Evidence analysis on the utilization of platelet-rich plasma as an adjuvant in the repair of rotator cuff tears

Table 1 Characteristics of the included studies

Sl. No	Ref.	Publication date	Publication journal	Literature search date	No. of studies included
1	Chahal et al[32], 2012	June 14, 2012	Arthroscopy: The Journal of Arthroscopic and Related Surgery	December 30, 2011	5
2	Moraes et al[31], 2013	December 23, 2013	Cochrane Database of Systematic Reviews	March 25, 2013	19
3	Zhang et al[30], 2013	July 12, 2013	PLoS One	April 20, 2013	7
4	Li et al[33], 2014	June 7, 2014	Arthroscopy: The Journal of Arthroscopic and Related Surgery	May 1, 2013	7
5	Zhao et al[29], 2014	September 30, 2014	Arthroscopy: The Journal of Arthroscopic and Related Surgery	September, 2013	8
6	Warth et al[35], 2014	November 13, 2014	Arthroscopy: The Journal of Arthroscopic and Related Surgery	September, 2013	11
7	Vavken et al[36], 2015	March 12, 2015	The American Journal of Sports Medicine	August 1, 2014	13
8	Cai et al[38], 2015	October 8, 2015	Journal of Shoulder and Elbow Surgery	January, 2015	5
9	Xiao et al[37], 2016	October 30, 2016	International Journal of Clininical and Experimental Medicine	February 1, 2016	15
10	Hurley et al[40], 2018	February 21, 2018	The American Journal of Sports Medicine	March 24, 2017	18
11	Han et al[39], 2019	June 20, 2019	Journal of Orthopaedic Surgery and Research	September, 2016	13
12	Wang et al[41], 2019	July 29, 2019	PLoS One	September 15, 2018	8
13	Chen et al[42], 2019	November 19, 2019	The American Journal of Sports Medicine	December, 2017	18
14	Cavendish et al[43], 2020	May 1, 2020	Journal of Shoulder and Elbow Surgery	May 23, 2018	16
15	Hurley et al[44], 2020	July 30, 2020	The American Journal of Sports Medicine	March, 2020	13
16	Yang et al[45], 2020	October 14, 2020	Nature research	February 15, 2020	7
17	Zhao et al[46], 2020	November 18, 2020	Journal of Shoulder and Elbow Surgery	March, 2020	10
18	Ryan et al[1], 2021	March 17, 2021	Arthroscopy: The Journal of Arthroscopic and Related Surgery	June, 2020	17
19	Xu et al[48], 2021	July 13, 2021	The Orthopaedic Journal of Sports Medicine	June 20, 2020	14
20	Li et al[47], 2021	May 27, 2021	Arthroscopy: The Journal of Arthroscopic and Related Surgery	October 29, 2020

Table 2 Search methodology used by each study

Sl. No	Search parameters	Chahal (2012)	Moraes (2013)	Zhang (2013)	Li (2014)	Zhao (2015)	Warth (2015)	Vavken (2015)	Cai (2015)	Xiao (2016)	Hurley (2018)	Han (2019)	Wang (2019)	Chen (2019)	Cavendish (2020)	Hurley (2020)	Yang (2020)	Zhao (2021)	Ryan (2021)	Xu (2021)	Li (2021)
1	Publication language restriction	X	X	NA	X	X	X	X	NA	X	NA	X	NA	√	√	NA	NA	√	√	X	NA
2	Publication status restriction	X	NA	NA	NA	X	NA	NA	NA	X	X	NA	NA	X	NA	X	NA	NA	NA	X	NA
3	PubMed	√	X	√	√	√	√	√	√	√	X	√	√	√	√	X	√	√	√	X	√
4	Medline	√	√	X	X	X	X	X	X	X	√	X	X	√	X	√	X	X	√	√	X
5	Embase	X	X	X	√	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X
6	Cochrane library	X	X	X	√	X	X	X	X	X	X	X	X	X	X	X	X	X	X	√	X
7	Web of Science	X	√	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X
8	Scopus	√	√	√	√	√	√	√	√	√	√	√	√	X	√	√	√	√	X	√	√
9	Google Scholar	√	√	√	X	√	X	√	X	√	√	√	√	√	X	√	√	√	√	√	√
10	CINAHL	X	X	X	X	X	X	X	√	√	X	X	X	X	X	X	X	X	X	X	√
11	AMED	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X
12	CNKI	X	X	X	X	X	X	X	X	√	X	X	X	X	X	X	√	X	X	X	X
13	Wan Fang	X	X	X	X	X	X	√	X	X	X	X	X	X	X	X	X	X	X	X	X
14	CBM literature	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X	X
15	VIP	X	X	X	X	X	X	X	X	X	√	X	X	X	X	√	X	X	X	X	X

AMED: Allied and Complementary Medicine; CBM: Chinese BioMedical database; CINAHL: Cumulative Index to Nursing and Allied Health Literature; CNKI: Chinese National Knowledge Infrastructure; NA: Not available; VIP: Chinese Scientific Journals Database.

Table 3 Methodological information of each study

Sl. No	Search parameters	Chahal (2012)	Moraes (2013)	Zhang (2013)	Li (2014)	Zhao (2015)	Warth (2015)	Vavken (2015)	Cai (2015)	Xiao (2016)	Hurley (2018)	Han (2019)	Wang (2019)	Chen (2019)	Cavendish (2020)	Hurley (2020)	Yang (2020)	Zhao (2021)	Ryan (2021)	Xu (2021)	Li (2021)
1	Primary study design	RCT, CCT,RCS	RCT	RCT	RCT	RCT	RCT CCT	RCT	RCT	RCTCCT	RCT	RCT	RCT	RCT	RCT	RCT	RCT	RCT	RCT	RCT	RCT
2	Level of Evidence	III	I	I	II	I	II	I	I	II	I	I	I	I	II	I	I	II	I	I	II
3	Software Used	RevMan 5.3	RevMan 5.3	RevMan 5.3	NA	RevMan 5.3	Open Meta	STATA 10	RevMan 5.3	RevMan 5.3	RevMan 5.3	RevMan 5.3	RevMan 5.3	STATA 15.1	STATA 13	R Foundation (netmeta package Version 0.9-6 in R)	RevMan 5.3	RevMan 5.3	R Foundation for Statistical Computing, Vienna, Austria	STATA 15	RevMan 5.3
4	GRADE Used	X	√	X	X	√	X	X	X	X	X	X	√	X	X	X	X	X	X	X	X
5	Sensitivity Analysis	√	√	X	√	√	√	√	X	√	X	√	√	√	X	X	X	√	X	X	√
6	Subgroup Analysis	√	√	√	X	√	√	√	√	X	√	√	√	√	√	X	√	√	√	√	X
7	Publication Bias	X	√	√	X	√	√	√	√	√	X	√	√	√	√	X	X	X	X	X	X

CCT: Controlled clinical trial; GRADE: Grading of Recommendations Assessment, Development and Evaluation system; NA: Not available; RCTs: Randomized controlled trials; RCS: Retrospective cohort study.

Table 4 AMSTAR scores and AMSTAR 2 grading for included studies

Sl. No	AMSTAR domains	Chahal (2012)	Moraes (2013)	Zhang (2013)	Li (2014)	Zhao (2015)	Warth (2015)	Vavken (2015)	Cai (2015)	Xiao (2016)	Hurley (2018)	Han (2019)	Wang (2019)	Chen (2019)	Cavendish (2020)	Hurley (2020)	Yang (2020)	Zhao (2021)	Ryan (2021)	Xu (2021)	Li (2021)
1	Was a priori design provided?	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1
2	Were there duplicate study selection and data extraction?	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1
3	Was a comprehensive literature search performed?	1	1	0	1	0	0	1	0	1	1	0	0	1	0	1	1	0	0	1	1
4	Was the status of publication (i.e. grey literature) used as an inclusion criterion?	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
5	Was a list of studies (included and excluded) provided?	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
6	Were the characteristics of the included studies provided?	1	1	1	1	1	1	0	1	1	1	1	1	1	1	1	1	1	1	1	1
7	Was the scientific quality of the included studies assessed and documented?	1	1	1	1	1	1	1	1	1	1	1	1	0	1	1	1	1	1	1	1
8	Was the scientific quality of the included studies used appropriately in formulating conclusions?	1	1	1	1	1	1	1	0	1	1	1	1	0	1	1	1	1	1	1	1
9	Were the methods used to combine the findings of studies appropriate?	1	1	1	1	1	1	1	0	1	1	1	1	1	1	1	1	1	1	1	1
10	Was the likelihood of publication bias assessed?	0	1	1	0	1	1	1	1	1	0	1	1	1	1	1	0	0	0	0	0
11	Was the conflict of interest stated?	1	1	1	1	1	1	0	1	0	1	1	1	1	1	1	1	1	1	1	1
	Total AMSTAR score	8	8	10	8	8	7	8	6	8	8	8	8	7	9	8	8	6	7	8	8
	Critical Methodological Flaw	3	3	1	3	2	2	3	5	2	3	2	3	4	1	3	3	4	4	3	2
	Non-Critical Flaw	1	1	1	1	1	3	1	1	2	1	1	1	1	1	1	1	2	1	1	1
	AMSTAR 2 Grade	CL	CL	CL	CL	CL	CL	CL	CL	CL	CL	CL	CL	CL	CL	CL	CL	CL	CL	CL	CL

AMSTAR: Assessing the Methodological Quality of Systematic Reviews; CL: Critically low.

Table 5 I² statistic values of variables analyzed in each meta-analysis

Sl. No	Outcome variables	Chahal (2012)	Zhang (2013)	Moraes (2013)	Li (2014)	Zhao (2015)	Warth (2015)	Vavken (2015)	Cai (2015)	Xiao (2016)	Hurley (2018)	Han (2019)	Wang (2019)	Chen (2019)	Hurley (2020)	Yang (2020)	Cavendish (2020)	Zhao (2021)	Ryan (2021)	Xu (2021)	Li (2021)
1	VAS Score – Short term			29.9%+						0%-	38%-		0%-			60.5%+		0%+	0%+	0%+
2	VAS Score – Long term			67%-			0%-			0%-	0%-	0%+	0%-	87.5%-	0%+	0%-		0%+		4%+	63%+
3	DASH Score – Short term									0%-			32%-			30%-
4	DASH Score – Long term			0%-						NR-			0%-			0%-					32%-
5	Constant Score – Short term									30%+			0%+			0%+				23%+
6	Constant Score – Long term	NR-	17%-	50%+	86%-	0%-	26%-		0%-	0%-	0%-	0%+	0%-	30.7%+	0%+	0%-		19%+	36%+	47%+	0%+
7	UCLA Score – Short term									0%+			8.9%+			0%+				0%+
8	UCLA Score – Long term	NR-	0%-	35.18%-	75%-	0%-	0%-		60%-	47%-	0%-	47%+	12%+		0%+	0%-		49%+	64.18%-	63%+	46%+
9	ASES Score		0%-	0%-	46%-		58%-		0%-	54%-	0%-	26%-						0%-	41%-	52%-	0%+
10	SST Score	NR-	47%-	0%+	90%-		0%-		0%-	47%-		0%+							0%+		0%-
11	Operative time									85%-
12	Patient Satisfaction			0%-						0%-
13	Tendon healing rate								0%+	0%-					0%+			10%-
14	Retear rate – Short term		0%-	25%+				15.2%-		30%-			0%+					0%+		0%-
15	Retear rate – Long term	0%+	11%-	14%-	22%-	43%-		0%-	0%-	71%-		0%+	0%-	0%+	0%+	0%+	0%+	0%+	NA+	4.7%+	22%+

ASES: American Shoulder and Elbow Surgeons; DASH: Disabilities of the Arm, Shoulder and Hand; SST: Simple Shoulder Test; UCLA: University of California Los Angeles; VAS: Visual analog scale.

Table 6 Systematic Reviews or Meta-analyses with their level of evidence with the authors’ rationale for repeating the systematic review along with their concluding remarks

Sl. No.	Ref.	Date of publication	Date of last literature search	Level of evidence	Rationale for repeating meta-analysis	Conclusion
1	Chahal et al[32], 2012	June 14, 2012	December 30, 2011	III	Earliest meta-analysis	No effect of PRP on overall retear rates or shoulder-specific outcomes after ARCR
2	Moraes et al[31], 2013	December 23, 2013	March 25, 2013	I	Only included studies with intra-operative PRP application after ARCR	Some benefit of PRP in improving pain with comparable rates of retear (after 2 yr) between PRP and non-PRP groups
3	Zhang et al[30], 2013	July 12, 2013	April 20, 2013	I	Included studies with high methodological quality and provided results without significant heterogeneity supported by larger number of patients	No benefit of PRP on overall clinical outcomes and retear rate in full-thickness rotator cuff tears and decrease in rate of retears with PRP for small- and medium-sized rotator cuff tear
4	Li et al[33], 2014	June 7, 2014	May 1, 2013	II	All high-quality (7 studies) RCTs included (compared with previous studies)	No benefit with PRP regarding retear and clinical outcomes for ARCR
5	Zhao et al[29], 2014	September 30, 2014	September, 2013	I	Newer RCTs as compared with previous meta-analysis	No benefit of PRP in ARCR of full-thickness tears in terms of similar retear rates and clinical outcomes
6	Warth et al[35], 2014	September 13, 2014	September, 2013	II	Meta-regression analyses to evaluate the effects of 6 covariates such as inclusion of Level II studies, initial tear size, single- vs double-row repair constructs, varying PRP preparation, manual vs commercially available PRP preparation systems, method of PRP application on overall clinical and structural outcomes	No statistically significant differences in outcome scores or retear rate with the use of PRP. However, significant improvement in Constant scores when PRPs applied at tendon-bone interface and significant reduction in retear rate with PRP in tears > 3 cm repaired with double-row technique
7	Vavken et al[36], 2015	March 12, 2015	August 1, 2014	I	To know if addition of PRP to ARCR results in statistically relevant as well as clinically meaningful reduction in retear rates along with analysis of its safety with difference in complication rates and its cost-effectiveness	PRP proved to be an effective and safe way of reducing retear rates in the arthroscopic repair of small- and medium-sized rotator cuff tears. However, no evidence to support its use in large and massive tear
8	Cai et al[38], 2015	October 8, 2015	January, 2015	I	Meta-analysis of level I studies	PRP in full-thickness rotator cuff repairs showed no statistically significant difference in clinical outcome but demonstrated significant reduction in failure-to-heal rate for small-to-moderate tears
9	Xiao et al[37], 2016	October 30, 2016	February 1, 2016	II	All level I and II evidence studies – included to enhance power of meta-analysis (15 studies)	No significant difference in the re-tear rates and clinical efficacy
10	Hurley et al[40], 2018	February 21, 2018	March 24, 2017	I	First study to find that PRP was associated with significant improvement in tendon healing rates in tears > 3 cm with 9 new studies that have been published till Cai et al[38], 2015	Use of PRP in rotator cuff repair improves the healing rates, pain levels, and functional outcomes. But PRF shows no benefit in improving tendon healing rates or functional outcomes
11	Han et al[39], 2019	June 20, 2019	September, 2016	I	Inclusion of new RCTs, as compared with previous meta-analysis with improved pooled effect size	PRP treatment with ARCR showed decreases retear rate and improves clinical outcome
12	Wang et al[41], 2019	July 29, 2019	September 15, 2018	I	To ensure homogeneity of data, only studies using PRP in full-thickness tears included along with addition of new high-level RCTs	PRP improved the short-term outcomes such as pain, retear rate, and shoulder function after ARCR in full-thickness rotator cuff tears. PRP when used in single-row fixation of ARCR demonstrated improved clinical outcomes.
13	Chen et al[42], 2019	September 19, 2019	December, 2017	I	Exclusively reviewed only level 1 RCTs with multiple sub-groups, and comparative quantitative analysis with MCID on effects of LR-PRP vs LP-PRP, gel vs non-gel preparations, and tendon-specific outcomes analyzed	Long-term retear significantly decreased with PRP. Several PROs such as constant score, VAS, retear rate significantly improved in PRP-treated patients. However, all analyzed PROs failed to reach the 5% MCID threshold. Hence authors neither recommended nor discouraged the use of PRP for rotator cuff injuries
14	Cavendish et al[43], 2020	May 1, 2020	May 23, 2018	II	Included 7 out of 16 studies published in the past 4 yr with larger sample size to reduce risk of type II error noted in previous studies	Intraoperative use of PRP reduces the failure risk following rotator cuff repair and has a consistent effect regardless of tear size and showed 25% reduction in the overall risk of failure in rotator cuff repairs
15	Hurley et al[44], 2020	July 30, 2020	March, 2020	I	To ascertain whether there is evidence to support the use of LP- or LR-PRP as an adjunct to ARCR	LP-PRP reduces rate of retear and/or incomplete tendon healing after ARCR and improves patient-reported outcomes as compared with control whereas whether LP-PRP improves the tendon healing rate when compared with LR-PRP remained unclear
16	Yang et al[45], 2020	October 14, 2020	February 15, 2020	I	Inclusion of studies that dealt with PRP application on bone–tendon interface only during arthroscopic repair and studies that administered only PRP and not any other platelet-rich matrix to lower bias caused by different materials. All included RCTs were conducted on patients with full thickness rotator cuff tear who received diagnoses based on preoperative MRI or sonography	Application of PRP shown to be beneficial in reducing the retear rate and improving the functional outcomes during the short-term follow-up of single-row repair
17	Zhao et al[46], 2020	November 18, 2020	March, 2020	II	Meta-analysis of level I and II studies based on MCID values to comprehensively assess clinical efficacy of LP-PRP only for ARCR mainly to avoid heterogeneity due to different types of PRP	LP-PRP - significantly reduces the postoperative retear rate in medium and long term regardless of tear size and method used for repair. But no clinically meaningful effects in terms of postoperative pain and patient-reported outcomes were noted
18	Ryan et al[1], 2021	March 17, 2021	June, 2020	I	Involved stratified pooled data on basis of leukocyte concentration, liquid and solid formulation, and all 4 types of PRP (P-PRP, P-PRF, LP-PRP, LP-PRF)	This analysis demonstrates significant reductions in retear when rotator cuff repair is augmented with PRP. LP-PRP appears to be most effective formulation, resulting in significantly improved retear rates and clinical outcome scores when compared with controls
19	Xu et al[48], 2021	May 27, 2021	October 29, 2020	II	Analyzed PRP and PRF separately and PRP was sub grouped into leukocyte-poor and leukocyte-rich PRP. Compared with study by Hurley et al 5 more RCTs included. Cochrane Collaboration risk of bias tool- adopted and retear rate was analyzed based on duration of follow-up into 2 subgroups with a cut off of 2 yr	PRP in ARCR improved pain and functional outcome, reduces retear rates. PRF improved only the Constant score. Significant reduction of retear rate in leukocyte-poor PRP when followed-up > 2 yr
20	Li et al[47], 2021	July 13, 2021	June 20, 2020	I	Strict eligibility criteria enforced in the inclusion of RCTs along with subgroup analysis, based on PRP preparation, time of administration, size of tear, type of repair, to assess the real utility of PRP	ARCR with PRP significantly improved long-term retear, shoulder pain and long-term shoulder function scores and intraoperative application of leukocyte-poor plasma for large to massive tears contributed to significant decrease in retear rates

ARCR: Arthroscopic rotator cuff repair; LP: Leukocyte poor; LP-PRF: Leucocyte poor – platelet rich fibrin; LP-PRP: Leucocyte poor – platelet rich plasma; LR: Leucocyte rich; MCID: Minimum clinically identifiable difference; P-PRF: Pure platelet rich fibrin; P-PRP: Pure platelet rich plasma; PRF: Platelet rich fibrin; PRO: Patient reported outcomes; PRP: Platelet rich plasma; RCTs: Randomized controlled trials.