(Hypertension. 1995;25:92-97.)
© 1995 American Heart Association, Inc.
Articles |
Ramipril-Induced Regression of Left Ventricular Hypertrophy in Treated Hypertensive Individuals
From the HYCAR Study Group. See "Acknowledgments" for a complete listing of participants.
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Abstract |
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Abstract The objective of this trial was to assess the effects of 6-month daily treatment with two doses of ramipril on left ventricular mass and the dependence of this on blood pressure changes in hypertensive patients with left ventricular hypertrophy. After a selection phase of 4 to 6 weeks with patients under antihypertensive therapy with 20 mg furosemide daily, 115 patients with either controlled or uncontrolled hypertension and left ventricular hypertrophy were randomized in a double-blind manner to receive either placebo (n=40), 1.25 mg (low dose, n=38), or 5 mg (regular dose, n=37) ramipril daily for 6 months. Treatment with furosemide was continued unchanged during this phase. The main outcome measured was left ventricular hypertrophy regression as assessed from central blind reading of echocardiograms recorded at randomization and after 6 months. No significant differences were observed for changes in casual or ambulatory blood pressure between the three groups. Left ventricular mass index was found to be significantly reduced in patients receiving 5 mg ramipril compared with those receiving placebo (-10.8±3.7 versus +4.1±4.0 g/m2, P=.008); in patients receiving 1.25 mg ramipril, the difference was close to borderline significance compared with placebo (-7.0±4.3 g/m2, P=.06). Similar results were observed for changes in left ventricular mass (-20.3±6.6 and -13.0±7.8 g in the 5- and 1.25-mg ramipril groups, respectively, versus +9.1±7.2 g in the placebo group; P=.004 and .04, respectively). In a multiple regression model testing 10 potential explicative variables, we found that this reduction was correlated with treatment, both 1.25 and 5.0 mg ramipril (P=.03 and .01, respectively), and with the baseline value of the left ventricular mass index (P=.005). Changes in ambulatory or casual systolic and diastolic blood pressures were not predictive of changes in left ventricular mass (P=.15 and .16, respectively). Ramipril at 1.25 and 5 mg daily for 6 months can induce left ventricular hypertrophy regression, independent of changes in blood pressure, in patients under furosemide (20 mg/d) antihypertensive therapy. The implications of this regression for cardiovascular morbidity and mortality in hypertensive patients should now be assessed.
Key Words: clinical trials • hypertrophy, left ventricular • hypertension, essential • angiotensin-converting enzyme inhibitors
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Introduction |
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In the early 1970s, the results from the Framingham Study showed that left ventricular hypertrophy (LVH) assessed electrocardiographically was linked with a high risk of coronary heart disease.1 More recently, the echocardiographic assessment of left ventricular mass (LVM) has been shown to be a valuable tool in predicting cardiovascular morbid events in hypertensive patients.2 In the Framingham Study, the prognostic value of echocardiographically determined LVH was subsequently demonstrated in a large population. This is now considered as an independent risk factor,3 and therefore, reduction of LVM represents a potential independent therapeutic objective in the treatment of hypertension. Before the validity of left ventricular regression is evaluated as a therapeutic goal, it is necessary to demonstrate that regression can occur independently of any fall in blood pressure. Afterwards, large clinical trials may be undertaken to assess the benefits of this regression in terms of morbidity and mortality.
In many uncontrolled studies on antihypertensive therapies, a reduction in echocardiographically determined LVM has been observed. The results from a recent review4 suggest that most of the therapeutic classes that are currently used to decrease blood pressure, ie, angiotensin-converting enzyme (ACE) inhibitors, ß-blockers, calcium antagonists, and more controversially, diuretics, seem to be able to reduce LVH. However, only six placebo-controlled trials have been reported, five of which assessed calcium antagonists.5 6 7 8 9 10 In one of these trials,5 significant LVM regression in the treatment group compared with the placebo group was associated with body weight reduction but not antihypertensive treatment. In the other five trials,6 7 8 9 10 the results were analyzed separately for each group, with no intergroup comparisons. Although no direct comparative trial has been performed, ACE inhibitors are thought to have a more pronounced effect on LVH regression than the other drug classes, and this raises the question of the role of the renin-angiotensin system in this disease.11
Previous studies in animal models of LVH have shown, at the same level of blood pressure reduction, a pronounced effect of the ACE inhibitor ramipril (1 mg/kg) on left ventricular weight, whereas in the same experiment, calcium antagonists and dihydralazine showed no significant effect.12 In the same experiment, a very low dose of ramipril (0.01 mg/kg) that has no effect on blood pressure was able to reduce LVH, suggesting a direct cardiac effect of the drug. These results are consistent with further experiments at the same dose in the same model with treatment over 1 year.13
To evaluate the effect of ramipril on LVH regression (assessed echocardiographically) and the possible independence of this and its blood pressure–lowering effect, we conducted a 6-month randomized, double-blind, placebo-controlled multicenter trial in hypertensive patients with LVH: the HYCAR (HYpertrophie CArdiaque et Ramipril) study. Two doses (low dose and regular dose) of the ACE inhibitor ramipril were assessed. LVM was assessed by echocardiography and blood pressure by casual measurements and 24-hour ambulatory monitoring. Since it would have been unethical to leave hypertensive patients with LVH untreated for 6 months (ie, those allocated to placebo), it was decided that all patients would receive antihypertensive treatment during the selection phase and in addition to the study treatment during the double-blind phase. Furosemide at 20 mg daily was chosen because this antihypertensive therapy is currently used in France. The doses of ramipril chosen were 5 mg (regular dose), which has been shown to have a clear-cut antihypertensive effect in a dose-ranging study, and 1.25 mg (low dose), which has been shown to have no statistically significant antihypertensive effect.14
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Methods |
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Patient Selection
Patients with treated (diastolic blood pressure <110 mm Hg) or untreated (diastolic blood pressure between 95 and 110 mm Hg; systolic blood pressure >160 mm Hg) hypertension and LVH were recruited. LVH was defined as a ratio of LVM to body surface area of more than 120 g/m2 for men and 98 g/m2 for women. These limits correspond to the upper 90th percentiles of the index in a sample population of 225 healthy subjects.15 LVM was calculated using the formula of Devereux and Reichek.16 All patients gave written informed consent, and the protocol was approved by the Claude Bernard University Hospital Ethics Committee. Patients older than 70 years and those with low echogenicity, cardiac disorders impairing the interpretation of the echocardiogram, recent myocardial infarction, angina pectoris, hyperkalemia or hypokalemia, or already receiving an ACE inhibitor were excluded.
Study Design
Selection Phase
After being evaluated for eligibility, including a preselection
echocardiogram, all patients gave informed written consent before
entering the selection phase, which lasted for between 4 and 6 weeks.
During this phase, they all received 20 mg/d furosemide as an
antihypertensive therapy. All other antihypertensive therapy was
discontinued, with precautions being taken to avoid withdrawal
problems.
Double-blind Treatment Phase
At the end of the selection phase, patients with diastolic blood
pressure less than 110 mm Hg and no signs of intolerance to furosemide
were eligible for the treatment phase. Before entry to this second
phase, a baseline echocardiogram was recorded, and 24-hour ambulatory
blood pressure monitoring was performed for all patients. The eligible
patients continued to receive furosemide at the same dose in an open
manner and were randomized to receive ramipril in a once-daily dose of
1.25 or 5 mg or a matching placebo in a double-blind manner using an
on-line centralized procedure. Randomization was stratified by study
center and in blocks of three. Patients were seen 1, 3, and 6 months
after randomization for follow-up. At the 6-month visit, the final
echocardiogram was recorded, and 24-hour ambulatory blood pressure
monitoring was performed. In the event of minor adverse events, thought
to be caused by the study treatment, a reduced dose was available for a
maximum of 10 days on two occasions (2.5 mg daily for patients assigned
to receive 5 mg ramipril, and placebo for the other patients). All
study treatments (ramipril, furosemide, and placebo) were supplied by
Laboratories Hoechst.
Echocardiography
All patients had three echocardiograms recorded, the first to
determine their eligibility, the second at the end of the selection
phase to be used as the study baseline, and the third at the end of the
treatment phase. All echocardiograms were recorded by trained
cardiologists who had obtained the approval of the Study
Echocardiography Committee after submission of a sample echocardiogram.
In some cases the investigators referred their patients to an approved
center for echocardiography.
M-mode echocardiograms were recorded with the patients lying in a left lateral position and the head of the bed elevated 30°. The transducer was placed in the third or fourth intercostal space, and echoes from the left ventricle were recorded just distal to the tip of the mitral leaflets for three to five consecutive cardiac cycles. Prior two-dimensional mode examination allowed the best parasternal line, ie, a perpendicular line spanning from the interventricular septum to the left ventricular posterior wall, to be selected.
The preselection echocardiograms were read locally to determine patient eligibility. The baseline and final echocardiograms were read independently by two members of the Central Echocardiography Evaluation Committee who were unaware of the order of recording and the patients' treatment. The left ventricular internal dimension in diastole (LVIDd), the interventricular septum thickness (IVST), and the posterior wall thickness (PWT) were measured at the peak of the QRS complex on a simultaneously recorded electrocardiogram according to the Penn convention.16 LVM was calculated from measurements performed on several complexes (up to five) for each recording, using Devereux's formula: LVM (g)=1.04x{(IVST+PWT=LVIDd)3-LVIDd3}-13.6.
The estimate thus obtained for LVM has been shown to be similar to that determined anatomically.16 The LVM index (LVMI) was calculated by dividing this estimate by the patient's body surface area (in meters squared).15 When the estimates for this index, calculated by the two independent central readers, differed by more than 5%, the traces were reanalyzed by the two physicians together to reach a consensus.
Blood Pressure Monitoring
Casual blood pressure measurements were performed at
inclusion, to determine eligibility, and at each visit. Ambulatory
blood pressure was recorded at the beginning and end of the
double-blind phase over a 24-hour period using fully automatic monitors
that were set to record every 15 minutes during the day and every 30
minutes during the night. Time limits for day and night were set to
coincide with the patient's usual sleeping habits.
Sample Size Considerations
It was calculated that a sample of 120 patients (40 in each
group) was necessary to detect a difference in LVMI of 8 to 12
g/m2 between the group receiving 1.25 mg ramipril and that
receiving placebo with a power of 80% (two-tailed test). This
calculation was based on the assumption that the standard deviation of
the change for this index in the placebo group would lie between 10 and
18 g/m2.
Statistical Analysis
Statistical analysis was performed using the SAS software
package (version 6.07). Qualitative variables were compared using
either a 
2 test or Fisher's exact test.
Quantitative variables were compared using Student's t test
or the Wilcoxon rank test. Comparisons of treatment effects in the
three groups were performed using ANOVA. Two analyses of the changes in
LVMI were performed, the first using all the available data, and the
second, an intention-to-treat analysis. For this latter
analysis, it was considered that the LVMI for patients for whom
values were missing was unchanged. Comparisons of ambulatory blood
pressure were made using the mean of the available data for each
patient. Multiple regression analyses were performed using a backward
elimination procedure. All probability values are given for two-tailed
tests.
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Results |
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Study Population
Between January 1990 and March 1992, 125 patients were recruited in 20 centers. Ten patients were not randomized at the end of the selection phase before randomization: 4 withdrew consent, 1 had exceeded the age limit, 1 had received an ACE inhibitor before entry, 2 had poor echogenicity, 1 had an asymmetric septal hypertrophy, and the reason is unknown for the last patient. At entry to the double-blind treatment phase, the baseline characteristics of the 115 remaining patients allocated to the three treatment groups did not differ significantly with the exception of previous cardiovascular disorders (Table 1). During the selection phase, under furosemide, the mean casual blood pressure decreased from (mean±SEM) 161.6±1.5 to 155.4±1.3 mm Hg (systolic) and from 95.0±1.0 to 91.2±0.9 mm Hg (diastolic). At the end of the selection phase, 77 (67%) patients had a casual diastolic blood pressure of 95 mm Hg or less (28 of 40 in the placebo group, 23 of 38 in the 1.25-mg ramipril group, and 26 of 37 in the 5-mg ramipril group). From the baseline echocardiograms, mean LVMI was estimated as 137 g/m2 (134 g/m2 in the placebo group, 134 g/m2 in the 1.25-mg ramipril group, and 143 g/m2 in the 5-mg ramipril group).
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Compliance and Missing Data
Two patients in the 1.25-mg ramipril group and 1 in the 5-mg
ramipril group were lost to follow-up. Study treatment was discontinued
prematurely for 2 patients in the placebo group (1 because of
myocardial infarction and the other because of hypotension), 1 in the
1.25-mg ramipril group (because of persistent cough), and 3 in the 5-mg
ramipril group (all because of persistent cough). These 6 patients had
a final echocardiogram and their data were used in the analysis.
Each of 9 patients (5 in the placebo group, 3 in the 1.25-mg ramipril
group, and 1 in the 5-mg ramipril group) had one echocardiogram that
could not be interpreted because of poor quality; therefore,
interpretable echocardiograms were available for 103 (89.6%) patients.
Ambulatory blood pressure recordings were available for 104 (90.4%)
patients, and casual blood pressure data were available for all
patients.
Blood Pressure
There was no statistically significant difference in blood
pressure changes between the study groups (Table 2). At
the end of the study, 97 (86.6%) of the 112 patients who completed the
follow-up had casual diastolic blood pressure of 95 mm Hg or less (35,
32, and 30 patients in the placebo group, 1.25-mg ramipril group, and
5-mg ramipril group, respectively).
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Estimates for Left Ventricular Variables
The discrepancy between the two readers' estimates was more than
5% in 70% of the cases, so a consensus was reached by joint
evaluation, as planned in the protocol. From the analysis of the
data for the 103 patients with interpretable echocardiograms, we found
that the changes in LVM and posterior wall thickness were significant
for both ramipril groups compared with changes for the placebo group
(Figure). The change in LVMI was significantly different
in the 5-mg ramipril group compared with that in the placebo group
(-10.8±3.7 versus +4.1±4.0 g/m2,
P=.008), but in the 1.25-mg group, the difference was on the
borderline of significance (-7.0±4.3 g/m2,
P=.06) (Table 2). After replacing the nine unknown values
(for the patients with uninterpretable echocardiograms) and those for
the 3 patients lost to follow-up by zero, the decrease in LVMI was
still significant in the 5-mg ramipril group compared with that in the
placebo group (P=.006) but not in the 1.25-mg ramipril group
(P=.062). No significant differences were observed between
the groups for interventricular septal thickness or left ventricular
internal dimension in diastole.
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Multiple Regression Analysis
Multiple regression analysis was performed, with the change in
LVMI as the predicted variable, using models testing the following
variables: initial LVMI value, 1.25-mg ramipril treatment, 5-mg
ramipril treatment, age, sex, duration of hypertension, previous
treatment of hypertension, smoking status, and changes in ambulatory
systolic and diastolic blood pressures from baseline. Changes in
ambulatory blood pressures were forced into the model. At the end of
the backward elimination procedure, it was concluded that the change in
LVMI between randomization and 6 months was significantly dependent
only on the first three variables, ie, the initial value of the index
(P=.005) and both 1.25-mg (P=.03) and 5-mg
(P=.01) ramipril treatments, but not on ambulatory systolic
or diastolic blood pressures (P=.15 and .16, respectively).
After adjustment for all the variables initially included in the model,
the mean decrease in LVMI compared with that in the placebo group was
10.7±6.0 g/m2 in the 1.25-mg ramipril group and 15.7±6.0
g/m2 for the 5-mg ramipril group. Similar results were
obtained when the casual blood pressures were tested in similar models
and when a change in LVM was the predicted variable.
Adverse Events
Only one major complication was reported during the study for a
patient in the placebo group (myocardial infarction); no deaths were
reported. At least one minor complication was reported by 22 patients
(7 in the placebo group, 5 in the 1.25-mg ramipril group, and 10 in the
5-mg ramipril group). The only minor complications that could be
attributed to the diuretic or ACE inhibitor or both were 3 cases of
urinary urgency (1 in each group), 4 cases of dry cough (1 in the
1.25-mg and 3 in the 5-mg ramipril groups), and 1 case of symptomatic
hypotension (in the placebo group). Two patients in the placebo group
and 1 in the 5-mg ramipril group had blood potassium levels less than
3.5 mmol/L at 6 months.
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Discussion |
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The results from this study show that daily treatment for 6 months with either 5 mg ramipril (a regular antihypertensive dose) or 1.25 mg ramipril (a dose with no marked antihypertensive effect) reduces LVM significantly in middle-aged hypertensive patients treated with 20 mg furosemide daily. These effects were observed independent of changes in blood pressure. A consequence of the furosemide pretreatment was that approximately 67% of patients had controlled hypertension at the time of randomization. This may explain why there were no significant changes in the casual and ambulatory blood pressures for the patients in the ramipril groups compared with those in the placebo group during the double-blind treatment phase. Another explanation could be the lack of statistical power, since with the observed variance in the change in ambulatory blood pressure, the number of patients included gives a statistical power (ß risk) of only 70% for the detection of a difference in blood pressure of at least 5 mm Hg between any two study groups (one-tailed test,
risk= .05). The patients were recruited
mainly by private practice cardiologists (only 8 were included by
general practitioners), and they had a low-risk profile, since only 4
patients had experienced a cardiovascular event before inclusion in the
study. Thus, although LVH was present, the selection process
excluded higher-risk patients with cardiovascular conditions other than
hypertension. At entry to the treatment phase (after at least 4 weeks
of furosemide treatment), the mean LVMI for all patients was found to
be 137 g/m2, which is higher than the 97.5th
percentile for Devereux's reference male population,15
indicating that the target population, ie, patients with LVH, had been
attained. After 6 months of treatment, the decrease in LVMI was
statistically significant in the 5-mg ramipril group compared with
placebo and on the borderline of significance in the 1.25-mg ramipril
group; the decrease in LVM was statistically significant in both
ramipril groups compared with placebo. The decrease observed in the
ramipril groups was essentially caused by a statistically significant
reduction in posterior wall thickness. Although not statistically
significant, the decrease in interventricular septal thickness
contributed to the decrease in the calculated LVM and LVMI. Recently, the results from the Treatment of Mild Hypertension (TOMH) study,17 a 4-year randomized, placebo-controlled, double-blind trial in mild to moderate hypertensive patients with or without LVH, showed a significantly greater decrease in LVM in the group treated with chlorthalidone compared with that in the group treated with enalapril. This difference seems to be partially due to the reduction in the left ventricular internal dimension observed in the chlorthalidone group but not in the enalapril group. In the HYCAR study, the left ventricular internal dimension remained unchanged during the double-blind treatment phase in the three groups, but this may be explained either by the low dose of diuretic administered or by the fact that furosemide was started at least 4 weeks before the baseline echocardiogram.
Compared with studies in which all echocardiograms were recorded by a single, highly trained operator, the accuracy and reproducibility were obviously impaired by the multicenter design of this trial. The variance observed for the change in LVMI for all patients was higher than expected (observed variance, 539 g2/m4; expected variance, <324 g2/m4).
In a review of 147 before/after comparison studies of the effects of antihypertensive therapy on LVH, 23 studies investigated the effects of ACE inhibitors in 321 patients.18 An indirect comparison suggested that ACE inhibitors were more effective for the reduction in LVM than vasodilators, dihydropyridine calcium antagonists, and ß-blockers, with an average decrease in LVM of approximately 17 g over a mean treatment duration of 7 months. The percentage change in the value for LVM and the decrease in mean arterial blood pressure were independent under ACE inhibitor treatment, but they were negatively correlated under ß-blocker treatment. Although this review has many methodological weaknesses, the two main ones being the use of before/after estimates of the changes in LVM and indirect comparisons of these, the results seem to support our present findings. In a 6-month double-blind controlled study involving 44 patients (of whom only 30 were analyzed), captopril significantly reduced LVMI and posterior wall and interventricular septal thicknesses compared with minoxidil, with similar levels of blood pressure control in both groups.19 In another 6-month double-blind controlled study, LVMI decreased significantly compared with pretreatment values in hypertensive patients taking perindopril, an ACE inhibitor, or nifedipine.20 In this latter study, the decrease was found to be correlated with the reduction in ambulatory blood pressure in the nifedipine group but not in the perindopril group.
The results of the HYCAR study suggest that in humans the effect of ramipril on LVM is independent of blood pressure reduction. Multiple regression analysis showed that the decrease in LVMI was dependent on the treatment (either 1.25 or 5 mg ramipril daily) and the baseline value of the index only and not on blood pressure changes. These are consistent with results from animal experiments. For example, in one study, rats receiving a high dose of captopril (30 mg/kg daily for 22 days) had a smaller LVM and myocyte diameter than rats with the same blood pressure that did not receive captopril.21 A very low dose of ramipril (0.01 mg/kg daily for 6 weeks) induced regression of LVH in aortic-stenosed hypertensive rats without modifying their blood pressure.12
One possible explanation for the activity of ACE inhibitors in LVH regression is the potential role of angiotensin II in the pathogenesis of LVH. In embryonic chick myocytes, the increase in total cellular protein and in the rate of protein synthesis observed after exposure to angiotensin II was blocked by an antagonist, [Sar1,Ile8]angiotensin II.22 The concentration of angiotensinogen mRNA was found to be higher in the hypertrophic left ventricles of abdominal aorta–constricted rats than in control, sham-operated rats 15 days after operation.23 The plasma renin activity increased only temporarily for 1 day in the abdominal aorta–constricted rats, but enalapril prevented the development of LVH in these animals, suggesting that a localized cardiac renin-angiotensin system may play a role in the development of LVH. Effects from a local accumulation of bradykinin cannot be excluded because cardiac tissue has a local kallikrein-kinin pathway.24 In rats with aortic constriction, it was confirmed that the beneficial effects of ramipril on the prevention of LVH but not its regression could be inhibited by a specific bradykinin B2-receptor antagonist.25
We cannot exclude the possibility that the use of a diuretic in all patients included in the HYCAR study may have increased their sensitivity to ACE inhibition through a stimulation of the renin-angiotensin-aldosterone system. This may explain the small increase in LVM observed in the placebo group. However, since all patients had received low-dose furosemide, any stimulation of the renin-angiotensin-aldosterone system would have been minimal.
Since our study focused on changes in LVM and blood pressure, it did not have sufficient power to detect any treatment-induced changes in morbidity or mortality. However, we have identified a therapy that can decrease LVM independent of blood pressure changes in furosemide-treated hypertensive patients, and this provides the background for further testing of the effects of LVH regression on morbidity and mortality.
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Acknowledgments |
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This work was supported under an unrestricted grant from Laboratoires Hoechst, France. We would like to thank Rémi Genthon, Philippe Lendresse, Bernard Schölkens, Eric Tordjman, and Daniel Vasmant for their assistance.
The HYCAR Study Group included the following participants:
Investigators: Bordeaux: P. Cade; Brou sur Chantereine: L. Fischbein, A. Pleskof; Fontenay sous Bois: A. Ranglaret; Grenoble: E. Page; Henin Beaumont: E. Gras; La Rochelle: R. Lorillard; Le Blanc Mesnil: B. Manne; Lyon: J.M. Adelsbach, F. Bezot, P. Buisson, M.F. Le Goaziou, R. Rosenberg; Marseilles: A. Bourdon, J.P. Cabibel, B. Jauffret, J. Lefèvre; Nancy: M. Genot; Paris: P. Do Duc, A. Fitoussi, D. Guedj, M. Hidelsheim, A. Sebaoun; Rennes: B. Dupont, A. Michardière, J.A. Paulet; Saint Brieuc: R. Landel; Saint Laurent du Var: N. Balarac; Saint Priest: H. Guillaumot; Salon de Provence: J. Farese; Thionville: P. Guenoun, J.P. Houppe, M.P. Houppe-Nousse, S. Kownator; Toulouse: R. Bashoun; Villeurbanne: D. Rousson.
Coordinating Center: B. Barbe, J.P. Boissel, C. Cornu, S. Delair, M. Gaydarova, X. Joseph, H. Kolsky, M. Lièvre, C. Rolland, B. Salewski, F. Vitali.
Steering Committee: Three members of the Coordinating Center staff (J.P. Boissel, H. Kolsky, M. Lièvre), C. Gayet (Lyon), D. Rousson (Lyon).
Central Echocardiography Evaluation Committee: Three members of the Steering Committee (C. Gayet, H. Kolsky, M. Lièvre), P. Guéret (Creteil), R. Roudaut (Pessac).
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Footnotes |
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Reprint requests to Michel Lièvre, Service de Pharmacologie Clinique, 16 avenue Lacassagne, BP 3041, 69394 Lyon Cedex 03, France.
These results were presented in part at the 47th Annual Fall Conference of the Council for High Blood Pressure Research, San Francisco, Calif, September 28-October 1, 1993.
Received May 23, 1994; first decision July 27, 1994; accepted September 20, 1994.
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