Background Vasodilator therapy with nifedipine reduces leftventricular volume and mass and increases the ejection fractionin asymptomatic patients with severe aortic regurgitation.
Methods To assess whether vasodilator therapy reduces or delaysthe need for valve replacement, we randomly assigned 143 asymptomaticpatients with isolated, severe aortic regurgitation and normalleft ventricular systolic function to receive either nifedipine(20 mg twice daily, 69 patients) or digoxin (0.25 mg daily,74 patients).
Results By actuarial analysis, we determined that after sixyears a mean (±SD) of 34 ±6 percent of the patientsin the digoxin group had undergone valve replacement, as comparedwith only 15 ±3 percent of those in the nifedipine group(P<0.001). In the digoxin group, valve replacement (in atotal of 20 patients) was performed because of left ventriculardysfunction (ejection fraction <50 percent) in 75 percent,left ventricular dysfunction plus symptoms in 10 percent, andsymptoms alone in 15 percent. In the nifedipine group, all sixpatients who underwent valve replacement did so because of thedevelopment of left ventricular dysfunction. In addition, allthe patients in both groups who underwent aortic-valve replacementhad an increase of 15 percent or more in the left ventricularend-diastolic volume index. After aortic-valve replacement,12 of the 16 patients (75 percent) in the digoxin group andall six patients in the nifedipine group who had had an abnormalleft ventricular ejection fraction before surgery had a normalejection fraction.
Conclusions Long-term vasodilator therapy with nifedipine reducesor delays the need for aortic-valve replacement in asymptomaticpatients with severe aortic regurgitation and normal left ventricularsystolic function.
The role of long-term vasodilator therapy in the care of asymptomaticpatients with severe aortic regurgitation is of considerableinterest. Aortic regurgitation results in an increase in leftventricular volume and thus in afterload; the left ventricleadapts by increasing left ventricular mass1. In patients withaortic regurgitation, vasodilators produce arteriolar vasodilatation,thereby increasing forward flow and reducing the amount of regurgitation,2which results in a short-term improvement in hemodynamics andleft ventricular function3,4. In one symptomatic patient, hydralazinetherapy for 14 months produced beneficial effects in terms ofleft ventricular function and symptoms,5 but this finding wasnot confirmed in a larger number of patients6.
Nevertheless, the possibility remained that the early administrationof a vasodilator -- that is, its administration when patientswere asymptomatic and when left ventricular systolic pump functionwas also normal -- might have a beneficial effect on the naturalhistory of the disorder and on the need for valve surgery. Intwo trials -- one of hydralazine given for two years7 and oneof nifedipine given for one year8 -- in patients with aorticregurgitation, these agents were shown to have a beneficialeffect. Nifedipine was superior to hydralazine because the reductionin left ventricular volume at 12 months was greater with nifedipine,as was the increase in the ejection fraction, and there wasa reduction in left ventricular mass9; moreover, the side-effectprofile of nifedipine was more favorable than that of hydralazine,and almost all the patients completed the trial9. The next stepwas to evaluate whether these beneficial effects resulted ina reduction or delay in the need for valve surgery.
We therefore performed a long-term randomized trial of nifedipinein asymptomatic patients with chronic, severe aortic regurgitationand normal left ventricular systolic function. Our goal wasto determine whether this therapy delayed or reduced the needfor aortic-valve replacement.
Methods
We evaluated consecutive asymptomatic patients with isolated,chronic, severe aortic regurgitation and normal left ventricularsystolic function who were seen at the University of Padua,Italy. Aortic regurgitation was quantitated in all patientsby mapping of the regurgitant jet into the left ventricle byDoppler color-flow imaging. The severity of the regurgitationwas graded with use of the ratio of the height of the jet tothat of the left ventricular outflow tract. The height of theregurgitant jet was measured at its origin, immediately beneaththe aortic valve, in the parasternal long-axis view. Ratiosgreater than 45 percent were categorized as indicating grade3+ aortic regurgitation, and those greater than 65 percent asgrade 4+10.
Patients with any of the following characteristics were excluded:recent development or worsening of aortic regurgitation (withinthe preceding six months), diastolic blood pressure above 90mm Hg, a history of coronary artery disease, mixed aortic stenosisand regurgitation (valve gradients 20 mm Hg), evidence of additionalvalvular or congenital heart disease on echocardiographic orDoppler study, absence of a high-quality echocardiographic studyof the left ventricle, and an abnormal left ventricular ejectionfraction (<50 percent). The initial studies included a completeclinical evaluation (history, physical examination, 12-leadelectrocardiogram, and chest roentgenogram in the posteroanteriorand lateral projections) and a complete echocardiographic study.
On completion of the base-line studies, 143 patients were consideredeligible for the study; 74 patients were randomly assigned totreatment with digoxin (0.25 mg daily) and 69 to treatment withnifedipine (20 mg twice daily). The characteristics of the 143patients enrolled in the trial are listed in Table 1. The causeof aortic regurgitation was rheumatic in 87 of the 143 patients(61 percent) and nonrheumatic in 56 (39 percent). The nonrheumaticcauses were aortic-valve prolapse in 24 of the 56 (43 percent)and a bicuspid aortic valve in 32 (57 percent). The completeclinical evaluation and echocardiographic studies were repeatedand compliance with the drug regimen was assessed every sixmonths. If a substantial increase in the left ventricular end-diastolicvolume index or a decrease in the left ventricular ejectionfraction was found, the echocardiographic study was repeatedone month later. The use of angiotensin-converting-enzyme inhibitorswas not allowed in any patient.
Table 1. Base-Line Characteristics of 143 Patients with Severe Aortic Regurgitation and Normal Left Ventricular Function, According to Treatment Group.
Echocardiographic Analysis
Two-dimensional echocardiograms were recorded with a Hewlett-Packardphased-array ultrasonoscope and a 2.5-MHz or 3.5-MHz transducer.Left ventricular endocardial and epicardial echocardiogramsin apical four-chamber and parasternal short-axis views in atleast three to five cardiac cycles were digitized at end-diastole(the peak of the R wave) and at end-systole (the time when thecavity area was smallest). Each echocardiographic study wasread by two independent observers who did not know the patient'sidentity or treatment assignment or the order of the studies.If these readings differed by 10 ml or more for left ventricularvolume and 10 g or more for left ventricular mass, the echocardiographicdata were analyzed by a third observer. Agreement was achievedby consensus. In our laboratory, the degree of interobserverand intraobserver correlation for left ventricular area (r =0.98 and r = 0.97, respectively) and for left ventricular length(r = 0.98 and r = 0.96, respectively) was reasonable8.
Left ventricular volumes were calculated by an ellipsoid biplanearea-length method11; the ejection fraction was calculated as(EDV - ESV)/EDV, where EDV is the left ventricular end-diastolicvolume and ESV the end-systolic volume. Left ventricular myocardialmass was calculated by multiplying the myocardial volume bythe specific weight of myocardial muscle (1.05 g per milliliter)12.
At our institution, the results of cardiac catheterization andechocardiographic findings could be compared for 82 patientswith aortic regurgitation who over the years had undergone bothprocedures within a short period of time. The mean (±SD)cardiac-catheterization and echocardiographic values for theleft ventricular end-diastolic volume index were 144 ±26ml per square meter and 136 ±27 ml per square meter,respectively (P not significant), and those for the left ventricularejection fraction were 56 ±11.1 percent and 54 ±9.2percent, respectively (P not significant).
In the comparison of echocardiographic with angiographic valuesfor the left ventricular end-diastolic volume index, the regressionequation was Y = 0.899X + 6.49, the standard error was 13.39,the correlation coefficient (r) was 0.88, and the P value was<0.01. In the comparison of echocardiographic with angiographicvalues for the left ventricular ejection fraction, the regressionequation was Y = 0.70X + 16.4 (SE = 5.76, r = 0.84, P<0.01).
In patients who underwent valve replacement, the echocardiographicstudy was repeated at the time of valve replacement and twoto three months thereafter. There was one perioperative death;in this patient, the echocardiographic evaluation had been performedin the first week after valve replacement.
Criteria for Aortic-Valve Replacement
Aortic-valve replacement was recommended for patients who metany of the following predetermined criteria: appearance of leftventricular systolic dysfunction, defined as a left ventricularejection fraction of less than 50 percent that was confirmedby an echocardiographic study one month later; a clinicallyimportant deterioration in the patient's condition (subjectivelydetermined), defined as an increase to New York Heart Associationfunctional class II or higher, the development of angina, orboth; and progressive left ventricular dilatation, defined asan increase of 15 percent or more in the left ventricular end-diastolicvolume index that was confirmed by an echocardiographic studyone month later.
Statistical Analysis
All data are expressed as means ±SD. Comparisons of continuousvariables in the two groups were made by repeated-measures analysisof variance. Within each group, we compared preoperative andpostoperative values by means of paired t-tests. The probabilityof valve replacement during follow-up was calculated by theKaplan-Meier method. A P value 0.05 by the two-tailed testwas considered to indicate statistical significance.
Results
Base-Line Comparison
The clinical characteristics of the patients and the valuesfor left ventricular size and function obtained from the base-lineechocardiogram were not significantly different in the two groups(Table 1). All the patients had left ventricular end-diastolicvolume indexes greater than the mean value +1.5 SD for normalsubjects in our laboratory. The ejection fraction was normal( 50 percent) in all patients; the lowest ejection fractionvalue was 56 percent. In our laboratory, the mean values and95 percent confidence intervals for these variables in normalsubjects are as follows: left ventricular end-diastolic volumeindex, 64 ml per square meter (54 to 74); left ventricular end-systolicvolume index, 29 ml per square meter (24 to 34); and ejectionfraction, 58 percent (53 to 63)8.
Follow-up and Progression to Aortic-Valve Replacement
Four patients who had been randomly assigned to receive nifedipineand four patients assigned to receive digoxin were excludedfrom the analysis because they did not return for the scheduledfollow-up visits. There was one perioperative death in the digoxingroup. The remaining patients completed the six-year follow-upevaluation.
The rate of progression to aortic-valve replacement was significantlylower in the nifedipine group at all times after the first-yearfollow-up evaluation (Figure 1). There were no valve replacementsin the first two years in the nifedipine group. By actuarialanalysis, at the end of the six years of follow-up, a mean (±SD)of 34 ±6 percent of the patients randomly assigned tothe digoxin group and 15 ±3 percent of those assignedto the nifedipine group had undergone valve replacement (P<0.001).All these patients underwent cardiac catheterization and angiographybefore surgery; none had coronary artery disease that requiredcoronary bypass surgery. All patients who met the predeterminedcriteria for surgery underwent valve replacement.
Figure 1. Cumulative Actuarial Incidence of Progression to Aortic-Valve Replacement in the Two Treatment Groups.
Table 2 shows the criteria for surgery and the base-line, preoperative,and postoperative values, determined echocardiographically,for the left ventricular end-diastolic volume index, end-systolicvolume index, and ejection fraction in the patients who underwentaortic-valve replacement. The table also shows the left ventricularejection fraction determined angiographically in each patientbefore surgery. Aortic-valve replacement was performed in 20patients in the digoxin group; 1 patient (5 percent) died duringthe perioperative period (10 days after surgery [Patient 20]).Six patients in the nifedipine group underwent aortic-valvereplacement; there were no perioperative deaths. Total perioperativemortality among the patients who underwent valve replacementwas 4 percent (1 of 26). No additional deaths occurred duringfollow-up.
Table 2. Left Ventricular Volume and Ejection Fraction in Patients Who Underwent Aortic-Valve Replacement, According to Treatment Group.
Of the 20 patients in the digoxin group who underwent aortic-valvereplacement, 15 (75 percent) did so because they had left ventricularejection fractions below 50 percent, 2 (10 percent) becauseof an abnormal left ventricular ejection fraction and the developmentof symptoms, and 3 (15 percent) because symptoms developed inspite of their having a normal left ventricular ejection fraction.In the nifedipine group, all six patients who underwent aortic-valvereplacement did so because of a persistently abnormal left ventricularejection fraction despite the absence of clinical symptoms.In the patients with left ventricular dysfunction, the ejectionfraction had fallen by more than 10 percentage points, and theabnormal value (<50 percent) was confirmed by preoperativeangiographic study. The left ventricular end-diastolic volumeindex increased significantly (by 15 percent or more; range,15 to 40 percent) in all the study patients in whom the ejectionfraction had become abnormal or who had become symptomatic andsubsequently underwent aortic-valve replacement.
Table 3 shows the left ventricular end-diastolic volume, end-systolicvolume, ejection fraction, and mass in the digoxin and nifedipinegroups both before randomization and at the end of the study(or at the time of valve replacement). As compared with thosein the digoxin group, the patients in the nifedipine group hadlower left ventricular end-diastolic and end-systolic volumeindexes and mass and higher ejection fractions; this was thecase because the patients in the nifedipine group had reductionsin volume and mass, whereas those in the digoxin group had increases.
Table 3. Left Ventricular Volume and Ejection Fraction before Randomization and at the End of the Study, According to Treatment Group.
Changes in Left Ventricular Size and Function after Aortic-Valve Replacement
After valve replacement, there was a decrease in the left ventricularend-diastolic volume index from 143 ±22 to 77 ±19ml per square meter (P = 0.001) in the nifedipine group andfrom 147 ±16 to 89 ±24 ml per square meter (P= 0.001) in the digoxin group; the left ventricular end-systolicvolume index also decreased, from 77 ±13 to 27 ±6ml per square meter (P = 0.001) in the nifedipine group andfrom 77 ±14 to 39 ±17 ml per square meter (P =0.001) in the digoxin group. The left ventricular ejection fractionincreased in both groups: from 46 ±1 percent to 65 ±4percent (P = 0.001) in the nifedipine group and from 48 ±6percent to 58 ±9 percent (P = 0.001) in the digoxin group.After the procedure, the left ventricular end-diastolic volumeindex was not significantly lower, but the postoperative ejectionfraction was significantly higher in the patients in the nifedipinegroup (65 ±4 percent vs. 58 ±8 percent, P = 0.04).In all the patients in the nifedipine group, the left ventricularejection fraction returned to normal after valve replacement,whereas it remained abnormal in four patients (20 percent) treatedwith digoxin (Table 2). A total of 63 patients in the nifedipinegroup and 54 patients in the digoxin group who did not havevalve replacement completed the six-year follow-up.
Side Effects
A total of 42 percent of the 69 patients in the nifedipine groupand 12 percent of the 74 patients in the digoxin group (P<0.001)had at least one new mild symptom during the first three monthsof the study. The most common side effects were tachycardiaand headache in the nifedipine group and fatigue in the digoxingroup. At the 12-month follow-up visit, side effects were stillpresent in 6 percent of both groups. After six years of follow-up,5 percent of patients in the nifedipine group had adverse effects,as had 6 percent in the digoxin group (P not significant). Nopatient in either study group refused to take the trial medicationor to return for follow-up visits because of side effects.
Discussion
This randomized trial demonstrates that in asymptomatic patientswith chronic, severe aortic regurgitation and normal left ventricularejection fractions, treatment with nifedipine, as compared withdigoxin, results in a lower incidence of left ventricular dysfunctionand of symptoms for up to six years and thus reduces the needfor aortic-valve replacement (rate of valve replacement, 34±6 percent vs. 15 ±3 percent at six years; P<0.001).Left ventricular dysfunction that occurred during nifedipinetherapy was uniformly reversible if treated promptly with surgery.
The life-table event curve in the digoxin group in our studyis similar to that reported for asymptomatic patients receivingno medical therapy13,14. Routine therapy with digoxin has beenrecommended for all asymptomatic patients with severe aorticregurgitation15 on the basis of data from studies of animals;however, its efficacy in patients with this condition has notbeen documented. In a one-month trial in symptomatic patients,digoxin increased the ejection fraction both at rest and duringexercise16. Because of its many actions,17 including those onthe myocardium, digoxin might be expected to have the beneficialeffect of reducing the incidence or delaying the onset of leftventricular dysfunction or symptoms. Thus, we chose to testnifedipine against another potentially useful medication ratherthan against a placebo.
Nifedipine, administered in a previous randomized trial forone year,8 was found to reduce systolic and diastolic bloodpressure and to produce an important reduction in left ventricularvolume and mass and a large increase in the ejection fraction.Therefore, the hypothesis on which our study was based was thatthese changes would result in a reduction or delay in the needfor valve replacement. In our trial, nifedipine had similarbeneficial effects on left ventricular function during up tosix years of follow-up, and no patient in the nifedipine groupneeded valve replacement for the first two years. Moreover,the indications for valve replacement were defined before thetrial, and the hemodynamic criterion for valve replacement wasan objective one (left ventricular ejection fraction <50percent); this was the indication for aortic-valve replacementin 85 percent of the digoxin-treated patients and in all thenifedipine-treated patients who underwent the procedure. Previously,it had been shown that patients with chronic, severe aorticregurgitation could have normal left ventricular ejection fractionsin spite of having symptoms18. Consequently, the developmentof symptoms with normal left ventricular function was also anindication for surgery.
As it increases in severity, aortic regurgitation produces anincreasing volume load on the heart, which compensates by aprogressive increase in left ventricular volume and hypertrophy,while left ventricular systolic function remains normal. Patientsmay remain asymptomatic for a long period of time. In thosewith severe regurgitation, the subsequent clinical course isusually characterized by the onset of left ventricular systolicdysfunction, symptoms, or both. With the development of leftventricular dysfunction, the outcome for patients treated medicallyis unsatisfactory, and with valve replacement it is also lesssatisfactory than when valve replacement is performed in thepresence of normal left ventricular function19,20,21,22,23,24;this finding indicates the need for valve replacement beforethe development of irreversible myocardial damage. However,there is no reliable evidence that early valve replacement isof benefit in asymptomatic patients with normal left ventricularfunction25,26,27,28.
The chief indication for valve replacement in patients withsevere aortic regurgitation is therefore the onset of symptoms,and in the absence of symptoms the chief indication is the developmentof left ventricular systolic dysfunction13,14,29,30,31,32. Leftventricular systolic dysfunction is usually completely reversibleif successful valve replacement is performed within 12 to 14months of its onset,30 indicating that the probable initialcause of the dysfunction is afterload mismatch or reversiblemyocardial dysfunction rather than irreversible myocardial dysfunction24,25,27.Thus, the main goals of secondary prevention in asymptomaticpatients with severe, chronic aortic regurgitation and normalleft ventricular systolic function are the reduction of leftventricular volume and mass and the preservation of left ventricularfunction. These effects translate into a substantial prolongationof the asymptomatic period and of normal ventricular function,thereby reducing or delaying the need for valve replacement.
One concern about the use of any agent that appears to preservethe ejection fraction is that it may mask progressive myocardialdysfunction; thus, when the ejection fraction falls or becomesabnormal, myocardial dysfunction may have progressed to sucha degree that successful valve replacement may no longer improvethe ejection fraction. This was not the case in our patients,since all those in the nifedipine group in whom the ejectionfraction had become abnormal had normal values after surgery;20 percent of patients in the digoxin group, however, continuedto have abnormal values. This finding indicates that when patientsare treated with nifedipine, left ventricular dysfunction isdetectable by careful follow-up at the stage of afterload mismatchand before irreversible myocardial damage has occurred. It shouldbe emphasized, however, that valve replacement has to be performedas soon as possible after the onset of ventricular dysfunction30.
In our study, the vasodilator calcium-channel-blocking agentnifedipine was effective in delaying the need for surgery andthus represents an advance in the management of severe, chronicaortic regurgitation.
Source Information
From the Division of Cardiology, Department of Internal Medicine, University of Padua Medical School, Padua, Italy (R.S., G.F., S.N., S.D.V.), and the Griffith Center and Division of Cardiology, Los Angeles County-University of Southern California Medical Center, Los Angeles (S.H.R.).
Address reprint requests to Dr. Scognamiglio at the Cattedra di Cardiologia, Policlinico, Via Giustiniani, 2, 35100 Padova, Italy.
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Nifedipine in Severe Aortic Regurgitation
Manyari D. E., Yunus A., Klein L. J., Reichert C. L.A., Arnold A. E.R., Coats A. J.S., Scognamiglio R., Rahimtoola S. H.
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20 mm Hg), evidence of additional valvular or congenital heart disease on echocardiographic or Doppler study, absence of a high-quality echocardiographic study of the left ventricle, and an abnormal left ventricular ejection fraction (<50 percent). The initial studies included a complete clinical evaluation (history, physical examination, 12-lead electrocardiogram, and chest roentgenogram in the posteroanterior and lateral projections) and a complete echocardiographic study. 
0.05 by the two-tailed test was considered to indicate statistical significance. 
