Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
    • Reprint Information
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Reprint Information
    • Subscriptions
    • Feedback
  • ASN Kidney News
  • Other
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
    • Reprint Information
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Reprint Information
    • Subscriptions
    • Feedback
  • ASN Kidney News
  • Visit ASN on Facebook
  • Follow CJASN on Twitter
  • CJASN RSS
  • Community Forum
Diabetes and the Kidney
You have accessRestricted Access

Design of Combination Angiotensin Receptor Blocker and Angiotensin-Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D)

Linda F. Fried, William Duckworth, Jane Hongyuan Zhang, Theresa O'Connor, Mary Brophy, Nicholas Emanuele, Grant D. Huang, Peter A. McCullough, Paul M. Palevsky, Stephen Seliger, Stuart R. Warren, Peter Peduzzi and ; for VA NEPHRON-D Investigators
CJASN February 2009, 4 (2) 361-368; DOI: https://doi.org/10.2215/CJN.03350708
Linda F. Fried
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William Duckworth
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jane Hongyuan Zhang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Theresa O'Connor
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mary Brophy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nicholas Emanuele
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Grant D. Huang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter A. McCullough
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul M. Palevsky
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephen Seliger
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stuart R. Warren
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter Peduzzi
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

Abstract

Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can slow the progression of diabetic nephropathy. Even with ACEI or ARB treatment, the proportion of patients who progress to end-stage renal disease (ESRD) remains high. Interventions that achieve more complete blockade of the renin–angiotensin system, such as combination ACEI and ARB, might be beneficial. This approach may decrease progression of nondiabetic kidney disease. In diabetic nephropathy, combination therapy decreases proteinuria, but its effect in slowing progression is unknown. In addition, the potential for hyperkalemia may limit the utility of combined therapy in this population. VA NEPHRON-D is a randomized, double-blind, multicenter clinical trial to assess the effect of combination losartan and lisinopril, compared with losartan alone, on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria.

The primary endpoints are time to (1) reduction in estimated GFR (eGFR) of > 50% (if baseline < 60 ml/min/1.73 m2); (2) reduction in eGFR of 30 ml/min/1.73 m2 (if baseline ≥ 60 ml/min/1.73 m2); (3) progression to ESRD (need for dialysis, renal transplant, or eGFR < 15 ml/min/1.73 m2); or (4) death. The secondary endpoint is time to change in eGFR or ESRD. Tertiary endpoints are cardiovascular events, slope of change in eGFR, and change in albuminuria at 1 yr. Specific safety endpoints are serious hyperkalemia (potassium > 6 mEq/L, requiring admission, emergency room visit, or dialysis), all-cause mortality, and other serious adverse events.

This paper discusses the design and key methodological issues that arose during the planning of the study.

In 2003, approximately 50% of incident ESRD was due to diabetes; of these cases, 90% were due to type 2 diabetes (1). The overall rate of ESRD secondary to diabetes has risen 68% since 1992 (1). Use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) can slow the progression of diabetic kidney disease. For example, the Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study examined losartan versus placebo added to a standard antihypertensive regimen in 1513 individuals with type 2 diabetes and overt nephropathy (2). Losartan decreased the risk of doubling of serum creatinine, ESRD, or death by 16%; decreased the risk of doubling of serum creatinine by 28%; and decreased the risk of ESRD by 25% compared with placebo. In the Irbesartan in Diabetic Nephropathy (IDNT) study, which examined irbesartan versus amlodipine versus placebo in 1715 individuals with overt nephropathy, use of ARBs decreased the risk of doubling of serum creatinine, end-stage renal disease or death by 20%, decreased the risk of doubling of serum creatinine by 33% and decreased the risk of end-stage renal disease by 23% compared with placebo (3). Despite the benefit of ARBs in these studies, progression of kidney disease still occurred in approximately 30% of ARB-treated individuals (2,3), highlighting the urgent need for additional therapies to reduce this risk of progression.

Combination ACEI and ARB has been proposed as a potential approach to slow the progression of nephropathy (4). COOPERATE (Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease), a study of 238 individuals with nondiabetic nephropathy (mainly IgA nephropathy) found that combination trandolapril and losartan decreased proteinuria and progression of kidney disease by 50% (5). However, the results of this study have recently been called into question (6,7). The Ongoing Telmisartan Alone and in Combination with Rampiril Global Endpoint Trial (ONTARGET) study was designed to test the effects of combined ACEI and ARB treatment on cardiovascular disease events in patients at high cardiovascular risk. A recent analysis of renal endpoints was published (8). Their overall findings, that combination ACEI/ARB therapy was no better than monotherapy and may in fact increase risk of certain renal outcomes, needs to be tempered by the fact that only a small subset of their patients had proteinuria and the ONTARGET renal endpoints were all secondary endpoints of the main study. Indeed, in patients with overt diabetic nephropathy in ONTARGET, there was an 8% statistically insignificant benefit with combination therapy. Although combination therapy has been shown in several relatively short trials to decrease proteinuria in individuals with diabetes (9–15), benefits may be limited by a potential increased risk of serious hyperkalemia in these patients (16). These factors all underscore the need for a larger study that examines the long-term effect of combination ACEI and ARB on progression of diabetic nephropathy.

In this article, we describe the key design and methodological issues that arose during the development of a Department of Veterans Affairs (VA) Cooperative Studies Program (CSP)-sponsored study: Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy: VA NEPHRON-D Study: NEPHROpathy iN Diabetes Study (CSP #565).

Overview of Study Design

VA NEPHRON-D is designed as a multicenter, prospective, randomized, parallel group trial to test the efficacy of the combination of an ACEI with an ARB as compared with standard treatment with an ARB alone on the progression of diabetic nephropathy (Figure 1). Participants are individuals with type 2 diabetes with overt nephropathy and an eGFR between 30 and 89.9 ml/min/1.73 m2. Specific inclusion and exclusion criteria are listed in Table 1. The inclusion criteria were designed to select a study sample that was as reflective as possible of the larger population of Veterans Health Administration outpatients with type 2 diabetes and nephropathy who would be candidates for ACEI and ARB therapy. The specific study endpoints are listed in Table 2. If individuals meet the primary endpoint as assessed by decline in eGFR, they will continue to receive study medication and will be followed for development of ESRD or death.

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Interventions in the VA Nephron-D study.

View this table:
  • View inline
  • View popup
Table 1.

Inclusion and exclusion criteria

View this table:
  • View inline
  • View popup
Table 2.

Study outcomes

All participants will receive open label (unblinded) losartan 100 mg. Individuals who are enrolled in the study and are not currently being treated with losartan 100 mg (either on another ARB or ACEI or no ACEI or ARB) will change to treatment with losartan 50 mg/d. There will not be a washout of prior ACEI or ARB medication. Two weeks later, if this dose is tolerated, with no more than a 30% increase in serum creatinine and a potassium level < 5.5 mEq/L, the dose of losartan will be increased to 100 mg/d. The purpose of uniform and unblinded treatment with losartan is twofold: (1) to achieve an accepted standard of care; and (2) to reduce variation in both arms with respect to the pharmacologic blockade of the renin angiotensin system with background medications. If losartan at 100 mg/d is tolerated, the participant will be randomized to receive either blinded study ACEI (lisinopril 10 mg) or matching placebo. Randomization will be stratified by site and within site by baseline albuminuria (< 1 versus ≥ 1 g/g creatinine) and eGFR < 60 ml/min/1.73 m2 (stage 3 CKD) versus ≥ 60 ml/min/1.73 m2 (stage 2 CKD). These strata were chosen as both GFR and albuminuria are not only influential independent determinants of progression of kidney disease, but also may modify the effect of ACEI and ARB on progression (5,17). The dose of lisinopril/placebo will be titrated in 2-wk intervals to 20 mg, then to 40 mg/d or maximally tolerated dose. Potassium and creatinine will be assessed after each adjustment. After titration to the highest tolerated ACEI dose, all participants will be followed every 3 months for endpoints and assessment of adverse events until the study ends, for up to 5 yr.

It is anticipated that the most common complication associated with study therapy will be hyperkalemia. The aggressiveness of treatment of hyperkalemia will depend on the degree of elevation and the presence or absence of ECG findings. If during follow-up, a participant's potassium level increases to >5.0 mEq/L, she or he will be prescribed a low-potassium diet. If the potassium level increases to >5.5 mEq/L, conservative measures, including adjustment in diuretics, administration of chronic alkali supplements, liberalization of salt intake, or chronic use of low-dose sodium polystyrene sulfonate, will be instituted. If the potassium level is > 6.0 mEq/L, the study medications will be stopped until the level decreases to < 5.5 mEq/L. The medication will then be reinstituted at 50% of the prior dose. If the potassium level is > 6.5 mEq/L, study medication will be stopped permanently. If study medications are stopped, individuals will continue to be followed for study endpoints. The study also includes a biorepository of serum, plasma, and urine for samples collected at 1 yr after randomization and a DNA substudy for future studies on factors related to diabetic nephropathy and its complications. The study will be monitored for safety and efficacy by an independent data-monitoring committee.

Sample size was calculated using the method of Lachin and Foulkes (18) for the log rank test and was based on a 5-yr cumulative event rate in the monotherapy arm of 45% (based on event rate in RENAAL [2] and the older age of the VA population, which would be expected to increase the mortality rate), 18% reduction in the cumulative event rate with combination therapy (i.e., 23% reduction in the hazard rate), 85% power, type I error of 5% (2-sided), 10% loss to follow-up, and a 5-yr study with 3 yr of recruitment and minimum 2 yr of follow-up. The target sample size will be 1850 participants and is expected to generate 758 primary events by the end of the study. This sample size will provide 80% power to detect a 16.7% reduction in the cumulative event rate with combination therapy (i.e., 21% reduction in the hazard rate).

Methodological Issues

A number of methodological issues, summarized in Table 3, arose during the design of the current study. They are detailed below.

View this table:
  • View inline
  • View popup
Table 3.

Main methodological issues during design of VA NEPHRON-D

Selection of Study Treatments

Should Monotherapy Be an ACEI or an ARB?

The initial plan was to use an ACEI as baseline monotherapy and add an ARB/placebo, because ACEI is currently the VA standard of practice. However, scientific reviewers raised the concern that ACEI has not been clearly proven to be effective in delaying progression of nephropathy in type 2 diabetes, as compared with type 1 diabetic nephropathy. An ARB, and in particular an ARB that was FDA approved for type 2 diabetes, was recommended.

ACEI and ARB have been found to be of comparable benefit in heart failure or after myocardial infarction, but some individuals discontinue ACEIs because of their side effects (19,20). The major difference in side effects is due to the development of cough with ACEIs. Of the few studies that directly compared the effect of ACEI versus ARB on changes in albumin excretion, most have found that the two are equivalent. Human studies protection was a primary factor in deciding the class of medications to use as monotherapy. Because progression to diabetic nephropathy is a serious condition and there is an effective therapy, the control group should include a therapy that has been shown to be effective (21). Although the planning committee felt that ACEIs and ARBs were likely equally effective in nephroprotection, there were no definitive data to demonstrate equivalence. Therefore, an ARB was selected as the monotherapy treatment for VA NEPHRON-D because it offered the best option from both clinical and scientific standpoints.

Should There Be Three Arms or Two?

Given the uncertainty of whether there is a difference in the efficacy of ACEI and ARB on progression of kidney disease, the question of whether the study should be a three-arm study (ACEI alone versus ARB alone versus combination) was also considered. This uncertainty could be conceptualized as two study questions: (1) Are ACEI and ARB equivalent treatments? and (2) is combination therapy more effective (superior) than monotherapy for slowing progression of diabetic nephropathy in type 2 diabetes? This conceptualization has implications for sample size requirements. A very large sample size would be required to address equivalence (> 4000 individuals to address the ACEI versus ARB question alone, assuming a 3% difference in proportion reaching endpoint; > 2500 if a 4% difference). Thus, to address both questions in a single trial with equal allocation would require sizing the trial to address the equivalence comparison, which was not feasible and also complicates the trial's ability to address multiple hypotheses. An alternative would be to use an unbalanced design and to allocate more individuals to the monotherapy arms (equivalence question) and fewer to the combination therapy arm (superiority question). This approach would still require a large sample size and would detract from the more clinically relevant question of whether combination therapy slows the progression of diabetic nephropathy. The study was therefore designed as a two-arm trial to compare ARB to a combination of ARB plus ACEI.

Should the Study Standardize and Manage Diabetes and Kidney Disease-Related Care?

The issue of what aspects of kidney and diabetes care should be managed by the study was raised. Because it has been suggested that the benefit of ACEIs and ARBs is related to BP control (22), it was felt that it would be important for interpretation of study results to manage BP as part of the study protocol. The target systolic BP was 110 to 130 mmHg, and the target diastolic BP was < 80 mmHg. BP management will follow an algorithm of medications if the BP is not controlled, avoiding other agents that inhibit the renin-angiotensin-aldosterone system (Table 4). A low-sodium diet will be recommended, unless it is felt it would exacerbate a tendency to hyperkalemia.

View this table:
  • View inline
  • View popup
Table 4.

Management of hypertensive medications

Other aspects of diabetes care (e.g., lipid and glucose management) or nephrology care (e.g., anemia and mineral metabolism) will be managed by the participant's usual medical provider, with emphasis on the targets in VA clinical practice guidelines. Although the study is designed to assess the efficacy of combination therapy, allowing these aspects of care to be managed in accordance with usual medical practice will decrease the complexity of the study intervention, and the study results will be more generalizable. This strategy strikes a balance between the more explanatory protocol design of an efficacy trial versus the more pragmatic, real-world approach of an effectiveness trial.

Endpoints

How Should the Change in Kidney Function Endpoint Be Defined?

The primary and secondary endpoints in this study can be viewed as a combination of a surrogate endpoint (change in kidney function) with harder events (end-stage renal disease or death). The endpoint needed to be one that was feasible for the resources available for a randomized study. To use ESRD or death as an endpoint would require either a very long follow-up or enrollment of only advanced CKD, i.e. those patients that would be expected to could reach ESRD in the time frame of a typical randomized trial. We therefore chose an endpoint that incorporates a decremental change in kidney function. While progression to development of end-stage disease is an endpoint of greater clinical significance to patients than is a decline in kidney function, a progressive decline in kidney function is a prerequisite for this progression to end-stage disease. The composite outcome of doubling of serum creatinine, end-stage renal disease or death has become a standard outcome in kidney disease progression studies. Furthermore, the FDA has accepted a doubling in serum creatinine as a surrogate measure of change in renal function. Since serum creatinine is inversely related to eGFR, a doubling of serum creatinine is approximately equivalent to a 50% decline in eGFR (23). To standardize the outcome, serum creatinine will be measured at a central laboratory at the University of Maryland, using a IDMS traceable method. Urine albumin levels will be measured locally.

The upper limit of estimated GFR for inclusion in this study is less than 90 ml/min/1.73m2. The range of GFR is somewhat larger than that for RENAAL or IDNT. As a result, participants may be enrolled earlier in their course of disease than those in either the RENAAL or IDNT studies. Since the rate of decline in GFR over time in an individual is relatively constant, inclusion of participants with a higher baseline estimated GFR will decrease the number who would be expected to double their serum creatinine (or halve GFR) over duration of the study. For example, for a person with a baseline eGFR of 80 ml/min/1.73m2, the absolute change in eGFR necessary for a 50% reduction would be 40 ml/min/1.73m2 as compared with a decline of only 20 ml/min/1.73m2 if the baseline eGFR was 40 ml/min/1.73m2. At the same rate of decline of renal function, it would take twice as long for a participant with the higher eGFR to reach this endpoint than one with the lower baseline eGFR. Thus to reach the endpoint during the study time, the participant would either need to be a fast progressor or have a low eGFR at baseline (24).

A wider GFR range enables generalizability to a larger proportion of patients, while still identifying a group at high risk for progression of kidney disease, given presence of overt nephropathy. Since the endpoint of doubling of serum creatinine (halving of eGFR) is an arbitrary cutoff, it was felt that a more appropriate measure of change in renal function would be to include an absolute decline in GFR for those participants with a higher baseline value. A cutoff of 30 ml/min/1.73m2, which corresponds to a change in one KDOQI stage of CKD, was chosen. This approach of using different cutoffs for decline in GFR for different baseline is similar to the approach of the Modification of Diet in Renal Disease Study, which had two clinical renal stopping points for decline in GFR (25).

Thus, the composite endpoint includes both end-stage renal disease and GFR change and covers both end-stage and pre-end-stage renal disease. It also increases the event rate and makes the study more feasible. To address the concern that change in kidney function is a surrogate measure, participants will not exit from the study once the eGFR endpoint is reached and will continue to be followed on study medication for development of ESRD or death. However, it is expected that the study endpoint will be driven by change in kidney function.

Include mMortality in the Primary Endpoint?

Death is included in the composite endpoint because it may be a competing risk for progression of kidney disease and/or development of ESRD. That is, individuals with diabetic kidney disease have an increased mortality and may die before reaching the GFR decline or ESRD endpoints, particularly for the older individual with diabetes (26). If combination therapy alters mortality independent of the effect on progression of kidney disease, it may confound the interpretation of the renal endpoint. However, this view should be balanced against the findings of RENAAL and IDNT where the use of an ARB did not decrease mortality (2,3). One possible reason for the lower effect size observed in RENAAL and IDNT for the primary composite endpoint compared with earlier studies in nondiabetic kidney disease or type 1 diabetes (effect sizes closer to 50%) is the higher mortality in patients with type 2 diabetes (17,27–29).

Including mortality in the composite endpoint increases the potential number of events (increasing power), but if mortality is not impacted by the intervention, the effect size would be smaller (decreasing power). Because the VA population is typically older, mortality may be greater than prior studies and could be a competing risk. For this reason, mortality was included in the primary endpoint, and renal outcomes alone (change in eGFR and progression to ESRD) make up the secondary endpoint.

Should Cardiovascular Events Be Endpoints?

Studies on the effect of monotherapy with ACEI or ARB on the risk of cardiovascular disease in individuals with type 2 diabetes without nephropathy have shown only modest effects on cardiovascular events. In IDNT and RENAAL, ARB use was associated with a 10% decreased risk of the composite outcome of cardiovascular endpoints (2,3). However, losartan decreased the risk of heart failure in RENAAL and IDNT (2,3). Studies of the association of combination ACEI and ARB therapy with cardiovascular events have found mixed results (Table 5). Three large studies examined the efficacy of combination therapy in patients with heart failure. In all three, combination of ACEI/ARB led to a reduction in hospitalization for heart failure (19,30,31), but the combination of ACEI and ARB did not decrease overall mortality compared with monotherapy. Combination therapy with ACEI and ARB did reduce cardiovascular mortality and cardiovascular events in the Candesartan in Heart Failure - Assessment of Reduction in Mortality and Morbidity study, although part of the reduction could be related to the greater reduction in BP that was achieved with combination therapy (31). The ONTARGET study did not find a benefit of combination therapy (Table 5) (32). Importantly, there was a higher risk of hyperkalemia (K+ > 5.5 mEq/L, n = 480, [5.6%] with combination therapy versus 283 [3.3%] with ramipril and 287 [3.4%] with telmisartan).

View this table:
  • View inline
  • View popup
Table 5.

Effect of combination ACEI/ARB on cardiovascular events

On the basis of these data, we could not assume a larger effect for combination therapy on a cardiovascular endpoint than what was observed for monotherapy (RENAAL and IDNT (2,3), that is, 10%. Therefore, our study would be underpowered to detect the expected small effect of combination therapy on cardiovascular outcomes given for the target sample size.

Although cardiovascular events were felt to be an important outcome, collecting sufficiently complete data on these events to allow central adjudication would be costly and increase the workload of site staff. Therefore, a compromise was reached in which local adjudication of cardiovascular events was used, with a prespecified set of criteria for diagnosis. If the event occurred outside of the VA system, the site staff would seek the discharge summary. For VA admissions, these data would be readily available because the VA medical record is completely electronic. Serious adverse event reports will also be used to ascertain completeness of event capture.

In conclusion, VA NEPHRON-D will be a large trial evaluating the safety and efficacy of ACEI/ARB combination compared with ARB alone on progression of diabetic nephropathy. The study began enrollment July 2008.

Appendix

Planning committee members

Linda F. Fried, MD, MPH, VA Pittsburgh Healthcare System/University of Pittsburgh Medical School

William Duckworth, MD, Phoenix, VA/Arizona State University/University of Arizona, Phoenix

Stephen Davis, MD, Vanderbilt University School of Medicine

Nicholas Emanuele, MD, Hines/North Chicago VA and Loyola University Medical Center

Thomas Hostetter, MD, Albert Einstein Medical College

Peter A. McCullough, MD, MPH, William Beaumont Hospital

Paul Palevsky, MD, VA Pittsburgh Healthcare System/University of Pittsburgh Medical School

Mark Pfeffer, MD, PhD, Brigham and Women's Hospital

Stephen Seliger, MD, MS, VA Maryland Medical Center/University of Maryland School of Medicine

Robert Star, MD, NIDDK

Robert Toto, MD, University of Texas Southwestern Medical Center at Dallas

West Haven Cooperative Studies Coordinating Center, West Haven, CT

Jane Hongyuan Zhang, PhD

Theresa O'Connor, PhD

Peter Peduzzi, PhD

VA Cooperative Studies Program Research Pharmacy, Albuquerque, NM

Stuart Warren, JD, PharmD

MAVERIC Core Laboratory, Boston, MA

Mary Brophy, MD, MPH, VA Boston Healthcare System/Boston University School of Medicine

Health Economics Resource Center (HERC), PAlo Alto, CA

Patricia Sinnott, PT, PhD, MPH

VA Central Office Research and Development

Grant D. Huang, MPH, PhD

Timothy O'Leary, MD, PhD

Disclosures

VA NEPHRON-D is funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development and is supported in part by a grant of study drug from the Investigator-Initiated Studies Program of Merck & Co., Inc. The opinions in this paper are those of the authors and do not represent those of Merck & Co., Inc.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • Received July 7, 2008.
  • Accepted October 2, 2008.
  • Copyright © 2009 by the American Society of Nephrology

References

  1. ↵
    United States Renal Data System: USRDS 2003 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, in, edited by National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD,2003
  2. ↵
    Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med345 :861– 869,2001
    OpenUrlCrossRefPubMed
  3. ↵
    Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med345 :851– 860,2001
    OpenUrlCrossRefPubMed
  4. ↵
    Azizi M, Menard J: Combined blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Circulation109 :2492– 2499,2004
    OpenUrlFREE Full Text
  5. ↵
    Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T: Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial. Lancet361 :117– 124,2003
    OpenUrlCrossRefPubMed
  6. ↵
    Bidani A: Controversy about COOPERATE ABPM trial data. Am J Nephrol26 :629 , 632,2006
    OpenUrlCrossRefPubMed
  7. ↵
    Kunz R, Wolbers M, Glass T, Mann JF: The COOPERATE trial: A letter of concern. Lancet371 :1575– 1576,2008
    OpenUrlCrossRefPubMed
  8. ↵
    Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, Wang X, Maggioni A, Budaj A, Chaithiraphan S, Dickstein K, Keltai M, Metsarinne K, Oto A, Parkhomenko A, Piegas LS, Svendsen TL, Teo KK, Yusuf S: Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): A multicentre, randomised, double-blind, controlled trial. Lancet372 :547– 553,2008
    OpenUrlCrossRefPubMed
  9. ↵
    Cetinkaya R, Odabas AR, Selcuk Y: Anti-proteinuric effects of combination therapy with enalapril and losartan in patients with nephropathy due to type 2 diabetes. Int J Clin Pract58 :432– 435,2004
    OpenUrlCrossRefPubMed
  10. Jacobsen P, Andersen S, Rossing K, Hansen BV, Parving HH: Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy. Nephrol Dial Transplant17 :1019– 1024,2002
    OpenUrlCrossRefPubMed
  11. Rossing K, Jacobsen P, Pietraszek L, Parving HH: Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: A randomized double-blind crossover trial. Diabetes Care26 :2268– 2274,2003
    OpenUrlAbstract/FREE Full Text
  12. Rossing K, Christensen PK, Jensen BR, Parving HH: Dual blockade of the renin-angiotensin system in diabetic nephropathy: A randomized double-blind crossover study. Diabetes Care25 :95– 100,2002
    OpenUrlAbstract/FREE Full Text
  13. Jacobsen P, Andersen S, Rossing K, Jensen BR, Parving HH: Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy. Kidney Int63 :1874– 1880,2003
    OpenUrlCrossRefPubMed
  14. Agarwal R: Add-on angiotensin receptor blockade with maximized ACE inhibition. Kidney Int59 :2282– 2289,2001
    OpenUrlCrossRefPubMed
  15. ↵
    Tutuncu NB, Gurlek A, Gedik O: Efficacy of ACE inhibitors and ATII receptor blockers in patients with microalbuminuria: A prospective study. Acta Diabetol38 :157– 161,2001
    OpenUrlCrossRefPubMed
  16. ↵
    Palmer BF: Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med351 :585– 592,2004
    OpenUrlCrossRefPubMed
  17. ↵
    Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med329 :1456– 1462,1993
    OpenUrlCrossRefPubMed
  18. ↵
    Lachin JM, Foulkes MA: Evaluation of sample size and power for analyses of survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and stratification. Biometrics42 :507– 519,1986
    OpenUrlCrossRefPubMed
  19. ↵
    Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM: Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med349 :1893– 1906,2003
    OpenUrlCrossRefPubMed
  20. ↵
    Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, Konstam MA, Riegger G, Klinger GH, Neaton J, Sharma D, Thiyagarajan B: Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomised trial–the Losartan Heart Failure Survival Study ELITE II. Lancet355 :1582– 1587,2000
    OpenUrlCrossRefPubMed
  21. ↵
    Emanuel EJ, Miller FG: The ethics of placebo-controlled trials–A middle ground. N Engl J Med345 :915– 919,2001
    OpenUrlCrossRefPubMed
  22. ↵
    Casas JP, Chua W, Loukogeorgakis S, Vallance P, Smeeth L, Hingorani AD, MacAllister RJ: Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: Systematic review and meta-analysis. Lancet366 :2026– 2033,2005
    OpenUrlCrossRefPubMed
  23. ↵
    Lewis J, Greene T, Appel L, Contreras G, Douglas J, Lash J, Toto R, Van Lente F, Wang X, Wright JT, Jr.: A comparison of iothalamate-GFR and serum creatinine-based outcomes: Acceleration in the rate of GFR decline in the African American Study of Kidney Disease and Hypertension. J Am Soc Nephrol15 :3175– 3183,2004
    OpenUrlAbstract/FREE Full Text
  24. ↵
    Stevens LA, Greene T, Levey AS: Surrogate end points for clinical trials of kidney disease progression. Clin J Am Soc Nephrol1 :874– 884,2006
    OpenUrlFREE Full Text
  25. ↵
    Beck GJ, Berg RL, Coggins CH, Gassman JJ, Hunsicker LG, Schluchter MD, Williams GW: Design and statistical issues of the Modification of Diet in Renal Disease Trial. The Modification of Diet in Renal Disease Study Group. Control Clin Trials12 :566– 586,1991
    OpenUrlCrossRefPubMed
  26. ↵
    Collins AJ, Li S, Gilbertson DT, Liu J, Chen SC, Herzog CA: Chronic kidney disease and cardiovascular disease in the Medicare population. Kidney Int SupplS24– 31,2003
  27. ↵
    Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med334 :939– 945,1996
    OpenUrlCrossRefPubMed
  28. Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G: Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet354 :359– 364,1999
    OpenUrlCrossRefPubMed
  29. ↵
    The GISEN Group: Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet349 :1857– 1863,1997
    OpenUrlCrossRefPubMed
  30. ↵
    Cohn JN, Tognoni G: A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med345 :1667– 1675,2001
    OpenUrlCrossRefPubMed
  31. ↵
    McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA: Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: The CHARM-Added trial. Lancet362 :767– 771,2003
    OpenUrlCrossRefPubMed
  32. ↵
    ONTARGET Investigators: Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med358 :1547– 1559,2008
    OpenUrlCrossRefPubMed
View Abstract
PreviousNext
Back to top

In this issue

Clinical Journal of the American Society of Nephrology
Vol. 4, Issue 2
February 2009
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in CJASN.
Enter multiple addresses on separate lines or separate them with commas.
Design of Combination Angiotensin Receptor Blocker and Angiotensin-Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D)
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Design of Combination Angiotensin Receptor Blocker and Angiotensin-Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D)
Linda F. Fried, William Duckworth, Jane Hongyuan Zhang, Theresa O'Connor, Mary Brophy, Nicholas Emanuele, Grant D. Huang, Peter A. McCullough, Paul M. Palevsky, Stephen Seliger, Stuart R. Warren, Peter Peduzzi
CJASN Feb 2009, 4 (2) 361-368; DOI: 10.2215/CJN.03350708

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Design of Combination Angiotensin Receptor Blocker and Angiotensin-Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D)
Linda F. Fried, William Duckworth, Jane Hongyuan Zhang, Theresa O'Connor, Mary Brophy, Nicholas Emanuele, Grant D. Huang, Peter A. McCullough, Paul M. Palevsky, Stephen Seliger, Stuart R. Warren, Peter Peduzzi
CJASN Feb 2009, 4 (2) 361-368; DOI: 10.2215/CJN.03350708
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Abstract
    • Overview of Study Design
    • Methodological Issues
    • Appendix
    • Disclosures
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease
  • Network Meta-Analysis of Novel Glucose-Lowering Drugs on Risk of Acute Kidney Injury
  • Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria (ESAX-DN)
Show more Diabetes and the Kidney

Cited By...

  • Incidence, Severity, and Outcomes of AKI Associated with Dual Renin-Angiotensin System Blockade
  • Differential renal effects of candesartan at high and ultra-high doses in diabetic mice-potential role of the ACE2/AT2R/Mas axis
  • Contrast-Induced Acute Kidney Injury
  • Drug therapies to delay the progression of chronic kidney disease
  • Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Trainee of the Year
  • Author Resources
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • CJASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About CJASN
  • CJASN Email Alerts
  • CJASN Key Impact Information
  • CJASN Podcasts
  • CJASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe

© 2021 American Society of Nephrology

Print ISSN - 1555-9041 Online ISSN - 1555-905X

Powered by HighWire