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

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.

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.

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).

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.