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, a randomised clinical trial

Gordon W. Blair, Jason P. Appleton, Katie Flaherty, Fergus Doubal, Nikola Sprigg, Richard Dooley, Carla Richardson, Iona Hamilton, Zhe Kang Law, Yulu Shi, Michael S. Stringer, Michael J. Thrippleton, Julia Boyd, Kirsten Shuler, Philip M. Bath, Joanna M. Wardlaw

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Lacunar stroke, a frequent clinical manifestation 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 25 mg bd, cilostazol 100 mg 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, vascular function, and neuroimaging. 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%) females, 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 (Chi-square 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. Funding: Alzheimer's Society (AS-PG-14-033).

Original languageEnglish
JournalEClinicalMedicine
DOIs
Publication statusPublished - 1 Jan 2019

Fingerprint

isosorbide-5-mononitrate
Lacunar Stroke
Randomized Controlled Trials
Pharmacology
Safety
Pharmaceutical Preparations
Blood Vessels
Pulse Wave Analysis
Hematology
Random Allocation
Secondary Prevention
cilostazol
Platelet Count
Neuroimaging
Cognition
Headache
Disease Progression
Hemoglobins
Blood Platelets
Heart Rate

Keywords

  • Blood–brain barrier
  • Cerebrovascular reactivity
  • Cilostazol
  • Endothelium
  • Isosorbide mononitrate
  • Lacunar stroke
  • Randomised controlled trial
  • Small vessel disease
  • White matter hyperintensities

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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, a randomised clinical trial. / Blair, Gordon W.; Appleton, Jason P.; Flaherty, Katie; Doubal, Fergus; Sprigg, Nikola; Dooley, Richard; Richardson, Carla; Hamilton, Iona; Law, Zhe Kang; Shi, Yulu; Stringer, Michael S.; Thrippleton, Michael J.; Boyd, Julia; Shuler, Kirsten; Bath, Philip M.; Wardlaw, Joanna M.

In: EClinicalMedicine, 01.01.2019.

Research output: Contribution to journalArticle

Blair, Gordon W. ; Appleton, Jason P. ; Flaherty, Katie ; Doubal, Fergus ; Sprigg, Nikola ; Dooley, Richard ; Richardson, Carla ; Hamilton, Iona ; Law, Zhe Kang ; Shi, Yulu ; Stringer, Michael S. ; Thrippleton, Michael J. ; Boyd, Julia ; Shuler, Kirsten ; Bath, Philip M. ; Wardlaw, Joanna M. / 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, a randomised clinical trial. In: EClinicalMedicine. 2019.
@article{09b4462f064a4e09869d67673d50d884,
title = "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, a randomised clinical trial",
abstract = "Background: Lacunar stroke, a frequent clinical manifestation 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 25 mg bd, cilostazol 100 mg 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, vascular function, and neuroimaging. 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{\%}) females, 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 (Chi-square 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. Funding: Alzheimer's Society (AS-PG-14-033).",
keywords = "Blood–brain barrier, Cerebrovascular reactivity, Cilostazol, Endothelium, Isosorbide mononitrate, Lacunar stroke, Randomised controlled trial, Small vessel disease, White matter hyperintensities",
author = "Blair, {Gordon W.} and Appleton, {Jason P.} and Katie Flaherty and Fergus Doubal and Nikola Sprigg and Richard Dooley and Carla Richardson and Iona Hamilton and Law, {Zhe Kang} and Yulu Shi and Stringer, {Michael S.} and Thrippleton, {Michael J.} and Julia Boyd and Kirsten Shuler and Bath, {Philip M.} and Wardlaw, {Joanna M.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.eclinm.2019.04.001",
language = "English",
journal = "EClinicalMedicine",
issn = "2589-5370",
publisher = "Lancet Publishing Group",

}

TY - JOUR

T1 - Tolerability, safety and intermediary pharmacological effects of cilostazol and isosorbide mononitrate, alone and combined, in patients with lacunar ischaemic stroke

T2 - The LACunar Intervention-1 (LACI-1) trial, a randomised clinical trial

AU - Blair, Gordon W.

AU - Appleton, Jason P.

AU - Flaherty, Katie

AU - Doubal, Fergus

AU - Sprigg, Nikola

AU - Dooley, Richard

AU - Richardson, Carla

AU - Hamilton, Iona

AU - Law, Zhe Kang

AU - Shi, Yulu

AU - Stringer, Michael S.

AU - Thrippleton, Michael J.

AU - Boyd, Julia

AU - Shuler, Kirsten

AU - Bath, Philip M.

AU - Wardlaw, Joanna M.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Lacunar stroke, a frequent clinical manifestation 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 25 mg bd, cilostazol 100 mg 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, vascular function, and neuroimaging. 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%) females, 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 (Chi-square 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. Funding: Alzheimer's Society (AS-PG-14-033).

AB - Background: Lacunar stroke, a frequent clinical manifestation 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 25 mg bd, cilostazol 100 mg 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, vascular function, and neuroimaging. 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%) females, 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 (Chi-square 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. Funding: Alzheimer's Society (AS-PG-14-033).

KW - Blood–brain barrier

KW - Cerebrovascular reactivity

KW - Cilostazol

KW - Endothelium

KW - Isosorbide mononitrate

KW - Lacunar stroke

KW - Randomised controlled trial

KW - Small vessel disease

KW - White matter hyperintensities

UR - http://www.scopus.com/inward/record.url?scp=85064642674&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064642674&partnerID=8YFLogxK

U2 - 10.1016/j.eclinm.2019.04.001

DO - 10.1016/j.eclinm.2019.04.001

M3 - Article

AN - SCOPUS:85064642674

JO - EClinicalMedicine

JF - EClinicalMedicine

SN - 2589-5370

ER -