Long-term observational study in Japanese hemodialysis patients who completed a 3-year clinical study of lanthanum carbonate
LC is widely used to manage hyperphosphatemia in patients with CKD on dialysis and has contributed to improved clinical outcomes in these patients. The short-term safety profile of LC has been reported [19]; the most common adverse events of LC- and Ca-containing PB were gastrointestinal reactions. No significant difference was found in nausea (RR 1.72, 95 % CI 1.00–2.98, p?=?0.05), vomiting (RR 2.17, 95 % CI 0.87–5.41, p?=?0.10), diarrhoea (RR 1.26, 95 % CI 0.84–1.89, p?=?0.27), or constipation (RR 0.78, 95 % CI 0.50–1.21, p?=?0.27) between the two treatments.
Some studies were evaluated the efficacy, tolerability, and safety of LC monotherapy over 2 years [7], 3 years [8], and 6 years [9] have consistently reported that LC is well tolerated, with no evidence of safety concerns. The majority of LC adverse drug reactions were related to the gastro-intestinal tract (mainly nausea, diarrhoea, and flatulence) [9] and are primarily mild/moderate in severity, consistent with those observed with other phosphate binders. However, there is no insufficient safety data for a prolonged period or for Japanese.
Accordingly, the authors think that it is important to accumulate more evidence of the long-term effects of LC treatment in the clinical practice and explore how LC can be used for a prolonged period in a safe and appropriate manner.
Therefore, we retrospectively investigated the long-term tolerability of LC among Japanese hemodialysis patients who completed the phase III study study of LC treatment, in an observational multicenter study in order to follow safety outcomes for further 5 years regardless of these patients’ LC administration. In this follow-up observational study, 18 of 30 patients (60.0 %) received LC with or without some other PBs, and in 10 of 30 patients (33.3 %), the PB was switched from LC to another PB and in 2 of 30 patients (6.7 %) PB was no longer used.
During the phase III study, LC-related adverse events occurred in 16 patients (53.3 %); however, no adverse events that were considered by the investigators to be related to any PB, including LC, were reported during the 5-year follow-up observational study. Although the dosage of LC was reduced in some patients and other patients switched to another PB from LC after the phase III study, these results strongly suggest that no evidence exists of delayed adverse events after 3 years of LC exposure or any increase in the incidence of LC-related adverse events with increasing LC exposure.
The most common drug-related adverse events that occurred during the phase III study were vomiting and nausea, which are already known to be common adverse events associated with LC [20]; however, there were no treatment discontinuations due to gastrointestinal adverse events. Hutchison et al. reported that no gastrointestinal events occurred in US patients after 3 years of LC exposure or in European patients after 4 years of exposure [9]. These results indicate that long-term LC treatment is possible provided gastrointestinal events that tend to occur more frequently in the early phase of treatment can be controlled.
Another potential safety concern of LC treatment is toxicity in bone, liver, and the central nervous system [11–15]. The long-term safety profile of LC in hemodialysis patients receiving treatment for up to 6 years have been reported and appear to show no evidence of adverse effects on the liver, bone, or the central nervous system [9].
Two patients (6.7 %) during the phase III study, 5 of 18 patients (27.8 %) who continued LC use and 3 of 12 patients (25.0 %) who did not continue LC experienced a serious adverse event during the 5 year follow-up observational study; however, all of these events except for 1 were not drug-related. The types of serious adverse events are those peculiar to dialysis patients with multiple complications. There was no difference in frequency of serious adverse events between patients who continued LC and patients who did not continue LC.
La deposition in a mesenteric lymph node found at autopsy of an ESRD patient 3 years after LC administration was reported [21]. Although the clinical significance of this deposition of La is not clear, further investigation of its potential long-term toxic effects is needed. Thus, the long-term safety of LC treatment, especially in clinical practice, has not been completely established. In recent years, several case reports about La deposition in gastric mucosa have been published [22–25]. Although every report indicated for lanthanum deposition in gastric mucosa, there is no relationship to gastrointestinal symptoms. In a nod to these reports, further long-term and large number observation should be needed.
Although several laboratory parameters showed statistically significant changes after 4 or 8 years, none of these parameters except for intact PTH and blood pressure were clinically significant when the mean changes from baseline and their confidence intervals are taken into account. At the start of the follow-up observational study (2009), a pronounced decrease of more than 100 pg/mL in intact PTH was observed. This decrease may be due to the introduction of cinacalcet in 2008. Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) also decreased significantly after 3 years. Although it is unknown why a clinically significant decrease in blood pressure was observed, the degree of decrease in SBP and DBP after 8 years (i.e. SBP ?18.83 mmHg, DBP ?13.39 mmHg) was a positive effect.
The serum P concentrations were maintained within the management target range (3.5–6.0 mg/dL) recommended in the JSDT guidelines [6] for the entire 8 years. The long-term therapeutic effects of LC and other PBs on hyperphosphatemia were also confirmed in this study.
Hyperphosphatemia has been shown to increase mortality among patients with CKD [26]. Given this finding, management of serum P in patients with CKD has been recognized as a treatment priority. Recent data suggest improved survival when PB is used in the dialysis of patients [27, 28]. The results of other studies also suggest that there is a survival benefit associated with LC treatment [29, 30].
The present study has several limitations, the first of which is selection bias. We selected the patients who had completed the phase III study of LC, so we cannot exclude the possibility that only patients with no safety issues were enrolled in the study. Another potential limitation, as with any other long-term follow-up study, is the small number of enrolled patients. Regardless of these limitations, the results of the present study revealed no evidence of delayed adverse events or any increase in the incidence of LC-related adverse events with increasing LC exposure.
This study was might not able to put out the conclusion to safety about LC, as there were a limited number of the cases available. However, these results are valuable to evaluate LC exposure for up to 8 years.