As reported on UKidney, earlier in July 2013, Jamal et al published a systematic review comparing calcium-based phosphate binders with non-calcium-based phosphate binders in terms of their impact on cardiovascular outcomes. This pivotal work shows a small but statistically significant advantage of non-calcium-based binders over calcium vis-à-vis mortality outcomes in patients with chronic kidney disease and hyperphosphatemia.
Calcium dose has been implicated in the development of vascular calcification and in the excess cardiovascular morbidity common in patients with CKD, especially those on dialysis. The hope for non-calcium-based phosphate binders has always been that by limiting calcium intake, patients taking non-calcium-based binders would benefit from phosphate reduction without the exposure to potentially harmful dosages of calcium. While individual clinical trials have failed to show any clear advantage of non-calcium-based phosphate binders in terms of reducing cardiovascular morbidity and mortality, this latest systematic review now shows a statistically significant advantage of non-calcium-based phosphate binders over calcium in terms of limiting mortality in patients with CKD.
So where do we go from here? There will likely be discussion as to whether the finding in this systematic review is valid. Furthermore, even if the effect is indeed real, the cost of non-calcium-based binders over calcium-based binders is substantial. Nevertheless, it is likely time to consider whether calcium-based phosphate binders should be made obsolete. There are now substantial data supporting at least a modest effect of calcium dose on mortality and the rationale for using phosphate binders that are not calcium-based. An important question remains as to whether hyperphosphatemia should be treated at all – that is, with binders of any sort. It is entirely possible that non-calcium-based phosphate binders are superior to calcium simply because they limit calcium intake and that the drugs themselves do not offer any other outcome advantage - even if they lower phopshate.
And so, while this systematic review comes closer to answering a long-standing question in nephrology related to optimal phosphate binder class, it underscores an important lingering question as to whether hyperphosphatemia requires treatment at all. To answer this critical question, we require a long overdue placebo-controlled trial of hyperphosphatemia treatment. Objections to a placebo-controlled trial in this area have often centered around the ethics of withholding treatment for hyperphohsphatemia in the form of phosphate binders. However, there appears to be equipoise in this area; there is real uncertainty as to the saftey of calcium-based phosphate binders and whether hyperphosphatemia truly mediates cardiovascular illness in patients with CKD, or if it is only a disease association and nothing more.