I would wager that pound-for-pound, there is no drug with less solid outcome-based data than phosphorus binders. We are aware that phosphorus binders do an acceptable job of lowering the serum phosphorus in the face of kidney failure. We also know that these drugs cause a host of adverse events, including diarrhea, nausea, and hypercalcemia. But the question that stalks nephrologists is whether these agents affect mortality. And if they do alter survival, is the phosphorus level alone to blame, or does the specific agent matter, too?
I pose this issue as a “pound-for-pound” one, not because I am a boxing enthusiast but because phosphorus binders are the most prescribed medication by nephrologists. A typical dialysis patient takes 2 grams of calcium acetate or 2.4 grams of sevelamer three times daily, which works out to about 5 to 6 lbs per year:
- 2 g/meal × 3 meals/day × 365 days/year = 2,190 g/year (or just short of 5 lbs)
- 2.4 g/meal × 3 meals/day × 365 days/years = 2,628 g/year (or 5.8 lb)
(Keep in mind that a liberal phosphorus diet of 2,000 mg/day comes out to a mere 1.6 pounds of phosphorus a year.)
In the 2009 KDIGO (Kidney Disease: Improving Global Outcomes) Guideline for Chronic Kidney Disease-Mineral and Bone Disorder, only two of the recommendations related to phosphorus binder use were rated as strong (Level 1):
- In patients with chronic kidney disease (CKD) stages 3-5D and hyperphosphatemia, restrict the use of calcium-based phosophorus binders in the presence of recurrent hypercalcemia (recommendation 4.1.5; rating, 1B).
- In patients with CKD 3-5D, avoid long-term use of aluminum-containing phosphorus binders (recommendation 4.1.6; rating, 1C).
Every other recommendation is tagged as a weak (Level 2). These weak recommendations involve such fundamental questions such controlling serum phosphorus near the normal range (recommendation 4.1.1.; strength, 2C) and using phosphate binders for hyperphosphatemia in patients treated with dialysis (recommendation 4.1.4.; strength, 2B).
The level of uncertainty surrounding phosphorus binder use is striking when considering the massive doses used for these drugs, the related costs ($500 million dollars annually in the United States), and the high mortality experienced by our dialysis patients. Pharmaceutical companies have attempted to show survival benefits with a particular phosphorus binder (most notably in the DCOR [Dialysis Clinical Outcomes Revisited] trial), but this question should probably take a backseat to the question of whether any binder is better than placebo.
Given the lack of adequately powered studies asking the appropriate clinical questions, we are left to puzzle out an answer through systematic reviews. A 2013 meta-analysis by Jamal et al showed non-calcium–based phosphorus binders to be superior to calcium-based binders in regards to total mortality. This study set the stage for a recent report by Palmer et al in AJKD.
Palmer et al performed a network meta-analysis of binders in dialysis patients, a technique that allowed them to look at multiple drugs that focus on a similar end-point or condition. The primary outcome was total mortality and the secondary outcomes included the following:
- cardiovascular mortality
- myocardial infarction
- abdominal pain
- achievement of a serum phosphorus target
- serum phosphorus levels hypercalcemia
- coronary artery calcification
After combing the medical literature (English and non-English), they found a total of 77 studies representing 12,562 patients. Of these, 20 reported total mortality with 6,362 patients (a third of which came from the DCOR trial). This averages 318 patients per study, a value that falls to 224 if you exclude the DCOR participants. Survival analysis showed no advantage of binders versus placebo, though placebo-controlled trials were short (4 weeks to 3 months):
Iron: odds ratio (OR), 0.45; 95% confidence interval (CI), 0.08−2.66
- Sevelamer: OR, 0.47; 95% CI, 0.08−2.56
- Colestilan: OR, 0.66; 95% CI 0.10−4.31
- Lanthanum: OR, 0.93; 95% CI 0.11−8.00
- Calcium: OR, 1.20; 95% CI 0.21−6.75
While sevelamer showed a survival benefit when compared to a calcium-based binder (OR, 0.39; CI, 0.21–0.74), the other binders were unable to show similar benefits:
- Lanthanum: OR, 0.78; 95% CI, 0.16–3.72
- Colestilan: OR, 0.55; 95% CI, 0.07–4.43
- Iron: OR, 0.37; 95% CI, 0.09–1.60
These benefits came with significant adverse events: lanthanum caused nausea, sevelamer caused constipation, and iron-based agents caused diarrhea.
This meta-analysis is largely in agreement with Jamal et al, which concluded that sevelamer and lanthanum should be first-line therapy for the management of phosphorus in CKD. However, Palmer et al are forthright with their concern that this conclusion is difficult to reconcile with their concurrent finding that no binder offered a survival benefit compared to placebo. They are also concerned that the positive association of sevelamer- over calcium-based binders was largely dependent on the INDEPENDENT trial. Without the results of this 466-person trial, the meta-analysis would have shown no survival benefit of sevelamer use.
To close, I would like to share a excerpt from the thoughtful discussion from Palmer et al, with which I concur enthusiastically:
Given the widespread use of phosphate binders in clinical practice, randomized trials are an urgent priority to support and inform the extensive prescribing of these medications. Such trials should include comparisons of phosphate binders with placebo (perhaps with rescue treatment for severe hyperphosphatemia and or hyperparathyroidism) and head–to–head comparisons between available agents – focusing on clinically relevant outcomes such as mortality and cardiovascular events. Given the significantly lower phosphorus levels associated with iron, and the potential association of sevelamer with lower mortality, future trials should focus on these two classes of agent, compared to placebo, calcium, or each other. Finally, the high absolute risk of adverse events with all binders suggests that there is value to considering patient preferences when selecting an approach to phosphorus control in kidney patients, especially those who are concerned about treatment harms. Further, the failure of any agent to reduce mortality versus placebo suggests that a less aggressive approach to phosphate-lowering treatment may be entirely appropriate in all patients pending the availability of new evidence.
Joel Topf, MD
AJKDBlog Advisory Board Member