Vasodilators in Aortic Regurgitation — Where Is the Evidence of Their Effectiveness?
http://www.100md.com
《新英格兰医药杂志》
Although aortic regurgitation imposes a volume load on the left ventricle, it became clear more than two decades ago that the resulting large stroke volume and wide pulse pressure also lead to systolic hypertension and concomitant left ventricular pressure overload.1,2 In fact, afterload is much higher in aortic regurgitation than in mitral regurgitation and may be as high as that in the more typically recognized pressure overload of aortic stenosis.3 The excess afterload in aortic regurgitation, in turn, forms the basis for the idea that afterload-reducing agents, such as vasodilators, might be beneficial in the medical treatment of this disease.
After several smaller reports showing beneficial hemodynamic and positive remodeling effects of various vasodilators in patients with aortic regurgitation,4,5,6,7 Scognamiglio et al. reported more than a decade ago in the Journal that the vasodilator nifedipine forestalled the need for aortic-valve replacement as indicated by the development of either symptoms or left ventricular dysfunction.8 In that randomized trial, nifedipine was compared with digoxin rather than placebo. The same group subsequently reported that the benefit from preoperative administration of nifedipine persisted years after aortic-valve replacement.9
In striking contrast, in this issue of the Journal, Evangelista et al. report that neither enalapril nor the same dose of nifedipine as that used by Scognamiglio et al. delayed or reduced the need for aortic-valve replacement, as compared with placebo.10 In other words, the two studies came to virtually opposite conclusions with regard to the usefulness of vasodilators in the treatment of patients with asymptomatic aortic regurgitation.
How can this discrepancy be reconciled? Looking first at the digoxin group in the study by Scognamiglio et al. and the placebo group in the study by Evangelista et al., it is clear that the need for aortic-valve replacement was similar in the two groups. Obviously, many arguments could be and have been leveled against the use of an active cardiovascular drug such as digoxin in the control group of a trial, as was done by Scognamiglio et al. Even so, the main differences appear to be in the nifedipine groups. In the study by Evangelista et al., the need for aortic-valve replacement at six years in the nifedipine group was about 22 percent, a rate similar to that in the placebo group, whereas in the study by Scognamiglio et al., the corresponding rate was only 10 percent. Evangelista et al. note that the other researchers may have waited a longer time before performing aortic-valve replacement, since the patients in that study had more advanced left ventricular dysfunction. Waiting a longer time would decrease the rate of aortic-valve replacement, but a delay in surgery should have affected both groups in the trial equally.
In the study by Evangelista et al., it is not surprising that nifedipine failed to improve the outcome, because the drug appeared to have almost no effect on any measured variable. The drug did not significantly alter blood pressure, heart rate, or ventricular geometry over the course of the study. In fact, given these data, it would have been surprising if nifedipine had had a positive effect. This obviously raises the question as to why nifedipine was effective in the study by Scognamiglio et al. Although this group reported that nifedipine had impressive hemodynamic and volumetric effects at one year,11 there is no evidence that these responses persisted for a longer period. Indeed, in both the study by Evangelista et al. and the study by Scognamiglio et al., nifedipine failed to reduce the end-systolic volume or increase the ejection fraction — changes that would be expected with a reduction in afterload.8,10
Perhaps the patients in the two studies differed. Systolic blood pressure appeared to be higher (without statistical comparison) in the study by Scognamiglio et al. Perhaps their patients were thus more likely to have a reduction in blood pressure and afterload, although if that were so, end-systolic volume should also have been reduced.
Perhaps the studies did not differ at all. Although there appear to have been statistical differences, the total number of events was small in both trials. In the study by Scognamiglio et al., 20 patients in the digoxin group and 6 patients in the nifedipine group underwent aortic-valve replacement, a difference of 14 between the groups. In the trial by Evangelista et al., 12 patients in the control group and 13 in the nifedipine group required surgery. Are 20, 13, 12, and 6 really that different from one another?
In comparisons of evidence-based medicine in the various subspecialties of cardiology, valvular heart disease represents a glaring exception. Overall, there are probably more than 3000 randomized trials in cardiologic subspecialties exploring outcomes in well over 150,000 patients.12 However, there are fewer than a dozen randomized trials involving patients with valvular heart disease, and most involve fewer than 200 patients. In the 1998 guidelines for the management of valvular heart disease issued by the American Heart Association–American College of Cardiology, the level of evidence in support of recommendations was not listed.13 However, in the upcoming revision of these guidelines, which will provide supporting evidence, it is unlikely that any recommendation regarding the treatment of valvular heart disease will be accompanied by the highest level of supporting evidence (recommendations based on the results of two or more large randomized trials). In the current conundrum, 143 patients underwent randomization in the trial by Scognamiglio et al. and 95 did so in the study by Evangelista et al., as compared with the tens of thousands of patients who underwent randomization in the Thrombolysis in Myocardial Infarction (TIMI), Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI), or Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) trials or scores of other studies.
Large trials have not been conducted in patients with valvular heart disease for several reasons. First, fewer patients have valvular disease than coronary disease or heart failure. Second, the smaller numbers of patients, together with the lack of specific and therefore profitable therapeutic drugs or devices, limit the financial support necessary to conduct large and expensive trials. Finally, valvular disease is often treated quite differently from one institution to the next, making comparison of data difficult.
The findings reported by Evangelista and colleagues certainly diminish enthusiasm for the use of vasodilator therapy in patients with severe asymptomatic aortic regurgitation and normal left ventricular function. However, there is also no compelling evidence that vasodilators cause harm in such patients, and the findings reported by Scognamiglio et al. provide obvious support for the use of nifedipine. Unfortunately, practitioners caring for patients with valvular heart disease will continue to grope for the best therapies until the evidence-based medicine so prevalent in the rest of cardiology becomes available.
Source Information
From the Michael E. DeBakey Veterans Affairs Medical Center and the Department of Medicine, Baylor College of Medicine — both in Houston.
References
Wisenbaugh T, Spann JF, Carabello BA. Differences in myocardial performance and load between patients with similar amounts of chronic aortic versus chronic mitral regurgitation. J Am Coll Cardiol 1984;3:916-923.
Taniguchi K, Nakano S, Kawashima Y, et al. Left ventricular ejection performance, wall stress, and contractile state in aortic regurgitation before and after aortic valve replacement. Circulation 1990;82:798-807.
Carabello BA. Aortic regurgitation: a lesion with similarities to both aortic stenosis and mitral regurgitation. Circulation 1990;82:1051-1053.
Greenberg BH, 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.
Schon HR, Dorn R, Barthel P, Schomig A. Effects of 12 months quinapril therapy in asymptomatic patients with chronic aortic regurgitation. J Heart Valve Dis 1994;3:500-509.
Sondergaard L, Aldershvile J, Hildebrandt P, Kelbaek H, Stahlberg F, Thomsen C. Vasodilatation with felodipine in chronic asymptomatic aortic regurgitation. Am Heart J 2000;139:667-674.
Fioretti P, Benussi B, Scardi S, Klugmann S, Brower RW, Camerini F. Afterload reduction with nifedipine in aortic insufficiency. Am J Cardiol 1982;49:1728-1732.
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, Negut CH, Palisi M, Fasoli G, Dalla-Volta S. Long-term survival and functional results after aortic valve replacement in asymptomatic patients with chronic severe aortic regurgitation and left ventricular dysfunction. J Am Coll Cardiol 2005;45:1025-1030.
Evangelista A, Tornos P, Sambola A, Permanyer-Miralda G, Soler-Soler J. Long-term vasodilator therapy in patients with severe aortic regurgitation. N Engl J Med 2005;353:1342-1349.
Scognamiglio R, Fasoli G, Ponchia A, Dalla-Volta S. Long-term nifedipine unloading therapy in asymptomatic patients with chronic severe aortic regurgitation. J Am Coll Cardiol 1990;16:424-429.
Kloner RA, Birnbaum Y, eds. Cardiovascular trials review. 9th ed. Darien, Conn.: Le Jacq, 2004.
ACC/AHA guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). J Am Coll Cardiol 1998;32:1486-1588.(Blase A. Carabello, M.D.)
After several smaller reports showing beneficial hemodynamic and positive remodeling effects of various vasodilators in patients with aortic regurgitation,4,5,6,7 Scognamiglio et al. reported more than a decade ago in the Journal that the vasodilator nifedipine forestalled the need for aortic-valve replacement as indicated by the development of either symptoms or left ventricular dysfunction.8 In that randomized trial, nifedipine was compared with digoxin rather than placebo. The same group subsequently reported that the benefit from preoperative administration of nifedipine persisted years after aortic-valve replacement.9
In striking contrast, in this issue of the Journal, Evangelista et al. report that neither enalapril nor the same dose of nifedipine as that used by Scognamiglio et al. delayed or reduced the need for aortic-valve replacement, as compared with placebo.10 In other words, the two studies came to virtually opposite conclusions with regard to the usefulness of vasodilators in the treatment of patients with asymptomatic aortic regurgitation.
How can this discrepancy be reconciled? Looking first at the digoxin group in the study by Scognamiglio et al. and the placebo group in the study by Evangelista et al., it is clear that the need for aortic-valve replacement was similar in the two groups. Obviously, many arguments could be and have been leveled against the use of an active cardiovascular drug such as digoxin in the control group of a trial, as was done by Scognamiglio et al. Even so, the main differences appear to be in the nifedipine groups. In the study by Evangelista et al., the need for aortic-valve replacement at six years in the nifedipine group was about 22 percent, a rate similar to that in the placebo group, whereas in the study by Scognamiglio et al., the corresponding rate was only 10 percent. Evangelista et al. note that the other researchers may have waited a longer time before performing aortic-valve replacement, since the patients in that study had more advanced left ventricular dysfunction. Waiting a longer time would decrease the rate of aortic-valve replacement, but a delay in surgery should have affected both groups in the trial equally.
In the study by Evangelista et al., it is not surprising that nifedipine failed to improve the outcome, because the drug appeared to have almost no effect on any measured variable. The drug did not significantly alter blood pressure, heart rate, or ventricular geometry over the course of the study. In fact, given these data, it would have been surprising if nifedipine had had a positive effect. This obviously raises the question as to why nifedipine was effective in the study by Scognamiglio et al. Although this group reported that nifedipine had impressive hemodynamic and volumetric effects at one year,11 there is no evidence that these responses persisted for a longer period. Indeed, in both the study by Evangelista et al. and the study by Scognamiglio et al., nifedipine failed to reduce the end-systolic volume or increase the ejection fraction — changes that would be expected with a reduction in afterload.8,10
Perhaps the patients in the two studies differed. Systolic blood pressure appeared to be higher (without statistical comparison) in the study by Scognamiglio et al. Perhaps their patients were thus more likely to have a reduction in blood pressure and afterload, although if that were so, end-systolic volume should also have been reduced.
Perhaps the studies did not differ at all. Although there appear to have been statistical differences, the total number of events was small in both trials. In the study by Scognamiglio et al., 20 patients in the digoxin group and 6 patients in the nifedipine group underwent aortic-valve replacement, a difference of 14 between the groups. In the trial by Evangelista et al., 12 patients in the control group and 13 in the nifedipine group required surgery. Are 20, 13, 12, and 6 really that different from one another?
In comparisons of evidence-based medicine in the various subspecialties of cardiology, valvular heart disease represents a glaring exception. Overall, there are probably more than 3000 randomized trials in cardiologic subspecialties exploring outcomes in well over 150,000 patients.12 However, there are fewer than a dozen randomized trials involving patients with valvular heart disease, and most involve fewer than 200 patients. In the 1998 guidelines for the management of valvular heart disease issued by the American Heart Association–American College of Cardiology, the level of evidence in support of recommendations was not listed.13 However, in the upcoming revision of these guidelines, which will provide supporting evidence, it is unlikely that any recommendation regarding the treatment of valvular heart disease will be accompanied by the highest level of supporting evidence (recommendations based on the results of two or more large randomized trials). In the current conundrum, 143 patients underwent randomization in the trial by Scognamiglio et al. and 95 did so in the study by Evangelista et al., as compared with the tens of thousands of patients who underwent randomization in the Thrombolysis in Myocardial Infarction (TIMI), Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI), or Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) trials or scores of other studies.
Large trials have not been conducted in patients with valvular heart disease for several reasons. First, fewer patients have valvular disease than coronary disease or heart failure. Second, the smaller numbers of patients, together with the lack of specific and therefore profitable therapeutic drugs or devices, limit the financial support necessary to conduct large and expensive trials. Finally, valvular disease is often treated quite differently from one institution to the next, making comparison of data difficult.
The findings reported by Evangelista and colleagues certainly diminish enthusiasm for the use of vasodilator therapy in patients with severe asymptomatic aortic regurgitation and normal left ventricular function. However, there is also no compelling evidence that vasodilators cause harm in such patients, and the findings reported by Scognamiglio et al. provide obvious support for the use of nifedipine. Unfortunately, practitioners caring for patients with valvular heart disease will continue to grope for the best therapies until the evidence-based medicine so prevalent in the rest of cardiology becomes available.
Source Information
From the Michael E. DeBakey Veterans Affairs Medical Center and the Department of Medicine, Baylor College of Medicine — both in Houston.
References
Wisenbaugh T, Spann JF, Carabello BA. Differences in myocardial performance and load between patients with similar amounts of chronic aortic versus chronic mitral regurgitation. J Am Coll Cardiol 1984;3:916-923.
Taniguchi K, Nakano S, Kawashima Y, et al. Left ventricular ejection performance, wall stress, and contractile state in aortic regurgitation before and after aortic valve replacement. Circulation 1990;82:798-807.
Carabello BA. Aortic regurgitation: a lesion with similarities to both aortic stenosis and mitral regurgitation. Circulation 1990;82:1051-1053.
Greenberg BH, 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.
Schon HR, Dorn R, Barthel P, Schomig A. Effects of 12 months quinapril therapy in asymptomatic patients with chronic aortic regurgitation. J Heart Valve Dis 1994;3:500-509.
Sondergaard L, Aldershvile J, Hildebrandt P, Kelbaek H, Stahlberg F, Thomsen C. Vasodilatation with felodipine in chronic asymptomatic aortic regurgitation. Am Heart J 2000;139:667-674.
Fioretti P, Benussi B, Scardi S, Klugmann S, Brower RW, Camerini F. Afterload reduction with nifedipine in aortic insufficiency. Am J Cardiol 1982;49:1728-1732.
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, Negut CH, Palisi M, Fasoli G, Dalla-Volta S. Long-term survival and functional results after aortic valve replacement in asymptomatic patients with chronic severe aortic regurgitation and left ventricular dysfunction. J Am Coll Cardiol 2005;45:1025-1030.
Evangelista A, Tornos P, Sambola A, Permanyer-Miralda G, Soler-Soler J. Long-term vasodilator therapy in patients with severe aortic regurgitation. N Engl J Med 2005;353:1342-1349.
Scognamiglio R, Fasoli G, Ponchia A, Dalla-Volta S. Long-term nifedipine unloading therapy in asymptomatic patients with chronic severe aortic regurgitation. J Am Coll Cardiol 1990;16:424-429.
Kloner RA, Birnbaum Y, eds. Cardiovascular trials review. 9th ed. Darien, Conn.: Le Jacq, 2004.
ACC/AHA guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). J Am Coll Cardiol 1998;32:1486-1588.(Blase A. Carabello, M.D.)