NEFROLOGÍA. Volumen 25. Número 5. 2005 Doxazosin associated to the combination renin-angiotensin axis blocker and calcium-channel blocker in patients with chronic renal failure N. R. Robles1, F. Gómez Campderá2, J. Ocón3, M. Manjón4, L. Pastor5, J. Herrera6, J. Villatoro7, J. Calls8, J. Torrijos8, I. Rodríguez Villareal9, M. A. Rodríguez Martínez10, M. L. Méndez11, A. Morey12, I. Martínez Fernández13, J. Marco14, A. Liébana15, B. Rincón16 and F. Tornero16 Hospital Infanta Cristina. Badajoz. 2Hospital Gregorio Marañón. Madrid. 3Fundación Puigvert. Barcelona. 4Hospital Clínico. Granada. Hospital Miguel Servet. Zaragoza. 6Hospital General de Asturias. Oviedo. 7Hospital General de Castellón. Castellón de la Plana. 8Hospital Fundación de Manacor. Menorca. 9Hospital Severo Ochoa. Leganés. Madrid. 10Hospital La Inmaculada. Huercal-Overa. Almería. 11Hospital Nuestra Señora de la Candelaria. Tenerife. 12Clínica Miramar. Barcelona. 13Hospital de Galdácano. Bilbao. 14Hospital Son Dureta. Mallorca. 15 Hospital Ciudad de Jaén. Jaén. 16Hospital Virgen de la Luz. Cuenca. 5 1 SUMMARY Objective. To evaluate the safety and effectiveness of the alfa-blocker doxazosin GITS in CRF patients. Design and methods. The study recruited 203 CRF patients (creatinine > 1,4 mg/dl for males, creatinine > 1,2 mg/dl for females, or creatinine clearance < 80 ml/min). All patients were receiving ACE inhibitores (63.4%) or angiotensin II antagonist (36.6%) therapy but they had higher blood pressure than recommended for CRF (130/85 mmHg). Patients were clinically evaluated 1, 3 and 6 moths after starting treatment with lercanidipine (10 mg once daily). Patients with high blood pressure in spite of combined therapy with two drugs added doxazosin GITS 4-8 mg once daily to treatment. Result: 57 patients rendered evaluable for the study (age 64.8 ± 12.7 years, 47.4% males and 52.6 females). BP significantly decrease from 164 ± 17/92 ± 9 mmHg to 135 ± 13/78 ± 8 mmHg. 67.6% patients showed a significant BP reduction and 32.4% gets optimal BP control ( < 130/85 mmHg). Two patients (3.6%) showed untoward effects. No biochemical changes were detected. Conclusions: Doxazosin showed a good antihypertensive effect in CRF patients when used as third drug in resistant severe hypertension. It has a good tolerability profile and showed a neutral profile on biochemical parameters. Key words: Doxazosin. Chronic renal failure. Hypertension. DOXAZOSINA ASOCIADA A LA COMBINACIÓN BLOQUEANTE DEL EJE-RENINA ANGIOTENSINA Y CALCIOANTAGONISTA EN PACIENTES CON INSUFICIENCIA RENAL CR´ONICA RESUMEN Objetivo. El estudio ZAFRA se diseñó para evaluar la seguridad de un nuevo bloqueante de los canales del calcio, lercanidipino, en la insuficiencia renal crónica, y Correspondence: Dr. Nicolás Roberto Robles Servicio de Nefrología. Hospital Infanta Cristina Carretera de Portugal s/n 06080 Badajoz E-mail: nroblesp@meditex.es 515 N. R. ROBLES y cols. su posible sobre la función renal en los pacientes tratados con fármacos que bloquean el eje renina-angiotensina. Los pacientes que no controlaron su PA con estos fármacos fueron tratados con doxazosina. Diseño y métodos. El estudio reclutó 203 pacientes con insuficiencia renal (creatinina > 1,4 mg/dl en varones o > 1,2 mg/dl en mujeres, o aclaramiento de creatinina < 80 ml/min). Todos los pacientes estaban siendo tratados con IECA o antagonistas de receptores y la medicación se mantuvo a lo largo del estudio, sin que pudieran recibir diuréticos a lo largo del seguimiento. Los pacientes eran evaluados clínica y analíticamente 1, 3 y 6 meses después de iniciar tratamiento con lercanidipino. Aquellos pacientes que en la segunda visita no estaban controlados añadieron doxazosina GITS (4 mg en dosis única) al tratamiento. Resultados: 57 pacientes que iniciaron el estudio fueron tratados con doxazosina (edad media 64,8 ± 12,7 años, 47,4 varones y 52,6 mujeres). La PA se redujo significativamente desde 164 ± 17/92 ± 9 hasta 135 ± 13/78 ± 8 mmHg (p < 0,001). Se produjeron reducciones significativas de la PA en el 67,6% de los enfermos y el 32,4% de los pacientes redujeron su PA hasta los límites recomendados ( <130 85 mmhg únicamente 2 3 6 pacientes han presentado reacciones adversas no se detectó aumento de la incidencia edema creatinina plasmática 1 9 0 mg dl había modificado al final del estudio 8 ni el aclaramiento 38 7 15 vs 5 14 también un descenso significativo urato plasmático p < 0,05). Conclusiones: La doxazosina ha presentado un excelente perfil de seguridad en los pacientes renales, destacando la ausencia de edemas a pesar de la insuficiencia renal de los pacientes. Palabras clave: Doxazosina. Insuficiencia renal crónica. Hipertensión arterial. INTRODUCTION It is well known that the cardiovascular system is severely affected by the presence of chronic renal failure.1 The Hypertension Detection and Follow-up Program (HDFP) study2 showed that initial plasma creatinine levels have a prognostic value for mortality from any origin at 5 and 8 years of patient followup. Hypertension is also an important determinant of renal disease progression, independently of the cause of the latter. The risk for developing end-stage chronic renal failure (comparing to patients with optimal arterial blood pressure) is increased three fold when DBP reaches 90 mmHg.3 Proteinuria presence in hypertensive patients is also a strong predictor of high morbidity and mortality from cardiovascular origin.4 More importantly, strict blood pressure control is the main mechanism to prevent progression to chronic renal failure, and thus, it is recommended in most of the therapeutic guidelines.5,6 Anti-hypertensive agents that block the renin-angiotensin axis, such as ACEIs and angiotensina receptor antagonists (ARA) seem to have a protector role, besides its hypotensive effect, and their use has been recommended for renal disease.5 By contrast, the renoprotective effect of calcium channel blockers is controversial, in spite of experimental data 516 that suggested this capability.6 In this sense, it has been suggested that calcium channel blockers may improve renal function in patients previously treated with ACEIs.7 The ZAFRA study was aimed at assessing the safety and efficacy of lercanidipine in patients with chronic renal failure, and secondarily the potential renoprotective effect of calcium channel blockers.8 A specific objective was to assess edema incidence, a complication less frequent with lercanidipine treatment, in a group of patients with a tendency to water-salt retention, as do patients with renal failure. Recently, the ALLHAT study has raised some concern with the use of doxazosin in hypertensive patients due to the increase of the incidence of cardiac failure in the diuretics-treated arm.9 This article comprises the results of the subgroup of patients from the ZAFRA study that were treated with doxazosin due to poorly control blood pressure in spite of combined treatment with lercanidipine and ACEI or ARA with no diuretic treatment.8 DESIGN AND METHODS Two hundred and three patients were recruited, meeting the criteria of being hypertensive, suffering DOXAZOSIN IN IRC from renal failure, and having BP > 130/85 mmHg in spite of treatment with ACEI or angiotensin receptor antagonist. Patients were not allowed to be treated with diuretics or other hypotensive drugs before the study beginning. The protocol was presented to and approved by the Clinical Trials Committee of the Fundación Puigvert of Barcelona. Chronic renal failure was defined by presence of plasma creatinine 1.4 in male and 1.2 in female patients, or creatinine clearance < 80 mL/min. All patients were on ACEI treatment (67.4%) or angiotensin receptor antagonists (32.6%), at appropriate doses (equal or similar to 20 mg/d of enalapril). All patients had arterial hypertension in spite of treatment with renin-angiotensin axis blockers, defined by recommendations of the WHO-HIS Clinical Guidelines for renal patients (SBP 130 and/or DBP 85 mmHg). Lercanidipine treatment was started at a 10-mg dose in a single daily intake. Patients were followed for 4 months according to a four-visits schedule (inclusion, 1, 3, and 6 months). When the blood pressure goal was not reached at the first month visit, treatment with alpha- or beta-blockers was added. Use of diuretics was not allowed throughout the study to avoid interference with edema assessment. In that case, patients were scheduled for a visit with faculty staff within 30 days (2 months). If blood pressure persisted elevated, patients could be excluded, according to the investigator's clinical judgment. BP and pulse rate were taken at each visit, and patients were asked about the presence of symptoms and adverse events, and about adherence to treatment. BP was measured with a mercury sphingomanometer, in a sitting position, approximately 24 hours after the last medication intake, with two measurements with a 3-minutes interval aside. Blood samples were also collected at each visit for biochemical determinations (including creatinine), and 24-hour urine (to measure creatinine clearance, proteinuria, and microalbuminuria). A blood count was also performed. Slow-releasing doxazosin treatment (4 mg in a single daily dose) was prescribed to 51 patients at the first month follow-up visit, according to treatment schedule. Six additional patients started doxazosin treatment at the third month visit; these patients have been included in the tolerability analysis, but have been excluded from the anti-hypertensive efficacy analysis. Doxazosin-treated patients were 27 men and 30 women, with a mean age of 64.8 ± 12.7 years. An independent company performed the statistical analysis of the data. Data have been presented as mean ± standard deviation. The differences between continuous variables were compared by means of Table I. Arterial blood pressure changes SBP Baseline 1 month 3 months 6 months 164.2 ± 17.3 151.3 ± 13.9* 137.7 ± 14.1* 134.7 ± 12.4* DBP 91.6 ± 9.1 86.0 ± 8.2* 79.9 ± 8.0* 78.4 ± 7.8* PR 76.4 ± 11.1 75.6 ± 9.7 75.5 ± 9.6 75.1 ± 7.2 *SBP and DBP expressed in mmHg, PR in heat bits per min. Doxazosin was introduced within the first month. Student's t test for related samples. The differences in frequency values were compared by means of the McNemar test because of paired values. RESULTS After one month of treatment, SBP and DBP significantly decreased with lercanidipine (from 151.3 ± 13.9 / 86.0 ± 8.2 to 144.9 ± 16.8 / 81.0 ± 7.6 mmHg; p < 0.001). The addition of doxazosin achieved a further decrease in BP levels at the following visits (see values in Table I). At the 6th month, mean BP decrease from baseline values was ­16.4 / -6.3 mmHg (relative reduction 10.0 / 8.1%). There were no significant differences in pulse rate (Table I). At the end of the follow-up period, the percentage of patient that had reached BP goal (optimal control, BP < 130/85 mmHg) was 32.4%, and 50.0% had favorably responded to administration of the drug without reaching the BP goal (fig. 1). 38.2% of the patients achieved a suboptimal control (BP 130/85 mmHg). Doxazosin treatment did not induce significant changes in hematological values. Progression of evaluated biochemical parameters is shown in Table II. There were no changes in cholesterol and triglycerides. There were no observed changes in plasma urea and creatinine levels, or in creatinine clearance. Uricemia significantly decreased at the third and sixth months (p < 0.05). There were no changes in proteinuria either. A total of 22 patients discontinued treatment because of poor adaptation to it (n = 1), poor BP control in spite of treatment (n = 18=, and treatment withdrawal (n = 3). Two patients (3.5%) notified adverse events during the treatment period (erectile dysfunction in one case, and urinary incontinency in another). No patient complained about edema or lower limb heaviness, and edema was not detected at the patients' clinical inspection performed at each visit. 517 N. R. ROBLES y cols. 50.00% 45.00% 40.00% 35.00% 30.00% % 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% < 130/85 < = 130/85 Responders Fig. 1.--Number of controlled patients and responders at the end of the follow-up period; p < 0.001 as compared to month 1 (McNemar's test). Responder is considered when SBP decreases > 10 mmHg or DBP > 5 mmHg. DISCUSSION Doxazosin, an alpha-1 receptor antagonist, seems to be an effective and safe agent in patients with renal failure when used in combination with drugs that block the renin-angiotensin axis and with calcium channel blockers. This is the first published study on the safety of this association and the largest studied sample on the clinical effects of doxazosin in renal failure. There are few studies on doxazosin safety in chronic renal failure. Generally, the adverse events are few and there is no need for dose reduction or treatment discontinuation, since pharmacokinetics is not modified. Plasma renal flow is not modified, but the effects on glomerular filtration are less known and may occur with mild decreases of the former.10-14 Our study results are in agreement with what had been published, confirming this in a large series of patients. Table II. Biochemistry values changes Baseline Creatinine Urea Urate Cholesterol Triglycerides Glucose Proteinuria Cr. Clearance 1.9 ± 0.6 70.0 ± 34.6 7.0 ± 1.9 209 ± 47 139 ± 47 111 ± 39 0.9 ± 0.7 38.7 ± 15.7 1 month 1.9 ± 0.5 70.5 ± 32.4 6.6 ± 1.5 207 ± 36 139 ± 54 114 ± 41 0.9 ± 0.8 40.9 ± 18.5 3 months 1.9 ± 0.6 79.5 ± 28.3 6.4 ± 1.7# 210 ± 32 141 ± 46 105 ± 22 0.8 ± 0.6 40.0 ± 15.3 6 months 2.0 ± 0.8 Units mg/dL 80.3 ± 30.3 mg/dL 6.7 ± 1.6# mg/dL 202 ± 36 138 ± 44 104 ± 36 0.8 ± 0.8 mg/dL mg/dL mg/dL g/24 h 38.5 ± 14.5 mL/min #p < 0.05 from baseline. Doxazosin was given within the firts month. Alpha-1 adrenergic antagonists seem to produce water-salt retention. In 1984, increase of plasma volume, interstitial volume, and extracellular volume was detected after treatment with prazosin, both in a short and long term.15 Other studies found weight increase as well as biochemical changes compatible with volume expansion due to prazosin.16,17 In the Veteran Administration Cooperative Study on Anti-hypertensive Agents a significant weight increase was observed within 8 weeks of follow-up in the group treated with prazosin, as compared to both baseline weight and weight changes in the other groups (that were inexistent or showed a decrease in body weight). However, mean weight gain from baseline was not significant within one year of follow-up. Patients treated with terazosin also showed a tendency to gain weight (approximately 1 kg), whereas those on placebo lost weight.19 Similarly, in two randomized trials that included a wash-out period of the active treatment with alpha-1 antagonists, it was shown that a mean loss of 1.3 kg occurred after discontinuation of the drug.20 Doxazosin has also been associated to volume expansion. One study demonstrated body fluid volume expansion of about 10% from baseline values.21 Some larger trials have shown that doxazosin treatment may induce some weight gain, but the Treatment of Mild Hypertension Study (TOMHS), the largest controlled trial performed with doxazosin, is a remarkable exception. This study did not find any body weight change. The five treatment groups received comprehensive dietary counseling for loosing weight and, likely as a result of this, weight reduc- 518 DOXAZOSIN IN IRC tion was homogeneous among the different study arms.22 The final report on the doxazosin arm of the ALLHAT study presented unexpected outcomes, due to the potential association between diuretics use and the risk for sudden death,23 and the favorable effect of alpha-1-adrenergic antagonists on plasma cholesterol and triglycerides levels.22 The ALLHAT study showed a significant increase in the incidence of heart failure (almost twice) in the doxazosintreated group in comparison with those treated with chlorthalidone. However, there were no differences in the primary end-point (outcomes in ischemic heart disease) or in the secondary end-point of global mortality. Since renal failure is a disease in which there is a tendency to overhydration and edema occurrence, the ALLHAT outcomes raised a number of questions about doxazosin safety in renal failure patients, not as much with regards to occurrence of heart failure as to the chance of water-salt retention occurrence, which most frequent clinical manifestation is edema formation. In this sense, follow-up studies published with doxazosin in renal failure patients have short, both in follow-up time and in number of included patients. Our data do not show any increase in the incidence of edema or fluid retention in renal failure patients. No heart failure episodes were detected either, although some adverse effects were noticed on the urinary tract. It has been suggested that heart failure occurrence in the doxazosin-treated group in the ALLHAT study was only the expression at the beginning of treatment of a latent condition that controlled with diuretics. It is important to know that 90% of the recruited patients to each group were switched from the hypotensive treatment they were already receiving.24 The design of the ZAFRA study excluded recruitment of patients on diuretic treatment in order to avoid masking the occurrence of edema in the patients; for the same reason, diuretic treatment was not allowed during the follow-up. This is an important difference with the doxazosin arm of ALLHAT study, where most of the patients were previously treated with diuretics. Our results, with a shorter follow-up period than ALLHAT, seem to indicate that in renal failure patients not previously treated with diuretics, doxazosin treatment, assessed from a clinical perspective, does not produce clinically detectable body water retention. 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