Timing of Laparoscopic Cholecystectomy After Mild Biliary Pancreatitis: A Systematic Review and Meta-Analysis

Abstract

Aim:

To compare the safety of cholecystectomy in early laparoscopic cholecystectomy (ELC) and delayed laparoscopic cholecystectomy (DLC).

Methods:

We systematically searched PubMed, EMBASE, and Cochrane Library for studies that were published from January 1992 to March 2017. We included studies on patients with mild biliary pancreatitis and that reported the timing of cholecystectomy and the number of complications, readmissions, and conversion to open cholecystectomy. Moreover, we assessed the quality and bias risks of the included studies.

Results:

After screening 4651 studies, we included 3 randomized clinical trials and 10 retrospective studies. The included studies described 2291 patients, of whom 1141 (49.8%) underwent ELC and 1150 (50.2%) underwent DLC. The reported rate of complications for ELC (6.8%) was lower than that for DLC (13.45%). The reported rate of readmission for ELC was lower than that for DLC. The length of hospital stay was longer with DLC than with ELC. ELC and DLC did not have significantly different rates of conversion to open cholecystectomy and duration of surgery.

Conclusion:

This meta-analysis provides evidence that ELC is better than DLC in many aspects for acute mild pancreatitis patients undergoing laparoscopic cholecystectomy. ELC associated with few complications and readmissions, as well as a short length of hospital stay.

Introduction

Acute pancreatitis is one of the most common gastrointestinal diseases. The annual incidence of acute pancreatitis ranges from 13 to 45/100,000 persons.¹ Gallstones are the most common cause of acute pancreatitis.² With the development of surgical technology, laparoscopic cholecystectomy has gradually become the gold standard for the surgical treatment of gallbladder disease over the past two decades.³

Current international guidelines recommend early cholecystectomy in patients with mild biliary pancreatitis. However, different guidelines provide different definitions for “early.” The International Association of Pancreatology recommends cholecystectomy during the index admission of patients with mild biliary pancreatitis.⁴ The American Gastroenterological Association suggests that cholecystectomy should be performed within the period of hospital admission and not beyond 2–4 weeks after discharge.⁵ The British Society of Gastroenterology recommends cholecystectomy within the period of hospital admission or up to 2 weeks after admission.⁶ This lack of consensus is reflected by several audits from the United Kingdom, Germany,⁷ Italy,⁸ and a large database study from the United States.⁹

To determine the risk of recurrent biliary events in the period after mild biliary pancreatitis but before interval cholecystectomy and to determine the safety of cholecystectomy during index admission, van Baal et al.¹⁰ conducted a systematic review of nine studies published until July 31, 2010. They found that a high rate of readmissions is clearly associated with interval cholecystectomy. They also suggested that randomized controlled studies on mild biliary pancreatitis should be performed. A meta-analysis¹¹ reported no difference in the number of complications between early laparoscopic cholecystectomy (ELC) and delayed laparoscopic cholecystectomy (DLC). However, this meta-analysis only included four articles with low methodological quality.

The related literature on the timing of surgery in mild biliary pancreatitis has grown substantially, and a multicenter randomized controlled trial (RCT) has been performed by the Dutch Pancreatitis Study Group.

In this study, we present an updated meta-analysis of the timing of cholecystectomy after mild biliary pancreatitis. We compare the outcomes of ELC and DLC in terms of the number of complications, readmission, and conversion to open cholecystectomy.

Materials and Methods

Literature search

We performed this systematic review and meta-analysis in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis.¹² We searched the electronic databases PubMed, EMBASE, and Cochrane Library for “cholecystectomy” and “pancreatitis.” The language of full texts was limited to English. We only included studies that were published from January 1, 1992 to March 20, 2017. References to studies with potential relevance and review articles were manually screened to identify any previously unidentified eligible resources.

Inclusion and exclusion criteria

In this study, we defined ELC as initial cholecystectomy or laparoscopic cholecystectomy performed within 14 days after admission. The control group was defined as DLC. Mild pancreatitis was defined by either Ranson criteria or computed tomography criteria.

We included studies that: (1) compared ELC and DLC; (2) clearly defined ELC and DLC; (3) and provided information on the following essential outcomes: number of complications, readmission, and conversion to open cholecystectomy.

We excluded studies if they: (1) included children and pregnant patients; (2) included patients with pancreatitis of other origins; (3) included severe pancreatitis without separately reporting the results of mild pancreatitis; (4) included open cholecystectomy without separately reporting laparoscopic cholecystectomy; (5) did not report essential outcomes; and (6) were abstracts, case reports, case series, in vitro studies, and animal studies.

Outcome assessment

Primary outcomes included gallstone-related complications, which were defined as recurrent acute biliary pancreatitis, acute cholecystitis, cholangitis, or biliary colic.¹³

Secondary outcomes included readmission, which was defined as rehospitalization before or after cholecystectomy; conversion to open cholecystectomy; duration of surgery; and length of hospital stay.

Data extraction

After the exclusion of duplicated studies, 2 investigators (D.-J.Y. and H.-M.L.) independently evaluated the studies for eligibility. Disagreements between the reviewers concerning the inclusion or exclusion of a study were resolved by consensus and by consultation with a third reviewer (Q.G.) when necessary. We extracted the following information from each eligible article: name of the first author, publication year, country, study design, sample size, demographic characteristics, number of complications, hospital readmission, number of conversion to open cholecystectomy, duration of surgery, and length of hospital stay.

Quality assessment

Two authors (D.-J.Y. and H.-M.L.) used the Newcastle–Ottawa Scale (NOS) to assess the methodological quality of the included studies. Quality was calculated based on the following three aspects of study design: patient selection, cohort compatibility, and outcome. Funnel plots were used to examine publication bias.

Statistical analyses

Dichotomous variables were analyzed by estimating the odds ratio (OR) with a 95% confidence interval (95% CI), whereas continuous variables were analyzed using the weighted mean difference with 95% CI. If continuous variables in the article only included the median and range or interquartile range, we converted these variables to mean and standard deviation (SD) using a formula.^14,15 Heterogeneity across trials was investigated using the Cochran Q test and measured with the I² statistic. I² values that exceeded 25%, 50%, and 75% represented low, moderate, and high heterogeneity, respectively.¹⁶ If no heterogeneity was absent, then a fixed effects model based on the Mantel and Haenszel estimator was used. Otherwise, a random effects model based on the DerSimonian and Laird estimator was used. For all statistical analyses, except for heterogeneity and publication bias, at two-sided, P < .05 was regarded as statistically significant. Statistical analyses were performed with Review Manager Software program version 5.3.

Results

The flow diagram of the study is shown in Figure 1. A search of the electronic databases, PubMed, EMBASE, and Cochrane Library, yielded 7736 records. After duplicates were removed, 4651 records remained. After screening titles and abstracts, 54 abstracts were selected for detailed assessment, and 41 articles were excluded. The reasons for excluding these articles are detailed in Figure 1. Finally, 13 studies^17–29 were included for data extraction.

FIG. 1.

The flow diagram.

Study characteristics

The characteristics of the included studies are presented in Table 1. We included 13 studies with 2291 patients in our meta-analysis, including 3 randomized clinical trials^19,21,24 and 10 retrospective studies.^{17,18,20,22,23,25–29} The sample size of the studies varied from 44 to 350. A total of 1141 patients underwent ELC and 1150 patients underwent DLC.

Table 1.

Characteristics of Studies

Author	Country	Study design	Group	Definition of group	n	Men/women	Age mean ± SD/median (IQR/range)
Guadagni et al.¹⁷	Italy	Retrospective	ELC	<3 days	98	37/61	61.4 (21–90)
Guadagni et al.¹⁷	Italy	Retrospective	DLC	>3 days	218	105/113	66.9 (23–94)
Aksoy et al.¹⁸	Turkey	Retrospective	ELC	<3 days	75	20/55	44.7 (21–82)
Aksoy et al.¹⁸	Turkey	Retrospective	DLC	4–10 weeks	87	25/62	44.7 (21–82)
Jee et al.¹⁹	Malaysia	RCT	ELC	Same index admission	38	18/20	42.5 (29.75–52)
Jee et al.¹⁹	Malaysia	RCT	DLC	Discharge 6 weeks	34	13/21	42.5 (30.75–54.25)
Borreca et al.²⁰	Italy	Retrospective	ELC	Serum amylase was decreasing, and abdominal tenderness was improving	24	9/15	59 ± 16
Borreca et al.²⁰	Italy	Retrospective	DLC	Interval cholecystectomy	55	28/27	61 ± 16
Costa et al.²¹	Dutch	RCT	ELC	3 days after randomization	128	52/76	53 (38–66)
Costa et al.²¹	Dutch	RCT	DLC	25–30 days after randomization	136	52/84	54 (41–68)
Al-Qahtani²²	Kingdom of Saudi Arabia	Retrospective	ELC	Index admission	267	75/192	43.2 ± 9.8
Al-Qahtani²²	Kingdom of Saudi Arabia	Retrospective	DLC	6–12 weeks	83	27/56	44.1 ± 8.8
Falor et al.²³	United States	Retrospective	ELC	<48 hours	117	66/237	35 (28–45)
Falor et al.²³	United States	Retrospective	DLC	>48 hours	186	66/237	40 (31–56)
Aboulian et al.²⁴	United States	RCT	ELC	<48 hours	25	23/2	33 (29–51)
Aboulian et al.²⁴	United States	RCT	DLC	>48 hours	25	22/3	41 (30–50)
Nebiker et al.²⁵	Switzerland	Retrospective	ELC	<14 days	32	11/21	60 (29–83)
Nebiker et al.²⁵	Switzerland	Retrospective	DLC	>14 days	67	30/37	61 (23–94)
Sinha²⁶	India	Retrospective	ELC	<7 days	81	35/84	41.1 (18–70)
Sinha²⁶	India	Retrospective	DLC	>6 weeks	26	35/84	41.1 (18–70)
Ito et al.²⁷	United States	Retrospective	ELC	Index admission	162	46/116	59 (20–93)
Ito et al.²⁷	United States	Retrospective	DLC	Discharge from index admission	119	47/72	57 (20–99)
Griniatsos et al.²⁸	United Kingdom	Retrospective	ELC	<2 weeks	20	9/35	62
Griniatsos et al.²⁸	United Kingdom	Retrospective	DLC	>2 weeks	24	9/35	62
McCullough et al.²⁹	Canada	Retrospective	ELC	Inhospital	74	25/49	55.4
McCullough et al.²⁹	Canada	Retrospective	DLC	Discharge	90	30/60	51.2

DLC, delayed laparoscopic cholecystectomy; ELC, early laparoscopic cholecystectomy; IQR, interquartile range; n, number of patients; RCT, randomized clinical trial; SD, standard deviation.

Quality assessment using the NOS showed that the 13 included studies were of high quality (Table 2).

Table 2.

Outcomes of Studies

							NOS
Author	Group	COC	Complications	Readmission	LOS mean ± SD	DOS mean ± SD	Selection	Comparability	Outcome	All
Guadagni et al.¹⁷	ELC	2	4	2	6.5 ± 5.7	103.7 ± 45	4	2	2	8
Guadagni et al.¹⁷	DLC	3	7	2	8.9 ± 6	103.9 ± 52.5	4	2	2	8
Aksoy et al.¹⁸	ELC	30	5	NR	NR	NR	4	2	2	8
Aksoy et al.¹⁸	DLC	25	2	NR	NR	NR	4	2	2	8
Jee et al.¹⁹	ELC	4	3	0	8 ± 2.96	80 ± 25.9	4	2	2	8
Jee et al.¹⁹	DLC	4	15	8	9 ± 2.22	85 ± 44.4	4	2	2	8
Borreca et al.²⁰	ELC	1	1	NR	9	NR	4	2	2	8
Borreca et al.²⁰	DLC	2	1	NR	13	NR	4	2	2	8
Costa et al.²¹	ELC	5	6	6	4.1	58 ± 19.3	4	2	2	8
Costa et al.²¹	DLC	4	62	23	3.8	60 ± 25.2	4	2	2	8
Al-Qahtani²²	ELC	11	3	3	5.4 ± 1.2	65.1 ± 1.9	4	1	2	7
Al-Qahtani²²	DLC	3	1	21	10.4 ± 1.5	60.5 ± 2.1	4	1	2	7
Falor et al.²³	ELC	3	5	4	3.4 ± 0.2	NR	4	1	2	7
Falor et al.²³	DLC	14	9	2	6.3 ± 0.2	NR	4	1	2	7
Aboulian et al.²⁴	ELC	0	0	0	3.5 ± 0.4	NR	4	2	2	8
Aboulian et al.²⁴	DLC	0	0	0	5.8 ± 1.1	NR	4	2	2	8
Nebiker et al.²⁵	ELC	2	2	0	NR	NR	4	2	2	8
Nebiker et al.²⁵	DLC	2	5	15	NR	NR	4	2	2	8
Sinha²⁶	ELC	NR	0	0	NR	16.5 ± 4.2	4	1	2	7
Sinha²⁶	DLC	NR	0	3	NR	15.7 ± 4.7	4	1	2	7
Ito et al.²⁷	ELC	20	37	0	5 ± 7.3	NR	4	2	2	8
Ito et al.²⁷	DLC	8	34	39	7 ± 5.8	NR	4	2	2	8
Griniatsos et al.²⁸	ELC	NR	1	NR	NR	75 ± 33.3	4	1	2	7
Griniatsos et al.²⁸	DLC	NR	1	NR	NR	75 ± 44.4	4	1	2	7
McCullough et al.²⁹	ELC	8	11	0	15.5 ± 17	NR	4	1	2	7
McCullough et al.²⁹	DLC	9	16	18	10.7 ± 16	NR	4	1	2	7

COC, conversion to open cholecystectomy; DLC, delayed laparoscopic cholecystectomy; DOS, duration of surgery; ELC, early laparoscopic cholecystectomy; LOS, length of hospital stay; NOS, Newcastle–Ottawa Scale; NR, not reported; SD, standard deviation.

Meta-analysis results

The results of data extraction are shown in Table 2 and those of meta-analysis are shown in Figures 2 –6.

FIG. 2.

Gallstone-related complications. 95% CI, 95% confidence interval; DLC, delayed laparoscopic cholecystectomy; ELC, early laparoscopic cholecystectomy; NRCT, nonrandomized controlled trial; RCT, randomized clinical trial.

FIG. 3.

Readmission. 95% CI, 95% confidence interval; DLC, delayed laparoscopic cholecystectomy; ELC, early laparoscopic cholecystectomy; NRCT, nonrandomized controlled trial; RCT, randomized clinical trial.

FIG. 4.

Conversion to open cholecystectomy. 95% CI, 95% confidence interval; DLC, delayed laparoscopic cholecystectomy; ELC, early laparoscopic cholecystectomy; NRCT, nonrandomized controlled trial; RCT, randomized clinical trial.

FIG. 5.

Duration of surgery. 95% CI, 95% confidence interval; DLC, delayed laparoscopic cholecystectomy; ELC, early laparoscopic cholecystectomy; SD, standard deviation.

FIG. 6.

Length of hospital stay. 95% CI, 95% confidence interval; DLC, delayed laparoscopic cholecystectomy; ELC, early laparoscopic cholecystectomy; SD, standard deviation.

Complications

All studies reported primary outcome. The overall rate of complications is 231/2291 (10.1%). The rate of complications was 78/1141 (6.8%) and 154/1150 (13.45%) in the ELC and DLC groups, respectively. The result of the meta-analysis showed that complications between ELC and DLC group were significantly different (OR: 0.45, 95% CI: 0.33, 0.61; P < .00001; Fig. 2) with a high degree of heterogeneity (I² = 76%, P < .00001).

Readmission

The overall readmission rate reported in 10 articles^{17,19,21–27,29} was 146/2027 (7.2%). ELC (1.5%) and DLC (13.0%) had significantly different rates of readmission (OR: 0.11, 95% CI: 0.07, 0.19; P < .00001; Fig. 3) with a high degree of heterogeneity (I² = 77%, P < .00001).

Conversion to open cholecystectomy

Conversion to open cholecystectomy was reported in 11 studies^{17–25,27,29} that included 2140 patients. Conversion to open cholecystectomy occurred in 160 patients (7.5%). ELC (8.3%) and DLC (6.7%) did not have significantly different rates of conversion to open cholecystectomy (OR: 1.26, 95% CI: 0.88, 1.78; P = .20; Fig. 4) and without heterogeneity (I² = 0%, P = .66).

Duration of surgery

Six articles^{18,19,21,22,26,28} reported the duration of surgery. The duration of surgery was not significantly different between groups (OR: 1.44, 95% CI: −1.77, 4.65; P = .38; Fig. 5) and had a high degree of heterogeneity (I² = 75%, P < .00001).

Length of hospital stay

Nine articles^{17,19–24,27,29} reported the length of hospital stay, and only seven articles^{17,19,22–24,27,29} provided data. The length of hospital stay in the remaining two articles^20,21 was not estimated due to incomplete data. The length of hospital stay was significantly different between groups (OR: −2.46, 95% CI: −3.47, 1.44; P = .38; Fig. 6; P < .00001) and with a high degree of heterogeneity (I² = 96%, P < .00001).

Subgroup and sensitivity analysis

Complications and readmission exhibited substantial heterogeneities of I² = 76% and I² = 77%, respectively. Therefore, subgroup and sensitivity analyses were performed (Table 3). The included studies were divided into subgroups on the basis of study design, publication date, and study area. The types of study design included RCT and non-RCT (NRCT). The boundary point for publication date was set at 2011.

Table 3.

Subgroup and Sensitivity Analysis of the Meta-Analysis

		Heterogeneity
Analysis item	Subgroup	I²	P_Het	OR (95% CI)	P
Complications	NRCT	0	.91	0.89 (0.62, 1.29)	.55
	RCT	0	.46	0.07 (0.03, 0.15)	<.00001
	BEFORE	0	.99	0.07 (0.50, 1.19)	.24
	AFTER	83	<.00001	0.57 (0.15, 2.07)	.39
	European and American	78	<.0001	0.63 (0.26, 1.49)	.29
	Others	79	.008	0.63 (0.07, 5.70)	.68
Readmission	NRCT	82	<.0001	0.12 (0.02, 0.78)	.03
	RCT	28	.24	0.12 (0.03, 0.48)	.02
	BEFORE	0	.71	0.02 (0.01, 0.10)	<.00001
	AFTER	82	.0002	0.33 (0.06, 1.72)	.19
	European and American	82	<.0001	0.20 (0.03, 1.29)	.09
	Others	0	1.00	0.04 (0.02, 0.13)	<.00001

95% CI, 95% confidence interval; NRCT, nonrandomized controlled trial; OR, odds ratio; RCT, randomized clinical trial.

No heterogeneity (I² = 0%) was observed in the RCT, NRCT, and BEFORE subgroups. High heterogeneity was observed in the AFTER (I² = 83%), European and American (I² = 78%), and Others (I² = 79%) subgroup. RCT was statistically significantly different between ELC and DLC. The Other subgroups were not different between ELC and DLC.

Readmission was not heterogeneous (I² = 0%) in the BEFORE and Others subgroup. High heterogeneity (I² = 82%) was observed in the NRCT, AFTER, and European and American subgroup. And RCT had a moderate degree of heterogeneity (I² = 28%). There was significant difference in the rate of readmission between ELC and DLC in NRCT, RCT, BEFORE, and Others subgroup. AFTER and European and American subgroups were not different.

Assessment of publication bias

To examine any publication bias in the included studies, we constructed funnel plots of the included ORs using Review Manager 5.3. The funnel plots are shown in Figure 7. Performance bias was observed in complications (Fig. 7A) and readmission (Fig. 7B). No evidence of publication bias of conversion to open cholecystectomy was observed (Fig. 7C).

FIG. 7.

Outcomes of studies as funnel plots. (A) Complications; (B) readmission; (C) conversion to open cholecystectomy; (D) duration of surgery; and (E) length of hospital stay. OR, odds ratio; NRCT, nonrandomized controlled trial; RCT, randomized clinical trial; SE, standard error.

Discussion

We found that DLC resulted in higher rates of complications and readmission than ELC. The rates of conversion to open cholecystectomy between ELC and DLC were comparable. However, we cannot be certain that the two groups are truly comparable given that baseline characteristics were often not provided in the included articles.

We found that ELC and DLC had significantly different complication rates (Fig. 2). The outcomes of the subgroup analysis of 10 retrospective articles (NRCT subgroup) showed no difference in complications between ELC and DLC, whereas those of 3 RCT articles (RCT subgroup) showed that DLC has a higher rate of complications than ELC. The results of RCT are more reliable than those of retrospective studies owing to the study design and control of confounding factors in RCT. Therefore, in RCT, the characteristics of the patients in different groups are homogenous. By contrast, retrospective studies are prone to selection bias. For example, interval cholecystectomy might be performed in patients with advanced age, with substantial comorbidity, or with severe pancreatitis. ELC decreases the risk of recurrent gallstone-related complications. Cholecystectomy in patients with mild gallstone pancreatitis can be performed safely during ELC. ELC and DLC in the BEFORE and AFTER subgroups did not have significantly different complication rates (Table 3).

The overall readmission rate reported in eight articles was 146/2017 (7.2%), which was lower than the 18% reported in an accent systematic review.¹⁰ This result indicated that ELC decreases the rate of readmission. In subgroup analysis, the RCT and NRCT groups showed the same result, which favors DLC in mild blood pressure, resulting in readmission (Fig. 3). The high heterogeneity of the NRCT group was contributed by the studies of Falor et al.²³ and Guadagni et al.¹⁷ Removing these studies decreased the heterogeneity of NRCT to 0%. In cases where gallstones were untreated, the recurrence rate of BP was 32%–61%.³⁰ Therefore, ELC during the first admission is safe and recommended.^4,31

The rates of conversion to open cholecystectomy have been reported in the literature as 0%–27.7%.^3,32,33 We found that the rate of conversion to open cholecystectomy is 7.5%, indicating that DLC does not increase the need for conversion to open surgery. However, we were unable to analyze the reason for this result because some studies did not report the reasons for conversion. An accent article reported that the risks of conversion might be related to gender, age, acute cholecystitis, previous upper abdominal surgery, and the experience of the surgeon.³⁴

Only one in six analysis articles directly provided the mean and SD of surgery duration. We calculated other mean and SD values from formula, thus causing a high degree of heterogeneity. The timing of laparoscopic cholecystectomy did not affect the duration of surgery. This outcome is different from the assumption that ELC will increase the difficulty of surgery. We also converted the data on the length of hospital stay using formula. We found that DLC is associated with a significantly longer length of hospital stay and that DLC patients require readmission and a longer duration of conservative treatment. Thus, DLC increases hospitalization costs and consumes more medical resources.

An accent review article¹⁰ provided an important information on the high readmission rates (18%) for interval cholecystectomy, leading to delayed multicenter RCT.²¹ However, several included articles did not provide comparison groups. Moreover, some articles may be considered as reporting on outcomes before and after cholecystectomy and not on the outcomes of early and delayed cholecystectomy. The methodological quality of most articles is moderate or low. An accent meta article¹¹ defined early cholecystectomy as cholecystectomy within 48 hours and thus included only four articles for analysis. Three of the four articles were written by the same research group and had poor or extremely poor methodological quality. Therefore, the result of this meta-analysis may be inaccurate.

Although most guidelines recommend early cholecystectomy, many studies have shown that interval cholecystectomy is usually performed in mild biliary pancreatitis patients. For example, a Swedish study³⁵ that included more than 1500 patients with mild acute biliary pancreatitis showed that up to 10% of LC cases are performed with interval procedures within 30 days of admission and that 68% of patients do not receive surgery or sphincterotomy within 30 days of admission. A British study reported that only 14.7% of 25,000 patients with gallstone-related disease underwent cholecystectomy within the same admission period after acute hospitalization.³⁶ Several international audits^10,37 had shown that cholecystectomy is often not performed until 6 weeks after discharge and not at all in many patients.

The recurrent attack of biliary pancreatitis could be severe and threaten life.^27,38 Why, then, do so many doctors delay cholecystectomy? On the one hand, inflammation and edema are believed to distort the anatomy of the biliary tract, thereby complicating dissection and increasing the risks of conversion to open cholecystectomy and of surgical complications, such as bile duct injury, during early cholecystectomy.^39,40 On the other hand, emergency resources are often scarce; thus, by delaying cholecystectomy, the surgeon could schedule surgical treatment. Doctors who support ELC believe that it reduces the risk of recurrent gallstone-related events (e.g., recurrent acute biliary pancreatitis, acute cholecystitis, cholangitis, or biliary colic).^6,41

Our study was limited by the following factors: First, the unclear definition of ELC. In 13 articles, ELC was performed within 2, 3, 7, or 14 days within admission, or even within the same time as admission (without providing the specific time). Therefore, the precise timing of early cholecystectomy remains unclear. Second, the included studies were highly heterogeneous because of their different study designs. Finally, we only included three randomized trials.

Footnotes

Author Contributions

All of the authors contributed to the collection and analysis of the data and to the preparation of the report. The corresponding author had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Disclosure Statement

No competing financial interests exist.

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