We believe that this is the only double blind, randomised, placebo controlled trial evaluating aprotinin in Achilles tendinopathy. We compared aprotinin and exercises with placebo and exercises in order to see if aprotinin offered a benefit in both the short and long term. We used the VISA‐A scale as a functional grade of severity as the primary outcome measure.
Our results do not indicate any statistically significant improvement in the aprotinin group over placebo at any follow up visit for either the primary or secondary outcome measures. Despite this, there was a consistent trend towards improvement in the aprotinin group as measured by the VISA‐A and secondary outcome measures.
The lack of statistical significance may be due to the small sample size. In order to detect a difference in VISA‐A score of 60–70, with standard deviation of 13, power of 80%, and a significance level of 5%, approximately 28 patients per group would be required. It was difficult to recruit patients to this study involving a placebo injection, because all patients were given the choice between active treatment or enrolment in the study, and the majority chose active treatment.
Our results at 3 months are not as good as previous studies for eccentric exercises.10,29
Only 13% of the placebo group and 31% of the aprotinin group had returned to their previous level of sport. It is not apparent whether the low levels of return to sport at 3 months compared with the previous studies were due to chance, different methods of subject recruitment, negative effects of using injections, or poorer compliance with eccentric training because an injection was used. However, at 12 months, the overall results were markedly better, as 85% in the placebo and 77% in the aprotinin group had returned to their previous levels of sport.
Four patients with bilateral tendon involvement received placebo on one side and aprotinin on the other. One patient did very well, with both tendons scoring 100 on the VISA‐A 100 at 12 months. One patient was similar at all follow up points, except at 12 months, with VISA‐A of 87 for the aprotinin treated tendon and 76.5 for the placebo treated tendon. This patient did not elect to have the aprotinin injection following the study. One patient was similar at all follow up points except 12 months, when VISA‐A was 100 for the aprotinin treated tendon and 81 for the placebo treated tendon. This patient elected to have an aprotinin injection following the study period due to dissatisfaction with the placebo treated tendon. One patient did poorly with both tendons and withdrew from the study after the third injection. These observations of randomly allocated tendons within the same patient suggest a trend towards better results with aprotinin than placebo.
Of the two patients (three tendons) that withdrew from the study because of dissatisfaction, two tendons were treated with placebo and one with aprotinin. One patient with a placebo allocated tendon elected to have the aprotinin following withdrawal from the study, and returned to full activities after the crossover aprotinin injection.
The dosing regimen used was 30
000 IU in three injections spaced 1 week apart. The literature shows a range of doses (20
and there seems to be no standard number of injections. The doses used in this study were the same as we had previously used successfully in private practice.28
It may be that the lack of statistical significance was due to an insufficient aprotinin dose.
We note that a significant problem with aprotinin is the risk of allergic reaction. Aprotinin is derived from bovine lung and possesses antigenic properties in humans.30
Hypersensitivity and anaphylaxis are <0.1% with no prior exposure and 2.7% with re‐exposure.25
Anaphylaxis upon re‐exposure in cardiac patients was confirmed in 2.5% of patient's.31
In the two previous studies with aprotinin and in our study there were no anaphylactic reactions.1,3
Orchard et al
reviewed 422 injections, and showed a systemic allergy rate of 2.6% upon re‐exposure.28
The described regimen of aprotinin therapy in the literature is three injections spaced 1–2 weeks apart.1,3
The risks of systemic allergic reaction on re‐exposure may mean that a preferable regimen is to space the injections further apart.25
In our study, no patient had any clinically significant allergic reaction, nor was there any infection or tendon rupture during the study period. No statistically significant difference for postinjection itch or for injection pain was shown.
What is already known on this topic?
- Aprotinin is a well documented collagenase inhibitor
- Previously there have been two randomised trials using aprotinin, one on patellar tendinopathy showing a significant improvement over placebo and one semi‐randomised trial on Achilles tendinopathy showing a significant improvement over placebo
What this study adds
- Using a functional grade of severity and a functional outcome measure in a double blind placebo controlled trial we failed to confirm the benefit of aprotinin in tendinopathy
The typical histopathological changes of tendinopathy include degenerated and disordered collagen, hypercellularity, vascular ingrowth and an increase in ground substance.8
The exact pathogenesis of these changes and the source of the pain are still not well understood.
A proposed mechanism for tendinopathy is a change in the balance between matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinases (TIMP).32,33,34
MMPs and TIMP are responsible for tissue remodelling.34
Recent studies suggest that there are alterations in these levels in diseased tendons.32,33,34,35
Specifically, MMPs may increase and TIMP decrease, leading to excess collagen degradation33,35
and thus tendinopathy.
MMPs are endopeptidases that cleave constituents of the extracellular matrix.30
Specifically, MMP‐1 cleaves collagen type 130
the main collagen found in tendons. In a study comparing diseased and control patellar tendons, the diseased tendons showed an increased expression of MMP‐1 and a decreased expression of TIMP.35
It is still not clear whether increased expression of MMPs is responsible for causing tendinopathy.
Aprotinin has level 1b evidence as a treatment for patellar tendinopathy.1
There is also level 2b and level 3b evidence for aprotinin in Achilles tendinopathy.3,26
The histological appearance of patellar and Achilles tendinopathies is indistinguishable.36
We propose that a larger trial would be required to adequately assess the efficacy for aprotinin in achilles tendinopathy.