Platelet-rich Plasma

The Platelet-Rich Plasma recommendation has been downgraded two levels because of inconsistent evidence.

There were two high (Rayegani; 2014, Gormeli; 2017) and one moderate (Akan; 2018) study with 30 people per group comparing PRP vs. control. There were mixed results in the studies for pain and function. A meta-analysis was not performed due to heterogeneity. Two studies (Akan; 2018, Gormeli; 2017) looked at PRP in severe OA with mixed results. Two studies (Rayegani; 2014, Gormeli; 2017) looked at change in all stages of OA at a six-month timeframe. The studies had mixed results. One study (Gormeli; 2017) looked at Kellgren-Lawrence 1-3 stage OA with improvement in IKDC and EQ-VAS. Therefore, due to the heterogeneity of results and the difference in early and late stage OA results, we downgraded the recommendation to Limited from Strong. We feel these recommendations may change with future research on the use of PRP in different levels of severity of OA.

The number of PRP injections had mixed results with the studies with three PRP injections (Akan; 2018, Gormeli; 2017) having positive results outcomes for pain and function. Studies with one and two PRP injections had mixed results, with the positive being less likely clinically significant changes in pain and function. Further research should be done to determine the number of PRP injections for treatment of KOA. Currently, three IA-PRP injections appear to have more favorable results.

Adverse events from PRP injections has been investigated in one high-quality study (Huang; 2018) reported adverse events for PRP vs. control. They reported hypertension and proteinuria were treatment-related side-effects. These met Common Toxicity Criteria grade ≥3. This raises questions on the safety of PRP, which needs further evaluation. Therefore, the strength of recommendation was downgraded to Limited.

When evaluating the effectiveness of PRP vs HA, there were eight high-quality studies (Sanchez; 2012, Vaquerizo; 2013, Filardo; 2015, Gormeli; 2017, Cole; 2017, Buendia-Lopez; 2018, Di Martino; 2019, Yaradilmis; 2020) and six (6) medium quality studies (Spakova; 2012, Raeissadat; 2015, Lana; 2016, Duymus; 2017, Raeissadat; 2017, Ahmad; 2018) and one low-quality studies (Sanchez; 2008) that investigated IA-PRP vs. IA-HA. Four studies were included in a meta-analysis of Total WOMAC results at the 9- OR 12-months mark. This analysis showed a clinically significant difference for IA-PRP over IA-HA. The results between IA-PRP vs IA-HA diverged after 6 months. Most studies showed similar results between IA-PRP and IA-HA at six months, except one (Yaradilimis 2020) where the LR-PRP total WOMAC was better at all time points than the IA HA. Both the patients in the IA HA and IA PRP improved in total WOMAC at six months. Patients in the IA-PRP-arms maintained improvement after 6 months at the 9- OR 12-months mark for total WOMAC vs. IA-HA which started to have a worsening score. The standard is to inject IA-HA every six months in patients with painful KOA. The preparation of the PRP (LR-PRP vs LP-PRP) was noted to be different with the LR-PRP had higher MID values than LP-PRP vs. IA-HA. The research highlights the prolonged effect of IA-PRP over IA-HA, though both appear to be equivalent at 6 months.

Patient-related outcome measures (OARSI-OMERACT responders, percentage of subjects meeting a percentage reduction in VAS Pain OR WOMAC Pain scores) (Sanchez; 2008, Sanchez; 2012, Vaquerizo; 2013, Buendia-Lopez; 2018) more often favorited IA-PRP at both the six month and 12-month time frame. Further, research is needed using standardized PROM’s to investigate the effectiveness of IA-PRP to determine if more patients will benefit from IA-PRP at six months over IA-HA.

Adverse events were higher in the PRP group than IA HA, both local soreness and injection pain (two studies (Spakova; 2012, Yaradilmis; 2020)) and one study (Huang; 2018)) systemic events (proteinuria and hypertension). One study (Vaquerizo; 2013) did not find a difference comparing any adverse event, and one study (Raeissadat; 2017) did not see a difference for minor injection-site adverse events. Therefore, there appears to be more studies finding IA-PRP to have more adverse events vs. IA-HA, more research is need to determine if the adverse events outweigh the benefit of IA-PRP over IA-HA at 9 and 12 months. This is another reason for the downgrade in evidence from Strong to Limited.

Comparisons between IA-PRP and IA-CS, there were three high (Joshi Juber; 2017, Khan; 2018, Nabi; 2018) and one moderate quality study (Huang; 2019). One study (Joshi Juber; 2017) was KL IV end-stage OA and did not find a difference. One study (Khan; 2018) was repeat injections every other month (0, 2, 4 months) with follow up at six months in KL II OAK with no difference. One study (Nabi; 2018) used patients with KL II-III given three injections one month apart showed improvement at three months (one month after the last injection) and six months (4 months after the final injection). One study (Huang; 2019) did three PRP injections every three weeks on KL I-II OAK showed improvement in pain and function at six months (4 months after last injection) and 12 months (10 months after last injection). Therefore, the IA-PRP given in three injections evaluated at 4 months post last injection is more likely to show benefit in KL II and III stages of KOA. More research is needed to evaluate long-term benefits of IA-PRP vs IA-CS over a two- or five-year period to determine if IA-PRP is cartilage sparing vs IA-CS concern for possible cartilage damage over time.

PRP is defined in LR-PRP and LP-PRP. There may be a difference in the effectiveness in knee osteoarthritis between these two preparations. Currently, there is limited data from one direct comparison (Yaradilimis; 2020) and our meta-analysis (Figure 45) of IA-PRP and IA-HA that would demonstrate that intra-articular LR-PRP vs. LP-PRP for KOA is more likely to demonstrate a benefit at 9 and 12 months. The number of studies is limited, therefore determining the better choice between LR-PRP vs. LP-PRP is still inconclusive, but at this time appears to favor LR-PRP.

Benefits/Harms of Implementation

Some patients may experience temporary local soreness or injection pain.

Outcome Importance

Pain and function improvement through intra-articular therapies for the treatment of knee osteoarthritis may have high impact on symptoms and overall health.

Cost Effectiveness/Resource Utilization

The cost-effectiveness of different intra-articular therapies is still to be determined, in comparison to other treatment strategies and among different intra-articular alternatives.

Acceptability

Currently intra-articular treatments are commonly utilized approach in treating symptomatic knee osteoarthritis, hence there should be no issues implementing this recommendation as it does not influence a major change in clinical practice, and it provides further evidence to support and guide these practices.

Feasibility

These recommendations do not interfere with other interventions or clinical practice therefore it is deemed very feasible in patients with symptomatic knee osteoarthritis.

Future Research

Future research in this area should embrace detailed osteoarthritis characterization including sub-group analyses and osteoarthrosis severity stratification. Furthermore, using clinically relevant outcomes and controls for bias are warranted along with cost-effectiveness analysis. Specifically, to platelet rich plasma it will be of outmost importance to include comprehensive platelet rich plasma characterization and description of platelet rich plasma preparation protocol.