Dr. Petra Jenkins
Strong similarities exist between the pathogenesis of degenerative aortic stenosis and atherosclerotic vascular disease. However, despite encouraging data from initial retrospective series, the first prospective randomised trial examining the role of lipid lowering therapy in patients with degenerative aortic stenosis has shown no impact on disease progression. Whilst further larger randomised trials are awaited, lipid lowering cannot be routinely recommended in this situation in the absence of other indications for treatment.
Major advances in imaging techniques and interventional/surgical procedures coupled with improved understanding of underlying pathophysiology have improved the diagnosis and treatment of valvular heart disease. Yet, as the population ages and rheumatic fever declines, calcific degenerative aortic stenosis (AS) remains common and is now the most frequent cardiac disease in developed nations after hypertension and ischaemic heart disease (IHD). Despite the excellent outcomes of aortic valve replacement (AVR), this degenerative disorder presents a significant medical and economic burden.Consequently, the last decade has seen a surge in interest in the identification of novel secondary prevention targets to delay or arrest the progression of AS, thereby deferring (and possibly obviating) the need for AVR.
Initial clues to possible medical strategies for the treatment of AS arose from observational studies and small non-randomised series suggesting that calcific AS was the product of an active inflammatory process, mirroring the risk profile, pathophysiology and progression of atherosclerosis. Both are characterised by lipid infiltration, inflammation, neoangiogenesis and calcification and the two diseases often co-exist. Increasing awareness of the relationship between modifiable risk factors and the pathophysiology of AS led to several studies reporting independent predictors of disease progression, including an adverse lipid profile. The widespread availability of statins with potent lipid lowering properties and additional pleiotropic anti-atherosclerotic effects allowed the design of studies to address the hypothesis that lipid lowering may delay or arrest the progression of AS.Initial small, non-randomised retrospective observational studies demonstrated conflicting findings, some supporting the hypothesis whilst others generated negative results. However, trial design limitations, methodological omissions and exclusions confounded their conclusions. Nevertheless, these studies generated sufficient interest to set the stage for larger prospective randomised clinical trials.
a) Negative findings The first of these studies investigating the effect of lipid modulation on the progression of calcific AS reported outcome earlier this year. In the Scottish SALTIRE trial, a total of 155 patients with moderate AS were randomly assigned to receive placebo or high dose statin therapy (atorvastatin 80mg daily). Haemodynamic progression of AS was determined by serial echocardiographic measurement of aortic-jet velocity and assessment of aortic valve calcification by means of helical computed tomography. Seventy seven patients were assigned to atorvastatin and 78 to placebo, with a median follow up of 25 months. Although atorvastatin produced a marked statistically significant fall in serum LDL cholesterol levels, increases in aortic jet velocity and aortic valve calcification did not differ from the placebo control group. Pre-specified sub-group analyses also excluded variation in outcome related to baseline severity of AS or duration of follow up. Furthermore, there was no relationship between serum LDL cholesterol concentrations and the progression of AS, nor did atorvastatin have a demonstrable effect on clinical outcome.
b) Underlying explanations What explanations may underlie these unexpected negative findings? Although the demographic characteristics of patients in the prospective Scottish trial were similar to those in the previous retrospective observational studies, patients in whom statins were indicated for the treatment of hyperlipidaemia were excluded, thereby negating some of the potential non-valvular benefits of lipid lowering. Furthermore, only patients with an aortic jet velocity greater than 2.5m/s were included whereas intervention at an earlier stage of the disease process may have been more beneficial. Similarly, two years of treatment may have been insufficient to influence disease progression, though sub-group analyses favour against this possibility. Finally, at mechanistic level, whilst features of atherosclerosis may drive the initiation of AS, disease progression may depend on other, as yet undetermined factors. Thus, in contrast to atherosclerosis, AS is associated with virtual absence of smooth muscle cell proliferation and lipid laden macrophages, but dominated by earlier and more extensive mineralization. Reduction of the lipid pool and strengthening of the fibrous cap may be less relevant to the progression of AS than for the reduction of events related to plaque rupture in patients with IHD.
Thus, as ever, further trials are required to clarify the role of lipid lowering in the modulation of calcific AS. Ideally, future prospective randomised trials should incorporate the evaluation of both statin and alternative lipid lowering agents in patients with and without hyperlipidaemia to assess the role of lipid-dependent and -independent mechanisms in preventing disease progression. Two such studies, the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial and the Aortic Stenosis Progression Observation: Measuring the Effect of Rosuvastatin (ASTRONOMER) study, are ongoing. a) The SEAS study The SEAS study is a European multicentre, double blind, randomised placebo-controlled trial to evaluate the effects of the combination of ezetimibe, an inhibitor of intestinal cholesterol absorption, and simvastatin on the clinical outcome of patients with asymptomatic AS. The study design incorporates a 1:1 randomisation to the combination of ezetimibe 10mg and simvastatin 40mg daily or placebo with approximately 4 year follow-up assessing a primary composite endpoint of major cardiovascular events (cardiac death, AVR, congestive heart failure due to progressive AS, non-fatal myocardial infarction, coronary revascularisation, or hospital admission due to unstable angina or non-haemorrhagic stroke). Secondary analyses will include echocardiographic assessment of disease progression and measures of treatment safety. Enrollment of 1400 patients is now complete and results are anticipated in 2007.
b) The ASTRONOMER study The ASTRONOMER study is a similarly designed Canadian multicentre comparison of the effects of Rosuvastatin 40mg daily versus placebo in asymptomatic patients with moderate AS and at low risk of IHD over a three year follow up period. As in the SALTIRE trial, patients with mild AS (aortic jet velocity < 2.5m/s) are excluded from this study. Primary endpoints are changes in peak transvalvular velocity and gradient and predetermined secondary endpoints will also determine whether time to clinical outcome events (cardiac death or AVR) is delayed by statin therapy. Enrollment of a target of 264 patients commenced in 2002 and completion is anticipated in 2008.
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Despite the promising basic scientific hypotheses we therefore await clinical proof that lipid lowering therapy exerts beneficial effects in patients with degenerative AS. Whilst the results of further prospective randomised trials are keenly awaited, their inability to recruit patients at the earliest stages of disease and exclusion of patients with significant vascular risk profile due to ethical considerations seems likely to limit their conclusions. Ultimately, sensible clinical application of the trial data with diligent clinical follow-up for rapid disease progression and early symptom onset seems the likely way forward for the successful management of patients with degenerative AS.
1) Freeman RV, Otto CM. Spectrum of Calcific Aortic Valve Disease: Pathogenesis, Disease Progression and Treatment Strategies. Circulation 2005;111:3316-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15967862&query_hl=1 2) Bellamy MF, Pellika PA, Klarich KW, et al. Association of cholesterol levels, HMGCoA reductase inhibitors, treatment and progression of aortic stenosis in the community. J Am Coll Cardiol 2002;40:1723-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12446053&query_hl=3 3) Cowell SJ, Newby DE, Prescott RJ, et al for the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) Investigators. A Randomised Trial of Intensive Lipid Lowering in Calcific Aortic Stenosis. N Engl J Med 2005;352:2389-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed
Dr Petra Jenkins MB ChB MRCP Specialist Registrar Cardiology Dr Bernard Prendergast DM FRCP Consultant Cardiologist Wythenshawe Hospital, Manchester UK
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