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Meta-Analysis
. 2023 Aug 4;8(8):CD013573.
doi: 10.1002/14651858.CD013573.pub2.

Pharmacological interventions for asymptomatic carotid stenosis

Caroline Nb Clezar  1 , Carolina Dq Flumignan  1 , Nicolle Cassola  1 , Luis Cu Nakano  1 , Virginia Fm Trevisani  2 , Ronald Lg Flumignan  1
Affiliations
Meta-Analysis

Pharmacological interventions for asymptomatic carotid stenosis

Caroline Nb Clezar et al. Cochrane Database Syst Rev. .

Abstract
in English, Persian

Background: Carotid artery stenosis is narrowing of the carotid arteries. Asymptomatic carotid stenosis is when this narrowing occurs in people without a history or symptoms of this disease. It is caused by atherosclerosis; that is, the build-up of fats, cholesterol, and other substances in and on the artery walls. Atherosclerosis is more likely to occur in people with several risk factors, such as diabetes, hypertension, hyperlipidaemia, and smoking. As this damage can develop without symptoms, the first symptom can be a fatal or disabling stroke, known as ischaemic stroke. Carotid stenosis leading to ischaemic stroke is most common in men older than 70 years. Ischaemic stroke is a worldwide public health problem.

Objectives: To assess the effects of pharmacological interventions for the treatment of asymptomatic carotid stenosis in preventing neurological impairment, ipsilateral major or disabling stroke, death, major bleeding, and other outcomes.

Search methods: We searched the Cochrane Stroke Group trials register, CENTRAL, MEDLINE, Embase, two other databases, and three trials registers from their inception to 9 August 2022. We also checked the reference lists of any relevant systematic reviews identified and contacted specialists in the field for additional references to trials.

Selection criteria: We included all randomised controlled trials (RCTs), irrespective of publication status and language, comparing a pharmacological intervention to placebo, no treatment, or another pharmacological intervention for asymptomatic carotid stenosis.

Data collection and analysis: We used standard Cochrane methodological procedures. Two review authors independently extracted the data and assessed the risk of bias of the trials. A third author resolved disagreements when necessary. We assessed the evidence certainty for key outcomes using GRADE.

Main results: We included 34 RCTs with 11,571 participants. Data for meta-analysis were available from only 22 studies with 6887 participants. The mean follow-up period was 2.5 years. None of the 34 included studies assessed neurological impairment and quality of life. Antiplatelet agent (acetylsalicylic acid) versus placebo Acetylsalicylic acid (1 study, 372 participants) may result in little to no difference in ipsilateral major or disabling stroke (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.47 to 2.47), stroke-related mortality (RR 1.40, 95% CI 0.54 to 3.59), progression of carotid stenosis (RR 1.16, 95% CI 0.79 to 1.71), and adverse events (RR 0.81, 95% CI 0.41 to 1.59), compared to placebo (all low-certainty evidence). The effect of acetylsalicylic acid on major bleeding is very uncertain (RR 0.98, 95% CI 0.06 to 15.53; very low-certainty evidence). The study did not measure neurological impairment or quality of life. Antihypertensive agents (metoprolol and chlorthalidone) versus placebo The antihypertensive agent, metoprolol, may result in no difference in ipsilateral major or disabling stroke (RR 0.14, 95% CI 0.02 to1.16; 1 study, 793 participants) and stroke-related mortality (RR 0.57, 95% CI 0.17 to 1.94; 1 study, 793 participants) compared to placebo (both low-certainty evidence). However, chlorthalidone may slow the progression of carotid stenosis (RR 0.45, 95% CI 0.23 to 0.91; 1 study, 129 participants; low-certainty evidence) compared to placebo. Neither study measured neurological impairment, major bleeding, adverse events, or quality of life. Anticoagulant agent (warfarin) versus placebo The evidence is very uncertain about the effects of warfarin (1 study, 919 participants) on major bleeding (RR 1.19, 95% CI 0.97 to 1.46; very low-certainty evidence), but it may reduce adverse events (RR 0.89, 95% CI 0.81 to 0.99; low-certainty evidence) compared to placebo. The study did not measure neurological impairment, ipsilateral major or disabling stroke, stroke-related mortality, progression of carotid stenosis, or quality of life. Lipid-lowering agents (atorvastatin, fluvastatin, lovastatin, pravastatin, probucol, and rosuvastatin) versus placebo or no treatment Lipid-lowering agents may result in little to no difference in ipsilateral major or disabling stroke (atorvastatin, lovastatin, pravastatin, and rosuvastatin; RR 0.36, 95% CI 0.09 to 1.53; 5 studies, 2235 participants) stroke-related mortality (lovastatin and pravastatin; RR 0.25, 95% CI 0.03 to 2.29; 2 studies, 1366 participants), and adverse events (fluvastatin, lovastatin, pravastatin, probucol, and rosuvastatin; RR 0.76, 95% CI 0.53 to1.10; 7 studies, 3726 participants) compared to placebo or no treatment (all low-certainty evidence). The studies did not measure neurological impairment, major bleeding, progression of carotid stenosis, or quality of life.

Authors' conclusions: Although there is no high-certainty evidence to support pharmacological intervention, this does not mean that pharmacological treatments are ineffective in preventing ischaemic cerebral events, morbidity, and mortality. High-quality RCTs are needed to better inform the best medical treatment that may reduce the burden of carotid stenosis. In the interim, clinicians will have to use other sources of information.

پیشینه: تنگی شریان کاروتید عبارت است از باریک شدن شریان‌های کاروتید. تنگی کاروتید بدون نشانه زمانی است که این تنگی در افراد بدون سابقه یا نشانه‌های این بیماری رخ می‌دهد. این عارضه ناشی از آترواسکلروز (atherosclerosis) است؛ یعنی تجمع چربی، کلسترول و دیگر مواد داخل و روی دیواره‌های شریان. احتمال بروز آترواسکلروز در افرادی که عوامل خطر متعددی دارند، مانند دیابت، هیپرتانسیون، هیپرلیپیدمی و مصرف سیگار، بیشتر است. از آنجایی که این آسیب می‌تواند بدون نشانه ایجاد شود، اولین نشانه می‌تواند یک سکته مغزی کشنده یا ناتوان کننده باشد که به عنوان سکته مغزی ایسکمیک شناخته می‌شود. تنگی کاروتید منجر به وقوع سکته مغزی ایسکمیک در مردان بالای 70 سال شایع‌تر رخ می‌دهد. سکته مغزی ایسکمیک یک مشکل سلامت عمومی در سراسر جهان است. اهداف: ارزیابی تاثیرات مداخلات دارویی در درمان تنگی کاروتید بدون نشانه به منظور پیشگیری از بروز‌اختلالات نورولوژیکی، سکته مغزی ماژور یا ناتوان کننده یک طرفه (ipsilateral)، مرگ‌ومیر، خونریزی شدید، و دیگر پیامدها. روش‌های جست‌وجو: پایگاه ثبت کارآزمایی‌های گروه سکته مغزی (stroke) در کاکرین، CENTRAL؛ MEDLINE؛ Embase؛ دو بانک اطلاعاتی دیگر، و سه پایگاه ثبت کارآزمایی را از زمان شروع به کار تا 9 آگوست 2022 جست‌وجو کردیم. هم‌چنین فهرست منابع مرورهای سیستماتیک مرتبط را که شناسایی شدند، بررسی کرده و برای یافتن منابع بیشتر برای کارآزمایی‌ها با متخصصان این زمینه تماس گرفتیم. معیارهای انتخاب: همه کارآزمایی‌های تصادفی‌سازی و کنترل شده (randomised controlled trials; RCTs) را بدون در نظر گرفتن وضعیت انتشار و زبان نگارش مقاله وارد کردیم، که به مقایسه یک مداخله دارویی با دارونما (placebo)، عدم درمان، یا مداخله دارویی دیگر در درمان تنگی کاروتید بدون نشانه پرداختند. گردآوری و تجزیه‌وتحلیل داده‌ها: از پروسیجرهای استاندارد روش‌شناسی (methodology) کاکرین استفاده کردیم. دو نویسنده مرور به‌طور مستقل از هم به استخراج داده‌ها و ارزیابی خطر سوگیری (bias) در کارآزمایی‌ها پرداختند. در صورت لزوم، نویسنده سوم اختلاف‌نظرات را حل‌وفصل کرد. قطعیت شواهد را برای پیامدهای کلیدی با استفاده از رویکرد درجه‌بندی توصیه، ارزیابی، توسعه و ارزشیابی (Grading of Recommendations Assessment, Development and Evaluation; GRADE) ارزیابی کردیم. نتایج اصلی: تعداد 34 RCT را با 11,571 شرکت‌کننده وارد کردیم. برای انجام متاآنالیز، داده‌هایی از فقط 22 مطالعه با 6887 شرکت‌کننده در دسترس بودند. میانگین دوره پیگیری 2.5 سال بود. هیچ یک از 34 مطالعه وارد شده اختلالات نورولوژیکی و کیفیت زندگی را ارزیابی نکردند. عامل ضد پلاکت (استیل‌سالیسیلیک اسید) در برابر دارونما استیل‌سالیسیلیک اسید (acetylsalicylic acid) در مقایسه با دارونما (1 مطالعه، 372 شرکت‌کننده) ممکن است تفاوتی اندک تا عدم تفاوت را در سکته مغزی ماژور یا ناتوان کننده یک طرفه (خطر نسبی (RR): 1.08؛ 95% فاصله اطمینان (CI): 0.47 تا 2.47)، مورتالیتی ناشی از سکته مغزی (RR: 1.40؛ 95% CI؛ 0.54 تا 3.59)، پیشرفت تنگی کاروتید (RR: 1.16؛ 95% CI؛ 0.79 تا 1.71)، و عوارض جانبی (RR: 0.81؛ 95% CI؛ 0.41 تا 1.59) ایجاد کند (همگی دارای شواهد با قطعیت پائین). تاثیر استیل‌سالیسیلیک اسید بر خونریزی شدید بسیار نامطمئن است (RR: 0.98؛ 95% CI؛ 0.06 تا 15.53؛ شواهد با قطعیت بسیار پائین). این مطالعه اختلالات نورولوژیکی یا کیفیت زندگی را اندازه‌گیری نکرد. عوامل آنتی‌هیپرتانسیو (متوپرولول و کلرتالیدون) در برابر دارونما عامل آنتی‌هیپرتانسیو، متوپرولول (metoprolol)، در مقایسه با دارونما ممکن است هیچ تفاوتی را در سکته مغزی ماژور یا ناتوان کننده یک طرفه (RR: 0.14؛ 95% CI؛ 0.02 تا 1.16؛ 1 مطالعه، 793 شرکت‌کننده) و مورتالیتی ناشی از سکته مغزی (RR: 0.57؛ 95% CI؛ 0.17 تا 1.94؛ 1 مطالعه، 793 شرکت‌کننده) ایجاد نکند (هر دو دارای شواهد با قطعیت پائین). با این حال، کلرتالیدون (chlorthalidone) در مقایسه با دارونما ممکن است سرعت پیشرفت تنگی کاروتید را کاهش دهد (RR: 0.45؛ 95% CI؛ 0.23 تا 0.91؛ 1 مطالعه، 129 شرکت‌کننده، شواهد با قطعیت پائین). هیچ یک از این مطالعات، اختلالات نورولوژیکی، خونریزی شدید، عوارض جانبی یا کیفیت زندگی را اندازه‌گیری نکردند. عامل آنتی‌کوآگولانت (وارفارین) در برابر دارونما شواهد در مورد تاثیرات وارفارین (warfarin) (1 مطالعه، 919 شرکت‌کننده) بر خونریزی شدید بسیار نامطمئن است (RR: 1.19؛ 95% CI؛ 0.97 تا 1.46؛ شواهد با قطعیت بسیار پائین)، اما ممکن است عوارض جانبی را در مقایسه با دارونما کاهش دهد (RR: 0.89؛ 95% CI؛ 0.81 تا 0.99؛ شواهد با قطعیت پائین). این مطالعه اختلالات نورولوژیکی، سکته مغزی ماژور یا ناتوان کننده یک طرفه، مورتالیتی ناشی از سکته مغزی، پیشرفت تنگی کاروتید یا کیفیت زندگی را اندازه‌گیری نکرد. عوامل کاهنده لیپید (آتورواستاتین، فلوواستاتین، لوواستاتین، پراواستاتین، پروبوکل و رزوواستاتین) در برابر دارونما یا عدم درمان عوامل کاهنده لیپید ممکن است تفاوتی اندک تا عدم تفاوت را در سکته مغزی ماژور یا ناتوان کننده یک طرفه (آتورواستاتین (atorvastatin)، لوواستاتین (lovastatin)، پراواستاتین (pravastatin)، و رزوواستاتین (rosuvastatin)؛ RR: 0.36؛ 95% CI؛ 0.09 تا 1.53؛ 5 مطالعه، 2235 شرکت‌کننده) مورتالیتی ناشی از سکته مغزی (لوواستاتین و پراواستاتین؛ RR: 0.25؛ 95% CI؛ 0.03 تا 2.29؛ 2 مطالعه، 1366 شرکت‌کننده) و عوارض جانبی (فلوواستاتین (fluvastatin)، لوواستاتین، پراواستاتین، پروبوکول (probucol) و رزوواستاتین؛ RR: 0.76؛ 95% CI؛ 0.53 تا 1.10؛ 7 مطالعه، 3726 شرکت‌کننده) در مقایسه با دارونما یا عدم درمان ایجاد کنند (همگی دارای شواهد با قطعیت پائین). این مطالعات اختلالات نورولوژیکی، خونریزی شدید، پیشرفت تنگی کاروتید یا کیفیت زندگی را اندازه‌گیری نکردند. نتیجه‌گیری‌های نویسندگان: اگرچه شواهدی با قطعیت بالا برای حمایت از مداخله دارویی وجود ندارد، این مساله بدان معنا نیست که درمان‌های دارویی در پیشگیری از رویدادهای ایسکمیک مغزی، موربیدیتی و مورتالیتی بی‌اثر هستند. انجام RCTهایی با کیفیت بالا برای آگاهی از بهترین درمان طبی که ممکن است بار (burden) تنگی کاروتید را کاهش دهد، مورد نیاز است. در این مدت، متخصصان بالینی باید از دیگر منابع اطلاعات استفاده کنند.

Trial registration: ClinicalTrials.gov NCT00134238 NCT00225589 NCT00000469 NCT00711919 NCT00185185 NCT00000514 NCT00368589 NCT00654394 NCT02546323 NCT01776424 NCT04730973.

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Conflict of interest statement

CNBC: none known. NC: none known. CDQF: none known. LCUN: none known. VFMT: none known. RLGF: none known.

Figures

1
1
Longitudinal view of carotid bifurcation with methods of measuring carotid stenosis at angiography A: narrowest ICA diameter
B: normal distal cervical ICA diameter
C: estimated original diameter at the site of the most stenosis CCA: common carotid artery
ECA: external carotid artery
ECST: European Carotid Surgery Trial
ICA: internal carotid artery
NASCET: North American Symptomatic Carotid Endarterectomy Trial
2
2
Study flow diagram
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
5
5
Sensitivity analysis (Ipsilateral major or disabling stroke): fixed effect.
6
6
Sensitivity analysis (Ipsilateral major or disabling stroke): fixed effect.
1.1
1.1. Analysis
Comparison 1: Antiplatelet agent versus placebo, Outcome 1: Ipsilateral major or disabling stroke
1.2
1.2. Analysis
Comparison 1: Antiplatelet agent versus placebo, Outcome 2: Stroke‐related mortality
1.3
1.3. Analysis
Comparison 1: Antiplatelet agent versus placebo, Outcome 3: Major bleeding
1.4
1.4. Analysis
Comparison 1: Antiplatelet agent versus placebo, Outcome 4: Progression of carotid stenosis
1.5
1.5. Analysis
Comparison 1: Antiplatelet agent versus placebo, Outcome 5: Adverse events
2.1
2.1. Analysis
Comparison 2: Antihypertensive agent versus placebo, Outcome 1: Ipsilateral major or disabling stroke
2.2
2.2. Analysis
Comparison 2: Antihypertensive agent versus placebo, Outcome 2: Stroke‐related mortality
2.3
2.3. Analysis
Comparison 2: Antihypertensive agent versus placebo, Outcome 3: Progression of carotid stenosis
3.1
3.1. Analysis
Comparison 3: One antihypertensive agent plus lipid‐lowering agent versus another antihypertensive agent plus lipid‐lowering agent, Outcome 1: Ipsilateral major or disabling stroke
4.1
4.1. Analysis
Comparison 4: Anticoagulant agent versus placebo, Outcome 1: Major bleeding
4.2
4.2. Analysis
Comparison 4: Anticoagulant agent versus placebo, Outcome 2: Adverse events
5.1
5.1. Analysis
Comparison 5: Lipid‐lowering agent versus placebo or no treatment, Outcome 1: Ipsilateral major or disabling stroke
5.2
5.2. Analysis
Comparison 5: Lipid‐lowering agent versus placebo or no treatment, Outcome 2: Stroke‐related mortality
5.3
5.3. Analysis
Comparison 5: Lipid‐lowering agent versus placebo or no treatment, Outcome 3: Adverse events
6.1
6.1. Analysis
Comparison 6: Lipid‐lowering agent plus antihypertensive agent versus antihypertensive agent, Outcome 1: Ipsilateral major or disabling stroke
6.2
6.2. Analysis
Comparison 6: Lipid‐lowering agent plus antihypertensive agent versus antihypertensive agent, Outcome 2: Adverse events
7.1
7.1. Analysis
Comparison 7: One lipid‐lowering agent versus another lipid‐lowering agent, Outcome 1: Ipsilateral major or disabling stroke
7.2
7.2. Analysis
Comparison 7: One lipid‐lowering agent versus another lipid‐lowering agent, Outcome 2: Adverse events
8.1
8.1. Analysis
Comparison 8: Two lipid‐lowering agents versus one lipid‐lowering agent, Outcome 1: Ipsilateral major or disabling stroke
8.2
8.2. Analysis
Comparison 8: Two lipid‐lowering agents versus one lipid‐lowering agent, Outcome 2: Adverse events
9.1
9.1. Analysis
Comparison 9: One antihypertensive agent versus another antihypertensive agent, Outcome 1: Ipsilateral major or disabling stroke
9.2
9.2. Analysis
Comparison 9: One antihypertensive agent versus another antihypertensive agent, Outcome 2: Adverse events
10.1
10.1. Analysis
Comparison 10: Higher dose of lipid‐lowering agent versus lower dose of the same lipid‐lowering agent, Outcome 1: Ipsilateral major or disabling stroke
10.2
10.2. Analysis
Comparison 10: Higher dose of lipid‐lowering agent versus lower dose of the same lipid‐lowering agent, Outcome 2: Adverse events
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD013573

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    1. Côté R, Battista RN, Abrahamowicz M, Langlois Y, Bourque F, Mackey A. Lack of effect of aspirin in asymptomatic patients with carotid bruits and substantial carotid narrowing. The Asymptomatic Cervical Bruit Study Group. Annals of Internal Medicine 1995;123(9):649‐55. [DOI: 10.7326/0003-4819-123-9-199511010-00002] - DOI - PubMed
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Crouse 2007 {published data only (unpublished sought but not used)}
    1. Bots ML, Palmer MK, Dogan S, Plantinga Y, Raichlen JS, Evans GW, et al. Intensive lipid lowering may reduce progression of carotid atherosclerosis within 12 months of treatment: the METEOR study. Journal of Internal Medicine 2009;265:698-707. [DOI: 10.1111/j.1365-2796.2009.02073.x] - DOI - PubMed
    1. Crouse JR 3rd, Grobbee DE, O'Leary DH, Bots ML, Evans GW, Palmer MK, et al. Measuring effects on intima media thickness: an evaluation of rosuvastatin in subclinical atherosclerosis - the rationale and methodology of the METEOR Study. Cardiovascular Drugs and Therapy 2004;18(3):231-8. [DOI: 10.1023/B:CARD.0000033645.55138.3d] - DOI - PubMed
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ELSA 2002 {published data only}
    1. Bond G, Dal Paly C, Hansson L, Magnani B, Mancia G, Neiss A, et al. The ELSA trial: protocol of a randomized trial to explore the differential effect of antihypertensive drugs on atherosclerosis in hypertension. Journal of Cardiovascular Pharmacology 1994;23 Suppl 5:S85-7. - PubMed
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Furberg 1994 {published data only (unpublished sought but not used)}
    1. Adams HP, Byington RP, Hoen H, Dempsey R, Furberg CD. Effect of cholesterol-lowering medications on progression of mild atherosclerotic lesions of the carotid arteries and on the risk of stroke. Cerebrovascular Diseases 1995;5:171-7. [DOI: 10.1159/000107847] - DOI
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Hedblad 2001 {published data only (unpublished sought but not used)}
    1. BCAPS. BCAPS: Beta-blocker Cholesterol-lowering Asymptomatic Plaque Study. Cardio-Vascular Clinical Trials Forum: Registry of Recent and On-Going Clinical Trials (BioMedNet) 1998.
    1. Berglund G, Wikstrand J, Janzon L, Wedel H, Hedblad B. Low dose metoprolol and fluvastatin slow progression of atherosclerosis: main results from BCAPS. Atherosclerosis 2000;151(1):4.
    1. Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G. Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness. Main results from a B-blocker Cholesterol-lowering Asymtomatic Plaque Study (BCAPS). Circulation 2001;103:1721-6. [DOI: 10.1161/01.CIR.103.13.1721] - DOI - PubMed
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    1. Ostling G, Gonçalves I, Wikstrand J, Berglund G, Nilsson J, Hedblad B. Long-term treatment with low-dose metoprolol CR/XL is associated with increased plaque echogenicity: the Beta-blocker Cholesterol-lowering Asymptomatic Plaque Study (BCAPS). Atherosclerosis 2011;215(2):440-5. [DOI: 10.1016/j.atherosclerosis.2010.12.031] - DOI - PubMed
Hu 2009 {published data only (unpublished sought but not used)}
    1. Hu Y, Tong G, Xu W, Pan J, Ryan K, Yang R, et al. Anti-inflammatory effects of simvastatin on adipokines in type 2 diabetic patients with carotid atherosclerosis. Diabetes and Vascular Disease Research 2009;6(4):262-8. [DOI: 10.1177/1479164109339966] - DOI - PubMed
Ikeda 2013 {published data only (unpublished sought but not used)}
    1. Koji I, Tomosaburo T, Hiroyuki Y, Kiyoaki M, Takahisa S, Takashi M, et al. Effect of intensive statin therapy on regression of carotid intima-media thickness in patients with subclinical carotid atherosclerosis (a prospective, randomized trial: PEACE (Pitavastatin Evaluation of Atherosclerosis Regression by Intensive Cholesterol-lowering Therapy) study). European Journal of Preventive Cardiology 2013;20(6):1069-79. [CLINICALTRIALS.GOV IDENTIFIER:: NCT00711919] [DOI: 10.1177/2047487312451539] [UNIQUE ID ISSUED BY UMIN: UMIN000001229] - DOI - PubMed
    1. NCT00711919. Pitavastatin on carotid intima-media thickness (PEACE). clinicaltrials.gov/ct2/show/record/NCT00711919 (first received 7 July 2008). [CLINICAL TRIALS REGISTER: NCT00711919]
Kadoglou 2010 {published data only (unpublished sought but not used)}
    1. Kadoglou NP, Sailer N, Moumtzouoglou A, Kapelouzou A, Gerasimidis T, Liapis CD. Aggressive lipid-lowering is more effective than moderate lipid-lowering treatment in carotid plaque stabilization. Journal of Vascular Surgery 2010;51:114-21. [DOI: 10.1016/j.jvs.2009.07.119] - DOI - PubMed
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Meaney 2009 {published data only (unpublished sought but not used)}
    1. Meaney A, Ceballos G, Asbun J, Solache G, Mendoza E, Vela A, et al. The VYtorin on Carotid intima-media thickness and overall arterial rigidity (VYCTOR) study. Journal of Clinical Pharmacology 2009;49:838-47. [DOI: 10.1177/0091270009337011] - DOI - PubMed
Mercuri 1996 {published data only (unpublished sought but not used)}
    1. Baldassarre D, Veglia F, Gobbi C, Gallus G, Ventura A, Crepaldi G, et al. Intima-media thickness after pravastatin stabilizes also in patients with moderate to no reduction in LDL-cholesterol levels: the carotid atherosclerosis Italian ultrasound study. Atherosclerosis 2000;151(2):575-83. [DOI: 10.1016/s0021-9150(99)00434-7] - DOI - PubMed
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Nohara 2012 {published data only (unpublished sought but not used)}000001174
    1. Kurabayashi M, Sakuma I, Kawamori R, Daida H, Yamazaki T, Yoshida M, et al. Can intensive lipid-lowering therapy with statins ameliorate atherosclerosis in Japanese patients? Journal of Atherosclerosis and Thrombosis 2009;17(4):416-22. [DOI: 10.5551/jat.2899] [UMIN ID: UMIN000001174] - DOI - PubMed
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Norris 1990 {published data only (unpublished sought but not used)}
    1. Carotid Stenosis Study Group. Failure of metoprolol and aspirin to regress carotid stenosis. Stroke 1990;21:169. [DOI: 10.1161/01.STR.21.1.156] - DOI
    1. Norris JW, Ziliotto C, Taylor DW, Chambers BR, Bornstein NM, D'Alton JG, et al. Failure of metoprolol and aspirin to regress carotid stenosis. Neurology 1990;40 Suppl 1:415. [DOI: 10.1212/WNL.40.4_Suppl_1.1] - DOI
Reid 2005 {published data only (unpublished sought but not used)}
    1. Reid JA, Wolsley C, Lau LL, Hannon RJ, Lee B, Young IS, et al. The effect of pravastatin on intima media thickness of the carotid artery in patients with normal cholesterol. European Journal of Vascular and Endovascular Surgery 2005;30:464-8. [DOI: 10.1016/j.ejvs.2005.05.007] - DOI - PubMed
Salonen 1995 {published data only (unpublished sought but not used)}
    1. Salonen R, Nyyssonen K, Porkkal-sarataho E, Salonen JT. The Kuopio Atherosclerosis Prevention Study (KAPS): effect of pravastatin treatment on lipids, oxidation resistance of lipoproteins, and atherosclerotic progression. American Journal of Cardiology 1995;76:34C-39C. [DOI: 10.1016/s0002-9149(99)80468-8] - DOI - PubMed
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Sawayama 2002 {published data only (unpublished sought but not used)}
    1. Sawayama Y, Hayashi J, Maeda N, Shimizu C, Tanaka Y, Kashiwagi S. The therapeutic effects of probucol and pravastatin on common carotid intima-media thickness in asymptomatic hypercholesterolemic Japanese patients. Atherosclerosis 2000;151(1):130.
    1. Sawayama Y, Shimizu C, Maeda N, Tatsukawa M, Kinukawa N, Koyanagi S, et al. Effects of probucal and pravastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia. Fukuoka atherosclerosis trial (FAST). Journal of the American College of Cardiology 2002;39(4):610-6. [DOI: 10.1016/s0735-1097(01)01783-1] - DOI - PubMed
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Semplicini 2000 {published data only (unpublished sought but not used)}
    1. Semplicini A, Maresca A, Simonella C, Chierichetti F, Pauletto P, Meneghetti G, et al. Cerebral perfusion in hypertensives with carotid artery stenosis: a comparative study of lacidipine and hydrochlorothiazide. Blood Pressure 2000;9:34-9. [DOI: 10.1080/080370500439407 · S] - PubMed
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Shinoda‐Tagawa 2002 {published data only}
    1. Shinoda-Tagawa T, Yamasaki Y, Yoshida S, Kajimoto Y, Tsujino T, Hakui N, et al. A phosphodiesterase inhibitor, cilostazol, prevents the onset of silent brain infarction in Japanese subjects with type II diabetes. Diabetologia 2002;45(2):188-94. [DOI: 10.1007/s00125-001-0740-2] - DOI - PubMed
Stumpe 2007 {published data only (unpublished sought but not used)}
    1. Ludwig M, Stumpe KO, Agabiti-Rosei E, Scholze J, Stumpe I, Zielinski T. Quantification of antihypertensive treatment effects on carotid atherosclerosis by 3-dimensional ultrasound: first report from the MORE trial. Stroke 2006;37(2):664.
    1. NCT00185185. Olmesartan Medoxomil in Atherosclerosis. clinicaltrials.gov/ct2/show/NCT00185185 (first received 12 September 2005). [CLINICALTRIALS.GOV IDENTIFIER:: NCT00185185]
    1. Stumpe KO, Agabiti-Rosei E, Zielinski T, Schremmer D, Scholze J, Laeis P, et al. Carotid intima-media thickness and plaque volume changes following 2-year angiotensin II-receptor blockade. The Multicentre Olmesartan atherosclerosis Regression Evaluation (MORE) study. Therapeutic Advances in Cardiovascular Disease 2007;1(2):97-106. [DOI: 10.1177/ 1753944707085982] - PubMed
Sutton‐Tyrrell 1994 {published data only (unpublished sought but not used)}
    1. Davis BR, Vogt T, Frost PH, Burlando A, Cohen J, Wilson A, et al. Risk factors for stroke and type of stroke in persons with isolated systolic hypertension. Stroke 1998;29:1333-40. - PubMed
    1. NCT00000514. Systolic Hypertension in the Elderly Program (SHEP). clinicaltrials.gov/ct2/show/NCT00000514 (first received 27 October 1999). [CLINICALTRIALS.GOV IDENTIFIER: ClinicalTNCT00000514]
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Tang 2009 {published data only (unpublished sought but not used)}
    1. ISRCTN64894118. A 12-week, randomised, double-blind study evaluating the effects of low-dose (10 mg) and high-dose (80 mg) atorvastatin on macrophage activity and carotid plaque inflammation as determined by ultra small super-paramagnetic iron oxide (USPIO) enhanced carotid magnetic resonance imaging (MRI). www.isrctn.com/ISRCTN64894118 (first applied 3 March 2006). [DOI: 10.1186/ISRCTN64894118] - DOI
    1. Li Z-Y, Tang T, Gillard J. Aggressive atorvastatin decreases wall shear stress in the carotid artery. Stroke 2012;43 Suppl 1:A2790.
    1. Li ZY, Tang TY, Jiang F, Zhang Y, Gillard JH. Reduction in arterial wall strain with aggressive lipid-lowering therapy in patients with carotid artery disease. Circulation Journal 2011;75(6):1486-92. [DOI: 10.1253/circj.cj-10-1210] - DOI - PubMed
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Terpstra 2004 {published data only}
    1. Terpstra WF, May JF, Smit AJ, De Graeff PA, Meyboom-de Jong B, Crijns HJ. Effects of amlodipine and lisinopril on intima-media thickness in previously untreated, elderly hypertensive patients (the ELVERA trial). Journal of Hypertension 2004;22:1309-16. [DOI: 10.1097/01.hjh.0000125412.50839.b5] - DOI - PubMed
Underhill 2008 {published data only (unpublished sought but not used)}
    1. Du R, Cai J, Ping Y, Wang Q, Liu D, Wu H. Effect of low dose rosuvastatin therapy on regression of carotid plaque and vasa vasorums in Chinese population: a prospective clinical trial by MRI. Journal of the American College of Cardiology 2013;61(10 Suppl 1):E938.
    1. Hatsukami TS, Zhao XQ, Yuan C, Tessier JJ, Miller E, Pears JS. Study design for a randomized, double-blind trial to assess the effect of 24 months of dosing with rosuvastatin on progression of carotid artery atheroma in moderately hypercholesterolemic patients with asymptomatic carotid stenosis. Atherosclerosis. Supplements 2001;2:47-8. [DOI: 10.1016/s1567-5688(01)80057-x] - DOI
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VHAS 1998 {published data only}
    1. Magnani B, Dal Palu C, Zanchetti A. Preliminary clinical experience with calcium antagonists in atherosclerosis. Drugs 1992;44 Suppl 1:128-33. - PubMed
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Yamada 2009 {published data only (unpublished sought but not used)}UMIN000001114
    1. UMIN000001114. Effects of lipid lowering by atorvastatin on carotid atherosclerotic plaque (ACAP) study: a randomized trial for analysis of qualitative change in carotid atherosclerrotic plaque with IB echo and Black Blood MRI. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000001347 (first received 01 June 2006). [UNIQUE ID ISSUED BY UMIN: UMIN000001114]
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Yamamoto 2011 {published data only (unpublished sought but not used)}C000000319
    1. C000000319. The effect of losartan and amlodipine on left ventricular diastolic function in patients with mild-to-moderate hypertension. upload.umin.ac.jp (first received 01 February 2006). [UMIN-CTR CLINICAL TRIAL REGISTER:: C000000319]
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Zanchetti 2004 {published data only (unpublished sought but not used)}
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Zeng 2004 {published data only (unpublished sought but not used)}
    1. Zeng X, Zeng X Sr, Li Y, Zeng Y II. Effects of pravastatin on carotid plaques and preventing stroke in patients with hypercholesterolemia. Stroke 2004;35(1):257. [DOI: ]
Zheng 2022 {published and unpublished data}
    1. Wang Y, Wang A, Li H, Li Z, Hu B, Li X, et al. Measuring effects on intima-media thickness: an evaluation of rosuvastatin in Chinese subjects with subclinical atherosclerosis - design, rationale, and methodology of the METEOR-China study. Trials 2020;21(1):921. [DOI: 10.1186/s13063-020-04741-0] - DOI - PMC - PubMed
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Zhu 2006 {published data only (unpublished sought but not used)}
    1. Zhu S, Su G, Meng QH. Inhibitory effects of micronized fenofibrate on carotid atherosclerosis in patients with essential hypertension. Clinical Chemistry 2006;52(11):2036-42. [DOI: 10.1373/clinchem.2006.074724] - DOI - PubMed

References to studies excluded from this review

Anand 2018 {published data only (unpublished sought but not used)}
    1. Anand SS, Bosch J, Eikelboom JW, Connolly SJ, Diaz R, Widimsky P, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391(10117):219-29. [DOI: 10.1016/ S0140-6736(17)32409-1] - PubMed
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Davidson 2012 {published data only}
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Esposito 2004 {published data only}
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Hosomi 2001 {published data only}
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Huang 2006 {published data only (unpublished sought but not used)}
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Ichihara 2006 {published data only}
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Igase 2012 {published data only (unpublished sought but not used)}
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Ito 2004 {published data only (unpublished sought but not used)}
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Koeijvoets 2005 {published data only (unpublished sought but not used)}
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Ludwig 2002 {published data only}
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Mazzone 2006 {published data only}
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Meuwese 2009 {published data only}
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Mizuguchi 2008 {published data only (unpublished sought but not used)}
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Mok 2010 {published data only (unpublished sought but not used)}
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Mortsell 2007 {published data only (unpublished sought but not used)}
    1. Mortsell D, Malmqvist K, Held C, Kahan T. Irbesartan reduces common carotid artery intima-media thickness in hypertensive patients when compared with atenolol: the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) study. Journal of Internal Medicine 2007;261:472-9. [DOI: 10.1111/j.1365-2796.2007.01775.x] - DOI - PubMed
Oyama 2008 {published data only (unpublished sought but not used)}
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Pontremoli 2001 {published data only (unpublished sought but not used)}
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Saremi 2013 {published data only (unpublished sought but not used)}
    1. Saremi A, Schwenke DC, Buchanan TA, Hodis HN, Mack WJ, Banerji M, et al. Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors. Atherosclerosis, Thrombosis and Vascular Biology 2013;33:393-9. [DOI: 10.1161/ATVBAHA.112.300346] - DOI - PMC - PubMed
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Stumpe 1994 {published data only}
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Tasić 2006 {published data only}
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Vukusich 2010 {published data only (unpublished sought but not used)}
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Yamasaki 2010 {published data only}
    1. Yamasaki Y, Katakami N, Furukado S, Kitagawa K, Nagatsuka K, Kashiwagi A, et al. Long-term effects of pioglitazone on carotid atherosclerosis in Japanese patients with type 2 diabetes without a recent history of macrovascular morbidity. Journal of Atherosclerosis and Thrombosis 2010;17:1132-40. [DOI: 10.5551/jat.4663] - DOI - PubMed
Yilmaz 2004 {published data only (unpublished sought but not used)}
    1. Yilmaz R, Altun B, Kahraman S, Ozer N, Akinci D, Turgan C. Impact of amlodipine or ramipril treatment on left ventricular mass and carotid intima-media thickness in nondiabetic hemodialysis patients. Renal Failure 2010;32(8):903-12. [DOI: 10.3109/0886022X.2010.502276] [PMID: ] - DOI - PubMed
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Yokoyama 2005 {published data only (unpublished sought but not used)}
    1. Yokoyama H, Kawasaki M, Ito Y, Minatoguchi S, Fujiwara H. Effects of fluvastatin on the carotid arterial media as assessed by integrated backscatter ultrasound compared with pulse-wave velocity. Journal of the American College of Cardiology 2005;46(11):2031-7. [DOI: 10.1016/j.jacc.2005.06.084] - DOI - PubMed

References to ongoing studies

Aranzulla 2021 {published data only (unpublished sought but not used)}
    1. Aranzulla TC, Piazza S, Ricotti A, Musumeci G, Gaggiano A. Carotid plaque stabilization and regression with evolocumab: rationale and design of the CARUSO study. Catheter Cardiovascular Intervention 2021;98(1):E115-21. [DOI: 10.1002/ccd.29743] - DOI - PubMed

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