Effect of cinacalcet availability and formulary listing on parathyroidectomy rate trends

Secondary hyperparathyroidism is a common and serious disease that develops early in chronic kidney disease and continues to progress after subjects reach dialysis. A primary consequence of secondary hyperparathyroidism is the development of renal osteodystrophy, which may manifest as fractures, bone pain and avascular necrosis [1]. Prevention and treatment of secondary hyperparathyroidism remain a continuous challenge for the nephrologist, despite availability of phosphate binders, active vitamin D analogues and more recently, cinacalcet.

Cinacalcet, a calcimimetic, was approved in March 2004 in the United-States (US) and in September 2004 in Canada. Parathyroidectomy (PTX) is primarily reserved for symptomatic patients with elevated parathyroid hormone (PTH) levels despite optimal medical therapy.

While cinacalcet has been shown in trials to reduce PTH levels [2] and to lower incidence of PTX [3, 4], it remains unclear how availability of this new drug influenced PTX rate trends in a real-world setting. While PTX may be avoided initially by using cinacalcet, the surgery may only be delayed to a later time, which would not be observed in a short-term study. Moreover, efficacy of cinacalcet may be limited in some patients by its gastrointestinal adverse effects, which may be more frequent in real-world patients compared to selected patients enrolled in a randomized-controlled trial. In a recent placebo-controlled trial, 18% of patients in the cinacalcet group discontinued the drug because of adverse events and 7% underwent a PTX [4].

Rates of PTX varied considerably between 1992 and 2007 [5‐8]. These fluctuations were attributed to availability of new therapeutic options (vitamin D analogs and non-calcium-containing phosphate binders) and publication of practice guidelines [5]. Only one study evaluated PTX rate trends after availability of cinacalcet, which showed a decreasing PTX rate until 2005 followed by an increase in rates in 2006–2007. However, this study was limited to 2007 (less than three years after cinacalcet marketing) [5]. In addition, the effect of formulary listing of cinacalcet for reimbursement on PTX rates has not been studied.

The aim of this study was to investigate the trend in annual PTX rates between 2001 and 2010, and evaluate if availability and formulary listing of cinacalcet modified that trend.

There were 12 795 patients on maintenance dialysis in Québec between January 1, 2001 and December 31, 2010. Derivation of the study cohort is detailed in Figure 1. At the beginning of follow-up, the mean age was 63.9 years (SD = 14.6), females represented 39%, and 82% of patients were on hemodialysis. The mean follow-up was 3.3 years (SD = 2.6). Most patients had at least part of follow-up covered by the drug plan (partly for 19.5%, and full for 64.0%), as only 16.5% had only private coverage during follow-up. Almost half of all patients (49%) died during follow-up and 15% were transplanted. As shown in Table 1, patient age increased with time, while proportions of incident patients and of patients on peritoneal dialysis decreased with time.

During follow up, 267 PTX were identified, which translated to an average rate of 7.0 per 1000 py. Bimonthly rates of PTX are given in Figure 2. The average rate before cinacalcet approval was 11.4 /1000 py and was 3.6 /1000 py after cinacalcet reimbursement. The best fitting ARIMA model did not include a trend term over time. In other words, rates did not appear to increase or decrease over time except at the intervention point. Only January 1, 2006 as an intervention date was statistically significant (estimate = −5.58; p = 0.03). Other intervention dates were not associated with a reduction in PTX rates: September 2004, estimate = −2.98, p = 0.3; January 2005, estimate = −5.04, p = 0.07; June 2005, estimate = −4.51, p = 0.09; June 2006, estimate = −3.72, p = 0.2; January 2007, estimate = −2.53, p = 0.4. Using a Poisson regression as a sensitivity analysis, rates were 68% lower after cinacalcet introduction compared to before (incidence rate ratio = 0.32; 95% confidence interval: 0.23-0.42; p < 0.001). Results for the ARIMA and Poisson analyses were similar when time periods not covered by the drug plan were excluded, except that June 2005 became statistically significant in addition to January 2006. As expected, PTX rates appeared higher for young patients than older patients, and in prevalent patients compared to incident patients (Figure 3). PTX rates did not differ by gender. However, trends of PTX rates were similar across strata.

Trends in medication use are given in Figure 4 and average daily doses are shown in Table 2. The proportion of patients using calcium-containing phosphate binders remained stable over time, but the average daily dose decreased with time. On the contrary, the proportion of patients using sevelamer increased until 2005 then remained fairly stable. The average daily dose of sevelamer followed the same pattern of use. Overall, the average daily combined dose of phosphate binders increased with time. The percentage of patients on vitamin D was stable until 2005, and then started to rise. The average daily dose of alfacalcidol increased only very slowly however, and calcitriol daily dose remained stable. Use of cinacalcet increased steadily after 2006, while lanthanum was introduced in 2007. For both, the average daily dose increased slowly with time. Use of magnesium or aluminium-containing binders was negligible.

As previously mentioned, before provincial reimbursement of cinacalcet in June 2006, some patients were receiving cinacalcet from Amgen. According to Amgen internal data, 4 patients received cinacalcet through this program in 2004, 40 in 2005, and 58 in 2006. Some private insurance companies may have reimbursed cinacalcet for patients not covered by the provincial RAMQ drug plan. Unfortunately, the exact number of patients receiving cinacalcet via private insurance is not available in our database. According to Amgen data, cinacalet claims were estimated at 241 in 2005 and 385 in 2006 (Amgen internal data). Assuming monthly claims (12 claims per patients per year), it can be estimated that 20 patients received cinacalcet through private insurance companies in 2005 and 32 patients in 2006.

In this large population-based study, a significant drop in PTX rates among patients receiving dialysis after January 1, 2006 is shown. This drop coincides with cinacalcet introduction, but an increasing trend in the use of phosphate binders (but less calcium-based binders) and vitamin D across the time period is also shown.

Our results are consistent with a pooled analysis of short duration trials that showed a reduce incidence of PTX with cinacalcet (from 41 /1000p-y in the placebo group to 3 /1000 p-y in the cinacalcet group) [3]. More recently, a large placebo-controlled trial designed to evaluate cardiovascular endpoints showed a 69% decreased risk of PTX in the cinacalcet group [4]. Few studies have evaluated trends in PTX rates, and only one has reported rates after the release of the KDOQI clinical practice guidelines in 2003, and none have included patients well beyond introduction of calcimetics [5‐8]. Li et al. [5] described PTX rates in the US from 1992 to 2007. A PTX peak rate was found in 2002 (12.8 /1000 py) followed by a decreasing rate until 2005 (5.4 /1000 py) and then an increase again in 2006–2007 (8.6 /1000 py) [5]. The current data shows a different pattern where the peak annual PTX rate was in 2004 (16.0 /1000 py) instead of 2002, followed by a decrease in 2006 (3.9 /1000 py). After 2006, annual PTX rates remained between 3.0 and 4.6 /1000 py. While January 2006 was the only statistically significant cut-off point in our model, visually the change in rate appeared slightly before that and all cut-off dates between January 2005 and June 2006 showed a trend for a lower PTX rates. This is consistent with the fact that cinacalcet market penetration was progressive over that period of time, and the lack of statistical power may explain why most were not statistically significant. Despite not being widely available before June 2006, carefully selected patients could have received cinacalcet from Amgen or private insurance companies. In the context where cinacalcet was probably given to patients who would otherwise have undergone a PTX and because the annual counts of PTX ranged from 29 to 57 before 2005, only a few patients receiving cinacalcet could have highly influenced the observed PTX rates. For this reason, it is not unexpected to see a flat trend for PTX rates after 2006 while cinacalcet market share continued to increase constantly. Because severe secondary hyperparathyroidism may not be completely controlled in all patients using cinacalcet and because some patients may not tolerate cinacalcet or would prefer to undergo a PTX, it is expected that rates of PTX would not fall indefinitely. It is unknown why PTX rates did not increase in 2006–2007 as was observed in the US. However, it is speculated that wider availability of cinacalcet through reimbursement in Québec may be a factor. It is also possible that, despite the KDOQI guidelines opinion-based recommendation for PTX in patients “with severe hyperparathyroidism (persistent serum levels of intact PTH >88.0 pmol/L [800 pg/mL]), associated with hypercalcemia and/or hyperphosphatemia that are refractory to medical therapy” [19], Canadian physicians may be more inclined to wait for symptomatic hyperparathyroidism before sending a patient for a PTX. The higher PTX rates observed here among prevalent and younger patients are consistent with previous studies and with the physiopathology of secondary hyperparathyroidism [5, 20].

The portrait of phosphate binders and vitamin D use has changed in the last decade. This data shows a clear shift to lower dosing of calcium-based binders and an increasing utilization of non-calcium-based binders such as sevelamer and lanthanum. While the average dose of vitamin D remains fairly low (alfacalcidol increased slightly and calcitriol remained stable), the proportion of prescribed vitamin D increased considerably, reaching 70% in 2010. Unfortunately, only intravenous vitamin D analogues were available in Li et al. [5] study, therefore use of phosphate binders, cinacalcet and oral vitamin D was not reported. Nevertheless, this switch from calcium-based to non-calcium based phosphate binders is expected after the publication of studies associating high calcium-phosphorus product with a higher risk of mortality and cardiovascular calcifications [21, 22]. In 2003, KDOQI guidelines [19] recommended a maximum dose of 1500 mg/day of elemental calcium, which was significantly lower than the usual practice. The increased of phosphate binders and vitamin D within this RAMQ data is also probably explained by the impact of KDOQI Guidelines on clinical practice and targets for serum phosphorus and PTH, and initial vitamin D dose. Additionally, cinalcalcet reimbursement was conditional on specific criteria as detailed previously, and physicians were encouraged to use vitamin D and phosphate binders to gain access to cinacalcet for their patients.

This study reports on changes of PTX trends over time, but cannot establish a causal link between cinacalcet and lower PTX rates. A stronger design would have been to compare PTX rates in patients receiving cinacalcet with rates in patients who did not. However, in the absence of available PTH levels, it was not possible to identify a control group that would have had the same severity of hyperparathyroidism and did not receive cinacalcet. Therefore, results would have suffered from an indication bias. Change in rates may be due to other factors occurring simultaneously with the introduction of cinacalcet. For example, following the publication of the KDOQI Guidelines use of more aggressive treatments such as higher doses of phosphate binders and vitamin D may explain lower PTX rates with time [1, 19]. Decreased use of calcium-based phosphate binders may also explain decreased PTX rates by decreasing serum calcium, which would allow increase vitamin D use. Another explanation would be a change of indication or physician attitude toward PTX. For example, physicians may now tolerate higher PTH level thresholds before considering a PTX. However, these clinical practice changes are usually not acute in time and cinacalcet introduction remains the most probable explanation for the reduction in PTX rates observed. Despite the fact that the drop in PTX rates is visually convincing during the intervention period, we tested six different intervention dates and statistically significant results may be due to chance by multiple testing (limited power precluded applying correction factors such as Bonferroni). The unadjusted PTX rates are presented, since small numbers precluded standardization. An aging population may lead to lower PTX rates while an increasing proportion of prevalent patients may increase PTX rates. However, the population characteristics did not change much during the study years and the same PTX trend pattern was seen among subgroups (Figure 3). Moreover, adjusting PTX rates in the Li et al. [5] study did not make a significant difference in the time period of the current study.

Some PTX procedures may have been missed if they were not coded. However, claims are required from surgeon compensation and it would be unlikely that a PTX would have been missed. RAMQ codes for PTX did not change during the study period. If any percutaneous ethanol ablation procedures of the parathyroid were carried out, these would not be captured, as there is no specific code for this new technique. But this technique was carried out on one or two anecdotal cases only and cannot explain the reduced rates. As with most retrospective studies using dispensed medications, there is uncertainty with patient compliance. In addition, intravenous vitamin D analogue claims are not captured within the RAMQ database, since vitamin D analogues are dispensed by the dialysis unit and a claim would not be submitted by the patient to the RAMQ. However, intravenous vitamin D is not commonly used in Québec, in part for economic reasons and health care organization. Finally, medication use among patients covered by private drug plans who are generally younger patients (an important risk factor for severe secondary hyperparathyroidism) could not be assessed. However, the main analysis on PTX trends included all patients regardless of age and availability of private insurance. Moreover, because the ARIMA model relied on time points and not on patient-level exposure, incomplete ascertainment of exposure does not influence our results. Finally, this study is limited to a single Canadian province, and results may not be generalized to other populations with different healthcare practices.

A decreased annual rate of PTX was found after January 2006, corresponding to cinacalcet availability. However, decreased rates may be due to other factors occurring simultaneously with cinacalcet introduction and further studies are needed to confirm these findings.