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    Joc 31359

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    © All Rights Reserved
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    Him ORIGINAL CONTRIBUTION Screening for Proteinuria in US Adults A Cost-effectiveness Analysis L-Bbony Boulware, MD, MPH Bernard GJaar, MD, MPH Mie = MD, PhD Frederick L, Brancati, MD, MAS Neil. Powe, MD, MPH, MBX alle E, Tarver HRONIC KIDNEY DISEASE 15 growing public health prob- Tem. More than 10 milion US adults havesome kidney dam- age (serum creatinine levels =1.5 mg/dl [152.6 pmol/L), and the number of per- sons with end-stage renal disease (ESRD) exceeds 300000. Persons with ESRD, who have a poor quality of life and ace crue high health care costs, are pro- jected to exceed 600000 in 2010." Early identification and treatment of patients ‘who are more likely to progress to ESRD to decrease mortality, morbidity, and costs associated with chronic kidney dis- cease has been debated. Controversy ists because many patients do not progress to ESRD, however, the major- lty of those who do progress go und tected until itis too late to intervene.’ Growing evidence indicates that the presence of relatively low levels of urine protein can be an early marker of in- creased risk of progressive kidney dis- cease, poor cardiovascular outcomes, and death.*” Prescription of angiotensin- converting enzyme (ACE) inhibitor or angiotensin I-receptor blocker (ARB) therapy in persons with proteinuria and chronic kidney disease has been dem- onstrated to decrease both the progres sion of kidney disease toward ESRD as well the incidence of cardiovascular events and death.°*" Dipstick urinalysis has imperfect ac- ‘curacy in the diagnosis of persistent pro- teinuria, but itisan inexpensive test that Context Chronic kidney disease is «growing publi health problem. Screning for cary identcation could mprove health but could also leadto unnecessary harms and excess costs Objective To assess the value of periodic, population-based dipstick screening for early detection of urine proteln in adults wih nether hypertension nor dabetes and in adults with hypertension Design, Setting, and Population Costetfectivenessanalyisusing a Markov de- ison analyte model to compare asvategy of anrualscreening with no eeening (ual Gare) for proteinuria at age 50 years followed by treatment with an anglotensin- converting enzyme (ACE) inhibitor or an angloteni I-eceptor blocker (ARB). Main Outcome Measure Cost per qully-adjustedlfe-year (QALY). Results For persons with neither hypertension nor diabetes, the costeectveness tati for screening ven screening (ual care) was unfavorable (5282818 per QALY, Incremental cost of $616 anda gal of 0.0022 QALY’ per person). However, sreen- ing such persons beginning at age 60 yeas yielded a more favorable ratio ($53372 per QALY). For persons with hypertension, the rao was high favorable ($1862% per QALY; incremental cost of $476 and again of 0.03 QALYs per person). Cost tffecvenes was mediated by bath cronckdney diease progresion and death pre- ‘enon benefits of ACE Inhibtor and ARB therapy Influential parameters that might make screening forthe general population more costeflectve include a greater ic dence of proteinuria, age at screening ($5372 per QALY for persons beginning screen- Ing at age 60 yeas), or lower fequency ofsereening (very 10 years: $80700 per QALY atage 50 years, $6195 per QALY at age 60 yeas, and $5486 per QALY a age 70 year) Conclusions ary detection of urine protein to slow progression of chronic kidney disease and decrease mortality isnot cost-effective ures selecvely dicted toward high-risk groups (older persons and persons with hypertension of conducted at an infequent inteal of 10 years, {JAMA 20032903101-3114 wer jama com can be performed in most medical set- implementation of ACE inhibitor of ARB. tings.” For persons with diabetes, rou- therapy were beneficial in slowing pro- Line screening for urine protein hasbeen gression toward ESRD, patients could shown tobe cost-effective." In con- benefit from lengthened survival and im- trast, although there is accruing ev dence that the use of ACE inhibitor — Auth Aflatons: Department of Medicne Jos dl tascethe incidence of death H0bsAS University School of Medre (Ds ou! therapy decreases the incidence of death fe Jan Branca and Powe, Deparment o Ep and slows clinical progression of dis- demilay.Jotns Hopkins Boorber senel of Pub tase for persons with chronie, nondia. leMeat (Os Boulware, Brana and Powe), Welk per = (Center for Prevenbon, Epidemiology and Citic betic proteinurie nephropathies, there is Research, Js Hoping Medes nsttutone (Drs little evidence addressing the cost. foulware, ua Taner Car, Branca and Powe) sony Balbmoe, Ma, elfectiveness of routine screening?!" Ea Me ag Reprints: Loony Bout {snot clear whether screening ofthe en- ware, MD, ME, Wein Cente fo Prevention, Ee i ‘demsoloy ands Reser, Jone opine ed. tire US adult population by physicians cy'isttutions, 2024 E Manument St, Suite 2-635, {is warranted. I'screening followed by the Balimore, MD 21205 (ema boubw20}hmi es). (©2003 American Medical Association, All rights reserved. (Reprints) JAMA, Desrer 17,2002 Vol 290, No.23 3104 ‘COST-EFFECTIVENESS ANALYSIS OF SCREENING FOR PROTEINURIA proved quality of life, and the societal economic burden of treatment of ESRD, which is approaching $45000 per al= fected patient annually, could be averted * In contrast, inappropriate screening of persons could lead to unnecessary harms and costs. Therefore, we assessed the costelectiveness of periodic, population- based dipstick sereening for urine pro- tein and subsequent teatment with an ACE inhibitor of ARB therapy in US adults METHODS: ‘Study Design The study design isa cost-ffectiveness analysis from a societal perspective for which a state-transition Markov ana- lytic model was developed to simulate the clinical path of patients from nor mal kidney function to ESRD, We com- pared a strategy of annual screening for proteinuria and subsequent treatment ‘with ACE inhibitor or ARB therapy with strategy of routine clinical practice for persons with neither hypertension nor diabetes and for persons with hyperten- sion. Although screening for persons with type 2 diabetes is already widely performed in clinieal practice, we also analyzed these strategies for persons with type 2 diabetes (many of whom would, also have hypertension) to assess the va- lidity ofthe Markoy analytic model and to providea relerence point for the com- parative magnitude of cost-effective ness ratios derived from screening non- diabetic populations.** The base-case model consisted of US adults aged 50 years (with demo- graphic characteristics similar to persons in the third National Health, and Nutrition Examination Survey [NHANES III]; 52% were female, 80% non-Hispanic white, 11% non-His- panicblack, 5% Mexican American) pre- senting to & primary care physician for aanannusl physical examination with pre- viously undetected proteinuria.” This {group was chosen because the most de- Finiuive evidence on interventionsand the natural history of chronic kidney dis- cease has included patients of this age These patients could undergo a sereen- Ing strategy or a no-screening strategy 3102 JAMA December 1003—Vol 250, No. 23 (Repited) The screening strategy consisted of a urine dipstick test to detect proteinuria Ge, L+resultona colorimetric urinedip- stick test for gross proteinuria) during anannual vist with a primary care phy- sician. Positive dipstick test results were followed up with asecond physician visit to reassess urine protein levels using quantitative random (albumin to creati- nine ratio) or timed urine specimens in addition to measurement of serum cre- atinine level and estimation of glome ular filtration rate (GFR) using recom- ‘mended equations.» Positive quantitative urine protein test results woulld prompt either subsequent treatment by a ps ‘mary care physician with an ACE inbibi- oror ARB therapy for persons with nor- ‘mal renal function of referral to and evaluation by anephrologist followed up by treatment with an ACE inhibitor or ARB therapy for persons with de- pressed renal function (defined as as a GER of <00 ml /imin per 1.73 m). Per- sons with positive screening dipstick test, resulisand negative quantitative assess ‘ments of urine protein were considered to have false-positive initial results or nonpersistent proteinuria. These per sons did not proceed with further evalu ation or treatment and could undergo rouline screening in subsequent years The no screening strategy consisted of no dipstick testing and natural progres- sion of chronic kidney disease with an annual opportunity for incidental test- ing or symptom development and dis- ease detection. Health states in the Markov model included normal kidney function (GER =90 m/min per 1.73 m’ or National Kidney Foundation Kidney Disease Outcomes Quality Initiative [KDOQI stage 1), chronic renal insuf- ficiency (GER of 15-89 mL/min per 1.73, rm or KDOQI stages 2-4), and ESRD (GER <15 mL/min per 1.73 m? oF the need for renal replacement therapy oF KDOQI stage 5) (FIGURE 1).” Distribu- tion of persons in the chronic renal insul- ficiency health state (KDOQI stages2-4) were based on prevalence data from NHANES IIL Ninety percent of persons have GFRs ranging [rom 60 to 89 ‘mL/min per 1.73 m® (KDOQI stage 2) 9.5%, 30 to 59 mL/min per 1.73 m= (KDOQ! stage 3); and 0.5%, 15 t0 29 sal /min per 1-73 m (KDOQL stage)? Sereening of ll persons occurred anni ally until age 75 yeas, the development of ESRD, oF death We categorized all evidence used in the model according to a hierarchy of research design put forth by the US Pre vventive Services Task Force and used the highest level of evidence." Probabilities Disease Incidence and Prevalence and Test Characteristics. We estimated the age-specific prevalence of proteinuria based on a positive dipstick test result among persons with varying degrees of renal function using data on the preva lence of gross proteinuria (urine pro- tein >20-30 mg/dl.) from the NHANES sohort. We also used these data to estimate the age-specific prevalence of proteinuria for persons with different clinical histories (persons with neither hypertension nor diabetes, persons with hypertension, and persons with dial tes). We estimated the incidence of pro- teimuria based on a positive dipstick: sult among all persons from published literature." We obtained estimates r garding the sensitivity and specifi dipstick testing in identifying asymp- tomatic proteinuria from published literature on test characteristics in ‘outpatient clinical practice settings (raBLE D2" ‘Adherence With Sereening and ACE. Inhibitor or ARE Therapy. We esti- mated adherence to hypothetical sreen- ing recommendations for primary care physicians [rom data for other primary ceare screening services." We esti- mated patient adherence with ACE in |hibitor or ARB therapy from data on dis- continuation of the medication due to clinical adverse effectsstuch as cough, hy- perkalemia, and hypersensitivity s well as from published data regarding anti- hypertensive medication adherence rates. For persons with either hyperten- sion ot diabetes, in both the screening and no screening (usual care) strat sles, we estimated the baseline rate of ACE inhibitor or ARB therapy use (al- ready instituted independent of screen- of (©2003 American Medical Association, All rights reserved. ‘COST-EFFECTIVENESS ANALYSIS OF SCREENING FOR PROTEINURIA ing from data on rates ofhypertensive 2diabetes Inmodelsofpersonswithnel- studying the effects of ACE inhibitor medication prescription patiernsas well ther hypertension nor diabetes or per- therapy’ in blacks reportinga41%RRre- as prevalence rates for comorbid con- sons with hypertension, ACE inhibitor duction in progression toward ESRD dltions (ie, cardiovascular disease risk therapy was presenbed for the sreen- (95% CI, 5%-63%).""° For persons with factors and heart failure), which could ingarm for persons with proteinuia:in diabetes, we used results from 2 tls prompt therapy with an ACE inhibitor models of persons with diabetes, ARB studying the ellects of ARB therapy r oF ARB therapy (Table 1). therapy was instituted (TABLE 2).°""" porting statistically significant RR r. Symptom Developmentandinciden-_ Weusedaconservative estimate 30%) _ductions for progression toward ESRD tal Testing. Forpersonsinthenosereen- fom4 randomized contoled tialsand of 3% (no Cl provided) and 28% (05% ing strategy, we estimated the rate of — metaanalysisfor the benefit provided respectively. * We used symptom development that would by ACEinhibitoror ARBtherapy inslow- reported Cls to set the extremes of ben prompt incidental testing witha urine ng progression toward ESRD forallsub- efit offered by ACE inhibitor oF ARB dipstick. Symptoms considered were groups studied. For persons with nei- therapy that were used in sensitivity those related to the genitourinary sys- ther hypertension nor diabetes, we used analyses. tem (eg, dysuria) orto the peripheral vas- results froma tral reporting 67% (but Similarly, we used conservative esti cculature or lymphatics (eg, leg edema) nonstatistically significant) relative risk mate (23%) for the benelit provided by (Table 1). (RR) reduction in progression toward ACE inhibitor or ARB therapy in redu: ESRD with ACE inhibitor therapy for ing the incidence of death for all sub- Potential Benefits and persons with IgA nephropathy, nterst-_groupsstudied. Thisestimate was based Harms of Screening Ualnephits, and polyeystickidneydis- on resulls from a cohort study of dia- Potential benefits resulting from screen ease.® For persons with hypertension, we beticand nondiabetic individuals (with ing included reductions inall-cause mor- used results froma meta-analysis oftrials and without hypertension) reporting ta- tality and progression toward ESRD con- of ACE inhibitor therapy reporting a30% —_usticallysignifieant RR reductionsof 21% ferred by ACE inhibitor or ARB therapy RR reduction in progression toward and 249% (no Cls provided) inall-cause cslimated from randomized controlled ESRD (95% confidence interval [Cl], mortality with use of ACE therapy, trials of persons with and without type 22%-44%) and we used a single trial respectively, and results froma random- Figure 1-ClnicalPathvaysn @ Markov Decsion Model for Sceening for rotemuta ‘Stage Detected Proteinuria Stages 2 Detected Petia and Chron Renal Ineulency ‘sersening ‘Slag Stages 2a ‘Undetecta Potinuia ana ‘Chron Renal Ineucency Undetected Protinua ‘ational Kidney Foudaton any Osease Outcores Quality itive dvorc Key Gsease stages: 1, doerlarRivabon ae (GFR) of 90 l/min pe 73m or {reser 2-4, CFR of 1 to 89 m/min per 1.73 m5, CFR of les than 18 mLJmun per 1.73 me Petsns with noe seas inal can develop pratt ogres to conc rena nutoency, progres to end-#age rena dete and de, Mot equen pathway ate denoted by heat tons le daced Ine represent ower rogeson tied on benef fom angotesi-convering enayne (ACE fibro” angoensn receptor cae (AR) therapy Persons who aren fe "no Screening” (usual ate) updo nt bene rm ACE bor or ARE therapy uns eases delcid va Icdetlesig or testing perormed asa result Palen symptoms (lg sweling dur, an par) wich sinatedby te upward srs om the no Sreenng path othe seeing path. The wansin om Fo aney dene cyt death not shown but wae incrprsed nto he mace (©2003 American Medical Association, All rights reserved. (Reprints) JAMA, Desemes 17,2002 290, No. 23. 8408 ‘COST-EFFECTIVENESS ANALYSIS OF SCREENING FOR PROTEINURIA ‘Table 1. Prevalence Incidence, and Screening Test Charactetsoes of Proteinuria Senaitty Analy, Base Ip Favor ‘Against Level of 350,% of Sevoning Screening Data Sources Evidenea" Frevalanos of potanura by omica ONT ‘Nether ryprtansion nor dbo oT TH om =e i Garget 2002 We Dabetes a ‘Teienea of protarana by cal tay ‘Nether hypertension nor labo oot a1 0.001 Wyatt al 1908 We Saas tara Fiperension 0S 1S oe Voyai et al" 2007 T Taba 7 5 7 Rian ata 1005 1 faa Matock ota 1 1 ‘Screarng est haractoraies ‘Senay (1 proteura) 76 95 45 Shaw ot 1985 We Woahareer aa 1050 1 Taree atal> 1072 1 Specoty > peTaMaTay 75 % ro Shaw ata TOES 1 Tarmance ‘Scroering and tstmont with ACE inher or ARS therapy 5 95 2 AAgedoa et a= 2001 H ‘Fameey tal 2007S Taner eS Puggarent ota" 1000 T Yuateta 2000 ‘Palaand Tayo 20 Barat ata 2007 12 ‘asain ale ol une of ACE PERS 2 a @ Mahia et a 1900 12 Finger stal= 2000 eae Tym OO Taeoneta 2000 ‘Sypigne aang esing by ToT GeFumLimn por 173m per yo 00 4 2 6 Chery and Woodwel 2002 We oa a = % Assumion Te © oo 3a oo ASUmOn Ta 104 JAMA December 17,2003 290, No 23 Reprinted (©2003 American Medical Association. All rights reserved Downloaded From: https:/ ‘COST-EFFECTIVENESS ANALYSIS OF SCREENING FOR PROTEINURIA ‘Table 2, isk and Seretis of Screening for Proteinuria an Heal Sate Utes SentvyAraiaes Base nFavorot Against, Level of caso,% __Seveoning Screening Data Sources Evidence Percentage Potental bereft of screening al ogroupst Fatrentonn progtensn toward ESPD ‘iloried by AGE Phir or ARE 2 8 6 afar atl? 2001 Ragptba etal" 2007 Teneetay” BOT Bremner ata 2007 Foggenent otal 2000 FReaaionn accama ara tered DByAGE retro AF 3 2 6 Gerstein et a 2001 1 Tichometa 0 Polenta pamofsosenng Persons undergeng renal bcp circa tory ‘ter perensen nor Gabel % 100 o on : ieee |] a Debates ri a Carleton do eal bapsy Feratirt cial hematont or oer carplzabon econ to biopsy 5 1 8 Mendebson and ol 1905, 3 Hac 1080 1 Harwah and Rota 1055 1 Paar 1082 1 Nassand Oe 1007 1 Timein peal or parsons unrgoha Tera boy. 23 ® 2 Nara aniKorbet* 1906, 3 RaalPinscans ecodaton, 2001 avgaarredeaon aoc raphy seconde to ACE nkibtoror ARO oot Thompson Mereradey. 20088 FRogoedimna sacondary to AE Wor z ‘om arn etal 07 7 Spars tale 19 Tabi tem SAD Posons wang htt wis on dis 10 ° 2 US Departnent of Heath We ‘sl aman Sens” 2000 cr 987 1 Ragone a 108917 SenManen eta 2007 Paso wating uiine ata ecaieg Tey vant “0 0 70 fa 1097 3 iNatateta> eT 13 — arnben tal" 12 — Tamber Lit for haath sas, GER n Linn pe 1.73 20 Without preter aso Datition NA =o Pon a6 oa Ta rasan Ni SR her wad oT) a 097 0.50 Teg and Watson = 2000 1 iB With awd prota 70 Oa ‘0.50 Tera and Wats" 2000 1 sewer oon 12 — ‘isi associ wih mecesion adherence OOH 7 DET and Wats 2000 12 ‘ecu at rues, a 7 3 Tpscomb ot 1058 NA (©2003 American Medical Association, All rights reserved. (Reprints) JAMA, Desems 17,2002 290, No.23. 8108 ‘COST-EFFECTIVENESS ANALYSIS OF SCREENING FOR PROTEINURIA ized controlled trial reporting 30% RR normal kidney function (KDOQL stage trolled trial of persons with nondi reduction (05% Cl, 26%-55%) in all- 1) toward chronic renal insufficiency _ betic, nonproteinuric nephropathies." with use of ARBtherapy _(KDOQl stages 2-4) and fromchronicre-_ Rates for persons with hypertension were for persons with diabetes."* nal insufficiency (KDOQLstages 2-4) to- obtained from 3 trials—2 examined the Potential harms incurred asa result ward ESRD (KDOQI stage 5) from data effect of ACE inhibitor therapy on pro- of screening were associated with re- obtained from both cohort studies and gression and one examined the elect, nal biopsy (including hematuria and clinical ials (TABLE 3).""""°"" Rates of diet on progression." clinical hematoma estimated [rom a for persons with neither hypertension groups in which insufficient evidence ‘cause mortal 93 Por sub- cease-series of patients) and adverse ef- nor diabetes with normal kidney func- _ wasavailable, we made conservative 2s- fects of ACE inhibitor or ARB therapy tion were obtained from observational sumptions regarding progression (see (including anaphylaxis or angio- studies reporting GFRs for healthy per- "Model Assumptions” below). edema requiring emergency depart- sons. Rates for persons with neither We oblained age and cause-specific ment visit and 24-hour observation) hypertension nor diabetes and GFRs of — mortality atesforthe US population from (Table 2).55 15 1089 mL/min per 1.73 m* were ob- the 1999 National Center for Health St. tained from tral esultsreportedon per tstics Mortality Data File." To estimate Natural Progression of Disease sons with IgA nephropathy, intersital the elect ofthe presence of prot For persons with each clinical history, nephritis, and pelyeystic kidney dis- on deaths among persons with varying c,we used data from mated rates of progression from ease enrolled in a randomized con- je 3. Annual Decne in Clomerulr Fiat Rate by lineal Hstory and Protenura Stats “Annual Decline Glomerular z Fatration Rat, Cinical History Base Ip Favor Level of and Kidney Function Case of Screening Data Sources evdence" ‘Rother rypertension nor aabeles Nopraoruna A010 1529 10 18 os Corech tal? 2008 a atonal Kaney Foundation = 2007 7 7 5 a ASSUTBDR wi 1a 1.65 0 NA az ae Zi T Fugganent eta 100 T Fiperenaon No protoria A010 15.69 1a 1.65 05s Assurption NA 1 2a oF ‘Agoda a= BOOT T 12 2a a6 Assurption NA Tew =1 a 3a 15 ‘goss eta T T T Rareatal 100d T Tata No proternia 010 1529 1 1.65 05s Nloon ot le 1996 a esac et 3 2000 1 Fachmar etal 2000 Tz Ze az i Tebow ale Tone T a 62 24 Goede a a 1900 ' Gaede etal 2008 T esac et a 2000 1 ime 32 Toa 28 Lowe et a” 2001 H H o a Puggene 00 3106 JAMA December 1 003 Vol 290, No. 23 (Reprinted) (©2003 American Medical Association. All rights reserved the NHANES 11 morality study.” Age and cause-specifi morality ratesfor pet sons with ESRD were estimated from the US Renal Data System." Costs We included direct costs of medical care aswell as the indirect costs of wages lost for persons disabled asa result of ESRD. Allcosts were in 2002 dollars and were discounted at arate of 3% per year.” Costs of screening incorporated ini- lial dipstick testing, initial and fol- low-up visits with generalist and sp. cialist physicians, and associated urin serum, radiological, and pathological testing.” Test costs were estimated us- ing Medicare reimbursement rates based on the Medicare resource-based ‘COST-EFFECTIVENESS ANALYSIS OF SCREENING FOR PROTEINURIA relative value seale for part B services (TABLE 4). ‘Costs of ACE inhibitor or ARB therapy were estimated by using a weighted av- erage of wholesale prices for § propri- lary products in the market and one nonproprietary product for ACE inhibi- totsand for 5 proprietary products in the market for ARB therapies.” Costs of emergency department visits related to adverse medication events (eg, anaphy- laxis or drug hypersensitivity) or hos- pital ime for patient observation after renal biopsy were estimated using data from the Centers for Medicare and Met fcaid Services." Costs of treatment for ESRD (KDOQI stage 5) were estimated using data from the US Renal Data Sys tem (Table 4) We estimated annual lost wages for nonworking persons with ESRD (KDOQL stage 5) usinga weighted average of pub- lished estimates of the mean percentage ‘of persons working full-time while receiv- ing either dislysis or transplantation treat- ment modalities." Personsinall other stages were considered to be working full- time until they turned age 65 years. We used data onaverage US wages from the UsDepartment of Labortodetermine the indirect cost associated with lost wages (Table 4)" Utilities Health tate utilities (ie, numerical values reflecting the relative importance of dil- ferent health states to patients) ranged from 0 (worst) to 1 (optimal) in the ‘Costs Used for fa ace Senstivty Analjeesn the Deckion Mage of Seeening for Proteinuria Senaitvty Analyses, 5 ‘Against ost Component Screening Data Sources Fla a NTE Tae ] Cort fe ed nd Mata Sein 208 Test ine dsioa 720 Fifa spect prysicin evaaion By ‘lnteal stay ‘Nether Ryprtansion nor dabotes e887 Fp ] Cort fe ed nd Mata Sein 208 Diabetes aT Falagrap speci fas Physiean 2124 81-727) centers fr Meccare and Metical Sences.” 2002 Testing 3a 1778 Kamalcost ot erapy [ACE ehibtert toast $8293 Changy" 2002 TAS Heath” 2002 dies Economies Ca" 2007 er Sia BEBE (Changs 2002 TMS Heath" 2000 adios Economies Ca" 2007 or TERT OO GEBTOSD — SEOOTST US Renal Data Sytem 200 ‘Tet wages fr nenaring parsons 27 S808 215362 —TSTEES? US Deparment of Heath and Human Senvees?™ 2000 Fane Fasgon eta? 10a van Manan 2007 Taconite © z 7 3 Tipsoonb et a> 1006 (©2003 American Medical Association, All rights reserved, (Rept) AMA, ber 17, 2003Vol 290, No. 23. 8107 ‘COST-EFFECTIVENESS ANALYSIS OF SCREENING FOR PROTEINURIA Markov model, The values werebased on standard gamble or time-tradeolf tech- niques.” Thedisuulity associated with ACE inhibitor or ARB therapy was est- mated from data reporting medicationad- verse clfects.” Uulities were discounted ata rate of 3% per year (Table 2) Analyses. Im our base-case analysis, we estimated, the cost-elfectiveness of screening be- fnning at age 50 years for persons with ceach clinical history, assuming the com- bined benefits of ACE inhibitor or ARB therapy to slow the progression to ESRD and (o prevent death. To more clearly identify the pathway through which ACE inhibitor therapy might mediate cost- effectiveness, we analyzed separate Markov models assuming only the pro- _gression-slowing benelits of ACE inhibi- tor therapy on chronic kidney disease or con death, We analyzed the Markov model us- ing cohort simulations for base-case and |-way sensitivity analyses. To ascertain whether there isan optimal age for be- sinning screening, we performed analy- ses for persons beginning screening at ages 30, 40, 50, 60, and 70 years. To as- certain whether there is an optimal fr quency of screening, we performed analyses for persons in each age group ‘with screening oceurring at intervals varying from annually to every 10 years. To determine other variables influen- Uial on costelfectiveness, we performed. sensitivity analyses in which model pa- rameters were changed individually to bias them in favor of or against sereen- ing (Table 1, Table 2, Table 3,and Table 4), We classified a change in the eost- effectiveness ratio of 50% oF more as being highly influential. We considered cost-effectiveness ratios of less than '$50000 per quality-adjusted life-year (QALY) highly favorable toward sereen- ing; $50001 to $100000 per QALY was considered moderately favorable; and seater than $100000 per QALY was considered unfavorable.” For multi- ‘way sensitivity analysis, we performed Monte Carlo analysis consisting of 1000 simulations in whichall parameters were varied simultaneously over their distri 3108 JAMA December 1003—Vol 250, No. 23 (Repited) butions (Table 1, Table 2, Table 3, and Table 4). We further tested the validity of the model by using first-order Monte Carlo analysis to assess average time spent in health states. We compared model output with nationally available data on disease incidence and mortal- lay, All analyses were performed using DATA software (Version 40, TreeAge Software Inc, Williamstown, Mass). ‘Model Assumptions Frequency of Screening. All persons without proteinuria as well as sereened persons with undetected proteinuria (alse-negative results) have the oppor- tunity to be rescreened annually. The ‘model incorporates the rate of expected rnonadherence torescreening and the [re- quency with which persons developing symptoms potentially associated with proteinuria would present to a physt- cian and have proteinuria detected us- ing routine dipstick testing methods, The number of persons not sereened but presenting with incidental symp- toms, which would prompt testing with urine dipstick, increases based on the severity of chronic kidney disease with all persons with GER of less than 15 mL rin per 1.73 m? (KDOQI stage 5) pre senting with symptoms. Persons diag- nosed as having proteinuria ater presenting with symptoms undergo the same work-up, evaluation, and subse- quent treatment with ACE inhibitor or ARB therapy as those who are detected through annual screening. Persons wn- able to tolerate ACE inhibitor or ARB therapy secondary to adverse identified early in the course of treat- ment; the long-term benefit of treat- ‘ment from such short courses (<1 year) of ACE inhibitor or ARB therapy are ‘minimal. The baseline rate at which pe sons with neither diabetes nor hype tension are already receiving ACE in- hibitor therapy (outside of screening strategy) is equal to zero. Finally, among persons with hypertension, those with newly diagnosed hypertension (approxi- rately 4%) undergo screening asa part of usual care.” Rates of Decline in GFR and Util. lies, Por persons with neither hyperte sion nor diabetes and with no protel ria, rates of GER decline from 15 10 89 mL/min per 1.73 m* (KDOQI stages 2 to) toless than 15 mL/min per 173m" (KDOQI stage 5) are no different than rates of GFR decline for persons with normal kidney function (KDOQ! stage 1) (Table 3). Among persons with net- ther hypertension nor diabetes and with proteinuria, rates of GER decline for pet sons with & GFR of 90 m/min per 1.73 m* or greater (KDOQI stage 1) are 10% greater than rates of GFR decline for their counterparts with no proteinuria (Table 3). Among persons with hyper- tension and with no proteinuria, rates of GER decline for persons with normal kidney function (KDOQI stage 1) are 10% greater than rates of GFR decline for persons with neither diabetes nor hy= pertension and with no proteinuria (Table 3). Finally, proteinuria is gener ally asymptomatic and s associated with ‘4 minimal decrement in health status, Effectiveness of ACE Therapy, Fre- quency of Physician Visits, and Costs. We asstume the ellects of ACE inhibitor therapy in reducing risk of death and in, reducing progression of renal disease are ‘equal among persons with neither hy- pertension nor diabetes and persons with, hypertension ** Persons with neither hy- pertension nor diabetes incur 3 gener alist follow-up visits per year as result fof a positive dipstick test result, Addi- ional generalist visits are not incorpo- rated for persons with hypertension oF diabetes, as they would already be un- dlr routine care. After initial specialist evaluation, persons with a GFR of 15 to {89 mL/min per 1.73 m* (KDOQI stages 2 to 4) incur one annual visit that in- ludes the measurement of serum atinine and other tests. In analyses iden- lifying the cost-efleciveness of beginning screening a different ages, we assume the effectiveness of ACE inhibitor or ARB therapy isthe sme among persons ofall, age groups. Finally, persons undergo- ing renal biopsy have a 23-hour hospi- lal stay, which increases to 48 hours in the event of complications (eg, hema- toma) (Table 2)."% Diagnostic Components, The diag- nostic components of urine tests, bi (©2003 American Medical Association, All rights reserved. iatologie, serologic, immunological, vi- rological, and radiological tests and. pathological evaluation were included. in costs for specialist evaluations of per- sons with « GFR of less than 90 mL/ min per 1.73 m?, Evaluation strategies ‘were tailored according to age and clini- cal history Urine Analyses. The urine analyses included urine microscopic examina lion, quantitative assessment of urine protein with random (albumin to cre- alinine ratio) or timed urine speci- men, urine protein electrophoresis (for persons >50 years), and urine micro- albumin (lor persons with diabetes) Hematologic and Serologic Tests These tests included a comprehensive metabolic panel, lipid profile, serum phosphate, magnesium, and calcium lev ls, complete blood count with manual differential blood count, prothrombin and partial thromboplastin times, gly- cated hemoglobin (for persons with diabetes), intact parathyroid hormone (for persons with a GFR <30 mL/min per 1.73 m), transferrin, and iron (for persons with a GFR <30 mL/min per 173m’) Immunological and Virological Tests, These tests included antinuclear anti- bodies, a rapid plasma reagent test, hepa- litis Band C serologic analysis, enzyme- linked immunosorbent assay for human immunodeficiency virus, serum pro- tein electrophoreseis (for persons >50 years; follow-up for positive serum pro- tein electrophoresis with C3, C4, and se- rum eryoglobulins). Radiological Tests. These tests in- cluded renal ultrasound and magnetic resonance angiogram of renal arteries (for persons with diabetes aged =50 years). Pathological Evaluation. This evall- ation inchided renal biopsy with ultra- sound guidance, pathological interpre- tation, and 23-hour hospital stay following uncomplicated biopsy. RESULTS Cost-effectiveness of Screening for Proteinuria Taking into account both the redue- lion in deaths and the slowing of chronic (©2003 American Medical Association, All rights reserved, ‘COST-EFFECTIVENESS ANALYSIS OF SCREENING FOR PROTEINURIA kidney disease progression with ACE in- hibitor o ARB therapy for persons with neither hypertension nor diabetes, the base-case cost-eflectiveness ratio for screening vs the usual care (no screen- ng) strategy was unavorable ($282818 per QALY saved). A gain of 0.0022 QALYs was mediated through the pre- Vention of 1 new case of ESRD and 7 deaths per I million persons per year in the screening strategy. For persons with hypertension, the costeffectiveness ra- lio for the screening strategy vs no screening (usual care) was highly favor- able ($18621 per QALY saved). A gain of 0.03 QALYs was mediated through the prevention of approximately 14 new cases of ESRD and 104 deaths per 1 mil- lion persons per year in the screening strategy. In contrast, for persons with diabetes, the screening strategy was dominant over the no screening strat- egy (savings of $217 and gain of 0.10 QALYs per person in the screening strategy). A gain of QALYs was medi- ated through the prevention of approxi- imately 84 new eases of ESRD and 541 deaths per | million persons per: the sercening strategy. The death ben- elit due to ACE inhibitor therapy had a more profound (cost-effective or cost-saving) impact on overall cost- elfectiveness than the slowing ofthe pro- gression of renal disease (TABLE 5) Harms of Screening Screening 1 million persons with ne ther hypertension nor diabetes 1: sulted in 135 biopsies, 7 biopsy com- plications, and complication costs of $91 Lo per year. Screening | million per- sons with hypertension resulted in 196 biopsies performed, 16 biopsy compli- cations, and complication costs of $2000 per year. Sensitivity Analyses Age When Screening Regins.For per- sons with neither hypertension nor dia betes, the cost-efectiveness ratio of an- nual screening vs no screening (usual care) was unfavorable until screening beginningat age 60 years (TABLE 6). For persons with hypertension, annual screening beginning at age 30 years resulted in highly favorable cost- effectiveness ratios when compared with the no screening strategy and re mained highly favorable for screening beginning at older ages (Table 6). Frequency of Screening. For 50- year-old persons with neither hype tension nor diabetes, screening less Frequently resulted in more favorable effectiveness ratios ($120727 for screening every 5 years and $80 700 for screening every 10 years). Similar re sults were found for sereening per- sons of older age at different intervals ($0195 per QALY for screening every 10 years beginning at age 60 years and ‘$5480 per QALY forsereening every 10 years beginning at age 70 years) (FIGURE 2). For persons with hype tension, screening at less frequent intervals resulted in improved cost- effectiveness for all age groups. Im- proved cost-effectiveness was medi- ated by decreased costs of screening but ‘was accompanied by a 50% to 70% de- crease in QALYs saved for persons in each screening group. Influential Parameters, FIGURE 3 shows the highly influential variables for sereening of persons with neither hy- pertension nordiabetes and persons with, hypertension. For persons with ne ther hypertension nor diabetes, scree ing approached moderately favorable cost-elfectiveness if the incidence of proteinuria and the frequency of screen- ing were set to their greatest and small- est extremes, respectively. The cost- cllectiveness of screening persons with hypertension remained highly favor- able for all variables biased against sereening at their extremes Results of multiway Monte Carlo analyses, in which all parameters were varied simultaneously over their distri butions, supported the base-case re- sults, The proportion of simulations in which screening yielded costeffectiv ness ratios ofless than $50000 per QALY, '$50000 to $100000 per QALY, greater than $100000 per QALY, and when the screening strategy was dominant over the no screening strategy (le, screening r sulted in less cost and improved quality of life) were 1.5%, 8.5%, 82.1%, and (Reprints) JAMA, Desees 17,2002 Vo 290, No. 23.8108 ‘COST-EFFECTIVENESS ANALYSIS OF SCREENING FOR PROTEINURIA ‘Table 5. cost etieciveness of Annual Dipstck Testing for Proteinuria” ‘lnical History and Screaning Gost of Stalegy, Inefomontal Effectiveness of Incremental “Seateoay inoo2 Us: ‘Gost 3 Strategy (QALY) _Effectvonass (QALY) ‘ath Death and GKD Progression Benaits Nother hypertension nor dabotes ‘Sererng 13745 616, 19.4607 one 2aoei8 No screen 13120 19.585 Fipertenson Sereenng 23007 6 0.03 18621 No screen 23a Death Benatt Only Nother hypertension nor dabotes ‘Sererng 13768 635, 19.4600 016 06600 Toscana T3137 Toasae Fipertenson Screening 2etot wor 172808 02. 7600 Toscana E T7208 ‘GKD Progression Bonaft Only Nother hypertension nor dabotes ‘Sererng 13128 12 19.4585, 9002 28 millon Toscana T3700 Toes Fipertenson Screening 23865 222 008 126645 Roscoe Zsa la 6. Conk eecivener ator for Annual DiprickTering Sartng st Ment Ager’ avslexpensive) ESRD css, ears of fe saved through the death pre ton el ‘Age Sereening Basins, fects of ACE inhibitor and ARB therapy Clinical History 6070 are augmented by the prevention of ESRD cases and their associated high 53872 _ 26929 mortality. Lack of cost-effectiveness TSE6TTSAET arises when the prevalence and inci- ‘hats aime cared Sonn and cane kne sao proterson beet sorvenng en- dence of proteinuria are very low (lead- ‘See ester oa or Ing to few preventable cases of ESRD) and when the risk of death is very low. 7.9%, respectively, for persons withnel- fied actors most likely wo alect the cost- When taking into account separately the ther diabetes nor hypertension and effectiveness of screening, Our results chronic kidney disease progression slow- 50.3%, 21.3%. 22.8%, and 5.6%, respec- show that for the majority of the US ing benefitsor the death prevention ben- lively, for persons with hypertension. population (persons with neither hy- efits of ACE inhibitor therapy for per- pertension nor diabetes), annual screen- sons with neither hypertension nor ‘COMMENT ing to detect proteinuria is not cost- diabetes, who have low incidence and Given the inexpensive and safe nature _elfective. However, based on the best _ prevalence of proteinuria, screening, of urine dipstick testing, physicians available evidence to date,selectivean-_averts very few ESRD cases and pre- right assume that frequent universal nual testing focusing on high-risk vents few deaths, The resulting mini- testing ofall adults for early detection groups shighly costellective. Forper- mal gain in QALYs is too small to of proteinuria would have value. This sons with neither hypertension nordia- balance the costs of screening and cost- study examined the cost-effectiveness betes, annual screening starting at age effectiveness ratios are very high. The of testing populations (other than 60 years or older is moderately cost- combined chronic kidney disease pro- persons with diabetes)" commonly effective. For persons with hyperten- gression slowing and death prevention seen in routine clinical settings, eluci- sion, annual screening from ages 30 to effects of ACE inhibitor or ARB therapy dated the relative mechanisms through — 70 years is highly cost-effective. for persons with neither hypertension or results in an additive gain in felding an improved bat stll effectiveness of sereening, and identi- achieved through the prevention of new unfavorable costelfectiveness ratio. In which ACE inhibitor or ARB therapy Directand indirect cost savings asso- dil mediate the presence or lack of cost- ciated with screening are primarily QALYs 3110 JAMA December 1 003 Vol 290, No. 23 (Reprinted) (©2003 American Medical Association. All rights reserved the subgroup of persons with neither by pertension nor diabetes who are aged 60 years or older, the incidence of ESRD Jh enough to balance ing and subsequent treatment with ACE inhibitor therapy. Costelfectiveness ratios are far more fs. vorable in persons with hypertension, in which the incidence and prevalence of proteinuria, renal disease progression, and the risk of death are greater Physicians must incorporate a varl- ety of considerations into decisions re- garding early disease detection. Our analysis helps to elucidate the most im- portant determinants of the value of sereening for proteinuria, Influential variables that might make cost- effectiveness more favorable include: adherence to ACE inhibitor of ARB therapy, the incidence of proteinuria, sensitivity and specificity of testing, the effectiveness of ACE inhibitor of ARB therapy in slowing progression to- ‘ward ESRD or preventing death, andde- creasing the frequency of sercening. is well-known that adherence to recommended screening and treat- ment strategies is associated with be ler outcomes, but it i less than opti- mal for many chronic illnesses.””" Reasons for poor adherence include: both patient and physician factors such as difficulty with taking medications duc oadverse effects or costs, patients perceived control over theirillness, trust in physician recommendations, abil- ity to understand how to correctly use prescribed medications, perceptions regarding the patient-physician rela- tionship, and physician adherence to recommendations.” of screening for urine protein will depend heavily on whether patientsand physicians are able to overcome such, barriers to adherence Fortunately, nationally repre live data were available to estimate the prevalence of proteinuria among US adults with varying degrees of renal function, which greatly strengthens our findings + While national evidence r garding incidence is not available, we ‘obtained estimates from the highest quality data sources available. For °°" The success (©2003 American Medical Association, All rights reserved, ‘COST-EFFECTIVENESS ANALYSIS OF SCREENING FOR PROTEINURIA persons with neither hypertension nor diabetes, slightly greater proteinuria in- idence could substantially improve cost-efectiveness estimates. The imperfect sensitivity and spect- ficity of dipstick testing as an initial, screening for urine protein pose a chal- lenge for clinicians. Inaccurate ident fication of persons with false-positive urine dipstick results could adversely allect the cost-effectiveness of sereen- ing by subjecting unaffected persons to unnecessary additional testing and evaluation by physicians, Misidentifi- cation of persons with false-negative re- sults could increase rates of ESRD with accompanying lesser quality of lifeand substantial costs of renal replacement therapy. Purther study is needed to de- termine whether the use of more sen- sitive and specific quantitative meth- ods for ascertainment of urine protein (which could be associated with in- creased cost and more difficult impl mentation) would enhance the cost- effectiveness of population-based sereening. Our estimates of the benefits of ACE Inhibitor or ARB therapy are based lirely on data from randomized con- trolled clinical trials, which are con- sidered to be the best study design for assessing the efficacy of pharmacologi- cal interventions."*"""* However, complete translation of therapeutic ef Fectiveness observed in the clinical trial setting is often difficult to achieve in routine clinical practice because prac licing physicians are faced with treat ing diverse patient populations that may not completely reflect the characteris lies of persons studied in trials. Thus, Figure 2. Cost-effectvenes of Screening vs Not Screening for Proteinuria at Diferent Frequencies and Different Ages | com] Fs SE 2 Soe | 22 : 8 ion © uo |= i 8 Fer parson wh nether ypartenson nor diabetes, he shaded wea mcentersering aocated wth more faverablecosttfecvenss aos (5100000 per quall-adusted eye (QALYD For pasos with Ry prrlenson,seening beging at al ages was high favorable toward seeing (80000 per QALY) (Reprints) JAMA, Decrer 17,2002 Vol 290, No.23 3141 ‘COST-EFFECTIVENESS ANALYSIS OF SCREENING FOR PROTEINURIA cost-effectiveness ratios could be dif- ferent for some practice settings. Identification of the optimal sereen- ing frequency requires consideration of both the clinical benefits patients may gain and the added cost." Infrequent screening yielded moderately favorable ccostelfectiveness ratios for persons with neither diabetes nor hypertension and. Iurther improved cost-effectiveness of screening for persons with hyper- tension. However, improved cost- elfectiveness resuilied from not only less costs acerued from screening and treat- ‘ment of persons with proteinuria butalso from decreased QALYs gained asa result of fewer persons beneliting from chronic kidney disease progression and death prevention benelits of ACE inhibitor or ARB therapy. Groups making recom- mendations on the frequency of screen- {ing will have vo decide whether the elini- Figure 3. Used for Parameters ostetfeciveness of Annual Screening for Protenuia When Different Values Are ‘rom sc0 te co mun per 72 nf Fem 6019 clamum per 7207 ‘GxD inaicates chronic Kidney disease, ESRD, end-stage renal disease. Bars represent how the cox ‘itectveness ato changes when eaere values for parameters ae used campured wth the paar a er ued nthe basecse analy of he model 3112 JAMA December 1003—Vol 250, No. 23 (Repited) calbenefitof preventing few more eases of ESRD or death outweighs the added cost of more frequent screening. Limitations of this analysis deserve mention. Fist, few data exist regarding the mannerin Which US physicians eur- rently evaluate proteinuria oF the f «quency with which USnephrologsts pe form diagnostie studies on patients with different clinical histories A variety of ‘other tests with different sensitivities and specificities for detection of proteinuria (cg, direct measurement of urine micro- albumin or assessment of urinary albu- min to creatinine ratio) are available. ‘Our sensitivity analyses provide insight into the cost-elfectiveness of more or less sensitive or specific tests. However, dence is needed to determine the mpor- lance of detecting microalbuminuria in the progression of chronic kidney di cease among persons without diabetes. Second, few data are available regard- ing the incidence with which intermi tent testing s performedas a result of pa Lient symptoms or in response to other abnormal laboratory test results (such as clevated serum creatinine measure- ments). Ifincidental testing were to 0c ccur at higher rates, the cost-effectiv ness ofsercening would be les favorable. Third, litle published evidence is avail- able 10 estimate the rates of decline in ‘kidney function for persons with nei- ther diabetes nor hypertension, for per sons with hypertension who have no pro- teinuria, and for persons in these groups ‘who have relatively normal kidney fure- tion." However, we made conserva Live estimates of progression rates when evidence was not available and sereet ing estimates were not highly influ cenced at the extremes of our estimates insensitivity analyses. Finally, while cost- effectiveness ratios for urine dipstick screening in certain groups may be termed favorable using conventional Unresholds for reporting cost-eflectiv. ness, this model portrays sereening, largely in isolation from other sereet ing practices being performed in clini- cal settings. Inaddition, this model does not account for often debated, lated health-care costs that may accrue asa result of the implementation of li (©2003 American Medical Association, All rights reserved. prolonging interventions." Consider ations regarding implementing strate- gies deemed cost-effective should incorporate recognition of the limited. total resources available for the provi sion of healthcare services to society and should seek to allocate resources in a manner that allows the maximum net benefit from their use." In conclusion, sereening of US adults, for early detection of urine protein to slow the progression of chronic kidn« disease and to decrease mortality is not cost-ellective unless selectively di- rected toward high-risk groups (older persons and persons with hypertension). Adherence to ACE inhibitor or ARB therapy, the incidence of proteinuria, the ellectiveness of ACE inhibitor or ARB therapy in preventing death or progres- sion toward ESRD, and the frequency of sereening play a prominent role in the ccost-elfeclveness of sereening inthe gen- eral population, ‘Author Cotibutions: Dr Boulware had ul aces to ditain ne study ana kes respons forthe eg Hy ofthe dala andthe sccracy of he ala ana Say concept and desig: Boulware lar, Sanat, Powe, ‘easton of dat Bouvae a, Tave-Car Powe ‘alysis and interpretation of data: Boulware, ‘averCar Powe. Drafting afte manuscrit: Bouware, Powe. (Cite eusin f the manus for important in fetecual content: Boulware, lar, Tavera Brana Powe Satsical expertise: Boulware, Taner-Car. bain enang Boulware Bravest. Powe Administrative, technical, of mate suppor: Boulware, Jar, Powe Funding Suporte. Thsworkwassiperted by ami gant tem tre Natonal Key Foundation of May lop (Os Boulware and Powe), gant RO IDKSSGT6. (731 (rBeutware) ana 4080063 Oe Powe) fom ‘he Nstonl tte of Diabetes and igesive ada ‘oy Dassen andthe Kobe Wao ebnsn nat ada acy Devdopmert Program (Boulware) Role ofthe Sponsor: Fung egarzatos hd no olen the design o conduct of te sty In aa {on the Sponsarspettomed ro data calecbon, dla nas, or interpretation of the dala. The mand Scop was reed on by te autos: the funding ‘ranzatone had no lem the preparon, reve rappel of te mansscrt ERR 4. Jones CA, McQhitan GM Kusek Vl Serum create eves the US popalabon Am Kidney Die 199832952 998, 2 cove), Aton 8, Greene T, Boyan ©, Levey As Prevalence of chrome adney dete and de (eased key function nthe adult US popuaton ‘an Rian Bs 2003 4-12 SMe MP, lager K, Dede FW, ea, Quy Gite pens on cvoric dass. Am Kidney Di ‘sr 2se382 (©2003 American Medical Association, All rights reserved, ‘Downloaded From: https://jamanetwork.com/ on 09/06/2023 ‘COST-EFFECTIVENESS ANALYSIS OF SCREENING FOR PROTEINURIA 4. US Renal Data Sytem. USRDS 2002 mua Data Repo asf En stage Real Deas inthe Utes States. Atala a: iti usds gach ‘Acceed Mate 30,2003, 5. Kinzen KS, Sade Fink N, et aL. The tinng of ‘pecaltevautonin cheney dase and mes {aly- An itn Med 2000-137 479-186. 6. Cestin HC, Mann, V1, Aburinutiaand Toko erdovascuar events, death na ea aure Indlabete ang nendabetc indie JANA. 2001 Beare 7. I Cestein HC, Pogue Bosch), Yast Renal mstene asa pei of carver et ‘oe andthe pt amp: the HOPErandor- ined ial Ann intr Med 200-134629-626 1 Lndnci osen Dante a. Cardona ‘ar morbity anamotalty patients win cae {erin the Loran tereton For Endpoint Ree. ‘on in Hypeteson Study (FE a andorssed al {gant tell, Lancet. 2002358 1004-1010 Stitt Sch CH Lands Me Angiotensin ‘envering ene instars nd progression of on ‘Gabetie eral vee: a meta-anayse of pate. tovel data Ann Item Med 200113573-97 40. Agoda LY, Appel L ake CL, eal. tect of fap vs amldipine on real utcomes in hyper {enavenephoslerossa randomized coiled Wa Tals 2001 285.719-2728, 41. Lewis, HunsterLG, Cake WR, ea Rene protective fect ofthe angotens-ecepior antago ‘stebetanin patents wth nepiropaty dus oe 2 dabetes. Enel Med. 2001388 851-860. 42 Brenner BM, Cooper ME, de ZeeuwO, et aE {ects of losartan on renal and cardovatutrou ‘comesinpabents ith ype diabetes and neptopa- {hy M gl Med. 2001345. B61-B63 1. Cac, Serbo Karns Avram A Ro he unas lapsed frdgs nase scenng of aati aus. Clin Chem 1987 3 21082106 4. Coan L,Bihmeyer ID, Witch HG. The cost,

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