What can we learn from null randomized controlled trials?

Cardiovascular disease is an important cause of mortality and morbidity in patients with CKD. Elevated serum phosphorus concentration is associated with an increased cardiovascular event rate. Recent data suggest that even in the normal range, serum phosphorus concentration is associated with an increased cardiovascular event rate.1 The mechanism of this association remains unclear. This issue of JASN contains a report of a randomized controlled trial by Chue et al. regarding the cardiovascular effects of sevelamer in stage 3 CKD.2 Before I discuss the trial, I congratulate the investigators for adding another randomized trial to the meager number of trials in nephrology. Their well conducted trial and transparent reporting are evident in their study. The editors also need to be congratulated for having the courage to publish a null trial in a prestigious journal. Chue et al. hypothesize that phosphorus concentration, even within the normal range, by increasing the plasma level of fibroblast growth factor 23 (FGF-23), would provoke left ventricular hypertrophy, diastolic dysfunction, and systolic heart failure, finally culminating in increased cardiovascular morbidity.2 Accordingly, they designed a single-center, double-blind, placebo-controlled, randomized trial to test the hypothesis that the noncalcium-containing phosphorus binder, sevelamer, would reduce gut phosphorus absorption, reduce FGF-23, reduce left ventricular mass and arterial stiffness, and improve systolic and diastolic cardiac performance. After a 4-week run-in with open-label sevelamer, in which 120 participants with stage 3 CKD were given 1600 mg of sevelamer with each meal, the authors then randomized 55 participants to the active drug, sevelamer, and 54 participants to placebo. During the run-in period, 8% of the patients became hypophosphatemic and had to drop out. Over the subsequent 36 weeks, the patients adhered to this regimen; as maybe expected, about 56%of the patients took.80%of their prescribed medication. Medication adherence was similar between the sevelamer and placebo groups. Several characteristics at baseline are noteworthy. Serum phosphorus concentration was not elevated before randomization; at baseline, the phosphorus concentration was 3.16 mg/dl. This was an a priori decision because higher serum phosphorus even within the normal range is associated with increased cardiovascular mortality.1 Thus, the hypothesis tested in this trial was based on epidemiologic observations alone. Furthermore, the parathyroid hormone (PTH) was not elevated, and both the median albumin/creatinine ratio and median BP that were near normal also improved. Because there was no placebo in the open-label run-in, it is unclear whether these effects are because of observation or because of drug. It is likely that this is a study effect, simply due to change in habits of participants due to observation. Somewhat contrary to expectation, there were no effects of the drug on lowering of serum phosphorus concentration, or reduction in the urinary excretion of phosphorus, PTH, and 1,25-dihydroxy vitamin D levels. Thus, there was little effect on mineral metabolism provided by the sevelamer therapy over the 36 weeks of the trial. Even among participants who took .80% of the prescribed treatment, both phosphorus concentration and vitamin D levels remained unchanged. In the adherent subgroup, the only change observed was the reduction in urinary phosphorus concentration and FGF-23. Therefore, in large measure, the drug was unable to affect mineral metabolism in the participants. One has to ask whether the drug is ineffective. However, this is unlikely to be the case because the drug is certainly approved with adequate trial data to support its use in people with hyperphosphatemia. In this trial, the drug in the doses used was not effective in reducing an already normal level of phosphorus concentration. Perhaps the participants increased the dietary phosphorus intake and therefore an overall decline in serum phosphorus concentration was not seen. In fact, there is some evidence that sevelamer reduced serum phosphorus concentrations; in four patients receiving the drug, hypophosphatemia was observed and three patients had to be excluded from further participation in the trial. Interestingly, three participants in the placebo drug group also developed hypophosphatemia, only one of which had to be excluded. Unsurprisingly, at the end of the trial, no differences were seen in cardiac structure or function as assessed by cardiac magnetic resonance imaging (MRI) or echocardiography. In addition, ambulatory BP and pulse wave velocity, a measure of arterial stiffness, remained unchanged. This trial was unable to reject the null hypothesis and it adds to the growing list of null trials in nephrology. The first question one has to answer is whether the trial was adequately powered. In the past, at least one trial of even a smaller sample size was able to show between-group improvement in left ventricular mass over a similar duration of the study.3 However, before we conclude that the study was adequately powered, we need to address the second question of whether a Published online ahead of print. Publication date available at www.jasn.org.