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Somatostatin analogues for pancreatic surgery

  1. Kurinchi Selvan Gurusamy*,
  2. Rahul Koti,
  3. Giuseppe Fusai,
  4. Brian R Davidson

Editorial Group: Cochrane Upper Gastrointestinal and Pancreatic Diseases Group

Published Online: 30 APR 2013

Assessed as up-to-date: 14 FEB 2013

DOI: 10.1002/14651858.CD008370.pub3


How to Cite

Gurusamy KS, Koti R, Fusai G, Davidson BR. Somatostatin analogues for pancreatic surgery. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD008370. DOI: 10.1002/14651858.CD008370.pub3.

Author Information

  1. Royal Free Campus, UCL Medical School, Department of Surgery, London, UK

*Kurinchi Selvan Gurusamy, Department of Surgery, Royal Free Campus, UCL Medical School, Royal Free Hospital,, Rowland Hill Street, London, NW3 2PF, UK. kurinchi2k@hotmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 30 APR 2013

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Characteristics of included studies [ordered by study ID]
Beguiristain 1995

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: Spain
Sample size: 35
Post-randomisation drop-out: not stated
Revised sample size: 35
Females: 10 (28.6%)
Mean age: 59.4 years
Malignancy: 30 (85.7%)
Chronic pancreatitis: 3 (8.6%)
Pancreatoduodenectomy: 35 (100%)
Follow-up: not reported

Inclusion criteria:

1. Pancreaticoduodenectomy


InterventionsThe participants were randomly assigned to 2 groups
Group 1: somatostatin (n = 21)
Further details: continuous infusion 4.5 mg/day starting immediately after surgery for 7 days
Group 2: control (n = 14)


OutcomesThe outcomes reported were mortality and perioperative morbidity


NotesPancreatic fistula definition: drainage of at least 10 mL of fluid with an amylase concentration of more than 5 Somogyi units (grade A)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
High riskComment: blinding was probably not performed

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: this information was not available

Selective reporting (reporting bias)High riskComment: some important outcomes were not reported

Free of source of funding bias?Unclear riskComment: this information was not available

Briceño Delgado 1998

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: Spain
Sample size: 34
Post-randomisation drop-out: not stated
Revised sample size: 34
Females: 9 (26.5%)
Mean age: 52.5 years
Malignancy: 28 (82.4%)
Chronic pancreatitis: 5 (14.7%)
Pancreatoduodenectomy: 34 (100%)
Follow-up: not reported

Inclusion criteria:

1. Pancreatoduodenectomy


InterventionsThe participants were randomly assigned to 2 groups
Group 1: octreotide (n = 16)
Further details: 0.1 mg sc 3 times a day for 7 days postoperatively
Group 2: control (n = 18)


OutcomesThe outcomes reported were mortality, perioperative morbidity and adverse effects of octreotide


NotesPancreatic fistula definition: drainage of at least 50 mL a day of fluid rich in amylase for more than 2 weeks (grade A)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
High riskComment: blinding was probably not performed

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: this information was not available

Selective reporting (reporting bias)Low riskComment: all important outcomes were reported

Free of source of funding bias?Unclear riskComment: this information was not available

Buccoliero 1992

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: Italy

Sample size: 16

Post-randomisation drop-out: not stated
Revised sample size: 16
Females: 6 (37.5%)
Mean age: 58.2 years
Malignancy: not stated
Chronic pancreatitis: (0%)
Pancreatoduodenectomy: (100%)
Follow-up: not reported

Inclusion criteria:

1. Pancreatoduodenectomy for tumour


InterventionsThe participants were randomly assigned to 2 groups
Group 1: somatostatin (n = 8)
Further details: continuous infusion of somatostatin at 250 μg/h for 6 days starting on induction
Group 2: control (n = 8)


OutcomesThe outcome reported was postoperative morbidity


NotesPancreatic fistula definition: not reported

Authors replied to questions related to bias risk assessment in May 2009


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "the patients sequence was generated according to random number table method" (author replies)

Allocation concealment (selection bias)Low riskQuote: "the allocation was concealed through the sealed envelope technique" (author replies)

Blinding (performance bias and detection bias)
All outcomes
High riskComment: blinding was probably not performed

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "there were not any drop-outs in either group" (author replies)

Selective reporting (reporting bias)High riskComment: some important outcomes were not reported

Free of source of funding bias?Unclear riskComment: this information was not available

Buchler 1992

MethodsRandomised clinical trial (parallel design)


ParticipantsCountries: Germany, Austria

Sample size: 322
Post-randomisation drop-out: 76
Revised sample size: 246
Females: 72 (29.3%)
Mean age: 52 years
Malignancy: 111 (45.1%)
Chronic pancreatitis: 112 (45.5%)
Pancreatoduodenectomy: 200 (81.3%)
Follow-up: 90 days

Inclusion criteria:

1. Elective pancreatic resection for tumours or chronic pancreatitis

Exclusion criteria:
1. Total pancreatectomy
2. Pancreatic transplantation
3. Pancreatic cyst anastomosis only


InterventionsThe participants were randomly assigned to 2 groups
Group 1: octreotide (n = 125)
Further details: 100 μg sc 3 times daily for 7 days starting at least 1 h preoperatively
Group 2: placebo (n = 121)
Further details: equal volume, frequency and duration as intervention


OutcomesThe outcomes reported were mortality, perioperative morbidity, adverse effects of octreotide and hospital stay


NotesReasons for post-randomisation drop-out: unresectable (n = 73); only pancreatic cyst anastomosis done (n = 3)
Pancreatic fistula definition: concentration of amylase and lipase in the drainage fluid later than 3 days postoperatively of more than 3 times the serum concentration and a drainage volume of more than 10 mL/h at the same time (grade A)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "on the day before the operation, the patients who satisfied the inclusion criteria were randomly assigned to receive a 7-day treatment of either 3 X 100 mcg octreotide (1 mL volume) subcutaneously (every 8 hours) or 21 subcutaneous placebo injections (1 mL each) in a double-blinded fashion"

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: post-randomisation drop-outs were related to the outcomes

Selective reporting (reporting bias)Low riskComment: all pre-defined outcomes were reported

Free of source of funding bias?Unclear riskComment: this information was not available

Fernandez-Cruz 2012

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: Spain
Number randomised: 58
Post-randomisation drop-outs: not stated
Revised sample size: 58
Average age: not stated
Females: not stated
Malignancy: not stated
Chronic pancreatitis: not stated
Pancreatoduodenectomy: 58 (100%)
Follow-up: 90 days
Inclusion criteria:

1. People undergoing pancreatoduodenectomy


InterventionsParticipants were randomly assigned to 2 groups
Group 1: somatostatin analogue (n = not stated)
Further details: octreotide (100 µg sc every 8 h)
Group 2: control (n = not stated)
Further details: no intervention


OutcomesThe outcomes reported were pancreatic fistula and proportion of people with complications


NotesAttempts were made to contact the authors in February 2013
The number of participants in each group was not stated. The authors stated that 26.6% of people with octreotide and 33.3% of people without octreotide developed complications


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: this information was not available

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: this information was not available

Selective reporting (reporting bias)Unclear riskComment: some important outcomes which will generally be assessed were not reported

Free of source of funding bias?Unclear riskComment: this information was not available

Friess 1995

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: Germany
Sample size: 280
Post-randomisation drop-out: 33
Revised sample size: 247
Females: 53 (21.5%)
Mean age: 48 years
Malignancy: 0 (0%)
Chronic pancreatitis: 247 (100%)
Pancreatoduodenectomy: 124 (50.2%)
Follow-up: 90 days

Inclusion criteria:
1. People with chronic pancreatitis
2. Suitable for pancreatic resection or pancreatic duct anastomosis


InterventionsThe participants were randomly assigned to 2 groups
Group 1: octreotide (n = 122)
Further details: 100 μg sc 3 times daily for 8 days starting at least 1 h preoperatively
Group 2: placebo (n = 125)
Further details: equal volume, frequency and duration as intervention


OutcomesThe outcomes reported were mortality, perioperative morbidity, adverse effects of octreotide and hospital stay


NotesReasons for post-randomisation drop-out: confirmation of cancer (n = 17); unresectable because of associated complications (n = 11); cystojejunostomy (n = 3); necrosectomy (n = 2)
Pancreatic fistula definition: concentration of amylase and lipase in the drainage fluid later than 3 days postoperatively of more than 3 times the serum concentration and a drainage volume of more than 10 mL/h at the same time (grade A)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "patients who satisfied the inclusion criteria were randomly assigned to receive a 8-day treatment of either 3 X 100 mcg octreotide (1 ml volume) subcutaneously (every 8 h) or 24 subcutaneous placebo injections (1 ml each) in a double blind manner"

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: post-randomisation drop-outs were related to the outcomes

Selective reporting (reporting bias)Low riskComment: all pre-defined outcomes were reported

Free of source of funding bias?Unclear riskComment: this information was not available

Gouillat 2001

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: France
Sample size: 75
Post-randomisation drop-out: 0
Revised sample size: 75
Females: 24 (32%)
Mean age: 60.2 years
Malignancy: 61 (81.3%)
Chronic pancreatitis: 4 (5.3%)
Pancreatoduodenectomy: 75 (100%)
Follow-up: not reported

Inclusion criteria:
1. Aged 18-75 years
2. Pancreaticoduodenectomy for presumed tumour
3. No evidence of chronic pancreatitis on preoperative imaging

Exclusion criteria:
1. Known allergy to somatostatin or mannitol
2. Received somatostatin or analogues within 3 days of surgery


InterventionsThe participants were randomly assigned to 2 groups
Group 1: somatostatin-14 (n = 38)
Further details: continuous infusion for 7 days after operation at 6 mg/day
Group 2: placebo (n = 37)
Further details: mannitol continuous infusion for 7 days after operation at 4 mg/day
Additionally, pancreatic juice diversion using a duct inserted into the pancreatic duct was used in both groups


OutcomesThe outcomes reported were mortality, perioperative morbidity, adverse effects of somatostatin and hospital stay


NotesPancreatic fistula definition: a clinical pancreatic fistula was defined as the drainage (more than 100 mL/day) of amylase-rich drainage fluid (greater than 5 times the upper limit of normal for amylase) after day 3, persisting after day 12 or in association with raised temperature (above 38 °C) or other symptoms requiring further surgery, percutaneous drainage or transfer to intensive care (grade B or C)

Authors replied to questions related to bias risk assessment in March 2009


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "computer generated"

Comment: author replies

Allocation concealment (selection bias)Low riskQuote: "sealed envelope"

Comment: "Author replies"

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "during the first 7 days after operation patients received total parenteral nutrition and continuous infusion of either 5-14 (Somatostatine®; UCB Pharma, Nanterre, France) at a dose of 6 mg per 24 h (days 1 - 6) and 3 mg per 24 h (day 7),or matching placebo (mannitol 4 mg)"

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: there were no post-randomisation drop-outs

Selective reporting (reporting bias)Low riskComment: all important outcomes were reported

Free of source of funding bias?High riskQuote: "this study was supported by a grant from UCB Pharma SA, Nanterre, France"

Comment: sponsored by entity with no vested interest in results

Hesse 2005

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: Belgium
Sample size: 105
Post-randomisation drop-out: 0
Revised sample size: 105
Females: 27 (25.7%)
Mean age: 59.5 years
Malignancy: 71 (67.6%)
Chronic pancreatitis: 26 (24.8%)
Pancreatoduodenectomy: 80 (76.2%)
Follow-up: not reported

Inclusion criteria:
1. Aged 16-86 years
2. Pancreaticojejunostomy


InterventionsThe participants were randomly assigned to 2 groups
Group 1: octreotide (n = 56)
Further details: at the time of operation in a dose of 0.1 mg sc 3 times a day for 7 days
Group 2: control (n = 49)
Further details: no intervention


OutcomesThe outcomes reported were mortality, perioperative morbidity and hospital stay


NotesPancreatic fistula definition: drainage of more than 100 mL/day of amylase rich fluid which had to be more than 5 times the upper limit of normal serum amylase after day 3 and persisting after postoperative day 7 with raising temperature and pre-septic conditions (grade B)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "was performed according to a computer generated random list"

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
High riskQuote: "single center open label prospectively randomized trial"

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: "There were no post-randomisation drop-outs"

Selective reporting (reporting bias)High riskComment: important outcomes like re-operation and adverse effects of octreotide were not reported

Free of source of funding bias?Unclear riskComment: this information was not available

Katsourakis 2010

MethodsRandomised clinical trial


ParticipantsCountry: Greece
Sample size: 67
Post-randomisation drop-out(s): not stated
Revised sample size: 67
Females: 28 (41.8%)
Mean age: 61.1 years
Malignancy: 53 (79.1%)
Chronic pancreatitis: 9 (13.4%)
Pancreatoduodenectomy: 13 (19.4%)
Inclusion criteria:

1. People undergoing pancreatic resection


InterventionsThe participants were randomised to 2 groups
Group 1: somatostatin analogue (n = 35)
Further details: somatostatin 14 intravenously 3.5 μg/kg/h starting 30 minutes before surgery and continued for 7 days
Group 2: control (n = 32)


OutcomesThe outcomes reported were postoperative complications and drug-related adverse events


NotesPancreatic fistula: peritoneal amylase levels (drain) > 3 × plasma amylase from day 3 onwards (grade A)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
High riskQuote: "open-label, parallel-group, simple randomized clinical trial"

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: there were no post-randomisation drop-outs

Selective reporting (reporting bias)High riskComment: some important outcomes were not reported

Free of source of funding bias?High riskQuote: "this work was supported in part by a grant from Faran laboratories s.a., Athens, Greece"

Klempa 1991

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: Germany
Sample size: 30
Post-randomisation drop-out: 6
Revised sample size: 24
Females: 9 (37.5%)
Mean age: 56.5 years
Malignancy: 24 (100%)
Chronic pancreatitis: 0 (0%)
Pancreatoduodenectomy: 24 (100%)
Follow-up: not reported

Inclusion criteria:
1. Pancreatic or papillary carcinoma
2. Partial duodenopancreatectomy


InterventionsThe participants were randomly assigned to 2 groups
Group 1: somatostatin (n = 12)
Further details: intravenous 250 μg/h for 6 days starting after operation
Group 2: control (n = 12)


OutcomesThe outcomes reported were mortality and perioperative morbidity


NotesReasons for post-randomisation drop-out: drain falling out or occlusion of drain (n = 4) and because of pancreatitis (n = 2)
Pancreatic fistula definition: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
High riskComment: blinding was not performed probably

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: post-randomisation drop-outs were related to the outcomes

Selective reporting (reporting bias)High riskComment: important outcomes such as re-operation were not reported

Free of source of funding bias?Unclear riskComment: this information was not available

Kollmar 2008

MethodsRandomised clinical trial (parallel design)


ParticipantsCountries: Germany, Switzerland
Sample size: 67
Post-randomisation drop-out: 0
Revised sample size: 67
Females: 26 (38.8%)
Mean age: 62.8 years
Malignancy: 33 (49.3%)
Chronic pancreatitis: 16 (23.9%)
Pancreatoduodenectomy: 67 (100%)
Follow-up: not reported
Inclusion criteria:
1. 18 years or older
2. Undergoing partial duodenopancreatectomy


InterventionsThe participants were randomly assigned to 2 groups
Group 1: octreotide (n = 35)
Further details: 100 μg sc 3 times daily for 7 days
Group 2: placebo (n = 32)
Further details: equal volume, frequency and duration as intervention


OutcomesThe outcomes reported were mortality, perioperative morbidity, hospital stay and ITU stay


NotesPancreatic fistula definition: output via an operatively placed drain (or a subsequently placed percutaneous drain) of any measurable volume of drain fluid on or after postoperative day 3, with an amylase content greater than 3 times the upper normal serum value (grade A)

The authors provided further information on the allocation concealment, different grades of pancreatic fistula and adverse reactions to octreotide


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "randomized to either the octreotide or the control group by means of a randomly generated number pattern"

Allocation concealment (selection bias)Low riskQuote: "octreotide and control saline placebo were prepared in the local investigational drug pharmacy and were identical in appearance, volume and labelling (consecutive numbers), masking the nursing staff, physicians and patients to their contents"

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "octreotide and control saline placebo were prepared in the local investigational drug pharmacy and were identical in appearance, volume and labelling (consecutive numbers), masking the nursing staff, physicians and patients to their contents"

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: there were no post-randomisation drop-outs

Selective reporting (reporting bias)Low riskComment: all important outcomes were reported

Free of source of funding bias?Low riskQuote: "there are no financial and personal relationships with other people or organizations that had inappropriately influenced our work"

Kurumboor 2012

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: India
Number randomised: 45
Post-randomisation drop-outs: not stated
Revised sample size: 45
Average age: not stated
Females: not stated
Malignancy: not stated
Chronic pancreatitis: not stated
Pancreatoduodenectomy: not stated
Inclusion criteria:

1. People with soft pancreas undergoing pancreaticoduodenectomy


InterventionsParticipants were randomly assigned to 2 groups
Group 1: somatostatin analogue (n = 24)
Further details: octreotide 100 μg sc
Group 2: control (n = 21)
Further details: no intervention


OutcomesThe outcomes reported were pancreatic fistula, overall complications and hospital stay


NotesAttempts were made to contact the authors in February 2013

Pancreatic fistula definition: grade A, grade B and grade C reported separately


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: this information was not available

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: this information was not available

Selective reporting (reporting bias)Unclear riskComment: some important outcomes which will generally be assessed were not reported

Free of source of funding bias?Unclear riskComment: this information was not available

Lange 1992

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: USA
Sample size: 21
Post-randomisation drop-out: not stated
Revised sample size: 21
Females: 10 (47.6%)
Mean age: 46.5 years
Malignancy: (100%)
Chronic pancreatitis: (0%)
Pancreatoduodenectomy: not stated
Follow-up: not reported

Inclusion criteria:

1. Pancreatic neuroendocrine tumours

Exclusion criteria:

1. Diabetes


InterventionsThe participants were randomly assigned to 2 groups
Group 1: octreotide (n = 10)
Further details: 50 μg sc every 8 h for first day starting immediately after operation, 100 μg every 8 h on second day, and 150 μg every 8 h continued until 3 days after drain removal
Group 2: placebo (n = 11)
Further details: saline through the same route and duration


OutcomesThe outcomes reported were mortality and perioperative morbidity


NotesPancreatic fistula definition: recurrent pancreatic drainage (grade A)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "after the operation, patients with a pancreatic incision were randomized to receive either octreotide or saline in a double blinded manner"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: this information was not available

Selective reporting (reporting bias)High riskComment: some important outcomes were not reported

Free of source of funding bias?Unclear riskComment: this information was not available

Matheus 2009

MethodsRandomised clinical trial


ParticipantsCountry: Brazil
Sample size: 35
Post-randomisation drop-out: not stated
Revised sample size: 35
Females: not stated
Mean age: not stated
Malignancy: not stated
Chronic pancreatitis: 0 (0%)
Pancreatoduodenectomy: 35 (100%)
Inclusion criteria:
1. People undergoing pancreaticoduodenectomy
2. Abdominal drain fluid containing amylase > 1000 IU/dL on the first postoperative day


InterventionsThe participants were randomised to 2 groups
Group 1: somatostatin analogue (n = not stated)
Further details: octreotide 100 μg sc 3 times daily for 10 days
Group 2: control (n = not stated)


OutcomesThe outcomes reported were proportion of participants with pancreatic fistula and hospital stay


NotesPancreatic fistula definition: drain output of any measure volume of fluid on or after postoperative day 3 with amylase content greater than 3 times the serum amylase (grade A)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
High riskComment: blinding was probably not performed

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: this information was not available

Selective reporting (reporting bias)High riskComment: some important outcomes such as clinically significant pancreatic fistulae were not reported

Free of source of funding bias?Unclear riskComment: this information was not available

Montorsi 1995

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: Italy
Sample size: 278
Post-randomisation drop-out: 60
Revised sample size: 218
Females: 87 (39.9%)
Mean age: 58.2 years
Malignancy: 139 (63.8%)
Chronic pancreatitis: 18 (8.3%)
Pancreatoduodenectomy: 143 (65.6%)
Follow-up: not reported

Inclusion criteria:
1. Elective pancreatic resection for neoplastic or chronic inflammatory disease of the pancreas and the periampullary region
2. Aged 18-75 years
3. ASA I or II

Exclusion criteria:
1. People with ongoing acute pancreatitis
2. Treatment with octreotide or native somatostatin within the last 48 h


InterventionsThe participants were randomly assigned to 2 groups
Group 1: octreotide (n = 111)
Further details: 100 μg sc 3 times daily for 7 days starting 1 h before operation
Group 2: placebo (n = 107)
Further details: equal volume, frequency and duration as intervention


OutcomesThe outcomes reported were mortality and perioperative morbidity


NotesReasons for post-randomisation drop-out: unresectable (n = 54); protocol violations (n = 6)
Pancreatic fistula definition: amylase-rich fluid (amylase more than 3 times normal serum concentration) collected from the peripancreatic abdominal drainage since the postoperative day 3, with a drainage volume of greater than 10 mL/day (grade A)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "octreotide or placebo was started in a double-blind fashion, 1 hour before operation, as follows: 1 ml (100 mcg octreotide or placebo) every 8 hours subcutaneously for 7 days"

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: post-randomisation drop-outs were related to the outcomes

Selective reporting (reporting bias)Low riskComment: important outcomes were reported

Free of source of funding bias?Unclear riskComment: this information was not available

Pederzoli 1994

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: Italy
Sample size: 303
Post-randomisation drop-out: 51
Revised sample size: 252
Females: 99 (39.3%)
Mean age: 53.1 years
Malignancy: 162 (64.3%)
Chronic pancreatitis: 90 (35.7%)
Pancreatoduodenectomy: 105 (41.7%)
Follow-up: until discharge

Inclusion criteria:

1. Adults undergoing elective pancreatic surgery

Exclusion criteria:
1. Total pancreatectomy
2. Pancreatic transplantation
3. Pancreatic resection combined with substantial intestinal resection


InterventionsThe participants were randomly assigned to 2 groups
Group 1: octreotide (n = 122)
Further details: 100 μg sc 3 times daily for 7 days starting at least 1 h preoperatively
Group 2: placebo (n = 130)
Further details: equal volume, frequency and duration as intervention


OutcomesThe outcomes reported were mortality, perioperative morbidity and adverse effects of octreotide


NotesReasons for post-randomisation drop-out: additional surgical procedures (n = 20); unresectable (n = 31)
Pancreatic fistula definition: drain output of fluid with amylase content more than 3 times the maximum normal value exceeding 10 mL per 24 h for at least 4 days from day 4 after operation (grade A)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "patients received octreotide or placebo according to randomization lists balanced in blocks of four that had been drawn up separately for each centre and risk stratum"

Allocation concealment (selection bias)Unclear riskQuote: "patients received octreotide or placebo according to randomization lists balanced in blocks of four that had been drawn up separately for each centre and risk stratum"

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "on the day of surgery, and for 7 complete days after operation, all patients received octreotide 0.1 mg subcutaneously in 1 ml ampoules or 1 ml placebo under double-blind conditions"

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: post-randomisation drop-outs were related to the outcomes

Selective reporting (reporting bias)Low riskComment: all pre-defined outcomes were reported

Free of source of funding bias?High riskQuote: "this study was supported by a grant from Sandoz Prodotti Farmaceutici SPA, Milan, Italy"

Comment: sponsored by entity with no vested interest in results

Sarr 2003

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: USA
Sample size: 381
Post-randomisation drop-out: 106
Revised sample size: 275
Females: 95 (34.5%)
Mean age: 62 years
Malignancy: 138 (50.2%)
Chronic pancreatitis: 0 (0%)
Pancreatoduodenectomy: 108 (39.3%)
Follow-up: 30 days

Inclusion criteria:
1. People undergoing an elective, anatomic, proximal or central pancreatectomy with a pancreaticoenteric anastomosis or a distal pancreatectomy with or without a pancreaticoenteric anastomosis
2. At least 18 years of age
3. An elective pancreatic resection because of a presumed pancreatic or periampullary neoplasm

Exclusion criteria:
1. Chronic pancreatitis
2. Emergency surgery
3. Total pancreatectomy
4. Duct-drainage procedures alone without any pancreatic resection
5. Enucleation of neoplasm
6. Enteric drainage of a pancreatic pseudocyst
7. Serum creatinine of twice the local upper limit of normal
8. Serum bilirubin > 20 mg/dL
9. Administration of a somatostatin analogue within the previous month


InterventionsThe participants were randomly assigned to 2 groups
Group 1: vapreotide (n = 135)
Further details: 0.6 mg sc 2 h before operation and then twice daily for 7 days postoperatively
Group 2: placebo (n = 140)
Further details: same times as intervention


OutcomesThe outcomes reported were mortality and perioperative morbidity


NotesReasons for post-randomisation drop-out: did not undergo pancreatic resection
Pancreatic fistula definition: drainage fluid (beginning on or after postoperative day 5) of both > 30 mL/day and amylase or lipase activity > 5-fold upper limits of the normal serum value (grade A)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "patients received vapreotide acetate (0.6 mg) or placebo subcutaneously within up to 2 hours before operation and then twice daily for 7 days postoperatively"

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "patients not resected were replaced"

Comment: this would have necessitated exclusion of the trial if there was no blinding (as replacing recruited patients with other patients introduces selection bias). However, we have treated the patients who were replaced as drop-outs because of adequate blinding

Selective reporting (reporting bias)High riskComment: all pre-defined outcomes were not reported

Free of source of funding bias?Low riskQuote: "we would like to thank J-M Dumont and K Besseghir from Debiopharm SA for their guidance and financial support"

Comment: in spite of obtaining financial support from a pharmaceutical company, the authors of this report do not support the use of the drug

Shan 2005

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: Taiwan
Sample size: 60
Post-randomisation drop-out: 6
Revised sample size: 54
Females: 26 (48.1%)
Mean age: 67 years
Malignancy: 45 (83.3%)
Chronic pancreatitis: 0 (0%)
Pancreatoduodenectomy: 54 (100%)
Follow-up: 60 days

Inclusion criteria:
1. People undergoing elective pancreaticoduodenectomy for pancreatic and periampullary lesions and extrapancreatic solid neoplasms involving the duodenum were also included in this study
2. Age more than 16 years
3. ASA I or II


InterventionsThe participants were randomly assigned to 2 groups
Group 1: somatostatin (n = 27)
Further details: intravenous 250 μg/h for 7 days starting after operation
Group 2: placebo (n = 27)
Further details: normal saline


OutcomesThe outcomes reported were mortality, perioperative morbidity and hospital stay


NotesReasons for post-randomisation drop-out: direct anastomosis of pancreatic duct to the jejunum (n = 3); obstructive pulmonary disease (n = 1); whole gastrointestinal tract MALToma (n = 1) and pancreatitis in the pancreatic head area (n = 1)
Pancreatic fistula definition: amylase-rich fluid with drain fluid volume greater than 10 mL/day, persistent elevation of the drain amylase level and 3 times higher than the serum level for longer than 7 days (grade A)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "patients meeting the inclusion criteria were randomized by a random number table before operation to receive either prophylactic somatostatin treatment or placebo"

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
Unclear riskComment: further details of placebo were not available

Incomplete outcome data (attrition bias)
All outcomes
High riskComment: post-randomisation drop-outs were related to the outcomes

Selective reporting (reporting bias)High riskComment: all pre-defined outcomes were not reported

Free of source of funding bias?Unclear riskComment: this information was not available

Suc 2004

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: France
Sample size: 230
Post-randomisation drop-out: 0
Revised sample size: 230
Females: 99 (43%)
Mean age: 56.5 years
Malignancy: 154 (67%)
Chronic pancreatitis: 30 (13%)
Pancreatoduodenectomy: 177 (77%)
Follow-up: not reported

Inclusion criteria:
1. Pancreatic resection was performed for either malignant or benign disease
2. Age more than 18 years

Exclusion criteria:
1. Resection for acute pancreatitis or trauma
2. Simple tumour excision
3. Total or central pancreatectomy
4. Pancreatoduodenectomy without immediate pancreatodigestive anastomosis
5. Duodenum-preserving pancreatectomy


InterventionsThe participants were randomly assigned to 2 groups
Group 1: octreotide (n = 122)
Further details: 100 μg sc during the operation every 8 h for 10 days
Group 2: control (n = 108)
Further details: no treatment


OutcomesThe outcomes reported were mortality, re-operation, perioperative morbidity and hospital stay


NotesPancreatic fistula definition: either chemically as fluid obtained through drains or percutaneous aspiration containing at least 4 times normal serum values of amylase for 3 days, irrespective of the amount of output and the date of appearance or clinically and radiologically as anastomotic leaks (type A, B, C - not available separately)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "allotment to octreotide or not, as generated by computerized random number tables, was decided by a telephone call to the coordinating center which collected and processed all data"

Allocation concealment (selection bias)Low riskQuote: "allotment to octreotide or not, as generated by computerized random number tables, was decided by a telephone call to the coordinating center which collected and processed all data"

Blinding (performance bias and detection bias)
All outcomes
High riskQuote: "patients were not aware of the treatment arm to which they were allotted (octreotide injection was considered as part of postoperative treatment), but the surgeon performing the operation, obviously, was (single-blind study without placebo). Complications, however, were assessed by a physician who was unaware of the allotted treatment"

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: there were no post-randomisation drop-outs

Selective reporting (reporting bias)Low riskComment: all pre-defined outcomes were reported

Free of source of funding bias?Unclear riskComment: this information was not available

Tulassay 1993

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: Hungary
Sample size: 33
Post-randomisation drop-out: not stated
Revised sample size: 33
Females: 5 (15.2%)
Mean age: 43 years
Malignancy: 0 (0%)
Chronic pancreatitis: 14 (42.4%)
Pancreatoduodenectomy: 0 (0%)
Follow-up: not reported

Inclusion criteria:

1. Abdominal surgery because of chronic pancreatitis or its complications


InterventionsThe participants were randomly assigned to 2 groups
Group 1: somatostatin (n = 15)
Further details: 125 μg/h continuous infusion started 12 h before surgery and continued for 48 h
Group 2: placebo (n = 18)
Further details: normal saline


OutcomesThe outcomes reported were postoperative morbidity


NotesPancreatic fistula definition: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskComment: this information was not available

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "one group of 15 patients received somatostatin perioperatively while the control group received a placebo of physiologic saline in continuous infusion"; "the study was carried out in a double blind"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComment: this information was not available

Selective reporting (reporting bias)High riskComment: some important outcomes were not reported

Free of source of funding bias?Unclear riskComment: this information was not available

Yeo 2000

MethodsRandomised clinical trial (parallel design)


ParticipantsCountry: USA
Sample size: 383
Post-randomisation drop-out: 172
Revised sample size: 211
Females: 100 (47.4%)
Mean age: 64.7 years
Malignancy: 147 (69.7%)
Chronic pancreatitis: 22 (10.4%)
Pancreatoduodenectomy: 211 (100%)
Follow-up: not reported

Inclusion criteria:
1. Anticipated elective pancreaticoduodenal resection

Exclusion criteria:
1. Did not undergo pancreatoduodenectomy
2. Total pancreatectomy


InterventionsThe participants were randomly assigned to 2 groups
Group 1: octreotide (n = 107)
Further details: 100 μg sc 3 times daily for 7 days starting at least 1 h preoperatively
Group 2: placebo (n = 104)
Further details: equal volume, frequency and duration as intervention


OutcomesThe outcomes reported were mortality, perioperative morbidity, adverse effects of octreotide and hospital stay


NotesReasons for post-randomisation drop-out: did not undergo pancreaticoduodenectomy (n = 118); total pancreatectomy (n = 14); did not receive at least a 5-day course of octreotide study drug (n = 40)
Pancreatic fistula definition: drainage of greater than 50 mL amylase-rich fluid (more than 3-fold elevation above upper limit of normal in serum) per day through the surgically placed drains on or after postoperative day 10, or pancreatic anastomotic disruption demonstrated radiographically (grade A, B, C - not available separately)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "enrolled patients (n = 383) were randomized before surgery to either the octreotide or the control group by means of a randomly generated number pattern"

Comment: further details were not available

Allocation concealment (selection bias)Unclear riskComment: this information was not available

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "the octreotide and control saline placebo were prepared in the Investigational Drug Pharmacy and were identical in appearance, volume, and labelling (labelled as “octreotide study drug”), thereby masking the nursing staff, physicians, and patients to their contents"

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "after enrolment and randomization, patients were excluded from the study for the following reasons: patient did not undergo pancreaticoduodenectomy (n = 118), patient underwent total pancreatectomy (n = 14), or patient did not receive at least a 5-day course of octreotide study drug (n = 40)"

Comment: post-randomisation drop-outs were related to the outcomes

Selective reporting (reporting bias)Low riskComment: all important outcomes were reported

Free of source of funding bias?Low riskQuote: "supported in part by NIH grants RO1-CA56130 and P50-CA62924"

Comment: sponsored by entity with no vested interest in results

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Barnett 2004Not a randomised clinical trial

Bassi 1994Review

Brennan 2000Comment on an included trial

Büchler 2001Letter to editor about an included trial

Droeser 2013Not a randomised controlled trial

Elhadad 1998Unable to obtain this reference identified by reference searching

Falconi 2002Cross-over trial

Frick 1996Letter to editor about an included trial

Friess 1989Not performed in people undergoing pancreatic surgery

Friess 1996Review

Habib 1998Not a randomised clinical trial (the groups were divided according to whether the pancreas was friable or sclerosed)

Klempa 1979Not a randomised clinical trial

Lowy 1997Quasi-randomised study (randomisation based on their number of medical record)

Shatverian 2004Not a randomised clinical trial

Van Berge 1997Performed on healthy volunteers and not on people who were about to undergo or had undergone pancreatic resection

Van Hee 1998Not a randomised clinical trial

Wang 2012The control group received somatostatin analogue but different regimens were used between intervention and control

Woltering 2003Comment on an included trial

Yeo 1999Editorial

 
Comparison 1. Somatostatin analogues versus none

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perioperative mortality182210Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.56, 1.16]

 2 Treatment withdrawal91220Risk Ratio (M-H, Fixed, 95% CI)1.55 [0.56, 4.33]

 3 Number with adverse effects due to treatment81199Risk Ratio (M-H, Random, 95% CI)2.09 [0.83, 5.24]

 4 Re-operation7687Risk Ratio (M-H, Random, 95% CI)1.26 [0.58, 2.70]

 5 Anastomotic leak91585Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.51, 1.27]

 6 Pancreatic fistula (all)172206Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.55, 0.79]

 7 Pancreatic fistula (clinically significant)4292Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.38, 1.28]

 8 Postoperative pancreatitis111667Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.32, 1.22]

 9 Sepsis71092Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.21, 0.85]

 10 Renal failure5998Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.25, 1.77]

 11 Bleeding141814Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.70, 1.44]

 12 Abdominal collections81589Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.56, 1.05]

 13 Infected abdominal collections131965Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.66, 1.32]

 14 Delayed gastric emptying5434Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.51, 1.23]

 15 Pulmonary complications91210Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.57, 1.39]

 16 Shock4812Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.46, 2.15]

 17 Number of complications7Rate Ratio (Fixed, 95% CI)0.70 [0.60, 0.82]

 18 Number with any complication121903Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.61, 0.80]

 19 Hospital stay101314Mean Difference (IV, Fixed, 95% CI)-1.29 [-2.60, 0.03]

 
Comparison 2. Somatostatin analogues versus none (stratified by different interventions)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perioperative mortality171935Risk Ratio (IV, Fixed, 95% CI)0.81 [0.54, 1.20]

    1.1 Somatostatin
7304Risk Ratio (IV, Fixed, 95% CI)0.39 [0.20, 0.76]

    1.2 Octreotide
101631Risk Ratio (IV, Fixed, 95% CI)1.19 [0.73, 1.93]

 2 Treatment withdrawal91220Risk Ratio (IV, Fixed, 95% CI)1.45 [0.45, 4.65]

    2.1 Somatostatin
2142Risk Ratio (IV, Fixed, 95% CI)6.82 [0.36, 127.64]

    2.2 Octreotide
71078Risk Ratio (IV, Fixed, 95% CI)1.08 [0.30, 3.85]

 3 Number with adverse effects due to treatment81199Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.99, 1.77]

    3.1 Somatostatin
2142Risk Ratio (M-H, Fixed, 95% CI)3.47 [0.58, 20.68]

    3.2 Octreotide
61057Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.95, 1.71]

 
Comparison 3. Somatostatin analogues versus none (stratified by different aetiologies)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perioperative mortality5844Risk Ratio (IV, Fixed, 95% CI)0.68 [0.29, 1.60]

    1.1 Malignancy
4400Risk Ratio (IV, Fixed, 95% CI)0.48 [0.18, 1.24]

    1.2 Chronic pancreatitis
3444Risk Ratio (IV, Fixed, 95% CI)2.75 [0.42, 17.87]

 2 Treatment withdrawal2Risk Ratio (IV, Fixed, 95% CI)Totals not selected

    2.1 Malignancy
1Risk Ratio (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

    2.2 Chronic pancreatitis
1Risk Ratio (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 3 Number with adverse effects due to treatment1Risk Ratio (IV, Fixed, 95% CI)Totals not selected

    3.1 Chronic pancreatitis
1Risk Ratio (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 
Comparison 4. Somatostatin analogues versus none (pancreatoduodenectomy)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perioperative mortality8639Risk Ratio (M-H, Fixed, 95% CI)1.39 [0.72, 2.69]

 2 Treatment withdrawal4387Risk Ratio (M-H, Fixed, 95% CI)5.15 [0.61, 43.28]

 3 Number with adverse effects due to treatment4387Risk Ratio (M-H, Fixed, 95% CI)13.05 [2.67, 63.92]

 
Summary of findings for the main comparison. Somatostatin analogues for pancreatic surgery

Somatostatin analogues for pancreatic surgery

Patient or population: people with pancreatic surgery
Settings: secondary or tertiary care
Intervention: somatostatin analogues

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlSomatostatin analogues

Perioperative mortality49 per 100040 per 1000
(28 to 57)
RR 0.8
(0.56 to 1.16)
2210
(18 studies)
⊕⊝⊝⊝
very low1,2,3

Treatment withdrawal8 per 100013 per 1000
(5 to 35)
RR 1.55
(0.56 to 4.33)
1220
(9 studies)
⊕⊝⊝⊝
very low1,2,3,4

Re-operation102 per 1000108 per 1000
(70 to 166)
RR 1.06
(0.69 to 1.63)
687
(7 studies)
⊕⊝⊝⊝
very low1,2,3,4,5

Anastomotic leak48 per 100039 per 1000
(25 to 61)
RR 0.81
(0.51 to 1.27)
1585
(9 studies)

Pancreatic fistula (clinically significant)151 per 1000104 per 1000
(46 to 191)
RR 0.69
(0.38 to 1.29)
292
(4 studies)
⊕⊝⊝⊝
very low1,2,3,4

Infected abdominal collections61 per 100056 per 1000
(40 to 80)
RR 0.93
(0.66 to 1.32)
1965
(13 studies)

Shock29 per 100029 per 1000
(14 to 63)
RR 1
(0.46 to 2.15)
812
(4 studies)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Most trials were of high risk of bias.
2 Confidence intervals overlap 1 and 0.75 or 1.25.
3 A total of fewer than 300 events in the comparison.
4 Fewer than 10 trials were included for this outcome. So, there is a suspicion of selective outcome reporting, which can indicate publication bias.
5 There was moderate heterogeneity as indicated by I² of 30%, tau² of 0.27; and lack of overlapping of confidence intervals.