(Hypertension. 1995;26:436-444.)
© 1995 American Heart Association, Inc.
Articles |
Comparison of Perindopril and Amlodipine in Cyclosporine-Treated Renal Allograft Recipients
From the Renal Unit, Academisch Ziekenhuis, Vrije Universiteit Brussel, Brussels, Belgium, and Institut de Recherches Internationales Servier (IRIS), Courbevoie, France.
Correspondence to Jacques Sennesael, Renal Unit, AZ-VUB, Laarbeeklaan 101, B 1090 Brussels, Belgium.
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Abstract |
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Abstract The objective of this study was to compare the antihypertensive efficacy and influence on renal function of perindopril and amlodipine in cyclosporine-treated renal allograft recipients with mild to moderate hypertension. We conducted a randomized, double-blind, double-dummy crossover trial in ambulatory patients. Four phases were conducted: 2 weeks on placebo, 8 weeks of maintenance (perindopril or amlodipine), and 2 weeks of washout between treatment periods. Ten hypertensive patients with stable renal allograft function transplanted more than 6 months previously and receiving cyclosporine as part of their immunosuppressive regimen were studied. The patients were allocated to perindopril (2 or 4 mg/d) and amlodipine (5 mg/d) in a random sequence. If office diastolic pressure was greater than or equal to 90 mm Hg after 4 weeks, the dosage was doubled and continued for another 4 weeks. The main outcome measures were office and 24-hour ambulatory blood pressure changes after 8 weeks of active treatment and treatment and time effect on glomerular filtration rate and effective renal plasma flow. Perindopril and amlodipine were equally effective in lowering office blood pressure and similarly efficacious for the 24-hour period of the day. Neither drug affected glomerular filtration rate or effective renal plasma flow. Both agents demonstrated equivalent capacity (timextreatment, P=.955) to reverse renal vascular resistance (amlodipine from 0.35±0.02 to 0.30±0.02 mm Hg/mL per minute per 1.73 m2; perindopril from 0.36±0.03 to 0.32±0.01) (time effect of all treatments together, P=.043). After amlodipine, hemoglobin was higher (148±5 versus 135±5 g/L, P=.002) and serum uric acid was lower (351±17 versus 398±24 µmol/L, P=.001) compared with perindopril.
Key Words: amlodipine • kidney transplantation • cyclosporine • hemodynamics • blood pressure monitoring, ambulatory
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Introduction |
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Multiple etiologic factors are associated with posttransplant hypertension, including steroids, native kidney disease, renal artery stenosis of the transplanted kidney, chronic rejection, recurrent disease, and more recently the use of cyclosporine.1 Before the widespread use of cyclosporine several authors agreed that most forms of posttransplant hypertension were associated with both an increase in RVR and activation of the RAS secondary to retained native kidneys. Thus, the use of an ACE inhibitor would seem logical and has been shown to be useful in the management of posttransplant hypertension.2 3 4 The addition of cyclosporine to the immunosuppressive regimen has further complicated the difficult problem of posttransplant hypertension. Cyclosporine appears to be a vasoconstrictor of the afferent arteriole of the glomerulus.5 This renal vasoconstrictive action involves many factors, including activation of the sympathetic nervous system6 ; increased intrarenal production of thromboxane A27 and endothelin8 ; upregulation of intrarenal renin biosynthesis9 10 ; and impaired nitric oxide–mediated, endothelium-dependent relaxation.11 Afferent arteriolar vasoconstriction and sympathetic nerve stimulation are associated with enhanced proximal tubular reabsorption and expanded plasma volume,12 13 resulting in a low-renin, volume-dependent form of hypertension.14 15 Because of the multifactorial etiology of posttransplant hypertension there is presently no consensus on the optimal antihypertensive therapy. At least in theory, CCBs may represent the drug of choice in cyclosporine-mediated hypertension by virtue of their vasodilator capacities on the afferent arteriole16 and the mild natriuretic properties of some CCBs of the dihydropyridine class.17 Alternatively, ACE inhibition therapy may decrease hyperfiltration and glomerular hypertension in posttransplant hypertensive patients18 and decrease proteinuria in long-standing grafts.19 20 Moreover, a low or normal active plasma renin level cannot be considered as an argument against participation of the RAS in posttransplant hypertension as ACE inhibition has proved effective in other cardiovascular disease models in which the circulating RAS is not elevated.21 CCBs, because of their predominant effect at the preglomerular level, have been advocated as the first line of treatment in cyclosporine-treated allograft recipients with hypertension.1 22 23 In short-term studies they appear to provide better BP control and more marked reduction in RVR than ACE inhibitors.24 25 26 27 28 However, a recent study found no difference between these classes of drugs during a period of 30 months after renal transplantation.29 Since most of our knowledge of the antihypertensive action of these drugs has been derived from short-term studies in parallel groups of patients, we conducted a long-term crossover trial to compare the effects of an ACE inhibitor (perindopril) with those of a CCB (amlodipine) on office BP, 24-hour ambulatory BP, and renal function. Perindopril was selected for comparison with amlodipine mainly because of its potent antihypertensive action and its pharmacokinetic properties, which, like amlodipine, allow once-a-day dosage.30 31 32 33 Ten patients were treated during 8 weeks with each drug in a randomized, double-blind, placebo-controlled design.
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Methods |
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Patients
Ten adult cadaveric renal transplant recipients (7 men, 3 women; age range, 36 to 71 years) with mild to moderate hypertension (supine DBP
95 and 
115 mm Hg) after successful renal transplantation were
included in the study. Their characteristics are presented in
Table 1. Patients had stable allograft function as
assessed by monthly serum creatinine and
creatinine clearance determinations. Three patients (Nos.
6, 7, and 8) had experienced one biopsy-proven interstitial
rejection episode during the first month after transplantation that had
responded to methylprednisolone pulses for 3 consecutive days. Digital
subtraction angiography and Doppler renal ultrasound were performed
in all patients to rule out renal artery stenosis and chronic
rejection. All patients were taking cyclosporine as part of
their immunosuppressive regimen. Cyclosporine was given as
a once-a-day dosage to all patients except one (No. 10, half the dose
BID); this regimen did not change over the course of the study.
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The protocol required that patients with a known intolerance to calcium antagonists or ACE inhibitors or with hepatic, hematologic, or other diseases prohibiting the use of these drugs be excluded from the trial. Women who were or intended to become pregnant within the study period were excluded. The protocol also excluded patients with congestive heart failure and recent (within the previous 6 months) myocardial infarction or cerebrovascular accident.
The study was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent of all patients and approval of the local hospital ethics committee was obtained before the start of the study.
Study Design
The study was a randomized, double-blind, double-dummy trial in
which all patients were treated with perindopril and amlodipine in a
crossover fashion (Fig 1). All
antihypertensive drugs were discontinued at study entry. After a
single-blind placebo run-in period of 2 weeks (W-2 to W0) the
patients received either perindopril or amlodipine in a randomized
order during 8 weeks (W0 to W8). After a second placebo washout period
of 2 weeks (W8 to W10) they were allocated to the other treatment for
another 8 weeks (W10 to W18).
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Patients were seen in the renal unit as outpatients every 2 weeks. At each visit body weight, pulse, and BP were recorded as well as any volunteered or observed adverse effect. BP (standard mercury sphygmomanometer) and pulse were measured in patients in the morning before drug intake after 10 minutes of supine rest and again after 2 minutes of standing. The mean value of three measurements was recorded. The initial dose of perindopril was 2 mg in patients with creatinine clearance greater than 60 mL/min per 1.73 m2 and 4 mg in the others.34 The starting dose of amlodipine was 5 mg. Patients took two capsules at all times (active agent plus placebo) so that the double-dummy design was respected. The dosage was doubled after 4 weeks of active treatment (at W4 or W14) if mean supine DBP was greater than 90 mm Hg. Renal function studies, 24-hour ABPM, and laboratory measurements were performed at the end of each placebo (W0 and W10) and active (W8 and W18) treatment period. So that these investigations could be performed within 24 hours after the last drug intake, the patient was instructed to take the test medication at 11 am the day before.
Renal Function Studies
On the morning of the hemodynamic study, which
started at 8 AM, patients ingested a tap water load (20
mL/kg body wt) to ensure a high urine flow, and urine losses were
replaced.
ERPF and GFR were determined simultaneously from the plasma clearances of 123I-hippuran and 51Cr-EDTA, respectively, with the use of a constant infusion method without urine collections.35 36 The isotopes (2.2 MBq of both) were diluted in saline and administered at a constant rate (1 mL/min IV); a bolus injection of 1.1 MBq of both tracers was administered first after the constant infusion was started to shorten the time necessary to reach equilibrium. One can assume that as soon as the plasma level is stabilized, the quantity of tracer infused per minute (I) is equal to the amount excreted by the kidney (UV). The clearance can therefore be calculated with the formula Clearance=I/P, instead of UV/P (P representing the tracer concentration at steady state). The equilibrium for both tracers is reached at 60 minutes. During the test the patients remained seated. Isotopes were continuously infused in one forearm, and blood samples were withdrawn through a venous cannula left in situ in the other forearm at 90, 100, and 110 minutes so that equilibrium could be checked.
ABPM
BP was measured noninvasively over a 24-hour period with an
automatic device by the oscillometric method (Spacelabs 90207,
Spacelabs Inc).37 The monitor was fitted to the patients
between 8 and 9 AM on the day before the
hemodynamic studies. BP and heart rate were measured
every 15 minutes from 7 AM to 10 PM (daytime)
and every 30 minutes from 10 PM to 7 AM
(nighttime). The ABPM recording was repeated if the total
number of correct readings during the 24-hour period was less than or
equal to 75%. Patients were instructed to pursue their usual daily
activities during ABPM.
Laboratory Examinations
Standard methods were used for routine hematology (hemoglobin,
hematocrit, white blood cell and platelet counts), clinical
chemistry (serum sodium, potassium, creatinine, uric acid),
and 24-hour urinalysis (glucose, protein, sodium, potassium,
creatinine, and uric acid clearance). Whole-blood
cyclosporine trough levels were determined by a nonspecific
fluorescence polarization immunoassay (TDx Abbott).
Plasma renin activity was determined by an immunoradiometric assay (ERIA Diagnostics Pasteur). Plasma aldosterone concentration was measured by radioimmunoassay (Sorin Biomedica) after plasma extraction with dichloromethane. Serum ACE activity was measured by a method derived from that described by Cushman and Cheung38 with the use of [14C]hippuryl-l-histidyl-l-leucine as the substrate.
Calculations
ERPF and GFR were corrected for a standardized body surface area
of 1.73 m2. Renal blood flow was calculated as
ERPF/(1-hematocrit) and expressed in milliliters per minute per
1.73 m2. RVR was calculated as MAP (DBP plus one third of
pulse pressure measured during the renal hemodynamic
study) divided by renal blood flow and expressed as millimeters of
mercury per milliliter per minute per 1.73 m2. Filtration
fraction (percent) was calculated as GFR/ERPFx100.
Ambulatory BP data were analyzed as (1) 24-hour average SBP, DBP, MAP, and heart rate; (2) daytime (7 AM to 10 PM) and nighttime (10 PM to 7 AM) average SBP, DBP, MAP, and heart rate; (3) hourly average SBP, DBP, MAP, and heart rate; and (4) minimal and maximal SBP and DBP.39
Statistical Analysis
Results are presented as mean±SEM. Two kinds of
crossover ANOVA were performed. The first one, performed for main
criteria only, took into account the measurements at baseline and at
the end of each treatment period. The second one, performed for all
criteria, took into account only measurements at the end of each
treatment period. If no sequence effect (order of treatment
administration for the first and second periods: perindopril then
amlodipine or the opposite) and no interaction with sequence effect,
other than sequencextreatment, were significant, then treatmentxtime
interaction and treatment effect were interpreted.40 41
The relationship between two quantitative values was graphically
represented; Pearson correlation was calculated.
All statistical tests were performed by the Biostatistics Division of
IRIS, Courbevoie, France, considering a usual type I error at a value
of 
=.05.
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Results |
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Drug Treatment
The mean±SEM daily doses of the antihypertensive drugs being taken at the end of the maintenance period were 6.4±0.7 mg for perindopril and 9.0±0.7 mg for amlodipine. At 8 weeks perindopril controlled BP in 4 patients: at a dose of 4 mg in 1 and 8 mg in 3. In the others BP control was not achieved despite a maximal dosage of the drug. At the end of the amlodipine sequence 2 patients were controlled on 5 mg OD, and 3 were controlled on 10 mg OD. Maximal dosage of the drug failed to control BP in the others. A correlation was found between the individual daily doses of perindopril and amlodipine required to achieve BP control during the treatment sequences (rs=.61, P=.030).
Office BP
Changes over time for office BP during treatment with
perindopril and amlodipine are summarized in Table 2 and
illustrated in Fig 2. Mean supine SBP and DBP decreased
similarly with both drugs (timextreatment, P=.951 and
P=.126, respectively). Mean supine SBP fell from 174.7±4.4
mm Hg at the end of the placebo run-in phase to 159.7±4.2 mm Hg
after 8 weeks of perindopril. At the end of amlodipine treatment supine
SBP decreased from a baseline of 171.5±4.5 mm Hg to 156.4±3.8
mm Hg. Mean supine DBP changed from 102.3±2.5 mm Hg at baseline to
95.4±1.9 mm Hg after treatment with perindopril and from 101.2±2.5
to 91.7±2.1 mm Hg after treatment with amlodipine. Three-way ANOVA
indicated that supine BP responses were time dependent
(P<.001 and P=.004; SBP and DBP,
respectively) but not treatment dependent (P=.351 and
P=.231, respectively). Supine DBP tended to be lower after
amlodipine compared with perindopril (treatment effect after 8 weeks,
P=.068). Mean standing SBP and DBP were equally reduced
(timextreatment, P=.588 and P=.224,
respectively). Standing SBP was reduced from 171.8±5.9 mm Hg at the
end of the placebo phase to 158.3±5.1 mm Hg after 8 weeks of
perindopril and from 169.8±5.4 to 153.5±4.9 mm Hg after 8 weeks of
amlodipine. Standing DBP fell from 104.0±3.2 mm Hg at baseline to
94.5±1.6 mm Hg in perindopril-treated patients and from 100.4±2.4 to
94.2±2.7 mm Hg in amlodipine-treated patients. Three-way ANOVA
indicated that standing BP changes were time dependent
(P=.005 and P=.015; SBP and DBP, respectively)
but not treatment dependent (P=.340 and P=.422,
respectively).
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Twenty-Four-Hour ABPM
Table 3 shows the average 24-hour, daytime, and
nighttime SBP, DBP, MAP, and heart rate values at the end of the
placebo periods and after 8 weeks of treatment with perindopril and
amlodipine. There were no statistically significant differences in the
BP values at baseline among the two treatment sequences of the
crossover study. Mean 24-hour, daytime, and nighttime ambulatory MAP
values were equally reduced with perindopril and amlodipine
(timextreatment, P=.610, P=.959, and
P=.247, respectively). ANOVA indicated that changes over
time for ambulatory MAP were time dependent (P<.001,
P=.001, and P=.001, respectively) but not
treatment dependent (P=.700, P=.721, and
P=.661, respectively). Comparison of groups after 8 weeks of
treatment showed similar values for SBP, DBP, MAP, and heart rate when
24-hour, daytime, and nighttime averages were considered (treatment
effect after 8 weeks, P=NS). Whereas SBP values were roughly
equal during the day and night, DBP, MAP, and heart rate values during
the daytime exceeded those recorded during the nighttime either
before or after treatment.
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Renal Hemodynamics
The hemodynamic responses to 8 weeks of active
treatment are shown in Table 4. GFR (measured by
51Cr-EDTA clearance), ERPF (measured by
123I-hippuran clearance), and calculated renal blood flow
remained unchanged after 8 weeks of treatment with either drug.
Filtration fraction was differently affected by treatment
(timextreatment, P=.003): it decreased from 37±3% to
32±3% with perindopril (P=.001) and remained unaltered
during amlodipine administration (35±2% and 37±2% at baseline and
end point, respectively; P=.141). RVR fell to the same
extent with both drugs (timextreatment, P=.955), from
0.36±0.03 to 0.32±0.01 mm Hg/mL per minute per 1.73 m2
during perindopril intake and from 0.35±0.02 to 0.30±0.02 mm Hg/mL
per minute per 1.73 m2 during amlodipine administration.
Three-way ANOVA indicated that the change in RVR was time dependent
(P=.043) but not treatment dependent
(P=.174).
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Biochemistry and Hematology
A comparison of selected biochemical and hematologic
parameters before and after perindopril and amlodipine
administration is summarized in Table 5. Serum
creatinine was higher after perindopril compared with
amlodipine (124±8 versus 115±8 µmol/L; treatment effect after 8
weeks, P=.020). Serum potassium remained constant throughout
both placebo and treatment periods. Uric acid concentration was not
affected by perindopril administration (387±12 versus 398±24
µmol/L) but decreased from 387±18 to 351±17 µmol/L after 8 weeks
of amlodipine (treatment effect after 8 weeks, P=.001).
Hemoglobin concentration was differently affected by both drugs
(timextreatment, P=.006), decreasing from 141±5 to 135±5
g/L (P=.005) after perindopril administration and increasing
from 138±5 to 148±5 g/L (P<.001) after amlodipine.
Whole-blood cyclosporine trough levels were differently
affected by treatment (timextreatment, P=.050); they
increased from 140.2±18.2 to 200.0±21.9 µg/L after amlodipine
(P<.001) and remained unaltered during perindopril
administration (173.1±23.7 and 157.4±20.4 µg/L at baseline and end
point, respectively; P=.278). Initial plasma renin activity
was increased by perindopril but not affected by amlodipine, resulting
in final values of 76.1±19.9 and 35.1±10.3 ng/L, respectively
(P=.018). In contrast, final plasma aldosterone
was higher after amlodipine than perindopril (233.8±29.9 versus
144.1±30.3 ng/L, P=.008).
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Clinical Tolerance
No significant changes in physical findings or body weight were
observed in either treatment group. Three patients reported headache
and one patient experienced transitory dyspnea at the start of
perindopril. Ankle edema and transitory epigastric pain were reported
by one patient while on amlodipine. No patient was withdrawn because of
side effects.
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Discussion |
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This double-blind, randomized, crossover study showed that in a selected group of posttransplant hypertensive patients both perindopril and amlodipine induced significant and similar reductions in SBP and DBP. The correlation between the individual daily doses of ACE inhibitor and CCB titrated to the maximal recommended doses34 and the antihypertensive response achieved during each sequence of the study suggest that perindopril and amlodipine are equally effective. However, at the end of the 8-week maintenance period mean office DBP exceeded 90 mm Hg because normalization of BP (ie, DBP
90 mm Hg) was achieved in only 50% of
patients with either medication. This is not totally unexpected because
of the multifactorial causes of hypertension in this
setting.22 In particular, the presence of multiple kidneys
and/or chronic cyclosporine nephrotoxicity might have been
responsible for the lack of adequate BP response in some patients.
Indeed, poor BP control was preferentially observed in those who had
retained their native kidneys and who were already severely
hypertensive while on hemodialysis. Whether chronic
cyclosporine nephrotoxicity played a role in the
maintenance of high BP cannot be determined because renal
biopsies were not performed. However, chronic rejection seems unlikely
with normal renal angiography and the absence of proteinuria.
Persistent hypertension under monotherapy might have responded to the
combination of CCB and ACE inhibition. For patients with refractory
hypertension we would recommend performance of renal allograft
biopsy and conversion to azathioprine in the case of morphological
evidence of cyclosporine nephrotoxicity. If renal histology
is normal, then removal of native kidneys could be
advocated.42 Recently, ABPM has become increasingly useful in the evaluation of drug efficacy because of its potential to overcome the well-known limitations inherent in conventional BP measurement.43 44 Thus, using 24-hour ABPM we directly compared perindopril with amlodipine in cyclosporine-treated allograft recipients with mild to moderate hypertension. As shown by the ambulatory BP recordings at baseline, SBP was comparably high during day and night, whereas the nocturnal fall in DBP was less than 20%. In normotensive subjects BP declines by approximately 20% at night.45 Loss or attenuation of diurnal BP variability may occur in essential hypertension.46 It is frequently observed in secondary causes of hypertension such as renovascular disease45 and in patients with chronic renal failure and remains common after renal transplantation.47 Lack of a nocturnal fall in BP has also been reported in patients without renal disease receiving cyclosporine and glucocorticoids after cardiac and liver transplantation.48 49 Because of the sodium retention associated with cyclosporine administration26 and because of the low dose of prednisolone taken by our patients (10 mg/d), volume expansion rather than glucocorticoid treatment48 49 50 may be the major determinant in the pathogenesis of the blunted diurnal BP changes in this study. Circadian heart rate variations were present in our patients. This is in accordance with earlier reports indicating that the rhythmic51 and tonic52 components of cardiac vagal innervation controlling heart rate are restored after renal transplantation.
When 24-hour, daytime, or nighttime average values are considered, perindopril and amlodipine are able to similarly and equally reduce DBP and SBP below baseline levels without induction of reflex tachycardia. Thus, once-daily perindopril or amlodipine provides superimposable therapeutic cover for a full 24-hour period.
The basic modes of action of perindopril and amlodipine are different: perindopril inhibits the conversion of angiotensin I to angiotensin II,30 31 and amlodipine is a slow CCB.32 33 Nevertheless, the hemodynamic profiles of the two agents were similar. Both lowered RVR to the same extent, while 51Cr-EDTA clearance, a reliable marker of GFR in renal transplant patients,53 and ERPF, measured as 123I-hippuran clearance, remained stable. Filtration fraction fell during treatment with perindopril but not with amlodipine, compatible with the facts that ACE inhibitors exert their predominant intrarenal effect on the efferent glomerular arteriole, whereas CCBs act at the afferent arteriole.16 These data are in accord with the findings of Mourad et al29 but at variance with earlier observations of Curtis et al25 and Abu-Romeh et al24 and the recent trial of van der Schaaf et al.28 In the study of Mourad et al, lisinopril and nifedipine had similar antihypertensive and renal hemodynamic effects in renal transplant patients during a 30-month follow-up period. In contrast, Curtis et al and Abu-Romeh et al reported both an increase in RVR and a decrease in ERPF in cyclosporine-treated renal allograft recipients given captopril or enalapril, respectively. The data of van der Schaaf et al indicate that amlodipine provides better BP control than lisinopril and that treatment with amlodipine but not with lisinopril is accompanied by an increase in GFR and ERPF and a decrease in RVR. The reasons for these different responses may be the nature of the studies, the heterogeneity in patient population, or the degree of pretreatment cyclosporine-induced renal vasoconstriction. Indeed, the unfavorable renal effects with ACE inhibition were mainly observed after short-term administration. Yet, it should be stressed that short-term ACE inhibitor therapy might not allow sufficient time for a potential autoregulatory response. Differences in the mechanisms responsible for posttransplant hypertension between the patient populations studied may also explain the divergent renal hemodynamics after ACE inhibitor administration. Therefore, studies with a crossover design might permit more meaningful comparisons. Finally, the smaller dose of cyclosporine administered to our patients, reflecting the fact that this trial was undertaken about 2 years after transplantation, is not without interest. Indeed, when ACE inhibitors are initiated in the presence of high levels of cyclosporine, the combination of cyclosporine with afferent constriction and ACE inhibitor with efferent dilatation might compromise GFR, even in the absence of transplant artery stenosis.54
Long-term treatment with perindopril was associated with a long-lasting stimulation of plasma renin activity, the anticipated response to ACE inhibition, whereas amlodipine did not affect plasma renin activity levels. Despite the sustained suppression of ACE activity, plasma aldosterone concentration stabilized at baseline values during perindopril administration and increased after amlodipine administration. Incomplete suppression of plasma aldosterone concentration has also been reported after continued use of other ACE inhibitors.55 This is in accord with the known fact that other factors besides angiotensin II are capable of stimulating aldosterone release, such as corticotropin or small changes in potassium balance.56 The present trial demonstrated a neutral effect on serum electrolytes, or in the case of amlodipine a slight reduction in serum uric acid. Although the changes were small and their clinical significance uncertain, this uricosuric effect of amlodipine might be of interest considering the increased incidence of hyperuricemia and gout in cyclosporine-treated renal allograft recipients.57 58 Perindopril and amlodipine had divergent effects on hemoglobin concentration. In contrast to the small decrease in hemoglobin after perindopril, an increase in hemoglobin of the same magnitude was observed within an 8-week treatment period with amlodipine. Inhibition of erythropoiesis by ACE inhibition has also been observed with other molecules, both sulfhydryl containing59 and not,29 60 61 and this property has been used in the treatment or prevention of posttransplant erythrocytosis.62 Cyclosporine trough levels were slightly higher after amlodipine and remained unchanged during perindopril. Since the difference reached statistical significance, an interaction between amlodipine and cyclosporine metabolism is possible. Van der Schaaf et al28 also observed slightly elevated cyclosporine trough levels (23% higher) during amlodipine, whereas Toupance et al63 demonstrated that cyclosporine biotransformation was not altered by amlodipine in renal transplant recipients not taking corticosteroids. It is thus reasonable to conclude that a cyclosporine-amlodipine metabolic interaction can be observed in the presence of prednisolone, a potential inhibitor of the cytochrome P-450 system.64 However, the clinical significance of this interaction remains questionable, as RVR decreased despite the higher cyclosporine blood levels.
In summary, in this group of selected patients both perindopril and amlodipine are equally effective in lowering BP and similarly efficacious for the full 24-hour period of the day. Regarding the long-term evolution of renal function, both agents have an equivalent capacity for reversing the renal hemodynamic disturbances encountered in cyclosporine-treated renal transplant hypertensive patients. In addition, this study also provides evidence that amlodipine may decrease serum uric acid, whereas perindopril affects hemoglobin concentration. Although these properties will require further investigation, they may influence our choice of a suitable antihypertensive agent in the individual patient.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We thank Institut de Recherches Internationales Servier for kindly providing the perindopril and amlodipine used in this study and for their financial support. We are indebted to Lieve De Smedt for skillful technical assistance in performing the renal studies and Viviane Roose for secretarial help.
Received March 8, 1995; first decision April 7, 1995; accepted May 3, 1995.
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References |
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