Statins for Aortic Stenosis
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《新英格兰医药杂志》
Calcific aortic stenosis is affecting an increasing number of patients in developed countries. It is a progressive disease that leads to a need for aortic-valve replacement when stenosis becomes severe and symptoms develop.1,2,3,4 The growing number of valve-replacement procedures is a burden on health care systems.
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,5,6 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.2,7 Also, endothelial dysfunction is present in patients with aortic stenosis.8
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. In addition, the use of statins might also lead to a reduction in cardiovascular end points in the group of patients at high risk for vascular complications.
Until now, 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.9,10,11,12 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.13 Each of these studies included between 65 and 211 patients, with a mean follow-up time between 21 and 44 months (Table 1). 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.
Table 1. Characteristics of Studies Assessing the Effects of Statin Therapy on the Progression of Aortic Stenosis.
In this issue of the Journal, Cowell et al.14 report the results of a prospective, randomized study of statin therapy in patients with calcific aortic stenosis. A total of 155 patients with aortic stenosis were randomly assigned to receive placebo or statin therapy (80 mg of atorvastatin daily). The hemodynamic progression of aortic stenosis was assessed by serial measurement of aortic-jet velocity with echocardiography, and the rate of change in aortic-valve calcification was measured by serial computed tomography. Information on disease progression was available for 134 patients, of whom 65 received statins, and 69 placebo.
Hemodynamic progression of aortic stenosis did not differ statistically between patients receiving statins and those receiving placebo. This finding was confirmed by the observation of similar changes in the aortic-valve calcification score between patients treated with statins and those who received placebo.
To rule out an effect of the severity of aortic stenosis or of the duration of treatment, subgroup analyses were performed. These showed no differences in disease progression between patients with mild-to-moderate aortic stenosis and those with severe stenosis or between patients with a follow-up duration of 24 months or less and those with longer follow-up.
The study by Cowell and colleagues is of particular importance since it may be the first prospective, randomized study assessing the effect of statins in aortic stenosis. Although the characteristics of the patients in this study and in the retrospective studies9,10,11,12,13 were similar (Table 1), 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.
In the study by Cowell et al., statins were prescribed at a high dose — patients received 80 mg of atorvastatin per day. In the retrospective studies, the doses were probably lower (in the range of the equivalent of 10 to 20 mg of atorvastatin). However, it is improbable that the use of a higher dose of statin was the reason for the negative results of the present study.
The observation periods in the various studies were similar. However, in the retrospective studies, the patients were already receiving therapy at the time of inclusion in the study. Many of these patients had 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. In addition, although all the studies9,10,11,12,13,14 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.
In view of the results of the prospective study by Cowell and colleagues, the prescription of statins is not justified for a stenotic aortic valve unless there are also other indications for therapy. This is an important study that underscores the necessity of conducting large randomized trials assessing the effects of statins on both hemodynamic progression and the outcome of aortic stenosis.
Source Information
From the Department of Cardiology, Vienna General Hospital, Medical University of Vienna, Vienna.
References
Otto CM, Pearlman AS, Gardner CL. Hemodynamic progression of aortic stenosis in adults assessed by Doppler echocardiography. J Am Coll Cardiol 1989;13:545-550.
Rosenhek R, Klaar U, Schemper M, et al. Mild and moderate aortic stenosis: natural history and risk stratification by echocardiography. Eur Heart J 2004;25:199-205.
Rosenhek R, Binder T, Porenta G, et al. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 2000;343:611-617.
Ross J Jr, Braunwald E. Aortic stenosis. Circulation 1968;38:Suppl 1:61-67.
Mohler ER III, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS. Bone formation and inflammation in cardiac valves. Circulation 2001;103:1522-1528.
O'Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of `degenerative' valvular aortic stenosis. Arterioscler Thromb Vasc Biol 1996;16:523-532.
Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med 1999;341:142-147.
Poggianti E, Venneri L, Chubuchny V, Jambrik Z, Baroncini LA, Picano E. Aortic valve sclerosis is associated with systemic endothelial dysfunction. J Am Coll Cardiol 2003;41:136-141.
Aronow WS, Ahn C, Kronzon I, Goldman ME. Association of coronary risk factors and use of statins with progression of mild valvular aortic stenosis in older persons. Am J Cardiol 2001;88:693-695.
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.
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.
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.
Shavelle DM, Takasu J, Budoff MJ, Mao S, Zhao XQ, O'Brien KD. HMG CoA reductase inhibitor (statin) and aortic valve calcium. Lancet 2002;359:1125-1126.
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.(Raphael Rosenhek, M.D.)
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,5,6 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.2,7 Also, endothelial dysfunction is present in patients with aortic stenosis.8
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. In addition, the use of statins might also lead to a reduction in cardiovascular end points in the group of patients at high risk for vascular complications.
Until now, 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.9,10,11,12 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.13 Each of these studies included between 65 and 211 patients, with a mean follow-up time between 21 and 44 months (Table 1). 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.
Table 1. Characteristics of Studies Assessing the Effects of Statin Therapy on the Progression of Aortic Stenosis.
In this issue of the Journal, Cowell et al.14 report the results of a prospective, randomized study of statin therapy in patients with calcific aortic stenosis. A total of 155 patients with aortic stenosis were randomly assigned to receive placebo or statin therapy (80 mg of atorvastatin daily). The hemodynamic progression of aortic stenosis was assessed by serial measurement of aortic-jet velocity with echocardiography, and the rate of change in aortic-valve calcification was measured by serial computed tomography. Information on disease progression was available for 134 patients, of whom 65 received statins, and 69 placebo.
Hemodynamic progression of aortic stenosis did not differ statistically between patients receiving statins and those receiving placebo. This finding was confirmed by the observation of similar changes in the aortic-valve calcification score between patients treated with statins and those who received placebo.
To rule out an effect of the severity of aortic stenosis or of the duration of treatment, subgroup analyses were performed. These showed no differences in disease progression between patients with mild-to-moderate aortic stenosis and those with severe stenosis or between patients with a follow-up duration of 24 months or less and those with longer follow-up.
The study by Cowell and colleagues is of particular importance since it may be the first prospective, randomized study assessing the effect of statins in aortic stenosis. Although the characteristics of the patients in this study and in the retrospective studies9,10,11,12,13 were similar (Table 1), 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.
In the study by Cowell et al., statins were prescribed at a high dose — patients received 80 mg of atorvastatin per day. In the retrospective studies, the doses were probably lower (in the range of the equivalent of 10 to 20 mg of atorvastatin). However, it is improbable that the use of a higher dose of statin was the reason for the negative results of the present study.
The observation periods in the various studies were similar. However, in the retrospective studies, the patients were already receiving therapy at the time of inclusion in the study. Many of these patients had 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. In addition, although all the studies9,10,11,12,13,14 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.
In view of the results of the prospective study by Cowell and colleagues, the prescription of statins is not justified for a stenotic aortic valve unless there are also other indications for therapy. This is an important study that underscores the necessity of conducting large randomized trials assessing the effects of statins on both hemodynamic progression and the outcome of aortic stenosis.
Source Information
From the Department of Cardiology, Vienna General Hospital, Medical University of Vienna, Vienna.
References
Otto CM, Pearlman AS, Gardner CL. Hemodynamic progression of aortic stenosis in adults assessed by Doppler echocardiography. J Am Coll Cardiol 1989;13:545-550.
Rosenhek R, Klaar U, Schemper M, et al. Mild and moderate aortic stenosis: natural history and risk stratification by echocardiography. Eur Heart J 2004;25:199-205.
Rosenhek R, Binder T, Porenta G, et al. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med 2000;343:611-617.
Ross J Jr, Braunwald E. Aortic stenosis. Circulation 1968;38:Suppl 1:61-67.
Mohler ER III, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS. Bone formation and inflammation in cardiac valves. Circulation 2001;103:1522-1528.
O'Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of `degenerative' valvular aortic stenosis. Arterioscler Thromb Vasc Biol 1996;16:523-532.
Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med 1999;341:142-147.
Poggianti E, Venneri L, Chubuchny V, Jambrik Z, Baroncini LA, Picano E. Aortic valve sclerosis is associated with systemic endothelial dysfunction. J Am Coll Cardiol 2003;41:136-141.
Aronow WS, Ahn C, Kronzon I, Goldman ME. Association of coronary risk factors and use of statins with progression of mild valvular aortic stenosis in older persons. Am J Cardiol 2001;88:693-695.
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.
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.
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.
Shavelle DM, Takasu J, Budoff MJ, Mao S, Zhao XQ, O'Brien KD. HMG CoA reductase inhibitor (statin) and aortic valve calcium. Lancet 2002;359:1125-1126.
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.(Raphael Rosenhek, M.D.)