Top

Published in:

01-12-2020 | Cerebral Small Vessel Disease | Research article

Assessing the effectiveness of statin therapy for alleviating cerebral small vessel disease progression in people ≥75 years of age

Authors: Yuqi Guo, Yunpeng Li, Xukui Liu, Yi Cui, Yingxin Zhao, Shangwen Sun, Qing Jia, Qiang Chai, Gary Gong, Hua Zhang, Zhendong Liu

Published in: BMC Geriatrics | Issue 1/2020

Abstract

Background

Statins have been recommended by several guidelines as the primary prevention medication for cardiovascular diseases. However, the benefits of statin therapy for cerebral small vessel disease (CSVD), particularly in adults ≥75 years of age, have not been fully evaluated.

Methods

We analyzed the data from a prospective population-based cohort study and a randomized, double-blind, placebo-controlled clinical trial to determine whether statin therapy might aid in slowing the progression of CSVD in adults ≥75 years of age. For the cohort study, 827 participants were considered eligible and were included in the baseline analysis. Subsequently, 781 participants were included in follow-up analysis. For the clinical trial, 227 participants were considered eligible and were used in the baseline and follow-up analyses.

Results

The white matter hyperintensities (WMH) volume, the WMH-to-intracranial volume (ICV) ratio, the prevalence of a Fazekas scale score ≥ 2, lacunes, enlarged perivascular spaces (EPVS), and microbleeds were significantly lower in the statin group than the non-statin group at baseline in the cohort study (all P < 0.05). During the follow-up period, in both the cohort and clinical trial studies, the WMH volume and WMH-to-ICV ratio were significantly lower in the statin/rosuvastatin group than the non-statin/placebo group (all P < 0.001). Statin therapy was associated with lower risk of WMH, lacunes, and EPVS progression than the non-statin therapy group after adjustment for confounders (all P < 0.05). There was no statistically significant difference in the risk of microbleeds between the statin and non-statin therapy groups (all, P > 0.05).

Conclusions

Our findings indicated that statin therapy alleviated the progression of WMH, lacunes, and EPVS without elevating the risk of microbleeds. On the basis of the observed results, we concluded that statin therapy is an efficient and safe intervention for CSVD in adults ≥75 years of age.

Trial registration

Chictr.org.cn: ChiCTR-IOR-17013557, date of trial retrospective registration November 27, 2017 and ChiCTR-EOC-017013598, date of trial retrospective registration November 29, 2017.

Available only for authorised users

Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689–701. https://doi.org/10.1016/S1474-4422(10)70104-6.CrossRefPubMed

Zwanenburg JJM, van Osch MJP. Targeting cerebral small vessel disease with MRI. Stroke. 2017;48:3175–82. https://doi.org/10.1161/STROKEAHA.117.016996.CrossRefPubMed

Cuadrado-Godia E, Dwivedi P, Sharma S, Ois Santiago A, Roquer Gonzalez J, Balcells M, et al. Cerebral small vessel disease: a review focusing on pathophysiology, biomarkers, and machine learning strategies. J Stroke. 2018;20:302–20. https://doi.org/10.5853/jos.2017.02922.CrossRefPubMedPubMedCentral

Mishra A, Chauhan G, Violleau MH, Vojinovic D, Jian X, Bis JC, et al. Association of variants in HTRA1 and NOTCH3 with MRI-defined extremes of cerebral small vessel disease in older subjects. Brain. 2019;142:1009–23. https://doi.org/10.1093/brain/awz024.CrossRefPubMedPubMedCentral

Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. STandards for ReportIng vascular changes on nEuroimaging (STRIVE v1). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822–38. https://doi.org/10.1016/S1474-4422(13)70124-8.CrossRefPubMedPubMedCentral

Kaffashian S, Tzourio C, Soumare A, Dufouil C, Zhu Y, Crivello F, et al. Plasma beta-amyloid and MRI markers of cerebral small vessel disease: three-city Dijon study. Neurology. 2014;83:2038–45. https://doi.org/10.1212/WNL.0000000000001038.CrossRefPubMed

Ji T, Zhao Y, Wang J, Cui Y, Duan D, Chai Q, et al. Effect of low-dose statins and Apolipoprotein E genotype on cerebral small disease in older hypertensive patients: A subgroup analysis of a randomized clinical trial. J. Am. Med. Dir. Assoc. 2018;19:995–1002.e4. https://doi.org/10.1016/j.jamda.2018.05.025.CrossRef

Xiong Y, Wong A, Cavalieri M, Schmidt R, Chu WW, Liu X, et al. Prestroke statins, progression of white matter hyperintensities, and cognitive decline in stroke patients with confluent white matter hyperintensities. Neurotherapeutics. 2014;11:606–11. https://doi.org/10.1007/s13311-014-0270-5.CrossRefPubMedPubMedCentral

Zhang H, Cui Y, Zhao Y, Dong Y, Duan D, Wang J, et al. Effects of sartans and low-dose statins on cerebral white matter hyperintensities and cognitive function in older patients with hypertension: a randomized, double-blind and placebo-controlled clinical trial. Hypertens Res. 2019;42:717–29. https://doi.org/10.1038/s41440-018-0165-7.CrossRefPubMed

10.

Vernooij MW, Ikram MA, Tanghe HL, Vincent AJ, Hofman A, Krestin GP, et al. Incidental findings on brain MRI in the general population. N Engl J Med. 2007;357:1821–8.CrossRef

11.

Zhang H, Cui Y, Zhao Y, Dong Y, Wang J, Duan D, et al. Association of circadian rhythm of blood pressure and cerebral small vessel disease in community-based elderly. J Gerontol A Biol Sci Med Sci. 2019;74:1322–30. https://doi.org/10.1093/gerona/gly212.CrossRefPubMed

12.

van Dijk EJ, Prins ND, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam scan study. Stroke. 2008;39:2712–9. https://doi.org/10.1161/STROKEAHA.107.513176.CrossRefPubMed

13.

US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW Jr, García FA, Gillman MW, et al. Statin use for the primary prevention of cardiovascular disease in adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2016;316:1997–2007. https://doi.org/10.1001/jama.2016.15450.CrossRef

14.

Mortensen MB, Nordestgaard BG. Comparison of five major guideline for statin use in primary prevention in a contemporary general population. Ann Intern Med. 2018;168:85–92. https://doi.org/10.7326/M17-0681.CrossRefPubMed

15.

Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease. Circulation. 2019. https://doi.org/10.1161/CIR.0000000000000678.

16.

Mortensen MB, Falk E. Primary prevention with statins in the elderly. J Am Coll Cardiol. 2018;71:85–94. https://doi.org/10.1016/j.jacc.2017.10.080.CrossRefPubMed

17.

Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019;393:407–15. https://doi.org/10.1016/S0140-6736(18)31942-1.CrossRef

18.

Martínez-Sánchez P, Rivera-Ordóñez C, Fuentes B, Ortega-Casarrubios MA, Idrovo L, Díez-Tejedor E. The beneficial effect of statins treatment by stroke subtype. Eur J Neurol. 2009;16:127–33. https://doi.org/10.1111/j.1468-1331.2008.02370.x.CrossRefPubMed

19.

Bezin J, Moore N, Mansiaux Y, Steg PG, Pariente A. Real-life benefits of statins for cardiovascular prevention in elderly subjects: a population-based cohort study. Am J Med. 2019. https://doi.org/10.1016/j.amjmed.2018.12.032.

20.

Kester MI, Goos JD, Teunissen CE, Benedictus MR, Bouwman FH, Wattjes MP, et al. Associations between cerebral small-vessel disease and Alzheimer disease pathology as measured by cerebrospinal fluid biomarkers. JAMA Neurol. 2014;71:855–62. https://doi.org/10.1001/jamaneurol.2014.754.CrossRefPubMed

21.

Banerjee G, Kim HJ, Fox Z, Jäger HR, Wilson D, Charidimou A, et al. MRI-visible perivascular space location is associated with Alzheimer’s disease independently of amyloid burden. Brain. 2017;140:1107–16. https://doi.org/10.1093/brain/awx003.CrossRefPubMed

22.

Jang JW, Park SY, Park YH, Baek MJ, Lim JS, Youn YC, et al. A comprehensive visual rating scale of brain magnetic resonance imaging: application in elderly subjects with Alzheimer’s disease, mild cognitive impairment, and normal cognition. J Alzheimers Dis. 2015;44:1023–34. https://doi.org/10.3233/JAD-142088.CrossRefPubMed

23.

Pocock SJ. Clinical trials: A practical approach. 1^st edition. Chichester: John Wiley & Sons Ltd. England; 1983. p. 123–41.

24.

Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, Rudolph AE, et al. Stroke prevention by aggressive reduction in cholesterol levels (SPARCL) investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549–59.CrossRef

25.

Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581–90. https://doi.org/10.1016/S0140-6736(12)60367-5.CrossRefPubMed

26.

Stone NJ, Robinson JG, Lichenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. American College of Cardiology/American Heart Association task force on practice guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. A report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation. 2014;129:S1–S45. https://doi.org/10.1161/01.cir.0000437738.63853.7a.CrossRefPubMed

27.

Yeramaneni S, Kleindorfer DO, Sucharew H, Alwell K, Moomaw CJ, Flaherty ML, et al. Hyperlipidemia is associated with lower risk of poststroke mortality independent of statin use: a population-based study. Int J Stroke. 2017;12:152–60. https://doi.org/10.1177/1747493016670175.CrossRefPubMed

28.

Orkaby AR, Rich MW, Sun R, Lux E, Wei LJ, Kim DH. Pravastatin for primary prevention in older adults: restricted mean survival time analysis. J Am Geriatr Soc. 2018;66:1987–91. https://doi.org/10.1111/jgs.15509.CrossRefPubMedPubMedCentral

29.

Tramacere I, Boncoraglio GB, Banzi R, Del Giovane C, Kwag KH, Squizzato A, et al. Comparison of statins for secondary prevention in patients with ischemic stroke or transient ischemic attack: a systematic review and network meta-analysis. BMC Med. 2019;17:67. https://doi.org/10.1186/s12916-019-1298-5.CrossRefPubMedPubMedCentral

30.

Mok VC, Lam WW, Fan YH, Wong A, Ng PW, Tsoi TH, et al. Effects of statins on the progression of cerebral white matter lesion: post hoc analysis of the ROCAS (regression of cerebral artery stenosis) study. J Neurol. 2009;256:750–7. https://doi.org/10.1007/s00415-009-5008-7.CrossRefPubMed

31.

Fu JH, Mok V, Lam W, Wong A, Chu W, Xiong Y, et al. Effects of statins on progression of subclinical brain infarct. Cerebrovasc Dis. 2010;30:51–6. https://doi.org/10.1159/000313614.CrossRefPubMed

32.

Goldstein LB, Amaremco P, Szarek M, Callahan A 3rd, Hennerici M, Sillesen H, et al. SPARCL investigators. Hemorrhagic stroke in the stroke prevention by aggressive reduction in cholesterol levels study. Neurology. 2008;70:2364–70. https://doi.org/10.1212/01.wnl.0000296277.63350.77.CrossRefPubMed

33.

Haussen DC, Henninger N, Kumar S, Selim M. Statin use and microbleeds in patients with spontaneous interacerebral haemorrhage. Stroke. 2012;43:2677–81. https://doi.org/10.1161/STROKEAHA.112.657486.CrossRefPubMed

34.

Román GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol. 2002;1:426–36.CrossRef

35.

Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 2013;12:483–97. https://doi.org/10.1016/S1474-4422(13)70060-7.CrossRefPubMed

36.

Moran C, Phan TG, Srikanth VK. Cerebral small vessel disease: a review of clinical, radiological, and histopathological phenotypes. Int J Stroke. 2012;7:36–46. https://doi.org/10.1111/j.1747-4949.2011.00725.x.CrossRefPubMed

37.

Fazekas F, Kleinert R, Roob G, Kleinert G, Kapeller P, Schmidt R, et al. Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous interacerebral hemorrhage: evidence of microangiopathy-related microbleeds. AJNR Am J Neuroradiol. 1999;20:637–42.PubMedPubMedCentral

38.

Mitaki S, Nagai A, Oguro H, Yamaguchi S. Serum lipid fractions and cerebral microbleeds in a healthy Japanese population. Cerebrovasc Dis. 2017;43:186–91. https://doi.org/10.1159/000456623.CrossRefPubMed

Title: Assessing the effectiveness of statin therapy for alleviating cerebral small vessel disease progression in people ≥75 years of age
Authors: Yuqi Guo
Yunpeng Li
Xukui Liu
Yi Cui
Yingxin Zhao
Shangwen Sun
Qing Jia
Qiang Chai
Gary Gong
Hua Zhang
Zhendong Liu
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Cerebral Small Vessel Disease
Statins
Rosuvastatin
Published in: BMC Geriatrics / Issue 1/2020
Electronic ISSN: 1471-2318
DOI: https://doi.org/10.1186/s12877-020-01682-w

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Assessing the effectiveness of statin therapy for alleviating cerebral small vessel disease progression in people ≥75 years of age

Abstract

Background

Methods

Results

Conclusions

Trial registration

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2020

The MAKS-s study: multicomponent non-pharmacological intervention for people with severe dementia in inpatient care – study protocol of a randomised controlled trial

Comparing the case-mix of frail older people at home and of those being admitted into residential care: a longitudinal study

Determinants of participation in a post-hospitalization physical exercise program for older adults

Clinical characteristics, treatment methods and prognoses of patients with oral squamous cell carcinoma in Japanese population: a single institution retrospective cohort study

Experiences of dementia and attitude towards prevention: a qualitative study among older adults participating in a prevention trial

Walking barefoot vs. with minimalist footwear – influence on gait in younger and older adults

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page