Nephrology Dialysis Transplantation

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1 Nephrol Dial Transplant (1998) 13: Original Article Nephrology Dialysis Transplantation Renal and haemodynamic effects of amlodipine and nifedipine in hypertensive renal transplant recipients Gopalakrishnan Venkat-Raman1, John Feehally2, Henry L. Elliott3, Peter Griffin4, Richard J. Moore5, Joel O. B. Olubodun6, and Robert Wilkinson6 1St Mary s Hospital, Portsmouth, 2Leicester General Hospital, 3Western Infirmary, Glasgow, 4Cardiff Royal Infirmary, 5University Hospital of Wales, Cardiff, and 6Freeman Hospital, Newcastle upon Tyne, UK Abstract Introduction Background. Immunosuppressive treatment with cyclosporin A (CsA) improves the survival of renal The use of cyclosporin A (CsA) as an immunosuppresallografts, but is associated with renal vasoconstriction sive agent has increased the success rate of renal and hypertension. Previous reports suggest that the transplantation [1]. Paradoxically, CsA induces vasocalcium-channel blockers nifedipine and amlodipine constriction, especially in the renal vasculature [2,3]. may improve graft function in CsA-treated patients. A single oral dose of CsA (3.5 mg/kg) administered to We have compared the effects of amlodipine (5 10 mg renal-transplant patients has been shown to reduce the once daily) and nifedipine retard (10 40 mg twice glomerular filtration rate (GFR) by about 50% within daily) on renal function and blood pressure in renal 6 h [2]. During long-term CsA treatment, the vast transplant recipients treated with CsA. majority of patients become hypertensive, with as many Methods. This was a multicentre, two-way, crossover as 15% of patients at risk of permanent renal damage study in 27 evaluable hypertensive patients with renal [4]. insufficiency following renal transplantation, who were Vasodilatation therapies may protect renal allografts maintained on a stable dose of CsA. Patients received from CsA-mediated nephrotoxicity, and calciumeither amlodipine (5 10 mg once daily) or nifedipine channel blockers (CCB) in particular may exert cytoretard (10 40 mg twice daily) for 8 weeks, and were then crossed over to the other treatment for a further protective effects in the kidney [5]. Amlodipine, a long- 8 weeks. acting CCB suitable for once-daily administration [6], Results. Trends were seen during amlodipine treatment has been shown to improve renal function and control towards larger improvements, in serum creatinine ( by blood pressure (BP) in hypertensive renal transplant 8% of baseline on amlodipine vs 4% on nifedipine), patients to a greater extent than angiotensin-converting lithium clearance ( 13% vs 2%), and glomerular filtrabeen shown to reduce the nephrotoxicity of cyclospo- enzyme (ACE) inhibitors [7,8]. Nifedipine has also tion rate 11% vs 7%). Effective renal plasma flow was increased by 11% of baseline on nifedipine vs 9% on rin [9]. amlodipine. There were no significant differences Although both amlodipine and nifedipine belong to between treatments. Amlodipine and nifedipine the dihydropyridine class of CCB, previous reports in lowered systolic blood pressure to a similar extent hypertensive patients with renal disease suggest that (21 mmhg vs 15 mmhg respectively, P=0.25), but the renal effects of amlodipine, as indicated by reducamlodipine was more effective than nifedipine in tions in albuminuria, are more marked and consistent lowering diastolic blood pressure (13 mmhg vs than those of nifedipine [10,11]. Furthermore, some 8 mmhg, P=0.006). Both treatments were well CCBs, especially verapamil, diltiazem, and nicardipine tolerated. (also a dihydropyridine CCB), inhibit the metabolism Conclusion. Once-daily amlodipine is at least as effect- of CsA at the level of P-450 and thereby increase blood ive as twice-daily nifedipine retard in controlling blood CsA concentrations [12 16]. The potential toxicity pressure and does not adversely affect graft function arising from elevated blood CsA could offset the in hypertensive renal allograft recipients. beneficial effects of calcium-channel blockade. Thus, the renal effects of individual CCB may differ, Key words: amlodipine; cyclosporin A; nifedipine; posteither between classes of CCB, or between individual transplant hypertension; renal transplantation dihydropyridine CCB. As these differences may be clinically relevant, it is important to compare such Correspondence and offprint requests to: Dr G. Venkat-Raman, St drugs directly in clinical trials in relevant patient Mary s Hospital, Portsmouth, Hants PO3 6AD, UK. populations. Amlodipine and nifedipine are 1998 European Renal Association European Dialysis and Transplant Association

2 Amlodipine vs nifedipine in hypertension following renal transplantation 2613 supine DBP exceeded 90 mmhg, nifedipine dosages were increased to 40 mg twice daily, and amlodipine dosages were increased to 10 mg once daily. These dose levels were main- tained for a further 4 weeks, until patients crossed over to the other treatment. well-established dihydropyridine CCBs which have not been compared directly in patients with impaired renal function. We have compared the renal and haemodynamic effects of these drugs in a single-blind, cross-over study in hypertensive renal transplant recipients treated with CsA. Assessments Subjects and methods Blood pressure was measured as the average of two duplicate readings made using an automated sphygmomanometer. Measurements were made by the same person, in the same Study design arm, and at about the same time of day ( a.m.) during each visit. Readings taken at baseline and at the end of each This was a multicentre, observer-blind, two-way, crossover treatment period were used in the efficacy analysis. study to compare the renal and haemodynamic effects of Serum creatinine concentration (as well as urea and electroamlodipine and a sustained-release, twice-daily formulation lytes) was measured in venous blood samples at each visit of nifedipine (Adalat RetardA, Bayer) in hypertensive, postduring the 12-week run-in and at the end of each treatment renal transplant patients who were maintained on a stable period. A venous blood sample was also used to measure dose of CsA. Following a 14-week run-in period, in which lithium clearance, glomerular filtration rate (GFR; standard prior antihypertensive treatment was withdrawn for the last 51Cr EDTA method) and effective renal plasma flow ( ERPF; 2 weeks, patients were allocated to two treatment groups by plasma clearance of 131I-labelled hippuran) at the end of using minimization (a standard statistical method for balan- the run-in period and at the end of each treatment period. cing important demographic variables between treatment CsA concentrations were measured using a standard radiogroups in comparative clinical trials [17]). The first active immunoassay in blood samples taken immediately before treatment period involved administration of either amlodip- oral administration of CsA. ine or nifedipine retard for 8 weeks; patients were then Adverse events noted during treatment were recorded and crossed over on to the alternative treatment for a further 8 designated as drug related, possibly drug related, or not weeks with no intervening washout period. Blinding of drug related. The onset date, duration and severity (mild, observers was assured by scheduling all tablet returns and moderate, or severe), and outcome were noted. The physician issuing of medication to be done by individuals other than made an overall assessment of adverse effects at the end of the investigator. each treatment period. A range of standard haematological and biochemical measurements were carried out at baseline Patients and following each treatment period. Vital signs (blood pressure, heart rate and body weight) were measured at Patients included in the study were outpatients of both each visit. genders, years of age, who had undergone renal allograft transplantation at least 3 months previously. Statistics Patients were hypertensive, defined as supine diastolic blood pressure (DBP) between 95 and 120 mmhg inclusive. An estimated sample size of 51 patients was required to Although renal function was impaired (serum creatinine was detect a difference in creatinine concentration of 20 mmol/l between 2 and 7 mmol/l/kg body-weight), this had been between treatments, with a power of 80% and a significance stable for at least 12 weeks prior to randomization. Patients level of P=0.05 (two-tailed), assuming a within-patient were on a stable dose of CsA for at least 2 months prior to standard deviation of treatment differences of 50 mmol/l. enrolment into the study. All patients gave informed consent. Patients who received at least one dose were included in the Criteria for exclusion from the study included patients safety analysis. Data from all patients with measurements in who had received any drug within the previous 3 months both active treatment periods were included in the efficacy that could interfere with study medication, clinically signific- analysis. The patient population evaluable for efficacy was ant concomitant disease, significant haematological or bio- defined as those patients with measurements following at chemical findings (apart from those associated with renal least 5 weeks of study treatments, who had no concomitant insufficiency), acute rejection of renal allograft within the medication or intercurrent illnesses that violated the study previous 3 months. protocol, and who showed at least 70% compliance with study treatment. Treatments No period effects were found in the data, therefore data from both treatment sequences were analysed as a whole. Throughout the 12-week run-in period and during the treata parametric analysis of variance appropriate to a two- Differences in means between treatments were explored using ment phase of the study, patients were given encapsulated CsA (SandimmunA) to ensure standardization of dosing. period, two-treatment crossover trial [18]. Patients were maintained on a stable immunosuppressive regimen throughout the treatment period. During the last 2 weeks of the run-in period, existing antihypertensive therapy Results was substituted by placebo. At baseline, patients received either amlodipine at a dose of 5 mg once daily, or nifedipine Patients retard, at a dose of 10 mg, twice daily. After 2 weeks of treatment, patients receiving nifedipine had their dosages Seven UK centres recruited a total of 64 patients, all increased to 20 mg twice daily if their supine DBP exceeded of whom completed the run-in phase and were alloc- 90 mmhg. After 4 weeks of treatment, in patients whose ated to active treatment. One patient withdrew because

3 2614 G. Venkat-Raman et al. of elevated serum creatinine before receiving study statistically or clinically significant differences between medication, and was excluded from all safety and treatments were seen. efficacy analyses. A further 11 patients withdrew Trough blood CsA concentration was because of adverse events or intercurrent illnesses after 312±275 ng/ml at baseline, and trough CsA values receiving only one study treatment, or withdrew early did not differ significantly after 8 weeks of amlodipine from both treatment periods (<5 weeks treatment in or nifedipine treatment (321±324 ng/ml vs each). A further cohort of 25 patients were excluded 288±267 ng/ml respectively; P=0.23). because of protocol violations. The population evaluable Both drugs induced marked falls in supine and for efficacy therefore comprised 27 patients. standing systolic blood pressure (SBP) and DBP, com- The treatment groups were well matched for demographic pared to baseline ( Table 3). Both treatments reduced variables ( Table 1). The mean time since trans- SBP to a similar extent, but amlodipine was significpared plant was virtually identical in each group, and only antly more effective than nifedipine in reducing supine minor differences between groups were apparent for DBP (P=0.006), with a strong trend towards a greater other demographic variables. No patients had diabetes reduction in standing DBP in favour of amlodipine mellitus. (P=0.057). Although there was a statistically significant difference between the treatments in heart rate Renal and haemodynamic efficacy (P=0.036), neither treatment exerted clinically significant effects on this parameter. The effects of amlodipine and nifedipine on parameters In the investigators overall evaluation of therapy, relating to renal function are shown in Table 2. efficacy was rated as excellent or good in 89% Compared with baseline, serum creatinine was lower (amlodipine) vs 93% (nifedipine), and as poor or no after amlodipine treatment, compared with nifedipine, efficacy in 11% (amlodipine) vs 7% (nifedipine). but the differences between treatments did not achieve statistical significance. Lithium clearance, glomerular filtration rate and effective renal plasma flow all tended Tolerability to improve during treatment with either agent, but no Both treatments were well tolerated, and 87 and 93% of patients receiving amlodipine and nifedipine respectively Table 1. Demographics: patients evaluable for safety either did not report an adverse event, or reported that the event did not significantly interfere with their Treatment group usual daily routines. There were no clear differences between the profiles of adverse events between treatments Amlodipine Nifedipine and no major shifts in laboratory or haematolog- 3 3 ical variables occurred. nifedipine amlodipine Number of patients Discussion Males5females Mean age (years) Age range (years) Once-daily amlodipine, and twice daily nifedipine Weight (kg) retard, induced marked falls in blood pressure, com- Mean daily CsA dose (mg) pared to baseline. Overall, amlodipine tended to reduce Median daily CsA dose (mg) blood pressure to a greater extent than nifedipine, with Duration of renal insufficiency (years) effects on supine DBP reaching statistical significance Mean time since transplant compared to nifedipine. However, further compar- (months) isons, including ambulatory blood pressure measure- Serum creatinine (mmol/l ) ments, would be required to establish a difference Supine diastolic blood pressure (mmhg) between the treatments definitively. Both treatments were well tolerated, and did not adversely affect any parameter of renal function. The pharmacokinetic profile of amlodipine contrib- utes to its antihypertensive efficacy. The long half-life Figures represent mean values where appropriate. Column headings refer to the order of treatments in the cross-over design. CsA, cyclosporin A. Table 2. Effects of amlodipine and nifedipine on renal function Baseline Amlodipine D (%) Nifedipine D (%) Serum creatinine (mmol/l ) 208±61 191± ±27 4 Lithium clearance (ml/min) 7.5± ± ±5.5 2 Glomerular filtration rate (ml/min) 37.4± ± ± Effective renal plasma flow (ml/min) 182±73 198± ±85 11 There were no significant differences between treatments for any parameter. D (%) refers to percentage change from baseline.

4 Amlodipine vs nifedipine in hypertension following renal transplantation 2615 Table 3. Haemodynamic effects of amlodipine and nifedipine Supine Standing DBP SBP HR DBP SBP HR Baseline 101±6 164±21 72±11 100±8 157±19 79±12 Amlodipine 88±9 143±11 72±7 88±9 139±12 78±7 Nifedipine 93±8 149±17 68±8 92±11 142±14 76±8 P value SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate. Patient populations were as defined in Subjects and methods. P values refer to differences between treatments. of amlodipine ( h) [6] is likely to provide more urinary albumin excretion are inconsistent, and most stable blood concentrations over time, and hence better studies report either no effect or an increase in albumin- 24-h blood pressure control, than sustained-release uria [11,31 34]. formulations of shorter-acting agents [19,20]. Patient There was no difference between treatments in compliance with antihypertensive medication also trough blood CsA concentration. These findings are improves as a function of the dosing interval, and has consistent with previous reports [9,24,35,36 ], which been shown to be higher for once-daily amlodipine showed that neither amlodipine nor nifedipine altered than for a twice-daily slow-release preparation of nifedipine CsA pharmacokinetics. Two further studies have [21]. The issues of compliance and continuously shown statistically, but not clinically significant, effective blood pressure control are thought to be increases in trough blood CsA concentrations after especially relevant to patients at increased risk of treatment with amlodipine [7,8], and a single report nephropathy [22]. has described such an effect with nifedipine [37]. The Nifedipine has also been shown to reduce BP in bioavailability of the CsA preparation used in the hypertensive renal transplant patients, without significant present study varies between 1 and 89% [4], so that effects on graft function, during short- or long- the ability of studies involving oral administration to term administration [9,23,24]. Previous studies in demonstrate pharmacokinetic interactions between hypertensive renal transplant patients have demon- CsA and other agents is limited. Overall, evidence strated clinically important reductions in BP after 4 8 from this and other clinical studies does not support a weeks of treatment with amlodipine [7,8,25]. The significant interaction between amlodipine and CsA. antihypertensive effects of amlodipine in renal transplant In conclusion, once-daily amlodipine is as effective patients appear superior to those of the ACE as a sustained-release formulation of nifedipine, admin- inhibitor lisinopril [8]. istered twice daily, in controlling BP in hypertensive The beneficial renal effects of amlodipine, as revealed CsA-treated renal-transplant recipients. Both agents by effects on serum creatinine in previous studies in were well tolerated, and neither agent adversely affected hypertensive renal transplant patients, were also super- renal function, or influenced trough blood CsA ior to ACE inhibitors [7,8]. The improvements in renal concentrations. function observed in CsA-treated transplant recipients during amlodipine treatment do not result solely from reductions in BP, as amlodipine significantly reduced serum creatinine, compared to placebo, in normotens- References ive renal transplant recipients treated for 8 weeks [26]. 1. Noble S, Markham A. CsA. A review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion In a further study, amlodipine significantly increased based formulation (NeoralA). Drugs 1995; 50: GFR in normotensive orthotopic liver transplant 2. Ruggenenti P, Perico N, Mosconi L et al. Calcium channel recipients with CsA-induced renal impairment, after blockers protect transplant patients from CsA induced daily only 3 weeks of treatment [27]. Beneficial effects on renal hypoperfusion. Kidney Int 1993; 43: renal function in the absence of significant reductions 3. Textor SC, Burnett JC, Carlos Romero J et al. 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