Welcome to tendinopathy blog 24.
Hello from sunny Manchester, have really enjoyed a couple of days here talking at a conference and learning lots about biomechanics from Andy Franklin-Miller and Simon Bartold, among others.
What are the best progressive rehab and energy storage programs and how do you individualise them? If this and other tendon clinical challenges keep you up at night join me in the upcoming Mastering Lower Limb Tendinopathy course series around in Adelaide, Perth, Melbourne, Sydney and Brisbane.
This blog this week (subscribe here) focuses on the use of platelet rich plasma (PRP) in tendinopathy. The popularity of PRP around the world is astounding given the relative lack of evidence. I will review a new randomised controlled trial in Achilles tendinopathy and then go into the nitty gritty of PRP – rationale, mechanisms, evidence and indications.
Hope you enjoy
What they did: This study by Krogh et al. from Denmark is hot off the press. One of the co-authors is Dr Ulrich Fredberg who has published widely in the area of tendinopathy. The authors investigated the clinical effects of platelet rich plasma (PRP) in managing Achilles tendinopathy (AT). They performed an RCT to determine whether a single PRP injections is more effective than a saline injection (placebo control) in treating AT.
24 patients with midportion AT were randomised in to the PRP or saline group. Follow was performed at 3, 6 and 12 months and included the primary outcome of VISA change at 3 months. Pain at rest, walking and when palpating the Achilles was rated (numeric rating scale). At 3 months those that were not satisfied had the option to leave the study and receive usual care. The patients were blind to the injection they received – to achieve this blood was taken from all participants, and they were blind folded whilst receiving the injection. 6mL of saline and PRP was injected with a ‘peppering’ technique at 7 points along the tendon. 54mL of blood was taken from participant’s arm and after spinning 6mL of PRP (8 fold greater platelet concentration than blood). Participants were advised to minimise Achilles load for 4 days then commence a very basic unloaded eccentric program, calf/quads stretching, and step ups.
What they found: There were no baseline group differences for key characteristics age, BMI, tendon thickness, and self reported pain/function on VISA (this was very low at 32-37 – these were end of the road patients presenting to a tertiary referral clinic). 10 (83%) in the PRP group and 6 (50%) in the saline group left the study at either 3 or 6 month follow up because they were unsatisfied, and after that were treated as ‘normal’ patients. At 3 months there was no significant difference in VISA outcome in either group and the mean improvement was tiny ie 3-5 points. There was also no significant change in pain at rest, walking and on palpation. Ultrasound imaging showed an increase in thickness in the PRP group compared with a small decrease in the saline group and the difference was significant. The authors report that one patient in the PRP group contacted the hospital with concerns about the level of increasing pain.
Clinical interpretation: The huge drop out of participants is interesting and suggests the treatments did not work - people in the PRP felt no benefit or thought they may have had the saline treatment so therefore dropped out to get the ‘real’ treatment. It seems they had limited guidance on what to expect/what may happen, so maybe this is part of the poor effect, ie their expectations were not met. So my concerns are twofold; 1) the education the went along with the injection – i.e. to expect an increase in pain after PRP, if there is benefit it will occur later. And 2) the rehab was, in my opinion, possibly not progressive enough to potentiate any effect of the injection (if that happens) or at least lead to some benefit independently.
There are two prior RCT’s comparing PRP or blood injections versus placebo in managing AT and they also found no effect favouring PRP. Both the de Vos et al. 2010 and Bell et al. 2013 studies found clinical benefit in both the placebo and control groups at 6 months with no group differences. The key difference between these studies and the current study by Krogh is that at 3 months these prior studies were getting significant VISA improvement (eg about 15 points in the Bell study), so again this is probably related to the rehab intervention. But, and importantly, we must consider these were tertiary referral patients ie the end of the road ‘basket cases’ – I love seeing these ones, but we know they often have complex pain presentations that is not just about the tendon.
The other interesting finding was a significant difference in Achilles thickness favouring a small increase in thickness (0.5mm) in the PRP group. It may be related to increased ground substance accumulation following cell stimulation with the PRP injection.
Interesting study but let’s not leave it there! Given PRP is such a tendinopathy hot potato, here is a brief review of rationale, effects, evidence and indications…
What are the proposed effects and rationale?
Platelets contain a many growth factors (GF) including platelet-derived epidermal GF, platelet-derived GF, transforming GF, insulin-like GF, vascular endothelial GF, endothelial cell GF, and basic fibroblast GF. Introducing PRP into a pathological tendon is thought to stimulate a healing response. Spinning the blood to concentrate platelets is thought to be important. Having easy access to all these potentially ‘healing’ GF’s is the attraction to PRP and explains why it has become so popular. It is an attractive idea.
What is the reality?
This view that GF can heal a degenerative tendon is simplistic. The healing cascade involves potentially hundreds of growth factors and other biochemical and has evolved over millions of years. Can we really replicate this with a single injection of PRP? We know from imaging studies that improvement in tendon structure in imaging either does not occur or occurs partially, for most people, after PRP injections (e.g. Abate et al. 2014, de Vos et al. 2011). So what does PRP actually do if it does not lead to healing? There is evidence that it is stimulatory to tendon cells in vitro (e.g. Hyunchal et al. 2012) and animal models (e.g. Lane et al. 2013) and leads to greater biochemical production (Foster et al. 2009). The question is whether this is positive or not? Picture a cell that is already stimulated and producing biochemicals that are contributing to pain and pathology – hard to see how anything but the right load stimulus will lead to a positive mechanotransductive response.
What does the clinical evidence say?
It is well known that there is almost a dichotomy of findings from poor and good quality studies. The poor quality case series almost always show that PRP is positive, a wonder drug! The limitations of this design include lack of placebo control group and often no blinding of outcome assessors.
When you look at randomised controlled studies of high quality you get a very different story. In the Achilles studies clearly show no benefit over placebo, 3 studies in total, 2 on PRP and 1 on blood injection. RCT’s in the patellar tendon show some benefit for PRP but compared to shockwave (Vetrano et al. 2013) or dry needling (Dragoo et al. 2014) – these are not fair comparisons and placebo control needs to be investigated in this tendon. A recent systematic review found there was strong evidence to suggest PRP is no better than placebo/control in tennis elbow (de Vos et al. 2014).
No surprise that in Australia the healthcare rebate for PRP was removed 2 years ago. It was becoming so popular, the government was spending millions, and the evidence was just not there.
The IOC consensus group on PRP said this in 2011: ‘With respect to PRP, its increasing popularity appears to have outreached in some respects the principle of medical ethics and the usual conservatism that new treatments are taken up by the clinicians. Part of the answer to this would be that PRP is presently marketed and widely perceived as a natural healing method with the implications of minimal maleficence (harm)’. Which I agree with totally.
What do the supporters say to this?
There are multiple factors that may influence the strength and concentration of PRP. These include delay between preparing and administering, concentration of leukocytes (which may have an inflammatory effect), the number of injections (evidence from case series (Charousset et al. 2014) suggests more is better – of course it is!), etc, etc. Basic scientists work hard to formulate the best potion, but little is known about how much differential healing and clinical effect various potions will have. Based on a fatal flaw of over simplified rationale, you could argue the effect may be limited.
Just before I was going to send this blog off for printing, this review by Fitzpatrick et al. 2016 was released online. They included 18 studies in their review and did something very different – they compared different PRP preparations. The main comparison was between leukocyte rich and leukocyte poor PRP, and they report a ‘strongly positive effect’ for leukocyte rich PRP. However, there was only 1 leukocyte poor PRP study compared to 11 leukocyte rich studies. And, they did something very cheeky, and that is they argued that all injections are active treatments (even saline), so they did not compare PRP to control, but instead simply looked at benefit with injections in all study arms (active and placebo) separately. So for example they included the de Vos 2010 study in the leukocyte rich analysis, but in this study this leukocyte rich PRP was clearly no different to a placebo saline injection. Maybe ’make the clinician rich’ is a better name than leukocyte rich, because clearly if you can get the same result with placebo this should be the bottom line and take home message in a review!!
Should we recommend it?
PRP, in my opinion, should be reserved as a very last resort for someone who has stable pain. Stable pain because from anecdotal evidence and experience this limits the chance they will have a really poor response (a flare in pain). The worst response I have seen is a severe flare for 6 weeks and the person needs high dose anti-inflamms for weeks just to be able to function again!
What are the alternatives?
The key issue with PRP is that there are very few alternatives that are any good. We know overall no injections in tendinopathy are supported by strong evidence. But some, like steroid, go a step further and actually may cause harm or lead to worse outcomes in the long term (e.g. Coombes et al 2013). There is no evidence that PRP leads to rupture or poorer outcomes in the long term. The other option is high volume injection – new paper just came out, the first RCT as far as I know, comparing high and low volume. More on this soon!
Here is a key points summary
Clinical gems and awesome management models. Your patients will love you for it!