A Randomized Trial of Intensive Lipid-Lowering Therapy in Calcific Aortic Stenosis

Cowell, S. Joanna; Newby, David E.; Prescott, Robin J.; Bloomfield, Peter; Reid, John; Northridge, David B.; Boon, Nicholas A.

doi:10.1056/nejmoa043876

Cited by 1,146Cardiac Valve Diseases and TreatmentsLipoproteins and Cardiovascular HealthCardiac Imaging and Diagnostics

A Randomized Trial of Intensive Lipid-Lowering Therapy in Calcific Aortic Stenosis

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Cowell, S. Joanna, Newby, David E., Prescott, Robin J., Bloomfield, Peter, Reid, John, Northridge, David B., Boon, Nicholas A.·2005·New England Journal of Medicine

DOI 10.1056/nejmoa043876

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Abstract

BACKGROUND: Calcific aortic stenosis has many characteristics in common with atherosclerosis, including hypercholesterolemia. We hypothesized that intensive lipid-lowering therapy would halt the progression of calcific aortic stenosis or induce its regression. METHODS: In this double-blind, placebo-controlled trial, patients with calcific aortic stenosis were randomly assigned to receive either 80 mg of atorvastatin daily or a matched placebo. Aortic-valve stenosis and calcification were assessed with the use of Doppler echocardiography and helical computed tomography, respectively. The primary end points were change in aortic-jet velocity and aortic-valve calcium score. RESULTS: Seventy-seven patients were assigned to atorvastatin and 78 to placebo, with a median follow-up of 25 months (range, 7 to 36). Serum low-density lipoprotein cholesterol concentrations remained at 130+/-30 mg per deciliter in the placebo group and fell to 63+/-23 mg per deciliter in the atorvastatin group (P<0.001). Increases in aortic-jet velocity were 0.199+/-0.210 m per second per year in the atorvastatin group and 0.203+/-0.208 m per second per year in the placebo group (P=0.95; adjusted mean difference, 0.002; 95 percent confidence interval, -0.066 to 0.070 m per second per year). Progression in valvular calcification was 22.3+/-21.0 percent per year in the atorvastatin group, and 21.7+/-19.8 percent per year in the placebo group (P=0.93; ratio of post-treatment aortic-valve calcium score, 0.998; 95 percent confidence interval, 0.947 to 1.050). CONCLUSIONS: Intensive lipid-lowering therapy does not halt the progression of calcific aortic stenosis or induce its regression. This study cannot exclude a small reduction in the rate of disease progression or a significant reduction in major clinical end points. Long-term, large-scale, randomized, controlled trials are needed to establish the role of statin therapy in patients with calcific aortic stenosis.

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Randomized trials have shown no effect of statins on haemodynamic progression or aortic stenosis-related clinical events.
“several randomized trials showed no effect of statins on haemodynamic progression or AS-related clinical events152–154.”
From Calcific aortic stenosis (2016) · cites this paper as [152]
The disease-progression results report no effect of atorvastatin on aortic-jet velocity, supporting the haemodynamic part of the claim. The adverse-events discussion says there was no demonstrable effect on clinical endpoints, but the trial was not powered to assess them and could not rule out a significant reduction; stating that it showed no effect on AS-related clinical events is too definitive. This paper reports one trial, not the results of the several trials cited in the sentence. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Three randomized clinical trials failed to show significant benefit of LDL lowering with statins on AS progression.
“However, three randomized clinical trials (RCTs) failed to demonstrate any significant benefit of LDL lowering with statins on the progression of AS152–154.”
From Calcific aortic stenosis (2016) · cites this paper as [152]
Several intervention studies tested whether lipid lowering with statins would slow aortic stenosis progression, but the results were generally disappointing.
“Several intervention studies have been performed to test the hypothesis that lipid lowering with statin medications would slow the progression of AS, however the results were generally disappointing152–154.”
From Calcific aortic stenosis (2016) · cites this paper as [152]
Randomized controlled trials failed to demonstrate any benefit of statin therapy on retarding CAVS disease progression.
“randomized controlled trials (RCTs) failed to demonstrate any benefit of statin therapy on retard disease progression6–8.”
From Genetic insights into causal effects of lipids and lipid-modifying targets on calcific aortic valve stenosis: a Mendelian randomized study (2025) · cites this paper as [6]
Several clinical trials evaluating statin therapy in mild to moderate aortic stenosis failed to demonstrate efficacy in lipid lowering as a strategy to mitigate adverse events.
“Several clinical trials evaluating statin therapy in mild to moderate AS failed to demonstrate efficacy in lipid lowering as a strategy to mitigate adverse events in the disease39–41.”
From Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction (2026) · cites this paper as [39]

Three randomized controlled trials of lipid-lowering therapy to delay AS progression all reported no significant benefit.
“lipid-lowering therapy to delay progression of AS has been evaluated in 3 randomized controlled trials; however, all trials reported no significant benefit.[12][13][14]”
From Rare Genetic Variants in LDLR , APOB , and PCSK9 Are Associated With Aortic Stenosis (2024) · cites this paper as [12]
The SALTIRE and ASTRONOMER trials, which tested statins in AS, were limited by small sample sizes (n=150 and n=269), short median follow-up (25 and 42 months), and advanced AS stages (mean peak velocity 3.43±0.64 and 3.18±0.42 m/s), factors that may have contributed to their neutral outcome.
“The SALTIRE (Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression) and ASTRONOMER (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin) trials, which evaluated statin efficacy in AS, were constrained by small sample sizes (n=150 and n=269), 12,13 limited median follow-up periods (25 and 42 months), and a focus on advanced AS stages (mean peak velocity, 3.”
From Rare Genetic Variants in LDLR , APOB , and PCSK9 Are Associated With Aortic Stenosis (2024) · cites this paper as [12]
The clinical trials aimed to halt progression of established AS.
“All of the clinical trials aimed to halt the progression of established AS.”
From Rare Genetic Variants in LDLR , APOB , and PCSK9 Are Associated With Aortic Stenosis (2024) · cites this paper as [12]
The authors addressed potential bias by observing similar associations with AVR as a strict procedural outcome.
“Second, we observed similar associations with AVR as a strict procedural outcome, which is particularly meaningful in the context of previous neutral clinical trials of lipid-lowering therapies that used AVR as the study end point.[12][13][14]”
From Rare Genetic Variants in LDLR , APOB , and PCSK9 Are Associated With Aortic Stenosis (2024) · cites this paper as [12]
Secondary prevention therapy with statins reduces the risk of recurrent stroke (by 12% per mmol/L reduction in LDL cholesterol), myocardial infarction, and vascular death.
“Secondary prevention therapy with statins reduces the risk of recurrent stroke (by 12% per mmol/L reduction in LDL cholesterol), MI, and vascular death [459,460].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [459]
In the SEAS trial, ischaemic events were reduced by 21%.
“Notably, ischaemic events were reduced by 21% in the SEAS trial.”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [377]
Early observational noncontrolled trials suggested aggressive lipid lowering slowed progression of aortic stenosis, but this was not confirmed in RCTs.
“Suggestions for an association between aortic stenosis, LDL-C and Lp(a), as well as between cholesterol and increased risk for calcification of bioprosthetic valves, were matched with early observational noncontrolled trials that showed beneficial effects of aggressive lipid lowering in slowing the progression of aortic stenosis. However, this was not confirmed in RCTs. 243,377,378”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [377]
In the SEAS trial, ischaemic events were reduced by 21%.
“Notably, ischaemic events were reduced by 21% in the SEAS trial.”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [377]

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Authors: Cowell, S. J., Newby, D. E., Prescott, R. J., Bloomfield, P., Reid, J., Northridge, D. B., & Boon, N. A.
Affiliations: Edinburgh Royal Infirmary (GB)
University of Edinburgh (GB)
Borders General Hospital (GB)
Western General Hospital (GB)
ORCID: Newby, David E.
Prescott, Robin J.
Bloomfield, Peter
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2005-06-09
Volume: 352
Issue: 23
Pages: 2389-2397
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa043876
OpenAlex: W2117330772
Cited by: 1,146
References: 41
Citations by year: 2026: 46 · 2025: 52 · 2024: 57 · 2023: 37 · 2022: 47 · 2021: 44 · 2020: 59 · 2019: 38 · 2018: 39 · 2017: 52 · 2016: 52 · 2015: 37 · 2014: 65 · 2013: 64 · 2012: 55
FWCI: 47.74
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Cardiac Imaging and Diagnostics
Keywords: calcific aortic stenosis, atorvastatin, statin therapy, lipid-lowering therapy, valve calcification, disease progression, aortic jet velocity, aortic valve calcium score, LDL cholesterol, hypercholesterolemia, atherosclerosis, echocardiography, CT angiography
MeSH terms: Atorvastatin, Anticholesteremic Agents, Aortic Valve, Aortic Valve Stenosis, Blood Flow Velocity, Calcinosis, Double-Blind Method, Heptanoic Acids, Humans, Cholesterol, LDL, Pyrroles, Echocardiography, Doppler, Treatment Failure, Disease Progression, Hydroxymethylglutaryl-CoA Reductase Inhibitors

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A Randomized Trial of Intensive Lipid-Lowering Therapy in Calcific Aortic Stenosis

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