Cinacalcet in Patients with Chronic Kidney Disease: A Cumulative Meta-Analysis of Randomized Controlled Trials

Giovanni Strippoli and colleagues report findings of a systematic review and meta-analysis examining the benefits and harms of calcimimetic therapy in adults with chronic kidney disease.Background: Calcimimetic agents lower serum parathyroid hormone levels in people with chronic kidney disease (CKD), but treatment effects on patient-relevant outcomes are uncertain. We conducted a systematic review and meta-analysis to summarize the benefits and harms of calcimimetic therapy in adults with CKD and used cumulative meta-analysis to identify how evidence for calcimimetic treatment has developed in this clinical setting. Methods and Findings: Cochrane and Embase databases (through February 7, 2013) were electronically searched to identify randomized trials evaluating effects of calcimimetic therapy on mortality and adverse events in adults with CKD. Two independent reviewers identified trials, extracted data, and assessed risk of bias. Conclusions: Cinacalcet reduces the need for parathyroidectomy in patients with CKD stage 5D, but does not appear to improve all-cause or cardiovascular mortality. Additional trials in CKD stage 5D are unlikely to change our confidence in the treatment effects of cinacalcet in this population. Background: Chronic kidney disease (CKD) refers to a progressive loss in kidney function over time and is caused by several conditions such as diabetes and high blood pressure. CKD is an increasingly common condition, affecting an estimated 26 million adults in the United States alone, with millions more at risk. People with CKD are at increased risk of death compared to the general population, and despite recent improvements in care, people with advanced CKD who are receiving dialysis experience an excess mortality rate of up to 20%. People with CKD also experience several biochemical imbalances—such as increased phosphorus (as a result of retention), low vitamin D and calcium (hypocalcemia), and increased parathyroid hormone—which lead to further health problems (such as a thinning of the bones) and pain. In light of this complication, clinical guidelines for people with CKD currently recommend that the blood levels of phosphorus and parathyroid hormone be maintained in a certain range to prevent the need for surgical removal of the gland (surgical parathyroidectomy). Why Was This Study Done?: There are several medical therapies that help to keep phosphorus and parathyroid hormone blood levels within the target range, and in 2004, the drug cinacalcet hydrochloride (cinacalcet) was approved in the United States for use in people with end-stage CKD for this purpose. However, despite increasing use and costs of this drug (in the US, cinacalcet has become the largest single drug cost for patients on dialysis, with an annual expenditure of at least US$260 million, and in the UK, prescribing costs increased by up to 33% from 2010 to 2011), the therapeutic value of this drug remains uncertain. So in this study, the researchers systematically reviewed appropriate published studies and analyzed relevant data to investigate whether treatment with cinacalcet improves clinical outcomes in adults with CKD. What Did the Researchers Do and Find?: The researchers identified relevant randomized controlled trials conducted in participants with end-stage CKD by thoroughly searching electronic databases and trial registries, specialist journals, and major conference proceedings. They then extracted data according to specific criteria and assessed the risk of bias. The researchers then graded the quality of evidence into the categories high, moderate, low, and very low quality. What Do These Findings Mean?: These findings suggest that routine cinacalcet (30 to 180 mg/day) therapy in people with end-stage CKD (stage 5D) reduces parathyroid concentrations and hypercalcemia, and may prevent surgical parathyroidectomy, but has little or no effect on all-cause mortality, has an unclear effect on cardiovascular death, and is frequently associated with adverse effects such as hypocalcemia, nausea, vomiting, and diarrhea—adverse gastrointestinal effects that may affect nutrition and quality of life. Although the evidence in people with CKD stages 3–5 is limited and generally of low quality, this analysis shows that despite the widespread use of cinacalcet and the associated high costs, this drug provides little clinical benefit. Therefore, routine use of cinacalcet therapy in people with CKD does not appear warranted; benefits may be limited to preventing parathyroidectomy in the small number of patients for whom surgery is contraindicated. Additional Information: Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001436.