Platelet-rich plasma versus lidocaine as tenotomy adjuvants in people with elbow epicondylopathy: a randomized controlled trial

The study protocol was approved by the local Ethics Committee of HUC, authorized by the Spanish Agency of Medicines (EudraCT 2013-000478-32), registered at clinicaltrials.​gov (NCT01945528) and was published previously [19].

Between April 2014 and May 2017, a total of 85 patients with elbow tendinopathy were referred to the Orthopaedic Department at Cruces University Hospital, by general practitioners or by other orthopaedic departments, and they were assessed for eligibility. Eighty-two patients met the inclusion/exclusion criteria and underwent blood tests. All patients provided written informed consent and could decide to leave the study at any time.

The experimental and control groups were ultrasound (US)-guided percutaneous tenotomy combined with PRP each alternate week for a total of two interventions and US-guided tenotomy combined with lidocaine each alternate week for a total of two interventions.

Twenty-four mL of peripheral blood (i.e., three 9 mL tubes containing 0.9 mL of sodium citrate, Vacuette, Greiner BioOne, Switzerland) were withdrawn from all patients at every intervention. Pure (leukocyte-free) PRP was prepared by single spinning at 570 G for 6 min and the plasma layer was collected, under laminar flow, avoiding aspirating the buffy coat, following our standard operating procedures. In doing so, we obtained approximately 6-8 mL of pure PRP (no leukocytes) without detectable leukocytes and a moderated enrichment of platelets (2.30 ± 0.68 times above peripheral blood baseline). According to previous classifications [20], it can be described as pure platelet-rich plasma (P-PRP) or leukocyte-poor platelet-rich plasma, i.e., preparations without leukocytes and with a low-density fibrin network after activation.

At the interventional radiologist office, PRP is activated with CaCl₂ (final concentration 22.5 mM) prior to loading 5 mL in a 10-mL Luer-lock syringe.

We performed all procedures with the patient in a supine position, the elbow flexed 120° and forearm in pronation (lateral) or supination (medial), guided with a 4-13 MHz high-frequency linear probe (Esaote MyLab 70 XVG, Esaote S.p.A. Genoa, Italy). A senior radiologist with more than 20 years of experience in musculoskeletal interventional ultrasonography performed all tenotomies.

A sterile protocol was followed as for any other musculoskeletal intervention. The subcutaneous tissues overlying the lateral epicondyle were infiltrated tangential to the plane of the lateral epicondyle with 2 mL lidocaine via a 22-gauge hypodermic needle. Then, the bulb containing the injectable (PRP or lidocaine) was connected to the needle, which was inserted parallel to the tendon long axis, from distal to proximal. The tendon was repeatedly fenestrated (15–25 times) by redirecting the needle in different directions, until softening of the tissue. In addition to piercing the tendon, the tip needle was used to abrade the periosteum. At the same time, the injectable was delivered in the areas of hypoechogenicity and the surround. A second intervention, involving approximately ten tendon perforations and no abrasions of the periosteum, was performed after 2 weeks. We injected 4.23 ± 1.09 mL (range 1–5) of lidocaine and 4.47 ± 1.11 (range 1–5) of PRP in the first intervention and 4.18 ± 1.14 mL (range 1–5) of lidocaine and 4.53 ± 0.88 mL (range 2–5) of PRP in the second intervention. There were no differences between the injected volumes. After each intervention, patients were instructed to rest for the first 48 h and avoid weight lifting. Patients did not follow any post-procedural exercise programme, but they modified their activities and resumed physical work upon demand.

The primary outcome measures were the number (percent) of patients who achieved clinically relevant improvement, defined as a reduction in Disabilities of the Arm, Shoulder and Hand self-reported questionnaires, Spanish version (DASH-E), of at least 25% relative to baseline [21] at 6 and 12 months. Secondary outcome measures were the number (percent) of patients who achieved a clinically relevant improvement in pain, VAS-P (0–10 Likert scale), at 6 and 12 months. For safety assessments, patients recorded any adverse reaction and needed medication in a diary that was collected at each hospital visit. Acetaminophen was the only drug allowed for pain.

We assumed that the relative improvement with the PRP intervention was 1.43, assuming that the differences between PRP and lidocaine would be similar to the differences reported with corticoids [22], and a patient loss of approximately 20%. A sample size of 80 patients was expected to provide an 80% potency to detect any significant difference between the success rates in both groups (P1 = 0.93 and P2 = 0.65) with a level of significance of 5%, with each arm formed by 40 patients.

An independent researcher performed randomization in blocks of four, using EPIDAT3.1, and created aluminium paper blinded envelopes with the numbered treatment allocation. The numbered envelopes were opened on the treatment day by the researcher who was in charge of the PRP preparation. All physicians (including orthopaedists involved in clinical outcome assessments and radiologists involved in ultrasound assessments), except one radiologist who performed the procedures, were unaware of treatment allocation. All patients were blinded to the treatment. Peripheral blood was drawn from all patients, and in each intervention, the syringe containing the treatment was wrapped with gauze hindering treatment visualization.

To test the overall effect of the treatment, [tenotomy + PRP] and [tenotomy + lidocaine], on an intention-to-treat basis, we compared changes in function and pain levels between the two groups over 12 months. No imputation method was used to handle the missing data. To confirm comparability between groups at baseline, Student’s t test was used for continuous variables due to the proven normal distribution of the data in both groups, and a x² test was used for categorical variables. Spearman’s tests were used to assess the association between outcome variables. Data are summarized as the mean and standard deviation for normally distributed variables, medians and interquartile ranges for non-normally distributed variables and the frequency and percentage for categorical variables. To evaluate the differences between the PRP and lidocaine groups, longitudinal generalized mixed models, with and without adjustments, were used, considering the repeated four follow-up measurements for each patient. The treatment, the time of measurement and treatment-by-time interaction were included as fixed effects in the models. Patients were included as random effects in the intercept of the different repeated measurements. Time evolution was considered as a categorical variable without autocorrelation within an individual. These options were chosen because they provided a better fit to our data. The overall effect of the treatment was assessed by testing the interaction between the treatment and time of measurement. Additionally, these models were also adjusted for baseline values of the outcome variables, socio-demographics and risk factors, possible determinants of pain and function. Likewise, to simplify the fixed effects structure, maximum likelihood ratio tests were used following backward, forward and stepwise strategies. Unadjusted and adjusted odds ratios with 95% confidence intervals (CI) and mean differences with 95% CI were calculated for categorical and continuous outcomes, respectively. Planned contrasts were used to determine whether changes in the PRP group between baseline and each of the follow-up points were different from those observed in the lidocaine group. For all the contrasts, p < 0.05 was considered the significance criterion.

A post hoc power calculation was performed based on longitudinal mixed effects models adjusted to the final sample size, actual data variability and clustering to detect differences with small (0.2 standard deviations), medium (0.5 standard deviations) and large (0.8 standard deviations) effect sizes between the comparison groups. All analyses were carried out using the SAS statistical package version 9.4.

Successful treatment was defined as more than 25% reduction in DASH-E or VAS-P scores after 1 year. Table 3 shows the rate of patients who met these criteria in each measurement. A high rate of patients showed enhanced function and pain reduction over the 12-month follow-up.

Data for functional improvement were available for 25 (71.43%) and 24 (68.57%) patients in the lidocaine group and 26 (72.22%) and 25 (69.44%) patients in the PRP group, at 6 and 12 months, respectively. There were no significant differences between therapies in terms of the rate of patients who achieved the minimum clinically important difference in function recovery at 6 or 12 months after treatment (Table 3). The differences in the percentage of success between [tenotomy+lidocaine] and the [tenotomy+PRP] were − 1.94% (95% CI, − 30.46 to 26.59) at 6 months and − 6.03% (95% CI, − 35.98 to 23.90) at 12 months.

In the case of pain, the frequencies for the available data were 29 (82.85%) and 25 (71.43%) in the lidocaine group and 26 (72.22%) and 22 (61.11%) in the PRP group. Likewise, there were no differences between tenotomy adjuvants (lidocaine versus PRP) in the rate of patients who achieved clinically important pain relief and differences in the percentage of success at 6 months, − 10.56% (95% CI, − 33.01 to 11.89), and at 12 months, − 11.51% (95% CI, − 32.29 to 9.27). The differences between the two groups in the short term were not statistically significant either. The difference in the percentage of patients with better functionality at 6 weeks was 7.53% (95% CI, − 27.62 to 42.67) and at 3 months was 26.62% (95% CI, − 0.82 to 54.06). The difference in the percentage of patients with pain reduction exceeding 25% at 6 weeks was 21.70% (95% CI, − 8.63 to 52.02) and 20.81% (95% CI, − 6.84 to 48.47) at 3 months.

Essentially, the time course was different between treatments. In the PRP group, the increase in the rates of patients who achieved functional improvement and pain reduction was steadier than in the lidocaine group, which reached a plateau at 3 months. Furthermore, there was no statistical evidence of a modification in treatment effects by the controlled patient’s factors. When data were adjusted for confounders, both groups showed enhanced function and pain reduction over the 12-month follow-up without significant differences between PRP and lidocaine (see Fig. 2 and Table 3).

There were no differences between lidocaine and PRP in DASH-E and VAS-P over time (Fig. 3a, b).

The estimated power calculated with our current data, for small, medium and big differences for DASH-E were 0.12, 0.26 and 0.93, respectively. Likewise, estimated powers for VAS-P were 0.18, 0.81 and 0.99, respectively.

Twenty-three adverse events in twelve patients (six patients from each treatment group) were reported as probably (n = 22) or likely (n = 1) related to treatment. Pain and swelling were the most commonly reported in the 6 weeks following tenotomy. In addition, throughout the 12-month follow-up, a total of 593 events were reported as unlikely or not related to the treatment. They included headache, migraines, back pain, shoulder pain, gastrointestinal discomfort and allergies, with cold and flu being the most common among others.