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Randomized Controlled Trial
. 2023 Jul 1;80(7):682-692.
doi: 10.1001/jamaneurol.2023.1526.

Isosorbide Mononitrate and Cilostazol Treatment in Patients With Symptomatic Cerebral Small Vessel Disease: The Lacunar Intervention Trial-2 (LACI-2) Randomized Clinical Trial

Joanna M Wardlaw  1 , Lisa J Woodhouse  2 , Iris I Mhlanga  2 , Katherine Oatey  3 , Anna K Heye  3 , John Bamford  4 , Vera Cvoro  1   5 , Fergus N Doubal  1 , Timothy England  2 , Ahamad Hassan  4 , Alan Montgomery  6 , John T O'Brien  7 , Christine Roffe  8 , Nikola Sprigg  2 , David J Werring  9 , Philip M Bath  2 ; Lacunar Intervention Trial-2 (LACI-2) Investigator Group
Collaborators, Affiliations
Randomized Controlled Trial

Isosorbide Mononitrate and Cilostazol Treatment in Patients With Symptomatic Cerebral Small Vessel Disease: The Lacunar Intervention Trial-2 (LACI-2) Randomized Clinical Trial

Joanna M Wardlaw et al. JAMA Neurol. .

Abstract

Importance: Cerebral small vessel disease (cSVD) is a common cause of stroke (lacunar stroke), is the most common cause of vascular cognitive impairment, and impairs mobility and mood but has no specific treatment.

Objective: To test the feasibility, drug tolerability, safety, and effects of 1-year isosorbide mononitrate (ISMN) and cilostazol treatment on vascular, functional, and cognitive outcomes in patients with lacunar stroke.

Design, setting, and participants: The Lacunar Intervention Trial-2 (LACI-2) was an investigator-initiated, open-label, blinded end-point, randomized clinical trial with a 2 × 2 factorial design. The trial aimed to recruit 400 participants from 26 UK hospital stroke centers between February 5, 2018, and May 31, 2021, with 12-month follow-up. Included participants had clinical lacunar ischemic stroke, were independent, were aged older than 30 years, had compatible brain imaging findings, had capacity to consent, and had no contraindications to (or indications for) the study drugs. Data analysis was performed on August 12, 2022.

Interventions: All patients received guideline stroke prevention treatment and were randomized to ISMN (40-60 mg/d), cilostazol (200 mg/d), ISMN-cilostazol (40-60 and 200 mg/d, respectively), or no study drug.

Main outcomes: The primary outcome was recruitment feasibility, including retention at 12 months. Secondary outcomes were safety (death), efficacy (composite of vascular events, dependence, cognition, and death), drug adherence, tolerability, recurrent stroke, dependence, cognitive impairment, quality of life (QOL), and hemorrhage.

Results: Of the 400 participants planned for this trial, 363 (90.8%) were recruited. Their median age was 64 (IQR, 56.0-72.0) years; 251 (69.1%) were men. The median time between stroke and randomization was 79 (IQR, 27.0-244.0) days. A total of 358 patients (98.6%) were retained in the study at 12 months, with 257 of 272 (94.5%) taking 50% or more of the allocated drug. Compared with those participants not receiving that particular drug, neither ISMN (adjusted hazard ratio [aHR], 0.80 [95% CI, 0.59 to 1.09]; P = .16) nor cilostazol (aHR, 0.77 [95% CI, 0.57 to 1.05]; P = .10) alone reduced the composite outcome in 297 patients. Isosorbide mononitrate reduced recurrent stroke in 353 patients (adjusted odds ratio [aOR], 0.23 [95% CI, 0.07 to 0.74]; P = .01) and cognitive impairment in 308 patients (aOR, 0.55 [95% CI, 0.36 to 0.86]; P = .008). Cilostazol reduced dependence in 320 patients (aHR, 0.31 [95% CI, 0.14 to 0.72]; P = .006). Combination ISMN-cilostazol reduced the composite (aHR, 0.58 [95% CI, 0.36 to 0.92]; P = .02), dependence (aOR, 0.14 [95% CI, 0.03 to 0.59]; P = .008), and any cognitive impairment (aOR, 0.44 [95% CI, 0.23 to 0.85]; P = .02) and improved QOL (adjusted mean difference, 0.10 [95% CI, 0.03 to 0.17]; P = .005) in 153 patients. There were no safety concerns.

Conclusions and relevance: These results show that the LACI-2 trial was feasible and ISMN and cilostazol were well tolerated and safe. These agents may reduce recurrent stroke, dependence, and cognitive impairment after lacunar stroke, and they could prevent other adverse outcomes in cSVD. Therefore, both agents should be tested in large phase 3 trials.

Trial registration: ClinicalTrials.gov Identifier: NCT03451591.

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Conflict of interest statement

Conflict of Interest Disclosures: Prof Wardlaw reported receiving grants from the British Heart Foundation, Alzheimer’s Society, and UK Dementia Research Institute Ltd (which receives its funding from the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK) and nonfinancial support from the National Institute of Health Research (NIHR) Clinical Research Network during the conduct of the study. In addition, Prof Wardlaw reported receiving grants from the Fondation Leducq, European Union Horizon 2020, Stroke Association, Weston Brain Institute, Engineering and Physical Sciences Research Council, Biological and Biomedical Research Council, Age UK, Wellcome Trust, and Chief Scientist Office outside the submitted work. Prof Wardlaw also reported serving as chair of the European Stroke Organisation Guideline Method Working Group on Small Vessel Diseases Part 1 Covert SVD (2021) and Part 2 Lacunar Ischemic Stroke (in preparation) and chaired the European Stroke Organisation Conference in 2021 and 2022. Ms Oatey reported serving as a member of the UK Trial Managers Network Executive Committee. Dr Doubal reported receiving grants from the Stroke Association and British Heart Foundation and research fellowships from the National Health Service (NHS) Scotland during the conduct of the study. Dr England reported receiving grants from the British Heart Foundation during the conduct of the study. Prof O’Brien reported receiving consulting fees from TauRx, Novo Nordisk, Biogen, Roche, and GE Healthcare; and grants from Avid/Lilly, Merck, and Alliance Medical outside the submitted work. Dr Roffe reported serving as a member of the LACI-2 Trial Steering Committee. Dr Sprigg reported receiving academic grants from the NIHR for clinical trials (NIHR HTA TICH-2, TICH-3, and RfPB DASH) outside the submitted work. Prof Werring reported receiving consulting fees from Novo Nordisk and honoraria and speaking fees from Bayer, Alexion, and Novo Nordisk outside the submitted work. In addition, Prof Werring reported serving on the OxHarp Data Safety Monitoring Committee, as an expert advisor on National Institute for Health Care and Excellence guidelines, and as president-elect of the British and Irish Association of Stroke Physicians outside the submitted work. Prof Bath reported receiving grants from the British Heart Foundation during the conduct of the study and serving on the advisory boards of CoMind, DiaMedica, Moleac, Phagenesis, and Roche outside the submitted work. In addition, Prof Bath reported chairing the ECST-2 Data Safety Monitoring Committee, co-chairing the World Stroke Organisation Industry Committee, and holding stock options in DiaMedica outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram
ISMN indicates isosorbide mononitrate.
Figure 2.
Figure 2.. Cognition at 12 Months Assessed Using 7-Level Ordinal Adjusted Analysis
aOR indicates adjusted odds ratio; ISMN, isosorbide mononitrate.
See this image and copyright information in PMC

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