JOURNAL FÜR HYPERTONIE

KOURILSKY O Iterium: Clinical benefits from an innovative antihypertensive treatment

Journal für Hypertonie - Austrian Journal of 2002; 6 (Sonderheft 4), 10-15

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mild and those with moderate hyper- the study per protocol in a compa- INTRODUCTION tension. After a placebo run-in period, rison between rilmenidine (1 to 2 mg rilmenidine was given in mono- daily) and nifedipine (40 mg daily). therapy for 4 weeks. Reduction in At the end of a year of treatment, The renaissance of interest in sympa- blood pressure by rilmenidine was blood pressure was adequately con- thetic overactivity as a candidate link significant in both the mild and mo- trolled on rilmenidine (DBP from between blood pressure elevation, derate hypertension group. Of all 102.7 ± 4.6 at baseline to 88.5 ± 7.1 insulin resistance and other cardio- rilmenidine treated patients, 61 % mmHg) and on nifedipine (DBP from vascular risk factors further under- were normalized (target SBP/ DBP < 102.7 ± 5.1 at baseline to 85.6 ±

lined the potential of I1-imidazoline 160/90 mmHg) after 4 weeks treat- 7.9). No significant difference was receptors as therapeutic targets for ment. In the mild hypertension group, observed in the antihypertensive antihypertensives. the normalization rate at 4 weeks on, efficacy of the treatments [13]. rilmenidine was 84 % [9]. It was against background that rilme- In a recent trial, 43 mild-to-moderate nidine began its clinical develop- Versus Diuretics hypertensives with risk factors com-

ment, and hence became the first I1- prising the metabolic syndrome were selective anti- In a study including 244 placebo- treated with rilmenidine (1 to 2 mg hypertensive to enter the therapeutic resistant mild-to-moderate hyperten- daily) or amlodipine (5 to 10 mg arena. Rilmenidine’s selective binding sive patients, rilmenidine was com- daily) for 4 months. The treatments

to I1-imidazoline receptors in the pared with hydrochlorothiazide over were comparable in their reductions lateral reticular nucleus of the brain- a period of 8 weeks. The 2 antihyper- of blood pressure (SBP/DBP) (rilmeni- stem [1] leads to a reduction in syste- tensive treatments were equally effec- dine from 152/99 mmHg to 138/85 mic sympathetic tone. Rilmenidine tive, each normalizing (target DBP < mmHg and amlodipine from 154.1/ exerts its antihypertensive effect 90 mmHg) 57 % of patients in mono- 98.5 mmHg to 136.5 ± 84.1 mmHg), mainly through reduced total peri- therapy [10]. which were not statistically different pheral resistance, mediated by reduc- (Fig. 1) [14]. tion in sympathetic overdrive [2]. These findings were broadly repro- duced in another study in elderly Versus ACE-Inhibitors Sympathoinhibition at renal level patients, with rilmenidine normali- and a direct effect through selective zing 67 % of patients over 8 weeks, Rilmenidine was compared with

binding I1 receptors [3] combine to and no significant difference bet- captopril in 51 mild-to-moderate inhibit the Na +/H + antiport in the ween rilmenidine and hydrochloro- placebo-resistant hypertensives over proximal convoluted renal tubule. in terms of either absolute 8 weeks’ treatment. The reductions Rilmenidine’s renal effects lead to a reduction or normalization rate [11]. in blood pressure in the rilmenidine decrease in sodium and water reten- (1 to 2 mg daily) and captopril (50 to tion, contributing to maintenance of Versus Beta-blockers 100 mg daily) groups were significant, blood pressure control in the long and there was no significant difference term [4–8]. Rilmenidine (1–2 mg daily) was between them. The number of patients compared with (50 to 100 requiring dose adaptation for nonres- mg daily) in 90 mild-to-moderate ponse was the same for rilmenidine hypertensive patients. Normalization treated as for captopril treated patients. rates at 12 weeks (target SBP/DBP < Normalization (target DBP < 90 ANTIHYPERTENSIVE EFFICACY 160/90 mmHg) were 66 % on rilme- mmHg) was achieved in 79 % of nidine and 65 % on atenolol. Fewer patients in the rilmenidine group patients in the rilmenidine group [15]. Comparability of the antihyper- Rilmenidine’s antihypertensive effi- (12 %) than in the beta-blocker trea- tensive efficacy of rilmenidine and cacy has been extensively tested in ted group (16 %) required of a second captopril is also demonstrated by double-blind, randomized trials antihypertensive for inadequate blood recent results showing similar blood versus placebo and against reference pressure control [12]. pressure reductions (SBP/DBP = antihypertensive drugs. –18/–14 on rilmenidine, –13/–19 on Versus Calcium-channel blockers captopril) over 6 months treatment Versus Placebo (Fig. 2) [16]. Trials of rilmenidine versus both nife- 126 hypertensive patients were dipine and amlodipine have been included in this multicenter trial. performed in placebo-resistant hyper- Patients were divided into those with tensives. Fifty-six patients completed

10 J. HYPERTON. Sonderheft 4/2002 For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. ITERIUM: CLINICAL BENEFITS FROM AN INNOVATIVE ANTIHYPERTENSIVE TREATMENT

Figure 1 Figure 2

Versus a agonists 2 patients required dose adaptations antihypertensive classes. Efficacy is demonstrated in both uncomplicated a for nonresponse in the rilmenidine Studies against both and - group [19]. and at-risk hypertensives, control methyl-dopa have been performed in being satisfactorily maintained in the placebo-resistant, mild-to-moderate Long-term maintenance long term without fading of effect. hypertensives, and these demonstra- ted both that rilmenidine is as effec- Rilmenidine’s longer term antihyper- tive as these older agents, and that it tensive efficacy has been studied in has a superior tolerance profile. Three two non-comparative trials. Mainte- hundred and thirty-three patients nance of blood pressure control in CLINICAL TOLERANCE PROFILE were randomized to rilmenidine rilmenidine-treated placebo-resistant (1 to 2 mg daily) or clonidine (0.15 mild-to-moderate hypertensives was to 0.3 mg daily) for 6 weeks’ treat- a studied over 1 year. Eight percent of Lack of 2 adrenoceptor-mediated ment. At the end of treatment identi- all study patients were controlled (to side effects cal blood pressure reductions were DBP < 90 mmHg) at 6 months (66 % seen in the two groups (–19 mmHg of them on rilmenidine monotherapy), Rilmenidine is pharmacologically systolic, –12 mmHg diastolic). Norma- and 84 % controlled at 1 year (60 % distinguished from antihypertensives lization rates (target SBP/DBP < 160/ on rilmenidine monotherapy) [20]. A acting either entirely or predomina- 90) were 57 % and 56 % for rilmeni- a second study of 12 months treatment tely through 2-adrenoceptors such dine treated and clonidine treated included 18,235 unselected hyper- as clonidine and a-methyl-dopa. patients respectively [17]. Another tensive patients. No fading of effect Many of the undesirable effects of study compared rilmenidine (1 to 2 these central agents are a -adreno- a was seen, with both the reductions in 2 mg daily) and -methyl-dopa 0.5 to pressure and the rate of normali- ceptor-mediated (such as sedation 1 g daily in 157 hypertensives. There zation on rilmenidine (60 % at 1 mg via a -agonism in the locus ceruleus, was no significant difference in 2 a daily) being maintained throughout. drying of the mouth via 2-agonism blood pressure normalization rates Furthermore, antihypertensive effi- in the salivary glands). between the groups, fewer patients cacy was comparable in several in the rilmenidine group requiring defined at-risk subpopulations – Rilmenidine’s good tolerance, through addition of a second antihyperten- those with isolated systolic hyper- selective binding to I1-imidazoline sive agent (hydrochlorothiazide) for tension, aged over 70 with severe receptors has been demonstrated in a inadequate response [18]. Rilmenidine large number of clinical studies. a hypertension, diabetes mellitus, dys- and -methyl-dopa were also compar- lipidemia, coronary disease, arrhyth- able in their antihypertensive effi- mias, heart failure, and renal failure A double-blind comparison of cacy in fragile elderly hypertensive (Fig. 3) [21]. rilmenidine and placebo showed no requiring long-term geriatric admis- difference in incidence of adverse sion. Normalization (target DBP < 90 The antihypertensive efficacy of effects between placebo-treated mmHg) was achieved in 83 % and rilmenidine is thus entirely compar- patients and those taking rilmenidine 85 % of patients on rilmenidine and at the usual 1 mg daily dose [9]. a able with that of reference represen- -methyl-dopa respectively. Fewer tatives of the four most prescribed Head-to-head comparisons of rilmeni-

J. HYPERTON. Sonderheft 4/2002 11 ITERIUM: CLINICAL BENEFITS FROM AN INNOVATIVE ANTIHYPERTENSIVE TREATMENT

Figure 3 Figure 4

dine against clonidine and a-methyl- Lack of rebound phenomena trials lasting between 4 weeks and dopa show a clear differentation in 1 year [9, 11, 12, 15, 18]. terms of side-effect profile. Against The lack of clinical rebound pheno- clonidine, the incidence of dry mouth menon on cessation of rilmenidine Preserved cardiovascular adaptation and drowsiness induced by rilmeni- treatment is well documented. In a dine was 2 to 3 times less and of comparative, double-blind, control- Cardiovascular responses to posture weaker intensity than that of the led trial, 59 patients were randomi- and exercise during rilmenidine treat- comparator. These differences were zed to clonidine (0.15 to 0.30 mg) or ment were specifically assessed and statistically significant, and clinically rilmenidine (1 to 2 mg daily). After 8 shown to be preserved in a double- relevant as no rilmenidine treated weeks of active treatment the anti- blind trial versus atenolol. This was patient stopped treatment, whereas hypertensive effects of the two treat- in contrast to the impaired responses 10 % of clonidine-treated patients ments were similar. Active treatment seen in the atenolol-treated group left the study due to side effects [17]. was then ceased and all patients [23]. Preservation of postural and Versus a-methyl-dopa, in a study switched to placebo. Cessation of exercise responses is of importance including 157 patients, no clinically clonidine treatment was associated in the treatment of elderly, and of significant side effects were observed with significant tachycardia, whereas young and active hypertensive patients during 4 months of rilmenidine treat- there was no evidence of rebound respectively. Lack of postural hypo- ment. The marked difference between phenomenon on cessation of rilmeni- tension during rilmenidine treatment a rilmenidine and 2-agonist antihyper- dine treatment [22]. This lack of has been noted in trials specifically tensive was therefore again under- clinical symptoms on withdrawal of treating elderly patients. No cases lined [18]. rilmenidine treatment was reprodu- arose during 6 weeks’ rilmenidine ced in other clinical studies, inclu- treatment of patients aged over 70 Clinical tolerance in long-term ding placebo periods at the end of years and requiring long-stay inpatient treatment treatment [12, 18, 19]. care [19], and another trial including 46 elderly patients in the rilmenidine Further strong support for the good Lack of sodium and water retention group produced no symptomatic tolerance of rilmenidine can be orthostatic during 8 found in the results of a very large Clinical evidence for lack of sodium weeks of treatment [11]. Hence, pharmacoepidemiological study. and water retention during rilmenidine review of the study evidence provi- Luccioni reported this trial, including treatment is provided by the trends in des clinical proof that none of the 18,235 unselected hypertensive patients’ weight in clinical studies. In classic a-mediated adverse effects of patients. Despite more than 35,000 contrast experience of centrally centrally acting agents is clinically a coprescriptions, only 3,6 % of acting 2-adrenoceptor agonists, which significant during rilmenidine treat- patients withdrew due to any adverse induce sodium and water retention ment. The reduction of sympathetic effect during a year of treatment with due to their effects on the Na+/H+ overdrive by rilmenidine is achieved rilmenidine 1 to 2 mg daily [21]. antiport rilmenidine was weight- without compromising postural or neutral in a number of controlled exercise responses.

12 J. HYPERTON. Sonderheft 4/2002 ITERIUM: CLINICAL BENEFITS FROM AN INNOVATIVE ANTIHYPERTENSIVE TREATMENT

treatment. Measured lipid parameters Additional data confirm the stability PRESERVATION OF METABOLIC (TC and TG) were unchanged during of glucose and lipid parameters in a year of rilmenidine treatment of type 2 diabetics over 6 months’ treat- PARAMETERS mild-moderate hypertensives [20] ment in a comparative study versus and in the study population, neither captopril treatment [16]. Metabolic fasting glucose, lipids, electrolytes, tolerance in the longer term was In uncomplicated hypertensive nor uric acid were significantly seen in the diabetic population in patients altered over 1 year of treatment in the Luccioni study, where a small but more than 18,000 hypertensives non-significant tendency for fasting In a comparison with atenolol over [21]. glucose to decrease was observed 12 weeks’ treatment, rilmenidine after 1 year of rilmenidine therapy significantly reduced low-density In elderly patients (7.2 to 6.8 mmol/L) [21]. lipoprotein (LDL) and preserved high-density lipoprotein (HDL). This Lipid profiles were unchanged in a In dyslipidemic patients lipid neutrality contrasted with the study in elderly patients over 6 classic pattern of lipid abnormalities weeks of treatment [19], a finding In mild-to-moderate placebo-resistant produced by beta-blocker therapy, in confirmed in a second study over 8 hypertensives with type 2a or 2b the atenolol group there was a signi- weeks [11]. In this second study the hyperlipidemia, who were not taking ficant reduction of HDL and a ten- fact rilmenidine did not alter electro- lipid-lowering agents, rilmenidine dency to increase triglycerides [12]. lyte and uric levels contrasted with (1 to 2 mg daily) was compared with the significant reduction in potassium captopril (50 to 100 mg daily) over In another controlled study, patients and chloride, and increase in uric 1 year of treatment. Total cholesterol treated with hydrochlorothiazide acid produced by the comparator, (TC), HDL, LDL, apoprotein A1, and show significant elevations in total hydrochlorothiazide. apoprotein B remained stable in the cholesterol and uric acid, and a two groups, with no significant inter- reduction in potassium level. Rilmeni- The elderly subpopulation analysis of group differences observed [15]. In dine’s preservation of lipid profile is the Luccioni study confirmed rilmeni- patients, with high triglycerides as part confirmed in this study, as well as its dine’s neutrality as regards electro- of the metabolic syndrome, rilmeni- respect for electrolyte and lipid lytes, lipids, glucose, and uric acid dine’s neutrality with respect to profiles. Rilmenidine treatment in [21]. These tolerance data support lipids was further demonstrated TC, fact produced a small statistically the role of rilmenidine as a first-line HDL, and TG were stable throughout significant reduction in total chole- antihypertensive choice in this fragi- the 4 months of treatment [14]. The sterol (TC). Rilmenidine’s neutrality le and frequently polymedicated validity of these observations in regarding these parameters was there- population. chronic administration is confirmed fore highlighted against the adverse by analysis of lipid parameters in the effects of a reference diuretic [10]. In diabetic patients dyslipidemic subpopulation of a Rilmenidine treatment was asso- large pharmacoepidemiological ciated with significant reductions in Rilmenidine’s efficacy and accepta- study, where no changes in TG or TC TC and LDL levels in mild-to-mode- bility were studied over 4 months in arose over 1 year of treatment [21]. rate hypertensives over a 12 weeks’ 29 hypertensive insulin-dependent treatment in another study. There diabetes. Neither random blood glu- Hence, rilmenidine does not alter was a parallel but non-significant cose values, urine glucose excretion, lipid, glucose or electrolyte profiles tendence for fasting plasma glucose insulin requirements, nor glycosylated in long-term treatment, in any popu- to improve (5.63 to 5.39 mmol/L) in hemoglobin were significantly chan- lation of hypertensive patients, inclu- this population. The glucose trend ged during treatment [24]. ding the elderly, diabetics, and with was significantly different (p < 0.05) established dyslipidemia. from that observed with a-methyl- Results in non-insulin-dependent dopa – a comparator agent (5.38 to diabetics were similar, 3 months’ 5.60 mmol/L) [18]. treatment with rilmenidine (1 to 2 mg daily) changed neither require- In long-term treatment ments for hypoglycemic medication, nor any parameters of glucose or Open studies provide further inci- lipid metabolism in hypertensive dence of the metabolic neutrality of type 2 diabetic patients [25]. rilmenidine, and confirm the persi- stence of this benefit in long-term

J. HYPERTON. Sonderheft 4/2002 13 ITERIUM: CLINICAL BENEFITS FROM AN INNOVATIVE ANTIHYPERTENSIVE TREATMENT

Reduction of microalbuminuria ADDITIONAL BENEFITS IN AT CONCLUSION Rilmenidine has recently been com- RISK HYPERTENSIVES pared with captopril in type 2 dia- betics with placebo resistant mild-to- Rilmenidine, the first antihyperten- moderate hypertension and micro- sive with high selectivity for brainstem

Reduction of left ventricular albuminuria (30 < microalbuminuria and renal I1-imidazoline receptors, hypertrophy < 300 mg/24 h). Median microalbu- has amply shown its suitability for minuria level reduction over 6 months first-line use in the treatment of mild- One year of treatment with rilmeni- on rilmenidine (160 to 56 mg/24 h) to-moderate essential hypertension. dine (1 to 2 mg daily) reversed left was similar to that observed on capto- Experience in both controlled trials ventricular hypertrophy (LVH) (from pril (144 to 54 mg/24 h). There was and in conditions of daily practice 152 ± 5 to 131 ± 4 g/m2, p < 0.05). no significant difference between the confirm the very good efficacy, accep- This significant 14 % reduction in two treatment groups. Rilmenidine’s tability, and tolerability of this agent. left ventricular mass index (LVMI) use first-line in the hypertensive dia- Clinical development is ongoing, as was accompanied by decreases in betic is hence further supported by a evidenced by recent studies in speci- intraventricular septum and posterior potentially nephroprotective treat- fic at-risk populations. wall thicknesses, and without changes ment (Fig. 5) [16]. in endsystolic or end-systolic internal New results showing improvement in diameters [16]. These findings were Improvement in insulin resistance pressure-independent cardiovascular reproduced in a double-blind placebo risk factors during treatment with controlled trial against nifedipine, The effects of rilmenidine were studied rilmenidine reinforce both the impor- where rilmenidine reduced LVMI by recently in patients with metabolic tant role of the sympathetic overdrive 12.5 % over 1 year. This reduction syndrome (syndrome X). Fifty-two in pathogenesis of the syndrome of was not significantly different from patients with obesity, hypertension, hypertension, and draw attention to that produced by slow-release nife- impaired glucose tolerance, and the therapeutic value of this original dipine (40 mg per day) [13]. hypertriglyceridemia (body mass molecule. index (BMI) > 29 kg/m2, 95 < DBP < These results have been reinforced 114 mmHg, TG > 2 mmol/L 6.1 < by a-year multicenter study involving fasting plasma glucose < 7.0 mmol/L References: 219 mild-to-moderate hypertensive or 7.8 < plasma glucose at 2 hours 1. Bricca G, Zhang J, Greney H, Donten- patients with left ventricular hyper- on an oral glucose tolerance test will M, Stutzmann J, Belcourt A, Bousquet trophy and/or left ventricular diabetic (OGTT) < 11 mmol/L) were included. P. Human brain imidazoline receptors: further characterization with (3H)cloni- dysfunction treated with rilmenidine They were treated with rilmenidine dine. Eur J Pharmacol Mol Pharmacol 1 to 2 mg/ day. After a 1-year treat- (1 to 2 mg daily) for 6 months. 1994; 266: 25–33. ment, rilmenidine in monotherapy 2. Zannad F, Aliot E, Florentin J, Saulnier significantly decreased the left Rilmenidine significantly improved JP, Gilgenkrantz JM. Hemodynamic and ventricular mass index (LVMI) by glucose metabolism compared with electrophysiologic effects of rilmenidine for 16.4 %. This decrease was related to the comparator amlodipine, as judged systemic hypertension. Am J Cardiol 1988; the significant cumulative decrease on the oral glucose tolerance test by 61: 67D–71D. of the posterior wall thickness (PWT) significant reduction in plasma glu- 3. Senechau P, Bousquet P, Dontenwill M. Imidazoline specific blinding sites in the of 11.8 % and the intervention cose at 2 hours and in the area under human kidney. Arch Pharmacol 1998; 358: septum thickness (IVST) of 12.5 %. the curve. These findings suggest a R747. More over these results have been specific effect of rilmenidine on insulin 4. Kline RL, Cechetto DF. Renal effects of accompagnied by an improvement resistance, most likely mediated by rilmenidine in anesthetized rats: importa- of the ventricular diastolic function reduction in sympathetic overdrive nce of renal nerves. J Pharmacol Exp Ther in both E/A ratio of peak velocities (Fig. 6) [14]. 1993; 266: 1556–62. (from 0.78 ± 0.1 to 0.92 ± 0.2, P < 5. Kline RL, van der Mark J, Cechetto DF. 0.001) and DT value (deceleration Thus in addition to the well-demonstra- Natriuretic effect of rilmenidine in anesthe- time of the E-wave, from 232 ± 23.1 ted antihypertensive efficacy, clinical tized rats. Am J Cardiol 1994; 74: 20A– to 217 ± 27.1 ms, P < 0.01) echo and metabolic tolerability of rilmeni- 24A. parameters (Fig. 4) [27]. dine, use in at-risk hypertensive 6. Bidet M, Poujeol P, Parini A. Effect of imidazoline on Na+ transport and intra- patients is supported by specific bene- cellular pH in renal proximal tubule cells. fits in those with ventricular hyper- Bioch Bioph Acta 1990; 1024: 173–8. trophy, diabetic microalbuminuria, 7. Smyth DD, Penner SB. Renal I1 imidazo- and impaired glucose tolerance. line receptor-selective compounds mediate

14 J. HYPERTON. Sonderheft 4/2002 ITERIUM: CLINICAL BENEFITS FROM AN INNOVATIVE ANTIHYPERTENSIVE TREATMENT

Figure 5 Figure 6

natriuresis in the rat. J Cardiovasc Pharma- patinets with metabolic syndrome X. A 23. Panfilov V, Morris A, Donnelly R, Reid col 1995; 26 (Suppl 2): S63–S67. double-blind parallel study versus JL. Comparative effects of rilmendine and 8. Penner SB, Smyth DD. Renal denerva- anlodipite. J Hypertens 2000; 18: 1519–22. atenolol on tests of autonomic function tion altered the hemodynamic and renal 15. Scemama M, Fervier B, Beucler I, and mental and dynamic exercise in effects following intracerebrovascular Dairou F, et le groupe des médecins Euraxi patients with essential hypertensive. J Cardiovasc Pharmacol 1995; 26 (Suppl 2): administration of the I1 imidazoline recep- SA. Lipid profile and antihypertensive effi- tor agonist, rilmenidine, in pentobarbital cacy in dyslipidemic hypertensive patients: S44–S47. anaesthetized rats. Neurochem Int 1997; comparison of rilmenidine with captopril. J 24. Mpoy M, Vandeleene B, Ketelslegers 30: 55–62. Cardiovasc Pharmacol 1995; 26 (Suppl 2): JM, Lambert AE. Treatment of systemic 9. Ostennann G, Brisgand B Schmitt J, S34–S39. hypertension in insulin-treated diabetes Fillastre JP. Efficacy and acceptability of 16. Dupuy O, Beauduceau B, Mayandon mellitus with rilmenidine. Am J Cardiol rilmenidine for mild-to-moderate systemic H. Rilmenidine in the hypertensive type-2 1988; 61: 91D–94D. hypertension. Am J Cardiol 1988; 61: 76D– diabetic: a controlled pilot study versus 25. Lubetzki J. Etude chez l’hypertendu 80D. captopril. J Cardiovasc Risk 2000; 7: 57– diabetique non insulino-dépendant de 10. Fiorentini C, Guillet C, Guazzi M. 61. I’activité antihypertensive et de l’accep- Etude multicentrique en double aveugle 17. Fillastre JP, Letac B, Galinier F, Le tabilité de la rilménidine (S3341). Essai comparant la rilmenidine 1 mg rt l’hydro- Bihan G, Schwartz J. A multicenter double- réalisé chez 16 patients traités pendant chlorothiazide 25 mg chez 244 patients. blind comparative study of rilmenidine and trois mois aux posologies journalières de 1 Arch Mal Coeur Vaiss 1989; 82 (Suppl): clonidine in 333 hypertensive patients. Am et 2 mg. Expert study 1996. 39–46. J Cardiol 1988; 61: 81D–85D. 26. Trimarco B, Rosiello G, Sarno D, 11. Pelemans W, Corcoran C, van Dessel, 18. United Kingdom Working Party on Argenziano L, Rubattu S, de Luca N, Volpe Opsomer M. Efficacy and safety of rilmeni- Rilmenidine. Rilmenidine in mild-to-mode- M. Rilmenidine in patients with left ventri- dine in elderly patients: comparison with rate essential hypertension. Curr Ther Res cular hypertrophy due to essential hyper- hydrochlorothiazide. Am J Cardiol 1994; 1990; 47: 194–211. tension: beyond the reduction of left ventri- 74: 51A–57A. cular mass. J Cardiovasc Pharmacol 1995; 19. Galley P, Manciet G, Hessel JL, Michel 26 (Suppl 2): S29–S33. 12. Dallocchio M, Gosse P, Fillastre JP, et JP. Antihypertensive efficacy and accepta- al. Rilmenidine, a new antihypertensive bility of rilmenidine in elderly hypertensive 27. Lengyel M, Borbas S, Zorandi A. Re- agent, in the first-line treatment of essential patients. J Am Cardiol 1988; 61: 86D–90D gression of left ventricular hypertrophy in mild-to-moderate hypertension in one year hypertension. A multicentre double-blind 20. Beau B Mahieux F, Paraire M, Laurin S, study versus atenolol. Arc Mal Coeur Vaiss of treatment with rilmenidine. Eur Heart J Brisgand B, Vitou P. Efficacy and safety of 2000; 21 (suppl): 101. 1991; 84 (special issue): 42. rilmenidine for arterial hypertension. Am J 13. Sadowski Z, Szwed H, Kuch-Wocial A, Cardiol 1988; 61: 95D–102D. et al. Regression of left ventricular hyper- 21. Luccioni R. Evaluation pharmaco-épi- Corresponding address: trophy in hypertensive patients after 1 year démiologique de la chez 18335 hyper- Ass. Prof. of treatment with rilmenidine: a double- tendus. Presse Med 1995; 34: 1857–64. blind, randomized, controlled (versus Dr. Olivier Kourilsky (CMHP) nifedipine) study. J Hypertens 1998; 16 22. Velasco M, Soltero I, Sukerman M, et Head of Nephrology Department, (Suppl 3): S55–S62. al. Double-blind, randomized study of the Centre Hospitalier Sud Francilien, efficacy, tolerance and rebound effects of 14. De Luca N, Izzo H, Fontana D, the rilmenidine: Hôpital Louise Michel Trimarco B. Haemodynamic and metabolic comparative evaluation with clonidine. Cir F-91014 Evry effects of rilmenidine in hypertensive Ther Res 1993; 54: 202–7. E-mail: [email protected]

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