Table 3.

Main methodological issues during design of VA NEPHRON-D

Study treatment
Should the study be three arms (ACEI vs. ARB vs. both) or two (monotherapy vs. combined therapy)?
If three arms, should there be equal allocation to the three groups or should the allocation account for the probable smaller difference in ACEI vs. ARB as compared to a monotherapy vs. combined therapy?
Should the monotherapy be an ACEI or an ARB?
Management of other care issues
Should this be part of the study or as part of clinical care and which factors should be part of the study management?
How should blood pressure be managed?
How should hyperkalemia be managed?
Endpoints
Should the primary endpoint include mortality?
Should doubling of serum creatinine/halving of eGFR be used, or should the endpoint be an absolute decline in kidney function? Does this choice weight the endpoints to individuals with more severe kidney disease at baseline?
Should cardiovascular events be considered in the primary or secondary endpoints, when IDNT and RENAAL found a nonsignificant 10% reduction in cardiovascular events?

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.