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Headline
Losartan administered over 12 months did not alter brain atrophy in Alzheimer’s disease.
Abstract
Background:
Medications that modify the renin–angiotensin system may reduce Alzheimer’s disease pathology and reduce the rate of disease progression.
Objective:
This study investigated whether taking the antihypertensive drug losartan, in addition to normal care, would slow the progression of Alzheimer’s disease when compared with a placebo.
Design:
A double-blind multicentre randomised controlled trial, after a 4-week open-label phase, with follow-up at 14 days and at 3, 6, 9 and 12 months. The primary outcome was based on measured imaging differences in brain volume between baseline and 12 months.
Setting:
Twenty-three NHS hospital trusts across England, Scotland and Northern Ireland.
Participants:
Patients diagnosed with mild-to-moderate Alzheimer’s disease were eligible to participate if they met the following criteria: (1) aged ≥ 55 years; (2) a Mini Mental State Examination score of 15–28; (3) a modified Hachinski Ischaemic Score of ≤ 5; (4) a previous computerised tomography, single-photon emission computed tomography or magnetic resonance imaging scan consistent with a diagnosis of Alzheimer’s disease; (5) a study companion who was willing to participate in the study; and (6) capacity to consent for themselves. Patients were ineligible if they were (1) taking or intolerant to renin–angiotensin system-related medications, (2) unlikely to undergo magnetic resonance imaging or (3) unlikely to complete the trial protocol. People who had blood pressure outside the normal ranges, defined cardiovascular issues, impaired liver or renal function, or a primary neurodegenerative disease that was not Alzheimer’s disease were also excluded, as were women who had not reached menopause and were unwilling to take relevant protocol-specific safety precautions.
Intervention:
The intervention was either 100 mg of overencapsulated losartan (Teva Pharmaceuticals Industries Ltd, Petah Tikva, Israel) daily or a matched placebo for 12 months.
Main outcome measures:
Difference in brain atrophy, represented by measurement of whole-brain volume before and following 12 months of treatment post randomisation, was measured using volumetric MRI and determined by boundary shift interval analysis. Secondary outcomes included changes in rates of Alzheimer’s disease progression (as assessed using the ADAS-Cog, Mini Mental State Examination and Neuropsychiatric Inventory), the volume of white matter hyperintensities, cerebral blood flow (assessed by magnetic resonance imaging), blood pressure, magnetic resonance imaging measures of atrophy and association with measures of cognitive decline, and drug compliance and tolerability.
Results:
A total of 261 participants entered the open-label phase, of whom 211 were randomised to the intervention (n = 105) or placebo (n = 106) arms. Of the 197 people (93%) who completed the study, 81% (n = 171) had a valid primary outcome. The difference in brain volume between arms was consistent with chance (–2.79 ml, 95% confidence interval –6.46 to 0.89 ml; p = 0.19), and there was no evidence of benefit for any of the secondary outcome measures.
Limitations:
Our study had 82% power to detect treatment-based changes and, as a result, may have been underpowered or, more likely, the intervention, which may not have crossed the blood–brain barrier as much as expected, may have been given too late or for an insufficient amount of time in the disease process to influence the outcomes.
Conclusions:
Losartan administered over 12 months did not alter brain atrophy in Alzheimer’s disease.
Future work:
Other related ‘sartans’ could be tested in patient groups with mild cognitive impairment and for longer to fully test this hypothesis.
Trial registration:
Current Controlled Trials ISRCTN93682878 and EudraCT 2012-003641-15.
Funding:
This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 19. See the NIHR Journals Library website for further project information.
Contents
- Plain English summary
- Scientific summary
- Chapter 1. Introduction (including scientific background and explanation of rationale)
- Scientific background
- The timeliness of the RADAR trial
- Hypothesis
- Study design
- Duration of treatment and follow-up
- Patient and public involvement
- Open-label phase
- Randomised phase
- Study setting
- Intervention
- Ethics approval and research governance
- Participants
- Inclusion criteria
- Exclusion criteria
- Recruitment procedure
- Enhancing site recruitment
- Informed consent
- Randomisation
- Blinding
- Outcome measures and assessments
- Primary outcome
- Secondary outcomes
- Sample size
- Adherence to intervention
- Statistical analysis
- Preliminary analyses
- Primary analysis
- Secondary analyses
- Sensitivity analyses
- Exploratory analyses
- Chapter 2. Results
- Chapter 3. Sensitivity analyses
- Chapter 4. Discussion
- Acknowledgements
- References
- Appendix 1. Details of cognitive assessments, measures of daily life and quality of life
- Appendix 2. Supplementary adverse event details
- Glossary
- List of abbreviations
About the Series
Declared competing interests of authors: Patrick G Kehoe has previously undertaken advisory work for Novartis in the development and use of dual-acting inhibitors of angiotensin receptors and neprilysin for the treatment of different forms of cardiovascular disease. He is also an unfunded co-investigator of the ongoing Alzheimer’s Association (USA)-funded HEART Phase 1b study of telmisartan and its use as an intervention against the renin–angiotensin system in non-dementia African Americans at risk of developing dementia by parental history. Carole H Sudre was a recipient of an Alzheimer’s Society Junior Fellowship (AS-JF-17–011) during the conduct of the study. J Athene Lane is a co-director of a Clinical Trials Unit (CTU) that receives National Institute for Health Research (NIHR) CTU infrastructure support and is a member of the NIHR CTU Standing Advisory Committee. Peter Passmore received honoraria for talks on a variety of antihypertensive medications over a number of years. This included losartan (losartan potassium; Teva Pharmaceuticals Industries Ltd, Petah Tikva, Israel) and similar medications. Nick Fox reports personal fees from Biogen Inc. (Cambridge, MA, USA), GE Healthcare (Chicago, IL, USA) and Lilly (Hampshire, UK) and Roche (Roche Diagnostics, Hertford, UK), outside the submitted work. Yoav Ben-Shlomo has received funding from the NIHR HTA programme as a co-investigator of the CHolinesterase Inhibitors to prEvent Falls in Parkinson’s Disease (CHIEF-PD) trial. He is a member of the NIHR Parkinson’s Portfolio Development Group (PDG) and the Care, Implementation and Public Health Grant Advisory Board for the Alzheimer’s Society and is the cohort representative for the Caerphilly Prospective Study (CaPS) that is part of the Dementia Platform UK collaboration.
Article history
The research reported in this issue of the journal was funded by the EME programme as project number 11/47/03. The contractual start date was in March 2013. The final report began editorial review in October 2019 and was accepted for publication in April 2020. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The EME editors and production house have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the final report document. However, they do not accept liability for damages or losses arising from material published in this report.
Last reviewed: October 2019; Accepted: April 2020.
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