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Interact CardioVasc Thorac Surg 2008;7:684-689. doi:10.1510/icvts.2008.178038 © 2008 European Association of Cardio-Thoracic Surgery
Do statins slow the progression of aortic valve stenosis?Department of Cardiothoracic Surgery, Hippocratio General Hospital, Athens, Greece Received 15 February 2008; received in revised form 30 March 2008; accepted 1 April 2008
*Corresponding author. 29 Bournazou Street, 11521, Athens, Greece. Tel.: +30-210-6468674; fax: +30-210-7757545.
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether therapy with statins significantly slows the progression of aortic valve stenosis. Altogether 226 papers were found using the reported search, of which twelve represented the best evidence to answer the clinical question. The authors, journal, date, country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The results of the reported studies provided conflicting results. There are twelve studies. Ten retrospective studies and one prospective had been promising with a slower rate of hemodynamic progression in patients taking statins. One retrospective and one randomized controlled trial did not halt the progression of calcific aortic stenosis or induce its regression. The data are discrepant as to whether this effect is related to serum lipid levels or to other effects of statins. While the data are not yet strong enough to change clinical practice, two large randomized controlled trials (ASTRONOMER and SEAS) which have recruited 272 and 1873 patients, respectively, will provide important new evidence in this area in the near future.
Key Words: Statins; Aortic valve stenosis; Thoracic surgery
A best evidence topic was constructed according to a structured protocol. This is fully described in the ICVTS [1].
In [patients with calcific aortic valve stenosis] do [statins] significantly [slow the progression of the disease]?
You are seeing a 61-year-old patient with calcific aortic valve stenosis and an aortic valve peak gradient of 69 mmHg who is completely asymptomatic on an exercise test and has a normal left ventricle. Cholesterol>230 mg/dl, HDL<35 mg/dl, LDL>135 mg/dl. Other parameters are normal. You say to him that there is no indication for aortic valve replacement now, although he may need a valve replacement in the future. The patient asks if there is something he can do to stop the progression of stenosis. You wonder whether statins reduce significantly or not the hemodynamic progression of aortic valve stenosis.
Medline 1950 to February 2008 using OVID interface. [exp Anticholesteremic Agents/OR exp Simvastatin/OR statins.mp OR Simvastatin.mp OR rosuvastatin.mp OR Atorvastatin.mp OR ceruvastatin.mp OR pravastatin.mp OR mevastatin.mp OR lovastatin.mp OR fluvastatin.mp] AND [exp aortic valve/OR aortic valve.mp].
Using the reported search, 226 papers were identified of which 12 papers provided the best evidence to answer the question. These papers are summarized in Table 1.
The search was wide but the range and quality of relevant papers was poor. There were ten retrospective studies, one prospective non-randomized and one randomized controlled trial. Aronow et al. [2] performed a retrospective analysis of older patients with mild valvular aortic stenosis (AS) and showed that independent predictors of the progression of AS were male gender, smoking, diabetes mellitus, LDL, HDL and statins (inverse association). Novaro et al. [3] in their study excluded patients who had greater than moderate aortic regurgitation, depressed ventricular function, severe aortic stenosis or if <2 echocardiograms failed to generalize the findings to patients. The statin-treated patients were taking low doses of medication. The authors found that statins slowed the disease. Pohle et al. [4] observed that there was a strong influence of LDL cholesterol level on the progression of aortic valve calcification, suggesting that lipid-lowering therapy might decrease the progression of aortic valve calcification. Patients with symptoms suggestive of severe aortic valve stenosis were excluded. Shavelle et al. [5] found that statins slowed the disease. But no information was available about the doses of statins and lipid concentrations were restricted to total cholesterol levels. The patients might not be representative of most patients with calcific aortic valvular disease as they were referred by their primary physicians. Bellamy et al. [6] in their study with the longest follow-up showed that AS progression was unrelated to cholesterol levels, total or fractions. The degree of obstruction qualifying as AS was not well defined. Statins were associated with slower progression of the disease. Rosenhek et al. [7] included patients with severe AS and demonstrated that statins slowed the hemodynamic progression in mild-to-moderate and severe AS. Besides this effect was independent of cholesterol levels. Antonini-Canterin et al. [8] showed that statins could be beneficial in retarding the progression of valvular aortic sclerosis to aortic stenosis. Patients with more than mild aortic regurgitation were excluded from the study. Rajamannan et al. [9] in their experimental study with rabbits provided the evidence that chronic hypercholesterolemia produced bone mineralization in the aortic valve which was inhibited by atorvastatin. Rajamannan et al. [10] in another experimental study supported the hypothesis that degenerative valvular aortic stenosis was the result of active bone formation in the aortic valve, which might be mediated through a process of osteoblast differentiation and that statins inhibited this calcification process. Cowell et al. [11] performed the 1st RCT evaluating this issue and showed that intensive lipid-lowering therapy did not halt the progression of calcific aortic stenosis. There was no relationship between LDL and the progression of AS. They also excluded patients with an aortic-jet velocity of <2.5 m/s even though knowing that intervening at this earlier stage might be more beneficial. In this way they might have missed a modest treatment benefit especially for younger patients with mild disease. Moura et al. [12] showed that statin therapy was associated with slowing of the hemodynamic progression of aortic stenosis and reduction of CPR levels, IL-6, sCD40L and serum LDL levels. This was a non-randomized, prospective, open-label observational study that suggested that the earlier treatment with statins was more efficacious in the prevention of progression of AS than late treatment. Mohler et al. [13] did not demonstrate any statistically significant reduction in the accumulation of calcium in the aortic valve for the statin group compared to the non-statin group, although there was a trend towards a lesser progression of calcification in the former case. The results of two RCTs (SEAS and ASTRONOMER) are pending. The ASTRONOMER (The Aoric Stenosis Progression Observation: Measuring Effects of Rovustatin) trial is a double-blind placebo-controlled trial. Patients with mild to moderate AS are randomized to receive 40 mg/day of rovustatin or placebo. Patients with any clinical indication for the use of cholesterol-lowering agents according to the 2000 Canadian guidelines are excluded. The recruitement of 272 patients was completed in December 2005. The patients are younger (58.1±13.6 years) and 48.9% of them have a bicuspid aortic valve. The mean aortic jet velocity is 3.2±0.4 m/s. The results will be available at the end of 2008. The SEAS (The Simvastatin and Ezetimibe in Aortic Stenosis) study is a randomized double-blind, placebo-controlled, multicenter study of a minimum four years' duration that will investigate the effect of lipid lowering with ezetimibe/simvastatin 10/40 mg/day in patients with asymptomatic AS with peak transvalvular jet velocity 2.5–4.0 m/s. Primary efficacy variables include aortic valve surgery and ischemic vascular events such as cardiovascular mortality and the effect on echocardiographically evaluation of progression of AS. From January 2003 to March 2004, a total of 1873 patients from 173 hospitals and outpatient clinics in Europe have been randomly assigned in the study. Some baseline characteristics are: age 68±10 years and mean transaortic maximum velocity 3.1±0.5 m/s. The SEAS study is the largest randomized trial in patients with AS.
The results of the reported studies provided conflicting results. There are twelve studies. Ten retrospective studies and one prospective had been promising with a slower rate of hemodynamic progression in patients taking statins. One retrospective and one randomized controlled trial did not halt the progression of calcific aortic stenosis or induce its regression. The data are discrepant as to whether this effect is related to serum lipid levels or to other effects of statins. While the data are not yet strong enough to change clinical practice, two large randomized controlled trials (ASTRONOMER and SEAS) which have recruited 272 and 1873 patients, respectively, will provide important new evidence in this area in the near future.
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Abstract
1. Introduction
