title: Design of combination angiotensin receptor blocker and angiotensin-converting enzyme inhibitor for treatment of diabetic nephropathy (VA NEPHRON-D).
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 m(2)); (2) reduction in eGFR of 30 ml/min/1.73 m(2) (if baseline > or = 60 ml/min/1.73 m(2)); (3) progression to ESRD (need for dialysis, renal transplant, or eGFR < 15 ml/min/1.73 m(2)); 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.
authors.affiliation: Veterans Affairs Pittsburgh Healthcare System and Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylviania 15240, USA. Linda.Fried@va.gov
authors.forename: Linda F
authors.initials: LF
authors.lastname: Fried
authors.forename: William
authors.initials: W
authors.lastname: Duckworth
authors.forename: Jane Hongyuan
authors.initials: JH
authors.lastname: Zhang
authors.forename: Theresa
authors.initials: T
authors.lastname: O'Connor
authors.forename: Mary
authors.initials: M
authors.lastname: Brophy
authors.forename: Nicholas
authors.initials: N
authors.lastname: Emanuele
authors.forename: Grant D
authors.initials: GD
authors.lastname: Huang
authors.forename: Peter A
authors.initials: PA
authors.lastname: McCullough
authors.forename: Paul M
authors.initials: PM
authors.lastname: Palevsky
authors.forename: Stephen
authors.initials: S
authors.lastname: Seliger
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Warren
authors.forename: Peter
authors.initials: P
authors.lastname: Peduzzi
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000503:physiopathology; D018450:Disease Progression; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D016030:Kidney Transplantation; D017706:Lisinopril / Q000009:adverse effects / Q000627:therapeutic use*; D019808:Losartan / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D011507:Proteinuria / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000503:physiopathology; D006435:Renal Dialysis; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D014493:United States Department of Veterans Affairs
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D017706:Lisinopril; D019808:Losartan