A Randomized Multicenter Trial Comparing Autologous Chondrocyte Implantation with Microfracture: Long-Term Follow-up at 14 to 15 Years

Knutsen, Gunnar MD, PhD; Drogset, Jon Olav MD, PhD; Engebretsen, Lars MD, PhD; Grøntvedt, Torbjørn MD, PhD; Ludvigsen, Tom C. MD; Løken, Sverre MD, PhD; Solheim, Eirik MD, PhD; Strand, Torbjørn MD; Johansen, Oddmund MD, PhD

Journal of Bone & Joint Surgery - American Volume:
doi: 10.2106/JBJS.15.01208
Scientific Articles
Abstract

Background: The management of cartilage and osteochondral lesions in the knee remains problematic and controversial. Our group reported the 2-year and 5-year results of a randomized controlled trial comparing autologous chondrocyte implantation (ACI) and microfracture in patients with focal femoral cartilage injuries. The objective of the present study was to report the long-term results.

Methods: Eighty patients with a single symptomatic chronic cartilage defect on the femoral condyle without general osteoarthritis were included in the study at the time of the index operation (January 1999 to February 2000). We used the International Cartilage Repair Society (ICRS), Lysholm, Short Form-36 (SF-36), and Tegner forms to collect data at the time of inclusion and at follow-up evaluations. Standing weight-bearing radiographs were evaluated for evidence of osteoarthritis according to the method described by Kellgren and Lawrence. For the long-term follow-up in 2014, we used the Synaflexer frame to standardize the radiographs. The operation was considered to have failed if a reoperation was performed because of symptoms from a lack of healing of the treated defect.

Results: At the long-term follow-up evaluation, no significant differences between the treatment groups were detected with respect to the results on the clinical scoring systems. At the 15-year evaluation, there were 17 failures in the ACI group compared with 13 in the microfracture group. We observed that more total knee replacements were needed in the ACI group than in the microfracture group (6 compared with 3). The surviving patients in both groups, i.e., those who had not had a failure, had significant improvement in the clinical scores compared with baseline. Fifty-seven percent of the surviving patients in the ACI group and 48% of such patients in the microfracture group had radiographic evidence of early osteoarthritis (a Kellgren and Lawrence grade of ≥2); the difference was not significant.

Conclusions: The survivors in both groups improved their clinical scores in the short, medium, and long-term evaluations, and no significant difference between the groups was found at the long-term follow-up. The risk of treatment failure and the frequency of radiographic osteoarthritis are problematic. Our findings raise serious concerns regarding the efficacy of these procedures in delaying osteoarthritis and preventing further surgery. Continued basic and clinical research is needed in this field.

Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Author Information

1University of Tromsø – The Arctic University of Norway and University Hospital North-Norway, Tromsø, Norway

2St. Olav’s Hospital, Trondheim University Hospital, Trondheim, Norway

3Oslo University Hospital, Oslo, Norway

4Deaconess University Hospital Bergen, Bergen, Norway

E-mail address for G. Knutsen: gunnar.knutsen@unn.no

Article Outline

The hyaline cartilage and the synovial fluid result in a smooth gliding surface with very low friction in the joint. Damage to the cartilage may cause pain, swelling, and catching1. Several studies have shown that cartilage injuries over time increase the risk of osteoarthritis2. Over the last two decades, tissue engineering and cartilage repair have been a focus of researchers all over the world. Despite all efforts, so far no technique that can reproducibly regenerate normal hyaline cartilage in adults has been established3. A myriad of different new procedures as well as newer generations of previously used methods have been introduced. However, to date, no method has been judged to be superior to others. In addition, no surgical treatment been shown to be better than rehabilitation alone4. A randomized controlled trial (RCT) is regarded as the best method to detect clinical differences between treatments; however, external validity may be of concern5.

Microfracture, the most widely used marrow-stimulation procedure, has been rated by many as the first-line treatment for smaller, contained cartilage lesions6-11. Autologous chondrocyte implantation (ACI) and newer-generation cell-based techniques, including the use of stem cells instead of chondrocytes, are indicated for larger lesions according to many surgeons12-22.

Over the last several years, we also have seen the development of newer generations of microfracture, or marrow stimulation-procedures, including combinations with scaffolds23-25. These techniques are cell-based in contrast to osteochondral grafting (autogenous grafts or allografts)26,27.

In 2004 and 2007, our group reported the 2-year and 5-year results, respectively, of an RCT comparing ACI and microfracture in the treatment of focal cartilage defects in the knee28,29. At the time of the more recently reported follow-up study in 2007, we had not found a significant difference between the treatment groups with respect to the clinical results, and both groups had a 23% rate of treatment failures. The 2-year follow-up included biopsy and histological evaluation. There was a tendency for the ACI procedure to result in more hyaline-like repair, but the difference was not significant.

At the 5-year mark, a better-quality cartilage (compared with histological findings at the 2-year follow-up) was associated with a reduced risk of later failure.

After >20 years of modern cartilage repair procedures worldwide, these techniques have not been proven to reduce the risk of osteoarthritis3. The patients in this study underwent ACI or microfracture between January 1999 and February 2000, and the purpose of this update was to evaluate the long-term clinical results and radiographic evidence of osteoarthritis. In this context, we wanted to compare the groups. Our primary null hypothesis was that there would be no difference in the mean Lysholm score between the microfracture and ACI groups at the long-term follow-up evaluation.

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Materials and Methods

As described in detail in our previous reports28,29, 80 patients (40 patients in each group) with relatively large (range, 1.44 to 11.25 cm2) chronic focal cartilage defects in their knees were included in this RCT (Fig. 1). The inclusion and exclusion criteria and the baseline characteristics are listed in the Appendix. Further details regarding the 2 cohorts and the specifics of treatment are described in our previous reports.

The first author (G.K.) in collaboration with the surgeons from each center carried out the long-term follow-up evaluation during the period from March 2014 until March 2015 (14 to 15 years after treatment). However, the failure status for all patients was recorded after a minimum of 15 years following the index surgery. Twenty patients who were not able or willing to attend the follow-up evaluation in person were contacted by mail or telephone. Two patients were lost to follow-up.

As in the previous follow-up studies, we used the International Cartilage Repair Society (ICRS) form to collect demographic data and to record the history, symptoms, functional score, pain as indicated on a visual analog scale (VAS), and findings of the clinical examination. In addition, the Lysholm score, Tegner score, and Short Form-36 (SF-36) were used. As in our 2 previous publications, the surgery was considered to have failed if the patient needed a reoperation because of symptoms resulting from a lack of healing of the treated defect28,29. The need for shaving or trimming of a lesion was not considered a failure. The patients who had a failure were offered a new cartilage repair procedure, a high tibial osteotomy (HTO), or a total knee arthroplasty (Table I).

We also performed a modified failure analysis adding clinical failures (defined as a Lysholm score of ≤64) and also including the 2 patients lost to follow-up. The purpose for doing this was to study whether this modification influenced the comparison between the treatments. The Lysholm score refers to the rating scale developed by Tegner and Lysholm30, and the grading of the Lysholm score as poor, fair, good, and excellent was subsequently published in 199031. In the present study, a poor result was defined as a score of <65. Informed consent was obtained from all patients included in the study, and the study was approved by the National Review Board.

At the time of the final follow-up, standing radiographs, including those with the knee in 30° of flexion, were made using a standardized frame (Synaflexer; Synarc). The Synaflexer device was first registered internationally in 2007 and was not available for the earlier follow-up studies. We chose to use the Synaflexer device for this long-term follow-up study to try to identify all patients who had radiographic evidence of osteoarthritis. The Kellgren and Lawrence classification system was used32. A Kellgren and Lawrence grade of ≥2 was defined as radiographic osteoarthritis. Patients who had a failure had radiographs made, but they were not included in the results regarding radiographic osteoarthritis. The patients who did not return to the outpatient clinic did not have their planned radiographs at the long-term follow-up.

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Statistical Methods

The original sample-size estimation showed that 40 patients in each group would be required to demonstrate a difference in the Lysholm and SF-36 scores between the groups of ≥0.75 standard deviation from the mean, with an alpha level of 0.05 and a power level of 90%. T tests, the Pearson chi-square and Mann-Whitney U tests, and multiple linear regression models were used. The level of significance was p < 0.05.

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Results

The failure rate at 15 years (March 2015) after the index surgery was 42.5% (n = 17) in the ACI group and 32.5% (n = 13) in the microfracture group (Fig. 2); the difference was not significant (p = 0.356). Two patients in the microfracture group who had not had a failure after 5 years were lost to follow-up, resulting in a loss-to-follow-up rate of 2.5%. The modified failure analysis also showed no difference between treatments (p = 0.366).

Six patients in the ACI group and 3 in the microfracture group had received a total knee replacement. Four patients in each group had had an HTO in the study period.

We found differences in failure rates at the 4 hospitals (30%, 35%, 40%, and 45%, in random order), but they were not significant. One center had a failure rate of 60% in the ACI group compared with failure rates of 30% to 40% following this procedure in the other 3 centers. The clinical status of the patients who had a failure is given in Table I.

The survivors, i.e., those who had not had a failure, in both groups had significant improvement in the clinical scores (Lysholm, VAS for pain, and SF-36 physical component score) at the short, medium, and long-term evaluations (p < 0.05). No significant difference between the treatment groups was found with respect to the Lysholm score (Fig. 3), VAS pain score (Fig. 4), or SF-36 physical component score (Fig. 5). At the latest follow-up, both groups had a median Tegner score of 4, representing the ability to participate in recreational cycling, cross-country skiing, and jogging twice a week on an even surface. Figure 6 shows the Lysholm score for the survivors at the different time points.

At the same time point, approximately 50% of the patients who had not had a failure had early radiographic signs of osteoarthritis, defined as a Kellgren and Lawrence grade of ≥2. There was no significant difference between the groups, although the microfracture group had the lowest frequency of osteoarthritis (48% versus 57%). Among the survivors, 20 patients (13 in the ACI group and 7 in the microfracture group) had not had planned radiographs made because they did not return to the outpatient clinic; however, they were contacted by mail or telephone to determine the clinical scores.

In contrast to the earlier follow-up studies, 1 failure occurred in a patient in the group that had repair tissue with the best histological quality. This patient had an HTO performed 9 years after the ACI. As a result, the association between histological quality and risk for later failure seen at 5 years was no longer significant.

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Discussion

The most important finding in this prospective randomized study of large chronic cartilage defects was that there were no major differences between microfracture and ACI. Further, it is remarkable that 30 of the 80 patients had treatment failure and that approximately 50% of the remaining patients (excluding 20 who had not returned for the final radiographic evaluation) had radiographic signs of early osteoarthritis at the latest follow-up. These findings raise serious concerns regarding the efficacy of these procedures in delaying osteoarthritis and preventing further surgery in this patient group. At the start of this study, we included only relatively large (median, 4.5 cm2), chronic lesions (median, 36-month duration of symptoms). In contrast to the study by Steadman et al., this study did not include any acute lesions9. The frequency of radiographic evidence of osteoarthritis in our study should be evaluated in light of the chronicity and size of the defects treated. Information regarding osteochondritis dissecans and osteoarthritis was discussed in our first study28. At the long-term follow-up, we did not find more radiographic evidence of osteoarthritis in the osteochondritis dissecans group (using linear regression). For the previous follow-up evaluations, standing radiographs with the knee in extension were used. This time, the use of standardized, fixed flexion standing radiographs (Synaflexer) may have identified more patients with early osteoarthritis33; however, this discrepancy has not influenced the comparison between groups.

Most studies have described good clinical results in the short and mid-term follow-up after different types of cartilage repair surgery; however, to our knowledge, this RCT is the first to compare ACI and microfracture with a follow-up as long as 14 to 15 years6-9,11-13,15,16,18,20-22,24,27,34,35. Compared with other studies with >10 years of follow-up, few patients (2.5%) were lost to follow-up. In our report on the results at 5 years, we used the intention-to-treat principle. However, clinical scores were missing at the time of failure in some cases. In addition, 17 of the patients underwent major surgery such as total knee replacement and HTO so their final score after surgery could not been used for comparison in this RCT.

The article by Brittberg et al. in The New England Journal of Medicine, introducing ACI and clinical tissue-engineering principles, had a positive impact in the orthopaedic community15. The enthusiasm and optimism in the 1990s and the first years of the new millennium have changed, and most clinicians and researchers realize that there is a long way to go before we can regenerate hyaline cartilage on a regular basis in adults3,36. On the other hand, ACI and its newer generations have been one of the more frequently studied modern surgical treatments in the two last decades. Many surgical techniques in daily use have never been tested in RCTs. Tissue engineering has become established, and it will hopefully lead to important clinical advances.

In the same period, microfracture gained popularity as a low-cost 1-stage procedure resulting in acceptable clinical results that seemed better than previous drilling procedures9,37.

Surgeons such as Haggart and Magnussen in the 1940s and Pridie in the 1950s used open debridement, abrasion, and drilling for cartilage repair38. The results reported by Pridie need to be compared with the results that we achieve today. He noted that 77% of his patients were satisfied with the result of their operation, and 64% rated the result as good at a mean follow-up of 6.5 years. Perhaps we need to realize that the progress since that time regarding clinical results is not so impressive.

Peterson et al. reported long-term results at a mean of 12.8 years following ACI21. Compared with our study, the rate of patients lost to follow-up was much higher (35%) and some preoperative data were missing. Information regarding failures and reoperations were lacking in that study. They reported that 92% of the patients were satisfied with the result and would have the operation again. The mean Lysholm score improved from 60.3 preoperatively to 69.5 postoperatively. Patients who had not had a failure in our study had a mean Lysholm score of 81.7 in the ACI group and 86.0 in the microfracture group at the last follow-up (Fig. 3). These numbers cannot be directly compared since (as explained above) our patients who had a failure are not included in the final analysis. Minas et al. reported that survivorship following ACI was 71%, and 75% of patients with symptomatic cartilage defects of the knee had improved function at a minimum of 10 years after surgery18.

Steadman et al. reported outcomes of microfracture for traumatic chondral defects of the knee after a mean of 11 years9. The mean Lysholm score had improved from 59 to 89, and 80% of the patients rated themselves as improved at 7 years postoperatively. This cohort (75 knees) consisted of 25% of the patients at their institution who were treated with microfracture during this period. Two patients were lost to follow-up, and 2 knees were considered treatment failures.

It is difficult to compare studies because of different design and patient characteristics. However, our study and the studies mentioned above do not indicate that one of the methods is better than the other.

Very few RCTs have described long-term results. In a mid-term outcome study comparing characterized chondrocyte implantation (CCI) and microfracture22, the clinical outcomes for CCI and microfracture at 5 years were comparable and in line with our findings. However, in the early treatment group, CCI was significantly better. No long-term results exist. So far, that study does not prove that the cell cultivation performed in vitro improves the outcome. The CCI study was very well designed and performed; however, it was conducted in cooperation with the cell-culture company TiGenix NV Belgium, which could be a potential bias.

Newer generations of both ACI and microfracture have been introduced12,23-25,39,40. Despite developments and enthusiasm from both industry and surgeons, the evidence that these techniques are really improvements is lacking. However, the trend to less invasive surgery for newer tissue-engineering approaches is a step forward, and 1-step procedures seem to be more popular than they were only a few years ago17.

At the 15-year follow-up, contrary to our 5-year results, we did not find a relationship between the likelihood of failure and the quality of the repair tissue evaluated after biopsies were performed at the 2-year follow-up. However, the numbers were small, and as mentioned above, the treatment failure in 1 patient in the group with the best-quality cartilage in the last follow-up period made the difference.

Our study has several limitations. The 2-year evaluation was performed by an independent observer, while the later follow-up examinations were performed by an author of the study. This may introduce a potential bias; however, as mentioned in our previous reports, this risk was reduced by using patient-based outcome questionnaires. Furthermore, the lack of a control group that was not treated with surgery is a limitation of our study. However, it is a major challenge to include such a group when the majority of patients have chronic pain and have already had some form of conservative treatment. External validity is problematic with RCTs, and in the future, register data could also help us in building up a better evidence base in this field. There is a need for innovation to reach our goal3.

The survivors in both groups had improved clinical scores at the short, intermediate, and long-term evaluations, and there was no significant difference between the ACI and microfracture groups at the long-term follow-up. The risk of treatment failure and the frequency of radiographic osteoarthritis are problematic. Our findings raise serious concerns regarding the efficacy of these procedures in delaying osteoarthritis and preventing further surgery. Continued basic and clinical research is needed in this field.

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Appendix Cited Here...

Tables showing the inclusion and exclusion criteria and the baseline data are available with the online version of this article as a data supplement at jbjs.org.

NOTE: The authors thank Tom Wilsgaard for statistical assistance and Ann Kristin Hansen for assistance with graphics.

Investigation performed at the University of Tromsø – The Arctic University of Norway and University Hospital North-Norway, Tromsø, St. Olav’s Hospital, Trondheim University Hospital, Trondheim, Oslo University Hospital, Olso, and Deaconess University Hospital Bergen, Bergen, Norway

A commentary by Freddie H. Fu, MD, and Ashish Soni, MD, FRCS, is linked to the online version of this article at jbjs.org.

Disclosure: A grant from the Norwegian Ministry of Health funded the study, and no other external funding sources are involved. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had other relationships or activities that could be perceived to influence, or have the potential to influence, what was written in this work.

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