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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 4  |  Page : 159-167

Meaningful effectiveness of platelet-rich plasma in treating patients with osteoarthritis of the knee: Meta-analysis and review


1 Neuroscience Center/Physical Medicine and Department of Rehabilitation, King Fahd Specialist Hospital, Dammam, Saudi Arabia
2 Independent Scientist, New Jersey, NJ, USA
3 Pathology, Microbiology, Immunology and Forensic Medicine, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA

Date of Submission26-Apr-2019
Date of Decision28-Jun-2019
Date of Acceptance02-Jul-2019
Date of Web Publication12-Nov-2019

Correspondence Address:
Abdulhafez Selim
Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jisprm.jisprm_58_19

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  Abstract 


Background: Osteoarthritis (OA) of the knee is a significant cause of disability. The current conservative treatment options include physiotherapy, analgesia, intra-articular injection of platelet-rich plasma (PRP), hyaluronic acid, or corticosteroids. Regarding PRP, some meta-analyses studies have been reported. However, these studies focused on the effectiveness of intra-articular PRP when compared to other controls, and none thoroughly investigated the anchored-based effectiveness concerning the minimal clinically important difference (MCID). Objective: We, therefore, conducted this work to address this apparent knowledge gap and to provide objective data that could be used by decision-makers. Methods: Electronic databases were searched to identify relevant publications. We included controlled trials that evaluated the efficacy of PRP for the treatment of OA of the knee. All included studies must have had a minimum follow-up of 24 weeks as well as pre- and post-injection Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores. Results: A total of 12 studies, involving 405 patients, were included in this analysis. The primary endpoint of this study was to compare the treatment effect measured by WOMAC scores improvement to MCID. For WOMAC score analyses, the mean difference (MD) between baseline and 6-month scores was utilized. The pooled data established significant functional improvement as demonstrated by MD of 25.5 ± 3.3 (95% confidence interval: 19.1–31.9, P< 0.001). In addition, the overall comparison of MD (25.5) to MCID (7.9) showed that the MD was approximately three-fold higher. Due to the known impact of the baseline scores on the MD, we conducted further analyses comparing MD values to the corresponding MCID for various baseline severity grades (i.e. high, intermediate, and low). The analyses showed significantly higher MD values in all categories. Conclusions: In conclusion, evidence from studies of low-to-moderate methodological quality shows that intra-articular PRP has the potential to provide a clinically meaningful symptomatic benefit for OA of the knee, at least in the short term.

Keywords: Knee osteoarthritis, meta-analysis, minimal clinically important difference, minimal clinically important difference, platelet-rich plasma, Western Ontario and McMaster Universities Arthritis Index score


How to cite this article:
Hegazy A, Karabelas P, Selim A. Meaningful effectiveness of platelet-rich plasma in treating patients with osteoarthritis of the knee: Meta-analysis and review. J Int Soc Phys Rehabil Med 2019;2:159-67

How to cite this URL:
Hegazy A, Karabelas P, Selim A. Meaningful effectiveness of platelet-rich plasma in treating patients with osteoarthritis of the knee: Meta-analysis and review. J Int Soc Phys Rehabil Med [serial online] 2019 [cited 2020 Apr 9];2:159-67. Available from: http://www.jisprm.org/text.asp?2019/2/4/159/270831




  Introduction Top


Osteoarthritis (OA) of the knee is a major cause of incapacity.[1] The need for knee arthroplasty has significantly increased, resulting in a substantial economic burden.[2] The current conservative/non-surgical treatment options include physiotherapy, analgesia, nonsteroidal anti-inflammatory drugs, and intra-articular injections, such as platelet-rich plasma (PRP),[3] hyaluronic acid (HA), corticosteroids, stem cells, or Ozone, with the objective of reducing pain and improving function.[4],[5]

PRP has a higher concentration of platelets than baseline values. Platelet activation causes the release of growth factors. Among these are growth factors from the transforming growth factor-beta family, platelet-derived growth factor, insulin-like growth factor, and fibroblast growth factor. Therefore, PRP has regenerative and anti-inflammatory effects that positioned it as a potential treatment option for OA of the knee.[6]

Some randomized controlled trials,[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20] and several systematic reviews had evaluated the clinical performance of PRP in patients with OA of the knee.[21],[22],[23] These studies focused mainly on the effectiveness of the PRP when compared to other controls such as saline, HA, stem cells, corticosteroids, and analgesics. However, none of these reviews focused on the anchored-based effectiveness of PRP relating to the minimal clinically important difference (MCID).

A clinically important difference is defined as a change or difference in the outcome measure that would be perceived as beneficial/meaningful by the clinician and the patient.[24] An MCID is, therefore, a threshold value for such change. It can be estimated with an anchor-based approach (correlates the score of interest with a known measure of clinical change) or a distribution-based approach (suggests that one-half of a standard deviation [SD] of a continuous outcome score constitutes a clinically meaningful difference).[25] In outcome measures in rheumatology meetings 5–7, the anchor-based method was recommended as the method of choice.[26] The MICD gives clinicians, patients, and health authorities a tool to assess various therapeutic options and to adopt appropriate management guidelines.

Considering the risk, as well as the cost associated with injectables such as PRP, we believe that it is vital to evaluate its endurance. None of the previous systemic reviews examined endurance with MCID.

Given this critical knowledge gap regarding anchored effectiveness and endurance, we believe that it is essential to conduct a new meta-analysis to evaluate the success of PRP treatment when compared to MCID at 6 months' postinjection and beyond.

Our objective was to examine if PRP injection could bring a clinically meaningful improvement for at least 6 months. We addressed this objective through two steps:First, by finding the average of the pooled mean difference (MD) between the baseline and the postinjection Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores, and second, by comparing the pooled MD to crude MCID. Evidence from the pooled data demonstrated that intra-articular PRP could provide a clinically meaningful benefit for OA of the knee, at least in the short term.


  Methods Top


Inclusion–exclusion criteria

We included published controlled trials evaluating the efficacy of PRP for the treatment of symptomatic patients with OA of the knee. Studies must have included patients aged 18 years or older with a minimum follow-up of 24 weeks (i.e. 6 months). We excluded the studies where PRP was used in combination with other injectables and/or procedures. We also excluded the studies that did not have sufficient information on the preoperative and postoperative of the total WOMAC scores.[27] To ensure homogeneity of the outcomes, studies that used other functional assessment instruments such as Knee Injury and OA Outcome Score, or EQ-visual analog scale were also excluded.

Study outcomes

For data synthesis, the primary outcome was to compare the PRP treatment effect (i.e. the difference between the total WOMAC scores at preinjection and 6-month postinjection) to the WOMAC's MCID values. For this comparison, we used the data by Tubach et al.,[28] since their data represent the most challenging MCID, and also provide values of a subgroup reference that reflect different levels of disease severity.

Two groups of investigators have proposed two different MCID values for OA of the knee, Williams et al.,[29] and Tubach et al. Williams et al. proposed an MCID of 6.8[29] while Tubach et al. proposed a higher MCID of 7.9 with a confidence interval (CI) of 5–8.8.[28] Moreover, Tubach et al. proposed the use of three estimates of MCID, corresponding to the categories of the baseline scores, which reflect disease severity. We used the values below[28] for the subgroup analyses [Table 1].
Table 1: MCID Values as proposed by Tubach et al.,

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Search strategy

Two investigators performed a systematic search of PubMed, Cochrane library, and Google Scholar independently on December 19, 2018, and updated on January 19, 2019. All searches were conducted based on the following terms “OA,” “knee,” “HA,” “gonarthrosis,” “prolotherapy,” and “PRP” with the Boolean operators “AND or.” Keywords included plasma, PRP, knee OA, gonarthrosis, and prolotherapy. The English language was used as a filter. We also reviewed the references of prior publications to obtain potential eligible studies.

In addition, manual searches of the reference lists of all included studies were conducted to identify trials that the electronic search may have missed. Two researchers evaluated the relevance of titles and abstracts. When we met uncertainty, a full-text review was performed. Additional information is available in [Figure 1]. The data pooling in this study followed the guidelines of Cochrane handbook version 5.1(http://handbook-5-1.cochrane.org/).
Figure 1: PRISMA flow diagram

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Data extraction

Two reviewers performed data extraction using a predeveloped extraction table. We extracted the basal characteristics of each study as well as the clinical data including global/total WOMAC scores (average/mean, and SD at preinjection and 6 months), the volume of injected PRP, intervals, number of injections, and the number of PRP spinning rounds. We checked the data for consistency, and discrepancies were debated until a consensus was reached.

Data analysis

For the WOMAC score improvement analyses, the MD between baseline and postinjection scores was used. We used the random effects model in all analyses. In the random effect model, both within-study sampling error (variance) and between-studies variation are included in assessing the uncertainty or CI of the results of the meta-analysis. P < 0.05 was considered statistically significant. We used the following software to analyze the data: OpenMeta Analyst,[30] OpenBugs,[31] and BugsXLA.[32]


  Results Top


Study characteristics

We analyzed a total of 12 studies. These studies were published between 2012 and 2018. One study had two arms for the PRP: (1) A single injection arm and (2) an arm with two injections.[19] The analysis included a total of 405 patients treated with PRP. The number of patients per study ranged from 14 to 60, with an average of approximately 31 patients. In most of the studies (6 out of 12), the investigators used the single PRP spinning protocol with an average volume of approximately 5.5 mL per injection. The maximum injection volume was 9 mL, and the minimum was 3 mL. The number of injections ranged from 1 to 4, with an average of 2 injections. The most commonly used intervals were weekly (5 out of 12) and monthly (3 out of 12). The patients in these studies had a disease severity range between I and IV (IV being the most severe). All studies had data for the total WOMAC score (0–100) at the baseline, as well as at several postinjection time points, including 6 months. For additional information, please see [Table 2].
Table 2: Baseline characteristics

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Comparison of the Western Ontario and McMaster Universities Arthritis Index score improvement to crude minimal clinically important difference

We used the meta-analysis approach comparing the pre- and post-injection WOMAC scores. The data demonstrated a statistically significant difference with a point estimate of 25.5 ± 3.3 (95% CI: 19.1–31.9, P < 0.001) [Figure 2].
Figure 2: Forest plot of the meta-analysis outcomes. Black square and black line represent the mean, and the confidence interval of each study, respectively. The diamond shape represents the pooled mean (i.e. point estimate), and confidence interval of all studies. At 6 months' postinjection, data showed a Western Ontario and McMaster Universities Arthritis Index score improvement of 25.5 points with a confidence interval between 19.1 and 31.9

Click here to view


To evaluate if the MD was clinically meaningful, we compared it to MCID. The comparison demonstrated that the MD was about three-fold higher than MCID (25.5 vs. 7.9) [Figure 2] and Table 3].
Table 3: Summary and comparisons of the mean difference values versus the corresponding minimal clinically important difference reference values

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Comparison of the Western Ontario and McMaster Universities Arthritis Index scores improvement to severity-specific minimal clinically important difference: Subgroup analysis

In the previous section, we compared the WOMAC score improvement to the crude[28] MCID value (7.9). As we explained in the methods section, crude MCID is a change in the difference of the threshold measure of the response but does not consider the baseline disease severity. Therefore, we conducted additional analyses comparing WOMAC score improvement to severity-specific MCID values (further details are available in the method section). Our analyses are as follows:

First, we categorized the 12 published controlled studies from our analysis according to the baseline WOMAC scores. This step yielded two studies with low (L), four with high (H), and six with intermediate (I) baseline scores [Figure 3]. We then conducted a subgroup analysis of these three categories (H, I, and L). The data demonstrated dissimilar WOMAC score improvements for each category; H: 36.0, I: 22.0, and L: 7.0 [Figure 3] and [Table 4].
Figure 3: Forest plot of the subgroup analysis of the mean difference according to the baseline score levels; H: High level (>51.5), I: Intermediate level (35.4–51.4), L: low level (≤35.3). See also Table 4 for additional information. At 6 months' postinjection, data demonstrated different levels of Western Ontario and McMaster Universities Arthritis Index improvements of about 7, 22, and 25 points in the low, intermediate, and high subgroups, respectively. Yellow diamonds represent the mean and confidence interval of each subgroup

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Table 4: Outcomes of the subgroup meta-analysis according to the baseline score classification

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Thirdly, we compared the values of various categories (H: 36.0, I: 22.1, and L: 7.0) to the corresponding severity-specific MCID (15.1, 14.8, and 2.6, respectively). The comparison demonstrated that WOMAC score improvements were consistently higher than their corresponding MCID reference [Table 3] and [Figure 4].
Figure 4: Boxplot representation of the mean difference values compared to the corresponding minimal clinically important difference. (a) Overall mean difference versus crude minimal clinically important difference. (b) Mean difference of the high baseline subgroup versus the high baseline minimal clinically important difference. (c) Mean difference of the intermediate baseline subgroup versus the intermediate baseline minimal clinically important difference. (d) Mean difference of the low baseline subgroup versus the low baseline minimal clinically important difference. White and black boxes represent mean difference and minimal clinically important difference respectively. The mean and median were represented by the line and the x in the middle, respectively. Upper and lower borders of the boxes represent the confidence interval limits. Boxplots represents pooled data from Figures 1 and 2

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Comparison of the Western Ontario and McMaster Universities Arthritis Index score improvement to severity-specific minimal clinically important difference: Individual study analyses

The objective of this analysis was to examine if the individual studies were showing results similar to the meta-analysis outcomes (i.e. WOMAC score improvement is higher than the severity-based reference MCID). In all 12 studies, the WOMAC score improvement was higher than the reference MCID [Table 5].
Table 5: Qualitative analysis of the data

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In summary, the trend of individual studies, as well as the subgroup analyses, is similarly showing clinically meaningful outcomes when compared to the reference MCID. These findings are also in agreement with the overall conclusion of the meta-analysis.


  Discussion Top


Although previous meta-analyses concluded that PRP was an effective alternative to treat OA of the knee when compared to other treatment options, the meaningful temporal effectiveness was not thoroughly analyzed. In this study, we addressed this critical knowledge gap.

To evaluate the efficacy, we calculated the difference between baseline and 6 months' post-injection functionality scores (i.e. WOMAC). We then pooled the MD and then compared it to MCID. At 6 months' postinjection, the data showed that PRP could bring an overall improvement of 25.5 points [Figure 2], which is approximately three-fold higher than MCID [Figure 4]a and [Table 3].

Due to the heterogeneity of patient populations regarding disease severity, it was essential to conduct further analyses. We performed a subgroup meta-analysis based on severity as reflected by the baseline score categorization (high, intermediate, and low scores) followed by comparisons of the MD to the appropriate MCID reference values. The analysis demonstrated that while MD values differ among the groups [Figure 4], they remained higher than the corresponding MCID values [Figure 3] and [Figure 4], [Table 3] and [Table 5].

In addition, we conducted a qualitative analysis comparing score improvements in each study to the appropriate MCID reference value, and the data showed constantly higher MD [Table 5]. It is important to note that our study is the first study that proposes the use of the MD/MCID ratio as a normalized way to evaluate effectiveness. In addition, the study data reinforced the concept of considering the baseline scores when judging treatment success. This comparative approach meets the recommendation of Crosby and associates for estimating MCID in health-related quality of life criteria to anchor baseline severity of individual patients.[26]

In this study, we observed that patients with a low baseline score (i.e. early-stage OA) achieved the best response with MD/MCID ratio of 2.7 [Table 4]. The suggestion that patients with early OA of the knee respond better to PRP has also been indicated by other authors.[38]

The duration of the beneficial effect of PRP injections remains unclear. Our study demonstrated that PRP was effective for over 6 months. These data are in agreement with the results from a study by Filardo et al. who investigated the persistence of the favorable effect of PRP during a 24-month follow-up.[39] The results of Filardo et al. showed that the median duration of clinical improvement was 9 months.[39]

Notably, there is virtually no conclusive evidence on the dose or frequency of PRP in the setting of the treatment of patients with OA of the knee.

PRP's injection volume and frequency are widely varied among published studies, with no clear standardization yet proposed. In our study, the injection volume has ranged from as little as 3 mL to as high as 9 mL [Table 2] with an average of 5.7 mL. While very small volume (such as 3 mL) may offer a more concentrated dose, it may also fail to fill the entire intra-articular space. Alternatively, an extremely large volume (such as 9 mL) may be very diluted. In our data, despite the trend in favor of smaller volume, we did not see a statistically significant correlation between the injected volume and the MD/MCID ratio (P = 0.95). Nevertheless, since most of the clinical studies have used 4–5 mL,[40] and there is no sufficient evidence showing a correlation between extreme volumes, and efficacy, we recommend adopting the volume of 4–5 mL for the majority of the patients unless there is a reason to modify the volume.

Regarding the number of injections, most investigators have elected to perform multiple injections at weekly, biweekly, every-3-week, or monthly intervals to maximize effects [Table 2]. Nevertheless, positive effects have been reported with a single injection.[19],[37] In our dataset, we did not see any correlation between the number of injections and the MD/MCID ratio (data not shown). Considering the resources, logistics, and patient compliance, needed for multiple injections along with the lack of supporting evidence, it is plausible to recommend adopting the single injection protocol for most of the patients with an option of repeated injection for those who fail to show a meaningful improvement after the first dose.

It is important to mention some of the limitations of our study. First, the studies included were heterogeneous regarding PRP preparation methods (the use of the single vs. double-spinning technique, speed, length of centrifugation, and whether used an activator), and PRP administration plans (frequency and injection volume). Second, we only included studies published in English, which might lead to a language or cultural bias.

At this time, intra-articular PRP injection is not a standard treatment of knee OA. The current AAOS guidelines on the management of OA of the knee have stated that they cannot recommend either for or against the use of PRP, given the lack of high-quality trials investigating PRP.[41]

Collectively, in this meta-analysis, the best available evidence with a low risk of bias suggested that PRP is an effective intervention for OA of the knee. Therefore, we have relative confidence in recommending the use of PRP in treating patients with OA of the knee.

Financial support and sponsorship

Personal.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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Abstract
Introduction
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