Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy
Barry M. Brenner, M.D., Mark E. Cooper, M.D., Ph.D., Dick de Zeeuw, M.D., Ph.D., William F. Keane, M.D., William E. Mitch, M.D., Hans-Henrik Parving, M.D., Giuseppe Remuzzi, M.D., Steven M. Snapinn, Ph.D., Zhonxin Zhang, Ph.D., Shahnaz Shahinfar, M.D., for the RENAAL Study Investigators
Background Diabetic nephropathy is the leading cause of end-stagerenal disease. Interruption of the reninangiotensin systemslows the progression of renal disease in patients with type1 diabetes, but similar data are not available for patientswith type 2, the most common form of diabetes. We assessed therole of the angiotensin-IIreceptor antagonist losartanin patients with type 2 diabetes and nephropathy.
Methods A total of 1513 patients were enrolled in this randomized,double-blind study comparing losartan (50 to 100 mg once daily)with placebo, both taken in addition to conventional antihypertensivetreatment (calcium-channel antagonists, diuretics, alpha-blockers,beta-blockers, and centrally acting agents), for a mean of 3.4years. The primary outcome was the composite of a doubling ofthe base-line serum creatinine concentration, end-stage renaldisease, or death. Secondary end points included a compositeof morbidity and mortality from cardiovascular causes, proteinuria,and the rate of progression of renal disease.
Results A total of 327 patients in the losartan group reachedthe primary end point, as compared with 359 in the placebo group(risk reduction, 16 percent; P=0.02). Losartan reduced the incidenceof a doubling of the serum creatinine concentration (risk reduction,25 percent; P=0.006) and end-stage renal disease (risk reduction,28 percent; P=0.002) but had no effect on the rate of death.The benefit exceeded that attributable to changes in blood pressure.The composite of morbidity and mortality from cardiovascularcauses was similar in the two groups, although the rate of firsthospitalization for heart failure was significantly lower withlosartan (risk reduction, 32 percent; P=0.005). The level ofproteinuria declined by 35 percent with losartan (P<0.001for the comparison with placebo).
Conclusions Losartan conferred significant renal benefits inpatients with type 2 diabetes and nephropathy, and it was generallywell tolerated.
Interruption of the reninangiotensin system with angiotensin-Iconvertingenzyme inhibitors slows the progression of renal disease bothin patients with type 1 diabetes and in nondiabetic patientswho have overt nephropathy.1,2,3 However, postponing end-stagerenal disease in patients with type 2 diabetes, the leadingcause of chronic renal failure in many countries, remains anelusive goal. We undertook a study in patients with type 2 diabetesand nephropathy in order to determine whether the angiotensin-IIreceptorantagonist losartan, alone or in combination with conventionalantihypertensive therapy, would increase the time to a doublingof the serum creatinine concentration, the onset of end-stagerenal disease, or death. In addition, we assessed the effectsof losartan and placebo on the following secondary end points:a composite of morbidity and mortality from cardiovascular causes,proteinuria, and the rate of progression of renal disease.
Methods
Study Design
The Reduction of Endpoints in NIDDM with the Angiotensin IIAntagonist Losartan Study was an investigator-initiated, multinational,double-blind, randomized, placebo-controlled study designedto evaluate the renoprotective effects of losartan in 1513 patientswith type 2 diabetes and nephropathy. The study design has beendescribed previously.4 In brief, 250 centers in 28 countriesin Asia, Europe, Central America, South America, and North Americaparticipated. The study protocol was approved by the institutionalreview board of each center, and all patients gave written informedconsent. The study was overseen by steering and safety committees,each of which contained one nonvoting member who was an employeeof the sponsoring pharmaceutical company. The steering committeeoversaw the study design, the conduct of the trial, and themanagement and analysis of the data. A writing subcommitteeof the steering committee prepared this report. An independentend-points committee whose members were unaware of the patients'treatment assignments reviewed the data to determine which patientshad reached the end points.
We planned to complete the study 3.5 years after the last patientunderwent randomization, which would have resulted in a meanfollow-up time of 4.5 years. However, the study was discontinuedearly (February 10, 2001) by a unanimous vote of the steeringcommittee, whose members were unaware of the treatment assignments.Their decision was based on new evidence suggesting that angiotensin-Iconvertingenzyme inhibitors, which were excluded by design from the study,may be effective in reducing the incidence of cardiovascularevents in patients with renal impairment, including those withdiabetes.5 Therefore, the results reported here represent amean follow-up time of 3.4 years (range, 2.3 to 4.6).
Patients
The study involved male and female patients, ranging in agefrom 31 to 70 years, who had received diagnoses of type 2 diabetesand nephropathy. Nephropathy was defined by the presence ontwo occasions of a ratio of urinary albumin (measured in milligramsper liter) to urinary creatinine (measured in grams per liter)from a first morning specimen of at least 300 (or a rate ofurinary protein excretion of at least 0.5 g per day) and serumcreatinine values between 1.3 and 3.0 mg per deciliter (115and 265 µmol per liter), with a lower limit of 1.5 mgper deciliter (133 µmol per liter) for male patients weighingmore than 60 kg. Patients were excluded if they had receiveda diagnosis of type 1 diabetes or nondiabetic renal disease,including renal-artery stenosis. We also excluded patients whohad had a myocardial infarction or had undergone coronary-arterybypass grafting within the previous month, who had had a cerebrovascularaccident or had undergone percutaneous transluminal coronaryangioplasty within the previous six months, who had had a transientischemic attack within the previous year, or who had any historyof heart failure before enrollment.4
Treatment
During the six-week screening phase, patients with hypertensioncontinued to receive their standard antihypertensive therapy.If they had been taking angiotensin-Iconverting enzymeinhibitors or angiotensin-IIreceptor antagonists, however,these medications were discontinued and replaced by alternativeopen-label medications (diuretics, calcium-channel antagonists,alpha- or beta-blockers, centrally acting agents, or some combinationof these types of medication). Patients were stratified accordingto their base-line level of proteinuria (a urinary albumin-to-creatinineratio <2000 or 2000) and randomly assigned to receive eitherlosartan (50 mg) or placebo once daily, along with conventionalantihypertensive therapy. After four weeks, the dose of losartanor placebo was increased to 100 mg or the placebo equivalentonce daily if the trough blood pressure with the patient sittingwas above the target level of a systolic blood pressure of lessthan 140 mm Hg and a diastolic blood pressure of less than 90mm Hg. After an additional eight weeks, antihypertensive agentsof the types described above (but not angiotensin-Iconvertingenzyme inhibitors or angiotensin-IIreceptor antagonists)were added or their doses increased to achieve the target bloodpressure.
Throughout the study, patients received the standard of carefor the treatment of diabetes, including measurements of glycosylatedhemoglobin and fasting serum glucose concentrations. Visitswere scheduled every three months, or more often if necessary,to monitor the blood pressure and laboratory measurements andto assess whether adverse events had occurred or end pointshad been reached. Patients who discontinued the study drugsearly had follow-up visits every three months until the endof the study; at these visits, the primary and secondary endpoints reached were recorded, the blood pressure was measured,and laboratory measurements were performed. Those who couldnot return for clinic visits or a family member was contactedby telephone to determine whether they had reached the end pointsof the initiation of dialysis, renal transplantation, or death.
Outcome Measures
The primary efficacy measure was the time to the first eventof the composite end point of a doubling of the serum creatinineconcentration, end-stage renal disease, or death. The doublingof the serum creatinine concentration was defined as the firstserum creatinine value that was twice the base-line value, asconfirmed by a second serum creatinine value obtained at leastfour weeks after the initial doubling. End-stage renal diseasewas defined by the need for long-term dialysis or renal transplantation.The prespecified secondary end point, morbidity and mortalityfrom cardiovascular causes, was a composite of myocardial infarction,stroke, first hospitalization for heart failure or unstableangina, coronary or peripheral revascularization, or death fromcardiovascular causes. Analyses of the components of both theprimary and secondary composite end points were also prespecified.Other secondary end points included the progression of renaldisease6 and changes in the level of proteinuria.
Statistical Analysis
Analyses of the primary and secondary end points were performedaccording to the intention-to-treat principle; we included datafrom all randomized patients (with the exception of three patientswho were lost to follow-up), from the time of randomizationthrough the date of study termination. In a second, per-protocolanalysis, we excluded patients who violated the criteria forinclusion and exclusion and censored patients' data 14 daysafter they permanently discontinued the study medication. ACox regression model7 that included the base-line level of proteinuriaas a stratification factor and the geographic region as a covariatewas used to determine the hazard ratio for the primary end pointand its 95 percent confidence interval. The risk reduction wascalculated as 100 percent x (1 hazard ratio). In analysesof nonfatal end points, data for the patients who had died wereconsidered to have been censored. Event curves are based onKaplanMeier analysis.8 We examined the effect of differencesbetween the groups in the control of blood pressure by addingthe mean arterial pressure during treatment as a time-dependentcovariate in the Cox model and comparing the effect of losartanestimated by this model with that estimated by the primary analysis.
The analyses of the progression of renal disease and changesin the level of proteinuria were based on an on-treatment approach.For the analysis of the progression of renal disease, we comparedthe slopes of the reciprocal of the serum creatinine concentration6of the two treatment groups using a linear random-effects model.Changes in the level of proteinuria in the two groups were comparedby means of a mixed-effects model9 whose terms included thetreatment at each point and the base-line level of proteinuria.
Because one interim analysis used a stopping boundary that wasbased on an alpha spending function of the O'BrienFlemingtype,10 a critical P value of 0.048 was required for the primaryhypothesis. For other outcomes, a P value of less than 0.05was considered to indicate statistical significance. All statisticaltests were two-sided.
Results
A total of 1513 patients were randomly assigned to receive losartanor placebo once daily, along with conventional antihypertensivetherapy as needed but excluding angiotensin-Iconvertingenzyme inhibitors and angiotensin-IIreceptor antagonists.The daily dose of losartan ranged from 50 to 100 mg, with 71percent of the patients receiving 100 mg. The base-line characteristicswere similar in the two groups (Table 1). More patients discontinuedthe study treatment in the placebo group (53.5 percent) thanin the losartan group (46.5 percent). Adverse clinical eventsresulted in discontinuation in 17.2 percent of the patientsin the losartan group, as compared with 21.7 percent of thosein the placebo group. Increased serum concentrations of creatinineor potassium led to the discontinuation of the study medicationin 1.5 percent and 1.1 percent, respectively, of the patientsin the losartan group, as compared with 1.2 percent and 0.5percent of the patients in the placebo group. A total of 7.5percent of the patients in the losartan group and 7.8 percentof those in the placebo group withdrew their consent. We wereable to determine the status of all patients (except for threepatients in the losartan group who could not be contacted) withrespect to dialysis, transplantation, and death.
Table 1. Base-Line Characteristics of the Patients.
Blood Pressure
At base line, 93.5 percent of the patients (92.3 percent inthe losartan group and 94.6 percent in the placebo group) werereceiving antihypertensive therapy. An additional 3 percentof the patients had hypertension but were not receiving antihypertensivetherapy. The trough blood pressure declined progressively duringthe course of the study. The trough blood pressure at base lineaveraged 152/82 mm Hg in the losartan group and 153/82 mm Hgin the placebo group; the mean arterial pressure was 105.5 mmHg in the losartan group and 106.0 mm Hg in the placebo group(P=0.38); and the pulse pressure was 69.4 mm Hg in the losartangroup and 70.8 mm Hg in the placebo group (P=0.13). At one year,the values averaged 146/78 mm Hg in the losartan group and 150/80mm Hg in the placebo group (mean arterial pressure, 100.9 mmHg and 103.1 mm Hg, respectively [P<0.001]; pulse pressure,67.8 mm Hg and 69.8 mm Hg, respectively [P=0.05]); at two years,the values were 143/77 mm Hg and 144/77 mm Hg, respectively(mean arterial pressure, 99.1 mm Hg and 99.7 mm Hg, respectively[P=0.38]; pulse pressure, 66.2 mm Hg and 67.1 mm Hg, respectively[P=0.37]); and at the end of the study they were 140/74 mm Hgand 142/74 mm Hg, respectively (mean arterial pressure, 95.9mm Hg and 96.8 mm Hg, respectively [P=0.59]; pulse pressure,66.7 mm Hg and 67.4 mm Hg, respectively [P=0.77]). The variousclasses of conventional antihypertensive drugs that were usedbefore and during the study are listed in Table 2.
Table 2. Use of Conventional Antihypertensive Medications at Base Line and during Study Treatment.
Primary Outcomes
According to the intention-to-treat analysis, the primary compositeend point of a doubling of the serum creatinine concentration,end-stage renal disease, or death was reached in 327 patientsin the losartan group (43.5 percent), as compared with 359 inthe placebo group (47.1 percent) (Figure 1A). Treatment withlosartan resulted in a 16 percent reduction in the risk of theprimary composite end point (P=0.02) (Table 3). The decreasein risk remained essentially unchanged (15 percent) after adjustmentfor blood pressure (P=0.03). Furthermore, according to the per-protocolanalysis, among the patients who continued to receive theirassigned study treatment, losartan conferred a 22 percent reductionin the risk of the primary composite end point (P=0.008).
Figure 1. KaplanMeier Curves of the Percentage of Patients with the Primary Composite End Point (Panel A) and Its Individual Components, a Doubling of the Serum Creatinine Concentration (Panel B), End-Stage Renal Disease (Panel C), and the Combined End Point of End-Stage Renal Disease or Death (Panel D).
The mean follow-up time was 3.4 years (42 months).
Table 3. Incidence of the Primary Composite End Point and Its Components.
The intention-to-treat analyses of the individual componentsof the primary composite end point are also shown in Table 3.The risk of a doubling of the serum creatinine concentrationwas 25 percent lower in the losartan group than in the placebogroup (P=0.006) (Figure 1B). Losartan also reduced the riskof end-stage renal disease by 28 percent (P=0.002) (Figure 1C).Approximately 20 percent of the patients died, but there wasno significant difference in mortality between the two groups(P=0.88). The risk of the combined end point of end-stage renaldisease or death was 20 percent lower in the losartan groupthan in the placebo group (P=0.01) (Figure 1D and Table 3).The reductions in the risk of end-stage renal disease and ofend-stage renal disease or death changed little after correctionfor blood pressure (26 percent, P=0.007, and 19 percent, P=0.02,respectively).
Secondary Outcomes
There was no significant difference between the losartan groupand the placebo group in the composite end point of morbidityand mortality from cardiovascular causes. Approximately onethird of the patients had a fatal or nonfatal cardiovascularevent (247 in the losartan group [32.9 percent] and 268 in theplacebo group [35.2 percent]; risk reduction, 10 percent; P=0.26).There were no significant differences in the rates of most ofthe cardiovascular end points; the exception was the first hospitalizationwith heart failure (89 patients in the losartan group [11.9percent], as compared with 127 in the placebo group [16.7 percent]),for which the risk was reduced by 32 percent (P=0.005) (Figure 2).There was a difference between the number of myocardialinfarctions in the losartan group (50 patients [6.7 percent])and the number in the placebo group (68 patients [8.9 percent];risk reduction, 28 percent), but this difference was not statisticallysignificant (P=0.08).
Figure 2. KaplanMeier Curves of the Percentage of Patients with a First Hospitalization for Heart Failure in the Losartan and Placebo Groups.
Subsequent hospitalizations for heart failure were not assessed. There were 88 patients (44 in each group) who had preexisting heart failure at the time of randomization. When these patients were excluded from the analysis of this component, there remained a significant difference in the rate of first hospitalization for heart failure between the two treatment groups. The mean follow-up time was 3.4 years (42 months).
Losartan also led to an average reduction in the level of proteinuria(the urinary albumin-to-creatinine ratio) of 35 percent, whereasin the patients in the placebo group, the urinary albumin-to-creatinineratio tended to increase (P<0.001 for the overall treatmenteffect) (Figure 3). Losartan reduced the rate of decline inrenal function, as assessed by the reciprocal of the serum creatinineconcentration, by 18 percent (median slope, 0.056 dlper milligram per year in the losartan group, as compared with0.069 dl per milligram per year in the placebo group;P=0.01). Likewise, losartan was associated with a 15.2 percentreduction in the estimated decline in the glomerular filtrationrate (median rate of decline, 4.4 ml per minute per 1.73 m2of body-surface area per year in the losartan group, as comparedwith 5.2 ml per minute per 1.73 m2 per year in the placebo group;P=0.01).12,13 These reductions in the rate of decline are farsmaller than those reported for captopril as compared with placeboin patients with type 1 diabetes nearly a decade ago.1
Figure 3. Median Changes from Base Line in the Level of Proteinuria.
Proteinuria was measured as the urinary albumin-to-creatinine ratio in a first morning specimen. The mean follow-up time was 3.4 years.
Discussion
Our study establishes that losartan, along with conventionalantihypertensive treatment as needed, confers strong renal protectionin patients with type 2 diabetes and nephropathy. The risk ofthe primary end point, a composite of a doubling of the serumcreatinine concentration, end-stage renal disease, or deathfrom any cause, was reduced by 16 percent with losartan. Theprimary benefit appeared to be the effect on the renal componentsof this composite end point. In particular, the risk of end-stagerenal disease was reduced by 28 percent with losartan duringan average follow-up of 3.4 years. Extrapolating from the observeddata, we estimate that this reduction corresponds to an averagedelay of two years in the need for dialysis or transplantation.The risk of a doubling of the serum creatinine concentrationwas also reduced by 25 percent with losartan. The differencebetween the slopes of the reciprocals of the serum creatininevalues and the lower level of proteinuria provide further evidenceof global renal protection with losartan.
There was a small, time-averaged difference in the trough bloodpressure between the losartan group and the placebo group. Wecannot exclude the possibility that this small difference hada beneficial effect on the renal outcomes. However, statisticalanalysis that corrected for these small differences confirmedthat the renal protection conferred by losartan exceeded thatattributable to any small differences in blood pressure. Thisstudy extends our knowledge of the efficacy of antihypertensivetherapy in patients with type 2 diabetes and nephropathy. Previousstudies involving angiotensin-Iconverting enzyme inhibitorshave demonstrated beneficial effects on proteinuria but havenot demonstrated the superiority of blockade of the reninangiotensinsystem in slowing the progression to end-stage renal diseaseover nonblockade forms of therapy.14,15,16,17,18,19,20 Indeed,studies of the effects of angiotensin-Iconverting enzymeinhibitors on the progression of renal disease and end-stagerenal failure have yielded conflicting results.14,15,20,21,22,23,24Therefore, in the absence of a direct comparison between angiotensin-Iconvertingenzyme inhibitors and angiotensin II antagonists, any extrapolationfrom the results obtained with different classes of drugs isspeculative at best.
The benefits of losartan were observed among our patients, manyof whom were already receiving other therapies, such as aspirin,beta-blockers, and lipid-lowering agents, as part of sound medicalpractice. Similarly, simultaneous therapy with calcium-channelantagonists did not detract from the beneficial effects of losartan,despite the recent controversy regarding the role of calcium-channelantagonists in the protection of the kidneys and the heart.25,26,27In this regard, it should be noted that in related studies inpatients with type 1 and type 2 diabetes,1,28,29 the benefitsof captopril or irbesartan were not tested in the presence ofconcurrent calcium-channelantagonist therapy. Furthermore,calcium-channel antagonists have been shown to augment the productionof angiotensin II,30 a response that may be counteracted byconcomitant angiotensin-IIreceptor blockade.
There was no significant difference between the losartan groupand the placebo group in the composite secondary end point ofmorbidity and mortality from cardiovascular causes. This similarityof incidence may have resulted in part from the relatively smallsample and the strict criteria for enrollment that excludedpatients at high risk for cardiovascular events including heartfailure. We did find a significant difference in favor of losartanwith regard to the rate of a first hospitalization for heartfailure, a component of this secondary composite end point.This finding in patients without clinical heart failure at baseline accords well with findings from the Studies of Left VentricularDysfunction Prevention study.31 That study, however, did notinclude patients with impaired renal function. The Heart OutcomesPrevention Evaluation (HOPE) Study32 and its substudy of patientswith diabetes, MICRO-HOPE,20 showed benefits of angiotensin-Iconvertingenzyme inhibition in terms of the signs and symptoms of heartfailure but failed to show significant differences in hospitalizationsfor heart failure. Furthermore, the evaluation of a subgroupof the HOPE population with renal insufficiency5 did not showa significant effect on this outcome. Our findings suggest thatangiotensin II blockade in patients with renal disease decreasesthe risk of overt heart failure resulting in hospitalization.
In this population, losartan (plus conventional antihypertensivetherapy) demonstrated excellent tolerability, similar to thatof placebo (plus conventional antihypertensive therapy), asevidenced by the similar numbers of patients in the two groupsin whom the study treatment was discontinued because of adverseevents. The addition of losartan to a conventional antihypertensivetreatment regimen did not increase the incidence of adverseevents.
End-stage renal disease continues to be a worldwide public healthconcern. Recent estimates by the National Institutes of Healthindicate that diabetes represents the single largest cause ofend-stage renal disease, accounting for approximately 40 percentof all cases in the United States between 1994 and 1998.33 Furthermore,the incidence of end-stage renal disease in patients with type2 diabetes is rising sharply in many regions of the world andis expected to double by 2010. The annual costs associated withend-stage renal disease in the United States reached $12 billionin 1998 and are expected to surpass $28 billion by 2010.34 Preventingor delaying the progression of diabetic nephropathy is thereforean essential management goal. We believe our findings go a longway toward achieving this goal and may also have an importanteconomic effect.
In summary, losartan led to significant improvement in renaloutcomes that was beyond that attributable to blood-pressurecontrol in patients with type 2 diabetes and nephropathy.
Supported by Merck and Company.
Dr. Brenner has served as a consultant to Merck, Bayer, Bristol-MyersSquibb, Aventis, AstraZeneca, Glaxo, and King. He has receivedresearch grants from Merck, Bayer, Bristol-Myers Squibb, andNovartis. He has been a member of speakers' bureaus sponsoredby Merck, AstraZeneca, Bristol-Myers Squibb, and Novartis.
Dr. Cooper has served as a consultant to Pfizer, Sanofi, andAlteon. He has received research grants from AstraZeneca, Bristol-MyersSquibb, Merck, and Servier. He has been a member of speakers'bureaus sponsored by AstraZeneca and Solvay.
Dr. de Zeeuw has served as a consultant to Boehringer Ingelheim,Dade Behring, Merck Sharp & Dohme, Pfizer, Takeda, and Yamanouchi.He has received research grants from Bristol-Myers Squibb, BoehringerIngelheim, Dade Behring, Merck Sharp & Dohme, Sanofi, andYamanouchi. He has been a member of speakers' bureaus sponsoredby Bristol-Myers Squibb, Dade Behring, and Merck Sharp &Dohme.
Dr. Keane has served as a consultant to Bayer, Merck, AstraZeneca,and Monarch. He has received research grants from Bayer andMerck. He has been a member of speakers' bureaus sponsored byBayer, Merck, AstraZeneca, and Monarch.
Dr. Mitch has served as a consultant to Merck and Biogen.
Dr. Parving has served as a consultant to Merck, Bristol-MyersSquibb, Sanofi, Pfizer, and BioStratum. He has received researchgrants from Merck, Bristol-Myers Squibb, Sanofi, and AstraZeneca.He has been a member of speakers' bureaus sponsored by Merck,Bristol-Myers Squibb, Sanofi, Pfizer, and AstraZeneca.
Dr. Remuzzi has received research grants from Aventis Pharma.
Drs. Snapinn, Zhang, and Shahinfar are employees of Merck andmay own stock or hold stock options in Merck.
We are indebted to Roger L. Simpson, Denise R. Ramjit, Dr. RaymondP. Bain, and Dr. David J. van Dijk for their substantial contributions.
* The investigators who participated in the RENAAL (Reductionof Endpoints in NIDDM with the Angiotensin II Antagonist Losartan)Study are listed in the Appendix.
Source Information
From the Renal Division, Brigham and Women's Hospital, Boston (B.M.B.); the Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia (M.E.C.); the Department of Clinical Pharmacology, University of Groningen, Groningen, the Netherlands (D.Z.); the Department of Medicine, Hennepin County Medical Center, Minneapolis (W.F.K.); the Renal Division, Emory University, Atlanta (W.E.M.); Steno Diabetes Center, Gentofte, Denmark (H.-H.P.); Laboratori Negri Bergamo, Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy (G.R.); and Merck Research Laboratories, Blue Bell, Pa. (S.M.S., Z.Z., S.S.).
Address reprint requests to Dr. Brenner at the Renal Division, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115, or at bbrenner{at}partners.org.
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Appendix
The following persons participated in the Reduction of Endpointsin NIDDM with the Angiotensin II Antagonist Losartan Study:Independent Steering Committee: B.M. Brenner, M.E. Cooper, D.de Zeeuw, J.P. Grunfeld, W.F. Keane, K. Kurokawa, J. McGill,W.E. Mitch, H.-H. Parving, G. Remuzzi, A.B. Ribeiro, M. Schluchter;Independent Data Safety Monitoring Committee: C.E. Mogensen,M. Fifer, L. Fisher, P. Kowey, D. Schlondorff, G. Viberti, P.Whelton; Independent Endpoint Committee: S. Haffner, J. Carrozza,D. Kolansky, L. Raij, D. Sica, R. Toto; Primary Investigators(the numbers in parentheses are the numbers of patients in eachcountry): Argentina (17) F. Inserra, L. Juncos; Austria(15) C. Gurdet, J.R. Patsch, H. Toplak; Brazil (58) S. Silveiro, V. Woronik, T. Zanella; Canada (1) E. Burgess, T.C. Monchesky; Chile (26) F. González;Costa Rica (33) M. Vinoccour; Czech Republic (33) P. Boucek, R. Chlup, J. Olsovsky, P. Sifalda; Denmark (16) P. Christensen; France (12) T. Hannedouche, P. Passa,M. Rodier; Germany (12) B. Boehm, H.-D. Bundschu, U.Leonhardt; Hong Kong, China (92) J. Chan, J. Critchley,K. Lam; Hungary (10) S. Sonkodi; Israel (37) D.J. van Dijk; Italy (26) G. Piras, G. Remuzzi, F. Santeusanio;Japan (96) R. Abe, Y. Ando, T. Fujita, T. Hanafusa,M. Haneda, T. Haneda, Y. Hashimoto, T. Ida, Y. Iino, S. Ishibashi,S. Ito, H. Kakuta, M. Kanazawa, T. Kanda, M. Kasuga, M. Kato,T. Koike, H. Kurahachi, H. Kuzuya, K. Matoba, D. Nagasaku, K.Ohshiro, K. Okada, S. Owada, H. Sakai, J. Seino, C. Shigemasa,T. Shoji, Y. Tsubakihara, N. Ujihara, N. Ura, T. Watanabe, I.Yamaji, Y. Yamasaki, M. Yoshinari, N. Yoshioka; Malaysia (21) C.T. Chua, Z. Morad; Mexico (67) R. Correa,J. Herrera; the Netherlands (7) J.-E. Heeg, R. Gansevoort,P.L. Rensma; New Zealand (3) R. Scott; Peru (42) R. Zavala; Portugal (10) B. Carvalho; Russia (26) M. Shestakova, G. Zalevskaya; Singapore (11) K.S. Wong;Slovak Republic (2) M. Pavlovic; Spain (67) J.M. Bronsons, M.M. Campos Pastor, D. del Castillo-Caba, F.Diz-Lois, F. Escobar-Jiménez, M.T. Gonzalez-Alvarez,D. Lorenzo, A. Martínez-Castelao, J.M. MartínezGarcía, A. Tejedor-Jorge, M. Valles-Prats; United Kingdom(56) C. Fox, E. Hillhouse, M. MacLeod, M. MacMahon,J. Mclay, P. O'Hare, V. Patel, H. Tindall, J.P. Vora, J.U. Weaver;United States, including Puerto Rico (686) S. Abramson,J.R. Allison III, J. Anderson, G. Appel, M. Avram, G. Bakris,Y. Barri, J. Beard, D. Bell, J. Benabe, R. Benedetti, W. Bennett,W.K. Bolton, J.P. Brennan, M. Broder, M. Cabezas-Mijuste, D.Calhoun, A. Carr, L. Chan, B. Chandler, Jr., G. Chao, D. Chapman,J. Chinn, J. Christensen, J. Chung, C. Clinkingbeard, G. Collins,C. Corder, D. Crittenden, P. Dandona, M. Davis, R. DeFronzo,V. DeQuattro, G. Dolson, J. Douglas, M. Doyle, M. Eckert-Norton,A. Edin, M. El Shahawy, D. Elson, J.G. Evans, G. Fain III, T.Ferguson, J. Fica, C. Fisher, D. Fitz-Patrick, D. Frid, R. Galagan,L. Gaudiani, J. Geohas, M. Goldberg, R. Goldberg, J. Gorkin,R. Goulah, R. Graf, M. Greenspan, A. Guasch, C. Guerin, N. Gupta,C.E. Guthrow, S. Haffner, J. Hamilton, L.L. Hamm, L. Hancock,J. Hawkins, K. Hershon, W. Herzog, J. Holtzman, J. Insel, G.Jilly, L. Jovanovic, L. Katz, G. Kaysen, G. Keightley III, D.Kereiakes, G. Kershaw, B. Kerzner, R. Khairi, C. Kilo, M. Kipnes,R. Kipperman, L.D. Knoll, W. Kraus, J. Lash, J. LeLevier, S.Lerman, F.M. Lester, B. Levine, R. Louard, K. Ma, R. Maddox,D. Mapel, S. Martin, R. Mayfield, J. McGill, J.F. McNeer, J.Miller, S. Miller, B. Miskin, M. Mohan, T. Mooney, B. Musa,P. Nachman, A. Nafziger, J. Nardandrea, Jr., M. Nunez, L. Olansky,P. Pagnozzi, J. Pappas, T. Parker, T. Patel, B. Phillipson,J. Pino, D. Pitts, P. Raskin, P. Reber, E. Reisin, J. Ringold,V. Roberts, D. Roh, J. Rosenstock, N. Rossi, E. Rubin, L. Rubin,D. Ruff, M. Salem, R. Santangelo, Y. Segal, K.S. Self, S. Sharma,J. Sloand, L.K. Smith, R. Solomon, C. Spellman, B. Spinowitz,D. Steward, W. Suki, S. Swan, A. Swislocki, M. Tonkon, R. Toto,N.D. Vaziri, S. Vicks, J. Villamizar, R. Vranian, T. Walden,F. Wei, M. Weinberg, M. Weir, C. Williamson, L. Wruble, W. Yeung,F. Ziel; Venezuela (31) A. Perez, J. Weisinger; CoordinatingCenter, Merck Research Laboratories: Program Coordinators R. Simpson, D. Ramjit, S. Thompson-Bell, B. McVan, D. Fong,R. Poston, G. Drucker, M. McFadden-Neyer, M. Hinz, C. Assang,D. Brown, S. Mereminsky, C. Curry, G. McPeters, B. Bertino,International Liaisons J. Lorfing, B. Koslowski, C.Wagner, C. Arena; Statisticians S. Snapinn, H. Zhang,C. White, A. Carides, D. Snavely; Data Coordinators D. Wolf, J. Sickel, C. Shanahan, K. Morgan, S. Plourde; ClinicalSupply Coordinator B. Vanslembrouck.
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