Overview of clinical trials on calcific aortic stenosis
Centre for Preventive Medicine, Ullevål University Hospital, Building 19, Kirkeveien 166 N-0407 Oslo, Norway
* Corresponding author. Tel: +47 22 11 79 32; fax: +47 22 60 19 00. E-mail address: t.r.pedersen{at}medisin.uio.no
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Abstract |
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 Top Abstract IntroductionPrevious prospective studiesOngoing studiesSummaryFundingAcknowledgementsReferences |
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Lipid-lowering therapy may slow the progression of calcific aortic stenosis (AS). Three completed studies on the effect of statin therapy on AS, as well as two ongoing trials, are summarised. Evidence that lipid-lowering therapy slows the progression of AS relative to non-statin therapy has been suggested by several retrospective studies. Further evidence that statin treatment can slow the progression of AS derives from the prospective (non-randomised), open-label Rosuvastatin Affecting Aortic Valve Endothelium (RAAVE) study, which was potentially subject to bias, but not by the randomised, double-blind, placebo-controlled Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) study, which enrolled 155 patients and had a follow-up period of 2.1 years. At present, two larger randomised clinical trials in AS are ongoing with a longer duration than the SALTIRE study. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study with 1873 patients has the longest planned treatment duration (4–7 years), while the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial includes 272 patients with AS who are receiving rosuvastatin 40 mg/day or placebo for 3–5 years and is designed to study progression of the disease. These and other ongoing studies are intended to evaluate the effects of lipid-lowering therapy on AS progression and aortic valve degradation, as well as the need for surgical valve replacement and mortality and morbidity, in patients with AS. Findings from recent clinical studies on lipid-lowering therapy for the management of AS (e.g. SALTIRE and RAAVE trials) are somewhat contradictory. The ongoing clinical trials—the SEAS study and the ASTRONOMER study—will probably resolve the question of the benefit of intensive lipid-lowering treatment in AS.
Key Words: Aortic stenosis • Aortic valve replacement • Echocardiography • Cardiovascular disease • Lipid-lowering therapy
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Introduction |
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Calcific aortic stenosis (AS) is a progressive disease that is a frequent source of anxiety and distress, especially in older patients confronted with symptoms of angina, syncope, or heart failure, as well as sudden cardiac death.1,2 The prevalence of AS is of almost epidemic extent: its preceding stage, in which there is aortic sclerosis without obstruction to left ventricular (LV) outflow, is present in about 25% of adults over 65 years of age.1 Valve replacement because of AS is the most frequent cardiac surgical procedure second to aortocoronary bypass and requires large health care resources. Therefore, the possibility that the progression of AS may be slowed by HMG-CoA reductase inhibitor (statin) therapy, as shown in the Novaro et al.3 study and the Rosuvastatin Affecting Aortic Valve Endothelium (RAAVE) study,4 is of considerable clinical importance. This article reviews these trials, as well as the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE), which did not detect an effect of statin therapy on the progression of AS.5 The present review also describes the design of two ongoing studies on the effect of statin therapy on AS: the Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) study6 and the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study.7
Study by Novaro et al.
Among the completed and ongoing studies evaluating statins in patients with AS (Table 1) is a retrospective study by Novaro et al.3 This trial had a mean follow-up of 21 months, involved 174 patients who had been studied in an echocardiographic laboratory between 1 January 1996 and 31 December 1999. For inclusion in the study, patients had to have mild-to-moderate calcific AS with aortic valve area (AVA)=1.0–1.8 cm2, normal LV function [ejection fraction (EF) 
50%], and at least two transthoracic echocardiograms 12 or more months apart. Patients were excluded if they had >2+ aortic regurgitation or echocardiographic evidence of rheumatic mitral valve disease.
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During the study period, 57 of the 174 patients (33%) received statin therapy and 117 (67%) did not. At baseline, the median serum low-density lipoprotein (LDL)-cholesterol level was 3.39 mmol/L (131 mg/dL) [interquartile range, 2.90–3.70 mmol/L (112–143 mg/dL)] in the non-statin group and 3.32 mmol/L (128 mg/dL) [interquartile range, 2.43–3.78 mmol/L (94–146 mg/dL)] in the statin group (P = 0.49). On average, the statin group was older and had a higher frequency of hypertension, diabetes mellitus, and coronary heart disease (CHD), and higher triglyceride levels. Baseline echocardiographic parameters; mean levels of total cholesterol, high-density lipoprotein-cholesterol, and serum creatinine; and proportions of patients with congenitally bicuspid aortic valves were similar in the two groups.3
At baseline, the two groups had about the same extent of AS by echocardiography, with similar or identical values for median AVA, 1.2 cm2 (1.0–1.4 cm2; P = 0.71) in both the non-statin- and statin-treated groups; mean gradient, 15 mmHg (12–22 mmHg; P = 0.47) in both groups; peak gradient, 29 mmHg (21–38 mmHg) in the non-statin group compared with 28 mmHg (22–37 mmHg) in the statin group (P = 0.80); and EF, 0.57 ± 0.4 in both groups (P = 0.63).
On an annualised basis, the decrease in the AVA for the non-statin group was 0.11 ± 0.18 cm2 compared with 0.06 ±0.16 cm2 in the statin-treated group (P = 0.03). Over the entire study period, peak and mean pressure gradients increased in both groups, with lesser increases in the statin group (P = 0.02 and P = 0.10 for peak and mean pressure increases, respectively, by the multivariate analysis).3
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Previous prospective studies |
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Prospective, double-blind, randomised, controlled clinical trials that follow well-established methodological rules are cumbersome and difficult to conduct but are considered the gold standard for assessing the efficacy and the safety. Prospective trials that are conducted open-label do not offer the protection against the bias offered by controlled trials.
A need exists for well-designed prospective, randomised, double-blind, controlled clinical trials of the effects of statins in AS. Landmark prospective studies of statins in the treatment of cardiovascular conditions other than AS have not provided information about the value of these agents for AS: some have excluded patients with haemodynamically important valvular heart disease [Treating to New Targets (TNT), Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE-IT-TIMI 22)],8–10 whereas others have not specifically excluded patients with AS but have not identified any patient who had AS [Collaborative Atorvastatin Diabetes Study (CARDS), Pravastatin in the Elderly at Risk (PROSPER), Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL)]11–14 or have reported that some patients had a cardiovascular disease other than the one being studied without specifying that AS was one of them [Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA), Heart Protection Study (HPS)].15–17
RAAVE study
This prospective, open-label study used echocardiographic, serum lipid, and inflammatory marker determinations, at baseline and every 6 months, for 18 months (mean follow-up=73 ± 24 weeks) to evaluate outcomes in patients with asymptomatic moderate-to-severe AS who were treated with or without rosuvastatin.4
The study enrolled 121 consecutive patients (mean age 73.7 ± 8.9 years; 57 men and 64 women) presenting with asymptomatic, moderate-to-severe AS (AVA 1.0–1.5 cm2). Excluded were patients with CHD; echocardiographic evidence of rheumatic mitral valve disease; previous statin therapy; congenital heart disease, including a bicuspid aortic valve; subaortic obstruction; mild aortic regurgitation; previous aortic valve surgery; or vascular, neoplastic, or metabolic diseases.4
Treatment was not assigned by randomisation: patients (n = 61, 50.4%) with elevated LDL-cholesterol [mean, 4.14 ± 0.87 mmol/L (159.7 ± 33.4 mg/dL)] received rosuvastatin 20 mg/day; the control group, consisting of patients (n = 60, 49.6%) without profoundly abnormal LDL-cholesterol [3.07 ± 0.97 mmol/L (118.6 ± 37.4 mg/dL)], received no statin. Mean peak jet velocity and AVA in the two groups were closely matched at baseline; for the rosuvastatin and control groups they were, respectively: 3.65 ± 0.64 and 3.62 ± 0.61 m/s, and 1.23 ± 0.42 and 1.20 ± 0.35 cm2.4
The AVA decreased in both groups during the study, with the annual decrease being significantly less pronounced in the statin group (0.05 ± 0.12 cm2) compared with the control group (0.10 ± 0.09 cm2; P = 0.041). The annual increase in peak aortic jet valve velocity was also significantly less marked in the statin group (0.04 ± 0.38 m/s) compared with the control group (0.24 ± 0.30 m/s; P = 0.007). Significant improvements in mean and peak aortic valve gradients, as well as serum lipid levels, were also observed in the statin (vs. control) group. This study demonstrated that the treatment of serum LDL-cholesterol with rosuvastatin slowed the progression of AS, including haemodynamic indices of progression.4
The investigators of the RAAVE study indicated that their trial was the first to offer positive evidence for the potential of targeted therapy in asymptomatic AS. However, they advised that, because this was a non-randomised, prospective, open-label, observational study, it should be considered as hypothesis-generating, not hypothesis-confirming.4
SALTIRE
Unlike the study by Novaro’s group and the RAAVE trial, the SALTIRE did not detect a short-term impact of statins on echocardiographic progression of AS. This was a randomised, double-blind, placebo-controlled trial with a median follow-up of 25 months (range, 7–36) involving 155 patients with calcific AS and aortic jet velocity 2.5 m/s. Patients were treated with either atorvastatin 80 mg/day (n = 77) or placebo (n = 78). Patents were excluded if they had severe mitral valve stenosis (mitral valve area <1 cm2), severe mitral or aortic regurgitation, EF < 35% or total cholesterol <3.89 mmol/L (150 mg/dL).5
Aortic stenosis and calcification were assessed using Doppler echocardiography and helical computed tomography, respectively. Primary endpoints were change in aortic jet velocity and aortic valve calcium score. Secondary endpoints included a composite of death from cardiovascular causes, aortic valve replacement, or hospitalisation attributable to severe AS; aortic valve replacement; death from any cause; hospitalisation for any cause; and hospitalisation for cardiovascular causes.
Baseline values for the atorvastatin and placebo groups, respectively, were: age, 68 ± 11 and 68 ± 10 years; LDL-cholesterol, 3.55 ± 0.88 and 3.44 ± 0.78 mmol/L (137 ± 34 and 133 ± 30 mg/dL); aortic jet velocity 3.39 ± 0.62 and 3.45 ± 0.67 m/s; peak gradient 47.8 ± 17.4 and 49.5 ± 19.5 mmHg; AVA 1.03 ± 0.4 and 1.02 ± 0.41 cm2; and aortic valve median calcium score 5424 and 6221.5
At the conclusion of the study, atorvastatin significantly lowered serum LDL-cholesterol to 1.63 ± 0.60 mmol/L (63 ± 23 mg/dL) while LDL-cholesterol remained near the baseline value [3.37 ± 0.78 mmol/L (130 ± 30 mg/dL)] in the placebo group (P < 0.001). Aortic jet velocity increased annually by 0.199 ± 0.210 m/s in the atorvastatin group and 0.203 ± 0.208 m/s in the placebo group [P = 0.95; adjusted mean difference, 0.002; 95% confidence interval (CI) –0.066–0.070 m/s/year].5
Progression in valvular calcification was 22.3 ± 21.0%/year in the atorvastatin group and 21.7 ± 19.8%/year in the placebo group (P = 0.93; ratio of posttreatment aortic valve calcium score, 0.998; 95% CI 0.947–1.050). Proportions of patients reaching secondary clinical endpoints were somewhat lower in the atorvastatin group, but none of the differences between groups achieved statistical significance. There were slightly lower, but not statistically significantly different, incidences of all secondary endpoints except death from cardiovascular causes in the atorvastatin group compared with the placebo group.5
Reviewing these data, the SALTIRE investigators contended that intensive lipid-lowering therapy did not halt the progression of calcific AS or induce its regression. However, the study was not powered to assess the benefits of lipid-lowering therapy on cardiovascular endpoints, such as non-fatal and fatal myocardial infarction, and investigators could not exclude a small reduction in the rate of AS progression or a significant reduction in major clinical endpoints. Finally, nearly one-quarter of the study population [n = 19 in the atorvastatin group (25%); n = 17 in the placebo group (22%)] had severe AS, as evidenced by changes in mean aortic jet velocity and aortic valve calcium score. In these patients, the disease may have been too advanced to be affected by statin therapy within the study’s duration.5
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Findings from the foregoing studies were somewhat contradictory. Two ongoing studies that might assist in clarifying the relationships between lipid-lowering therapy and the progression of AS have had their study design and baseline data published: the ASTRONOMER trial6 and the SEAS study.7 Three unpublished, ongoing studies are listed in ClinicalTrials.gov of the US National Institutes of Health: the Randomized Study to Evaluate the Efficacy of Fluvastatin on Inflammatory Markers in the Haemodynamic Progression of Degenerative Aortic Stenosis (AORTICA 1), at the Universitario de Salamanca, Spain, scheduled to be completed in November 2008;18 the Statin Therapy in Asymptomatic Aortic Stenosis (STAAT) study at the University of Leipzig Heart Center, scheduled to be completed in December 2008;19 and the Effect of Statin Therapy (Atorvastatin) on the Progression of Calcific Valvular Aortic Stenosis (STOP-AS) trial being conducted at the Cleveland (Ohio) Clinic, with an estimated completion date of June 2008.20 The ongoing AORTICA 1 and STAAT prospective studies have relatively few patients enrolled: 164 and 100, respectively. The STOP-AS prospective study has only 59 patients enrolled and has the further inherent weaknesses of being an open-label rather than a double-blind study and having historical rather than concurrent controls.
ASTRONOMER trial
This Canadian randomised, double-blind, placebo-controlled study is being conducted to determine whether patients with mild-to-moderate asymptomatic AS who are randomised to rosuvastatin 40 mg/day will experience less progression in AS severity during a 3- to 5-year follow-up period. Patients with any clinical indication for the use of cholesterol-lowering agents were excluded. Recruitment of 272 patients from 23 sites was completed in December 2005. Compared with patients with AS evaluated in previously published trials, patients in the ASTRONOMER trial are younger (58.1 ± 13.6 years), have mild-to-moderate AS (AS jet velocity 3.2 ± 0.4 m/s), and include a large proportion (48.9%) of patients with bicuspid aortic valves. The primary endpoint of the trial is progression in AS severity, as measured by aortic transvalvular gradients and AVA. Secondary endpoints include rates of cardiac death and aortic valve replacement, as well as time to reaching an endpoint. Trial results are anticipated at the end of 2008.6
SEAS study
The ongoing SEAS study is a multicentre, double-blind, placebo-controlled trial. Following a 4-week open-label placebo/diet run-in, patients will be treated once daily with simvastatin 40 mg, together with the cholesterol absorption inhibitor ezetimibe 10 mg, or placebo.7 The minimum follow-up is 4 years. The study objectives are three-fold: to delineate the effects of ezetimibe plus simvastatin on aortic valve events (including aortic valve replacement); peak flow velocity, and other haemodynamic and anatomic features of the aortic valve as determined by echocardiography; and ischaemic events in patients with asymptomatic mild-to-moderate AS at study entry. The trial has enrolled 1873 men and women ages 45–85 years from Ireland (n = 17), the UK (n = 187), Germany (n = 292), Norway (n = 425), Sweden (n = 401), Finland (n = 221), and Denmark (n = 330). Excluded from the trial were patients on statin therapy or with an indication for statins, and patients with CHD, other important valvular disease, diabetes, or other conditions precluding participation.7 Patients in the SEAS study had less advanced AS at baseline than those evaluated in SALTIRE, as evidenced by mean aortic jet velocities of 3.09 and 3.39 m/s, respectively.5,7
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Summary |
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TopAbstractIntroductionPrevious prospective studiesOngoing studiesSummaryFundingAcknowledgementsReferences |
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Calcific AS is a common, progressive disease and a potential cause of angina, syncope, heart failure, and sudden cardiac death. Deceleration of AS progression in humans by statin therapy has been suggested by two hypothesis-generating studies: the retrospective study by Novaro et al. and the prospective open-label RAAVE study. On the other hand, the randomised, double-blind, placebo-controlled SALTIRE, which followed a small patient population for only about 2 years, did not show deceleration of disease progression among patients treated with a high-dose statin.5 However, this study was not powered to assess the benefits of lipid-lowering therapy on cardiovascular endpoints; included patients whose disease may have been too advanced to be affected by statin therapy; and had a relatively short treatment duration, with only few patients followed beyond 2 years. At this writing, there is suggestive, but still preliminary and somewhat contradictory, evidence from clinical trials lasting approximately 2 years that LDL-C-lowering treatments can help to retard the progression of AS. It is likely that the ongoing randomised placebo-controlled studies—the SEAS and ASTRONOMER studies—will resolve the question of potential benefit of intensive lipid-lowering therapy in AS, because of the power and long durations of the studies. If a reduced progression of the severity of AS is demonstrated, such therapy is likely to be used at earlier stages of the disease, and increased screening of patients at the susceptible age should be discussed.
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The author has received research grants from Merck Sharp & Dohme (MSD), Merck/Schering-Plough, and Pfizer, and has received consultant honoraria and speaker’s fees from MSD, Merck/Schering-Plough, Pfizer, AstraZeneca, and Merck KgaA.
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Assistance in manuscript preparation was provided by Rete Biomedical Communications Corp. (Ridgewood, NJ, USA).
Conflict of interest: none declared.
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References |
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