Vasodilators in Aortic Regurgitation
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《新英格兰医药杂志》
To the Editor: In the study by Evangelista et al. regarding long-term vasodilator therapy in patients with severe aortic regurgitation (Sept. 29 issue),1 both nifedipine and enalapril failed to induce adequate vasodilation, because systolic blood pressure and diastolic blood pressure did not change significantly between baseline and follow-up among patients taking either drug. Therefore, it is not surprising that neither nifedipine nor enalapril improved the outcome of reducing or delaying the need for aortic-valve replacement.2 A reduction in the end-systolic volume or an increase in the ejection fraction, neither of which was seen in this trial, would have been expected with a reduction in afterload that was sufficient to cause a reduction in blood pressure. Evangelista et al. found only that administration of nifedipine (at a dose of 20 mg every 12 hours) or enalapril (at 20 mg per day) without adequate vasodilation did not decrease or delay the need for valve replacement in patients with chronic aortic-valve regurgitation.
Hisato Takagi, M.D., Ph.D.
Takuya Umemoto, M.D., Ph.D.
Shizuoka Medical Center
Shizuoka 411-8611, Japan
kfgth973@ybb.ne.jp
References
Evangelista A, Tornos P, Sambola A, Permanyer-Miralda G, Soler-Soler L. Long-term vasodilator therapy in patients with severe aortic regurgitation. N Engl J Med 2005;353:1342-1349.
Carabello BA. Vasodilators in aortic regurgitation -- where is the evidence of their effectiveness? N Engl J Med 2005;353:1400-1402.
To the Editor: We are not surprised by the neutral results of the underpowered study of vasodilators in severe aortic regurgitation by Evangelista et al. On the basis of the number of patients recruited (assuming no dropouts) and with data on the control group in the study by Scognamiglio et al.1 used to estimate the rate of progression to surgical repair (30 percent), the rate of progression would need to be 80 percent lower in the vasodilator groups than in the placebo group to achieve statistical significance. With the lower event rate, high dropout rate, and demonstrated drug underdosing, neutral results should be expected. We are also troubled by the lack of blood-pressure control during the study. Was it ethical not to manage blood pressure aggressively, given the well-established reductions in stroke, heart failure, and mortality seen with therapy?2 Avoidance of confounding should never supplant sound clinical judgment. We currently aim for a systolic blood pressure of less than 130 mm Hg, if tolerated, in patients with aortic regurgitation, using vasodilators first and adding thiazide diuretics if necessary. We are encouraged that valvular heart disease is finally being targeted for landmark trials, from lipid lowering in aortic stenosis3 to novel percutaneous therapies, including aortic-valve replacement and mitral-valve repair.4
Richard A. Krasuski, M.D.
Brian P. Griffin, M.D.
Cleveland Clinic Foundation
Cleveland, OH 44195
krasusr@ccf.org
References
Scognamiglio R, Rahimtoola SH, Fasoli G, Nistri S, Dalla Volta S. Nifedipine in asymptomatic patients with severe aortic regurgitation and normal left ventricular function. N Engl J Med 1994;331:689-694.
Staessen JA, Li Y, Thijs L, Wang JG. Blood pressure reduction and cardiovascular prevention: an update including the 2003-2004 secondary prevention trials. Hypertens Res 2005;28:385-407.
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.
Vassiliades TA Jr, Block PC, Cohn LH, et al. The clinical development of percutaneous heart valve technology: a position statement of the Society of Thoracic Surgeons (STS), the American Association for Thoracic Surgery (AATS), and the Society for Cardiovascular Angiography and Interventions (SCAI) endorsed by the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA). J Am Coll Cardiol 2005;45:1554-1560.
To the Editor: Evangelista et al. report that there were no significant differences in any of the echocardiographic variables in a comparison of baseline values and final results in the control group and the groups that received either enalapril or nifedipine, as shown in Table 2 of the article. However, the change in the left-ventricular-mass index in the nifedipine group is markedly less than that in the control group. The change in the left-ventricular-mass index in the nifedipine group is 57 percent of that seen in the enalapril group and 36 percent of that seen in the control group. The absence of a statistically significant difference among treatment groups is attributable to the low power of the study owing to the small sample size, rather than to a lack of clinical significance. The patients in the control group had the greatest change in the left-ventricular-mass index, indicating that without treatment they are prone to more severe left-ventricular enlargement than are the two treatment groups.
Farsad Afshinnia, M.D.
Brookdale University Hospital and Medical Center
Brooklyn, NY 11212
To the Editor: Evangelista et al. randomly assigned a highly selected group of patients to study groups. First, patients who had not had surgery in their prospective study1 were entered into the randomized trial; the duration of follow-up in the prospective study should be provided. Second, the mean (±SD) diastolic blood pressure in the nifedipine group was 78±11 mm Hg; in patients with severe aortic regurgitation, this measure is lower.1,2 This finding suggests that many patients in the nifedipine group did not have severe chronic aortic regurgitation. Moreover, the mean left ventricular end-diastolic volume index among these patients was 94±27 ml per square meter, whereas in the study by Scognamiglio et al.,2 it was 126±16 ml per square meter. Third, of the 32 patients in the nifedipine group, 7 (22 percent) dropped out at 2±7 months. The number of patients at risk at eight years should be provided. In the study by Scognamiglio et al.,2 of 69 patients in the nifedipine group, 4 were lost to follow-up; the rate of valve replacement at six years was 15±3 percent. Fourth, nifedipine (at a dose of 20 mg) was given every 12 hours, whereas in the study by Scognamiglio et al., long-acting nifedipine (also at a twice-daily dose of 20 mg) was administered.3
Shahbudin H. Rahimtoola, M.B., F.R.C.P.
University of Southern California
Los Angeles, CA 90033
References
Tornos MP, Olona M, Permanyer-Miralda G, et al. Clinical outcome of severe asymptomatic chronic aortic regurgitation: a long-term prospective follow-up study. Am Heart J 1995;130:333-339.
Scognamiglio R, Rahimtoola SH, Fasoli G, Nistri S, Dalla Volta S. Nifedipine in asymptomatic patients with severe aortic regurgitation and normal left ventricular function. N Engl J Med 1994;331:689-694.
Scognamiglio R, Rahimtoola SH. Nifedipine in severe aortic regurgitation. N Engl J Med 1995;332:1303-1304.
The authors reply: Takagi and Umemoto raise an interesting point: Should the dose of vasodilators be increased until there is evidence of an unloading effect? Although this is an important issue, it misses the point of our study. In a previous trial, nifedipine at a twice-daily dose of 20 mg was found to delay left ventricular deterioration and the need for valve-replacement surgery. Our intention was to replicate these findings and to better assess the echocardiographic time course, regardless of the degree of vasodilatation achieved. The reduction in blood pressure with vasodilator therapy is more marked when baseline blood pressure is higher. In our study, we excluded patients with severe hypertension (defined as a diastolic blood pressure above 90 mm Hg or a systolic blood pressure above 180 mm Hg). Other studies also failed to show a reduction in systolic or diastolic blood pressure among patients with aortic regurgitation who were treated with vasodilators.1,2 Our results merely suggest that evidence supporting the widely accepted recommendation of this vasodilator schedule for delaying surgery may not be sufficiently robust. Moreover, it is doubtful how the degree of vasodilatation should be measured. Our 22 percent dropout rate in the nifedipine group owing to vasodilatation symptoms suggests that such an effect was not negligible in all patients.
Krasuski and Griffin point out the all-too-obvious fact that our study was underpowered for major clinical events, as acknowledged in the article. However, the power of our study for evaluating echocardiographic variables was not limited, being 80 percent and more than 90 percent to detect 4-mm and 6-mm differences, respectively, in chamber diameters. We believe that the interest of the study lies in its not having reproduced, with a similar sample, the clinical and echocardiographic findings of Scognamiglio et al., thus casting doubt on a class I recommendation. Regardless of what the power for detecting major events may be, a clinically meaningful effect of vasodilators on left ventricular function is implausible on the basis of our findings. Regarding the ethical concerns raised by Krasuski and Griffin: the rationale for treating patients with aortic regurgitation and within our blood pressure range without other risk factors is debatable. The policy advocated by these correspondents seems to have better intentions than evidence supports.
Like Afshinnia, we were intrigued by our finding that patients in the nifedipine group had less change in the left-ventricular-mass index than did patients in the other groups. We have refrained from speculating on this finding, since the data are isolated and rest on indirect calculations.
In regard to issues raised by Rahimtoola: all patients in our clinical trial, which began after our prospective study was reported, had severe aortic regurgitation on carefully recorded Doppler echocardiography and received the same nifedipine preparation and schedule as he reports from the study by Scognamiglio et al. In our study, after seven years, only 11 patients in the nifedipine group who tolerated the drug (34 percent) were alive and had not undergone valve-replacement surgery, without any loss to follow-up. Intention-to-treat and on-treatment analyses yielded similar results.
Artur Evangelista, M.D.
Pilar Tornos, M.D.
Gaietà Permanyer-Miralda, M.D.
Hospital Universitari Vall d'Hebron
08035 Barcelona, Spain
aevangel@vhebron.net
References
Greenberg B, Massie B, Bristow JD, et al. Long-term vasodilator therapy of chronic aortic insufficiency: a randomized double-blinded, placebo-controlled clinical trial. Circulation 1988;78:92-103.
Sondergaard L, Aldershvile J, Hildebrandt P, Kelback H, Stálberg F, Thomsen C. Vasodilatation with felodipine in chronic asymptomatic aortic regurgitation. Am Heart J 2000;139:667-674.
Hisato Takagi, M.D., Ph.D.
Takuya Umemoto, M.D., Ph.D.
Shizuoka Medical Center
Shizuoka 411-8611, Japan
kfgth973@ybb.ne.jp
References
Evangelista A, Tornos P, Sambola A, Permanyer-Miralda G, Soler-Soler L. Long-term vasodilator therapy in patients with severe aortic regurgitation. N Engl J Med 2005;353:1342-1349.
Carabello BA. Vasodilators in aortic regurgitation -- where is the evidence of their effectiveness? N Engl J Med 2005;353:1400-1402.
To the Editor: We are not surprised by the neutral results of the underpowered study of vasodilators in severe aortic regurgitation by Evangelista et al. On the basis of the number of patients recruited (assuming no dropouts) and with data on the control group in the study by Scognamiglio et al.1 used to estimate the rate of progression to surgical repair (30 percent), the rate of progression would need to be 80 percent lower in the vasodilator groups than in the placebo group to achieve statistical significance. With the lower event rate, high dropout rate, and demonstrated drug underdosing, neutral results should be expected. We are also troubled by the lack of blood-pressure control during the study. Was it ethical not to manage blood pressure aggressively, given the well-established reductions in stroke, heart failure, and mortality seen with therapy?2 Avoidance of confounding should never supplant sound clinical judgment. We currently aim for a systolic blood pressure of less than 130 mm Hg, if tolerated, in patients with aortic regurgitation, using vasodilators first and adding thiazide diuretics if necessary. We are encouraged that valvular heart disease is finally being targeted for landmark trials, from lipid lowering in aortic stenosis3 to novel percutaneous therapies, including aortic-valve replacement and mitral-valve repair.4
Richard A. Krasuski, M.D.
Brian P. Griffin, M.D.
Cleveland Clinic Foundation
Cleveland, OH 44195
krasusr@ccf.org
References
Scognamiglio R, Rahimtoola SH, Fasoli G, Nistri S, Dalla Volta S. Nifedipine in asymptomatic patients with severe aortic regurgitation and normal left ventricular function. N Engl J Med 1994;331:689-694.
Staessen JA, Li Y, Thijs L, Wang JG. Blood pressure reduction and cardiovascular prevention: an update including the 2003-2004 secondary prevention trials. Hypertens Res 2005;28:385-407.
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.
Vassiliades TA Jr, Block PC, Cohn LH, et al. The clinical development of percutaneous heart valve technology: a position statement of the Society of Thoracic Surgeons (STS), the American Association for Thoracic Surgery (AATS), and the Society for Cardiovascular Angiography and Interventions (SCAI) endorsed by the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA). J Am Coll Cardiol 2005;45:1554-1560.
To the Editor: Evangelista et al. report that there were no significant differences in any of the echocardiographic variables in a comparison of baseline values and final results in the control group and the groups that received either enalapril or nifedipine, as shown in Table 2 of the article. However, the change in the left-ventricular-mass index in the nifedipine group is markedly less than that in the control group. The change in the left-ventricular-mass index in the nifedipine group is 57 percent of that seen in the enalapril group and 36 percent of that seen in the control group. The absence of a statistically significant difference among treatment groups is attributable to the low power of the study owing to the small sample size, rather than to a lack of clinical significance. The patients in the control group had the greatest change in the left-ventricular-mass index, indicating that without treatment they are prone to more severe left-ventricular enlargement than are the two treatment groups.
Farsad Afshinnia, M.D.
Brookdale University Hospital and Medical Center
Brooklyn, NY 11212
To the Editor: Evangelista et al. randomly assigned a highly selected group of patients to study groups. First, patients who had not had surgery in their prospective study1 were entered into the randomized trial; the duration of follow-up in the prospective study should be provided. Second, the mean (±SD) diastolic blood pressure in the nifedipine group was 78±11 mm Hg; in patients with severe aortic regurgitation, this measure is lower.1,2 This finding suggests that many patients in the nifedipine group did not have severe chronic aortic regurgitation. Moreover, the mean left ventricular end-diastolic volume index among these patients was 94±27 ml per square meter, whereas in the study by Scognamiglio et al.,2 it was 126±16 ml per square meter. Third, of the 32 patients in the nifedipine group, 7 (22 percent) dropped out at 2±7 months. The number of patients at risk at eight years should be provided. In the study by Scognamiglio et al.,2 of 69 patients in the nifedipine group, 4 were lost to follow-up; the rate of valve replacement at six years was 15±3 percent. Fourth, nifedipine (at a dose of 20 mg) was given every 12 hours, whereas in the study by Scognamiglio et al., long-acting nifedipine (also at a twice-daily dose of 20 mg) was administered.3
Shahbudin H. Rahimtoola, M.B., F.R.C.P.
University of Southern California
Los Angeles, CA 90033
References
Tornos MP, Olona M, Permanyer-Miralda G, et al. Clinical outcome of severe asymptomatic chronic aortic regurgitation: a long-term prospective follow-up study. Am Heart J 1995;130:333-339.
Scognamiglio R, Rahimtoola SH, Fasoli G, Nistri S, Dalla Volta S. Nifedipine in asymptomatic patients with severe aortic regurgitation and normal left ventricular function. N Engl J Med 1994;331:689-694.
Scognamiglio R, Rahimtoola SH. Nifedipine in severe aortic regurgitation. N Engl J Med 1995;332:1303-1304.
The authors reply: Takagi and Umemoto raise an interesting point: Should the dose of vasodilators be increased until there is evidence of an unloading effect? Although this is an important issue, it misses the point of our study. In a previous trial, nifedipine at a twice-daily dose of 20 mg was found to delay left ventricular deterioration and the need for valve-replacement surgery. Our intention was to replicate these findings and to better assess the echocardiographic time course, regardless of the degree of vasodilatation achieved. The reduction in blood pressure with vasodilator therapy is more marked when baseline blood pressure is higher. In our study, we excluded patients with severe hypertension (defined as a diastolic blood pressure above 90 mm Hg or a systolic blood pressure above 180 mm Hg). Other studies also failed to show a reduction in systolic or diastolic blood pressure among patients with aortic regurgitation who were treated with vasodilators.1,2 Our results merely suggest that evidence supporting the widely accepted recommendation of this vasodilator schedule for delaying surgery may not be sufficiently robust. Moreover, it is doubtful how the degree of vasodilatation should be measured. Our 22 percent dropout rate in the nifedipine group owing to vasodilatation symptoms suggests that such an effect was not negligible in all patients.
Krasuski and Griffin point out the all-too-obvious fact that our study was underpowered for major clinical events, as acknowledged in the article. However, the power of our study for evaluating echocardiographic variables was not limited, being 80 percent and more than 90 percent to detect 4-mm and 6-mm differences, respectively, in chamber diameters. We believe that the interest of the study lies in its not having reproduced, with a similar sample, the clinical and echocardiographic findings of Scognamiglio et al., thus casting doubt on a class I recommendation. Regardless of what the power for detecting major events may be, a clinically meaningful effect of vasodilators on left ventricular function is implausible on the basis of our findings. Regarding the ethical concerns raised by Krasuski and Griffin: the rationale for treating patients with aortic regurgitation and within our blood pressure range without other risk factors is debatable. The policy advocated by these correspondents seems to have better intentions than evidence supports.
Like Afshinnia, we were intrigued by our finding that patients in the nifedipine group had less change in the left-ventricular-mass index than did patients in the other groups. We have refrained from speculating on this finding, since the data are isolated and rest on indirect calculations.
In regard to issues raised by Rahimtoola: all patients in our clinical trial, which began after our prospective study was reported, had severe aortic regurgitation on carefully recorded Doppler echocardiography and received the same nifedipine preparation and schedule as he reports from the study by Scognamiglio et al. In our study, after seven years, only 11 patients in the nifedipine group who tolerated the drug (34 percent) were alive and had not undergone valve-replacement surgery, without any loss to follow-up. Intention-to-treat and on-treatment analyses yielded similar results.
Artur Evangelista, M.D.
Pilar Tornos, M.D.
Gaietà Permanyer-Miralda, M.D.
Hospital Universitari Vall d'Hebron
08035 Barcelona, Spain
aevangel@vhebron.net
References
Greenberg B, Massie B, Bristow JD, et al. Long-term vasodilator therapy of chronic aortic insufficiency: a randomized double-blinded, placebo-controlled clinical trial. Circulation 1988;78:92-103.
Sondergaard L, Aldershvile J, Hildebrandt P, Kelback H, Stálberg F, Thomsen C. Vasodilatation with felodipine in chronic asymptomatic aortic regurgitation. Am Heart J 2000;139:667-674.