Compliance with the provisions in this LCD may be monitored and addressed
through post payment data analysis and subsequent medical review audits.

Platelet rich plasma injections and/or applications are considered not
medically reasonable and necessary for any use outside of the National
Coverage Determination (NCD) 270.3 Blood-Derived Products for Chronic Non-
Healing Wounds.

**Introduction**

Platelet-rich plasma (PRP) is defined as a platelet-rich concentrate with
platelet levels greater than the baseline platelet count in whole blood. This
autologous derived substance, also referred to as autologous platelet-derived
growth factors, platelet gel, platelet-rich concentrate, autogenous platelet
gel, plasma rich in growth factors, or platelet releasate, has been proposed
for the treatment of multiple conditions to enhance healing. Theoretically,
these growth factors function as a mitogen for fibroblasts, smooth muscle
cells, osteoblasts, and vascular endothelial growth factors.2,3 While PRP may
work by activating the innate immune response and stimulating tissue
anabolism, its precise action mechanism is still unclear.3 The role that white
blood cells may play is particularly unclear, as the immune cells may act as
antimicrobial and/or proinflammatory agents. Furthermore, PRP preparations are
not standardized and exhibit wide variability in platelet and white blood cell
concentrations and the use of thrombin activators. How variations in PRP
composition may impact clinical outcomes is also unclear.4 Mishra et al5
proposed classifying these types in 3 categories: the presence of white blood
cells (e.g., leukocyte-rich or -poor), whether the PRP is activated or not,
and the concentration of platelets.

Several factors have contributed to the growing popularity of biologic
therapies despite the dearth of high-quality clinical trials supporting their
use. Musculoskeletal conditions are both severe and prevalent. Conventional
treatment, for the most part, is lacking in success. Platelet-rich plasma has
the appeal of a simple, minimally invasive treatment with little regulation,
which can be easily administered via local injection by clinicians. In
addition, the biotechnology companies that manufacture the equipment used to
assist in producing these therapies have conducted nationwide marketing
directly to clinicians and consumers, touting success with high profile
professional athletes.

A collection and preparation system is used to collect a small sample of blood
at the patient's point of care or clinical laboratory. The systems used for
preparing autologous platelet-derived growth factors are United States (U.S.)
Food and Drug Administration (FDA) approved under the 510(k) process.6
<https://www.fda.gov/vaccines-blood-biologics/substantially-
equivalent-510k-device-information/cleared-510k-submissions-supporting-
documents-2021>. While the technology to obtain PRP is FDA-approved, PRP
itself is currently not indicated for direct injection. Centrifugation of this
blood sample separates the denser red cells from the plasma. The plasma
components are divided into a buffy coat and an adjacent layer. The buffy coat
contains leucocytes and most of the platelets. The adjacent layer of plasma is
less rich in platelets and has few leucocytes.7

There are a variety of techniques used to harvest the buffy coat, the adjacent
plasma layer, or both. Some methods concentrate the buffy coat further using a
"double spin" technique. This process involves a second centrifugation of the
supernatant obtained from the initial centrifugation and produces a more
concentrated sample. Depending on the method used, the number of platelets in
PRP varies between 1 and 9 times that of whole blood. Techniques that produce
higher platelet concentrations (e.g., double spin) typically produce higher
leucocyte concentrations. Hence, PRP is often referred to as leucocyte rich
(LR-PRP) or leucocyte poor (LP-PRP).8

Some practitioners add exogenous calcium salts to the PRP prior to
administration to ensure platelet activation, while others assume that contact
with tendon collagen will suffice.9 PRP composition can also differ by donor
age, health status, gender, and even time of day when collected.10

Administration protocols also vary per type of injury. PRP may be injected
using a peppering technique, whereby the PRP is injected with several
penetrations of the tendon from a single skin penetration11 or may be injected
directly into a joint. The frequency of injections varies. For tendon
conditions, one to four intratendinous injections are given over two weeks.
Joint conditions typically have three injections given within a 6-month time
frame, usually performed 3-4 weeks apart.12 A local anesthetic is often
utilized, and an ultrasound (US) may provide guidance. Local anesthetics may
compromise the efficacy of the PRP.13 Patients need to refrain from non-
steroidal anti-inflammatory medications for two weeks before harvesting due to
the effect on platelet function.14 There are no accepted exercise protocols or
return-to-sport guidelines following PRP treatment. PRP usage can be broadly
separated into three categories which will be discussed further: primary
treatment for tendinopathies/non-tendon inflammation, the surgical
augmentation of repairs, and primary treatment for osteoarthritis.

**Primary Treatment for Tendinopathies/Non-Tendon Inflammation**

The evidence regarding PRP treatment of tendinopathies/non-tendon inflammation
includes multiple randomized control trials (RCT) and systematic reviews with
meta-analyses (SR/MA). Typical outcomes are pain relief and functional status.
The literature is clustered around usage for the following: lateral
epicondylitis (LE), carpal tunnel syndrome (CTS), rotator cuff (RC) tears,
plantar fasciitis (PF), Achilles tendinopathy (AT), and patellar tendinopathy
(PT).

Andia3 conducted a review of over 1,500 patients treated with PRP for
tendinopathies in 58 studies evenly distributed between lower and upper
extremities. Six of these were of Level 1 Evidence Quality, primarily
utilizing LR-PRP. Given the heterogeneity in tendinopathies and preparation of
PRP, they concluded the data was insufficient to make a recommendation for
treatment.

A 2014 systematic review of 19 randomized and quasi-randomized trials of PRP
for musculoskeletal soft tissue injuries, involving 1,088 participants, noted
no difference in clinically meaningful outcomes.15 The quality of these
studies was limited by small numbers of participants, non-standardization of
treatment preparation, and outcome measures that focused on subjective pain
scores rather than more objective measures of tendon tissue healing or
improvement in function. Additional limitations were the lack of accounting
for other confounding factors, such as differentiation between an overuse
injury vs. degenerative tendon rupture and whether or not bursal involvement
was present. As previously stated, the role of leukocytes in tendon healing is
controversial, but the few randomized trials that differentiated between LR-
PRP and LP-PRP suggest that LR-PRP may be more effective in the treatment of
tendinopathies.16 The evidence, examined in detail below, is insufficient to
determine the benefit of PRP on health outcomes for tendinopathies/non-tendon
inflammation.

**Lateral epicondylitis**

Lateral epicondylitis (LE), commonly known as "tennis elbow", affects
approximately 1-3% of the population, with men and women equally represented.
An overuse injury is characterized by angiofibroblastic hyperplasia.17
Patients typically complain of pain for 6-12 weeks, but in some cases, pain
can persist for up to two years. Eighty percent recover with no treatment.18
Although self-limiting, this condition still results in disability, lost
productivity, and health care utilization costs. Conservative efforts include
non-steroidal anti-inflammatory drugs, orthotic devices, physical therapy,
glucocorticoid injection, and extracorporeal shock wave therapy.

The Washington State Health Care Authority19 recently published a
comprehensive health technology assessment, in which they examined the
efficacy and safety of PRP when used in the patient with recalcitrant LE (> 6
months duration). The authors included five RCTs that compared PRP with
corticosteroid injection (CS)20-24 and two RCTs that compared PRP with an
anesthetic.11,25 In the short term, neither CS nor local anesthetic differed
from PRP regarding pain or function. While in the intermediate term, low
quality evidence suggested PRP was superior to CS (P = 0.007) for pain and
function, but not local anesthetic (P = 0.08). In the long term, low quality
evidence suggested PRP and CS were not different (P = 0.11), but PRP was
superior to local anesthetic (P < 0.00001).

Stratification of systematic review/meta-analysis (SR/MA) of eight RCTs by Mi
et al26 found that treatment with PRP appeared to be more effective than CS at
intermediate term (12 weeks) and long term (6 months and one year) intervals,
whereas CS demonstrated superiority in the short term (2-8 weeks).

Montalvan et al27 conducted an RCT, which found that two US guided PRP
injections in 25 patients were no more efficacious than saline injections at 6
and 12 months on either pain score reduction or functional improvement. Mishra
et al11 conducted an RCT of 112 patients with LE comparing LR-PRP and
bupivacaine injections, concluding there were no differences in global pain
scores at 12 weeks. Schoffl found no significant difference between PRP vs.
saline in functional improvement at three months in a double-blinded (DB) RCT
of 50 patients.28

Li et al29 conducted a systematic review and meta-analysis to compare the
effectiveness of PRP vs. corticosteroids for treatment of patients with
lateral elbow epicondylitis. Five RCTs were included in the meta-analysis.
Authors concluded local corticosteroid injections demonstrated significantly
lower DASH scores compared with local PRP treatments during short-term follow-
up (4 weeks and 8 weeks post-treatment). Whereas, at long-term follow-up (24
weeks post-treatment), PRP injections significantly improved pain and function
more than corticosteroid injections. Study limitations include small sample
size, varying follow-up times, and high to unclear risk of bias in included
trials.

Simental-Mendia et al30 performed a systematic review and meta-analysis to
compare the effects of PRP injection vs. placebo (saline injection) on pain
and joint function in lateral epicondylitis in randomized placebo-controlled
trials. Five RCTs comprised of 276 patients were included. Authors reported no
difference in improvement regarding joint pain and function between the PRP
and placebo injection groups. Study limitations include small sample size,
high heterogeneity across trials, possible confounding, lack of technique
protocols, and various tools used to report outcomes.

Tang et al31 conducted a systematic review, pairwise and network meta-analysis
of RCTs to compare PRP, autologous blood (AB) and corticosteroid injections
for lateral epicondylitis. Twenty RCTs with 1,271 patients were included in
this study. Pain intensity, strength, and function were outcomes measured with
standardized assessment tools. Authors concluded PRP achieved more improvement
than the comparators among pain intensity and function long term whereas,
corticosteroids achieved the most improvement in the short term follow-up.

Linnanmaki et al32 performed a parallel group, randomized, controlled
participant- and assessor-blinded study including adults with clinically
diagnosed LE. The participants were recruited from a secondary referral center
after not responding to initial nonoperative treatment. One hundred nineteen
participants were randomized to receive PRP, saline, or autologous blood.
Follow-up visits were at 4, 8, 12, 26, and 52 weeks after the injection. The
primary outcome measure was improvement in pain, measured with Visual Analog
Scale (VAS) in a 0-10 range, without specification as to whether the pain was
activity related or at rest, from baseline to 52 weeks. The secondary outcomes
were the Disabilities of the Arm, Shoulder, and Hand (DASH) score. There were
no clinically significant differences in the mean VAS pain or DASH scores
among the groups at any timepoint. Level of evidence Level II therapeutic
study.

One small study looked at PRP as an alternative to operative management. Mayo
Clinic33 conducted a non-randomized trial where 15 patients were treated with
a series of 2 LR-PRP injections, and 18 patients were treated with surgery.
Outcome measures included time to pain-free status, time to a full range of
motion (ROM), the Mayo Elbow Performance Score (MEPS), and the Oxford Elbow
Score (OES). Successful outcomes were observed in 80% of patients treated with
PRP and 94% of those treated operatively (P = 0.37). A statistically
significant improvement was noted in both time to full ROM (42.3 days for PRP
vs. 96.1 days for surgery; P < 0.01) and time to pain-free status (56.2 days
for PRP vs. 108.0 days for surgery; P < 0.01). No significant difference was
found in return-to-activity rates, overall successful outcomes, MEPS scores,
or OES scores.

Overall, the current evidence suggests that PRP may yield some long-term
benefits that are not apparent before six months, particularly when compared
with CS. However, the quality of evidence is limited by sample size too small
to be sufficiently powered and lack of correction for multiple comparisons.

**Carpal Tunnel Syndrome**

Literature reports comparing 5% Dextrose in Water (D5W), CS and PRP injections
with non-surgical management of carpal tunnel syndrome (CTS) were
systematically reviewed by Lin et al.34 Ten studies with 497 patients
comparing five treatments (D5W, PRP, splinting, CS, and normal saline [NS])
were included. The primary outcome was the standardized mean difference (SMD)
of the symptom severity and functional status scales of the Boston Carpal
Tunnel Syndrome Questionnaire at three months after injections. The results
showed that D5W injection was likely to be the best treatment, followed by PRP
injection, in terms of clinical effectiveness in providing symptom relief. For
functional improvement, splinting was ranked higher than PRP and D5W
injections. Lastly, CS and saline injections were consistently ranked fourth
and fifth in terms of therapeutic effects on symptom severity and functional
status. D5W and PRP injections are more effective than splinting and
corticosteroid or saline injection for relieving the symptoms of CTS. Compared
with splinting, D5W and PRP injections do not provide better functional
recovery.34

In 2009, the UK National Institute for Health and Clinical Excellence (NICE)
stated that current evidence on PRP's safety and efficacy for tendinopathy is
inadequate in quantity and quality.35 This was reiterated in recent systematic
reviews of the evidence.36

**Rotator Cuff Tears**

Rotator cuff (RC) tears are a common clinical problem in the geriatric
population with rates as high as 80% in those over age 80, and debate exists
over how to best provide pain relief and restore shoulder function. Treatment
options can be broadly divided into non-surgical and surgical, with most
patients initially placed on a trial of conservative therapy. A primary
concern with RC repairs in older patients is decreased vascularity and healing
potential of the tendons. With more inadequate healing, there is an increased
risk of re-rupture, and older age is associated with higher rates of failure
following repair. For those with irreparable RC tears, low functional demand,
or interest in nonoperative management, there are many non-surgical treatments
to consider, including rehabilitation and injections of CS, hyaluronic acid
(HA), and PRP.

Several meta-analyses have been published, but none have focused exclusively
on Level 1 RCTs until Chen's work.37

Eighteen Level I studies were evaluated. The VAS scores were significantly
improved short term ( -0.45 [95% CI, -0.75 to -0.15]; P < 0.01). Sugaya grade
IV and V retears in PRP-treated patients were significantly reduced long term
(odds ratio [OR], 0.34 [95% CI, 0.20-0.57]; P < 0.01). In PRP-treated patients
with multiple tendons torn, there were reduced odds of retears (OR, 0.28 [95%
CI, 0.13-0.60]; P < 0.01). Long-term odds of retears were decreased,
regardless of leukocyte content (LP-PRP: OR, 0.36 [95% CI, 0.16-0.82]; LR-PRP:
OR, 0.32 [95% CI, 0.16-0.65]; all P < 0.05) or usage of gel (non-gel: OR, 0.42
[95% CI, 0.23-0.76]; gel: OR, 0.17 [95% CI, 0.05-0.51]; all P < 0.01). The
conclusion was that long-term retear rates were significantly decreased in
patients with rotator cuff-related abnormalities who received PRP. Significant
improvements in PRP-treated patients were noted for multiple functional
outcomes, but none reached their respective minimal clinically important
differences. Overall, the results suggest that PRP may positively affect
clinical outcomes, but limited data, study heterogeneity, and poor
methodological quality hinder firm conclusions.

In their double-blind RCT of 40 patients (average age 51) with RC tears,
Kesikburun et al38 randomized patients to a single 5-mL injection of either
PRP or saline, in addition to a standard 6-week exercise program. At 1-year
follow-up, the authors found that PRP was no better than placebo at improving
quality of life, pain, disability, and shoulder ROM. In contrast, positive
results were reported by Rha et al39 in their study of 39 patients (average
age 45) with tendinosis or partial RC tears. Patients were randomized to
either two injections of PRP or dry needling spaced four weeks apart. At the
6-month follow-up, those treated with PRP had superior results regarding pain,
function, and ROM.

**Plantar Fasciitis**

Singh et al40 conducted an SR/MA study comparing PRP injections and CS
injections for plantar fasciopathy (PF). Studies were assessed using the
Cochrane Risk of Bias Tool and the Newcastle Ottawa Scale (NOS). The primary
endpoint was pain and function score at 3- and 6-month follow-up. Ten studies
with a total of 517 patients were included. Seven studies were randomized.
Studies reported outcomes using the VAS and American Orthopedic Foot and Ankle
Score (AOFAS). At 3-month follow-up, PRP injections were associated with
improved VAS scores (standard mean difference [SMD], -0.66; 95% CI, -1.3 to
-0.02; p = 0.04) and AOFAS scores (SMD, 1.87; 95% CI, 0.16-3.58; p = 0.03).
However, by the 6-month follow-up, there was no difference in VAS score (SMD,
-0.66; 95% CI, -1.65 to 0.3; p = 0.17) or AOFAS scores (SMD, 1.69; 95% CI,
-1.06 to 4.45; p = 0.23).

Sarah Johnson-Lynn et al41randomized 28 patients with six months or more of
magnetic resonance imaging (MRI)-proven PF to PRP or saline. Using the VAS,
both treatments resulted in a similar, significant improvement in symptoms at
six months. Levels of Evidence: Level II.

A larger, randomized trial of 115 patients42 compared CS to PRP using Foot
Function Index pain score (FFI) for chronic plantar fasciitis. In the control
group, FFI Pain scores decreased quickly and then remained stable during
follow-up. FFI Pain reduction was more modest in the PRP group but reached a
lower point after 12 months than in the control group. After adjusting for
baseline differences, the PRP group showed significantly lower pain scores at
the 1-year follow-up than the control group (mean difference, 14.4; 95% CI,
3.2-25.6). The number of patients with at least 25% improvement (FFI Pain
score) between baseline and 12-month follow-up differed significantly between
the groups. Of the 46 patients in the PRP group, 39 (84.4%) improved at least
25%, while only 20 (55.6%) of the 36 in the control group showed such an
improvement (P = 0.003). The PRP group showed significantly lower FFI
Disability scores than the control group (mean difference, 12.0; 95% CI,
2.3-21.6).

A 2014 study with fifty patients compared PRP to corticosteroids and reported
statistically significant higher visual analog scores in the PRP group at six
weeks and six months (p<0.001).43 This study's limitations include that it was
not randomized, and there were no placebo group results, no radiological or
biological results, a small sample size, and a short follow-up period.

A 2015 meta-analysis comparing PRP, shockwave therapy, and corticosteroids for
plantar fasciitis treatment showed a trend favoring PRP over corticosteroids
at three months but slightly inferior at six months. Shockwave therapy had the
highest likelihood of treatment success but less remarkable for pain reduction
at three and six months.44 This data was limited by substantial heterogeneity
in therapeutic protocols, definitions, and measurement of outcome variables
among the included studies, a small number of trials, the inclusion of non-
randomized trials, lack of comparison to the placebo group making the
conclusions suggestive of a trend but without sufficient data to draw reliable
conclusions.

A 2017 RCT comparing twenty-eight patients receiving PRP to corticosteroid
injections for plantar fasciitis who did not respond to conservative treatment
concluded both treatments were equally effective. The authors report the cost
and time for preparation of the PRP were disadvantages of the PRP treatment.45
Another small single-blinded RCT (n= 32) reported similar results and lacked
adequate sample size, blinding, and follow-up duration.46

A 2019 prospective, randomized double-blinded control trial compared PRP to
corticosteroid injections in sixty patients with chronic plantar fasciitis.
Statistically significant improvements were reported in the VAS, and AOFAS
score in both groups. Plantar fascia thickness was reduced in both groups.47
Limitations of the study include small sample size and variability of platelet
concentration among different patients. While the authors conclude that PRP is
an effective treatment for chronic plantar fasciitis when compared to
steroids, the authors acknowledge that lack of standardized preparation, the
concentration of platelets, and dosage were barriers to a critical evaluation,
and further research is necessary to understand the action of PRP.

Two 2020 systematic reviews draw different conclusions. Hurley et al48
reviewed nine RCTs (n= 239) and reported statistically significant differences
in VAS scores in favor of PRP at one through 12 months. They report at one and
three months no difference in AOFAS scores, but favorable towards PRP at 6 and
12 months. The authors conclude evidence to suggest PRP may lead to greater
improvement in pain and function for chronic plantar fasciitis and conclude
there is level 1 evidence to support its use. However, the authors acknowledge
significant heterogeneity, limiting the results of a meta-analysis and high
risk of bias among the majority of included studies. Another 2020 systematic
review included thirteen randomized controlled trials that reported
significant superiority of PRP in outcome scores when compared to
corticosteroids (VAS:MD= -0.85, p= <0.0001, I2= 85%; AOFAS: MD= 10.05, p=
<0.0001, I2= 85%) whereas there is no statistical difference in well-designed
double-blinded trials (VAS: MD= 0.15, p= 0.72, I2= 1%; AOFAS: MD= 2.71, p=
0.17, I2= 0%). In conclusion, the authors state there is no superiority of PRP
compared to corticosteroids in well-designed double-blind studies. The
advantage of PRP seen in some literature may be due to the lack of blinding in
these studies. The report is a trend to the improvement of PRP compared to
placebo.49 The heterogeneity was also significantly reduced in the double-
blinded randomized control trials allowing more meaningful conclusions.49

**Achilles Tendinopathy**

RCTs of 24 patients with an injection of PRP vs. saline into Achilles
Tendinopathy (AT) demonstrated no significant difference at three months in
the Victorian Institute of Sports Assessment-Achilles (VISA-A) score.50 A
1-year follow-up of 54 patients in a similar trial also found no
improvement.51

**Patellar Tendinopathy**

Patellar tendinopathy is a condition characterized by anterior knee activity
related pain, most commonly found in athletes who engage in jumping sports. A
well-designed multisite single-blind study randomized 57 athletes with
patellar tendinopathy to LR-PRP, LP-PRP, and saline ultrasound guided
injections. All participants received one injection followed by six weeks of
supervised rehabilitation training three times per week. Study retention was
93% at 12 weeks and 79% after one year. Using the outcome measure, Victorian
Institute of Sport Assessment-patellar (VISA-P), there was no significant
difference in mean change in VISA-P score, pain, or global rating of change
among the three treatment groups at 12 weeks or any other time point.52 A
SR/MA addressed 70 studies of patellar tendinopathy treatment involving 2,530
patients, reported in 22 studies on eccentric exercise, extracorporeal
shockwave therapy (ESWT), and PRP. Eccentric exercise therapies obtained the
best results (P < 0.05) at short-term (< 6 months, mean 2.7 +/- 0.7 months).
However, multiple injections of PRP obtained the best results (P < 0.05),
followed by ESWT and eccentric exercise at long-term follow-up (>/=6 months,
mean 15.1 +/- 11.3 months).53

A different SR looked at 15 studies comparing eccentric training, PRP, CS, and
ESWT. With or without core stabilization or stretching, eccentric training
improved symptoms by 61% in the VISA-P score with a 95% confidence interval.
Results from ESWT demonstrated 54% improvement, and PRP studies 55%
improvement with similar confidence intervals. Finally, CS injection provided
no benefit.54

In summary, RCTs and SR/MA findings have been mixed and have generally found
that PRP did not have a statistically and/or clinically significant impact on
pain or functional outcomes. In RCTs that have found significantly improved
pain outcomes for PRP injections, critical relevancy gaps and study conduct
limitations preclude reaching strong conclusions based on their findings. The
evidence is insufficient to determine the benefit of PRP on health outcomes
for patellar tendinopathy.

**Surgical Augmentation of Repairs**

Most RCTs with surgical repair of rotator cuff or Achilles tendon have not
demonstrated any clinically significant benefit.55-58 A MA of eight Level I or
Level II studies of rotator cuff surgery comparing preoperative and
postoperative risk for retears and gain in functional outcome showed no
statistically significant differences between those treated with PRP and those
without such an intervention.59 An additional MA of Level II and Level III
studies by Saltzman et al60 came to similar conclusions. A Cochrane review by
Moraes et al61 on platelet-rich therapies for musculoskeletal soft tissue
injuries identified two RCTs and two quasi-randomized studies (total n = 203
patients) specifically on PRP used in conjunction with anterior cruciate
ligament (ACL) reconstruction. Pooled data found no significant difference in
International Knee Documentation Committee (IKDC) scores between the PRP and
control groups. The evidence is insufficient to determine the benefit of PRP
on health outcomes for surgical augmentation of repairs.

**Primary Treatment for Osteoarthritis**

Osteoarthritis (OA) is a common disease involving joint damage, inadequate
healing response, and progressive deterioration of the joint architecture.
Presently, intra-articular injections of CS or viscosupplementation with HA
remain the mainstay of conservative treatment. The evidence for using PRP for
this condition includes multiple RCTs and systematic reviews. Most trials have
compared PRP with HA for knee osteoarthritis, though HA as a comparator is
questionable because the evidence demonstrating the benefit of HA for
osteoarthritis is not robust.

Systematic reviews have generally found that PRP was more effective than
placebo or HA in reducing pain and improving function. However, systematic
review authors have noted that their findings should be interpreted with
caution due to important limitations, including significant statistical
heterogeneity, questionable clinical significance, and a high risk of bias in
study conduct.62 One retrospective study compared PRP to HA in 190 patients
between January 2014 and October 2017. Western Ontario and McMaster
Universities Osteoarthritis Index (WOMAC), VAS, and ROM were measured before
injection, at 15 days, 6 months, 12 months, and at last follow-up. HA treated
patients experienced a higher arthroplasty rate (36.0% vs. 5.3%, p < 0.001),
lower ROM, worse VAS and WOMAC score, and increased risk of any arthroplasty
occurrence (log-rank < 0.001) than PRP patients.62

A 2014 systematic review of 10 randomized and non-randomized trials of PRP for
OA of the knee found intra-articular PRP injections were more effective for
pain reduction (mean difference [MD] -2.45; 95% CI -2.92 to -1.98; p value <
0.00001 and MD -2.07; 95% CI -2.59 to -1.55; p value < 0.00001, single and
double PRP injections, respectively) compared with placebo at six months post
injection. Intra-articular PRP injections were compared with hyaluronic acid
and showed a statistically significant difference in favor of PRP on pain
reduction based on the VAS and numeric rating scale (standardized mean
difference -0.92; 95% CI -1.20 to -0.63; p value <0.00001) at six months post
injection. Almost all trials revealed a high risk of bias.63

A similar SR/MA in 2020 of 18 studies (all level 1) met inclusion criteria,
including 811 patients undergoing intra-articular injection with PRP (mean
age, 57.6 years) and 797 patients with HA (mean age, 59.3 years). The mean
follow-up was 11.1 months for both groups. Mean improvement was significantly
higher in the PRP group (44.7%) than the HA group (12.6%) for WOMAC total
scores (P < 0.01). Of 11 studies based on the VAS, six reported PRP patients
to have significantly less pain at the latest follow-up when compared with HA
patients (P < 0.05). Of six studies based on the Subjective IKDC outcome
score, three reported PRP patients to have significantly better scores at the
latest follow-up when compared with HA patients (P < 0.05). Finally, LP-PRP
was associated with significantly better Subjective IKDC scores vs. LP-PRP (P
< 0.05).64

Park and colleagues65 conducted an RCT to evaluate the efficacy of inter-
articular PRP injections in knee osteoarthritis as compared with hyaluronic
acid (HA) injection and to determine if clinical efficacy is associated with
its biological characteristics. This RCT enrolled 110 symptomatic knee
osteoarthritis patients who received a single injection of leukocyte-rich PRP
or HA. Outcomes were assessed at baseline, six weeks, three and six months
after injection. Authors reported PRP showed significant improvement in IKDC
subjective scores at six months vs. HA. No significant differences were
observed between the clinical outcomes in other groups. The proportion of
individuals who scored above the minimal clinically important difference
(MCID) for VAS at six months was significantly greater in the PRP group (P=
0.044). Adverse events did not differ between the groups. Strengths of this
study include RCT design, clearly define protocol for and PRP preparation and
administration, and standardized tools for pain assessment. Limitations
include lack of placebo group and lack of radiological imaging. While it makes
valuable contribution comparison to other studies with confounder such as
leukocyte rich vs. poor, number of injections, type of preparation kit, and
underlying medical conditions, adjunctive therapies were not addressed.

To address these differences, several authors have attempted to use SR/MA
approach to pool data. Three meta-analyses comparing the literature on the
effectiveness and safety of PRP and HA in patients with adult knee
osteoarthritis were reviewed. Tan et al66 reviewed 26 RCTs with 2,430
individuals and reported PRP significantly reduced patient pain and improved
function as compared to HA.66 Chen et al67 reviewed 14 RCTs comprised of 1,350
patients and Han et al68 reviewed 15 RCTs comprised of 1,314 individuals
reporting PRP injections reduced pain more effectively than HA injections. All
three trials reported no significant difference in adverse events between the
two groups. However, meta-analysis cannot adequately address these factors as
they have not been adequately investigated in the trials included in the
analysis. The fundamental issues as multiple confounders such as the source of
stem cells, most effective delivery method, role of surgery and type and
amount of PRP used are not addressed in high-quality studies.69 This
significant heterogeneity subsequently affects the reliability of conclusions.
Additionally, despite the seemingly large body of evidence, it is important to
note that some RCTs were included in multiple SR/MAs.

A recent prospective study compared the efficacy of intra-articular injections
of PRP and HA with a control group of NS solution for knee OA. This was a
randomized, dose-controlled, placebo-controlled, double-blind, triple-parallel
clinical trial. A total of 87 osteoarthritic knees (53 patients) were randomly
assigned to 1 of 3 groups receiving three weekly injections of either LP-PRP
(31 knees), HA (29 knees), or NS (27 knees). WOMAC score and IKDC subjective
score were collected at baseline and at 1, 2, 6, and 12 months after
treatment. All three groups showed statistically significant improvements in
both outcome measures at one month; however, only the PRP group sustained the
significant improvement in both the WOMAC score (63.71  20.67, increased by
21%) and IKDC score (49.93  17.74, increased by 40%) at 12 months. The
conclusion was that intra-articular injections of LP-PRP could provide
clinically significant functional improvement for at least one year in
patients with mild to moderate OA of the knee.70

Osteoarthritis of the hip can also be a source of chronic pain. A 2021 double-
blind, randomized pilot study of leukocyte-poor PRP compared to low-molecular
weight hyaluronic acid for symptomatic osteoarthritis of the hip was reported
on thirty-four patients with hip OA. The patients were randomized to three
weekly PRP injections or hyaluronic acid, and conversion to total hip
arthroplasty or hip resurfacing procedure was the primary outcome with pain
scores as the secondary outcome. They reported fewer patients converted to
surgical management and lower pain score in the PRP group (n= 19) within six
months; however, an additional 15.8% of the PRP patients with improvements
went on the surgical management within the first year.71 Limitations include a
sample size too small for statistically significant findings, lack of placebo
group, short-term follow-up, and risk of bias. A 2021 systematic review using
GRADE methodology evaluated the effectiveness of PRP in the management of hip
OA. Four trials (334 participants, 340 hips) were included, and all were
marked as "moderate risk of bias". PRP's superiority against comparative
treatments was reported in one study, longer-term evaluations from four to
twelve months showed diverse results, and only one study reported
significantly better result for PRP. The authors recognize considerable
heterogenicity and small sample sizes among the studies, which were considered
moderate to low quality. They conclude while PRP may be beneficial and safe
for hip OA at mid-term follow-up, further research with high-quality designs,
larger sample sizes, and comparison to standard treatments are imperative.72

However, evidence is still limited due to the overall high risk of bias in
previous trials and great variability between studies regarding the number of
injections (generally 1 to 4), the interval between injections, preparation of
the PRP, and volume injected. Furthermore, the typical length of follow up was
only one year or less. There is also uncertainty regarding whether individuals
with less severe OA may benefit more from this intervention compared with
individuals with more advanced structural damage. Additionally, it is unclear
whether LR-PRP or LP-PRP should be utilized, though the latter appears to have
an advantage. Larger controlled studies comparing PRP with placebo and
alternatives other than HA are needed to determine the efficacy of PRP for
knee OA. Further studies are also needed to determine the optimal protocol for
delivering PRP. At present, the evidence is insufficient to determine the
effects of PRP on health outcomes for OA.

**Primary Treatment for Chronic Low Back Pain**

Low back pain (LBP) is now regarded as the first cause of disability
worldwide, causing morbidity and socioeconomic loss.73 Conventional treatments
include physical therapy, CS injection, medial bundle branch block (MBBB), and
surgery. Intervertebral disc (IVD) degeneration is an important pathogenesis
of LBP. Several animal studies have shown that the injection of PRP into
degenerated IVDs effectively restores structural changes (IVD height) and
improves the matrix integrity of degenerated IVDs as evaluated by MRI and
histology.74 Recently, a small number of studies have promoted PRP injection
as a relatively safe means of treating patients with degenerative disc disease
who have failed other means of managing their LBP. A small number of
prospective trials have suggested there may be some benefit to using PRP
injection in the treatment of pain or functional decline caused by facet joint
arthropathy.75

A 2016 double-blinded, randomized controlled trial compared PRP (n= 29) to
control (contrast agent) (n= 18) for moderate to severe lumbar discogenic pain
unresponsive to conservative treatment. While data was collected for one year
on patients randomized to the control group, 15/18 crossed over to PRP at
eight weeks. They concluded superiority of PRP to the control group.
Limitations included the comparative analysis was modified, limited follow-up
for the control group, underpowered to detect the demonstrated difference in
functional rating index score at eight weeks between the study groups, no data
collection on cell counts or biochemical analysis of the PRP, and there was no
routine radiologic follow-up to see if morphologic disk changes occurred with
clinical improvement.76

A 2016 study of 40 patients with chronic low back pain of sacroiliac joint
(SIJ) origin was randomized to corticosteroids with lidocaine or leukocyte-
free injections and evaluated at 2, 4 and 6 weeks, and 3 months. They reported
lower pain scores at both six weeks and three months in the PRP group,
concluding PRP is an effective treatment.77 Limitations of this study include
short follow-up time, no disease scoring, risk of bias, and small sample size.
This study was included as the only RCT in a 2020 systematic review, along
with two case series using GRADE to evaluate evidence and concluded very low-
quality evidence. The authors include inconsistent reporting of demographics,
patient diagnosis and selection, PRP preparation, storage and administration,
and con-interventions as limitations in the literature.78

A 2020 study of 50 patients with low back pain secondary to SIJ were injected
with platelet-rich plasma into the sacroiliac joint under ultrasound guidance.
Oswerty Disability Index (ODI) and Numeric Rating Scale (NRS) were measured at
baseline, two weeks, four weeks, three months, and six months after injection.
Authors concluded ultrasound-guided PRP injections into the SIJ were safe and
effective for reducing functional disability and decreasing low back pain.
They report most effects are seen at two to four weeks, with sustained
functional improvement and pain relief at six months. The authors reported
missed follow-up visits, selection of participants were recruited from a
single site, and the need for longer follow-up as study limitations.79

A non-randomized comparator study by Bise et al80 looked at the efficacy of
interlaminar computed tomography (CT) guided epidural PRP and CS injections in
60 patients. Utilizing the NRS and function with the ODI before and six weeks
after treatment. At six weeks, there was found to be no statistical difference
between the two groups.

The American Society of Interventional Pain Physicians reviewed the evidence
for PRP usage in LBP. They found Level III evidence for intradiscal injections
of PRP. In contrast, the evidence is considered Level IV for lumbar facet
joint, lumbar epidural, and sacroiliac joint injections of PRP (on a scale of
Level I through V) using a qualitative modified approach to the grading of
evidence based on best evidence synthesis.73 The evidence is insufficient to
determine the benefit of PRP on health outcomes for chronic LBP.

The use of autologous biologics to replace or restore damaged tissue is a
relatively new area of medicine that has yet to substantiate its outcomes.73
The American Academy of Orthopedic Surgeons (AAOS) announced at its November
2019 meeting that over the next five years, it would prioritize research and
development for biologics to create evidence-based position statements. Their
goals are to establish registries for post-market monitoring, standardize
reporting requirements and clarify by disease state a consensus approach for
biological markers and clinical trial design.81

PRP is a general term describing a therapy with no gold standard of
preparation or administration technique. This heterogeneity and the small
number of controlled trials make it difficult to assess the efficacy of PRP
for any disorder. There is a lack of standardization of the preparations of
PRP amongst the trials, with varying concentrations of platelet, frozen vs.
fresh preparations, and the filtration of white cells. While the body of
evidence of utility for PRP is large, the overall quality of evidence is low.
The studies are relatively small, observational studies, often confounded by
lack of treatment control, precluding cause-and-effect conclusions. RCTs that
compare outcomes in patients whose treatment is standardized are needed to
determine definitive patient selection criteria and clinical utility. The lack
of high quality studies, no clinical practice guideline endorsement, and no
commercial coverage argue strongly against current PRP coverage as reasonable
and necessary for treating Medicare patients.

For a treatment to be considered medically reasonable and necessary per
1862(a)(1)(A) of The Act the treatment must be appropriate, including duration
and frequency furnished in accordance with accepted standards of medical
practice for the condition.82 Novitas Solutions determines that the existing
evidence and lack of accepted standards of medical practice for PRP injections
do not meet the requirement of medically reasonable and necessary. Thus,
Novitas Solutions considers PRP injection and PRP combined with stem cells for
musculoskeletal injuries and/or joint conditions, whether primary or
adjunctive use, not medically reasonable and necessary. Once PRP preparations
are standardized, trials can more precisely highlight which factors are
associated with better outcomes, yielding more effective PRP preparations and
patient selection criteria. Novitas Solutions will continue to monitor
scientific developments and may adjust this coverage policy in accordance.