburgh
United Kingdom

Michael J. Thrippleton

University of Edinburgh - Centre for Clinical Brain Sciences

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

UK Dementia Research Institute - Edinburgh Dementia Research Centre

United Kingdom

University of Edinburgh - Edinburgh Imaging

Edinburgh
United Kingdom

Julia Boyd

University of Edinburgh

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

Kirsten Shuler

Pennsylvania State University - Milton S. Hershey Medical Center

PA
United States

Philip M. Bath

University of Nottingham - Stroke Trials Unit

Nottingham, NG5 1PB
United Kingdom

Joanna Wardlaw (Contact Author)

University of Edinburgh - Centre for Clinical Brain Sciences ( email )

Old College
South Bridge
Edinburgh, Scotland EH8 9JY
United Kingdom

UK Dementia Research Institute - Edinburgh Dementia Research Centre

United Kingdom

University of Edinburgh - Edinburgh Imaging

Edinburgh
United Kingdom

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