TITLE: The Use of Osteochondral Allograft for the Ankle, Knee, and Shoulder: Clinical Effectiveness and Cost-Effectiveness

Transcription

1 TITLE: The Use of Osteochondral Allograft for the Ankle, Knee, and Shoulder: Clinical Effectiveness and Cost-Effectiveness DATE: 09 February 2017 CONTEXT AND POLICY ISSUES Articular cartilage is the smooth, white tissue that covers the ends of bones in joints. 1 Healthy articular cartilage makes it easy for joints to move. 1 However, this tissue can be damaged through injury or normal wear-and-tear. 1 Because damaged articular cartilage does not heal by itself, if it is left untreated, significant destruction of the joint, or osteoarthritis, may ensue. 2 A number of treatment options are available for damaged articular cartilage but are often aimed at treating symptoms rather than providing a cure. 2 For example, non-surgical methods, such as physiotherapy, may relieve pain but cannot heal cartilage. 2 Surgical treatments aimed at preserving the joint are increasingly available. 2 Microfracture and drilling are minimally-invasive procedures that promote bleeding from the bone 2 to stimulate the growth of cartilage by creating a new blood supply. 1 Mosaicplasty is an autograft transplantation procedure, in which a block of osteochondral (i.e., bone and cartilage) tissues is harvested from a less-demanding (e.g., nonweight-bearing) area of a joint to cover a cartilage defect in a more important (e.g., weightbearing) area within a single patient. 2 If a cartilage defect is too large for an autograft 1,2 or in patients who failed other cartilage repair techniques, 3 an allograft transplantation treatment, in which osteochondral tissues are harvested from cadavers, may be used to cover the injured area. 1-3 Historically, allografts have been implanted fresh within 24 hours of procurement. However, concerns about disease transmission have led to required bacterial and viral testing before tissue release, which takes a minimum of 14 days. 3 Today, harvested tissues may be aseptically-processed and maintained at four degrees Celsius as prolonged fresh allografts, which are most common, or cryopreserved into frozen allografts until use. 3 To inform clinical practice on the treatment of patients who failed non-surgical or other surgical therapies for damaged articular cartilage, this report aimed to provide evidence on the clinical benefits and harms and cost-effectiveness of the use of fresh, prolonged fresh, or frozen osteochondral allografts for the lesions of the ankle, knee, and shoulder. Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic review s. The intent is to provide a list of sources of the best evidence on the topic that the Canadian Agency for Drugs and Technologies in Health (CADTH) could identify using all reasonable efforts within the time allow ed. Rapid responses should be considered along w ith other ty pes of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for w hich little information can be found, but w hich may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in w hich a third party ow ns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a w eb site, redistributed by or stored on an electronic system w ithout the prior w ritten permission of CADTH or applicable copyright ow ner. Links: This report may contain links to other information available on the w ebsites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the ow ners ow n terms and conditions.

2 RESEARCH QUESTIONS 1. What is the clinical effectiveness regarding the use of osteochondral allograft for the ankle? 2. What is the cost-effectiveness regarding the use of osteochondral allograft for the ankle? 3. What is the clinical effectiveness regarding the use of osteochondral allograft for the knee? 4. What is the cost-effectiveness regarding the use of osteochondral allograft for the knee? 5. What is the clinical effectiveness regarding the use of osteochondral allograft for the shoulder? 6. What is the cost-effectiveness regarding the use of osteochondral allograft for the shoulder? KEY FINDINGS Seven systematic reviews (SRs) were found on clinical benefits and harms of osteochondral allograft transplantation for the ankle, knee, and shoulder. For all three joints, while the operation can improve pain and functional outcomes, with a high level of patient satisfaction, high rates of complications, reoperations, and clinical failures were reported. The quality of the SRs was mixed, and the quality of the primary studies included in those SRs was generally poor, warranting caution in the interpretation of the findings. No economic evaluations fulfilling the selection criteria were found. METHODS Literature Search Methods A limited literature search was conducted on key resources, including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, and Canadian and major international health technology agencies. A focused Internet search was also conducted. Methodological filters were applied to limit retrieval to health technology assessments (HTAs), SRs, meta-analyses (MAs), and economic studies. Where possible, retrieval was limited to the human population. The search was also limited to English language documents, published between January 1, 2012 and January 10, Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed, and potentially-relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1. The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 2

3 Population Intervention Comparator Outcomes Study Designs Table 1: Selection Criteria Healthy, active patients between the ages of years, with a documented, painful lesion of the ankle, knee, or shoulder that involves cartilage or cartilage with bone and has failed non-operative and primary operative treatment Q1, Q2: Osteochondral allograft for the ankle Q3, Q4: Osteochondral allograft for the knee Q5, Q6: Osteochondral allograft for the shoulder Any comparator, including before-and-after Q1, Q3, Q5: Clinical effectiveness and functional outcomes Q2, Q4, Q6: Cost-effectiveness HTAs, SRs, MAs, and economic evaluations HTA = health technology assessment; MA = meta-analysis; SR = systematic review Exclusion Criteria Articles were excluded if they did not meet the selection criteria for the intervention, comparator, outcomes, and study designs that are outlined in Table 1, if they were duplicate publications or SRs superseded by more comprehensive SRs, or if they were published prior to For the selection criteria for the population outlined in Table 1, because selecting the literature based on the terms healthy, active, and ages of years was found to be too restrictive, only articles focusing on specific diseases, children, or seniors were excluded. For articles missing information on prior interventions, it was assumed that the patients had failed non-surgical or other surgical therapies for damaged articular cartilage. 3 Critical Appraisal of Individual Studies The included SRs were critically appraised, using the Assessment of Multiple Systematic Reviews (AMSTAR) tool. 4 Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included study were narratively described. SUMMARY OF EVIDENCE Quantity of Research Available A total of 150 citations were identified in the literature search. Following screening of titles and abstracts, 126 citations were excluded, and 24 potentially-relevant reports from the electronic search were retrieved for full-text review. No potentially-relevant publications were retrieved from the grey literature search. Of the 24 potentially-relevant articles, 17 publications were excluded for various reasons, while seven publications met the inclusion criteria and were included in this report. One SR 5 was identified that examined osteochondral allograft transplantation for the knee, but it focused on randomized controlled trials and did not identify any relevant studies, and therefore was not included in this report. Appendix 1 describes the PRISMA flowchart of the study selection. Additional references of potential interest that did not meet the selection criteria are provided in Appendix 5. The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 3

4 Summary of Study Characteristics A summary of the characteristics of the included literature is presented in Appendix 2. Clinical Benefits and Harms of Osteochondral Allograft for the Ankle A total of two SRs 6,7 provided information on the clinical effectiveness and safety of osteochondral allograft transplantation for the ankle. Study Design The SRs 6,7 included five case-series studies 6 or 13 studies, most of which were also caseseries. 7 Although all five case-series studies included in one SR 6 were also included in the other SR, 7 to present all outcomes described, both SRs 6,7 were included in this report. Neither of the SRs 6,7 included control groups. One SR 6 conducted searches up to 2016 and was published in 2017, and the other SR 7 did not provide search dates and was published in Country of Origin The SRs 6,7 were conducted in the United States (US). Patient Population The SRs 6,7 included patients with osteochondral lesions of the ankle. One SR 6 included adults aged 17 to 74 years, most of who had undergone one or more prior interventions on the ankle, whereas the other SR 7 included patients with unknown age and did not report on prior interventions on the ankle. Interventions and Comparators The SRs 6,7 included osteochondral allograft transplantation as the intervention and compared it to before the operation. One SR 6 included fresh allografts only, whereas the other SR 7 did not specify such restriction. Outcomes The SRs 6,7 included various measures of foot and ankle pain and function, including the American Orthopedic Foot and Ankle Society score (AOFAS), 6,7 foot function index (FFI) score, 6 and visual analog scale (VAS) pain score. 6 One SR 6 included patient satisfaction, reoperation, and failure rates. One SR 6 reported a mean follow-up of 45 months, whereas the other SR 7 did not report on follow-up durations. One SR 6 conducted quality assessment of the included studies, using the Coleman Methodology Score, which was based on the following 10 items: study size, follow-up duration, number of surgical procedures, study design, diagnostic certainty, description of surgical procedures, description of postoperative rehabilitation, outcome measures, outcome assessment, and selection process. The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 4

5 Cost-Effectiveness of Osteochondral Allograft for the Ankle No economic evaluations fulfilling the selection criteria were found. Clinical Benefits and Harms of Osteochondral Allograft for the Knee A total of four SRs 3,8-10 provided information on the clinical effectiveness and safety of osteochondral allograft transplantation for the knee. Study Design The SRs 3,8-10 included five cohort or case-series studies 8 or one, 9 three, 10 or 19 3 case-series studies. Although there was partial 3,8,10 or complete 9,10 overlap in the included studies across the SRs, to present all outcomes described, all four SRs 3,8-10 were included in this report. None of the SRs 3,8-10 included control groups. Three SRs 8-10 conducted searches up to 2014, , 8 or and were published in 2016, and the other SR 3 conducted searches up to 2012 and was published in Country of Origin Three SRs 8-10 were conducted in the US, and the other SR 3 was conducted in Canada. Patient Population The SRs 3,8-10 included patients with chondral 3,8-10 or osteochondral 8,9 lesions of the knee. One SR 8 included adults aged 15 to 69 years, most of who had undergone one or more prior interventions on the knee. Two SRs, 9,10 with overlapping patient populations, included athletic adults, with a mean age of 33 years and 1.33 previous knee surgeries on average. One SR 3 included adults aged 20 to 62 years, with 1.7 previous knee surgeries on average. Interventions and Comparators The SRs 3,8-10 included osteochondral allograft transplantation as the intervention and compared it to before the operation. One SR 8 included fresh allografts only, another SR 3 included fresh, prolonged-fresh, and fresh-frozen allografts, and the other SRs 9,10 did not specify any restriction on the type of allograft. Three SRs 3,8,10 reported that some patients were treated with concomitant procedures, including tibial tubercle transfer and extensor mechanism realignment, 8 osteotomy, 3,8 meniscal transplantation, 3,8 ligamentous reconstruction, 10 and retinacular release. 3 Outcomes The SRs 3,8-10 included various measures of knee pain and function, including the hospital special surgery (HSS) score, 8 Knee Society score (KSS), 8 Lysholm score, 3,8 knee injury and osteoarthritis outcome score (KOOS), 9,10 International Knee Documentation Committee (IKDC) score, 3,9 Marx score, 9 and Tegner scale score. 3,10 Three SRs 8-10 included return-to-activities 8 or return-to-sports 9,10 rates. Three SRs 3,8,9 included complication, 3,8,9 reoperation, 8,9 and failure 3,8 rates. Two SRs 3,8 included survival rates. One SR 3 included patient satisfaction rates. The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 5

6 One SR 8 included long-term follow-up only and reported a mean follow-up of 12.3 years, whereas the other SRs 3,9,10 reported a mean follow-up of 32 months to 58 months. The SRs 3,8-10 conducted quality assessment of the included studies, using the Coleman Methodology Score. Cost-Effectiveness of Osteochondral Allograft for the Knee No economic evaluations fulfilling the selection criteria were found. Clinical Benefits and Harms of Osteochondral Allograft for the Shoulder One SR 11 provided information on the clinical effectiveness and safety of osteochondral allograft transplantation for the shoulder. Study Design The SR 11 included three case-series studies, with no control groups. The SR 11 conducted searches up to 2014 and was published in Country of Origin The SR 11 was conducted in Italy. Patient Population The SR 11 included adult patients, aged 32 to 56 years, with shoulder instability. The SR 11 did not report on prior interventions on the shoulder. Interventions and Comparators The SR 11 included osteochondral allograft transplantation as the intervention and compared it to before the operation. The SR 11 did not specify any restriction on fresh or frozen allografts. Outcomes The SR 11 included various measures of shoulder pain and function, including the Constant score, recurrence rate of shoulder instability, and range of shoulder motion. The SR 11 also included complication rates. The SR 11 reported a mean follow-up of 54 months to 68 months across the included studies and conducted quality assessment of the included studies, using the Coleman Methodology Score. Cost-Effectiveness of Osteochondral Allograft for the Shoulder No economic evaluations fulfilling the selection criteria were found. Summary of Critical Appraisal A summary of the critical appraisal of the included literature is presented in Appendix 3. The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 6

7 Clinical Benefits and Harms of Osteochondral Allograft for the Ankle The two SRs 6,7 on osteochondral allograft transplantation for the ankle were of mixed quality, based on the assessment conducted with the AMSTAR tool. 4 One SR 6 conducted triplicate study selection, provided a list of the included studies and their characteristics, and used appropriate methods to combine data but did not describe data extraction, provide a search strategy or a flow diagram for the search results, or assess the scientific quality of the included studies. The other SR 7 conducted duplicate data extraction, provided a detailed search strategy and a flow diagram for the search results, and assessed the scientific quality of the included studies but did not conduct duplicate study selection, provide a list of the included studies or their characteristics, or describe the methods used to combine data. Neither of the SRs 6,7 provided an a priori design, conducted a comprehensive literature search, listed the excluded studies, or addressed publication bias. Both SRs 6,7 disclosed potential conflicts of interest. Clinical Benefits and Harms of Osteochondral Allograft for the Knee The four SRs 3,8-10 on osteochondral allograft transplantation for the knee were of mixed quality, based on the assessment conducted with the AMSTAR tool. 4 Most or all of the SRs provided a detailed search strategy, 3,8,10 a flow diagram for the search results, 3,8,10 or a list of the included studies and their characteristics; 3,8-10 used appropriate methods to combine data; 3,8-10 or assessed the scientific quality of the included studies. 3,8-10 However, none of the SRs 3,8-10 provided an a priori design, conducted a comprehensive literature search or fully duplicate study selection and data extraction, listed the excluded studies, or addressed publication bias. Three SRs 8,9,11 disclosed potential conflicts of interest. Clinical Benefits and Harms of Osteochondral Allograft for the Shoulder The one SR 3 on osteochondral allograft transplantation for the shoulder was of mixed quality, based on the assessment conducted with the AMSTAR tool. 4 The SR 3 conducted triplicate study selection and data extraction and a comprehensive literature search; provided a flow diagram for the search results and a list of the included studies and their characteristics; used appropriate methods to combine data; assessed the scientific quality of the included studies; and declared no conflict of interest. However, the SR 3 did not provide an a priori design, a detailed search strategy, or a list of the excluded studies and did not address publication bias. Summary of Findings A summary of the findings of the included literature is presented in Appendix 4. What is the clinical effectiveness regarding the use of osteochondral allograft for the ankle? Pain and Functional Outcomes One SR 6 reported that patients with osteochondral lesions of the ankle experienced improved pain and functional outcomes after osteochondral allograft transplantation, compared to before, assessed by the mean AOFAS, FFI, and VAS pain scores. Another SR 7 reported that the postoperative median AOFAS score indicated good to excellent results from the operation but did not provide the preoperative score. The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 7

8 Patient Satisfaction Rates One SR 6 reported that 70.5% of patients with osteochondral lesions of the ankle reported good to excellent satisfaction with the operation. Reoperation and Failure Rates One SR 6 reported that 25.3% of patients with osteochondral lesions of the ankle required at least one reoperation of any kind, with 8.8% of ankles requiring arthrodesis (i.e., ankle fusion) and arthroplasty (i.e., ankle replacement). The SR 6 reported that 13.2% of all operations were considered failures, defined as postoperative graft nonunion or resorption or persistence of symptoms leading to subsequent arthrodesis or arthroplasty. What is the clinical effectiveness regarding the use of osteochondral allograft for the knee? Pain and Functional Outcomes Four SRs 3,8-10 reported that patients with chondral 3,8-10 or osteochondral 8,9 lesions of the knee experienced improved pain and functional outcomes after osteochondral allograft transplantation, compared to before, assessed by the mean KSS, 8 Lysholm, 3,8 KOOS, 10 IKDC, 3,9 Marx, 9 and Tegner scale 3 scores. One SR 8 reported that the postoperative HSS 8 score indicated good results from the operation but did not provide the preoperative score. Survival Rates Two SRs 3,8 reported that patients with chondral 3,8 or osteochondral 8 lesions of the knee had 91-95%, 76-85%, and 71-76% survival rates at five, 10, and 15 years after the operation. One SR 8 reported that the largest decrease in estimated survival occurred between the 15- and 20-year time-points from 71% to 45%, respectively. No information on the relationship between the intervention and survival were provided, and no control group was used to determine how these rates might differ from the general population. Return-to-Activities and Return-to-Sports Rates One SR 8 reported that patients with chondral or osteochondral lesions of the knee returned to non-weight-bearing activities after 8.4 weeks on average and full activities after 5.9 months on average following the operation. It was unclear whether any patients were unable to return to full activities. Another SR 9 reported that the majority of the patients had returned to sports and to preinjury-level performance by 30 months and 9.6 months following the operation, respectively. Patient Satisfaction Rates One SR 3 reported that 86% of patients with chondral lesions of the knee reported being extremely or mostly satisfied with the operation. Complication, Reoperation, and Failure Rates Two SRs 3,8 reported complications after the operation, with two cases of infection 8 and 2.4% of knees having infections, deep vein thrombosis, hyperemic reaction, or early loosening of the graft. 3 One SR 9 reported that no complications were identified. The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 8

9 One SR 8 reported that 36% of patients had reoperations, including knee arthroplasty, meniscus surgery, and ligament reconstruction. One SR 9 reported that no reoperations were identified. Two SRs 3,8 reported that 25% of all operations 8 or 18% of knees that had operations 3 were considered failures that required conversion to knee arthroplasty or graft revision or removal. What is the clinical effectiveness regarding the use of osteochondral allograft for the shoulder? Pain and Functional Outcomes One SR 11 reported that patients with shoulder instability scored high on the Constant score after osteochondral allograft transplantation but did not provide the preoperative score. The SR 11 reported that no patient experienced recurrence of shoulder instability after the operation and that the range of motion of the arm was restored or increased after the operation, compared to before the operation. Complication Rates One SR 11 reported that 74% of patients with shoulder instability had complications after the operation. Complications included spontaneous avascular necrosis and collapse, persistent pain, clicking, catching, stiffness, and flattening. Limitations There was partial or full overlap in the included studies across six SRs 3,6-10. To present all outcomes included, all six SRs 3,6-10 were included in this report, and care was taken to avoid presenting redundant findings, where possible. Nevertheless, there may be redundancy in the study findings presented in this report. Most, if not all, of the studies included in the SRs were of the retrospective, case-series type, with no control groups. Therefore, the data reported by the SRs were generally preoperative and postoperative values, or differences between, before and after the operation. Two SRs 7,8 only reported postoperative values for pain and functional outcomes, probably because their included studies did not report preoperative values. 3,6 Further, two SRs 3,8 reported survival rates of patients following the operation, with no comparison to the baseline survival rates of individuals matched on age and other demographic factors. Therefore, the improvements observed following the operation may not be fully attributable to the intervention itself, and the impact of the intervention on survival rates is unclear. The patient populations included in the SRs were not always in full agreement with the selection criteria of this report. For example, the age ranges were either not within 18 to 55 years or not reported, and whether patients were healthy and active and prior interventions were not always reported. 7,11 Because selecting the literature based on the terms healthy, active, and ages of years outlined in Table 1 was found to be too restrictive, only articles focusing on specific diseases, children, or seniors were excluded. For articles missing information on prior interventions, it was assumed that the patients had failed non-surgical or other surgical therapies for damaged articular cartilage. 3 Therefore, the findings presented in this report may not be entirely applicable to the specific population of interest described in Table 1. The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 9

10 The term osteochondral appears to be used in the literature to indicate osteochondral (i.e., bone and cartilage), osseous (i.e., bone only), and chondral (i.e., cartilage only) surgery. The SRs included in this report listed osteochondral surgery as their intervention of interest but did not always fully describe what types of allografts were transplanted. Further, three SRs 3,8,10 reported that the operation had concomitant procedures. It is unclear whether the other SRs 6,7,9,11 failed to report concomitant procedures or if their included studies did not have any. Therefore, the findings presented in this report may not be solely attributable to osteochondral allograft transplantation. All seven SRs 3,6-11 identified heterogeneity in the patients populations (e.g., age, 11 functional abilities, 11 and lesion types 10 ) and outcome measures (i.e., different scales for pain and function or different definitions for failures 3 ) across the included studies as a concern that precluded a meta-analysis. 8 One SR 7 noted that a total of 38 different scoring systems were used to assess pain and functions outcomes in its included studies. Although four SRs 8-11 reported that their included studies were assessed to be of fair 8-10 or good 11 quality, based on the Coleman Methodology Score, several SRs 3,7,9,11 indicated that the current literature is of poor quality and with small samples. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING Two, four, and one SRs were found on clinical benefits and harms of osteochondral allograft transplantation for the ankle, knee, and shoulder, respectively. For all three joints, while the operation can improve pain and functional outcomes, with a high level of patient satisfaction, high rates of complications, reoperations, and clinical failures were reported. For the knee, decreasing survival rates over time were reported, with the largest drop estimated to occur between 15 and 20 years after the operation, though rates for a population not receiving osteochondral allografts were not reported, and a wide range of six to 30 months was reported as the time it took to return to activities or sports. The quality of the SRs was mixed, and the quality of the primary studies included in those SRs was generally poor, warranting caution in the interpretation of the findings. Prospective comparative studies with large samples, longer follow-up, and high quality are needed to confirm and clarify the findings presented in this report. No economic evaluations fulfilling the selection criteria were found. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 10

11 REFERENCES 1. Articular cartilage restoration. In: OrthoInfo [Internet]. Rosemont (IL): American Academy of Orthopaedic Surgeons; 2009 [cited 2017 Feb 9]. Available from: 2. Surgical treatment options (microfracture, drilling, mosaicplasty, and allograft transplantation) for cartilage injuries of the knee in adults. In: Our evidence [Internet]. London: The Cochrane Collaboration; 2016 Sep 3 [cited 2017 Jan 18]. Available from: 3. Chahal J, Gross AE, Gross C, Mall N, Dwyer T, Chahal A, et al. Outcomes of osteochondral allograft transplantation in the knee. Arthroscopy Mar;29(3): Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol [Internet]. 2007;7:10. Available from: 5. Gracitelli GC, Moraes VY, Franciozi CE, Luzo MV, Belloti JC. Surgical interventions (microfracture, drilling, mosaicplasty, and allograft transplantation) for treating isolated cartilage defects of the knee in adults. Cochrane Database Syst Rev Sep 3;9:CD VanTienderen RJ, Dunn JC, Kusnezov N, Orr JD. Osteochondral allograft transfer for treatment of osteochondral lesions of the talus: a systematic review. Arthroscopy Jan;33(1): Pinski JM, Boakye LA, Murawski CD, Hannon CP, Ross KA, Kennedy JG. Low level of evidence and methodologic quality of clinical outcome studies on cartilage repair of the ankle. Arthroscopy Jan;32(1): Assenmacher AT, Pareek A, Reardon PJ, Macalena JA, Stuart MJ, Krych AJ. Long-term outcomes after osteochondral allograft: a systematic review at long-term follow-up of 12.3 years. Arthroscopy Oct;32(10): Campbell AB, Pineda M, Harris JD, Flanigan DC. Return to sport after articular cartilage repair in athletes' knees: a systematic review. Arthroscopy Apr;32(4): Krych AJ, Pareek A, King AH, Johnson NR, Stuart MJ, Williams RJ, III. Return to sport after the surgical management of articular cartilage lesions in the knee: a meta-analysis. Knee Surg Sports Traumatol Arthrosc Aug Longo UG, Loppini M, Rizzello G, Ciuffreda M, Berton A, Maffulli N, et al. Remplissage, humeral osteochondral grafts, weber osteotomy, and shoulder arthroplasty for the management of humeral bone defects in shoulder instability: systematic review and quantitative synthesis of the literature. Arthroscopy Dec;30(12): The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 11

12 APPENDIX 1: Selection of Included Studies 150 citations identified from electronic literature search and screened 126 citations excluded 24 potentially-relevant articles retrieved for scrutiny (full text, if available) 0 potentially-relevant reports retrieved from other sources (i.e., grey literature or hand search) 24 potentially-relevant reports 17 reports excluded due to: irrelevant population (1) irrelevant intervention (5) irrelevant study design (i.e., nonsystematic reviews) (10) already included in at least one of the selected reports (1) 7 reports included in review The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 12

13 APPENDIX 2: Characteristics of Included Publications First Author, Publication Year, Country Ankle VanTienderen US Pinski US Types and Numbers of Primary Studies Included SR of 5 case-series studies, published between 2009 and 2012 No quality assessment SR of 13 studies* Quality assessment using modified Coleman Methodology Score Table A1: Characteristics of Included Systematic Reviews Population Characteristics 90 adult* patients, 74 of who had undergone one or more prior interventions**, with large osteochondral lesions of 91 ankles in total *Aged 17 to 74 years **Including arthroscopic microfractures, osteochondral autograft procedures, bone grafting procedures, ankle fracture fixations, and talar fracture fixations 267 patients* with osteochondral lesions of the ankle, with no information on prior interventions *Age: NR Intervention Comparator(s) Clinical Outcomes, Length of Follow-Up Osteochondral allograft* transplantation *Fresh only Osteochondral allograft transplantation Before operation Before operation AOFAS score, FFI score, VAS pain score, patient satisfaction rate, reoperation rate, and failure rate Mean follow-up of 45±3.3 months (range: 6-91 months) AOFAS score Follow-up duration: NR *While this SR included 83 studies in total, 70 of them were on irrelevant interventions. Most of 83 the included studies were case- The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 13

14 First Author, Publication Year, Country Knee Assenmacher US Types and Numbers of Primary Studies Included series, published between 1980 and SR of 1 cohort and 4 case-series studies, published between 1997 and 2015 Quality assessment using modified Coleman Methodology Score Table A1: Characteristics of Included Systematic Reviews Population Characteristics 291 adult* patients, the majority of who had undergone one or more prior interventions**, with chondral or osteochondral defects of 301 knees in total *Aged 15 to 69 years **Including open reduction and internal fixations, meniscectomy, arthrotomy, arthroscopy, osteotomy, debridement, microfractures, ACI, loose body removal, meniscal surgery, extensor alignment, chondroplasty, lateral release, tibial tubercle transfer, and ligament reconstruction Intervention Comparator(s) Clinical Outcomes, Length of Follow-Up Osteochondral allograft* transplantation** *Fresh only **Concomitant procedures were reported in 39% (tibial tubercle transfer and extensor mechanism realignment), 25% (distal femoral osteotomy), 15% (proximal tibial osteotomy), or 18% (meniscal allograft transplantation) of the patients. Before operation HSS score, KSS-F score, KSS-K score, Lysholm score, survival rate, returnto-activities rate, complication rate, reoperation* rate, and failure** rate Mean follow-up of 12.3 years (range: years)*** *Defined as any surgery on the same knee, whether it was related or unrelated to the intervention **Defined as conversion to unicompartmental or total knee arthroplasty, repeat cartilage restoration, imaging evidence of osteochondral allograft reabsorption or collapse revision graft fixation, graft removal, HSS scores >70, or both KSS and Lysholm scores >70 The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 14

15 First Author, Publication Year, Country Types and Numbers of Primary Studies Included Table A1: Characteristics of Included Systematic Reviews Population Characteristics Intervention Comparator(s) Clinical Outcomes, Length of Follow-Up ***Studies with a minimum mean follow-up of 9 years were included. Campbell US Krych US SR of 1 case-series study*, published in 2012 Quality assessment using Coleman Methodology Score *While this SR included 20 studies in total, 19 of them were on irrelevant interventions. SR of 3 case-series studies*, published between 2007 and 2015 Quality assessment using modified Coleman Methodology Score *While this SR included 44 studies in total, 41 of them were on irrelevant 43 athletic* adult** patients, who had 1.1 previous surgeries*** on average, with chondral defects or osteochondritis dissecans of the knee *Playing professional, collegiate, or recreational sports **Aged 18 to 49 years ***Not defined 96 athletic* adult** patients, who had 1.33 previous surgeries*** on average, with chondral defects of the knee *Playing mostly recreational sports **Mean age of 33±1 years ***Not defined Osteochondral allograft transplantation Osteochondral allograft* *60% of the patients had concomitant procedures, with ligamentous reconstruction being the most common. Before operation Before operation KOOS ADL score, IKDC-S score, Marx score, returnto-sports rate and performance, complication rate, and reoperation rate Mean follow-up of 2.5 years KOOS score, Tegner activity scale score, and return-to-sports rate Mean follow-up of 32±4 months (range: months)* *Studies with a minimum mean follow-up of 2 years were included. The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 15

16 First Author, Publication Year, Country Types and Numbers of Primary Studies Included interventions. Table A1: Characteristics of Included Systematic Reviews Population Characteristics Intervention Comparator(s) Clinical Outcomes, Length of Follow-Up Chahal Canada Shoulder Longo Italy SR of 19 caseseries studies, published between 1985 and 2012 Quality assessment using modified Coleman Methodology Score SR of 3 case series studies*, published between 1996 and 2010 Quality assessment Unknown number of adult* patients, who had 1.7 previous surgeries** on average, with chondral defects*** of 595 knees in total *Aged 20 to 62 years **Including debridement, loose body removal, microfractures, and lesion fixations ***Indications including post-traumatic defects, osteochondritis dissecans, osteonecrosis from all causes, idiopathic causes, osteoarthritis, and chondromalacia patella 23 adult* patients with posterior shoulder instability**, with no information on prior interventions Osteochondral allograft* transplantation** *Including fresh, prolonged fresh, and fresh frozen **46% of the patients had concomitant procedures, including osteotomy, meniscal transplantation, and retinacular release. Osteochondral allograft transplantation Before operation Before operation IKDC score, Lysholm score, Tegner scale score, survival rate, patient satisfaction rate, complication rate, and failure rate Mean follow-up of 58 months (range: months)* *Studies with a minimum mean follow-up of 12 months were included. Constant score, recurrence rate of shoulder instability, range of motion, and complication rate Mean follow-up of The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 16

17 First Author, Publication Year, Country Types and Numbers of Primary Studies Included using modified Coleman Methodology Score *While this SR included 26 studies in total, 23 of them were on irrelevant interventions. Table A1: Characteristics of Included Systematic Reviews Population Characteristics *Mean age of years (range: years) **Associated with Hill- Sachs or other types of fracture Intervention Comparator(s) Clinical Outcomes, Length of Follow-Up months (range: months) ACI = autologous chondrocyte implantation; ADL = activity of daily living; AOFAS = American Orthopaedic Foot and Ankle Society; FFI = foot functional index; HSS = hospital for special surgery; IKDC = International Knee Documentation Committee; IKDC-S = International Knee Documentation Committee-subjective; KOOS = knee injury and osteoarthritis outcome scale; KSS-F = Knee Society function score; KSS-K = Knee Society knee score; NR = not reported; SR = systematic review; US = United States; VAS = visual analog scale The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 17

18 APPENDIX 3: Critical Appraisal of Included Publications Table A2: Strengths and Limitations of Included Systematic Reviews Using AMSTAR 4 Strengths Limitations Ankle VanTienderen There was triplicate study An a priori design was not provided. selection. It is unclear whether data extraction was performed by A list of the included studies more than one reviewer. and their characteristics were provided. Although several literature databases were searched, grey literature was not included. Neither a search The methods used to combine the study findings were strategy nor a flow diagram for the search results was provided. appropriate. A list of the excluded studies was not provided. The scientific quality of the included studies was not assessed. The scientific quality of the included studies was not used in formulating conclusions. The likelihood of publication bias was not assessed. One of the authors disclosed a potential conflict of interest, receiving support from a medical device company. Pinski There was duplicate data An a priori design was not provided. extraction. There was no duplicate study selection. A detailed search strategy and a flow diagram for the search Although several literature databases were searched, grey literature was not included. results were provided. A list of the included studies and their characteristics The scientific quality of the were not provided. included studies was assessed A list of the excluded studies was not provided. and documented. The methods used to combine the study findings were The scientific quality of the not described. included studies was used The likelihood of publication bias was not assessed. appropriately in formulating One of the authors disclosed potential conflicts of conclusions. interest, receiving support from a medical device company and private donors. Knee Assenmacher A detailed search strategy and An a priori design was not provided. a flow diagram for the search results were provided. There was no duplicate study selection or data extraction. A list of the included studies and their characteristics were Although several literature databases were searched, grey literature was not included. provided. A list of the excluded studies was not provided. The scientific quality of the The likelihood of publication bias was not assessed. included studies was assessed Three of the authors disclosed potential conflicts of and documented. interest, receiving support from medical device The scientific quality of the companies. The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 18

19 Table A2: Strengths and Limitations of Included Systematic Reviews Using AMSTAR 4 Strengths Limitations included studies was used appropriately in formulating conclusions. The methods used to combine the study findings were appropriate. Campbell There was duplicate data extraction. An a priori design was not provided. Although study selection was performed by multiple A list of the included studies and their characteristics were provided. authors, in the event of disagreement, decisions were made by the corresponding author, instead of through discussion and consensus. The scientific quality of the included studies was assessed and documented. The methods used to combine the study findings were appropriate. Krych A detailed search strategy and a flow diagram for the search results were provided. A list of the included studies and their characteristics were provided. The scientific quality of the included studies was assessed and documented. The scientific quality of the included studies was used appropriately in formulating conclusions. The methods used to combine the study findings were appropriate. Chahal Data were extracted by one reviewer and verified by another. A detailed search strategy and a flow diagram for the search Although several literature databases were searched, grey literature was not included. Neither a search strategy nor a flow diagram for the search results was provided. A list of the excluded studies was not provided. The scientific quality of the included studies was not used in formulating conclusions. The likelihood of publication bias was not assessed. Two of the authors disclosed potential conflicts of interest, receiving support from medical device and publishing companies. An a priori design was not provided. There was no duplicate study selection and no duplicate data extraction. Although several literature databases were searched, grey literature was not included. A list of the excluded studies was not provided. The likelihood of publication bias was not assessed. Four of the authors disclosed potential conflicts of interest, receiving support from medical device companies and serving on various government, interest group, or journal boards. An a priori design was not provided. There was no duplicate study selection. Although several literature databases were searched, grey literature was not included. A list of the excluded studies was not provided. The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 19

20 Table A2: Strengths and Limitations of Included Systematic Reviews Using AMSTAR 4 Strengths Limitations results were provided. The likelihood of publication bias was not assessed. A list of the included studies and their characteristics were provided. The scientific quality of the included studies was assessed and documented. The scientific quality of the included studies was used appropriately in formulating conclusions. The methods used to combine the study findings were appropriate. No conflict of interest was declared. Shoulder Longo There was triplicate study An a priori design was not provided. selection and data extraction. A detailed search strategy was not provided. A comprehensive literature A list of the excluded studies was provided. search, including grey literature, was performed. The likelihood of publication bias was not assessed. A flow diagram for the search results was provided. A list of the included studies and their characteristics were provided. The scientific quality of the included studies was assessed and documented. The scientific quality of the included studies was used appropriately in formulating conclusions. The methods used to combine the study findings were appropriate. No conflict of interest was declared. AMSTAR = Assessment of Multiple Systematic Review s The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 20

21 APPENDIX 4: Main Study Findings and Authors Conclusions Table A3: Summary of Findings of Included Systematic Reviews Main Study Findings Authors Conclusions Ankle VanTienderen Pain and Functional Outcomes The mean AOFAS score, reported by three studies, improved from 48 to 80 between before and after the operation (p < ). The mean FFI score, reported by one study, improved from 5.56 to 2.01 between before and after the operation (no p-value provided). The mean VAS pain score, reported by three studies, improved from 7.1 to 2.7 between before and after the operation (p < ). Patient Satisfaction Rates Across four studies, 70.5% of patients (i.e., 62/88) reported good to excellent satisfaction with the operation. Reoperation and Failure Rates Across five studies, 25.3% of ankles (i.e., 23/91) required at least one reoperation, for a total of 28 operations. Reoperations included arthrodesis (i.e., ankle fusion) and arthroplasty (i.e., ankle replacement) on eight ankles. The most common indications for reoperations were development of moderate to severe osteoarthritis (14%), pain due to hardware (9%), extensive graft collapse (3%), and delayed or nonunion of osteotomy site (1%). Across five studies, 13.2% of all operations (i.e., 12/91) were considered failures. Failures were defined as postoperative graft nonunion or resorption or persistence of symptoms leading to subsequent arthrodesis or arthroplasty. Pinski Pain and Functional Outcomes The median AOFAS score, reported by 13 studies, was about 80 after the operation (data presented as bar graphs only). Study Quality The mean modified Coleman Methodology Fresh bulk osteochondral allograft transplantation of the ankle can substantially improve functional status and effectively prevent or delay the eventual need for ankle arthrodesis or replacement. However, patients must be carefully selected and counselled on the morbidity of the procedure, as well as the high incidence of clinical failures and need for reoperations. Most studies reported good to excellent results from osteochondral allograft transplantation of the ankle. Most studies reporting surgical treatment outcomes were of low levels of evidence and low methodological quality. The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 21

22 Table A3: Summary of Findings of Included Systematic Reviews Main Study Findings Authors Conclusions Score for the 13 included studies was 55.1 on a scale of 100 and considered poor quality. Knee Assenmacher Pain and Functional Outcomes The mean HSS score, reported by three studies, was 84.1 after the operation. The mean change was 23.1 in the KSS-F score (95% CI = 10.1 to 36.0, p < 0.01), 26.4 in the KSS-K score (95% CI = 10.4 to 12.3 years after surgery. 42.4, p < 0.01), and 53 in the Lysholm score (95% CI = 27.4 to 78.6, p < 0.01) between before and after the operation, all indicating improvements. Survival Rates The mean survival rate at 5, 10, 15, and 20 years after the operation, reported by three studies, was 94%, 84%, 71%, and 45%, respectively. The largest decrease in estimated survival occurred between the 15- and 20-year time-points. Return-to-Activities Rates Across four studies, patients returned to non-weight-bearing activities after a mean of 8.4 weeks following the operation. Patients returned to full activities, defined as clearance to return to sports, after a mean of 5.9 months following the operation. Complication, Reoperation, and Failure Rates Across two studies, two cases of infection after the operation were reported. One was deep infection, and the other was superficial cellulitis. Across five studies, 36% of patients had reoperations. Reoperations included unicompartmental or total knee arthroplasty (37%), debridement (24%), graft removal, fixation, or revision (14%), symptomatic hardware removal (9%), meniscus surgery (6%), patellofemoral realignment procedures (3%), and ligament reconstruction (4%). Across five studies, 25% of all operations were considered failures. Failures included conversion to unicompartmental (4%) or Osteochondral allograft transplantation of the knee demonstrated significant improvements in clinical outcome scores and good durability with successful outcomes in the majority of the patients at The orthopaedic literature is limited by heterogeneity in surgical techniques, lesion and patient characteristics, and reporting of non-standardized outcome measures. The Use of Osteochondral Allograft for the Talus, Knee, and Shoulder 22