Comparative effect of lercanidipine and nifedipine gastrointestinal therapeutic system on ankle volume and subcutaneous interstitial pressure in hypertensive patients: a double-blind, randomized, parallel-group study

CURRENT THERAPEUTIC RESEARCH@

VOL. 61, No. 12, DECEMBER2000

Comparative Effect of Lercanidipine and Nifedipine Gastrointestinal Therapeutic System on Ankle Volume and Subcutaneous Interstitial Pressure in Hypertensive Patients: A Double-Blind, Randomized, Parallel-Group Study Roberto Fogari, Gian Domenico Malamani, Annalisa Zoppi, Paola Preti, Alessandro Vanasia, Elena Fogari, and Amedeo Mugellini

Clinica Medica, IRCCS, Policlinico S. Matteo, Department of Internal Medicine, University of Pavia, Pavia, Italy ABSTRACT

Background: Ankle e d e m a is o n e o f t h e m o s t c o m m o n side effects o f a n t i h y p e r t e n s i v e t r e a t m e n t w i t h calcium c h a n n e l b l o c k e r s (CCBs). T h e i n c i d e n c e o f e d e m a is h i g h e r with d i h y d r o p y r i d i n e s t h a n w i t h v e r a p a m i l o r diltiazem. Objective: The aim o f t h i s s t u d y was t o c o m p a r e t h e effect o f a n t i h y p e r t e n s i v e t r e a t m e n t w i t h t h e n e w CCB l e r c a n i d i p i n e v e r s u s nifedipine gastrointestinal therapeutic system (GITS) on ankle-foot volume (AFV) and on pretibial subcutaneous tissue pressure (PSTP), considered objective measures of CCB-induced ankle edema. Methods: P a t i e n t s w i t h mild t o m o d e r a t e h y p e r t e n s i o n ( d i a s t o l ic >90 mm Hg a n d <110 n u n Hg) w e r e s t u d i e d . A f t e r a 4-week p l a c e b o r u n - i n p e r i o d , p a t i e n t s w e r e t r e a t e d with l e r c a n i d i p i n e 10 mg o n c e dally o r n i f e d i p i n e GITS 30 mg once daily for 12 w e e k s a c c o r d i n g t o a r a n d o m i z e d , d o u b l e - b l i n d , p a r a l l e l - g r o u p design. A t t h e e n d o f t h e p l a c e b o a n d a c t i v e - t r e a t m e n t p e r i o d s , b l o o d p r e s s u r e (BP), h e a r t r a t e , b o d y weight, AFV, a n d PSTP w e r e m e a s u r e d . AFV was measured using the principle of water displacement: the immersion of t h e f o o t a n d a n k l e i n t o a given q u a n t i t y o f w a t e r c a u s e s w a t e r disp l a c e m e n t e q u i v a l e n t t o t h e i m m e r s e d v o l u m e . This w a t e r was coll e c t e d a n d m e a s u r e d . PSTP was a s s e s s e d d i r e c t l y u s i n g a b a l a n c i n g o p e n s y s t e m c o n s i s t i n g o f a g r a d u a t e d c a p i l l a r y t u b e filled with sal i n e s o l u t i o n a n d c a p p e d w i t h a n e e d l e . W h e n t h e n e e d l e is t h r e a d e d i n t o t h e s u b c u t a n e o u s p r e t i b i a l t i s s u e t h e s y s t e m b e c o m e s closed. I t is t h e n c o n n e c t e d t o a w a t e r m a n o m e t e r w h e r e t h e P S T P is measured. Results: S i x t y p a t i e n t s (34 m e n a n d 26 w o m e n ) aged 36 t o 70 y e a r s w e r e e n r o l l e d . L e r c a n i d i p i n e a n d u i f e d i p i n e GITS prod u c e d s i m i l a r r e d u c t i o n s i n systolic a n d d i a s t o l i c BP ( l e r c a n i d i p i n e , -18.7/11.8 m m Hg; u i f e d i p i n e GITS, -18.8/11.5 n u n Hg; P < 0.001 vs p l a c e b o ) . Both d r u g s s i g n i f i c a n t l y i n c r e a s e d AFV a n d PSTP comAddress correspondence to: Roberto Fogari, Cliniea Medica, Polielinico S. Matteo, Piazza Golgi, 27100 Pavia, Italy.

Accepted for publication September 27, 2000. Printed in the USA. Reproduction in whole or part is not permitted. 850

0011-393X/00/$19.00

R. FOGARI ET AL.

pared with placebo. However, lercanidipine produced a significantly l e s s pronounced ( P < 0.001) increase in AFV (143.6 mL) and PSTP (0.9 cm H20 ) compared with nifedipine GITS (AFV, 284.2 mL; PSTP, 1.8 cm H20). In both t r e a t m e n t groups, correlation analysis showed an inverse relationship, although to a different degree, b e t w e e n AFV and PSTP changes, but not b e t w e e n absolute values o f AFV and PSTP during treatment. AFV increase was greater and PSTP increase was l o w e r with increasing age, which suggests a role for age in the type o f tissue r e s p o n s e to a stimulus for e d e m a formation. No relationship was found b e t w e e n AFV and PSTP changes and BP reduction. Conclusions: These data suggest that lercanidipine produces significantly l e s s increases in AFV and PSTP, 2 objective measures o f e d e m a formation, than nifedipine GITS. K e y words: ankle edema, pretibial subcutaneous t i s s u e pressure, lercanidipine, nifedipine. (Curr Ther Res Clin Exp. 2000;61: 850-862)

INTRODUCTION Ankle edema is one of the most common side effects of antihypertensive t r e a t m e n t with calcium channel blockers (CCBs). It occurs in 1% to 15% of patients treated with these agents and leads a significant number of patients to discontinue their treatment. 1-4 Among the heterogeneous group of CCBs, the incidence of edema formation is higher with dihydropyridines t h a n with verapamil or diltiazemS'6; this difference has been attributed to the higher vascular selectivity, and hence more pronounced vasodilatory effects, of dihydropyridines.7 The precise vascular mechanisms t h a t cause CCB-induced edema are still not completely understood. The most likely reason for net fluid filtration from blood to tissue during therapy with CCBs appears to be an increase in capillary hydrostatic pressure, caused by alterations in the relationship between precapillary and postcapillary resistance vessels, s-11 The vasodilation induced by CCBs leads to a relatively more pronounced inhibition of vascular tone in precapillary t h a n postcapillary resistance vessels, with a consequent rise in capillary hydrostatic pressure and transcapillary fluid loss. 12'13 The edema formation can also be partly ascribed to interference by CCBs with the local vascular control (probably the myogenic component) t h a t operates to protect dependent vascular regions from enhanced fluid filtration. 1°'13-16 CCBs have been shown to blunt postural vasoconstriction by modulating calcium fluxes t h a t maintain myogenic tone, an extracellular calcium-dependent process, 13'17 and this effect might contribute to subcutaneous edema formation. It has also been suggested t h a t CCB-related edema could be partly related to the increase in vascular permeability induced by these drugs, ls'19 Neither sodium retention nor cardiac inotropism are involved in the formation of edema. 9,20 851

CURRENT THERAPEUTIC RESEARCH@

The most recently developed dihydropyridines, characterized by high lipophilicity, short plasma elimination half-life, and long duration of action, are associated with a lower incidence of ankle edema and other vasodilation-related side effects. 21-25 Lercanidipine is the latest of this new generation of dihydropyridines. The high lipophilicity and membranebinding coefficient of this agent result in membrane-controlled pharmacokinetics characterized by a prolonged pharmacologic effect on blood pressure (BP) despite a short plasma half-life. 25-2v In clinical studies, the incidence of ankle edema associated with lercanidipine treatment was broadly comparable to that associated with placebo. 25'2s-3° Most reports on the incidence of CCB-induced ankle edema have some important limitations. First, they are generally based on a simple collection of spontaneously reported side effects, that is, on subjective parameters rather than objective estimates of the frequency and magnitude of these effects. Second, much of the information about vasodilation-related adverse effects of CCBs is derived from clinical experience and not from studies specifically designed to examine this issue. The present study was undertaken to compare the effect of lercanidipine versus nifedipine in the gastrointestinal therapeutic system (GITS) formulation 31 on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP), 2 quantitative measures of ankle edema formation. PATIENTS AND METHODS

This randomized, double-blind, parallel-group study enrolled patients with mild to moderate essential hypertension (diastolic blood pressure [DBP] >90 mm Hg and <110 mm Hg after a 4-week washout period). Exclusion criteria were significant cardiac, renal, endocrine, or hematologic disease; pregnancy; and known hypersensitivity to dihydropyridine therapy. None of the patients had signs of venous insufficiency. None of the female patients were using oral contraceptives, which are known to affect subcutaneous tissue pressure and water retention. The study protocol was approved by the local ethics committee, and written informed consent was obtained from each patient before enrollment. After a 4-week placebo washout period, eligible patients were randomly assigned to treatment with nifedipine GITS 30 mg once daily or lercanidipine 10 mg once daily for 12 weeks. Patients were required to take trial medication between 8:00 AM and 10:00 AM. The lercanidipine and nifedipine GITS capsules were identical in size, taste, and color. After 4 weeks of treatment, the medication dose was doubled in patients with DBP >90 mm Hg or a DBP reduction of <10 mm Hg. Patients were assessed before and after the washout placebo period and after 12 weeks of treatment. At each visit, BP, heart rate (HR), and body weight were measured. BP was measured in the morning before daily drug intake (ie, 24 hours 852

R. FOGARI ET AL.

after dosing, at trough) using a standard mercury sphygmomanometer (Korotkoff I and V) after patients had been seated for 5 minutes. The average of 3 consecutive measurements, with an interval of ->1 minute between them, was recorded. H R was measured by radial pulse palpation at 30-second periods. At the end of the placebo period and the 12-week active-treatment period, AFV and PSTP were measured. AFV was measured using the principle of w a t e r displacement. For each m e a s u r e m e n t a Perspex (Meditec, Pavia, Italy) water bath with a 15-L maximum capacity was filled with the same quantity of water. Subsequent immersion of the foot induces water displacement that equals the immersed volume. This water was collected and measured. In order to reach a fixed and reproducible degree of immersion of the foot and ankle, a stable chair with adjustable height was used, and patients maintained a rigidly standardized seated position with the thigh horizontal and the lower leg vertical. PSTP was assessed directly using the balancing open system, described by Lauderer 32 in 1884 and modified by Burch and Sodeman 33'34 in 1937, and the Malamani device. 3s'36 The method involves connecting the pretibial subcutaneous environment to a water manometer through a needle connected to a graduated capillary tube capped with a needle (Figure 1). Both the needle and the capillary tube are full of saline solution from the point of the needle to half-height of the tube, where the meniscus of the saline solution is visible. The needle is threaded into the subcutaneous pretibial tissue of the patient while he or she is lying in the supine position. Immediately after the needle is threaded into the subcutaneous tissue, the meniscus of the saline solution moves toward the manometer if the interstitial pressure is positive or toward the tissue if the interstitial pressure is negative. Using a micropump (Figure 1), the investigator attempts to achieve a pressure that does not produce any movement of the meniscus of the saline solution. Theoretically, the pressure read on the water manometer after saline solution balancing between manometer and interstitial tissue corresponds to the PSTP.

Statistical Analysis Statistical analysis of the data was performed using SAS ®version 6.12 (SAS, Inc, Cary, North Carolina). The treatment effect was evaluated by PROC GLM. Variability sources considered were treatments and patients. The relationship between the variables was assessed by multiple regression analysis, with changes in AFV and PSTP as the dependent variables, and age, BP changes versus baseline, and final BP values as independent variables. Spearman's rank test was also used for correlation analysis between these variables. In addition, 95% confidence intervals for means and differences between treatments were calculated. The homogeneity of pretreatment values of age, systolic blood pressure (SBP), DBP, and H R in 853

CURRENT THERAPEUTIC RESEARCH ®

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Figure 1. The Malamani device for interstitial pressure evaluation. On the left is the water manometer, on the right the needle connected to the capillary tube and the micropump used to balance the movement of the saline meniscus in the capillary tube.

t h e 2 t r e a t m e n t g r o u p s w a s a s s e s s e d b y t tests. O b s e r v e d differences in d a t a w e r e c o n s i d e r e d significant if P w a s <0.05.

RESULTS A t o t a l of 34 m e n a n d 26 w o m e n a g e d 36 to 70 y e a r s w e r e enrolled. B o t h t r e a t m e n t g r o u p s h a d 30 p a t i e n t s . T a b l e I outlines t h e m a i n d e m o g r a p h i c a n d clinical c h a r a c t e r i s t i c s of t h e s t u d y p o p u l a t i o n a t t h e e n d of t h e r u n in placebo period. No significant differences w e r e o b s e r v e d b e t w e e n t h e 2 t r e a t m e n t g r o u p s w i t h r e s p e c t to age, sex distribution, a n d b a s e l i n e v a l u e s of SBP, DBP, AFV, or P S T P . T h e m a i n r e s u l t s of t h e s t u d y a r e r e p o r t e d in T a b l e II. L e r c a n i d i p i n e a n d n i f e d i p i n e G I T S w e r e e q u a l l y effective in d e c r e a s i n g B P v a l u e s . S B P a n d D B P r e d u c t i o n s v e r s u s b a s e l i n e w e r e s t a t i s t i c a l l y significant a f t e r 854

R. FOGA~ ET AL.

Table I. Demographicand clinical characteristics (mean ± SD) of patients in the 2 treatment groups at the end of the placebo run-in period.* Lercanidipine (n = 30) Age, y Sex, no. (%) Male Female SBP, mm Hg DBP, mm Hg AFV, mL PSTP, cm H20

Nifedipine GITS (n = 30)

54.13 ± 10.10

53.63 ± 9.22

18 (60) 12 (40) 162.73 ± 4.93 97.90 ± 3.87 1281.23 ± 137.92 1.91 ± 2.10

16 (53) 14 (47) 162.40 ± 5.85 97.47 ± 4.01 1295.63 ± 138.46 1.99 ± 2.09

GITS = gastrointestinal therapeutic system; SBP = systolic blood pressure; DBP = diastolic blood pressure; AFV = ankle-foot volume; PSTP = pretibial subcutaneous tissue pressure. * No significant differences were observed between the 2 treatment groups.

t r e a t m e n t with both lercanidipine (-18.7/11.8 m m Hg; P < 0.001 vs placebo) and nifedipine GITS (-18.8/11.5 m m Hg, P < 0.001 vs placebo), with no significant difference between the 2 t r e a t m e n t s . Both CCBs caused a significant increase in AFV and P S T P compared with placebo; however, lercanidipine produced a less pronounced increase in AFV (143.6 mL, +11.2%) and P S T P (0.9 cm H20, 47.1%) compared with nifedipine GITS (AFV 284.2 mL, +21.9%; P S T P 1.8 cm H20, +90.4%); t he difference between the 2 t r e a t m e n t s was statistically significant (P < 0.001 for AFV and PSTP) (Figure 2). An inverse correlation was found between AFV and P S T P changes. With both lercanidipine and nifedipine GITS, although to different degrees (Figure 3, uppe r panel), the more pronounced increase in AFV corresponded to the less pronounced increase in P S T P and vice versa. Interestingly, this inverse relationship was m a r k e d l y reduced or nonexist e n t wh en we considered the relationship between AFV and P S T P absolute values during t r e a t m e n t (Figure 3, lower panel). We examined the correlations between age and t r e a t m e n t - i n d u c e d changes in AFV and P S T P

Table II. Mean ± SD values of systolic blood pressure (SBP), diastolic blood pressure (DBP), ankle-foot volume (AFV), and pretibial subcutaneous tissue pressure (PSTP) after 12 weeks' treatment with lercanidipine or nifedipine gastrointestinal therapeutic system (GITS).

SBP, mm Hg DBP, mm Hg AFV, mL PSTP, cm H20

Placebo

Lercanidipine

Placebo

Nifedipine GITS

162.73 + 4.93 97.90 ± 3.87 1281.23 ± 137.92 1.91 ± 2.10

144.00 ± 5.02* 86.07 ± 3.58* 1424.87± 156.05" 2.82 ± 2.46*

162.40 + 5.85 97.47 ± 4.01 1295.63± 138.46 1.99 ± 2.09

143.60 ± 5.36* 86.00 ± 3.22* 1579.83± 179.10 *~ 3.80 ± 9.76 *t

* P < 0.001 versus placebo. t p < 0.001 versus lercanidipine.

855

CURRENT THERAPEUTIC RESEARCH@

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Figure 2. Increases in ankle-footvolume (AAFV)and in pretibial subcutaneous tissue pressure (APSTP)induced by lercanidipine and nifedipine gastrointestinal therapeutic system (GITS).The thick line is the median value, the upper and lowerlimits of the rectangle correspond to the standard deviation, and the narrow columns correspond to the upper and lower range limits. (Figure 4) and found t h a t both lercanidipine and nifedipine GITS, although to a different extent, produced increases in AFV t h a t were great er with increasing age. Conversely, the increase in P S T P caused by both CCBs was reduced with increasing age. No significant correlation was found between the changes in AFV and P S TP and the decrease in DBP values either in the lercanidipine or nifedipine GITS group (Figure 5). DISCUSSION

The results of this study suggest that, despite equivalent antihypertensive efficacy, lercanidipine and nifedipine GITS produced qualitatively similar but quantitatively different effects on ankle volume. Both drugs caused a significant increase in AFV and P S T P compared with placebo. However, this increase was significantly less pronounced in patients t r e a t e d with lercanidipine compared with those given nifedipine GITS, Correlation analysis showed an inverse relationship between AFV and P S T P changes 856

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Figure 3. Relationship between ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP) changes (vs baseline values) induced by lercanidipine and nifedipine gastrointestinal therapeutic system (GITS) (upper panel) and relationship between AFV and PSTP absolute values during the 2 treatments (lower panel). w i t h both l e r c a n i d i p i n e a n d nifedipine GITS: the g r e a t e r the i n c r e a s e in AFV, t h e less t h e i n c r e a s e in P S T P , a n d vice versa. This i n v e r s e relationship, however, was m a r k e d l y r e d u c e d or n o n e x i s t e n t w h e n absolute v a l u e s of AFV a n d P S T P d u r i n g t r e a t m e n t w e r e compared. In b o t h t r e a t m e n t groups, y o u n g e r h y p e r t e n s i v e p a t i e n t s showed the g r e a t e s t i n c r e a s e in P S T P a n d the lowest i n c r e a s e in AVF, w h e r e a s t h e c o n t r a r y was observed in the older p a t i e n t s . T h e different a g e - r e l a t e d r e s p o n s e to the s a m e stimulus for e d e m a f o r m a t i o n is likely r e l a t e d to the different s t r u c t u r a l characteristics of tissue at v a r i o u s ages r a t h e r t h a n to different h e m o d y n a m i c m e c h a n i s m s c o n t r i b u t i n g to e d e m a formation. Thus, in y o u n g e r p a t i e n t s , who h a v e g r e a t e r tissue i n t e g r i t y a n d m o r e elastic tissue components, the t e n d e n c y t o w a r d fluid filtration from blood to t h e i n t e r s t i t i a l space m a y be c o u n t e r a c t e d by p r o n o u n c e d tension d e v e l o p m e n t in elastic tissue compo857

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Because of its high lipophilicity, lercanidipine accumulates in lipid-containing membrane depots, from where, over a prolonged period, it is slowly released and reaches its targets, namely, the L-type calcium c h a n n e l s . 25-27 How this may lead to reduced potential for edema formation remains to be clarified. Hypothetical mechanisms include (1) less discrepancy between arteriolar and venular vasodilation; (2) less impairment of the venoarteriolar reflex, which is weak or absent in patients who develop ankle edema during administration of nifedipine11; and (3) less effect on vascular permeability and consequent fluid extravasation. Additional studies are needed to clarify the contribution of the pharmacologic properties of lercanidipine to its edematigenous potential. e f f e c t . 25-27

CONCLUSIONS The results of this study suggest that in patients with mild to moderate hypertension, treatment with lercanidipine produces significantly less in859

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