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J Thorac Cardiovasc Surg 2009;137:e6-e9
© 2009 The American Association for Thoracic Surgery

Brief Communication

Do statins delay the progression of aortic stenosis?

Department of Cardiovascular Surgery, Shizuoka Medical Center, Shizuoka, Japan

Received for publication March 4, 2008; accepted for publication March 14, 2008.

^_* Address for reprints: Hisato Takagi, MD, PhD, Department of Cardiovascular Surgery, Shizuoka Medical Center, 762–1 Nagasawa, Shimizu-cho, Sunto-gun, Shizuoka 411–8611, Japan. (Email: kfgth973{at}ybb.ne.jp).

Calcific aortic stenosis (AS) is the most common form of valvular heart disease in the Western world, and the only established therapy for patients with severe symptomatic AS is surgical valve replacement. There are currently no effective disease-modifying treatments, and the possibility of halting the disease process would represent a therapeutic advance.¹ Although some observational studies^2-4 demonstrated that statins (hydroxymethylglutaryl-coenzyme A reductase inhibitors) delayed the progression of AS, a randomized controlled trial¹ concluded that intensive lipid-lowering therapy with atorvastatin did not halt its progression. Furthermore, no meta-analysis of studies of statins for AS has been conducted to date. Therefore, the appropriate role of statins for AS remains unclear. We performed a meta-analysis of comparative studies of statins for the prevention of the progression of AS.

Clinical Summary

All comparative studies of statins versus control (no statins or placebo) for AS were identified using a 2-level search strategy. First, a public domain database (MEDLINE) was searched using a Web-based search engine (PubMed). Second, relevant studies were identified through a manual search of secondary sources, including references of initially identified articles and a search of reviews and commentaries. The MEDLINE database was searched from January of 1966 to January of 2008. MeSH keywords included "hydroxymethylglutaryl-CoA reductase inhibitors" and "aortic valve stenosis." Studies considered for inclusion met the following criteria: The design was a comparative study, and the study population comprised patients with AS. Patients were assigned to statins versus control (no statins or placebo), and the main outcomes included annualized changes of echocardiographic characteristics. Data regarding detailed inclusion criteria, statin type, duration of follow-up, and echocardiographic characteristics were abstracted (as available) from each individual study. We conducted a meta-analysis of summary statistics from the individual studies because detailed, patient-level data were not available for all studies. For each study, data regarding annualized "increase" in peak aortic jet velocity (PAJV) and annualized "decrease" in aortic valve area (AVA) in both the statin and control groups were used to generate standardized mean differences (SMDs) (<0 favors statins; >0 favors control) and 95% confidence intervals (CIs). Study-specific estimates were combined using both fixed- and random-effects models. Between-study heterogeneity was analyzed by means of standard chi-square tests. Where statistically significant heterogeneity was identified, the random-effects estimate was used preferentially as the summary measure. Publication bias was assessed mathematically using an adjusted rank-correlation test.

Results

Our search identified 7 comparative studies^1-7 of statins versus control for AS. These included 1randomized controlled trial,¹ 3 prospective cohort studies,^2,4,5 and 3 retrospective cohort studies.^3,6,7 The baseline patient characteristics and outcomes are summarized in Table 1. We did not pool annualized changes in peak and mean aortic valve pressure gradients because only 2 studies reported them. For annualized "increase" in PAJV, 2 studies by Moura and associates² and Rosenhek and colleagues³ demonstrated a statistically significant benefit of statins over control. Pooled analysis (representing 812 patients) demonstrated a statistically significant reduction in annualized "increase" of PAJV with statins relative to control in the random-effects model (SMD, –0.28; 95% CI, –0.55 to –0.01; P = .04) ( Figure 1, A). There was significant between-study heterogeneity of results (P < .01) but no evidence of significant publication bias (P = .09). For annualized "decrease" in AVA, the study by Moura and coworkers² demonstrated a statistically significant benefit of statins over control, but the study by Mohler and associates⁵ demonstrated a statistically significant benefit of control over statins. Pooled analysis (representing 646 patients) demonstrated a statistically nonsignificant reduction in annualized "decrease" of AVA with statins relative to control in the random-effects model (SMD, –0.12; 95% CI, –0.44 to 0.20; P = .46) (Figure 1, B). There was significant between-study heterogeneity of results (P < .01) but no evidence of significant publication bias (P = 1.00). For a sensitivity analysis, the study by Mohler and colleagues⁵ was excluded, which only demonstrated a statistically significant benefit of control over statins; combining the remaining studies generated an attenuated and statistically significant result favoring statins (random-effects SMD, –0.26; 95% CI, –0.45 to –0.07; P < .01).

View larger version (17K): [in this window] [in a new window]   Figure 1. Outcomes and meta-analyses. A, Annualized "increase" in PAJV. B, Annualized "decrease" in AVA. SD, Standard deviation; SMD, standardized mean difference; CI, confidence interval.

On the basis of the present meta-analysis, statins are likely to delay the progression of AS: reducing not "decrease" in AVA but "increase" in PAJV. These results should be interpreted with caution, because the design was nonrandomized observational in all studies but one in our meta-analysis, and there was qualitative heterogeneity in patient selection. The completion of ongoing randomized controlled trials^8,9 is expected to confirm the present results.

References

1. Cowell SJ, Newby DE, Prescott RJ, et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med 2005;352:2389-2397.[Medline]
   
2. Moura LM, Ramos SF, Zamorano JL, et al. Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis. J Am Coll Cardiol 2007;49:554-561.[Abstract/Free Full Text]
   
3. Rosenhek R, Rader F, Loho N, et al. Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis. Circulation 2004;110:1291-1295.[Abstract/Free Full Text]
   
4. Bellamy MF, Pellikka PA, Klarich KW, Tajik AJ, Enriquez-Sarano M. Association of cholesterol levels, hydroxymethylglutaryl coenzyme-A reductase inhibitor treatment, and progression of aortic stenosis in the community. J Am Coll Cardiol 2002;40:1723-1730.[Abstract/Free Full Text]
   
5. Mohler 3rd ER, Wang H, Medenilla E, Scott C. Effect of statin treatment on aortic valve and coronary artery calcification. J Heart Valve Dis 2007;16:378-386.[Medline]
   
6. Antonini-Canterin F, Popescu BA, Huang G, et al. Progression of aortic valve sclerosis and aortic valve stenosis: what is the role of statin treatment?. Ital Heart J 2005;6:119-124.[Medline]
   
7. Novaro GM, Tiong IY, Pearce GL, Lauer MS, Sprecher DL, Griffin BP. Effect of hydroxymethylglutaryl coenzyme a reductase inhibitors on the progression of calcific aortic stenosis. Circulation 2001;104:2205-2209.[Abstract/Free Full Text]
   
8. Chan KL, Teo K, Tam J, Dumesnil JG. Astronomer Investigators. Rationale, design, and baseline characteristics of a randomized trial to assess the effect of cholesterol lowering on the progression of aortic stenosis: the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial. Am Heart J 2007;153:925-931.[Medline]
   
9. Rossebø AB, Pedersen TR, Allen C, et al. Design and baseline characteristics of the simvastatin and ezetimibe in aortic stenosis (SEAS) study. Am J Cardiol 2007;99:970-973.[Medline]
   

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Hisato Takagi Takuya Umemoto Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Takagi, H. Articles by Umemoto, T. Search for Related Content PubMed Articles by Takagi, H. Articles by Umemoto, T. Related Collections Valve disease Related Article