IN

Is it Over?

The Journal Club Conference Shadwan Alsafwah, MD Cardiology Fellow The University of Tennessee at Memphis

Introduction

     In the Western world, calcific aortic stenosis is the most common form of valvular heart disease, and its incidence increases with age such that 3% of adults over 75 years of age have aortic stenosis It is a progressive disease that leads to a need for aortic-valve replacement when stenosis becomes severe and symptoms develop Calcific aortic stenosis is now the leading indication for valve replacement in North America and Europe The growing number of aortic valve-replacement procedures (currently 50,000 cases annually in the US) is a burden on the health care systems However, there are currently no effective disease-modifying treatments, and the possibility of halting the disease process would represent a therapeutic advance

Pathogenesis of Calcific AS

   “Degenerative” calcific aortic valve disease was thought for many years to be a passive accumulation of calcium binding to the aortic surface of the valve leaflet Now, convincing data indicate aortic stenosis is an active disease process with active inflammatory component At the tissue level, the valve leaflets show the following features: -Accumulation of LDL and Lp(a) with evidence of oxidative modification

- An inflammatory cell infiltrate with activated T-lymphocytes and macrophages Activated macrophages and fibroblasts produce Osteopontin (a noncollagenous, glycosylated phosphoprotein that is a prominent matrix component of mineralized bone) Osteopontin has several structural characteristics that lend support to the potential roles it may play including: 1. Cellular adhesion via an Arg-Gly-Asp (RGD) motif 2. Hydroxyapatite binding via a sequence of nine consecutive aspartic acids 3. Calcium binding site 4. Also, osteopontin has been identified as a substrate for transglutaminase and factor XIII, which may serve to covalently anchor the protein to other extracellular matrix components. The noncollagenous matrix proteins such as osteopontin, as well as various enzymes and growth factors, control the calcific process

Photomicrographs showing the association of osteopontin and macrophages in a calcified aortic valve. A, Calcium staining with alizarin red S. B, Osteopontin identified with anti-osteopontin peptide antibody. C, CD68-positive macrophages (brown) with hematoxylin and eosin counterstaining. Macrophages were associated with osteopontin and calcific deposits. Mohler, III E, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:547-552

-Production and activity of angiotensin converting enzyme and AT1 and AT2 receptors -Other inflammatory mediators such as interleukin-1-beta and transforming growth factor beta-1 -Upregulation of adhesion molecules and alterations in matrix metalloproteinase activity - Hormones also influence the calcific process, as seen with states of altered calcium metabolism, such as hyperparathyroidism, Padget's disease, and renal failure, in which ectopic calcification is not uncommon

Rajamannan NM, Otto CM. Circulation. 2004;110:1180-82

AS and CAD

    The active inflammatory component of calcific aortic-valve disease has been recognized, and similarities with atherosclerotic disease have been identified Both calcific aortic-valve disease and atherosclerosis are characterized by lipid infiltration, inflammation, neoangiogenesis, and calcification, and the two diseases often coexist Patients with any degree of aortic-valve disease (e.g., aortic sclerosis, mild-to-moderate stenosis, or severe stenosis) have increased cardiovascular morbidity and mortality Also, endothelial dysfunction is present in patients with aortic stenosis

AS and Statins

  From these observations, the hypothesis has emerged that statins, which reduce the progression of atherosclerotic disease and significantly improve the clinical outcome among patients with coronary artery disease, might also be beneficial in patients with aortic stenosis Since aortic stenosis, like atherosclerosis, is an active disease process, it seems plausible that statins might slow its hemodynamic progression

AS and Statins in Animal Models

Light microscopy of rabbit aortic valves from a rabbit fed a conventional diet (left column), one fed a high-cholesterol diet (middle column), and one fed a high-cholesterol diet and treated with atorvastatin (right column). A1-A3, Hematoxylin and eosin stain. B1-B3, Masson trichrome stain for collagen (blue stain). C1-C3, Macrophage RAM-11 stain for macrophages and foam cells. D1-D3, Stain for proliferating cell nuclear antigen. Rajamannan NM, et al. Circulation 105:2660, 2002

AS and Statins in Humans

  Until recently, the effects of statin therapy on the progression of aortic stenosis have been assessed only in retrospective studies. Four such studies used echocardiography to evaluate hemodynamic progression and found a significantly lower rate of progression of aortic stenosis among patients treated with statins Furthermore, an additional retrospective study that used electron-beam computed tomography to determine the degree of valvular calcification identified a lesser degree of aortic-valve calcium accumulation among patients receiving statins

    Each of these studies included between 65 and 211 patients, with a mean follow-up time between 21 and 44 months. Although these studies consistently described a lower rate of progression of aortic stenosis with statin therapy, they were all limited by their nonrandomized, retrospective nature The slower rate of disease progression was related to lowering of cholesterol levels in some of these studies but not others, suggesting that pleiotropic effects of statins may play a role These observations provided the rationale for the first prospective randomized (SALTIRE) trial

Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE)

 The aim of the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE) was to establish whether intensive lipid-lowering therapy with 80 mg of atorvastatin daily would halt the progression or induce regression of the aortic-jet velocity on Doppler echocardiography, and of the aortic valve calcium score on computed tomography (CT), in patients with calcific aortic stenosis Cowell, SJ, Newby DE, Prescott RJ et al. N Engl J Med 2005; 352:2389

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Methods

The Patients

Patients older than 18 years of age with calcific aortic stenosis, an aortic jet velocity of at least 2.5 m per second, and aortic-valve calcification on echocardiography were eligible for inclusion Exclusion criteria were: -Child-bearing potential without contraception -Active or chronic liver disease -History of alcohol or drug abuse -Severe mitral-valve stenosis (mitral-valve area, <1 cm2), severe mitral or aortic regurgitation, left ventricular dysfunction (ejection fraction <35 percent), a planned aortic-valve replacement -Intolerance of statins, statin therapy or a potential benefit from statin therapy (according to the treating physician), a baseline serum total cholesterol concentration of less than 150 mg per deciliter -Presence of a permanent pacemaker or defibrillator Cowell, SJ, Newby DE, Prescott RJ et al. N Engl J Med 2005; 352:2389

Methods

Study Protocol

 Between March 2001 and April 2002, the blinded study coordinator randomly assigned eligible patients by the minimization technique with the use of a dedicated, locked computer program incorporating the following eight variables: age, sex, smoking habit, hypertension, diabetes mellitus, serum cholesterol concentration, aortic-jet velocity, and aortic-valve calcium score. Patients were assigned to either 80 mg of atorvastatin or matched placebo as a single daily dose

Methods

Study Protocol

    Patients were assessed at baseline, two months, and six months and every six months thereafter for a minimum of two years Clinical evaluation included assessment of functional status and adverse events, and the biochemical analysis of blood Echocardiography and CT were performed at baseline, at each annual visit, and before withdrawal from the study Patients who underwent randomization and who were subsequently started on open-label statin therapy by their attending physician were immediately withdrawn from the study

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Methods End Points

The two primary end points were: 1. Progression of stenosis, determined according to changes in aortic-jet velocity on Doppler echo 2. Progression of valvular calcification, as measured by CT Secondary end points were: -A composite of clinical end points (death from cardiovascular causes, aortic-valve replacement, or hospitalization attributable to severe aortic stenosis) -Aortic-valve replacement -Death from any cause -Death from cardiovascular causes -Hospitalization for any cause -Hospitalization for severe aortic stenosis

 The study was powered to detect a difference in the primary end points of 0.15 m per second per year in aortic-jet velocity and 500 agatston units (AU) per year in aortic-valve calcium score. These differences are equivalent to a reduction of more than 30 percent in the rate of progression of aortic stenosis. This would exclude a clinically significant effect in the majority of older patients with established disease, although a smaller effect may be clinically relevant in younger patients with mild aortic stenosis

 77 patients were assigned to atorvastatin, and  78 to placebo Median follow-up of 25 months (range: 7 to 36 months)  Baseline characteristics were well matched:

 Mean aortic-jet velocity was 3.43±0.64 m/s (range, 2.5 to 5.0)  Median aortic-valve calcium score was 5920 AU (range, 2485 to 14,231)  Of the 155 patients, 119 had mild-to-moderate aortic stenosis (aortic-jet velocity, 2.5 to 3.9 m/s), and 36 had severe stenosis (aortic-jet velocity, 4.0 m/s)

Results:

Serum Cholesterol Concentrations

  The mean serum low-density lipoprotein (LDL) cholesterol concentration remained at 130±30 mg per deciliter in the placebo group and decreased by 53 percent to 63±23 mg per deciliter in the atorvastatin group (P<0.001) Serum total cholesterol was 209±35 mg per deciliter and 132±27 mg per deciliter in the placebo and atorvastatin groups, respectively (P<0.001), and is in keeping with 97% adherence to the study treatment in both groups, which was confirmed by a pill count

Effect of Atorvastatin on Disease Progression

  Intensive lipid-lowering therapy with 80 mg of atorvastatin daily had no effect on the rate of change in aortic-jet velocity or valvular calcification. 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)

Secondary End Points

 The proportion of patients reaching secondary clinical end points seemed to be less in the atorvastatin group, but none of the comparisons achieved statistical significance

Subgroup Analysis

  Subgroup analysis of the primary end-point data was conducted in patients with mild-to-moderate aortic stenosis and severe aortic stenosis at baseline. As anticipated from earlier studies, patients with severe stenosis at baseline progressed more rapidly (P=0.04), but the study findings were consistent regardless of the severity of stenosis at baseline Likewise, the length of follow-up did not influence outcome. In those followed for more than 24 months , the increase in aortic-jet velocity was 0.21±0.20 m per second per year in the atorvastatin group and 0.17±0.14 m per second per year in the placebo group. In those followed for 24 months or less, the increase in aortic-jet velocity was 0.19±0.22 m per second per year in the atorvastatin group and 0.23±0.25 m per second per year in the placebo group

Conclusion

“We conclude that intensive lipid-lowering therapy with 80 mg of atorvastatin daily does not halt the progression of calcific aortic stenosis or induce its regression. Nevertheless, this trial does not rule out a small but potentially relevant reduction in the rate of disease progression or a significant reduction in major clinical end points. Our study reinforces the need for a long-term, large scale, randomized, controlled trial of intensive lipid-lowering therapy in patients with calcific aortic stenosis, particularly in those with early, mild disease. In the meantime, we do not recommend statin therapy for patients with calcific aortic stenosis in the absence of coexisting vascular disease” Cowell, SJ, Newby DE, Prescott RJ et al. N Engl J Med 2005; 352:2389

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Discussion: Results

In this randomized, double-blind, placebo-controlled, parallel group trial of lipid-lowering therapy in patients with calcific aortic stenosis, a single coordinating center used a consistent and reproducible approach to assess the severity of aortic stenosis It has clearly shown that high-dose atorvastatin reduces serum LDL cholesterol concentrations as anticipated, but it does not halt the progression or induce regression of the valvular disease process. This was shown with the use of two distinct measures of disease severity — aortic-jet velocity assessed with Doppler echocardiography and valvular calcification assessed with helical CT Moreover, there was no relationship between serum LDL cholesterol concentrations and the progression of aortic stenosis, nor did high-dose atorvastatin have a demonstrable effect on clinical end points

Strengths

1. The first prospective, randomized study assessing the effect of statins in aortic stenosis 2. Although the characteristics of the patients in this study and in the retrospective studies were similar, the present study differs not only because of its prospective design but also because the indications for therapy were different. In the retrospective trials, statin therapy was indicated for the treatment of hyperlipidemia, whereas in the prospective trial, patients in whom statins were indicated for the treatment of hyperlipidemia were excluded 3. In this study statins were prescribed at a high dose (80 mg of atorvastatin per day). In the retrospective studies, the doses were lower 10-20 mg per day of atorvastatin)

Weaknesses

1. The study excluded patients with an aortic-jet velocity of less than 2.5 m per second, although it acknowledged that intervening at this earlier stage of the disease process may have been more beneficial 2. The study was designed to detect a substantial delay in disease progression and was not powered to assess meaningful effects on clinical end points, such as valve replacement and cardiovascular death

Weaknesses

3. Although the study can exclude a treatment benefit of the magnitude previously reported in retrospective observational studies (a reduction in the aortic-jet velocity of 0.30 m per second per year and valvular calcification of 30 percent per year), the 95 percent confidence intervals indicate that the study may have missed a modest treatment benefit (a delay in disease progression of <0.07 m per second per year for aortic-jet velocity and <5 percent per year for valvular calcification). Although such modest reductions are unlikely to be meaningful in the majority of older patients, a small decrease in disease progression may be clinically important in younger patients with mild disease that may progress over many years

Weaknesses

4. Although the observation periods in this study in comparison to the prior retrospective studies were similar. However, in the retrospective studies, the patients were already receiving therapy at the time of inclusion in the study and many of them were started therapy long before the study. Thus, one cannot rule out the need for longer overall treatment periods to observe an effect of statin therapy 5. Although all the studies were similar in size, they were all relatively small, and it is too early to draw conclusions on the value of statin therapy in aortic stenosis

Given the strength of the data linking aortic stenosis with atherosclerosis and hypercholesterolemia, this study failed to halt the progression of calcific aortic stenosis?

One potential explanation is that, although these features may drive the initiation of aortic stenosis, the disease progression may depend on other factors

AS vs CAD

At the tissue and cellular level:  in contrast to atherosclerosis, aortic stenosis is associated with a significantly less degree of smooth muscle-cell proliferation and lipid-laden macrophages. On the other hand, it is dominated by earlier and more extensive mineralization  Hence, decreasing the lipid pool and strengthening the fibrous cap may be less relevant to the progression of aortic stenosis than they are for the reduction in atherosclerotic-plaque rupture with statin therapy in patients with coronary heart disease

AS vs CAD

 However, perhaps the most important difference is the mechanism of clinical events: In atherosclerosis, plaque instability is key; in aortic stenosis, the shear bulk of the lesion is the problem. Early in the disease process, small areas of inflammation and lipid infiltration are interspersed with areas of normal leaflet so that the valve leaflets remain flexible and open normally in systole. Late in the disease process, the abnormal areas become confluent with prominent calcification and increased fibrosis, resulting in increased leaflet stiffness and obstruction to left ventricular outflow

  Inhibition of lipid accumulation in the valve tissue is the first pathway to be studied; however, other more specific therapies targeting endothelial disruption, inflammation, or tissue calcification may be more effective Hence, therapy may need to be tailored to the stage of the disease process; some may prevent initiation of disease process, whereas others may be more effective in slowing calcium accumulation in end-stage disease

Rajamannan NM, Otto CM. Circulation. 2004;110:1180-82

So What is the Rest of the Story?

Other Proposed Mechanisms for the Development of AS

 Abnormalities in Calcium Metabolism: - Hyperparathyroidism Primary Secondary - Certain Vitamin D receptor genotype (allele B)  ACE activity

AS and Hyperparathyroidism

  Multiorgan soft tissue calcification commonly occurs in patients with chronic renal failure; secondary hyperparathyroidism is thought to be the major causative factor -Asymptomatic calcification of heart valves has been reported in up to a third of such patients -Hemodynamically significant AS is found in 3% in those patients In a postmortem study, parathyroid hyperplasia was found in all six patients with chronic renal failure, who were shown to have extensive cardiac calcification. ( Terman D, et al. Cardiac calcification in uremia. Am J Med. 1971;50:744-55)

AS and Hyperparathyroidism

Although up till recently enhanced progression of valve stenosis in the presence of secondary hyperparathyroidism has not been studied systematically, but there are many case reports in the literature to support that: -Depace NL, et al. Arch Intern Med 1981;141:1663-5 -McFalls EO, et al. Am Heart J 1990;120:206-8 -Fujise K, et al. Br Heart J 1993;70:282-4

The vitamin D receptor genotype predisposes to the development of calcific aortic valve stenosis

  The distribution of one polymorphism of the vitamin D receptor (BsmI B/b) was examined in 100 consecutive patients with calcific valvar aortic stenosis and compared with a control group of 100 patients (paired match for age, sex, and the presence of coronary artery disease from a total of 630 patients without calcified aortic valves) RESULTS: There was a significant difference in vitamin D receptor allele and genotype frequencies between the two groups. The allele B had a higher prevalence in patients with calcific aortic stenosis (B = 0.56, b = 0.44) than in the control cohort (B = 0.40, b = 0.60) (p = 0.001) Ortlepp, Jr, et al. Heart 2001;85:635-638

  This study found an association between the B allele which seems to predispose gene carriers to blunted calcium absorption, more rapid bone loss, reduced bone mineral density, and raised parathormone secretion and the prevalence of calcific aortic valve stenosis There might be several hypotheses to explain the relation between genotype and the development of aortic stenosis. Individuals with a slightly unfavorable bone mineral density might develop mechanisms to overcome this alteration of calcium homeostasis. Like parathormone, other hormones, proteins, or second messengers might trigger calcification of extraosseous structures like the aortic valve. The aortic valve is likely to be one of the first extraosseous structures involved because of the high level of mechanical stress to which it is subjected Ortlepp, Jr, et al . Heart 2001;85:635-638

Rajamannan NM, Otto CM. Circulation. 2004;110:1180-82

Angiotensin-Converting Enzyme Inhibitors and Change in Aortic Valve Calcium

  Background: Because lipoproteins, angiotensin-converting enzyme, and angiotensin II colocalize with calcium in aortic valve lesions, the study hypothesized an association between ACEI use and lowered aortic valve calcium (AVC) accumulation, as measured by electron beam computed tomography Rates of change in volumetric AVC scores were determined retrospectively for 123 patients who had undergone 2 serial electron beam computed tomographic scans. The mean (±SD) interscan interval was 2.5 (±1.7) years; 80 patients did not receive ACEIs and 43 received ACEIs. The relationship of ACEI use to median rates of AVC score change (both unadjusted and adjusted for baseline AVC scores and coronary heart disease risk factors) was determined Obrien, KD, et al. Arch Intern Med. 2005;165:858-862.

Association of angiotensin-converting enzyme inhibitor (ACEI) use with lower rate of change in aortic valve calcium (AVC) scores. Box plots display the median and 25th and 75th percentiles, and bars show the 10th and 90th percentiles. Median values are shown to the right of each box. Median rate of change was significantly lower for the ACEI group (Mann-Whitney test). Obrien, KD, et al. Arch Intern Med. 2005;165:858-862.

Association of angiotensin-converting enzyme inhibitor (ACEI) use with lower likelihood of definite progression in AVC scores (Fisher exact test). Obrien, KD, et al. Arch Intern Med. 2005;165:858-862.

Obrien, KD, et al. Arch Intern Med. 2005;165:858-862.

So, is this is the End of the Story for Statins and AS?

In The Horizon

 At least 2 prospective, randomized, placebo-controlled multicenter studies of lipid-lowering therapy to prevent disease progression in aortic stenosis are in progress: -The Aortic Stenosis Progression Observation  Measuring Effect of Rosuvastatin (ASTRONOMER) study in Canada -Simvastatin and Ezetimide in Aortic Stenosis (SEAS) study in Europe We should await the results of these trials to determine whether it will become appropriate to prescribe statin therapy routinely in patients with calcific valve disease.

Summary

     Calcific aortic stenosis is an active disease process with active inflammatory component There is evidence in the literature (animal models and retrospective studies) that statins may be beneficial in slowing down the progression of AS SALTIRE trial, the first randomized prospective trial, failed to show a beneficial effect of atorvastatin on AS progression.

However, SALTIRE trial had many limitations and final conclusions about the benefits of statins on the progression of AS should wait further studies Interfering with lipid metabolism in the valve tissue was the first pathway to be studied prospectively; however, further studies are needed to address the other pathways involved in the pathogenesis of AS including endothelial disruption, inflammation, tissue ACE system, and tissue calcification

Thank You