sábado, 4 de septiembre de 2010

Aliskiren mas losartan

Original Article

Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy

Hans-Henrik Parving, M.D., D.M.Sc., Frederik Persson, M.D., Julia B. Lewis, M.D., Edmund J. Lewis, M.D., and Norman K. Hollenberg, M.D., Ph.D. for the AVOID Study Investigators

N Engl J Med 2008; 358:2433-2446June 5, 2008

Abstract
Article
References
Letters

The pathogenesis of diabetic nephropathy is multifactorial, and the renin−angiotensin−aldosterone system plays an important role.1,2 Persistent proteinuria is the hallmark of diabetic nephropathy, a condition that is characterized by a progressive rise in blood pressure, a declining glomerular filtration rate, and a high risk of fatal or nonfatal cardiovascular events. The degree of proteinuria is closely associated with the rates of renal and cardiovascular events.3,4 Furthermore, a reduction in proteinuria is associated with a slowing of both the decline in the glomerular filtration rate5 and the progression to end-stage renal disease.6 In addition, decreasing proteinuria is associated with improved cardiovascular outcomes in patients with diabetic nephropathy7 and arterial hypertension.8 As a result, a reduction in proteinuria has been widely used as a surrogate end point for renoprotection.

During the past two decades, the outlook for patients with diabetes who have microalbuminuria or macroalbuminuria has improved, probably owing to early aggressive lowering of blood pressure and blocking of the renin−angiotensin−aldosterone system.3,4,9-12 However, there is still a large, unmet need to develop strategies for the prevention of diabetic nephropathy and its progression to end-stage renal disease. Diabetic nephropathy remains the leading cause of end-stage renal disease in the developed world.

The aim of this trial was to evaluate the potential renoprotective capacity of direct renin inhibition with aliskiren in patients with hypertension, type 2 diabetes, and proteinuria who were already receiving the maximal recommended renoprotective treatment with losartan (100 mg daily) and optimal treatment for hypertension. In addition, the safety of dual blockade of the renin−angiotensin−aldosterone system was monitored and recorded.

Methods

Patients

We enrolled patients with hypertension who were 18 to 85 years of age and who had type 2 diabetes and nephropathy (defined by an early-morning urinary albumin-to-creatinine ratio of >300 mg per gram, or >200 mg per gram in patients receiving therapy targeted at blockade of the renin−angiotensin−aldosterone system). The criteria for exclusion were known nondiabetic kidney disease, a urinary albumin-to-creatinine ratio of more than 3500 mg per gram, an estimated glomerular filtration rate of less than 30 ml per minute per 1.73 m2 of body-surface area,13 chronic urinary-tract infection, a serum potassium level greater than 5.1 mmol per liter at the time of randomization, severe hypertension, or major cardiovascular disease within the previous 6 months.

Study Design

In a randomized, double-blind, placebo-controlled study that was conducted in 15 countries and 150 centers worldwide, we evaluated the possible renoprotective effect of aliskiren in 599 patients with hypertension, type 2 diabetes, and nephropathy. We screened 1892 eligible patients at an enrollment visit (Figure 1Figure 1Numbers of Patients Who Were Screened for the Study, Who Underwent Randomization, and Who Completed the Study.). A total of 805 patients entered a 3-month open-label period during which all drugs that the patients had been taking that block the renin−angiotensin−aldosterone system were discontinued, except for beta-blockers, and treatment was initiated with the maximal recommended renoprotective dose of losartan (100 mg daily) plus additional antihypertensive therapy that was aimed at achieving an optimal target blood pressure (i.e., <130/80 mm Hg). During the 3-month open-label treatment period, 206 patients were excluded, leaving 599 patients who underwent randomization and were followed for a median of 6 months (Figure 1). Patients were randomly assigned to receive 150 mg of aliskiren once daily for 3 months, followed by 300 mg of aliskiren daily for another 3-month period, or matching placebo once daily for 6 months. The randomization list was generated by a validated system that automated the random assignment of treatment groups to randomization numbers. The study protocol was in accordance with the Declaration of Helsinki (2002) and was approved by local and central review boards. All patients provided written informed consent. The study was overseen by a steering committee that included nonvoting members from the sponsor, Novartis. The steering committee oversaw the design of the study, the conduct of the trial, and the management and analysis of all data. The sponsor was also involved in the design of the study and in the collection and analysis of the data. All authors had access to all study data and vouch for the accuracy and completeness of the data reported.

Procedures, Measurements, and Outcome

The patients were examined 13, 12, 8, 4, and 2 weeks before randomization; at the time of randomization; and 1, 4, 8, 11, 12, 16, and 24 weeks after randomization. To account for the delay in obtaining results of laboratory tests, the baseline urinary albumin-to-creatinine ratio, which was based on the median values in three early-morning urine collections, was calculated 2 weeks before randomization. Blood pressure and pulse, adverse events, concomitant medications, and adherence to medication regimens were assessed at each visit. Three early-morning spot urine specimens were collected on 3 sequential days 13 weeks and 2 weeks before randomization and 4, 8, 12, 16, and 24 weeks after randomization. Three overnight urine specimens were obtained on 3 sequential nights 2 weeks before randomization (baseline) and 12 and 24 weeks after randomization. All assessments of urine and blood were performed by the same company (CRL.Medinet) in a central laboratory in Europe or the United States. The urinary albumin concentration was determined by immunoturbidimetry,14 and the serum creatinine concentration was determined by means of the Jaffe reaction (with the use of a Roche kit).15 The Modification of Diet in Renal Disease (or MDRD) formula was used to estimate the glomerular filtration rate.13 Glycated hemoglobin was measured by means of high-performance liquid chromatography (Bio-Rad).16 All the other laboratory variables were also measured centrally with the use of conventional laboratory techniques.

Blood pressure, measured while the patient was seated, was assessed after at least 5 minutes of rest with the use of standard mercury sphygmomanometers and an appropriately sized cuff. Three measurements were obtained, 2 minutes apart at each time point, and the average of the three was used for the calculation of the 24-hour trough level (i.e., the level 24 hours after administration of the drug). The target blood pressure during the open-label and double-blind periods was less than 130/80 mm Hg for both groups. Consequently, further adjustments, as needed, in the dosing of blood-pressure–lowering medication were recommended after random assignment to bring the patient's blood pressure closer to the target. All classes of blood-pressure−lowering drugs were allowed, except for drugs that block the renin−angiotensin−aldosterone system. Patients continued to receive their usual care for diabetes and cardiovascular protection (Table 1Table 1Baseline Characteristics of the Randomized Population.). No restriction on dietary salt or protein was mandated. The primary efficacy measure was the percentage reduction in the early-morning urinary albumin-to-creatinine ratio from baseline to the end of the study (24 weeks) among patients who received aliskiren, as compared with patients who received placebo.

Statistical Analysis

Our target sample size for patients completing the study was approximately 396 patients (198 per treatment group). Assuming a dropout rate of 20%, we planned to randomly assign 496 patients. This sample size would have provided 90% power to detect, at a two-sided level of significance of 0.05, a treatment difference of 18% in the primary end point — the change in the urinary albumin-to-creatinine ratio from baseline to week 24 — between the group that received aliskiren and the group that received placebo (assuming a standard deviation of 55%). However, 599 patients were enrolled, mainly as a result of a long screening and run-in period, an increased rate of enrollment at the end of the recruitment phase, and a decreased rate of screening failure toward the end of the enrollment phase. With 599 patients enrolled, and with the same assumptions as stated above, the power was approximately 94%.

Changes in the log-transformed urinary albumin-to-creatinine ratio from baseline (2 weeks before randomization) to weeks 4, 12, and 16 and to week 24 (end point) were assessed for the intention-to-treat population with the use of an analysis of covariance (ANCOVA) model, with treatment and region as factors and baseline log-transformed albumin-to-creatinine ratio as the covariate. To adjust for differences in the change in systolic blood pressure from baseline, the log-transformed urinary albumin-to-creatinine ratio was also analyzed with the use of an ANCOVA model in which treatment and region were variables, with the baseline urinary albumin-to-creatinine ratio and the change from baseline in systolic blood pressure as covariates. For patients with missing albumin-to-creatinine ratio values for week 24 (13% and 9.7% in the aliskiren and placebo groups, respectively), the last post-baseline urinary albumin-to-creatinine ratio was carried forward for the week-24 end-point analysis. Patients who had an adverse event or an abnormal value on a laboratory test but who remained in the study were followed for its duration and included in the analysis of efficacy at 24 weeks. Patients who withdrew from the study were monitored for adverse events or abnormal values on laboratory tests for the duration of the study. Treatment comparisons between the patients who received aliskiren and those who received placebo were performed with the use of a two-sided test with a significance level of 0.05. Least-squares mean differences between the groups (aliskiren vs. placebo) for the change from baseline in the urinary albumin-to-creatinine ratio (and associated 95% confidence intervals) were back-transformed to provide aliskiren-to-placebo ratios. In addition, a mixed-effects model with the use of the appropriate procedure of the SAS package (SAS PROC MIXED) was implemented for the primary end point. The model included study group, visit, and the interaction term for these two factors, as well as region and baseline urinary albumin-to-creatinine ratio, as fixed effects and visits as repeated measurements. A common correlation structure for albumin-to-creatinine ratio was assumed for each patient.

Changes from baseline in the urinary albumin excretion rate, blood pressure, and estimated glomerular filtration rate were analyzed with the use of an ANCOVA model, with treatment, region, and baseline proteinuria classification as factors and respective baseline values for the urinary albumin excretion rate, blood pressure, and glomerular filtration rate as covariates. Analyses of the urinary albumin excretion rate and the estimated glomerular filtration rate were performed with the use of log-transformed data. Correlations between changes from baseline in blood pressure and changes from baseline in the urinary albumin-to-creatinine ratio were assessed by linear regression analysis. All statistical analyses were performed with SAS software, version 8.2 or higher (SAS Institute).

Results

Characteristics of the Patients

Baseline demographic, clinical, and biochemical characteristics and the number of patients who were receiving glucose-lowering and lipid-lowering therapies and aspirin (≤325 mg daily) were balanced between the two groups, except that the patients in the placebo group were slightly older (P=0.009) (Table 1). The mean glycated hemoglobin values remained unchanged, at 8.0%, in the aliskiren group and rose to 8.1% in the placebo group, and the numbers of severe hypoglycemic episodes were zero and one, respectively. Additional blood-pressure−lowering drugs that were taken by patients in the two groups are shown in Table 2Table 2Concomitant Antihypertensive Therapies Received at Baseline and during the Double-Blind Period among Patients with Type 2 Diabetes and Nephropathy..

Primary and Secondary Outcomes

By the end of the study period, treatment with aliskiren (150 mg daily for 3 months, followed by 300 mg daily for another 3 months) had reduced the mean urinary albumin-to-creatinine ratio by 20%, as compared with placebo (95% confidence interval [CI], 9 to 30; P<0.001) (Figure 2AFigure 2Changes from Baseline in the Urinary Albumin-to-Creatinine Ratio, Urinary Albumin Excretion Rate, and Blood Pressure According to Study Group.). The mixed-effects model yielded an identical reduction of 20% in the mean urinary albumin-to-creatinine ratio (95% CI, 11 to 29; P<0.001). After adjustment for the change from baseline in systolic blood pressure, the reduction was 18% (95% CI, 7 to 28; P=0.002). By week 12, 150 mg of aliskiren daily, as compared with placebo, had decreased the urinary albumin-to-creatinine ratio by 11% (95% CI, 2 to 20; P=0.02). At week 24, the overnight urinary albumin excretion rate showed a similar pattern, with a reduction of 18% in the aliskiren group (95% CI, 5 to 30; P=0.009 for the comparison with the placebo group) (Figure 2B). After adjustment for the change from baseline in systolic blood pressure, the reduction was 17% (95% CI, 4 to 29; P=0.02). Mean blood pressure, measured while the patient was seated, was nearly identical at baseline in the two groups. By the end of the study period (week 24), the mean blood pressure in the aliskiren group was 2/1 mm Hg lower than that in the placebo group (P=0.07 for systolic pressure, P=0.08 for diastolic pressure) (Figure 2C).

A reduction of 50% or more in albuminuria was seen in 24.7% of the patients who received aliskiren, as compared with 12.5% of the patients who received placebo (P<0.001). A comparison of baseline characteristics between patients who had a heightened response (a reduction of 50% or more in albuminuria) and those who had a normal response (a reduction of less than 50% in albuminuria) did not reveal any significant differences.

There were no significant differences in the response to aliskiren among subgroups of patients (Figure 3Figure 3Relative Change from Baseline in the Urinary Albumin-to-Creatinine Ratio after Treatment with Aliskiren as Compared with Placebo in Subgroups of Patients.). Even though aliskiren appeared to have a beneficial effect or trend in all subgroups, the effect was not always significant. The mean rate of decline in the estimated glomerular filtration rate during the 24-week study period was 2.4 ml per minute per 1.73 m2 (95% CI, 1.1 to 3.7) in the aliskiren group and 3.8 ml per minute per 1.73 m2 (95% CI, 2.5 to 5.1) in the placebo group (P=0.07).

Adverse Events

There was no difference in the overall incidence of adverse events between the aliskiren group and the placebo group (66.8% and 67.1%, respectively) (Table 3Table 3Serious Adverse Events, Adverse Events, and Prespecified Abnormal Laboratory Values during Double-Blind Treatment (Safety Population).). The rate of serious adverse events was also similar (9.0% and 9.4%, respectively), as was the percentage of patients who withdrew from the study owing to adverse events (5.6% and 6.4%, respectively). There were no deaths in the aliskiren group and two deaths in the placebo group. Hyperkalemia was reported in 5.0% of the patients in the aliskiren group and in 5.7% of the patients in the placebo group. A total of 14 patients (4.7%) in the aliskiren group had at least one value for the serum potassium level that was 6.0 mmol per liter or more, as compared with 5 patients (1.7%) in the placebo group (P=0.06). A total of 9 of the 14 aliskiren-treated patients had had a serum potassium level of 5.1 mmol per liter or more at baseline, a level that should have led to the exclusion of the patients from the study, according to the exclusion criteria described earlier. Of these 9 patients, 3 were excluded from the study when the laboratory value became available. One of the remaining 11 patients withdrew from the study because a subsequent laboratory test showed a serum potassium level of 6.3 mmol per liter. The mean (±SD) serum creatinine level in the aliskiren group at baseline was 1.4±0.6 mg per deciliter (123.76±53.04 μmol per liter). Only half of the patients in the two study groups who had at least one value for serum potassium that was 6.0 mmol per liter or more (a total of 16 patients) received a diuretic. None of the five patients in the placebo group had a serum potassium level of 5.1 mmol per liter or more at baseline, and the mean value for these five patients was 4.7±0.2 mmol per liter at baseline. The hyperkalemia was transient, and none of the five patients stopped taking the study medication.

Discussion

The present trial shows that treatment with 300 mg of aliskiren daily reduces albuminuria in patients with hypertension, type 2 diabetes, and proteinuria who are receiving the recommended maximal renoprotective treatment with losartan and optimal antihypertensive therapy. Furthermore, a 50% reduction in albuminuria was seen twice as often in the group that received 300 mg of aliskiren daily as in the group that received placebo. The benefits of aliskiren appear to be independent of the systemic blood pressure; average trough systolic and diastolic blood pressures during the study were only marginally lower in the aliskiren group than in the placebo group, and an analysis that adjusted for these small differences confirmed the renoprotective effect of aliskiren. In addition, the decline in kidney function tended to be smaller among the patients who received aliskiren than among those who received placebo.

The benefit of blocking the renin−angiotensin−aldosterone system in patients with diabetes who are at risk for end-stage renal disease is now well established.3,4,10-12 However, most studies to date also show that renal disease progresses in many patients despite treatment with angiotensin-converting−enzyme (ACE) inhibitors or angiotensin II−receptor blockers.3,4,10-12 Consequently, alternatives that optimize the blockade of the renin−angiotensin−aldosterone system are being explored in the hope that a more complete blockade will lead to a better therapeutic outcome.17 New renoprotective strategies include dual blockade of the renin−angiotensin−aldosterone system with the use of ACE inhibitors and angiotensin II–receptor blockers, very high doses of angiotensin II−receptor blockers,18-20 aldosterone blockade,21,22 and, as in the present study, direct renin inhibition.

Aliskiren, the renin inhibitor used in our study, has a 40-hour half-life and reduces both blood pressure and plasma renin activity. It is well established that a dose of 300 mg of aliskiren is optimal for the reduction of blood pressure.23 Further information concerning the development of oral renin inhibitors and their pharmacokinetic and pharmacodynamic properties, with a focus on aliskiren, is available in a recent review.24

In a study reported in 2000 that involved patients with type 2 diabetes, hypertension, and microalbuminuria, Mogensen et al.25 showed that treatment with a combination of submaximal doses of candesartan and lisinopril was more effective in reducing blood pressure (reductions in systolic pressure of approximately 10 mm Hg and in diastolic pressure of approximately 6 mm Hg) than therapy with only one agent; however, the effectiveness of the combined therapy in reducing albuminuria was not firmly established. Since then, numerous small studies, often using submaximal doses of ACE inhibitors in patients with diabetic nephropathy, have shown a significant reduction in blood pressure and albuminuria with this treatment strategy.26 In contrast, a large, randomized, controlled trial involving patients with type 2 diabetes, hypertension, and albuminuria who received the maximal recommended doses of ramipril and irbesartan failed to show a significant effect of combination therapy, as compared with monotherapy, on albuminuria,27 despite a significant reduction in systemic blood pressure. However, this study may have been underpowered, owing to a more marked variability in the urinary albumin excretion rate than anticipated. Our study was larger and adequately powered, and the results clearly support a specific renoprotective effect of aliskiren — namely, a beneficial effect on kidney function beyond the effect on hypertension. However, we cannot completely rule out the possibility that changes in antihypertensive medications after randomization might have confounded the results of our study.

Glomerular proteinuria is determined by four factors: the mean transcapillary hydraulic-pressure difference, the glomerular surface area, and the size selectivity and charge selectivity of the glomerular filter. In diabetic nephropathy several of these variables are abnormal, and blockade of the renin−angiotensin−aldosterone system has been shown to normalize directly measured or estimated glomerular hydraulic pressure,28-30 to reduce the shunt-like defects in the membrane, at least in part,31,32 and to restore the charge-selectivity properties of the glomerular membrane.33

In our study, the estimated glomerular filtration rate was nearly identical in the two groups at baseline, whereas the decline in the glomerular filtration rate tended to be smaller among the patients who were treated with aliskiren for 6 months than among the patients who were given placebo. Long-term studies (more than 2 years' duration) must be conducted to elucidate whether the beneficial effect on the kidney that is seen in the short term is sustained.

Previous studies with antihypertensive drugs have usually shown an initial drop in the glomerular filtration rate that is steeper than the sustained decline.11,34 Recently, a study of healthy people on a low-sodium diet has shown that renal vasodilatation with aliskiren far exceeds that seen with ACE inhibitors and angiotensin II−receptor blockers.35 These results indicate that aliskiren may provide greater and thus more effective blockade of the renin system in the kidney. Since the renin system is enhanced in patients with diabetes, as compared with controls,36 a more pronounced difference in renal vasodilatation may be expected during aliskiren therapy.

During the course of the trial, the average difference in blood pressure was only 2 mm Hg systolic and 1 mm Hg diastolic in favor of the dual blockade of the renin−angiotensin−aldosterone system. Studies of the same treatment approach (300 mg of aliskiren combined with 320 mg of valsartan37 or 10 mg of ramipril38) in patients with essential hypertension have shown at least a doubling of the difference in blood pressure in the combination-therapy groups as compared with the monotherapy groups. A likely explanation for this finding is that the patients in these two trials had a much higher average baseline blood pressure than the patients in our study, whose baseline blood pressure was well controlled. Even though many of the patients in both of our study groups received three or more antihypertensive agents, our systolic blood-pressure goal of 130 mm Hg was reached in less than half the patients, whereas our diastolic blood-pressure goal of 80 mm Hg was reached in the majority of patients in both groups. Previous studies among patients with diabetic nephropathy have also shown that ideal control of systolic blood pressure is very difficult to attain in patients with diabetes, probably owing to the presence of diabetic macroangiopathy.2-4

It is possible that aliskiren also differs from ACE inhibitors or angiotensin II−receptor blockers in other ways that might explain these results. In 2002, Nguyen et al.39 discovered a (pro)renin receptor that was detected in the brain, heart, liver, and kidney. Prorenin, when bound to the (pro)renin receptor, displayed enzymatic activity and activation of intracellular signaling pathways without proteolytic removal of the prosegment. Recent studies in animals with diabetes40,41 and in in vitro conditions with high glucose42 have shown that aliskiren reduces the number of (pro)renin receptors in the kidney, mitigates profibrotic activity in the kidney, and nearly abolishes the apoptotic effects on cultured podocytes. Furthermore, data from transgenic (mRen-2)27 rats with diabetes suggest that aliskiren has a greater renoprotective capacity than ACE inhibitors.43 These findings are consistent with the observation that an elevated plasma prorenin level is associated with the development of diabetic nephropathy.1

The combination therapy consisting of the maximal recommended doses of aliskiren and losartan had similar tolerability to therapy with placebo and losartan, consistent with findings in an earlier study of the combination of aliskiren and valsartan.37 Hyperkalemia was reported in 5.0% of the patients in the aliskiren group and in 5.7% of the patients in the placebo group. The number of patients with a serum potassium level of 6.0 mmol per liter or more was higher with the combined drugs than with placebo, although the occurrence of such cases, after adjustment for the nine patients who were mistakenly enrolled in the trial, was low.

In conclusion, aliskiren appears to have a renoprotective effect that is independent of its blood-pressure–lowering effect in patients with type 2 diabetes who are receiving the maximal recommended renoprotective treatment and optimal antihypertensive therapy.

Supported by Novartis Pharma.

Dr. Parving reports serving as a consultant for and receiving lecture fees from Novartis, Merck, Pfizer, and Sanofi-Aventis, having equity interest in Merck and Novo Nordisk, and receiving grant support from Novartis, AstraZeneca, and Sanofi-Aventis; Dr. Persson, having equity interest in Novo Nordisk; Dr. E. Lewis, receiving grant support from Keryx Biopharmaceuticals; Dr. J.B. Lewis, serving as a consultant to Merck and Novartis and receiving grant support from Keryx Biopharmaceuticals; and Dr. Hollenberg, receiving grant support from Novartis and Merck.

No other potential conflict of interest relevant to this article was reported.

Source Information

From the Department of Medical Endocrinology, Rigshospitalet, Copenhagen (H.-H.P.); the Faculty of Health Science, Aarhus University, Aarhus, Denmark (H.-H.P.); Steno Diabetes Center, Gentofte, Denmark (F.P.); Vanderbilt University School of Medicine, Nashville (J.B.L.); Rush University Medical Center, Chicago (E.J.L.); and Brigham and Women's Hospital and Harvard Medical School, Boston (N.K.H.).

Address reprint requests to Dr. Parving at the Department of Medical Endocrinology, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark, or at .

The investigators who participated in the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study are listed in the Appendix.

We thank Karl Baer, Deborah L. Keefe, Vipin Arora, Jessica Ford, and Balthazar Mascaro for their substantial contributions.

Appendix

The following investigators participated in the study: Canada — M. Lebel, M. Agharazi (Quebec, QC); N. Muirhead, A. House, F. Rehman (London, ON); V. Pichette, M. LeBlanc, A. Bomardeaux, M. Houde (Montreal); G. Pylypchuk, A. Ahmed, J. Barton (Saskatoon, SK); S. Jolly (Kitchener, ON); Greece — K. Siamopoulos, I. Theodorou (Ioannina); E. Pagkalos, M. Gavra, A. Klitsas, K. Soulis (Thessaloniki); Portugal — M.J. Pais, L. Parreira, A. Ribeiro da Cunha, P. Carmo (Carnaxide); A. Gomes da Costa, S. Morgado da Silva (Lisbon); D. Carvalho, Â. Magalhães, A. Oliveira, J. Queirós (Porto); Turkey — A. Oguz, A. Erenmemisoglu, S. Seker, C. Muderrisoglu, E. Altinoglu, A. Erenmemisoglu, T. Ecder, H. Yazici (Istanbul); M. Arici, A. Erenmemisoglu, R. Yilmaz (Ankara); K. Dilek, A. Erenmemisoglu, S. Kahvecioglu, I. Akdag (Bursa); Denmark — H.-H. Parving, F. Persson, K. Schjødt, L. Tarnow (Gentofte); O.L. Svendsen, T. M. Christensen, M.-B. Tanderup Petersen, H. Perrild (Copenhagen); T. Almdal (Hvidovre); B. Thorsteinsson, O. Snorgård (Hillerød); H. Juhl, H. Hansen (Slagelse); J. Henriksen, B. Vind (Odense); O. Østergaard, E. Christiansen (Roskilde); France — G. Choukroun, N. El Esper, C. Presne (Amiens); J. Aldigier (Limoges); P. Bataille, D. Nour (Boulogne-sur-Mer); J.-P. Fauvel (Lyon); P. Zaoui, P. Malvezzi (Grenoble); J.-M. Halimi, P. Lecomte (Tours); G. Charpentier, B. Boucherie (Corbeil); Germany — T. Jung, N. Jung (Deggingen); J. Jordan, H. Mehling, P. Budziarek, S. Engeli (Berlin-Buch); H. Haller, J. Menne, S. Niescken, A. Herrmann, S. Hellweg, S. David, A. Deines (Hannover); R. Schmieder, B. Schmidt, T. Schäufele (Nuremberg); J. Simon (Fulda); E. Oerter (Wuerzburg); M. Rambausek, M. Schoemig, M. Stephan (Heilbronn); E. Austenat, C. Grothe, T. Lederer, B. Al-Masry (Berlin); G. Blume (Quedlinburg); C. Hohberg, R. Butzer, T. Forst, P. Musholt, B. Wilhelm (Mainz); A. Gruenerbel, M. Gruenerbel, C. Richter (Munich); Italy — A. Santoro, M. Federico, M. Mandreoli, L. Stalteri (Bologna); G. Remuzzi, P. Ruggenenti, E. Perticucci, S. Rota (Bergamo); L. Gesuaido, M. Ktena, E. Pallotta (Foggia); S. David, C. Grasselli (Parma); C. Zoccali, F.M. Cambareri, G. Parlongo (Reggio Calabria); A. Balducci, M. Gamerini, G. Sorbo (Rome); E. Fanciulli, P. Freddi, E. Balestra (Torrette di Ancona); F. Quarello, R. Boero, S. Borsa, C. Mossara (Turin); A. Fabbri, E. degli Esposti, C. Baraccani, A. Sturani, M. Gentile (Ravenna); A. Baraldi, M.R. Federico (Carpi); the Netherlands — A. van den Meiracker, J. Rutten, J. Wijberga (Rotterdam); H.A.H. Kaasjager, L.J. Reichert (Arnhem); J. Breed (Weert); A. Hollander, P. van Meurs, F. Ciggaar, P. van Hoek ('s-Hertogenbosch); P.J. Smak Gregoor (Dordrecht); S. Landewé-Cleuren (Maastricht); P. Viergever, R. Timmerman (Den Helder); R.P. Verhoeven, J. Barendregt, R. Lieverse, J. Smit, S. Radema, M.A. van Dijk, T. van Bemmel (Apeldoorn); A.J. Woittiez, F. Visser (Almelo); Spain — J. Alegre Martin, C. Aleman Llanso, M. Duran Tabena, J. Recio Iglesias, T. Soriano Sanchez, L. Comas, X. Farres, A. Ledesma Casteltort, M. Terns, P. Fernandez, F. Gonzales-N, F. Ortiz-Herbener, A. Oliveras, S. Vazquez, A. Martinez Castelao, F. Moreso Mateos, M.T. Gonzalez Alvarez (Barcelona); J. Redon, A. Casanova, J. Gorriz, P. Molina Vila, A. Priego (Valencia); L. Ruilope, C. Roldan, J. Segura, C. Campo, A. Calle Pascual, J. Garcia Honduvilla, F. de Alvaro, O. Costero Fernandez, S. Garcia de Vinvera, M. Goicoechea, J. Luño (Madrid); J. Olivan, J. Pizarro Nunez, E. Gonzales-Serna, A. Rodriguez Botaro (Seville); P. Gomez, M. Eady Alonso (Cadiz); L. De Teresa Parreno, P. Garcia Hermosa, J. Gomez Gomez, S. Fuentes Luri, J. Blazquez (Alicante); P. Aranda (Málaga); C. Calvo, M. Rodriguez Fernandez, J. Lopez Paz (Coruña); United Kingdom — G. Viberti, J. Karalliedde, V. Mirenda, L. Gnudi (London); A. Rees, A. Roberts (Cardiff); J. Reckless, A. Robinson, R.Y. Mukhtar, J. Vora, A. Joshi, H. White, J. Franklin (Bath); J. Walker, T. Sandeep, A. Mukhtar, R. Gray (Livingston); S. Heller, A. Mackie, S.H. Song (Sheffield); J. O'Hare, M.V. Chittari, K. Kos, M. Pierides (Rugby); Romania — M. Voiculescu, N. Caceaune, L. Iliescu, R. Bobeica, C. Ionescu, G. Ismail, L. Luca, G. Tatu-Chitoiu, S. Cronaciu, R. Jumatate, D. Zamfir (Bucharest); M. Stefanescu, D. Muntoi, D. Dobreanu, D. Cromos, G. Dogaru, C. Caldararu (Tg. Mures); D. Zdrenghea, C. Roman, A. Malai, M. Cebanu, M. Ostace, D. Pop, R. Rosu (Cluj-Napoca); R. Mihaila, R. Mihaila, E. Rezi, M. Strugariu, M. Deac (Sibiu); Russia — V. Zadionchenko, T. Adasheva, O. Demicheva, M. Antsiferov, O. Koteshkova, I. Sretenskaya, K. Tsipuria, E. Vasilieva, I. Fomina, A. Tarzimanova, A. Vasileva, S. Martsevich, J. Semenova, A. Serazhim, V. Voronina, N. Dmitrieva (Moscow); O. Ershova, P. Kumzerov, N. Borisova, E. Ohapkina, E. Bolshakova (Yaroslavl); O. Lantsevsa, L. Strezhova, T. Terentieva, I. Karpova, E. Ostrovskaya, V. Panina (Saint Petersburg); Argentina — C. Majul, O. Paez, P. Puleio, M. Visser, I. Sinay, M. Nepote, A. Elbert, H. Beresan (Buenos Aires); L. Juncos, N. Garcia, M. Orias, M. Belen Barron, P. Novoa (Cordoba); United States — A. Wynne, J. Conrow (Topeka, KS); M. Rendell, J. Lane (Omaha); D. Robertson (Atlanta); R. Solomon (Burlington, VT); E. Himot (Marietta, GA); S. Schmidt (Philadelphia); W. Spisak (Portland, OR); J. Mossberg (Eugene, OR); R. Graf (Tacoma, WA); R. Cooper (Tempe, AZ); R. Ouseph (Louisville, KY); J. Liljenquist (Idaho Falls, ID); M. Seidner (Lansdale, PA); R. Culpepper, F. Lester (Mobile, AL); B. Wood, R. Butin (Kansas City, MO); V. Ram, R. Sachson, R. Toto, B. Zamora (Dallas); R. Busch (Albany, NY); K. Cohen (Golden, CO); A. Barreto (Oklahoma City); K. Hillner (Bryan, TX); N.P. Kopyt (Allentown, PA); R. Lipetz (Spring Valley, CA); J. LaSalle (Excelsior Springs, MO); J. Robertson (Riverside, CA); J. Mageli (St. Paul, MN); R. Cherlin (Los Gatos, CA); P. Snell (Greer, SC); E. Dyess (Jackson, MS); N. Sapin (Glendale, AZ); M. Reeves (Chattanooga, TN); P. Suchinda (Sumter, SC); T. Fagan, M. Parker (Tucson, AZ); D. Martinez (Moreno Valley, CA); R. Arakaki (Honolulu); N. Bohannon (San Francisco); M. Moustafa (Orangeburg, SC); A. Chen (Pensacola, FL); E. Barranco (Ponce, PR).

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