Rates and Outcomes of Parathyroidectomy for Secondary Hyperparathyroidism in the United States

Discussion

Using a representative national cohort in the United States, we found that rates of parathyroidectomy for sHPT rose from 2002 to 2003, declined abruptly from 2004 to 2005, and increased again during 2006, remaining relatively stable thereafter. In contrast to the 1990s and early 2000s, during which time parathyroidectomy rates reached 10/1000 patient-years, we observed generally lower parathyroidectomy rates thereafter. However, rates did not materially change from 2006 to 2011. Notably, in–hospital mortality rates after parathyroidectomy for sHPT steadily declined between 2002 and 2011 and were <1% in several recent years. Among patients undergoing parathyroidectomy for sHPT, heart failure and peripheral vascular disease were independently associated with in-hospital mortality. Although lengths of hospital stay for patients undergoing parathyroidectomy have decreased, hospital costs for the parathyroidectomy have increased.

In contrast to previous studies using the USRDS database that were restricted to patients with ESRD for whom Medicare was the primary payer, excluding younger patients and patients relatively new to dialysis (4–6), we used the NIS, allowing us to obtain rates among a broader spectrum of patients, irrespective of age or insurance coverage. We observed that the distribution of primary payer differed by patient’s age. Medicare was the most common insurance type among all age groups. However, Medicare covered 92.4% of patients ≥65 years old and only 74.9% of patients <65 years old. Younger patients were more likely to have insurance other than Medicare and undergo parathyroidectomy (4,5,13).

The findings are in contrast with a Canadian study (16) and the international Dialysis Outcomes and Practice Patterns Study (DOPPS) (17). The Canadian study, although restricted to a single province (Quebec), showed a sustained reduction in parathyroidectomy rates after 2006. The DOPPS reported that prescriptions of active vitamin D analogs and cinacalcet increased and that parathyroidectomy rates decreased between 1996 and 2011. Because the DOPPS investigators divided the timeframe into 3-year increments (1996–2001, 2002–2004, 2005–2008, and 2009–2011), their analysis could not identify the sharp changes that occurred during 2004 and 2005; these individual years were diluted by inclusion within 3-year blocks before and after.

The most likely explanation for the abrupt decline in parathyroidectomy for sHPT in 2005 is the introduction of cinacalcet. We found that the number of parathyroidectomies began to decrease from March of 2004. Cinacalcet was approved by the US Food and Drug Administration in March of 2004 and launched commercially soon thereafter. During 2004 and 2005, clinicians might have deferred parathyroidectomy in some patients, anticipating improved control of sHPT. However, parathyroidectomy rates rose through 2006. In addition to the anticipated and/or actual effects of cinacalcet, parathyroidectomy rates might have been affected by the publication of clinical practice guidelines. There were no published guidelines addressing parathyroidectomy for sHPT before 2003. However, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative Workgroup on bone and mineral disease in CKD recommended parathyroidectomy for patients with refractory hyperparathyroidism in guidelines published in October of 2003 (18). Guidelines put forth by the Kidney Disease Improving Global Outcomes Workgroup published in 2009 also stated that patients with refractory hyperparathyroidism should undergo parathyroidectomy (19). Adoption of these guidelines may have sustained parathyroidectomy rates through subsequent years.

Our examination of time trends in parathyroidectomy for patients with sHPT after introduction of cinacalcet contrasts sharply with results reported from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial (11). In the EVOLVE Trial, rates of parathyroidectomy (and of severe, unremitting hyperparathyroidism) were reduced by >50% with cinacalcet relative to placebo (used in combination with conventional therapy for sHPT), despite poor adherence to cinacalcet and the use of commercial cinacalcet in >20% of patients randomized to placebo. In fact, although parathyroidectomy rates dropped abruptly during late 2004 and early 2005, they increased and remained stable, despite more widespread use of cinacalcet in clinical practice. This discordance suggests that either the treatment benefit was overestimated in the randomized clinical trial or alternatively, cinacalcet use in clinical practice does not mirror the approach taken in the EVOLVE Trial. The latter is plausible in that the EVOLVE Trial protocol specified titration of cinacalcet to a maximum daily dose of 180 mg during the first 20 weeks of the trial. Observational studies in which the dose of cinacalcet was recorded suggests that relatively few patients are titrated to doses >60 or 90 mg daily (7,20,21). The relative frequency of gastrointestinal side effects seen with cinacalcet therapy—principally nausea and vomiting—may be limiting the observed benefit, at least vis-à-vis parathyroidectomy—a potential example of efficacy versus effectiveness. An intravenous calcimimetic agent currently under development may have a role as primary therapy for sHPT or in patients intolerant of or nonresponsive to oral or intravenous active vitamin D analogs and/or cinacalcet (22,23).

Although many studies have highlighted the risks associated with sHPT, relatively few published studies have reported risks associated with the parathyroidectomy procedure itself. Kestenbaum et al. (24) reported 30-day mortality of 3.1% using the USRDS data during the timeframe 1988–1999, whereas Ishani et al. (25) reported 30-day mortality of 2.0% and in-hospital mortality of 0.9% during the timeframe 2007–2009. Baseline clinical characteristics of patients undergoing parathyroidectomy were similar in both studies. In-hospital and short-term mortality of parathyroidectomy for sHPT has declined over time. Lower mortality rates in more recent years could reflect residual selection effects and/or advances in dialysis and related care. Moreover, Komaba et al. (26) studied the effect of parathyroidectomy on survival in patients with severe sHPT. They compared mortality among patients who underwent parathyroidectomy and propensity score–matched patients who did not undergo parathyroidectomy, despite severe sHPT, and suggested that parathyroidectomy reduced the risk for all-cause and cardiovascular mortality in patients with severe sHPT (26).

Strengths of this analysis include the large sample size, generalizability (results were derived from a database capturing a large fraction of all United States hospitals), inclusion of patients irrespective of age or insurance status, and the availability of multiple diagnosis and procedure codes to adjust for comorbid conditions and determine correlates of in-hospital mortality and lengths of stay. Important limitations include the lack of patient–specific follow-up information to determine longer-term associations of parathyroidectomy with mortality, cardiovascular events, fractures, and other complications and sustained biochemical control of sHPT. We could not distinguish patients by the severity of sHPT. In other words, there were no laboratory data (e.g., PTH, calcium, and bone–specific alkaline phosphatase) available in the NIS that might be used to gauge the severity of sHPT. The identification of comorbid conditions was limited to codes provided during hospitalization; no outpatient codes or inpatient codes from other hospitalizations could be included. Moreover, we used the USRDS population as a denominator to estimate the rate of parathyroidectomy. Not all of patients with sHPT are included in the USRDS, and therefore, our estimates may not precisely correspond to parathyroidectomy rates derived from the USRDS itself. Finally, because the NIS tracks hospital admissions and not patients per se, we may have included in our analysis some patients who underwent repeat parathyroidectomy, although these patients likely represent a very small minority of patients overall.

In summary, using a nationally representative database, we examined rates of parathyroidectomy for sHPT over the last decade for which data were available. We found an abrupt decline in rates after introduction of the calcimimetic cinacalcet, with stabilization of rates from 2006 to 2011. In–hospital mortality rates declined steadily over that timeframe, suggesting either improved surgical and perioperative medical care or selection effects. sHPT remains an important complication associated with advanced CKD and especially, ESRD, despite the use of multiple medical therapies. In which clinical settings and at what stage of CKD, ESRD, or sHPT that parathyroidectomy is best applied remain unknown. As with any surgical procedure, anticipated benefits over the long-term need to be balanced with the short–term perioperative increase in risk. Although clinical practice guidelines have suggested parathyroidectomy in patients refractory to medical therapy (15,16), treatment strategies must be individualized.