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Cochrane Database of Systematic Reviews Review - Intervention

Minimally invasive parathyroidectomy guided by intraoperative parathyroid hormone monitoring (IOPTH) and preoperative imaging versus bilateral neck exploration for primary hyperparathyroidism in adults

Authors' declarations of interest

Version published: 21 October 2020 Version history

https://doi.org/10.1002/14651858.CD010787.pub2
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Background

Bilateral neck exploration (BNE) is the traditional approach to sporadic primary hyperparathyroidism. With the availability of the preoperative imaging techniques and intraoperative parathyroid hormone assays, minimally invasive parathyroidectomy (MIP) is fast becoming the favoured surgical approach.

Objectives

To assess the effects of minimally invasive parathyroidectomy (MIP) guided by preoperative imaging and intraoperative parathyroid hormone monitoring versus bilateral neck exploration (BNE) for the surgical management of primary hyperparathyroidism.

Search methods

We searched CENTRAL, MEDLINE, WHO ICTRP and ClinicalTrials.gov. The date of the last search of all databases was 21 October 2019. There were no language restrictions applied.

Selection criteria

We included randomised controlled trials comparing MIP to BNE for the treatment of sporadic primary hyperparathyroidism in persons undergoing surgery for the first time.

Data collection and analysis

Two review authors independently screened titles and abstracts for relevance. Two review authors independently screened for inclusion, extracted data and carried out risk of bias assessment. The content expert senior author resolved conflicts. We assessed studies for overall certainty of the evidence using the GRADE instrument. We conducted meta‐analyses using a random‐effects model and performed statistical analyses according to the guidelines in the latest version of the Cochrane Handbook for Systematic Reviews of Interventions.

Main results

We identified five eligible studies, all conducted in European university hospitals. They included 266 adults, 136 participants were randomised to MIP and 130 participants to BNE. Data were available for all participants post‐surgery up to one year, with the exception of missing data for two participants in the MIP group and for one participant in the BNE group at one year. Nine participants in the MIP group and 11 participants in the BNE group had missing data at five years. No study had a low risk of bias in all risk of bias domains.

The risk ratio (RR) for success rate (eucalcaemia) at six months in the MIP group compared to the BNE group was 0.98 (95% confidence interval (CI) 0.94 to 1.03; P = 0.43; 5 studies, 266 participants; very low‐certainty evidence). A total of 132/136 (97.1%) participants in the MIP group compared with 129/130 (99.2%) participants in the BNE group were judged as operative success. At five years, the RR was 0.94 (95% CI 0.83 to 1.08; P = 0.38; 1 study, 77 participants; very low‐certainty evidence). A total of 34/38 (89.5%) participants in the MIP group compared with 37/39 (94.9%) participants in the BNE group were judged as operative success.

The RR for the total incidence of perioperative adverse events was 0.50, in favour of MIP (95% CI 0.33 to 0.76; P = 0.001; 5 studies, 236 participants; low‐certainty evidence). Perioperative adverse events occurred in 23/136 (16.9%) participants in the MIP group compared with 44/130 (33.9%) participants in the BNE group. The 95% prediction interval ranged between 0.25 and 0.99. These adverse events included symptomatic hypocalcaemia, vocal cord palsy, bleeding, fever and infection. Fifteen of 104 (14.4%) participants experienced symptomatic hypocalcaemia in the MIP group compared with 26/98 (26.5%) participants in the BNE group. The RR for this event comparing MIP with BNE at two days was 0.54 (95% CI 0.32 to 0.92; P = 0.02; 4 studies, 202 participants). Statistical significance was lost in sensitivity analyses, with a 95% prediction interval ranging between 0.17 and 1.74. Five out of 133 (3.8%) participants in the MIP group experienced vocal cord paralysis compared with 2/128 (1.6%) participants in the BNE group. The RR for this event was 1.87 (95% CI 0.47 to 7.51; P = 0.38; 5 studies, 261 participants). The 95% prediction interval ranged between 0.20 and 17.87.

The effect on all‐cause mortality was not explicitly reported and could not be adequately assessed (very low‐certainty evidence). There was no clear difference for health‐related quality of life between the treatment groups in two studies, but studies did not report numerical data (very low‐certainty evidence). There was a possible treatment benefit for MIP compared to BNE in terms of cosmetic satisfaction (very low‐certainty evidence).

The mean difference (MD) for duration of surgery comparing BNE with MIP was in favour of the MIP group (–18 minutes, 95% CI –31 to –6; P = 0.004; 3 studies, 171 participants; very low‐certainty evidence). The 95% prediction interval ranged between –162 minutes and 126 minutes. The studies did not report length of hospital stay.

Four studies reported intraoperative conversion rate from MIP to open procedure information. Out of 115 included participants, there were 24 incidences of conversion, amounting to a conversion rate of 20.8%.

Authors' conclusions

The success rates of MIP and BNE at six months were comparable. There were similar results at five years, but these were only based on one study. The incidence of perioperative symptomatic hypocalcaemia was lower in the MIP compared to the BNE group, whereas the incidence of vocal cord paralysis tended to be higher. Our systematic review did not provide clear evidence for the superiority of MIP over BNE. However, it was limited by low‐certainty to very low‐certainty evidence.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Plain language summary

available in

Minimally invasive parathyroidectomy versus bilateral neck exploration for primary hyperparathyroidism in adults

Review question

Is minimally invasive parathyroidectomy a better surgical treatment compared to classic bilateral neck exploration for people with sporadic primary hyperparathyroidism?

Background

Primary hyperparathyroidism is a condition where one or more of the four parathyroid glands (pea‐sized glands located behind or in the thyroid gland in the neck) may enlarge and produce excess parathyroid hormone, a hormone that normally controls calcium and bone metabolism. Excess production of parathyroid hormone results in high blood calcium levels as calcium is drawn out of bones, resulting in increased risk of osteoporosis (weakened bones) and kidney stones. The word 'primary' means that this disorder originates in parathyroid glands and is mostly due to a benign excessive growth of parathyroid cells. Most but not all people with primary hyperparathyroidism have no symptoms. Surgery to remove the diseased parathyroid gland(s) (called parathyroidectomy) is the first‐line therapy for people who develop symptoms, namely fractures and kidney stones. Minimally invasive parathyroidectomy is a shorter simpler procedure that uses scans to identify the diseased glands with potentially lower complication risk than bilateral neck exploration (where both sided of the neck are explored to identify which of the four glands are diseased).

Study characteristics

We identified five randomised controlled trials (clinical studies in which people are randomly assigned to one of two or more treatment groups) enrolling a total of 266 adults with primary hyperparathyroidism, who were assigned to one of two surgical techniques (136 participants to the minimally invasive parathyroidectomy group and 130 to the bilateral neck exploration group). One of the studies followed up participants up to five years, but the rest reported data until one year.

Key results

Within six months, operative success as measured by normal blood calcium levels after operation, was found in 97% of participants in the minimally invasive parathyroidectomy group compared with 99% in the bilateral neck exploration group. Five years after the surgery the proportions were 90% in the minimally invasive parathyroidectomy group compared to 95% in the bilateral neck exploration group. About 17% of participants in the minimally invasive parathyroidectomy group reported unwanted events around the time of the operation compared with 34% in the bilateral neck exploration group. These events consisted mostly of symptoms of low calcium levels (such as numbness, tingling cramps) occurring in 14% of the minimally invasive parathyroidectomy group and in 27% in the bilateral neck exploration group. A total of 5/133 (4%) participants in the minimally invasive parathyroidectomy group experienced vocal cord paralysis compared with 2/128 (2%) participants in the bilateral neck exploration group. Other events included bleeding, fever and infection, which were comparable in both groups. The effect on death from any cause was not explicitly reported. There were no clear differences for health‐related quality of life between the treatment groups in two studies. There was a possible treatment benefit for minimally invasive parathyroidectomy compared to bilateral neck exploration in terms of cosmetic satisfaction. The duration of surgery was 18 minutes less for the minimally invasive parathyroidectomy technique compared with bilateral neck exploration. Four studies reported a switch from minimally invasive parathyroidectomy to bilateral neck exploration during the operation where 24/115 (21%) participants underwent the more extensive surgery.

Quality of the evidence

The quality of the evidence was low or very low mainly because of the small number of studies and participants.

This evidence is current to 21 October 2019.

Authors' conclusions

Implications for practice

Based on very low‐certainty evidence, success rates between minimally invasive parathyroidectomy (MIP) or bilateral neck exploration (BNE), either in short‐term or long‐term follow‐up were comparable in people with primary hyperparathyroidism undergoing parathyroid surgery for the first time. There was very low‐certainty evidence suggesting that MIP was associated with shorter duration of surgery.

Implications for research

Perhaps the greatest value of this systematic review is that it highlights the gap in knowledge for two frequently used surgical interventions, although surgeons today seem to favour MIP over BNE, with no firm evidence to do so. There were only five randomised controlled studies about the subject, and only one had a long‐term follow‐up revealing a concerning tendency for recurrence in the MIP group. We highlight two important areas future research must focus on. An effort must be made to include a greater number of participants in order to optimise power in large multicentre, and possibly multinational studies, and such future RCTs must aim to implement designs that seek to emulate current practice. Since all patients with negative imaging should undergo BNE, we suggest a design wherein patients are randomised to either receive preoperative imaging or surgery without imaging. Those who receive imaging would then undergo MIP if findings suggest single gland disease, or BNE if the scan is found to be non‐localising. All patients who are randomised to surgery without imaging would receive BNE.

Summary of findings

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Summary of findings 1. Minimally invasive parathyroidectomy versus bilateral neck exploration for primary hyperparathyroidism in adults

Minimally invasive parathyroidectomy guided by intraoperative parathyroid hormone monitoring and preoperative imaging compared to bilateral neck exploration for primary hyperparathyroidism in adults

Participant: adults with primary hyperparathyroidism

Setting: hospitals

Intervention: minimally invasive parathyroidectomy

Comparison: bilateral neck exploration

Outcomes

Illustrative comparative risks (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with bilateral neck exploration

Risk with minimally invasive parathyroidectomy

Success rate (eucalcaemia)

(a) Follow‐up: up to 6 months

(b) Follow‐up: up to 5 years

(a) 992 per 1000

(b) 949 per 1000

(a) 972 per 1000 (933 to 1022)

(b) 892 per 1000 (787 to 1025)

(a) RR 0.98
(0.94 to 1.03)

(b) RR 0.94
(0.83 to 1.08)

(a) 266 (5)

(b) 77 (1)

(a) / (b)

⊕⊝⊝⊝
Very lowa

(b) 5‐year follow‐up: data available for 77/91 randomised participants.

Total incidence of perioperative adverse events (number)

Follow‐up: up to 48 hours postoperatively

338 per 1000

169 per 1000 (112 to 257)

RR 0.50
(0.33 to 0.76)

236 (5)

⊕⊕⊝⊝
Lowb

—

All‐cause mortality
Follow‐up: up to 5 years

See comment

⊕⊝⊝⊝
Very lowc

No study explicitly reported on the occurrence of perioperative mortality.

In 1 study with 5 years' follow‐up there were 16 deaths, no data per intervention group were reported.

Health‐related quality of life
Follow‐up: up to 6 months

See comment

⊕⊝⊝⊝
Very lowd

2 studies reported that there were no clear differences between intervention groups; however, data were not presented.

Cosmetic satisfaction

Follow‐up: up to 1 year

See comment

⊕⊝⊝⊝
Very lowe

3 studies reported some data associated with cosmetic satisfaction but measurements varied substantially; overall some findings indicated a benefit of minimally invasive parathyroidectomy.

Duration of surgery (time from skin incision to skin closure)

The mean duration of surgery ranged across control groups from 64 minutes to 82 minutes

The mean duration of surgery in the intervention groups was 18 minutes lower (31 minutes lower to 6 minutes lower)

—

171 (3)

⊕⊝⊝⊝
Very lowf

The 95% prediction interval ranged between –162 minutes and 126 minutes.

Length of hospital stay

Not reported

CI: confidence interval; RR: risk ratio.

GRADE Working Group grades of evidence

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level because of risk of bias in several risk of bias domains, one level because of inconsistency and indirectness (95% prediction interval ranging between 0.90 and 1.06 and surrogate outcome) and one level because of imprecision (low sample size, 95% CI consistent with benefit and harm) – see Appendix 13.
bDowngraded one level because of risk of bias in several risk of bias domains and one level because of imprecision (low sample size) – see Appendix 13.
cDowngraded one level because no study explicitly reported on this outcome and two levels because of serious imprecision (low sample size, low number of studies) – see Appendix 13.
dDowngraded one level because only two studies evaluated this outcome but did not report data and two levels because of serious imprecision (low sample size, low number of studies) – see Appendix 13.
eDowngraded one level because of risk of bias in several risk of bias domains, one level because of indirectness (surrogate outcome) and one level because of imprecision (low sample size, low number of studies) – see Appendix 13.
fDowngraded one level because of risk of bias in several risk of bias domains, one level because of inconsistency (95% prediction interval ranging between –162 minutes and 126 minutes) and one level because of imprecision (low sample size, low number of studies) – see Appendix 13.

Background

Description of the condition

Primary hyperparathyroidism (PHPT) is a common disorder of bone metabolism and hypercalcaemia, occurring in 28 per 100,000 individuals yearly in the US. In the Mayo Clinic series, the incidence rose to 82 per 100,000 in the period 1974 to 1982, was down to 29.1 per 100,000 throughout the years 1983 to 1992, and 21.6 per 100,000 in 1992 to 2001 (Wermers 2006). It can occur at any age, with an increase in incidence after age 45 years. It is more common in women than men, and can occur in 2% of the postmenopausal women. The most common aetiology for the disease is a single gland adenoma in 80% to 85% of cases, with the rest of the cases constituting multiple gland hyperplasia (10% to 15%), double adenomas (2% to 5%), and carcinoma (1%) (Kaplan 1992; Kunstman 2012; Salti 1992).

The molecular basis for sporadic hyperparathyroidism remains largely unknown. Described abnormalities include gain‐of‐function in genes that stimulate parathyroid gland growth for sporadic tumours, such as Cyclin1, (Costa‐Guda 2014) or loss of function mutations in genes that suppress tumour growth, such as Multiple Endocrine Neoplasia 1 (MEN 1) or HRPT2 in sporadic and familial tumours (Westin 2009).

Since the development of adequate screening techniques, the disorder has evolved in high‐income countries into a mostly asymptomatic disease, often detected as a laboratory abnormality with mild hypercalcaemia incidentally discovered via routine examinations. Conversely, in low‐ to middle income countries, classical presentations still prevail including bone pain, nephrolithiasis, nephrocalcinosis, bone loss, increased fractures and osteitis fibrosa cystica (Bilezikian 2000; Mishra 2001; Parfitt 1991). Skeletal effects seen through changes in bone mineral density (BMD) and histomorphometric analysis were originally thought to be most prominent at cortical bony sites. However, more recent studies have noted volumetric BMD loss at both sites and deterioration in bone structure at trabecular sites (Chen 2003; Pyram 2011; Stein 2013; Vu 2013). An increased fracture risk has been observed in both traditional cortical bony areas, such as the hip, the distal radius, as well as trabecular bony areas such as the vertebrae (Bilezikian 2014; Khosla 2002), but there are no randomised studies to validate such observations. A newly available US Food and Drug Administration (FDA)‐approved dual‐energy X‐ray absorptiometry (DXA)‐derived technology known as trabecular bone score (TBS) was evaluated in 24 postmenopausal women with PHPT and revealed deterioration in trabecular bone structure (Silva 2013; Stein 2013; Vu 2013).

Renal calcification or stones appear to be increased up to four‐fold in people with PHPT compared to controls, occurring in up to 20% of people (Bilezikian 2014; Starup‐Linde 2012; Suh 2008). Non‐classical manifestations of PHPT include neurocognitive changes such as impaired concentration, increased depression and anxiety, decreased non‐verbal learning process, difficulties in using direct memory, worse performance on tests of verbal memory, verbal fluency and visual constructive abilities (Babinska 2012; Coker 2005; Joborn 1988; McAllion 1989), and cardiovascular abnormalities such as hypertension, myocardial and vascular calcifications, and left ventricular hypertrophy with changes in endothelial function as well as increased vascular stiffness (Fitzpatrick 2008; Rubin 2005; Silverberg 2014; Walker 2012).

Description of the intervention

Parathyroidectomy is the only curative option in people with PHPT. In general, while surgery for hyperparathyroidism in the setting of chronic kidney disease often involves subtotal parathyroidectomy or total parathyroidectomy with autotransplantation (Welk 1987; Welsh 1984; White 1986). Surgery for PHPT aims to only resect the diseased gland(s) and, therefore, remove the source for excess parathyroid hormone (PTH) production. The goal is to thus decrease the incidence of nephrolithiasis and nephrocalcinosis, improve BMD, decrease fractures and possibly improve health‐related quality of life. Even in asymptomatic individuals, there is some evidence that surgery improves BMD (Rubin 2008), and possibly functional capacity and health‐related quality of life (Ramakant 2012). Therefore, surgery is indicated for all patients with symptomatic PHPT, and some patients with asymptomatic disease. The updated 2014 guidelines on the management of asymptomatic patients include age less than 50 years, serum calcium concentration of 1.0 mg/dL or more above upper limit of normal, creatinine clearance 60 mL/minute or less, BMD at any site with a DXA‐derived T‐score of –2.5 or less at spine, hip or forearm, vertebral fracture (documented by x‐ray, computerised tomography (CT), magnetic resonance imaging (MRI), or vertebral fracture assessment (VFA)), a creatinine clearance less than 60 mL/minute, a 24‐hour urine calcium more than 400 mg/day and an increased stone risk. Stone risk is assessed by biochemical stone risk analysis or the presence of nephrolithiasis or nephrocalcinosis identified by x‐ray, ultrasound or CT scan (Bilezikian 2014).

Bilateral neck exploration

Bilateral neck exploration (BNE) is the traditional approach to primary sporadic hyperparathyroidism, and when performed by experienced surgeons results in curative rates of 95% to 98%, and is associated with low complication rates (Allendorf 2007). It remains the mainstay treatment for people with unlocalised pathology, familial or hereditary cases, or concomitant thyroid disease.

Minimally invasive parathyroidectomy

Minimally invasive parathyroidectomy (MIP) has largely replaced BNE (Greene 2009), due to its safety and effectiveness as well as possible lower costs and morbidity (Udelsman 2014). The exploration is done via direct visualisation of all parathyroid glands, and may be performed under local or general anaesthesia, through an open traditional incision, minimally invasive incision or even via a videoscopic approach (Alesina 2010; Allendorf 2007; Lo 1999; Lowney 2000; Udelsman 2014).

We will use the 2002 summary statement on asymptomatic hyperparathyroidism definition for MIP. It is a set of techniques employing preoperative imaging and intraoperative PTH assays (IOPTH) to limit surgical visualisation only to the suspected gland (Bilezikian 2002; Carneiro 2003). There are currently several variations for MIP techniques satisfying these criteria (Udelsman 2011; Udelsman 2014). In general, focused parathyroidectomy aims towards visualisation of just the suspected gland, whereas unilateral exploration visualises the entire side suspected to have a pathology. Exploration is either open or endoscopic. Two common endoscopic techniques are described in the literature, and offer advantages of magnified vision and tactile control (Henry 1999; Gracie 2012; Miccoli 1999). The technique suggested by Henry 1999 uses a more lateral approach avoiding dissection of the strap muscles and allowing possible direct visualisation of the adenoma but may compromise the cardiorespiratory system through the frequent requirement of carbon dioxide insufflation in order to maintain an adequate working space. In contrast, the technique suggested by Miccoli and colleagues suggests a more medial approach, wherein gas insufflation is only maintained for a few minutes in order to allow for dissection of the strap muscles, after which a working space is maintained simply by using external retraction (Miccoli 1999). This 'gasless approach' promised to avoid emphysema, pneumomediastinum and neck swelling (Henry 1999; Henry 2008; Miccoli 1999; Miccoli 2011). Despite the nuances of slight differences in technique, the fundamental methods of all MIP are the same. Single gland disease is identified and localised by use of preoperative ultrasound, Sestamibi scan (Technetium (99mTc) nuclear medicine imaging), or both. A limited exploration then targets the suspicious side or gland in an attempt to avoid a cumbersome full neck exploration (Irvin 1991; Irvin 1994; Kuntsman 2013; Udelsman 2004). IOPTH monitoring is carried out generally through peripheral venous blood draws, with pre‐incision, pregland ligation, and 5, 10 and 20 minutes postgland ligation measurements. Criteria used for evidence of adequate incision, and thus termination of surgery, vary widely. The most accepted, the Miami criterion, considers a decrease in PTH measurement by more than 50% from the highest baseline to the 10‐minute postgland ligation value as evidence for adequate gland excision (Barczynski 2009; Carneiro 2003; Irvin 1993). In the event of inadequate decline using this criterion, surgery is then converted to a bilateral conventional technique, possibly due to location of abnormal gland on the opposite side or due to suspicion of multiglandular disease. MIP techniques are usually offered to people with preoperative localisation studies suggestive of single gland disease, in the absence of thyroid pathology, familial or hereditary hyperparathyroidism, or lithium intake. MIP techniques should only be implemented in centres that have sophisticated imaging and intraoperative PTH assays, and only performed by experienced endocrine surgeons (Udelsman 2014).

Adverse effects of the intervention

Apart from a theoretical concern for possibilities of subcutaneous emphysema following gas insufflation in the endoscopic technique described by Henry and colleagues (Henry 1999), both MIP and BNE have adverse events, which are rare for both interventions. These include anaesthesia‐related or postoperative complications, or both, such as hypocalcaemia, vocal cord paralysis, haematomas and infections. One retrospective review of 656 parathyroid operations found a 3% complication rate for BNE and a 1.2% complication rate for MIP (Udelsman 2002). Haematomas are potentially life‐threatening complications arising in 0.3% of all surgeries for PHPT, and may present with a variety of symptoms including neck pain, respiratory distress, dysphagia and wound drainage (Burkey 2001; Carty 2004). Hypoparathyroidism is commonly transient and presents with decreased calcium concentration in association with either mild symptoms of tingling or numbness, or more severe symptoms such as profound fatigue or carpopedal spasm. Other major complications, such as fever and severe hypocalcaemia are rare, unless after subtotal parathyroidectomy (Carty 2004). Such presentations are only transient and permanent hypoparathyroidism occurred in only 0.3% of 380 operations reviewed by Carty colleagues (Carty 2002). Similarly, permanent recurrent laryngeal nerve injury is very rare. In some reports, 0.2% of 1112 participants, and 0.7% of 401 bilaterally explored participants had permanent recurrent laryngeal nerve injury (Allendorf 2007; Udelsman 2002), and 0.3% of 380 participants and 0.4% of 255 participants receiving a minimally invasive surgery had similar injury (Carty 2002; Udelsman 2002). Differences in the incidence of adverse effects between MIP and BNE are controversial and the few randomised controlled trials (RCT) have differing findings. Apart from scar length differences, Slepavicius 2008 reported no significant differences in adverse events between intervention groups, Miccoli 1999 noted insignificant differences in one study and no adverse events in either group in another, while Bergenfelz and colleagues noted a greater incidence of severe hypocalcaemia in the bilateral group compared to MIP group (10% versus 0%) (Bergenfelz 2005; Miccoli 1999; Miccoli 2008; Rulli 2007; Slepavicius 2008).

How the intervention might work

The theoretical basis behind MIP is that most cases are caused by single gland pathology, and that modern tools can identify such pathology with acceptable accuracy, rendering the need for complete visualisation of both sides of the neck almost unnecessary. This may also decrease the rate of complications and thus decrease operative time and cost, although this has been debatable (Bergenfelz 2002; Miccoli 1999). Indeed, more than 80% of spontaneous PHPT is caused by a single solitary adenoma (Kunstman 2012; Ruda 2005). Improvements in imaging techniques have reached sensitivities between 71% to 80% for ultrasound imaging and a sensitivity greater than 90% for Sestamibi scanning (Arici 2001; Carty 1997; Dijkstra 2002; Hindié 2015; Ryan 1997; Ryan 2004). The advent of intraoperative PTH monitoring assays have optimised the accuracy of adequate resection, reaching accuracy greater than 96% for the Miami criterion (Barczynski 2009; Carneiro 2003), and encouraged the adoption of MIP by most surgeons. Indeed, by 2008, 68% of US surgeons were found to be practicing limited exploration techniques and only 10% practiced BNE exclusively (Greene 2009).

Why it is important to do this review

Despite the excellent short‐term curative rate and low morbidity profile with both MIP and BNE in PHPT, there is still no consensus on the preferred option to‐date (Udelsman 2014). The importance of our review stems from the large number of people undergoing these procedures yearly, without a definitive answer about the long‐term success of MIP compared to BNE. The greatest uncertainty in this subject stems from concerns about increased long‐term recurrence or missed multiglandular disease in people undergoing MIP. We are aware of only one RCT that had an extended follow‐up for five years postoperatively. The investigators noted 4/47 recurrent cases in the MIP group compared to 2/44 in the conventional exploration group (Bergenfelz 2002). One retrospective analysis by a high‐volume group found that the long‐term failure rate of the unilateral approach was 11 times higher than that of conventional bilateral surgery. However, that group is known for not using IOPTH monitoring (Norman 2012). Another group noted a higher than 8% recurrence rate after eight years of follow‐up in people undergoing MIP as opposed to 0% in the open parathyroidectomy group (Schneider 2012). The differences were not significant because of the small number of participants followed up for this duration. Identifying further publications with long‐term follow‐up may quell concerns, re‐ignite them, or highlight the urgent need for long‐term outcome studies.

This review will help characterise the respective risks and benefits of each type of surgery more clearly, both in the short term and longer term. Few RCTs have been published on this topic, often with differing conclusions (e.g. see 'Adverse effects of the intervention'). A properly conducted systematic review and meta‐analysis helps us provide an objective risk‐benefit assessment for both techniques, on prespecified participant outcomes, in both short‐term and long‐term follow‐up. This will serve to empower doctors and participants alike in making better educated choices. Furthermore, we only identified one systematic review comparing both approaches on the topic (Gracie 2012). The Gracie 2012 review had several limitations, and among which it excluded unilateral exploration. We also found the review deficient in key criteria reflecting a systematic methodological quality. On AMSTAR, a validated tool used for assessing methodological quality of systematic reviews (Shea 2007), the previous review scored low, with only two out of a possible 11 tool items scoring positively. Inclusion and exclusion criteria were provided in a table format but the type of studies, languages and publication status (grey literature) were not discussed. The methods of study selection and data abstraction were also not entirely clear, and there was no indication of whether these processes occurred in duplicate. While the search methodology was presented in the paper, the initial results, excluded studies and reasons for exclusions were not. No meta‐analysis was done for any of the outcomes of interest, and there was no assessment of risk of bias in the included studies. The review also did not address the greatest source of uncertainty in the topic, that is, long‐term success rate. We believe that inclusion of this outcome is extremely important in order to truly gauge the long‐term impact of potentially leaving residual enlarged tissue in people who undergo minimally invasive techniques, relying on localisation studies and IOPTH monitoring. Our review aims to address the above limitations in detail.

Objectives

To assess the effects of minimally invasive parathyroidectomy (MIP) guided by preoperative imaging and intraoperative parathyroid hormone monitoring versus bilateral neck exploration (BNE) for the surgical management of primary hyperparathyroidism.

Methods

Criteria for considering studies for this review

Types of studies

We included RCTs comparing MIP to BNE for people with sporadic PHPT presenting to surgery for the first time, as specified in our protocol (Kreidieh 2013).

Types of participants

We included studies of adults with PHPT presenting for first‐time parathyroidectomy.

We excluded studies of participants:

  • undergoing repeat surgeries;

  • with secondary hyperparathyroidism;

  • with tertiary hyperparathyroidism;

  • with parathyroid carcinoma;

  • with increased risk of multiglandular disease (i.e. children or people with genetic predispositions to have hyperparathyroidism such as people with multiple endocrine neoplasia);

  • with different types of hyperparathyroidism with no separate reporting of results by type;

  • with elevated mean creatinine at entry into study.

Diagnostic criteria for considered conditions
Hyperparathyroidism

We used the following definitions of hyperparathyroidism (Bilezikian 2002).

  • Elevated or inappropriately normal PTH level, with serum calcium levels above normal reference range.

  • Elevated serum PTH with normal calcium levels, after exclusion of secondary causes for elevation of PTH (mainly decreased calcium intake, vitamin D deficiency, renal insufficiency, hypercalciuria of renal origin).

Sporadic primary hyperparathyroidism

  • PHPT.

  • Exclusion of secondary causes such as renal insufficiency, vitamin D deficiency and familial hyperparathyroidism.

Types of interventions

We planned to investigate the following comparisons of intervention versus comparator.

Intervention

  • MIP (open unilateral parathyroidectomy) guided by IOPTH and preoperative imaging.

  • MIP (open focused parathyroidectomy) guided by IOPTH and preoperative imaging.

  • MIP (endoscopic unilateral parathyroidectomy) guided by IOPTH and preoperative imaging.

  • MIP (endoscopic focused parathyroidectomy) guided by IOPTH and preoperative imaging.

Comparator

  • BNE regardless of use of and results of any operative adjuncts.

Preoperative imaging

Localisation may be done prior to or after randomisation. We accepted either case, but downgraded the certainty of the evidence for studies with localisation procedures done prior to randomisation due to indirectness. This is because participants receiving BNE in the general population do not routinely receive preoperative imaging.

We accepted imaging results as suggestive of single gland disease, multiple gland disease and inconclusive as determined by an expert radiologist or surgeon, as reported in the paper.

Accepted preoperative localisation procedures included at least one of the following:

  • ultrasound imaging using a 5 MHz, 7.5 MHz or 10 MHz transducer;

  • technetium 99m‐Sestamibi scanning using single isotope dual phase scan, dual isotope subtraction scan and three‐dimensional single‐photon emission computerised tomography (SPECT) imaging scan;

  • thallium technetium scanning.

Intraoperative parathyroid hormone monitoring

We accepted the use of a second‐ or third‐generation rapid PTH assay intraoperatively for confirmation of adequate gland resection (Eastell 2014), per a commonly accepted criterion, such as the Miami criterion, of a fall in serum PTH of 50% at 10 minutes postgland excision. This fall is from the highest PTH value of either a preskin incision baseline or a pregland excision baseline (Barczynski 2009).

Types of outcome measures

We did not exclude a study if it failed to report one or several of our primary or secondary outcome measures. If the study reported none of our primary or secondary outcomes, we did not include the study but provided some basic information in the Characteristics of studies awaiting classification table.

We investigated the following outcomes using the methods and time points specified below.

Primary outcomes

  • Success rate.

  • Total incidence of perioperative adverse events.

Secondary outcomes

  • Specific adverse events.

  • Conversion rate from minimally invasive to open procedure.

  • Postoperative increase in PTH with eucalcaemia.

  • All‐cause mortality.

  • Health‐related quality of life.

  • Cosmetic satisfaction.

  • Bone fracture rate.

  • Nephrolithiasis rate.

  • Absence from work.

  • Duration of surgery.

  • Length of hospital stay.

  • Socioeconomic effects.

Method and timing of outcome measurement

  • Success rate: defined by authors as eucalcaemia or hypocalcaemia. We defined short‐term success rate as within six months of surgery, medium‐term success rate as between six months and five years and long‐term success rate as at five years or more after surgery.

  • Total incidence of perioperative adverse events: defined by authors as adverse events occurring within 48 hours of surgery.

  • Specific adverse events:

    • bleeding events (identified as such in the included study or one requiring transfer to an intensive care unit or requiring blood transfusion within 48 hours of surgery);

    • infection within one month of surgery;

    • hypocalcaemia within 48 hours, one month and six months of surgery (including transient, permanent, severe and mild hypocalcaemia as defined in the adverse events section of our protocol; Kreidieh 2013). We differentiated symptomatic hypocalcaemia, in which participants exhibit typical symptoms of hypocalcaemia, from biochemical hypocalcaemia, referring to any participant with calcium levels below the lower limit of normal for the laboratory in which the measurements were made. Transient hypocalcaemia was defined as hypocalcaemia resolving within six months of surgery, while permanent hypocalcaemia referred to hypocalcaemia persisting longer than six months postoperatively (Mehrabi 2012);

    • postoperative pain using a validated pain score such as the visual analogue scale at 48 hours postoperatively;

    • vocal cord paralysis identified as such in the study in the postoperative period (usually 48 hours);

    • anaesthesia‐related complications identified as such in the study occurring intraoperatively.

  • Conversion rate from minimally invasive to open procedure: defined as the proportion of participants who were planned to have a MIP but were converted to a BNE intraoperatively.

  • Postoperative increase in PTH with eucalcaemia: defined as a within normal serum level of calcium, with an above normal level of PTH at short term (within six months of surgery), medium term (between six months and five years after surgery) and long term (at five years or more after surgery) (Ning 2009).

  • Health‐related quality of life: measured by a validated instrument such as the medical outcomes study 36‐item Short Form Health Survey (SF‐36) at one month and six months postoperatively.

  • Cosmetic satisfaction: measured using a validated instrument such as a Holander Scale within 48 hours of surgery and at six months postoperatively.

  • Bone fracture rate: we considered bone loss as evidenced by a decrease in BMD as a surrogate for fracture rate in case data on fracture rate were not readily available. The minimal important difference in each centre was defined by the centre‐specific quality assurance protocol, if defined in the study. If it was not available, we considered as significant any decrease in BMD that exceeded 5% at any skeletal site, considering a precision of up to 2.5%, as recommended by the International Society of Clinical Densitometry (ISCD) (Baim 2008). However, this could have still resulted from random error in centres that did not report centre‐specific precision or could not abide by the ISCD quality assurance measures. For the pooled estimate, we considered the minimally important difference as the highest obtained from all studies. Both outcomes were considered within one and five years of surgery.

  • Nephrolithiasis rate: defined as percentage of participants having an incidence of nephrolithiasis within five years of surgery.

  • Absence from work: defined as the number of days of work missed and determined by study authors to have been caused by the surgery. Timing was not applicable to this item.

  • Duration of surgery: defined as time from skin incision to skin closure during surgery. Timing was not applicable to this item.

  • Length of hospital stay: defined as the number of days of hospitalisations prior to and following first admission for surgery. Timing was not applicable to this item.

  • Socioeconomic effects were not prespecified in the protocol but were detailed in the manuscripts, as provided in the respective studies. These included direct costs defined as admission/readmission rates, mean length of stay, in‐hospital charges, visits to general practitioner, accident/emergency visits; medication consumption; or indirect costs defined as resources lost due to illness by the participant or their family member.

Search methods for identification of studies

Electronic searches

We searched the following sources from inception to 21 October 2019 and placed no restrictions on the language of publication.

  • Cochrane Central Register of Controlled Trials (CENTRAL; via Cochrane Register of Studies Online) (searched 21 October 2019).

  • Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations and Daily 1946 to October 18, 2019 (searched 21 October 2019).

  • ClinicalTrials.gov (searched 21 October 2019).

  • World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal (apps.who.int/trialsearch/) (searched 21 October 2019).

For detailed search strategies, see Appendix 1.

Searching other resources

We tried to identify other potentially eligible studies or ancillary publications by searching the reference lists of retrieved included studies, systematic or other reviews, meta‐analyses and health‐technology assessment reports. We contacted study authors of included studies to request missing data and to identify any further studies that we may have missed.

Data collection and analysis

Selection of studies

Two review authors (OK, HA) independently scanned the abstract, title, or both, of every record retrieved in the literature searches, to determine which studies we should assess further. We obtained the full text of all potentially relevant records. We resolved disagreements through consensus or by recourse to a third review author (GEHF and EA). If we could not resolve a disagreement, we categorised the study as a 'Study awaiting classification' and contacted the study authors for clarification. We present an adapted PRISMA flow diagram to shown the process of study selection (Liberati 2009).

We obtained full‐text articles from the database searches available at the American University of Beirut. We aimed to translate any studies available in languages other than English, Arabic or French (Figure 1).

Figure 1
Study flow diagram. HTA: health technology assessment.

Study flow diagram. HTA: health technology assessment.

Data extraction and management

For studies that fulfilled our inclusion criteria, two review authors (OK, HA) independently extracted key participant and intervention characteristics and outcome data. We reported data on outcomes and adverse events using standardised data extraction sheets from the Cochrane Metabolic and Endocrine Disorders (CMED) Group. We resolved disagreements by discussion or, if required, by consultation senior review authors (GEHF and EA) (for details see Table 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6; Appendix 7; Appendix 8; Appendix 9; Appendix 10; Appendix 11; Appendix 12; Appendix 13; Appendix 14).

Open in table viewer
Table 1. Overview of study populations

Study (design)

Intervention(s) and comparator(s)

Description of power and sample size calculation

Screened/eligible
(n)

Randomised
(n)

Analysed
(n)

Finishing study
(n)

Randomised finishing study
(%)

Follow‐up

Bergenfelz 2005
(parallel RCT)

I: MIP guided by intraoperative PTH monitoring and preoperative imaging

—

233

25

25

25

100

First 4 days after surgery, 1 and 6 months

C: BNE

25

25

25

100

Total:

233

50

50

50

100

Bergenfelz 2002
(parallel RCT)

I: MIP guided by intraoperative PTH monitoring and preoperative imaging

—

47

47

47

38

80

First 4 postoperative days, 6 weeks, 1 and 5 years

C: BNE

44

44

44

33

75

Total:

91

91

91

71

78

Miccoli 2008
(parallel RCT)

I: focused endoscopic parathyroidectomy (MIVAP) – MIP guided by intraoperative PTH monitoring and preoperative imaging

—

20

20

20

20

100

First postoperative day; 1 and 6 months

C: BNE

20

20

20

20

100

Total:

40

40

40

40

100

Miccoli 1999
(parallel RCT)

I: MIVAP guided by intraoperative PTH monitoring and preoperative imaging

—

38

20

20

20

100

12, 24, and 48 hours after surgery; 1, 3 and 6 months

C: BNE

18

18

18

100

Total:

38

38

38

38

Slepavicius 2008
(parallel RCT)

I: MIP guided by intraoperative PTH monitoring and preoperative imaging

47

24

24

24

100

48 hours after surgery, 4 weeks, 1 and 6 months, 1 year

C: BNE

23

23

23

100

Total:

47

47

47

47

100

Overall total

All interventions

—

136

127

—

All comparators

130

119

All interventions and comparators

266

246

—: denotes not clearly described in the publication

BNE: bilateral neck exploration; C: comparator; I: intervention; MIP: minimally invasive parathyroidectomy; MIVAP: minimally invasive video‐assisted parathyroidectomy; n: number of participants; PTH: parathyroid hormone; RCT: randomised controlled trial.

We provided information including study identifier for potentially relevant ongoing trials in the Characteristics of ongoing studies table and in Appendix 7 'Matrix of study endpoints (publications and trial documents)'. We tried to identify the protocol for each included study and report in Appendix 7 primary, secondary, and other outcomes in comparison with data in publications.

We sent an email to all authors of included studies to enquire whether they were willing to answer questions regarding their studies. We presented the results of this survey in Appendix 15. We thereafter sought relevant missing information on the study from the primary study author(s), if required.

Dealing with duplicate and companion publications

In the event of duplicate publications, companion documents or multiple reports of a primary study, we maximised the yield of information by collating all available data and used the most complete data set aggregated across all known publications. We listed duplicate publications, companion documents, multiple reports of a primary study and trial documents of included trials (such as trial registry information) as secondary references under the study ID of the included study. Furthermore, we also listed duplicate publications, companion documents, multiple reports of a study and trial documents of excluded trials (such as trial registry information) as secondary references under the study ID of the excluded study. We attempted to resolve any remaining uncertainties by contacting the authors whenever possible.

Data from clinical trials registers

If data from included studies were available as study results in clinical trials registers, such as ClinicalTrials.gov, or similar sources, we made full use of this information and extracted the data. If there was also a full publication of the study, we collated and critically appraised all available data. If an included study was marked as a completed study in a clinical trial register but no additional information (study results, publication, or both) was available, we added this study to the Characteristics of studies awaiting classification table.

Assessment of risk of bias in included studies

Two review authors (HA, OK) independently assessed the risk of bias for each included study. We resolved disagreements by consensus, or by consultation with a senior review author (GEHF). In the case of disagreement, we consulted the remainder of the review authors team and made a judgement based on consensus. If adequate information was not available from the publications, study protocols or other sources, we contacted study authors to request missing data on 'Risk of bias' items.

We used the Cochrane 'Risk of bias' assessment tool (Higgins 2011a; Higgins 2017), assigning assessments of low, high or unclear risk of bias (for details, see Appendix 2; Appendix 3). We evaluated individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions, according to the criteria and associated categorisations contained therein (Higgins 2017).

Summary assessment of risk of bias

We presented a 'Risk of bias' graph (Figure 2) and a 'Risk of bias' summary figure (Figure 3).

Figure 2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (blank cells indicate that the particular outcome was not measured in some studies).

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (blank cells indicate that the particular outcome was not measured in some studies).

Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study (blank cells indicate that the study did not measure that particular outcome).

Risk of bias summary: review authors' judgements about each risk of bias item for each included study (blank cells indicate that the study did not measure that particular outcome).

We distinguished between self‐reported, investigator‐assessed and adjudicated outcome measures.

We defined the following outcomes as self‐reported by participants.

  • Total incidence of perioperative adverse events.

  • Postoperative pain.

  • Health‐related quality of life.

  • Cosmetic satisfaction.

We required the following outcomes to be investigator‐assessed and objectively measured by a study personnel.

  • Success rate.

  • Specific adverse events.

  • Conversion rate from minimally invasive to open surgery.

  • Postoperative increase in PTH with eucalcaemia.

  • All‐cause mortality.

  • Bone fracture rate.

  • Nephrolithiasis rate.

  • Duration of surgery.

  • Length of hospital stay.

  • Socioeconomic effects.

Risk of bias for a study across outcomes

Some 'Risk of bias' domains, such as selection bias (sequence generation and allocation sequence concealment), affect the risk of bias across all outcome measures in a study. In case of high risk of selection bias, we marked all endpoints investigated in the associated study as high risk. Otherwise, we did not perform a summary assessment of the risk of bias across all outcomes for a study.

Risk of bias for an outcome within a study and across domains

We assessed the risk of bias for an outcome measure by including all entries relevant to that outcome (i.e. both study‐level entries and outcome‐specific entries). We considered low risk of bias to denote a low risk of bias for all key domains, unclear risk to denote an unclear risk of bias for one or more key domains, and high risk to denote a high risk of bias for one or more key domains.

Risk of bias for an outcome across studies and across domains

These are the main summary assessments that we incorporated into our judgements about the certainty of the evidence in the 'Summary of finding' table. We defined outcomes as at low risk of bias when most information came from studies at low risk of bias, unclear risk when most information came from studies at low or unclear risk of bias, and high risk when a sufficient proportion of information came from studies at high risk of bias.

We graded the overall certainty of the evidence for each outcome using the GRADE approach. The approach classified the certainty of the evidence into four categories: high, moderate, low and very low. It took into account study design and the following factors: risk of bias, imprecision, inconsistency, indirectness, publication bias, large effect size, dose‐response effect and confounding (Guyatt 2011; Meader 2014).

Measures of treatment effect

We expressed dichotomous data as risk ratio (RR) or hazard ratio (HR) with 95% confidence intervals (CI). We expressed continuous data as mean differences (MDs) with 95% CI when studies used the same scale and standardised mean differences (SMD) with 95% CI when studies used difference scales (Deeks 2017; Hozo 2005; Riley 2011).

Unit of analysis issues

The unit of analysis was the individual participant for specific outcomes (clarification: the meta‐analyses is based on group‐level data). We took into account the level at which randomisations occurred, such as cluster‐randomised studies and multiple observations for the same outcome Higgins 2011b).

Dealing with missing data

We attempted to obtain relevant missing data from authors of included studies. If unsuccessful, we used a complete‐case approach in the main analysis. We then conducted sensitivity analyses using plausible assumptions about the outcomes of participants with missing outcome data to test the robustness of statistically significant results.

For both continuous and dichotomous data, we imputed plausible treatment effects using progressively stringent criteria, as outlined by Akl and Ebrahim (Akl 2013; Ebrahim 2013).

Assessment of heterogeneity

In the event of substantial clinical or methodological heterogeneity, we did not report study results as a pooled effect estimate in the meta‐analysis. We identified heterogeneity (inconsistency) by visual inspection of the forest plots and by using a standard Chi² test with a significance level = 0.1 (Deeks 2017). In view of the low power of this test, we also considered the I² statistic, which quantifies inconsistency across studies to assess the impact of heterogeneity on the meta‐analysis (Higgins 2002; Higgins 2003).

Had we found heterogeneity, we would have attempted to determine possible reasons for this by examining individual study and subgroup characteristics.

Assessment of reporting biases

If we included 10 or more studies that investigated a particular outcome, we used funnel plots to assess small‐study effects. Several explanations may account for funnel plot asymmetry, including true heterogeneity of effect with respect to study size, poor methodological design (and hence small‐study bias) and publication bias (Sterne 2017). Therefore, we interpreted the results carefully (Sterne 2011).

Data synthesis

We conducted meta‐analyses using a random‐effects model (Wood 2008). In addition, we performed statistical analyses according to the statistical guidelines referenced in the latest version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). In the event of substantial clinical, methodological or statistical heterogeneity, we considered whether to report the study results as meta‐analytically pooled effect estimates.

We planned to undertake (or display) a meta‐analysis only if participants, interventions, comparisons and outcomes were judged to be sufficiently similar to ensure an answer was clinically meaningful. Unless good evidence showed homogeneous effects across studies, we primarily summarised low risk of bias data using a random‐effects model (Wood 2008). We interpreted random‐effects meta‐analyses with due consideration to the whole distribution of effects, ideally by presenting a prediction interval (Borenstein 2017a; Borenstein 2017b; Higgins 2009). A prediction interval specifies a predicted range for the true treatment effect in an individual study (Riley 2011). For rare events such as event rates below 1%, we used Peto's odds ratio method, provided that there was no substantial imbalance between intervention and comparator group sizes and intervention effects were not exceptionally large. In addition, we performed statistical analyses according to the statistical guidelines presented in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017).

Subgroup analysis and investigation of heterogeneity

We expected some characteristics to introduce clinical heterogeneity, and we planned to carry out the following subgroup analysis including investigation of interactions (Altman 2003).

  • Surgeon speciality.

  • Academic versus non‐academic setting.

  • High‐volume versus low‐volume groups.

  • IOPTH criteria used.

Sensitivity analysis

We planned to performed sensitivity analyses to explore the influence of some factors (when applicable) on effect sizes by restricting analysis to the following.

  • Published studies.

  • Effect of risk of bias, as specified in the Assessment of risk of bias in included studies section.

  • Taking into account missing data information.

  • Very long or large studies to establish the extent to which they dominated the results.

  • Use of the following filters: diagnostic criteria, imputation, language of publication, source of funding (industry versus other) or country.

We tested the robustness of the results by repeating analysis using different measures of effect size (e.g. RR, OR, etc.) and different statistical models (fixed‐effect and random‐effects models).

Certainty of the evidence

We presented the overall certainty of the evidence for each outcome specified below according to the GRADE approach, which takes into account issues related to internal validity (risk of bias, inconsistency, imprecision, publication bias) and to external validity, such as directness of results. Two review authors (HA, OK) independently rated the certainty of the evidence for each outcome.

We included Appendix 13 entitled 'Checklist to aid consistency and reproducibility of GRADE assessments', to help with standardisation of the 'Summary of findings' table (Meader 2014). Alternatively, we used the GRADEpro GDT software and presented evidence profile tables as an appendix (GRADEpro GDT 2014). We presented results for the outcomes as described in the Types of outcome measures section. If meta‐analysis was not possible, we presented the results narratively in the 'Summary of findings' table. We justified all decisions to downgrade the certainty of the evidence by using footnotes, and we made comments to aid the reader's understanding of the Cochrane Review when necessary.

'Summary of findings' table

We presented a summary of the evidence in summary of findings Table 1. This provided key information about the best estimate of the magnitude of effect, in relative terms and as absolute differences for each relevant comparison of alternative management strategies, numbers of participants and studies that addressed each important outcome, and a rating of overall confidence in effect estimates for each outcome. We created summary of findings Table 1 using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2017) along with Review Manager 5 (Review Manager 2014).

The intervention presented in the 'Summary of findings' table was MIP and the comparator was BNE.

We reported the following outcomes, listed according to priority.

  • Success rate.

  • Total incidence of perioperative adverse events.

  • All‐cause mortality.

  • Health‐related quality of life.

  • Cosmetic satisfaction.

  • Duration of surgery.

  • Length of hospital stay.

Results

Description of studies

For a detailed description of studies, see Table 1, Characteristics of included studies table and Characteristics of excluded studies table.

Results of the search

Search in the electronic databases identified 773 articles after removal of duplicates. From reading titles and abstracts, we assessed 45 full‐text articles for eligibility after initial screening. After full‐text screening, we excluded 37 publications because they did not meet our inclusion criteria (see Characteristics of excluded studies table), leaving six publications reporting on five studies that were included in this review (see Characteristics of included studies table; Figure 1).

Included studies

A detailed description of the characteristics of included studies is included in the Characteristics of included studies table and Appendix 4; Appendix 5; Appendix 6; Appendix 9. The following is a succinct overview.

All five retrieved studies were written in English (Bergenfelz 2002; Bergenfelz 2005; Miccoli 1999; Miccoli 2008; Slepavicius 2008). The studies were published between 1999 and 2008, and all were conducted in European university hospitals (Germany, Italy, Lithuania, Sweden).

Source of data

All data were obtained from the published literature. We requested Information from all study authors, a reply was only received from Dr Bergenfelz via email correspondence (Bergenfelz 2002; Bergenfelz 2005).

Comparisons

Four studies employed a focused surgical technique in the MIP group, wherein the surgeon only targeted the suspicious gland identified on imaging (Bergenfelz 2005; Miccoli 1999; Miccoli 2008; Slepavicius 2008). Bergenfelz 2002 employed a unilateral technique where surgery was started on the side indicated by the preoperative scintigram or on the left side whenever the scintigram failed to localise any enlarged parathyroid glands. In participants with non‐localising preoperative imaging, Slepavicius 2008 performed bilateral intraoperative internal jugular vein PTH sampling to guide the surgery (Appendix 4).

Other observed differences included anaesthesia, use of a videoscopic technique, IOPTH criteria and criteria for conversion of surgery.

Overview of study populations

The five studies included 266 participants, 136 participants were randomised to MIP and 130 to BNE. Data were available for all participants postsurgery up until one year but data were missing for two participants in the MIP group and for one in the BNE group at one year and for nine participants in the MIP group and for 11 in the BNE group at five years (Table 1).

The mean age in four studies was 62 years, with a male to female ratio of 1:5 (Bergenfelz 2002; Bergenfelz 2005; Miccoli 1999; Miccoli 2008). In the study by Slepavicius and colleagues, authors reported an age range of study participants between 18 and 90 years, but did not specify gender (Slepavicius 2008). The mean preoperative serum calcium level for included studies was 2.83 mmol/L (11.32 mg/dL), with a mean PTH level of 22.75 pmol/L (206.81 pg/mL). Only one study reported that 13/91 participants were asymptomatic prior to surgery (Bergenfelz 2002). None of the studies reported the proportion of participants who had fractures or kidney stones at baseline (Appendix 5; Appendix 6).

Two studies reported on gender distribution in each treatment group, and had a male to female ratio of 1:4.6 in the MIP group and 1:4 in the BNE groups. In the three studies reporting age by treatment group, the intervention group age was 61.6 years old on average, while the control group was 64 years old (Bergenfelz 2002; Bergenfelz 2005; Miccoli 2008). The mean calcium concentration was 2.84 mmol/L (11.36 mg/dL) in the intervention group and 2.82 mmol/L (11.28 mg/dL) in the control group in all five studies. The mean PTH in the MIP group was 20.32 pmol/L (191.1 pg/mL), and 20.05 pmol/L (188.5 pg/mL) in the BNE group (Appendix 10; Appendix 11).

Criteria for entry into the individual studies are outlined in the Characteristics of included studies table.

Inclusion criteria were not explicitly stated in two studies (Miccoli 2008; Slepavicius 2008). One study included all participants with PHPT based on a serum calcium level of more than 2.60 mmol/L (10.4 mg/dL), a serum PTH level of more than 3.5 pmol/L (33.0 pg/mL), and a serum creatinine level of less than 200 μmol/L (2.26 mg/dL) (Bergenfelz 2002). The other two studies included only those participants with biochemical confirmed (Miccoli 1999), or sporadic hyperparathyroidism (Bergenfelz 2005), and concomitant suspicion for single gland disease on preoperative imaging (Bergenfelz 2005; Miccoli 1999).

Exclusion criteria were clearly delineated by all studies except in Miccoli 2008. Those studies excluded participants with prior history of neck surgery, those who had indications or anticipation of thyroidectomy, a family history of PHPT such as multiple endocrine neoplasia (MEN 1, MEN 2), hereditary PHPT and anticipated or planned simultaneous thyroid operations. Three studies also mentioned that participants were only allowed to participate if they could comprehend the information given to them (Bergenfelz 2002; Bergenfelz 2005; Slepavicius 2008). Two studies excluded pregnant or breastfeeding women, and people with hypercalcaemic crisis (Bergenfelz 2002; Slepavicius 2008). Slepavicius 2008 also excluded people with severe concomitant pathology making surgical treatment impossible, while Bergenfelz 2005 excluded people with allergy to drugs used for local anaesthesia.

Study design

Studies were RCTs employing a parallel‐group superiority design. The study protocols differed in randomisation timing. Two studies randomised participants into treatment groups (MIP or BNE) even before preoperative imaging determined the likelihood of a single gland disease, and participants randomised to the BNE group did not undergo any preoperative imaging (Bergenfelz 2002; Slepavicius 2008). The other three studies randomised participants into MIP or BNE only after preoperative diagnostic studies were performed (Bergenfelz 2005; Miccoli 1999; Miccoli 2008), but only two studies explicitly specified that they included only participants with suspicion of single gland disease on preoperative imaging prior to the randomisation process (Bergenfelz 2005; Miccoli 1999).

Slepavicius 2008 was run at two centres (Department of Abdominal and Endocrine Surgery of Klaipeda University Hospital and Second Department of Abdominal Surgery of Vilnius University Hospital "Santariskiu Klinikos", Vilnius, Lithuania). All other studies were run at a single university hospital.

In terms of blinding, no study was double‐blinded for participants and personnel, two studies were single‐blinded for participants (Bergenfelz 2002; Miccoli 2008), and the other three studies did not define blinding (Bergenfelz 2005; Miccoli 1999; Slepavicius 2008). Only one study blinded outcome assessors (Bergenfelz 2005).

Studies were performed between 1996 and 2008.

The duration of follow‐up ranged from six months to five years. No study was terminated early.

Settings

All studies were conducted in European university hospitals (Germany, Italy, Lithuania, Sweden). Surgeries were all performed in a hospital setting.

Interventions

Imaging techniques varied among studies as well prior to surgeries. Two studies used both ultrasound and Sestamibi scanning (Miccoli 2008; Slepavicius 2008), two studies only used Sestamibi scanning (Bergenfelz 2002; Bergenfelz 2005), and one study only used ultrasound (Miccoli 1999).

Outcomes

All studies reported some of our outcomes, but in some, there was no clear specification of which outcomes were primary or secondary (Appendix 7).

Excluded studies

We excluded 37 publications because they did not meet our inclusion criteria (see Characteristics of excluded studies table).

Studies awaiting classification

We found one study presently published as a conference poster that is awaiting classification (see Characteristics of studies awaiting classification table).

Ongoing studies

We found one ongoing study that was last updated on 24 June 2005 with no information available about the publication of the results of this trial (see Characteristics of ongoing studies table).

Risk of bias in included studies

For details on risk of bias of included studies see Characteristics of included studies table.

For an overview of review authors' judgements about each risk of bias item for individual studies and across all studies see Figure 2 and Figure 3. In general, the risk of bias was unclear to high in most cases.

Allocation

We judged three studies at low risk for selection bias regarding random sequence generation (Bergenfelz 2002; Miccoli 1999; Slepavicius 2008). Bergenfelz 2002 mentioned that they utilised block randomisation through computer software and concealed envelopes. Slepavicius 2008 randomised participants according to a double random principle. Miccoli 1999 randomly divided participants into two groups by flipping a coin. Miccoli 2008 provided no information about random sequence generation. Bergenfelz 2005 answered our query by email and confirmed randomisation was through block randomisation by computer software; however, this randomisation was not balanced. Therefore, we assessed the risk of bias as high for this study (Bergenfelz 2005).

As for allocation concealment, we judged two studies at low risk of selection bias, because they confirmed the use of sequentially numbered, concealed, opaque envelopes (Bergenfelz 2002; Bergenfelz 2005). Miccoli 1999 utilised coin flipping, but it was unclear if this was done prior to participant presentation or after inclusion, which would determine whether there was adequate allocation concealment. There was insufficient detail to allow a definite judgement in Miccoli 2008. Slepavicius 2008 used envelopes but there was no information about opaqueness of envelopes and accordingly, we judged the risk of bias as unclear.

Blinding

We assessed the risk of blinding of participants and personnel combined, and that of outcome assessors separately. For unreported outcomes, the risk of bias was automatically judged as unclear. Two studies did not provide sufficient information about the blinding of participants (Miccoli 1999; Slepavicius 2008). One study mentioned that participants were not blinded (Bergenfelz 2005). For the two studies that had blinding of their participants, we judged the risk of performance and detection bias to be high for certain outcomes, such as conversion rate from minimally invasive to open parathyroidectomy and duration of surgery, since these outcomes are dependent on the surgeon, who in this instance, was not blinded. Miccoli 1999 and Slepavicius 2008 provided insufficient information on the blinding of participants, but surgeons were not blinded. Hence for the self‐reported outcomes that depended on the participants, the risk of bias was judged as unclear. For the outcomes that depended on the surgeon, such as conversion rate or duration of surgery, the risk of bias was judged to be high. Bergenfelz 2005 mentioned that participants were not blinded. Based on our judgement, the risk of performance bias and detection bias was high for the self‐reported outcomes (Bergenfelz 2005).

We could obtain adequate information about blinding of outcome assessors in only two studies by email reply to our queries (Bergenfelz 2002; Bergenfelz 2005). Bergenfelz 2002 blinded outcome assessors, and therefore the risk of bias was low for adjudicated/investigator‐assessed and self‐reported outcomes. Bergenfelz 2005 did not blind outcome assessors, hence we considered the risk of bias to be high for both adjudicated/investigator‐assessed outcomes and self‐reported outcomes. The other studies did not mention blinding of outcome assessors. In Miccoli 1999, randomisation was done after a scintigraphy preoperatively identified a single adenoma, and therefore, for the outcomes that may have been affected by this approach, we judged the risk of bias to be high and for the other outcomes not affected by this approach, we judged the risk of bias as unclear. In the other two studies, we judged the risk of bias as unclear for both adjudicated/investigator‐assessed outcomes and self‐reported outcomes, due to the insufficient information on the blinding of the outcome assessors (Miccoli 2008; Slepavicius 2008).

Incomplete outcome data

Outcome data were incomplete in three studies: Bergenfelz 2002 had 47 participants in the MIP group and 44 in the BNE group at study entry, 45 in the MIP and 43 in the BNE at one year, and 38 in the MIP and 33 in the BNE at five years (Bergenfelz 2002). The study authors provided insufficient information regarding missing data and did not clarify how missing data were handled. Therefore, the risk of bias was unclear for outcomes reported at one and five years. However, for the outcomes where data were available for all the participants in the perioperative period, we judged the risk of bias as low. For the perioperative and specific adverse events, which included hypocalcaemia symptoms, reported in the first 24 hours and at six weeks, some data were missing at both times (e.g. at six weeks, data were only available in 19/39 participants (49%) in the BNE group and 12/43 in the MIP group (28%)). The proportion of participants with missing data was 5/43 (11.6%) in the BNE group and 1/44 (2%) in the MIP group, showing disparate attrition rates between the two groups and the study authors did not clarify how missing data were handled. Therefore, we judged the risk of bias for this outcome as unclear (Bergenfelz 2002). Two participants in Miccoli 1999 had multiglandular disease that was discovered during surgery and were excluded from the study. We judged the risk of bias as unclear for all outcomes, as there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias. Slepavicius 2008 excluded three participants who had a conversion from MIP to BNE and two participants who had hyperplasia, which in both instances were unlikely to have had an effect on the outcomes. Therefore, we considered the risk of attrition bias to be low for all outcomes.

Selective reporting

We identified no published protocols for any of the included studies, therefore no study could be assessed as having a low risk of reporting bias. Instead, we relied on comparisons between outcomes listed in the 'Methods' section to those reported in the 'Results' section for each study, and whether the results reported corresponded to the outcomes described under 'Methods' and were reported adequately. We judged all studies at high risk of reporting bias for at least one outcome measure (Appendix 8).

Other potential sources of bias

Four out of five studies provided no details of surgeon familiarity and experience with each surgical technique, and may be a source of bias whenever surgeons were more familiar with one of the tested techniques (Bergenfelz 2002; Miccoli 1999; Miccoli 2008; Slepavicius 2008). Only Bergenfelz 2005 specified that all surgeons performing operations were experienced, but did not detail the level of experience and familiarity with each technique in particular. At least two included studies tested techniques that were introduced by the principle investigator of the study (Miccoli 1999; Miccoli 2008).

None of the studies mentioned sources of funding.

The presence of conflict of interest could not be excluded as a result of those two factors. Therefore, we determined risk of bias as unclear for all those studies.

Effects of interventions

See: Summary of findings 1 Minimally invasive parathyroidectomy versus bilateral neck exploration for primary hyperparathyroidism in adults

Baseline characteristics

For details of baseline characteristics, see Appendix 5 and Appendix 6.

Primary outcomes

Success rate at six months and five years

All five studies reported success rate (eucalcaemia) within six months, one at six weeks postoperatively (Bergenfelz 2002), and another four at six months postoperatively (Bergenfelz 2005; Miccoli 1999; Miccoli 2008; Slepavicius 2008). One study had follow‐up data at one and five years postoperatively (Bergenfelz 2002). A total of 132/136 (97.1%) participants in the MIP group compared with 129/130 (99.2%) participants in the BNE group were judged as operative success. The RR of success in the MIP group compared to the BNE group up to six months was 0.98 (95% CI 0.94 to 1.03; P = 0.43; 5 studies, 266 participants; very low‐certainty evidence; Analysis 1.1). The 95% prediction interval ranged between 0.90 and 1.06.

Findings are summarised in Figure 4. One article did not report on success rate in the main text but mentioned in the abstract that "No cases of persistent PHPT were present in either group" (Miccoli 1999).

Figure 4
Forest plot of comparison: 1 Minimally invasive parathyroidectomy versus bilateral neck exploration, outcome: 1.1 Success rate at six months.

Forest plot of comparison: 1 Minimally invasive parathyroidectomy versus bilateral neck exploration, outcome: 1.1 Success rate at six months.

No study reported on the operative success rates between six months and five years. Only one study reported on the success rate at five years postoperatively (Bergenfelz 2002). Of 73 participants with deducible conclusions about operative success at five years, 34/38 (89.5%) participants in the MIP group compared with 37/39 (94.9%) participants in the BNE group were judged as operative success (Analysis 1.2). Six participants had persistent or recurrent disease, four in the MIP group and two in the BNE group. Interestingly, three of the four failures in the unilateral group went on to undergo a bilateral surgery. Two participants in the unilateral group and one in the bilateral group who failed surgery had mutations in the gene for MEN (Bergenfelz 2002).

Total incidence of perioperative adverse events

Five studies reported the total incidence of perioperative adverse events (Bergenfelz 2002; Bergenfelz 2005; Miccoli 1999; Miccoli 2008; Slepavicius 2008; Figure 5). These events occurred in 23/136 (16.9%) participants in the MIP group compared with 44/130 (33.9%) participants in the BNE group. The RR was 0.50, in favour of MIP (95% CI 0.33 to 0.76; P = 0.001; 5 studies, 236 participants; low‐certainty evidence). The 95% prediction interval ranged between 0.25 and 0.99. Perioperative adverse events included symptomatic hypocalcaemia, vocal cord palsy, bleeding, fever, infection and others. Miccoli 1999 reported a total incidence of perioperative adverse events (including fever, hypocalcaemia and recurrent laryngeal nerve palsy) occurring in 2/20 (10%) participants in the MIP group and in 8/18 (44.4%) participants in the BNE group. Miccoli 2008 did not report any postoperative adverse complications including haemorrhage, laryngeal nerve palsy or hypocalcaemia. Bergenfelz 2002 reported a total of perioperative adverse events occurring in 14/47 (29.8%) participants in the MIP group compared to 27/44 (61.4%) participants in the BNE group including severe biochemical and symptomatic hypocalcaemia. In addition, 2/47 (4.2%) participants in the MIP group and 5/44 (11.4%) participants in the BNE group had significant complications including tracheal oedema, paresis of recurrent laryngeal nerve, bleeding and serious hypocalcaemia (Bergenfelz 2002). Bergenfelz 2005 reported the occurrence of vocal cord palsy in one participant in the MIP group and the drainage of a wound seroma occurring in one participant in the BNE group. Furthermore, three participants in the MIP group and three in the BNE group reported hypocalcaemia postoperatively. Slepavicius 2008 reported that two (9.6%) participants in the MIP group and four (19%) participants in the BNE group sustained postoperative symptomatic hypocalcaemia. Furthermore, vocal cord palsy occurred in two participants, one each in both groups (Slepavicius 2008). Details on reported adverse events are found in Appendix 10; Appendix 11; and Appendix 12.

Figure 5
Forest plot of comparison: 1 Minimally invasive parathyroidectomy versus bilateral neck exploration, outcome: 1.3 Total incidence of perioperative adverse events.

Forest plot of comparison: 1 Minimally invasive parathyroidectomy versus bilateral neck exploration, outcome: 1.3 Total incidence of perioperative adverse events.

Secondary outcomes

Specific adverse events
Bleeding events

Two studies reported bleeding events within 48 hours of the intervention (Bergenfelz 2002; Miccoli 2008), and were provided by email reply for one study (Bergenfelz 2005). There was just one reported bleeding event for 91 participants in the three studies. The RR comparing MIP with BNE was 0.31 (95% CI 0.01 to 7.47; P = 0.47; 2 studies, 131 participants; Analysis 1.4).

Infection

There was one infection reported in the BNE group and none in the MIP group within 48 hours of the intervention in the postoperative period in each of the two studies assessing this outcome (Bergenfelz 2005; Miccoli 1999).

Hypocalcaemia

Five studies reported hypocalcaemia and symptomatic hypocalcaemia. Only four of the studies reported symptomatic hypocalcaemia within 48 hours of surgery (Bergenfelz 2002; Miccoli 1999; Miccoli 2008; Slepavicius 2008), whereas one study reported on participants needing calcium supplementation, an intervention that did not necessarily reflect the incidence of symptomatic hypocalcaemia (Bergenfelz 2005).

Comparing MIP with BNE showed a RR of 0.54 in favour of MIP (95% CI 0.32 to 0.92; P = 0.02; 4 studies, 202 participants; Analysis 1.5). The 95% prediction interval ranged between 0.17 and 1.74. In the MIP group, 15/104 (14.4%) participants experienced symptomatic hypocalcaemia compared with 26/98 (26.5%) participants in the BNE group. Findings are summarised in Figure 6.
However, we must note that if the reported cases who received calcium supplements were an accurate surrogate for the development of symptomatic hypocalcaemia, the results would have been different, with a RR of 0.74 (95% CI 0.42 to 1.31; data not shown). A main argument for the exclusion of Bergenfelz 2005 was that administration of calcium was defined in the 'Methods' section of the publication to be acceptable for all participants with either symptomatic or biochemical hypocalcaemia. Furthermore, the reasons for participants requesting calcium supplementation were not clearly elucidated.

Figure 6
Forest plot of comparison: 1 Minimally invasive parathyroidectomy versus bilateral neck exploration, outcome: 1.3 Symptomatic hypocalcaemia.

Forest plot of comparison: 1 Minimally invasive parathyroidectomy versus bilateral neck exploration, outcome: 1.3 Symptomatic hypocalcaemia.

Permanent hypocalcaemia or hypocalcaemia persisting for longer than six months occurred in only one participant, belonging to the BNE group (RR 0.33, 95% CI 0.01 to 7.81; P = 0.46; 5 studies, 236 participants; Analysis 1.6).

Postoperative pain

Slepavicius 2008 reported postoperative pain using a 100‐point visual analogue scale (0 indicating pain was absent to 100 indicating unbearable pain) at four, eight, 16, 24, 36 and 48 hours after surgery, while Miccoli 1999 reported pain using a 10‐point scale (1 indicating no pain to 10 indicating worst pain ever) at 12, 24 and 48 hours after surgery, Miccoli 1999 showed greater pain in the BNE group, but data could not be pooled because of missing data on standard deviations (SD). Bergenfelz 2002 reported pain at one, two, three and four days after surgery, using an undefined visual analogue pain scale supposedly with 0 indicating no pain. Bergenfelz 2005 reported that after surgery,10 participants in the BNE group compared with seven participants in the MIP group required analgesia for pain. At our prespecified 48‐hour postoperative time point, the SMD of the visual analogue scales comparing MIP with BNE was –0.70 (95% CI –1.69 to 0.28; P = 0.16; 2 studies, 133 participants; Analysis 1.7; random‐effects model). The fixed‐effect model showed an SMD of –0.51 in favour of MIP (95% CI –0.86 to –0.16).

Vocal cord paralysis

Four studies reported the incidence of vocal cord paralysis within 48 hours (Bergenfelz 2005; Miccoli 1999; Miccoli 2008; Slepavicius 2008), and one study before discharge (Bergenfelz 2002). Seven cases (five in MIP and two in BNE) resolved at one month postoperatively except for one case in Miccoli 1999 that persisted at six months postoperatively. Comparing MIP with BNE showed a RR of 1.87 (95% CI 0.47 to 7.51; P = 0.38; 5 studies, 261 participants; Analysis 1.8). The 95% prediction interval ranged between 0.20 and 17.87. A total of 5/133 (3.8%) participants in the MIP group compared with 2/128 (1.6%) participants in the BNE group experienced vocal cord paralysis.

Conversion rate from minimally invasive to open procedure

Four studies reported intraoperative conversion rate information (Bergenfelz 2002; Bergenfelz 2005; Miccoli 2008; Slepavicius 2008). Out of 115 included patients, there were 24 incidences of conversion in total, amounting to a conversion rate of 20.8%.

Postoperative increase in parathyroid hormone with eucalcaemia

Two studies reported postoperative eucalcaemic hyperparathyroidism (Bergenfelz 2002;Slepavicius 2008). A total of 13/68 (19.1%) participants in the MIP group compared with 16/65 (24.6%) participants in the BNE group showed a postoperative increase in PTH with eucalcaemia. The RR of eucalcaemic hyperparathyroidism comparing MIP with BNE was 0.81 (95% CI 0.43 to 1.53; P = 0.51; 2 studies, 133 participants; Analysis 1.9).

All‐cause mortality

No study explicitly reported on the occurrence of perioperative mortality; however, complete data reporting on all patients in four studies led us to deduce that there were no instances of perioperative mortality within six months (Bergenfelz 2005; Miccoli 1999; Miccoli 2008; Slepavicius 2008). Bergenfelz 2002 reported on all participants at six weeks postoperatively, and reported two deaths during the follow‐up period of one year without specifying in which treatment group these deaths had happened. Fourteen other deaths occurred in the same study within the five‐year follow‐up period, but neither the cause of death nor in which treatment group these had happened was stated (Bergenfelz 2002). The overall certainty of the evidence was very low.

Health‐related quality of life

One study reported health‐related quality of life only using the 36‐item Short Form (SF‐36) (Slepavicius 2008) (see Appendix 14). The authors found no difference between the treatment groups, but did not present data (very low‐certainty evidence). Similarly, in an email response, Dr Bergenfelz indicated that an SF‐36 survey was used in one study but the difference was judged to be clinically unimportant and was not published (Bergenfelz 2005).

Cosmetic satisfaction

Slepavicius 2008 reported cosmetic satisfaction using a modified Holander scale (ranging from 0 to 7, with 0 indicating optimal result and 1 to 7 suboptimal result), describing the overall cosmetic appearance of the wound at two days, one month, six months and one year postoperatively. There was a statistically significant difference in favour of the MIP group at the first three time points, with a score of 2 at two days, 1.4 at one month and 1.6 at six months for the MIP group compared to a score of 3.9 at two days, 3.4 at one month and 2.5 at six months for the BNE group. However, this difference became statistically non‐significant one year postoperatively.

Miccoli 1999 assessed cosmetic satisfaction using personal opinions by physicians about the aesthetics of the scar with an undefined 10‐point score at one month, three months and six months, postoperatively. Patient satisfaction was higher in the MIP group at all three time points.

Neither study provided SDs, and we were thus unable to pool the results. The consistency in findings among studies suggest that there was a treatment benefit for MIP as compared to BNE in terms of cosmetic satisfaction (very low‐certainty evidence).

Bergenfelz 2005 mentioned in his study that all participants in both groups stated that they were satisfied with the cosmetic result of the surgery, but did not report the scale used.

Some studies reported on surrogate outcomes related to cosmetic satisfaction that we had not identified as outcomes in our protocol. Slepavicius 2008 reported on scar length using a flexible tape at 12 months postoperatively, with median scar length being shorter in the MIP group (1.9 cm) than in the BNE group (8 cm).

Bone fracture rate

None of the studies reported bone fracture rates.

Nephrolithiasis rate

None of the studies reported nephrolithiasis rates.

Absence from work

Miccoli 1999 reported that the postoperative inactivity period was shorter in participants treated with MIP (mean 2 (SD 5.5) days in MIP group versus 16 (SD 6) days in BNE group) but did not specifically mention the number of days of work missed due to surgery.

Duration of surgery

All five studies reported on the duration of surgery from skin incision to wound closure. Data from Miccoli 2008 and Bergenfelz 2005 could not be included in our meta‐analysis. Bergenfelz 2005 reported a difference in the duration of surgery in favour of MIP, but reported the data as median and range (41 minutes, 19 minutes to 120 minutes) in the MIP group versus 63 minutes (35 minutes to 110 minutes) in the BNE group)). Miccoli 2008 reported that there was no statistically significant difference in operative time between treatment groups, with the mean duration of the MIP group being 33 minutes as opposed to 32 minutes in the BNE group (SDs were not reported).

In the three other studies, comparison of duration of surgery showed a benefit for the MIP group compared to the BNE group (MD –18 minutes, 95% CI –31 to –6; P = 0.004; 3 studies, 171 participants; very low‐certainty evidence; Analysis 1.10). The 95% prediction interval ranged between –162 minutes and 126 minutes.

Length of hospital stay

In Bergenfelz 2005, participants were asked to stay for four days for postoperative observation period. In Bergenfelz 2002, it was mentioned that after the first postoperative day the patient stayed at the hotel of the hospital and made individual visits on postoperative days two to four. Two studies discharged participants in the second day after surgery and it was not mentioned if there was a difference between the groups in the length of hospital stay (Miccoli 1999; Slepavicius 2008). One study mentioned that participants were discharged on the first postoperative day without stating if there was a difference between the two groups (Miccoli 2008).

Socioeconomic effects

Four studies reported on costs incurred from MIP and BNE. Bergenfelz 2002 calculated the costs from official in‐hospital charges obtained from different departments, and reported a trend towards extra cost in the MIP group compared with the BNE group (mean cost: USD 2258 (SD 509) with MIP versus USD 2097 (SD 505) with BNE). Slepavicius 2008 found a difference in costs of the procedures in favour of BNE (EUR 1428 with MIP versus EUR 1166 with BNE; P < 0.05). Miccoli 2008 compared costs of specific procedures but not of hospital charges and stated that MIP was relatively cheaper than BNE, with the difference in costs mainly resulting from the increased duration of operating room use. Miccoli 1999 reported that the overall costs of BNE was USD 1910 compared with USD 1720 in favour of MIP, but stated that the difference was minimal. Both Bergenfelz 2002 and Slepavicius 2008 performed preoperative localisation in the MIP group exclusively, and the costs for this localisation made up the greatest proportion of the difference in costs observed by other studies. Miccoli 1999 differed by including only participants with suspicion for single adenoma on preoperative imaging in their study. Both MIP and BNE groups had preoperative imaging prior to randomisation and the costs of these procedure were not included in the cost calculation. We performed no meta‐analyses because only one study provided SDs (Bergenfelz 2002).

Subgroup analyses

We did not perform subgroups analyses due to the small number of studies and study participants.

Sensitivity analyses

We used commonly suggested approaches for dealing with participants with missing outcome data in the meta‐analyses (Akl 2015). In the primary meta‐analysis, we used a complete‐case analysis (i.e. we excluded participants with missing outcome data).

When the primary meta‐analysis resulted in a statistically significant result, we tested its robustness by running sensitivity meta‐analyses. For those sensitivity meta‐analyses, we applied increasingly stringent but plausible assumptions about the outcomes of participants with missing data defined a priori (Akl 2013; Ebrahim 2013)

We conducted sensitivity analysis for hypocalcaemia and duration of surgery.

Hypocalcaemia

The sensitivity analysis found that the pooled effect estimate lost statistical significance for about half of these analyses. See Table 2 for detailed description of all the assumptions used.

Open in table viewer
Table 2. Sensitivity analyses

Protocol item

Symptomatic hypocalcaemia

Duration of surgery

Restricting to published

NA

NA

Restricting the analysis taking into account risk of biasa

The sensitivity analysis based on restricting to studies with low risk of bias showed that the pooled effect estimate lost statistical significance (RR 0.5, 95% CI 0.1 to 2.44).

The sensitivity analysis based on restricting to studies with low risk of bias showed that the pooled effect estimate did not lose statistical significance: MD was –28 minutes (95% CI –34 to –22).

Making plausible assumptions about the outcome of participants with missing data

The sensitivity analysis based on different assumptions for the outcomes of participants with missing data found that the pooled effect estimate lost statistical significance for about half of these analyses (Akl 2013; Akl 2015; Ebrahim 2013).

The sensitivity analysis based on different assumptions for the outcomes of participants with missing data found that the pooled effect estimate did not lose statistical significance for any of these (Akl 2013; Akl 2015; Ebrahim 2013).

Restricting the analysis to very long or large studies

NA

NA

Restricting by diagnostic criteria

NA

NA

Language of publication

NA

NA

Source of funding

NA

NA

Country of origin

NA

NA

aStudies judged at high risk of bias were: Bergenfelz 2005 (selection bias and reporting bias), Miccoli 1999 and Miccoli 2008 (reporting bias), Slepavicius 2008 (reporting bias) as assessed using the risk of bias graph (see Figure 2; Figure 3).

CI: confidence interval; MD: mean difference; NA: not applicable; RR: risk ratio.

Similarly, the sensitivity analysis based on restricting analyses to studies with low risk of bias (Miccoli 2008; Slepavicius 2008) showed that the pooled effect estimate lost statistical significance (Table 2).

Duration of surgery

The sensitivity analysis found that the pooled effect estimate did not lose statistical significance for any of these analyses (Table 2).

Similarly, the sensitivity analysis based on restricting to studies with low risk of bias (Slepavicius 2008) showed that the pooled effect estimate did not lose statistical significance (Table 2).

Assessment of reporting bias

We did not draw funnel plots due to limited number of studies (five).

Discussion

Summary of main results

Our review identified five studies comparing MIP to BNE. MIP was associated with a shorter duration of surgery and lower incidence of symptomatic hypocalcaemia; however, the latter finding lost significance in the sensitivity analyses. There was a tendency towards greater cosmetic satisfaction, lower total adverse events and increased vocal cord paralysis in the MIP group. There were clear differences in eucalcaemic hyperparathyroidism, all‐cause mortality and health‐related quality of life. Information on bleeding events, infections or aggregated costs was limited either due to a very low incidence of events or lack of meta‐analysable data.

Overall completeness and applicability of evidence

We conducted a comprehensive review of three major databases and reviewed each of them for potentially eligible studies. Identified studies encompassed a wide range of currently utilised minimally invasive and BNE techniques. We believe that we have adequately summarised all pertinent randomised controlled data available to date, but several important patient‐related outcomes, such as fracture rate, nephrolithiasis rate, missed days from work and length of hospitalisation, were not reported in the published literature. There was insufficient power to detect other patient‐related outcomes, such as bleeding rate, mortality, short‐term success rate and importantly, long‐term success rate. Furthermore, all studies are from European centres, and this limits the applicability to non‐European populations or low‐ and middle‐income countries.

Two types of indirectness pertaining mainly to patient populations and intervention designs were encountered in all studies (Guyatt 2011), and directly challenge the applicability of the evidence provided to everyday practice. Two studies included participants with suspicion of single gland disease. They therefore aimed to answer the question of optimal surgery in people who have had prior imaging, while our original aim was to explore the optimal strategy in the general population presenting with sporadic PHPT without any a priori knowledge of any imaging. Furthermore, three studies performed preoperative imaging even on people who eventually received BNE (Bergenfelz 2005; Miccoli 1999; Miccoli 2008). Surgeon knowledge of preoperative imaging findings may affect intraoperative decisions about which glands to excise, the thoroughness of the exploration and the timing of terminating the surgery. Conversely, the other two study designs employed randomised to MIP or BNE first, and then proceeded with localisation regardless of results (Bergenfelz 2005; Slepavicius 2008). We suggest a more direct and appropriate protocol that would provide an objective risk‐benefit assessment of both techniques, on prespecified patient outcomes, in the short term as well as in the long term.

Quality of the evidence

Details about study methodology were limited and brief. In general, the scarcity of published studies coupled with the small sample size of each contributed to imprecision in observed treatment effects for most outcomes of interest (see summary of findings Table 1). There was serious risk of bias, especially for self‐reported outcomes. Coupled with observed indirectness in answering our review's questions, these factors meant that the certainty of the available evidence ranged generally from low to very low (see summary of findings Table 1).

Potential biases in the review process

The main limitations in this review were the indirectness and the small number of retrieved studies. There were fewer than 400 events in all cumulative outcomes of interest, limiting precision and power to detect relevant differences between the two procedures. Furthermore, both MIP and BNE appeared to be safe procedures, with infrequent adverse effects and failures. Detecting differences between procedures would require large populations with the preferred randomisation approach as detailed above. However, this would be difficult to compile in RCTs in the near future.

Agreements and disagreements with other studies or reviews

Other reviews

We could not identify any meta‐analysis on the topic within the time frame under consideration. We only identified one other review discussing this topic (Gracie 2012). The review agreed with our findings that MIP and BNE were comparable in terms of success rate and complication rate. However, the review cited advantages in operative duration, learning curve, and cost‐analyses and recommend treatment with MIP for people with solitary parathyroid adenomas and those were based on data or expert opinion. Interestingly, the learning curve and cost‐effectiveness analyses were not outcomes of any of their reviewed papers. Three studies evaluated costs but not cost‐effectiveness. With regards to costs, our review found that, contrary to the Gracie 2012 findings, strategies employing BNE in all participants without exposing them to preoperative imaging are likely to be less costly than those that aim for MIP in participants employing localising preoperative scans (Gracie 2012). Our review confirms the observation that MIP takes less time, but we considered the observed MD of less than 20 minutes to be clinically irrelevant, especially since the CI for the finding included a time saving of about only six minutes.

Non‐randomised controlled trial data

We found no non‐RCT publications comparing nephrolithiasis rates, absenteeism from work or even cosmetic satisfaction.

Success rates

We found no difference in success rate between MIP and BNE at six months. In our search, most retrieved non‐RCT studies found no difference in success rates within six months between MIP and BNE, namely 97% in MIP and 99% in BNE (Adler 2008; Baliski 2008; Beyer 2007; Chen 1999; Genc 2003; Grant 2005; Irvin 2004). Success rates were similarly high to those observed in our review, and in fact were 100% in several studies (Adler 2008; Baliski 2008; Genc 2003). Others reported varying success rates, above 90%, namely 97% in MIP and 94% in BNE (Irvin 2004), 98% in MIP and 94% in BNE (Boggs 1999), 97% for both MIP and BNE (Grant 2005), 99% in MIP and 100% in BNE (Beyer 2007), 98% in MIP and 94% in BNE (Carneiro 2000), and 100% in MIP and 97.3% in BNE (Chen 1999).

One study described differences in outcomes between treatment strategies. Bergenfelz 2007 presented findings from a large audit of parathyroid surgeries performed in Scandinavian countries between 2004 and 2006. They showed in a multivariate analysis an increased chance for alleviation of hypercalcaemia in individuals who underwent unilateral or focused surgery as compared to those undergoing BNE. The audit showed that the overall cure rate was lower than reported in the literature and that of hypocalcaemia to be somewhat higher in MIP compared with BNE.

Viewed in total however, we consider the findings from the above retrospective and non‐randomised prospective studies to agree with our own conclusions. Fewer studies looked at recurrence beyond six months. Beyer 2007 reported a long‐term success rate of 107/109 participants in the BNE group, with both failures occurring after the six months' time interval, compared to 109/111 participants in the MIP group. Of note, the MIP had a significantly shorter median follow‐up of 3.7 (SD 5.6) months. Boggs 1999 and Carneiro 2000 found in a subset of participants having long‐term follow‐up and successful initial surgery, adjudicated at the six month time point, that 5/176 participants in the BNE group had recurrence with a mean follow‐up of 9.3 years (6 to 313 months); this was compared with 2/144 participants at 2.3 years (6 to 85 months) median follow‐up in the MIP group. The number of events, combined with the differences in follow‐up time between MIP and BNE, did not allow for a confident conclusion to be made about long‐term success rate.

Adverse events

In agreement with our findings, three non‐RCT studies reported no substantial differences in total complication rates between the two surgical approaches. Specifically, adverse event rates were 6.3% (Adler 2008), 8.9% (Baliski 2008), and 2.2% (Chen 1999) in the BNE group compared to 3.1% (Adler 2008), 5.3% (Baliski 2008), and 0% (Chen 1999) in the MIP group.

Postoperative increase in parathyroid hormone with eucalcaemia

We only found two RCTs reporting on eucalcaemic hyperparathyroidism with a RR of 0.81 (95% CI 0.43 to 1.53) in MIP compared with BNE (Bergenfelz 2002; Slepavicius 2008). Similarly, several non‐RCTs found no substantial differences in the incidence of eucalcaemic hyperparathyroidism following surgery. In two studies, the incidence of eucalcaemic hyperparathyroidism was 19/176 participants (Beyer 2007) and 34/109 participants (Carneiro 2000) in the BNE group, compared to 19/144 participants (Beyer 2007) and 50/111 participants (Carneiro 2000) in the MIP group.

All‐cause mortality

None of our included studies and very few studies in other literature explicitly stated the number of fatalities from surgery. We propose that this is mainly because of an expectation for a safe parathyroid surgery. Nonetheless, two non‐RCTs specifically reported having had no mortalities in 198 MIPs and 290 BNEs procedures (Adler 2008; Agrawal 2014).

Health‐related quality of life

Two RCTs found no substantial difference in health‐related quality of life between the different treatment groups using the SF‐36 questionnaire. In contrast, Adler 2008 in a non‐RCT measured similar SF‐36 health survey outcomes, and noted improvements at a one‐week time point in four scales for MIP (vitality, role‐emotional, mental health and mental component summary) versus just two scales in the BNE (vitality and general health). At the one‐year interval, MIP participants improved significantly in eight scales (physical functioning, role‐physical, bodily pain, vitality, social functioning, role‐emotional, mental health and the mental component summary scales) compared to only four scales (general health, vitality, mental health and the mental component summary scales) in the BNE group (Adler 2008).

Bone fracture rate

We found no fracture rate or bone fragility data stratified by treatment group in non‐RCT literature.

Duration of surgery

In our meta‐analysis, MIP had a shorter duration of surgery than BNE. However, in several non‐RCTs there was no significant difference in duration of surgery between groups. Baliski 2008 reported a mean procedure time of 93 minutes in 56 participants in the BNE group compared to 74 minutes in 19 participants in the MIP group. Agrawal 2014 also found similar durations, with the mean duration being 44 minutes in 93 participants receiving MIP successfully compared to a mean duration of 56 minutes in 20 participants receiving BNE. Of note, the duration of surgery for seven participants who were planned to receive MIP but had a BNE instead was considered. Beyer 2007 found a longer procedure time for participants receiving BNE without IOPTH (129 minutes) when compared to those with MIP and IOPTH (119 minutes). However, this difference may have been caused by the significantly greater proportion of people undergoing concomitant thyroid surgery in the BNE group. When these participants were excluded, the authors found no persistent significant difference in operative duration (Beyer 2007).

Length of hospital stay

In one of the included studies, participants were asked to stay for four days for a postoperative observation period (Bergenfelz 2005). In Bergenfelz 2002, it was mentioned that after the first postoperative day individual visits on postoperative days two to four were made in the patient hotel of the hospital. Slepavicius 2008 discharged patients on the second day after surgery and it was not mentioned if there was a difference between the groups in the length of hospital stay.

There was some variability in length of hospital stay in the literature retrieved, and this may pertain to physician preferences and practices. In one study, the mean length of hospital stay for a total of 33 participants undergoing MIP was 0.3 days compared with 1.8 days for BNE (Chen 1999). However, as several other studies did not report a relevant difference among treatment groups with regards to mean hospitalisation times for MIP being 0.2 days (Adler 2008), 1.06 days (Baliski 2008), and one day (Grant 2005), compared to 0.9 days (Adler 2008), 1.2 days (Baliski 2008), and 1 day (Grant 2005) for BNE.

Socioeconomic effects

RCT findings about cost efficiency were variable, with one reporting a significant cost saving for BNE (Slepavicius 2008), another a non‐significant difference (Bergenfelz 2002), and a third a relative cost‐effectiveness for MIP (Miccoli 1999). This variability may be explained by difference in hospital charges for imaging/procedures, as well as differences in the surgical protocol. Similarly, other literature produced variable results. It seems that cost‐effectiveness of a surgical approach may be more an institutional than a generalisable characteristic. Baliski 2008 used unit costs from the St. Paul's Hospital Cost Model (SPHCM) in conjunction with retrospectively collected data about hospital length of stay and intraoperative complications. Total costs were USD 4524 for BNE compared to USD 4961 for MIP, translating to a cost of USD 28,439 per complication avoided by using MIP. Diagnostic testing and operative duration were found to be the main determinants of differences in cost, with diagnostics in particular costing USD 750 more for MIP compared to BNE. Even when changing parameters such as success rates and unit costs to other values cited in the literature, the smallest cost per complication avoided for MIP was USD 11,599 (Baliski 2008). In contrast in Beyer 2007, participants undergoing MIP surgery with IOPTH had lower mean charges (USD 3667) when compared to those undergoing BNE without IOPTH (USD 4787) and those undergoing BNE with IOPTH (USD 4272) . Similarly, in Chen 1999, the mean total hospital charge for 33 participants who underwent MIP was USD 3174 compared with USD 6328 for BNE (Beyer 2007).

Hypocalcaemia

All five studies reported symptomatic hypocalcaemia. Only four of the studies reported symptomatic hypocalcaemia within 48 hours of surgery. One study reported on participants' needs for calcium supplementation, which we judged as insufficient information to accurately represent the incidence of symptomatic hypocalcaemia (Bergenfelz 2005). The incidence of perioperative hypocalcaemia was significantly lower in the MIP group compared to the BNE group, but it was lost on sensitivity analyses. Adler 2008 noted a slightly increased incidence of transient hypocalcaemia in the BNE group (3.8%) as compared to the MIP group (2.6%) in their postoperative results reported within two weeks, and it was mentioned that those participants required oral calcium supplements for a total duration of two weeks. However, all their complications results were not substantially different between the groups.

Study flow diagram. HTA: health technology assessment.

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Figure 1

Study flow diagram. HTA: health technology assessment.

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (blank cells indicate that the particular outcome was not measured in some studies).

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (blank cells indicate that the particular outcome was not measured in some studies).

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study (blank cells indicate that the study did not measure that particular outcome).

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study (blank cells indicate that the study did not measure that particular outcome).

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Forest plot of comparison: 1 Minimally invasive parathyroidectomy versus bilateral neck exploration, outcome: 1.1 Success rate at six months.

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Figure 4

Forest plot of comparison: 1 Minimally invasive parathyroidectomy versus bilateral neck exploration, outcome: 1.1 Success rate at six months.

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Forest plot of comparison: 1 Minimally invasive parathyroidectomy versus bilateral neck exploration, outcome: 1.3 Total incidence of perioperative adverse events.

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Figure 5

Forest plot of comparison: 1 Minimally invasive parathyroidectomy versus bilateral neck exploration, outcome: 1.3 Total incidence of perioperative adverse events.

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Forest plot of comparison: 1 Minimally invasive parathyroidectomy versus bilateral neck exploration, outcome: 1.3 Symptomatic hypocalcaemia.

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Figure 6

Forest plot of comparison: 1 Minimally invasive parathyroidectomy versus bilateral neck exploration, outcome: 1.3 Symptomatic hypocalcaemia.

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Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 1: Success rate up to 6 months

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Analysis 1.1

Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 1: Success rate up to 6 months

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Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 2: Success rate at 5 years

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Analysis 1.2

Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 2: Success rate at 5 years

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Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 3: Total incidence of perioperative adverse events

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Analysis 1.3

Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 3: Total incidence of perioperative adverse events

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Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 4: Bleeding

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Analysis 1.4

Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 4: Bleeding

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Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 5: Symptomatic hypocalcaemia

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Analysis 1.5

Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 5: Symptomatic hypocalcaemia

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Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 6: Permanent hypocalcaemia

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Analysis 1.6

Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 6: Permanent hypocalcaemia

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Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 7: Postoperative pain score

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Analysis 1.7

Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 7: Postoperative pain score

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Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 8: Vocal cord paralysis

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Analysis 1.8

Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 8: Vocal cord paralysis

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Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 9: Postoperative increase in parathyroid hormone with eucalcaemia

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Analysis 1.9

Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 9: Postoperative increase in parathyroid hormone with eucalcaemia

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Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 10: Duration of surgery

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Analysis 1.10

Comparison 1: Minimally invasive parathyroidectomy versus bilateral neck exploration, Outcome 10: Duration of surgery

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Summary of findings 1. Minimally invasive parathyroidectomy versus bilateral neck exploration for primary hyperparathyroidism in adults

Minimally invasive parathyroidectomy guided by intraoperative parathyroid hormone monitoring and preoperative imaging compared to bilateral neck exploration for primary hyperparathyroidism in adults

Participant: adults with primary hyperparathyroidism

Setting: hospitals

Intervention: minimally invasive parathyroidectomy

Comparison: bilateral neck exploration

Outcomes

Illustrative comparative risks (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with bilateral neck exploration

Risk with minimally invasive parathyroidectomy

Success rate (eucalcaemia)

(a) Follow‐up: up to 6 months

(b) Follow‐up: up to 5 years

(a) 992 per 1000

(b) 949 per 1000

(a) 972 per 1000 (933 to 1022)

(b) 892 per 1000 (787 to 1025)

(a) RR 0.98
(0.94 to 1.03)

(b) RR 0.94
(0.83 to 1.08)

(a) 266 (5)

(b) 77 (1)

(a) / (b)

⊕⊝⊝⊝
Very lowa

(b) 5‐year follow‐up: data available for 77/91 randomised participants.

Total incidence of perioperative adverse events (number)

Follow‐up: up to 48 hours postoperatively

338 per 1000

169 per 1000 (112 to 257)

RR 0.50
(0.33 to 0.76)

236 (5)

⊕⊕⊝⊝
Lowb

—

All‐cause mortality
Follow‐up: up to 5 years

See comment

⊕⊝⊝⊝
Very lowc

No study explicitly reported on the occurrence of perioperative mortality.

In 1 study with 5 years' follow‐up there were 16 deaths, no data per intervention group were reported.

Health‐related quality of life
Follow‐up: up to 6 months

See comment

⊕⊝⊝⊝
Very lowd

2 studies reported that there were no clear differences between intervention groups; however, data were not presented.

Cosmetic satisfaction

Follow‐up: up to 1 year

See comment

⊕⊝⊝⊝
Very lowe

3 studies reported some data associated with cosmetic satisfaction but measurements varied substantially; overall some findings indicated a benefit of minimally invasive parathyroidectomy.

Duration of surgery (time from skin incision to skin closure)

The mean duration of surgery ranged across control groups from 64 minutes to 82 minutes

The mean duration of surgery in the intervention groups was 18 minutes lower (31 minutes lower to 6 minutes lower)

—

171 (3)

⊕⊝⊝⊝
Very lowf

The 95% prediction interval ranged between –162 minutes and 126 minutes.

Length of hospital stay

Not reported

CI: confidence interval; RR: risk ratio.

GRADE Working Group grades of evidence

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

aDowngraded one level because of risk of bias in several risk of bias domains, one level because of inconsistency and indirectness (95% prediction interval ranging between 0.90 and 1.06 and surrogate outcome) and one level because of imprecision (low sample size, 95% CI consistent with benefit and harm) – see Appendix 13.
bDowngraded one level because of risk of bias in several risk of bias domains and one level because of imprecision (low sample size) – see Appendix 13.
cDowngraded one level because no study explicitly reported on this outcome and two levels because of serious imprecision (low sample size, low number of studies) – see Appendix 13.
dDowngraded one level because only two studies evaluated this outcome but did not report data and two levels because of serious imprecision (low sample size, low number of studies) – see Appendix 13.
eDowngraded one level because of risk of bias in several risk of bias domains, one level because of indirectness (surrogate outcome) and one level because of imprecision (low sample size, low number of studies) – see Appendix 13.
fDowngraded one level because of risk of bias in several risk of bias domains, one level because of inconsistency (95% prediction interval ranging between –162 minutes and 126 minutes) and one level because of imprecision (low sample size, low number of studies) – see Appendix 13.

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Summary of findings 1. Minimally invasive parathyroidectomy versus bilateral neck exploration for primary hyperparathyroidism in adults
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Table 1. Overview of study populations

Study (design)

Intervention(s) and comparator(s)

Description of power and sample size calculation

Screened/eligible
(n)

Randomised
(n)

Analysed
(n)

Finishing study
(n)

Randomised finishing study
(%)

Follow‐up

Bergenfelz 2005
(parallel RCT)

I: MIP guided by intraoperative PTH monitoring and preoperative imaging

—

233

25

25

25

100

First 4 days after surgery, 1 and 6 months

C: BNE

25

25

25

100

Total:

233

50

50

50

100

Bergenfelz 2002
(parallel RCT)

I: MIP guided by intraoperative PTH monitoring and preoperative imaging

—

47

47

47

38

80

First 4 postoperative days, 6 weeks, 1 and 5 years

C: BNE

44

44

44

33

75

Total:

91

91

91

71

78

Miccoli 2008
(parallel RCT)

I: focused endoscopic parathyroidectomy (MIVAP) – MIP guided by intraoperative PTH monitoring and preoperative imaging

—

20

20

20

20

100

First postoperative day; 1 and 6 months

C: BNE

20

20

20

20

100

Total:

40

40

40

40

100

Miccoli 1999
(parallel RCT)

I: MIVAP guided by intraoperative PTH monitoring and preoperative imaging

—

38

20

20

20

100

12, 24, and 48 hours after surgery; 1, 3 and 6 months

C: BNE

18

18

18

100

Total:

38

38

38

38

Slepavicius 2008
(parallel RCT)

I: MIP guided by intraoperative PTH monitoring and preoperative imaging

47

24

24

24

100

48 hours after surgery, 4 weeks, 1 and 6 months, 1 year

C: BNE

23

23

23

100

Total:

47

47

47

47

100

Overall total

All interventions

—

136

127

—

All comparators

130

119

All interventions and comparators

266

246

—: denotes not clearly described in the publication

BNE: bilateral neck exploration; C: comparator; I: intervention; MIP: minimally invasive parathyroidectomy; MIVAP: minimally invasive video‐assisted parathyroidectomy; n: number of participants; PTH: parathyroid hormone; RCT: randomised controlled trial.

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Table 1. Overview of study populations
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Table 2. Sensitivity analyses

Protocol item

Symptomatic hypocalcaemia

Duration of surgery

Restricting to published

NA

NA

Restricting the analysis taking into account risk of biasa

The sensitivity analysis based on restricting to studies with low risk of bias showed that the pooled effect estimate lost statistical significance (RR 0.5, 95% CI 0.1 to 2.44).

The sensitivity analysis based on restricting to studies with low risk of bias showed that the pooled effect estimate did not lose statistical significance: MD was –28 minutes (95% CI –34 to –22).

Making plausible assumptions about the outcome of participants with missing data

The sensitivity analysis based on different assumptions for the outcomes of participants with missing data found that the pooled effect estimate lost statistical significance for about half of these analyses (Akl 2013; Akl 2015; Ebrahim 2013).

The sensitivity analysis based on different assumptions for the outcomes of participants with missing data found that the pooled effect estimate did not lose statistical significance for any of these (Akl 2013; Akl 2015; Ebrahim 2013).

Restricting the analysis to very long or large studies

NA

NA

Restricting by diagnostic criteria

NA

NA

Language of publication

NA

NA

Source of funding

NA

NA

Country of origin

NA

NA

aStudies judged at high risk of bias were: Bergenfelz 2005 (selection bias and reporting bias), Miccoli 1999 and Miccoli 2008 (reporting bias), Slepavicius 2008 (reporting bias) as assessed using the risk of bias graph (see Figure 2; Figure 3).

CI: confidence interval; MD: mean difference; NA: not applicable; RR: risk ratio.
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Table 2. Sensitivity analyses
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Comparison 1. Minimally invasive parathyroidectomy versus bilateral neck exploration

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Success rate up to 6 months Show forest plot

5

266

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.94, 1.03]

1.2 Success rate at 5 years Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.3 Total incidence of perioperative adverse events Show forest plot

5

266

Risk Ratio (M‐H, Random, 95% CI)

0.50 [0.33, 0.76]

1.4 Bleeding Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.5 Symptomatic hypocalcaemia Show forest plot

4

202

Risk Ratio (M‐H, Random, 95% CI)

0.54 [0.32, 0.92]

1.6 Permanent hypocalcaemia Show forest plot

5

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.7 Postoperative pain score Show forest plot

2

133

Std. Mean Difference (IV, Random, 95% CI)

‐0.70 [‐1.69, 0.28]

1.8 Vocal cord paralysis Show forest plot

5

261

Risk Ratio (M‐H, Random, 95% CI)

1.87 [0.47, 7.51]

1.9 Postoperative increase in parathyroid hormone with eucalcaemia Show forest plot

2

133

Risk Ratio (M‐H, Random, 95% CI)

0.81 [0.43, 1.53]

1.10 Duration of surgery Show forest plot

3

171

Mean Difference (IV, Random, 95% CI)

‐18.33 [‐30.71, ‐5.95]
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Comparison 1. Minimally invasive parathyroidectomy versus bilateral neck exploration
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