Renal Failure. 1:73-^.2005Copyright C 2005 Toylor &. Francis tnc.ISSN: 0B86-O22X print / 1525-604'* onlinetX)I: 1O.IO8I/JUI-2(XXM28O1

Taylor Si FrancisTijilat bfrmcB Croup

CLINICAL STUDY

Lercanidipine in Patients with Chronic Renal Failure: The ZAFRA Study

N. R. RoblesUnidad de MTA, Hospital Infania Crisiina, Badajoz, Spain

J. OconFundacidn Puigvert. Barcelona. Spain

C. F. GomezHospital Grcgorio Maranbn, Madrid, Spain

M. ManjonHospital Clfnico, Granada, Spain

L. PastorHospital Miguel Servet, Zaragoza, Spain

J. HerreraHospital General de Asiurias, Oviedo, Spain

J. VillatoroHospital General de Castell6n. Castellbn de la Plana, Spain

J. Calls and J. TorrijosHospital Fundaci6n de Manacor, Menorca, Spain

V. I. RodriguezHospital Severo Ochoa, Leganes, Madrid, Spain

M. M. A. RodriguezHospital La Inmaculada, Huercal-Overa, Aimeria, Spain

M. L. MendezHospital Nuestra Seilora de la Candelaria, Tenerife, Spain

A. MoreyClinica Miramar, Barcelona, Spain

F. I. MartinezHospital de Galdacano, Bilbao, Spain

I - •

J. MarcoHospital Son Dureta, Mallorca, Spain

Address correspondence to Dr. Nicolas Roberto Robles,Unidad de HTA, Hospital Infanta Crisiina, Carrctcra de Portugals/n, Badajoz 06080, Spain; E-mail: nroblesp@meditex.es

73

74 N. Robles et al.

A. LiebanaHospital Ciudad de Jaen, Jaen, Spain

B. Rincon and F. TorneroHospital Virgen de la Luz, Cuenca, Spain

Objective: The objective was primary to evaluate ihe safeuse of a new calcium channel blocker, lercanidipine, in patientswith chronic retial failure (CRF). The secondary objective was tostudy Ihc protective effect of calcium channel blocker on renalfunction in CRF patients previously treated with ACE inhibitorsor angiotensin receptor blockers. Design and Methods: Thestudy recniited 203 CRF patients (creatinine >!.4 mg/dL formales, creatinine >1.2 mg/dL for females, or creatinineclearance <70 mL/minl. All patients were receiving ACEinhibitors (63.4%) or angiotensin II antagonist (36.6%) therapy,but they had higher blood pressure than recommended for CRF(130/85 mmHg). No patients were under diuretic treatment.Patients were clinically evaluated I. 3, and 6 months afterstarting treatment with lercanidipine. Samples for urine andblood examination were taken during the examination. Whenneeded, a third drug wa.s added to the treatment, excludingdiuretics. Creatinine clearance was measured using 24 h urinecollection. Results: 175 patients rendered valuable for [he study(age63.9±II.9 years, 52.9^ males and 47.1% females). Bloodpressure (BP) significantly decreased from 162± 17/93±8.3mmHg to l32±12/78±6 mmHg. 89.2% of patients showed asignificant BP reduction, and 58.1% achieved optimal BPcontrol (< 130/85 mmHg). Seven patients (3.4%) showeduntoward effects. Not one case of edema was detected, andlhe prevalence of adverse effects related to vastxlilatation wasextremely low (three patients, 1.48%). Plasmatic creatinine didnot change (I.9±0.5 baseline versus I.9±0.6 mg/dL), butcreatinine clearance increased ai the end visit (4I.8±I6.Obaseline versus 45.8± 18.0 mL/min, p = 0.0l9). Plasmaticcholesterol also decreased from 221 ±46 to 211 ±35 mg/dL(/j=O.OOI). Conclusions: Lercanidipine showed a high antihy-pertensive effect in CRF patients. It has u good toierabiiiiyprofile and showed an interesting effect on plasmatic lipids. Animprovement in renal function, measured through creatineclearance, was detected.

Keywords lercanidipine. chronic renal failure, hypertension

INTRODUCTION

Hypertension is a major determinant of progressionof renal disea.se, irrespective of cause, and the relative riskof developing end-stage renal disease in hypertensive

patients {compared with that of patients with "optimar"BP) increases threefold when diastolic BP increases to 90mmHg,'" It is widely known that the cardiovascularsystem is affected profoundly by the presence ofadvanced renal failure.'"' The Hypertension Detectionand Foilow-up Program (HDFP) study'"'' showed thatbaseline serum creatinine had a significant prognosticvalue for 5-and 8-year all-cause mortality. The presenceof proteinuria in hypertensive patients is also a powerfulpredictor of higher cardiovascular morbidity and mortal-ity.''*' Tighter BP control is the main mechanism forpreventing the progression of chronic renal failure.'*'''''Antihypertensive agents, such as angiotensin-convertingenzyme (ACE) inhibitors and angiotensin-receptor block-ers (ARB), seem to have an additional organ-protectiverole and are routinely used in renal disease.'" '̂

In spite of its antihypertensive efficacy, dihydropyr-idine calcium antagonists are often reported to induce sideeffects responsible for treatment withdrawal or replace-ment with a drug of a different class. Lercanidipine is anew dihydropyridine calcium antagonist with high lip-ophilicity and high va,scular selectivity, which confer it agradual and prolonged antihypertensive effect and a goodtolerability as compared with other dihydropyridinecalcium channel blockers.'^"' However, the renoprotec-tive effect of calcium antagonist is a controversial issue,in spite of a growing amount of information regarding itsbeneficial effect.""' In this way, it has been suggested thatcalcium antagonist could improve renal function inpatients previously treated with angiotensin-convertingenzyme inhibitors,""

This article reports the results of the ZAndip enFuncion Renal Alterada (ZAFRA) Study with the aim toassess the safety and effectiveness of lercanidipine inpatienis with chronic renal failure and the protectiveeffects of calcium channel blockers on renal function inpatients with reduced baseline renal function.

MATERIAL AND METHODS

A total of 203 hypertensive renal disease patientsfrom 16 Spanish centers was recruited. All patients were

Lercanidipine in CRF 75

Table ICauses of renal failure

Vascular nephropathyInterstitial nephropalhy/pyelonephritisDiabetic ncphropaihyGlomerulonephritisOthersUnknown

763420141213

receivitig treatmetit with either ACE itihibitors or ARBand have chronic renal failure defmed as iticreased plasmacreatinine (>1.4 for males or >1.2 for females) ordecreased creatinine clearance (<80 mL/min). To beincluded, the patients should have high blood pressuredefined by the Clinical Guidelines of the WHO-iHS forrenal disease patients (systolic BP> 130 or diastollcBP>85 mmHg). No patients received diuretic treatmentor other cardiovascular therapy simultaneous to angio-tensin axis blocking agents.

Antihypertensive therapy with the long-acting calci-um antagonist lercanidipine at a dose of 10 mg once a daywas given to ail patients. They were followed for 6 months,and four visits were scheduled (at inclusion. 1. 3. and 6months after beginning). Additional therapy (alfa blockeror beta blcKkers) was prescribed to reach the randomizedtarget BP when it was not achieved at I month: Patientswho did not reach the target BP were scheduled for afacultative visit 30 days alter adding a third antihyperten-sive agent (2 months). If BP was still higher than the targetvalue, tbe patient could be excluded for follow-up by theinvestigator clinic criteria. Blood pressure, heart rale,adverse effects, symptom checklist, and compliance totreatment were assessed at each visit, BP was measured bya standard mercury sphygmomanometer approximately24 h after the last drug intake. Two measurements, taken at3 min intervals in the sitting position, were averaged andused as the clinical BP reference value. Heart rate wasmeasured from the radial pulse tor 30 sec.

According to the protocol, serum creatinine had to bemeasut^d, at each recruiting center, by standard labora-

Tahle 2Changes in blood pressure

SBP DBP HR

Basal1 month3 months6 months

t62.0±16.6142.8±15.5''135.2±12.l''13L6±I!.6"

93.2 ±8.383.1 ±8.1"78.7 ±6.6"78.2 ±6.4"

76.3 ±10.376.2 ±10.375.4 ±10.874.7 ±9.8

"SBP and DBP arc expressed as mmHg. HR is expressed asbpm. /*<O.(X)I versus baseline.

tory techniques at every visit. Creatinine clearance wasestimated using 24 h urine collection, which was also usedto stimulate proieinuria or microalbuminuria. Blot>dsamples were also analyzed for cholesterol, triglycerides,glucose, urate. and ionogram. A complete hemogram wasalso performed at every visit.

Statistical analyses were performed by a computerprogram. Data are reponed as mean with one standarddeviation. Differences between continuous variables werecompared by the use of student's / test for paired samples.Differences in proportion were challenged using theMcMemar test due to the existence of paired values. A Pvalue of <0.05 was considered statistically significant; allP values are two-tailed.

RESULTS

Twenty-eight patients were excluded from evalua-tion due to protocol violations during the inclusion. Thestudy ended with 175 patients: 92 men ynd 82 women,mean age 63.9±11.0 years. There were 95 (54.3%)overweight patients (BM1>25 and <30 Kg/m'), and 45(25.7%) were obese (IMC>30 kg/m"). Twenty-ninepatients were smokers.

Causes of renal failure are shown in Table 1. Forty-two patients were diabetics (39 type 2 and three type 1).Forty-six patients have proteinuria >500 mg/day. Fifty(28.6%) patients have mild chronic renal failure (creat-inine clearance <80 mUmin and >50 mUmin): 103patients (58.9%) have moderate chronic renal failure(creatinine clearance <50 mL/min and > 25 mL/min). and22 (12.6%) showed advanced renal failure (creatinineclearance <25 mL/min),

A total of 43 patients discontinued the study becauseof adverse events (/i = l), poor compliance to treatment

90.00%

80.00%

70.00%

60,00%

50.00%

40,00%

30.00%

20,00%

10.00%

0.00%<U0/8S S130/85 Kcspondcn,

mo, (11.5% BP< 13(V85.24.0% BP< 130/85)(McNemar icsi).

Figure J. Number of controlled and responder patients at iheend of follow-up. p<0.001 versus 1.

76

1 .

CreatinineUreaUrateCholesterolTriglyceridesGlucoseNaKCaCreatinine clearance

Basal

1.9±0.568.0 ±31.3

7.2±1.8221 ±47140±51109±34141 ±2.74.7 ±0.59.5±0.5

4l.8±16.0

N. Robles et al.

Table 3BiocheETiical changes

1 month

1.9±0.569.7 ±28.5

7.0±1.6216±41137±53109±33141 ±2.74.7 ±0.59.5±0.5

42.6±17.7

.1 months

1.8±U.573.2 ±30.36.9±1.7218±38139 ±49103 ±20141±2.64.7 ±0.59.5 ±0.6

44.6±17.5

6 months

1.9±0.669.2±31.8

6.9 ±1.6211 ±35"134 ±45"108±34141 ±2.34.7 ±0.59.4±0.5

45.8±18.O'"

Units

mg/dLmg/dLmg/dLmg/dLmg/dLmg/dLmmol/Lmmol/Lmg/dLmL/min

V=0.001 versus baseline.''/j=0.018 versus baseline.'•p=0.019 versus baseline.

( n = l ) . high blood pressure in spite of treatment (n=26),poor compliance with study procedures (n= 10), end-stagerenal failure (n=\) and interruption of follow-up (n=4).Four patients showed untoward effects during the follow-up (erectile disfunction, n=\:. urine incontinence, n=l\mouth dryness: eosinophilia, n=\). No patients com-plained about lower limb swelling or heaviness, andedema was not detected at inspection. Three moresubjects from the group of patients excluded fromevaluation presented adverse reactions (flush, n=2\unspecific complains, n=\). These three latter patientshave been taken into account to calculate incidence ofadverse reactions.

After 1 month of treatment, SBP and DBP weresignificantly (/xO.OOl) reduced by lercanidipine (from162.0±l6.6/93.2±8.3 baseline to 142.8±15.5/83.I ±8,1mmHg). Similar results were observed for values enteringin the analysis at 3 and 6 months (see values in Table 2),At 6 months mean BP reduction from baseline was

50

45

40

30

25

200 1 3 6

Month

Figure 2. Creatinine clearance steadily increases along thetreatment with lercanidipine (p=O.OI9).

- 2 9 . 8 / - 1 4 . 5 mmHg (relative reduction 18.0/15.1%).Heart rate (Table 2) was similar before and duringtreatment. After 6 months of treatment, the percentage ofnormalized patients was 42.3%. and the proportion ofpatients who needed to add a third antihypertensive agentwas 41.5% (Figure I).

Treatment with lercanipine was accompanied byeither no change or by small and no significant variationsin the various hematology values considered in the study.Evolution of biochemical values has been reported inTable 3. Cholesterol (/J = O.OOI) and triglycerides(p=0 .0 l8 ) significantly decreased at 6 months. Noincrease in the number of patients with abnormal orhematologic findings was seen during treatment ascompared to pretreatment values. Creatinine clearancesignificantly improved at 6 months. (/ '=0.019) (Figure 2).No changes in plasmatic or urea creatinine were detected.Proteinuria diminished significantly at the end of the

3"SlD

4

3.5

3

2.5

2

1.5

1

Month

Figure 3, Proteinuria decrease after adding lercanidipine tcACE inhibilors/ARB therapy, although this change wassignificant at 6 months (./J=0.015J.

Lercanidipine in CRF 77

follow-up (2.8±2.8 versus baseline, 3.5±3.2 g/day.p=O.O155) (Figure 3).

i .t

DISCUSSION

The present study in kidney disease patients demon-strates that lercanidipine, a calcium antagonist, is a safeand effective antihypertensive drug in this kind of patient,with a clean side effect profile. In addition, it showed thata calcium channel blocker slightly improves the renalfunction at medium term and lowers proteinuria when itwas associated with an angiotensin axis-blocking drug.

Calcium antagonist is a widely used antihypertensiveagent, and its use has increased dramatically since the1980s. Its wide appeal can be attributed to several features,including its well-documented antihypertensive efficacyand metabolic neutrality.'^'^' Calcium antagonists havebeen tested against placebo and against other activetherapies in several studies. A careful prospective meta-analysis of all studies in December 1999 showed equalmorbidity and mortality reduction of calcium channelblockers when compared with diuretics, beta-blockers, andACE inhibitors."^' Another recent meta-analysis hasshown that calcium antagonists seem to be more effica-cious in preventing strokes tban conventional drugs.'"'*'More specifically, in diabetic nephropathy patients, ARBfailed to show significant differences in morbidity andmortality compared with calcium antagonists.'''^'

In spite of their antihypertensive efficacy, dihydro-pyridine calcium antagonists are often reported to induceside effects responsible for treatment withdrawal orreplacement with drugs of a different class. Lercanidipineis a new compound with high lipophilicity and highvascular selectivity, which ensures a gradual andprolonged antihypertensive effect.'^"'''^"'^' In all thesestudies, toierability of lercanidipine was very good, and,when compared with other dihydropyridine calciumantagonists, it appeared to be better. The most commonadverse effect of dihydropyridine is pedal edema. It seemsto be related to arterial dilation, which increases intra-capillary pressure and squeezes fluid from the intravas-cular space into the interstitium.""*' Compared withamiodipine and lacidipine, lercanidipine showed a lowerintercadence of pedal edema in essential hypertensives.'*'In our study, the incidence of edema and vasodilatoryrelated side effects was really low in spite of theproteinuria of a high nutnber of patients, a well-knownedema-prone status. Because vasodilatory edema associ-ated with dihydropyridine calcium antagonists respondswell to agents that dilate the postcapillary vessel, sucb asACE inhibitors or ARB,''"•''' the simultaneous treatmentwith those drug classes might have influenced our results.

It is well established that BP reduction, regardless ofthe antihypertensive agent used, slows the progression ofrenal disease.'^^"^^^ Moreover. ACE inhibitors and, morerecently. ARB, seem to provide an added degree ofprotection to the kidney damage, independent of theirarterial pressure-reducing effects.'' " ^"-̂ "' So, it wasconsidered ethically necessary for all patients in this studyto be previously treated with one of those drugs.

The results from this study should be viewed withcaution, as tbis study bas some potential limitations. Theyinclude the small number of studied subjects, tbe use ofcreatinine clearance rather tban a more precise marker ofglomeruiar filtration rate, and last, the use of an open labelrather than double-blind, double-dummy design. Tbe useof creatinine clearance as a marker is a potential limitationof this study. Although we are aware that it is imprecise asa measure of glomeruiar filtration rate, recent studiesfound it to be a good predictor of renal functiondecline. '"'"' Tberefore, even with the limitations of thismarker, we feel our data are reliable and meaningful.

There are scant reports on the protective effect ofcalcium antagonists. Data from the SYST-EUR studydemonstrate a protective effect of calcium channelblockers compared witb placebo in hypertensive patients,even those with diabetes and those with proteinuria.'^''^Verapamil treatment decreased proteinuria and renalfailure progression in diabetic nephropathy in AfricanAmericans.'-*"*' Tbe results of the INSIGHT study suggestthat antihypertensive treatment with nifedipine GITS alsooffers a renoprotective effect higher than do tbiazides.'^^'Our findings, combined with the evidence from otherintervention trials, raise the possibility that long-termantihypertensive therapy with long-acting dihydropyri-dine may produce specific reno protection beyond theireffect on blood pressure. On the other hand, severalstudies using amiodipine as calcium antagonist agentfailed to show any renal protective effect in diabetic ornondiabetic renal disease.''̂ •"'̂ -^ '̂

It bas been suggested that calcium antagonists mayimprove renal function wben it has been impaired by theprevious use of ACE inhibitors, and it must be taken intoaccount that all recruited patients were treated withangiotensin axis blocking drugs previously to initiatelercanidipine treatment.

Theoretically, tbe renal microcirculatory effects ofcalcium channel blockers cannot explain this renoprotec-tive effect, because tbey preferentially dilate the afferentglomeruiar arteriole. This does not favor a decrease ofglomeruiar hypertension, one of the postulated mecha-nisms to explain the protective effect of ACE inhibitorsand ARB.'"* '̂ But, it has been reported tbat lercanidipinecould dilate efferent arteriole in spontaneous hypertensiverats.'"**̂ ' However, there are possible mechanisms other

78 N. Robles et al.

than the reduction of intraglomerular capillary pressure,whereby calcium channel blockers could prevent renaldysfunction such as tbe attenuation of the mitogeniceffects of growth factors,' the modulation of macro-molecular traffic acros.s and entrapment within themesangium, the inhibition of the renal effects ofendothclin, and tbe decrease in free radical formation.'"^ '̂

Other possible reasons for differences in renalpreservation between drug groups are differences inantiproteinuric effects of tbe antihypertensive agents.Reduction in proteinuria in individuals witb insulin-dependent or noninsulin-dependent diabetes mellitus isknown to correlate witb the preservation of renalfunction.'"^" * '̂ A report by Hebert et al.'"*"' demonstratedtbat only tbose individuals wbo manifested reductions inproteinuria had a slowed progression of diabetic nephrop-athy. Two different meta-analyses, bowever, demonstratethat reductions in proteinuria observed with ACEinhibitors are out of proportion to the level of BPreduction.'"''"''' Thus, tbese and other studies suggest thatACE inhibitors and nondihydropyridine calcium channelblockers reduce proteinuria to a degree greater than

predicted by simple BP reduction.g

''" " Combinationtherapy of ACE inhibitors with either nondibydropyridineor dibydropyridine might bave a deeper effect on urineprotein reduction. "' Our data support this lattercontention, because there was a greater reduction inproteinuria when lercanidipine was added to ACEinhibitors or ARB therapy.

Lercanidipine shows good efficacy as an antihyper-tensive agent in renal disease. The incidence of untowardeffect was very low. Furthermore, this study supports theconcept that the dihydropyridine calcium channel blockerlercanidipine decreases proteinuria and improves theprogression of establisbed renal disease when it isassociated with an ACE inhibitor or ARB. It should beremembered that all subjects had chronic renal failurebefore entry into the study, and most of them have lost atleast .'iO'̂ of their renal function. Furtber large-scaleclinical trials are needed to confirm the observations madein tbis study.

ACKNOWLEDGMENT

Supported by grants from Recordati-Spain (Madrid,Spain).

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