Network meta-analysis of surgical treatment for secondary hyperparathyroidism

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Network meta-analysis of surgical treatment for secondary hyperparathyroidism Jianzhong Houa,1, Haojie Shanb,1, Yingchao Zhanga, Xianzhao Denga, Bomin Guoa, Jie Kanga, ⁎ ⁎ Bo Wua, , Youben Fana, a b

Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China

A R T I C LE I N FO

A B S T R A C T

Keywords: Secondary hyperparathyroidism Surgical treatment Network meta-analysis

Background: Main surgical treatments for secondary hyperparathyroidism (SHPT) include subtotal parathyroidectomy (sPTX), total parathyroidectomy with autotransplantation (tPTX+AT), and total parathyroidectomy (tPTX); however, determining the best treatment is debatable. We conducted a network metaanalysis (NMA) comparing three treatments in terms of postoperative hypocalcemia (or hypoparathyroidism), postoperative recurrence, and reoperation. Methods: We searched PubMed, Medline, the Cochrane Library, and Embase for relevant research from inception to July 30, 2019. We performed our Bayesian NMA using R 3.51 software to assess odds ratios (OR) and 95% confidence intervals (CI). Network and forest plots displayed study outputs. Potential publication bias was assessed with funnel plots using software Stata/MP 13.0. Results: Twenty-six articles comprising 5063 patients were included in our NMA, which showed that postoperative hypocalcemia (or hypoparathyroidism) occurred more frequently in tPTX than in sPTX (OR = 3.50, 95% CI 1.10–11.0) or tPTX+AT patients (OR = 1.80, 95% CI 0.66–5.20). Regarding postoperative hypocalcemia (or hypoparathyroidism), there was no significant difference between sPTX and tPTX+AT (OR = 0.53, 95% CI 0.24–1.10). As for recurrence rates, statistically significant differences were observed between sPTX and tPTX (OR = 25.0, 95% CI 5.1–260), tPTX+AT and tPTX (OR = 20.0, 95% CI 4.2–200), and sPTX and tPTX+AT (OR = 1.30, 95% CI 0.65–2.50). Regarding reoperation rates, sPTX experienced higher incidence compared with tPTX+AT (OR = 1.20, 95% CI 0.53–2.70) or tPTX patients (OR = 2.70, 95% CI 1.20–14.00). Conclusions: TPTX+AT is recommended as the most efficient and safe surgical SHPT treatment with minimal adverse effects. Large-scale randomized controlled trials are recommended to confirm the NMA results.

1. Introduction Secondary hyperparathyroidism (SHPT) is defined as hyperplasia of the parathyroids arises as a result of disordered metabolism producing hypocalcemia, as in chronic uremia due to renal disease, which is a common complication of chronic renal failure [1,2]. And SHPT accompanies persistently increased parathyroid hormone (PTH) levels due to hypocalcemia, hyperphosphatemia, and vitamin D deficiency [1]. Furthermore, SHPT has been associated with adverse effects, such as bone pain, cardiomyopathy, fracture, vascular and cardiac valve calcification, and other adverse clinical effects, which can affect quality of life and increase mortality [3,4]. In the early stage, SHPT can be managed with drug therapy, but some patients (refractory SHPT,

ineffective medication, or drug intolerance) still require surgical treatment [5]. According to an U.S. research, the annual resection rate of SHPT can reach 5.4‰ [1,6]. There are 3 surgical options for parathyroidectomy as follows: subtotal parathyroidectomy (sPTX), total parathyroidectomy with autotransplantation (tPTX+AT), and total parathyroidectomy (tPTX); however, there has been an ongoing discussion about the optimal surgical procedures [7,8]. Several traditional meta-analyses or systematic reviews comparing SHPT treatments have also been published [9–11]. Unfortunately, traditional meta-analysis methods only directly compare 2 different methods, and it is impossible to compare 3 treatments. Fortunately, Bayesian network meta-analysis is known for its effectiveness in comparing a mixture of treatments, and it can combine

⁎

Corresponding authors. E-mail addresses: [email protected] (H. Shan), [email protected] (B. Wu), [email protected] (Y. Fan). 1 Jianzhong Hou and Haojie Shan contributed equally to this work and should be considered as equal first coauthors. https://doi.org/10.1016/j.amjoto.2019.102370 Received 10 November 2019 0196-0709/ © 2019 Elsevier Inc. All rights reserved.

Please cite this article as: Jianzhong Hou, et al., Am J Otolaryngol, https://doi.org/10.1016/j.amjoto.2019.102370

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model within a Bayesian framework [14,15]. In the Bayesian framework, all parameters are treated as random variables. For each incorporated parameter, its posterior distribution is estimated by placing the appropriate prior distribution using the Markov chain [16]. The number of tuning and simulation iterations were set at 5000 and 20,000, respectively. The results were evaluated by odds ratios (OR) with 95% confidential intervals (CI). Network and forest plots displayed study outputs. Treatment outcomes were ranked using probability plots, which presented the rankings with different color columns representing the best, the second best, and so on. Furthermore, a funnel plot was used to assess publication bias in our meta-analysis. A funnel plot is a scatterplot of study effect size versus some measure of its precision.

direct and indirect comparisons to resolve this problem [12]. To establish the optimum SHPT treatment, we conducted a network meta-analysis (NMA) to compare 3 treatments including sPTX, tPTX +AT, and tPTX in terms of postoperative hypocalcemia (or hypoparathyroidism), postoperative recurrence, and reoperation. The results of our analysis may provide some evidence for surgeons in their selection of SHPT treatment. 2. Materials and methods 2.1. Search strategy Two experienced reviewers designed and carried out the search strategy. Relevant articles published from inception to July 30, 2019 were retrieved from PubMed, Medline, the Cochrane Library, and Embase. The following keywords were used for the search: parathyroidectomy, secondary hyperparathyroidism, chronic renal failure, chronic kidney disease, hemodialysis, and autotransplantation. In addition, the relevant references and cited papers were checked.

3. Results 3.1. Search results and methodological quality The titles and abstracts of 331 potentially relevant articles were reviewed for the initial screening. One hundred twenty-six studies were screened after removing duplications, and 99 were excluded due to ineligibility after reviewing the titles and abstracts. Finally, 26 eligible articles [17–42] with a total of 5063 patients were involved in this NMA, including 3 randomized controlled trials (RCT), 18 retrospective cohort studies (RCS), and 5 prospective cohort studies (PCS). Fig. 1 shows the study selection process. Baseline characteristics of the studies included in the NMA are summarized in Table 1. The studies were published over 31 years, from inception to July 30, 2019. The follow-up period ranged from 1 month to 9 years, and the sample size ranged from 22 to 1130 patients. Moreover, in our research, 22 studies were two-arm trials, and 4 studies were three-arm trials involving 3 different treatments. The networks of eligible comparisons for the multiple-treatments meta-analysis networks are shown in Fig. 2. The NOS score of 10 studies was > 5 stars, which was considered high quality for admission. The NOS assessments are listed in Table 1.

2.2. Inclusion and exclusion criteria We systematically reviewed the literature according to the following criteria: 1) randomized controlled trials (RCTs), cohorts or case-control studies evaluating 2 or 3 of the treatments, including sPTX, tPTX+AT, and tPTX; 2) comparison of short- and long-term duration outcomes between sPTX, tPTX, and tPTX+AT in SHPT; 3) clinical outcomes of the enrolled study should include at least one of the following endpoints: postoperative hypocalcemia (or hypoparathyroidism), postoperative recurrence, or reoperation. Exclusion criteria were: 1) enrolled patients with primary hyperparathyroidism or tertiary hyperparathyroidism (Tertiary hyperparathyroidism is a state of autonomously functioning parathyroid tissue typically manifesting as hypercalcemia after either prolonged SHPT or successful renal transplantation, when calcium levels fail to normalize within the first year [2]); 2) articles were letters, case reports, reviews, comments, editorials, or proceedings. In particular, if one surgical team or institution published more than one article, then repetitive publication was identified. If such duplicated articles could not be distinguished, then the article published most recently or the longest article would be selected; 3) we excluded studies containing only 1 or none of the 3 treatments.

3.2. Results of network meta-analysis 3.2.1. Postoperative hypocalcemia (or hypoparathyroidism) analysis Eighteen eligible studies with a total of 1491 patients mentioned the effect of postoperative hypocalcemia (or hypoparathyroidism) on SHPT (Fig. 2A). The results of our random-effects NMA for postoperative

2.3. Data extraction and quality assessment Two investigators working independently examined and selected all potentially eligible articles. Disagreements were resolved through discussions with a third reviewer. The following information was extracted in standardized form: name of the first author; year of publication; location of study; study type; population characteristics (age, sex, number); and duration of follow-up. The Newcastle-Ottawa Scale (NOS) was utilized to evaluate the quality of the non-randomized studies included. The NOS is a validated tool to assess non-randomized studies according to three criteria: patient selection (4 of 9 total points), comparability of study groups (2 of 9 points), and the outcome assessment (3 of 9 points). In this study, “Selection,” “Comparability,” and “Outcome” were evaluated, and each high-quality choice was awarded a “star.” Quality assessment was also performed by two independent reviewers, and a third reviewer was consulted to help resolve any uncertainties.

Studies identified through PubMed, Medline, the Cochrane Library and Embase (n=331)

Studies after duplicates(n=126) Studies excluded (n=81) Reasons: reviews, case reports,comments,irrelevant studies,letters and trial designs Full-text articles assessed(n=45) Studies excluded (n=19) Reasons: no comparison of interest surgical approach, no outcome of interest

2.4. Statistical analysis 26 studies included in meta-analysis

The statistical analysis was performed using software Stata/MP 13.0 and R 3.51 (main packages including gemtc and rjags) [13]. An NMA concerning multiple treatments was performed with a random-effect

Fig. 1. Flow diagram of the identification process for eligible studies. 2

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Table 1 Main characteristics of included studies. Study (year)

Takagi 1988 [17] Henry 1990 [18] Nichols 1990 [19] Rothmund 1991 [20] Gagne´ 1992 [21] Tominaga 1992 [22] Koonsman 1994 [23] Neonakis 1995 [24] Nicholson 1996 [25]

Country

Study design

Study period

Japan

RCT

1973–1981

France

RCS

1971–1988

UK

RCS

1978–1987

Germany

PCS

1984–1985

France

RCS

1980–1990

Japan

RCS

1973–1991

USA

RCS

1982–1993

UK

RCS

1981–1991

UK

RCS

1982–1993

Canada

RCS

1992–1996

Italy

RCS

–

Germany

RCS

1993–1999

Germany

RCS

1997–2006

Italy

PCS

1999–2006

Germany

PCS

1976–2010

He 2014 [32]

China

RCS

2008–2012

Kuo

USA

RCS

2008–2011

2014 [33] Liang 2015 [34]

China

PCS

2010–2014

Neagoe 2016 [35]

Romania

PCS

2010–2014

Rajeev 2016 [36] Schlosser 2016 [37] Anderson 2017 [38] Li 2017 [39]

Singapore

RCS

2006–2013

Germany

RCT

2007–2010

USA

RCS

2005–2013

China

RCS

2010–2014

Brazil

RCT

–

Sweden

RCS

1991–2013

UK

RCS

2006–2017

Hargrove 1999 [26] Coen 2001 [27] Ockert 2002 [28] Rayes 2008 [29] Conzo 2012 [30] Schneider 2012 [31]

Filho 2018 [40] Isaksson 2019 [41] Zmijewski 2019 [42]

Number of patients

sPTX: 20 tPTX+AT:23 sPTX: 79 tPTX+AT:152 sPTX:34 tPTX+AT:39 sPTX:20 tPTX+AT:20 sPTX: 21 tPTX+AT:28 sPTX: 19 tPTX+AT:212 sPTX: 53 tPTX+AT:24 sPTX: 15 tPTX+AT:52 tPTX: 24 tPTX + AT: 13 sPTX: 11 sPTX:28 tPTX+AT:8 tPTX: 10 tPTX + AT: 10 sPTX: 19 tPTX: 11 tPTX + AT: 11 tPTX: 17 sPTX: 16 tPTX: 20 tPTX + AT: 20 tPTX: 32 tPTX + AT: 504 sPTX: 21 tPTX: 33 tPTX+ AT: 14 sPTX:662 tPTX:236 tPTX: 21 tPTX+ AT: 21 sPTX:21 sPTX:24 tPTX+AT:19 sPTX:24 tPTX+AT:58 tPTX: 52 tPTX+AT: 48 SPTX:765 TPTX+AT:365 tPTX: 62 tPTX+ AT: 42 sPTX: 23 tPTX+AT: 46 sPTX: 436 tPTX: 388 sPTX: 23 tPTX+AT: 23

Mean age (years)

Follow up

Newcastle-Ottawa Scale Selection

Comparability

Outcome

Score

1 month-10 years

–

–

–

–

7 years

★★★

★

★★

6

9 years

★★★★

★

★★★

8

9–43 months

★★★

★

★★

6

1-11 years

★★★★

★

★★★

7

> 6 months

★★★

★

★

5

–

Mean 4.5 years

★★★

★

★★

6

52 (1.5–105)

52 months

★★★

★

★★

6

33–62

12–24 months

★★★

★

★★

6

–

★★★

★

★★

6

56 ± 11

sPTX:28.3 months tPTX+AT:22.9 months 3.3 ± 2.3 years

★★★

★

★★

6

27–68

23 months(range1–49)

★★★

★

★★★

7

–

31 months

★★

★

★★

5

52 (26–72)

1 years

★★★

★

★★

6

48.5 ± 0.57

57.6 ± 2.4 months

★★★★

★

★★

7

46 (28–71)

42 months

★★★★

★

★★★

8

sPTX: 49 (3–59) tPTX: 49 (38–57) 53.2 ± 12.7

30 days

★★★

★

★★

6

6 months

★★★★

★★

★★★

9

sPTX:50.0 ± 10.6 tPTX+AT:51.1 ± 11.1

sPTX:38(6–52) months tPTX+AT:18(1–36) months 4 years

★★★

★

★★

6

★★★

★

★★

6

36 months

–

–

–

–

SPTX:48(37–58) TPTX+AT:47(37–56) –

30 days

★★★

★

★★

6

12 months

★★★

★

★★

6

48 (36–56)

12 months

–

–

–

–

sPTX: 60 (14) tPTX: 61 (13) sPTX: 51.7 ± 15.1 tPTX+AT: 48.4 ± 11.5

sPTX: 6.0 (5.0) tPTX: 6.9 (4.9) > 6 months

★★★

★

★★

6

★★★★

★★

★★★

9

sPTX:33.8 tPTX+AT:45.2 – sPTX:41.2 tPTX+AT:41.6 sPTX:44.8 tPTX+AT:45.0 sPTX:44.8 ± 2.4 tPTX+AT:49.8 ± 2.3 44.6

sPTX:54 (26–75) tPTX+AT:56.5 (14–73) 49.2 ± 15.6

RCS: retrospective cohort study; PCS: prospective cohort study; RCT: randomized controlled trial.

highest probability of being ranked third.

hypocalcemia (or hypoparathyroidism) are summarized in Fig. 3A. Cases using tPTX had significant postoperative hypocalcemia (or hypoparathyroidism) compared to other surgical approaches (sPTX: OR = 3.50, 95% CI 1.10–11.0; tPTX+AT: OR = 1.80, 95% CI 0.66–5.20). Moreover, the effect of sPTX on postoperative hypocalcemia (or hypoparathyroidism) was similar to tPTX+AT (OR = 0.53, 95% CI 0.24–1.10). In Fig. 4A, we summarize the possibility value of the different rankings of each treatment strategy. TPTX had the highest probability of being ranked first for postoperative hypocalcemia (or hypoparathyroidism), whereas notably sPTX had the

3.2.2. Recurrence Of the 26 included articles, 21 studies with a total of 1969 patients reported recurrence (Fig. 2B). The results of our random-effects NMA for recurrence are summarized in Fig. 3B. SPTX and tPTX+AT were compared with tPTX independently; ORs and corresponding 95% CIs were calculated. We found that sPTX and tPTX+AT had significantly higher incidence rates of recurrence compared to tPTX (OR = 25.0, 95% CI 5.10–260); OR = 20.0, 95% CI 4.20–200, separately). At the 3

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Fig. 2. Network of eligible comparisons. The width of the lines reflects the number of trials comparing every pair of treatments, and the size of every node is proportional to the number of randomly assigned participants (sample size). (A) Network of eligible comparisons for postoperative hypocalcemia (or hypoparathyroidism); (B) Network of eligible comparisons for recurrence; (C) Network of eligible comparisons for reoperation.

Fig. 3. Forest plot of eligible comparisons. The results were evaluated by the odds ratio (OR) with a 95% confidential interval (CI). (A) Forest plot of network meta-analysis for postoperative hypocalcemia (or hypoparathyroidism); (B) Network diagram of eligible comparisons for recurrence; (C) Forest plot of network meta-analysis for reoperation.

in most practical guidelines [3,6], but the best available surgical option for SHPT is still greatly debated. In this NMA, we systematically reviewed postoperative hypocalcemia (or hypoparathyroidism), recurrence, and reoperation after operative treatment for SHPT. Five thousand sixty-three cases from 26 eligible articles were involved. Moreover, our study is the first article that assessed the 3 available surgical treatments for SHPT using network meta-analysis. Postoperative hypocalcemia (or hypoparathyroidism) continues to be a concern [43], as it seriously affects the quality of life of patients. Our NMA showed that the rates of postoperative hypocalcemia were similar in sPTX and tPTX+AT patients. Additionally, tPTX had the highest probability of hypocalcemia after surgery, which can easily cause patient convulsions, numbness, and even prolong the hospital stay. Postoperative recurrence could not be avoided in SHPT patients undergoing maintenance dialysis at the same time. When compared with recurrence, tPTX significantly decreased the postoperative recurrence rate. There was no significant difference between sPTX and tPTX +AT on OR values. We built a probability rank for the outcome (Fig. 3B). TPTX had the lowest probability of recurrence, whereas sPTX had the highest alternative (Fig. 4B). The cause of recurrence after sPTX may be due to excessive residual parathyroid tissue or missing ectopic parathyroid gland during surgery. Recurrence after tPTX+AT may be associated with excessive forearm graft volume. Schneider et al. [44] reported that the risk for persistent and recurrent disease based on intrathymic parathyroid glands is a relevant problem during initial surgery for SHPT. Low et al. [45] showed that parathyroidectomy with cervical thymectomy is a safe and effective way to manage SHPT. Therefore, it is important to search for ectopic parathyroid glands, such

same time, significant differences were found between sPTX versus tPTX+AT (OR = 1.30, 95% CI 0.65–2.50). The ranking of these 3 treatment strategies were displayed in Fig. 4B. SPTX was most likely ranked with the first probability of recurrence. In addition, tPTX+AT and tPTX were ranked as the second and third, respectively. 3.2.3. Reoperation Seventeen studies with a total of 4285 patients were involved in the analysis regarding reoperation (Fig. 2C). The direct and indirect results of the meta-analysis showed that there was significant differences between tPTX+AT and tPTX in reoperation rates (OR = 2.40, 95% CI 0.94–12.00). Furthermore, reoperation occurred more often in patients treated with sPTX than in patients treated with either tPTX+AT (OR = 1.20, 95% CI 0.53–2.70) or tPTX (OR = 2.70, 95% CI 1.20–14.00) (Fig. 3C). In Fig. 4C, we summarize the values of the different rankings of the 3 treatment strategies. The sPTX was most likely to be ranked first for reoperation. In contrast to sPTX, tPTX+AT and tPTX were most likely to be ranked as second and third, respectively. 3.3. Publication bias of included studies All data points are evenly distributed on both sides of the inverted funnel plot, suggesting that there is less likelihood of publication bias (Fig. 5). 4. Discussion Surgical treatment is playing a more and more important role in SHPT. For refractory SHPT, parathyroidectomy (PTX) is recommended 4

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Fig. 4. Values of the different rankings of the treatment strategies. (A) Postoperative hypocalcemia (or hypoparathyroidism); (B) Recurrence; (C) Reoperation.

referring to the rate of recurrent SHPT [10]. Similar results were also reported by Jia et al. [47]; the result is consistent with ours. As illustrated in our results, tPTX+AT was considered as the most efficient and safe surgical treatment. SPTX demonstrated the highest incidence rate of recurrence and reoperation. Meanwhile, tPTX was regarded as the surgical method with the highest incidence rate of postoperative hypocalcemia (or hypoparathyroidism). We recommend using tPTX+AT to treat SHPT because tPTX+AT has its unique advantages. If a patient experiences a recurrence after tPTX+AT, a graftdependent recurrence could be controlled by removing the autograft, which is convenient and quick [48]. However, there is still controversy about the number of parathyroid transplants, which has been reported in some literature. Albuquerque et al. [49] demonstrated that neither the quantity nor quality of parathyroid fragments influenced serum systemic iPTH levels, but sub-questions need further exploration. Nevertheless, other important key factors such as operative convenience, individual condition, and physician experience should be

as thymic and mediastinal glands, at the initial operation. Based on pooled evidence, statistically significant differences were observed between tPTX+AT and tPTX (OR = 2.4, 95% CI 0.94–12.00), sPTX and tPTX+AT (OR = 1.2, 95% CI 0.53–2.70), and sPTX and tPTX (OR = 2.7, 95% CI 1.20–14.00) when comparing reoperation rates. SPTX had the lowest probability of reoperation. The reason for the high rate of reoperation may be associated with its high recurrence rate. Our results were conclusive and consistent with previous results. As Wu et al. [11] reported in their meta-analysis involving 3656 patients, no significant difference was observed in the hypocalcemia rate (16.6%, 18.1%; P = .29), recurrence rate (9.2%, 7.1%; P = .76), and reoperation rate (5.3%, 5.8%; P = .66) between sPTX and tPTX+AT groups. The results were confirmed in our analysis, and they have also been demonstrated by Li et al. [46]. In their analysis, tPTX could reduce the risk of SHPT recurrence and reoperation because of recurrence or persistence of SHPT compared with tPTX+AT [46]. There is also a meta-analysis revealing that tPTX is superior to tPTX+AT, while 5

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Total parathyroidectomy with

Fig. 5. Funnel plot of this network meta-analysis, with different colors representing different comparisons.

taken into account when selecting surgical treatment. Nonetheless, several limitations should be acknowledged in the present study. First, we focused on adverse events such as postoperative hypocalcemia (or hypoparathyroidism), recurrence, and reoperation. However, we did not take surgical complications (postoperative infection, recurrent laryngeal nerve injury) and symptomatic improvement (pruritus relief) into consideration because the sample size was so small that we could not draw further conclusions. Additionally, the follow-up time involved in the study was also considered as a variable that may mislead the results. Finally, the quality of the recruited studies was not high; hence, selection bias or other confounding factors may have been included. In the future, well-designed, high-quality, large-scale RCT studies are necessary. In conclusion, a NMA combining both direct and indirect evidence from currently available studies was performed to compare postoperative hypocalcemia (or hypoparathyroidism), recurrence, and reoperation in SHPT patients. TPTX+AT was recommended as the most efficient and safe surgical treatment with less adverse effects. Based upon this research, the evidence supports promising surgical treatment of SHPT. Funding This work was supported by the National Natural Science Foundation of China (grant number 81670718). Informed consent Informed consent was obtained from all individual participants included in the study. Declaration of competing interest All authors declare no conflict of interest. References [1] Kim SM, Long J, Montez-Rath ME, Leonard MB, Norton JA, Chertow GM. Rates and outcomes of parathyroidectomy for secondary hyperparathyroidism in the United States. Clin J Am Soc Nephrol 2016;11:1260–7. [2] Shindo M, Lee JA, Lubitz CC, McCoy KL, Orloff LA, Tufano RP, et al. The changing landscape of primary, secondary, and tertiary hyperparathyroidism: highlights from the American College of Surgeons Panel, “What’s new for the surgeon caring for patients with hyperparathyroidism”[J]. J Am Coll Surg 2016;6:1240–50. [3] Erratum: Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl 2017;7:1–59.

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