Article Text

Effect of ripasudil after trabeculectomy with mitomycin C: a multicentre, randomised, prospective clinical study
  1. Aisyah Muhlisah1,
  2. Kazuyuki Hirooka1,
  3. Ariyanie Nurtania1,
  4. Hiromitsu Onoe2,
  5. Hideaki Okumichi3,
  6. Eri Nitta4,
  7. Tetsuya Baba5,
  8. Masaki Tanito6,
  9. Yotaro Matsuoka7,
  10. Shunsuke Nakakura8,
  11. Yoshiaki Kiuchi3
  1. 1Department of Ophthalmology and Visual Science, Hiroshima University Faculty of Medicine Graduate School of Biomedical and Health Sciences, Hiroshima, Hiroshima, Japan
  2. 2Hiroshima University Faculty of Medicine Graduate School of Biomedical and Health Sciences, Hiroshima, Hiroshima, Japan
  3. 3Ophthalmology, Hiroshima University Faculty of Medicine Graduate School of Biomedical and Health Sciences, Hiroshima, Hiroshima, Japan
  4. 4Department of Ophthalmology, Kagawa University Faculty of Medicine Graduate School of Medicine, Kita-gun, Kagawa, Japan
  5. 5Department of Ophthalmology, Shirai Eye Hospital, Mitoyo, Japan
  6. 6Shimane University Faculty of Medicine Graduate School of Medicine Department of Ophthalmology, Izumo, Shimane, Japan
  7. 7Department of Ophthalmology, Matsue Red Cross Hospital, Matsue, Japan
  8. 8Ophthalmology, Saneiekai Tsukazaki Hospital, Himeji, Japan
  1. Correspondence to Dr Kazuyuki Hirooka; khirooka9{at}gmail.com

Abstract

Background To investigate if there are improvements in trabeculectomy outcomes supporting filtration bleb formation caused by Rho-associated protein kinase (ROCK) inhibitors.

Methods This prospective, multicentre, randomised, open-label clinical study examined open-angle glaucoma patients who underwent trabeculectomy or trabeculectomy combined with cataract surgery followed by 3-month postoperative ripasudil treatments. After randomly allocating patients to ripasudil—ROCK inhibitor (ripasudil) or without ripasudil (non-ripasudil) groups. Mean intraocular pressure (IOP) changes, success rate, and number of eyedrops were compared for both groups.

Results A total of 17 and 15 subjects dropped out in the ripasudil group and non-ripasudil group, respectively. At baseline, the mean IOP was 16.8±5.0 mm Hg in the ripasudil group (38 patients) and 16.2±4.4 in the non-ripasudil group (52 patients). The IOP decreased to 11.4±3.2 mm Hg, 10.9±3.9 mm Hg and 10.6±3.5 mm Hg at 12, 24 and 36 months in the ripasudil group, while it decreased to 11.2±4.1 mm Hg, 10.5±3.1 mm Hg and 10.9±3.2 mm Hg at 12, 24 and 36 months in the non-ripasudil group, respectively. There was a significant decrease in the number of IOP-lowering medications after trabeculectomy in the ripasudil group versus the non-ripasudil group at 24 (p=0.010) and 36 months (p=0.016). There was no statistically significant difference between the groups for the 3-year cumulative probability of success.

Conclusion Although ripasudil application did not increase the primary trabeculectomy success rate, it did reduce IOP-lowering medications after trabeculectomy with mitomycin C.

  • Intraocular pressure
  • Glaucoma
  • Clinical Trial

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Fibroblast proliferation is significantly suppressed by Rho-associated protein kinase (ROCK) inhibitors. ROCK inhibitors have an indirect effect, by helping to maintain the filtering function. Therefore, it is important to investigate if there are improvements in trabeculectomy outcomes supporting filtration bleb formation caused by ROCK inhibitors.

WHAT THIS STUDY ADDS

  • Our present examination of ripasudil and non-ripasudil groups did not find any significant differences in the intraocular pressure (IOP) after trabeculectomy with mitomycin C (MMC). However, the number of IOP-lowering medications from the second to third year after the trabeculectomy with MMC may be reduced after the addition of ripasudil.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • Although ROCK inhibitor, ripasudil, application after trabeculectomy with MMC did not improve surgical outcomes, it did reduce IOP-lowering medications after trabeculectomy with MMC.

Introduction

Glaucoma is one of the leading causes of blindness, with around 70 million worldwide suffering from the condition.1 Reduction of the intraocular pressure (IOP) is the only evidence-based treatment reported for glaucoma, with this achieved through the use of medication, laser therapy, and/or surgery.

The standard glaucoma surgical technique involves the use of the common filtering surgery, trabeculectomy. In this procedure, a surgical bypass for aqueous humour is created from the anterior chamber to under the conjunctiva via the use of the scleral flap. This creates a filtering bleb in the conjunctiva, thereby leading to a reduction of the IOP.2 Achieving a constant shunting of the aqueous humour from the anterior chamber to the subconjunctival area is the target for a successful glaucoma filtering surgery. After glaucoma filtration surgery, the primary cause of failure is due to scar formation, which is associated with increased fibroblast proliferation, activation and collagen deposition.3 The physiological healing response to the surgical injury is responsible for the scarring that occurs. After the trabeculectomy, the initiation of wound healing and scar formation targets the fibroblasts in the Tenon’s capsule. Thus, scarring can be limited through the perioperative utilisation of antimetabolites, such as 5-fluorouracil and mitomycin C (MMC).4

Other regulators of tissue fibrosis that have recently been reported on include Rho GTPases and Rho-associated protein kinase (ROCK).5 Renal, cardiac, pulmonary and hepatic fibrosis models have found antifibrotic effects for fasudil (HA-1077), which is a ROCK inhibitor. Following exposure to transforming growth factor beta (TGF-β), Pitha et al reported that a ROCK inhibitor reduced the development of the myofibroblast phenotype in scleral fibroblasts. Reductions in the TGF-β-induced α-SMA (α-smooth muscle actin) expression and cell contractility of cultured primary human peripapillary sclera fibroblasts were also found after the administration of the ROCK inhibitors, Y27632, H1152 or fasudil.6 In addition, Ibrahim et al reported that human Tenon’s fibroblast (HTF)-mediated collagen gel contraction, expression of α-SMA and vimentin (fibrosis markers) and fibroblast proliferation without induction of apoptosis were significantly suppressed after administration of Y-27632.7 Isobe et al examined Y-27632 or HA-1077 on the inhibitory properties of ripasudil on serine-threonine type protein kinase. As compared with the other ROCK inhibitors, ripasudil had a 2–17 times stronger effect on the ROCK inhibition. Furthermore, as compared with other serine/threonine kinases, ripasudil was found to be selective for ROCKs.8

In 2014, the ROCK inhibitor ophthalmic solution, ripasudil (Glanatec ophthalmic solution 0.4%; Kowa Company, Japan), was approved by the Japanese government. Use of the solution in patients with open-angle glaucoma and ocular hypertension was shown to have acceptable safety, reduce the IOP and continue to have IOP-lowering effects after 1-year application of 0.4% ripasudil. In a rabbit model of glaucoma surgery, Honjo et al administered the ROCK inhibitor, Y-27632, and showed that it had an effect on the activities of HTFs and effectively prevented the fibroproliferative response and scar formation.9 ROCK inhibitors also have an indirect effect, by helping to maintain the filtering function. This suppresses the subconjunctival fibrosis, thereby preventing the fibrosis that can occur after trabeculectomy. Topical application of ripasudil is potentially effective after glaucoma surgery in maintaining filtration bleb formation by suppressing fibrogenic collagen deposition in the tissue surrounding the bleb thereby reducing IOP. However, there is no literature regarding the clinical use of ROCK inhibitors to improve trabeculectomy outcomes in humans. In the present study, we attempted to determine if there were any differences in the reduction of the IOP and the surgical outcomes in glaucoma patients after undergoing trabeculectomy.

Patients and methods

This prospective, multicentre, randomised, open-label clinical study was registered as UMIN in the University Hospital Medical Information Network Clinical Trials Registry. The study protocol (online supplemental material) was approved by the Institutional Review Board of Hiroshima University (C-43). Six hospitals participated in this study: Hiroshima University Hospital, Kagawa University Hospital, Shirai Hospital, Matsue Red Cross Hospital, Saneikai Tsukazaki Hospital and Shimane University Hospital. The study protocol was approved by institutional review boards of these institutions, and the study design complies with the Tenets of the Declaration of Helsinki and Ethical Guidelines for Medical and Health Research Involving Human Subjects of the Japanese Ministry of Health, Labour and Welfare.

Between September 2015 and December 2019, this study recruited open-angle glaucoma patients. To be included in the study, subjects had to be over 20 years of age, provide written consent and agree to the possibility of a 3-year follow-up after the surgery. Subjects were excluded if they had intraocular surgery within 6 months, there was difficulty in performing the IOP measurement with the Goldman applanation tonometer, there was a history of surgery with conjunctival incision, subjects had a hypersensitivity to the components of ripasudil or had used ripasudil within 1 month before surgery, were pregnant or nursing or due to a judgement of incompatibility by the study doctor in charge.

All patients underwent a baseline examination before the surgery, with preoperative data collected that included age at the time of surgery, gender, best corrected visual acuity (BCVA) and mean IOP. A Goldmann applanation tonometer was used to measure the IOP at every visit. In all eyes, 0.04% MMC was applied in the subconjunctival space for 3 min during the trabeculectomy procedure. Patients were randomly allocated to either the ripasudil group or the non-ripasudil group before the surgery. The assignment was performed using a stratified permutation block method. The allocation factor used was whether the cataract surgery had been performed at the same time as the trabeculectomy. Topical antibiotic eyedrops of levofloxacin and corticosteroid were used for postoperative management. In the case of cataract surgery, non-steroidal anti-inflammatory drugs were used three times a day and then tapered off at the doctor’s discretion. In the ripasudil group, the drug was instilled two times per day for 3 months in all patients. Postoperative management, which included items such as bleb massage, needle revision or using IOP-lowering medications, was determined by the individual surgeons at each of the clinical centres. All patients were required to visit the clinical centre a minimum of at least eight times, that is, at 1 day after the procedure, and at 1–2 weeks, 1, 3, 6, 12, 24 and 36 months postoperatively. At all of the postoperative consecutive visits, the data collected included IOP measurements, number of IOP-lowering medications, BCVA and complications.

Statistical analysis

All statistical analyses were performed using SPSS V.25 for Windows (SPSS, Chicago, Illinois, USA). Calculation of the sample size determined that each group needed 35 eyes in order to detect a 2 mm Hg difference in the IOP, with a SD of the IOP measurement of 3.0 mm Hg and a power of 80%.

A Student’s t-test was used to make the comparisons between the ripasudil and non-ripasudil groups for the clinical characteristics. Bonferroni correction was used to correct the analysis data, with a p value<0.0125 considered to be significant. The number of patients at baseline, 12, 24 and 36 months after surgery were compared for the analysis of the IOP and the number of IOP-lowering medications required after surgery. The long-term probability of success for the two groups (with or without additional medication) was assessed by Kaplan-Meier survival analyses, with two defined criteria used: (1) an IOP≤18 mm Hg and a reduction of IOP≥20% from baseline; and (2) an IOP≤15 mm Hg and a reduction of IOP≥20% from baseline. A successful outcome also required that there was no loss of light perception and no additional glaucoma surgery. Complete success was defined as being without any IOP-lowering medication or any additional intervention. If an IOP-lowering medication was required, this was defined as qualified success. Failure was defined based on postoperative IOPs that were outside of the success range on two consecutive study visits. Starting at 3 months from the date of surgery, IOP criteria were then applied. When the p value was less than 0.05, this difference was defined as being significant.

Results

The 122 enrolled patients were randomly assigned to two groups. In the ripasudil group, there were 55 eyes (Hiroshima University Hospital: 19 eyes, Kagawa University Hospital: 9 eyes, Shirai Hospital: 6 eyes, Matsue Red Cross Hospital: 4 eyes, Saneikai Tsukazaki Hospital: 0 eyes, Shimane University Hospital: 0 eyes), while there were 67 eyes in the non-ripasudil group (Hiroshima University Hospital: 25 eyes, Kagawa University Hospital: 16 eyes, Shirai Hospital: 4 eyes, Matsue Red Cross Hospital: 4 eyes, Saneikai Tsukazaki Hospital: 2 eyes, Shimane University Hospital: 1eye). Patients were required to undergo a 3-year follow-up after the surgery, with an attrition rate found to be approximately 20—30%. Figure 1 shows the progress of the study patients. A total of 17 subjects dropped out of the ripasudil group due to adverse events caused by the eye drops in 2 (blepharitis), personal reasons in 3, withdrawal of consent in 5, eligibility errors in 3, loss of follow-up during the first 3 months after the surgery in 3 and having to undergo cataract surgery in 1 patient. A total of 15 subjects dropped out of the non-ripasudil group, with consent withdrawn in 4, eligibility error in 7, loss of follow-up during the first 3 months after surgery in 1, malignant glaucoma in 1, cancellation of surgery in 1 and having to undergo surgery for epiretinal membrane in 1 patient. As a result, in the ripasudil group, there were 38 eyes analysed, while there were 52 eyes analysed in the non-ripasudil group.

Figure 1

Study flow chart of patient progress.

Table 1 presents the preoperative characteristics. The mean age for the ripasudil and non-ripasudil groups was 70.6±6.8 years and 70.1±7.3 years, respectively. No significant differences in gender were observed between the groups, and in the ripasudil and non-ripasudil groups the number of combined surgeries was 21 (55%) and 28 (54%), respectively.

Table 1

Preoperative characteristic

Baseline and follow-up IOP measurements are presented in table 2 for the ripasudil and non-ripasudil groups. Baseline IOPs were 16.8±5.02 mm Hg and 16.2±4.37 mm Hg in the ripasudil and non-ripasudil groups, respectively. At 12 months after drug administration, the mean IOP in the ripasudil group was 11.4±3.2 mm Hg, while it was 10.9±3.9 mm Hg and 10.6±3.5 mm Hg at 24 and 36 months, respectively. The IOP at 12 months in the non-ripasudil group was 11.2±4.1 mm Hg, while it was 10.51±3.1 mm Hg and 10.9±3.2 mm Hg at 24 and 36 months, respectively.

Table 2

Differences in postoperative intraocular pressure

For the ripasudil and non-ripasudil groups, the number of the IOP lowering medications administered prior to surgery (baseline) was 3.30±0.99 and 3.12±0.97. This decreased at 12 months to 0.16±0.59 and 0.35±0.79 in the ripasudil and non-ripasudil groups, respectively. As compared with the non-ripasudil group at 24 months, there was a significantly reduced number of IOP-lowering drugs in the ripasudil group (p=0.010). The number of IOP-lowering medications at 24 and 36 months in the ripasudil group was 0.11±0.41 and 0.20±0.53, as compared with 0.68±1.18 and 0.76±1.26 in the non-ripasudil group (table 3). The selected IOP-lowering medications were prostaglandin FP agonist (PGF) or PGF/β-blocker and PGF, PGF/β-blocker, brinzolamide/brimonidine or β-blocker/carbonic anhydrase inhibitor in the ripasudil and non-ripasudil groups, respectively. The bleb needling procedure was performed in 9 and 12 patients in the ripasudil and non-ripasudil groups, respectively.

Table 3

Differences in postoperative number of intraocular pressure-lowering medications

As seen in figure 2, the success rates between the two groups were compared using a Kaplan-Meier analysis. For criteria A, in the ripasudil group, the cumulative probability of qualified success rates were 67.6% at 1 year, 64.8% at 2 years and 64.8% at 3 years. For the non-ripasudil group, the success rates were 74.4% at 1 year, 68% at 2 years and 68% at 3 years (figure 2A, p=0.67). With regard to the complete success for criteria A, the rates were 68.4% at 1 year, 60.2% at 2 years and 52% at 3 years for the ripasudil group, while they were 63.8% at 1 year, 52.4% at 2 years and 43.3% at 3 years (figure 2B, p=0.38) in the non-ripasudil group. For criteria B, in the ripasudil group, the cumulative probability of qualified success rates were 64.9% at 1 year, 62% at 2 years and 62% at 3 years, while they were 70.4% at 1 year, 64.2% at 2 years and 64.2% at 3 years (figure 2C, p=0.77) in the non-ripasudil group. With regard to the complete success for criteria B, the rates were 65.8% at 1 year, 57.6% at 2 years and 49.3% at 3 years in the ripasudil group, while they were 63.8% at 1 year, 52.4% at 2 years and 43.3% at 3 years (figure 2D, p=0.52) in the non-ripasudil group.

Figure 2

Kaplan-Meier cumulative probability of success in open-angle glaucoma patients for criteria A, which is defined as an intraocular pressure (IOP) reduction ≤18 mm Hg and reduction of IOP ≥20% from baseline with (A) or without (B) IOP-lowering medication and for criteria B, which is defined as an IOP reduction ≤15 mm Hg and reduction of IOP ≥20% from baseline with (C) or without (D) IOP-lowering medication. Solid line: non-ripasudil group, dashed line: ripasudil group.

Hypotony was the most important complication observed for both the early and late postoperative phases. In the ripasudil group, this occurred in 7 (18.4%) of 38 cases and in 10 (19.2%) of 52 cases in the non-ripasudil group. Both groups developed choroidal detachment, with 4 (10.5%) cases in the ripasudil group and 2 (3.8%) in the non-ripasudil group. These differences were found not to be significant. In two cases, there were eyedrop complications related to the use of ripasudil, which included itchiness and contact dermatitis. None of the patients in either of the groups had conjunctiva injection.

Discussion

This study evaluated the clinical outcome of trabeculectomy with MMC in patients administered postoperative topical application of ripasudil, with the results compared with a non-ripasudil group. No significant difference was observed between the two groups for the IOP. However, there was a significantly lower number of IOP-lowering medications found for the postoperative ripasudil group when compared with the non-ripasudil group at 24 months (p=0.010) and 36 months (p=0.016).

Although surgical outcomes were not improved in terms of the IOP following the addition of the ROCK inhibitor, ripasudil, after a needling procedure with MMC, Mizuno et al did report that this potentially reduced the IOP-lowering medication’s half-life after needling with MMC.10 Even though trabeculectomy with MMC has been shown to be one of the most effective surgeries for reducing IOP, the effect can be compromised due to scarring of the Tenon’s capsule tissue. It has been reported that the scleral flap or conjunctiva can be exposed to cytokines and growth factors produced by various types of inflammatory cells and fibroblasts during and after glaucoma filtration surgery.11 During fibrosis, activated fibroblasts are produced and secreted via the extracellular matrix as collagen. The expression of extracellular matrix-degrading enzymes in fibroblasts can be suppressed by ROCK inhibitors and ROCK inhibitors also reduce extracellular matrix secretion.12 Two in vivo studies reported finding that ROCK inhibitors had an effect on IOP reduction and by suppressing scaring, helped sustain bleb formation during trabeculectomy.9 13 The ROCK inhibitor, Y-27632, was previously reported by Ibrahim et al to cause inhibition of the trans-differentiation of the Tenon’s fibroblasts into myofibroblasts as well as TGF-β and mitogen-activated protein kinase signal after surgery, thereby inhibiting fibrosis and improving the outcomes after glaucoma surgery.9

Futakuchi et al examined the mechanism of ripasudil in maintaining the filtering bleb formation and reported that the increase in α-SMA expression induced by TGF-β2, which is the predominant ocular isoform of TGF-β, was attenuated by ripasudil.14 In addition to the changes in the TGF-β2 in vitro, ripasudil also affected the activation of HConF (human conjunctival fibroblast) induced by a conditioned medium from macrophages. Furthermore, certain ROCK inhibitors have also been found in previous studies to reduce TGF-β1- and LPA (lysophosphatidic acid)-induced α-SMA expression.5 7 9

Honjo et al examined the use of a specific inhibitor Rock I, Y-27632, in a rabbit model of glaucoma filtration surgery, and showed that there was a significant decrease in the IOP between the Y-27632 treatment group and the control group at 7 days after trabeculectomy without MMC. Their results demonstrated that ROCK inhibitors inhibited HTF proliferation in vitro and reduced inflammation, angiogenesis and collagen deposition in conjunctival blebs after filtering surgery.9 Kojima et al similarly examined multiple applications of ripasudil in a canine glaucoma surgery model and reported that this maintained the IOP reduction and bleb formation via the suppression of cell proliferation and TGF-β activity. Moreover, they also reported that there was a significantly lower IOP in treated eyes as compared with the controls at 2 and 4 weeks postoperatively.15 We evaluated the morphological appearance of the filtration bleb using the Indiana Bleb Appearance Grading Scale in the current study every 6 months (data not shown).16 There were no differences with regard to the morphological appearance of the filtration bleb between the ripasudil and non-ripasudil groups.

Our present examination of ripasudil and non-ripasudil groups did not find any significant differences in the IOP after surgery. This could potentially be associated with the excellent results achieved when using trabeculectomy with MMC as the first glaucoma surgery, thereby making it unlikely there would be any observed effect on the IOP caused by ripasudil. The efficacy of MMC in helping to improve trabeculectomy outcomes has been reported in several previous clinical studies.17 As has been previously reported by Mimura et al, after trabeculectomy without MMC, the IOP was lower in patients who were being administered ripasudil as compared with a control group, which contained patients with glaucoma uveitis.18 Thus, it is possible that the intraoperative trabeculectomy with MMC could have masked the present results.

There was a statistically significant difference between the ripasudil and non-ripasudil groups for the postoperative number of IOP-lowering medications. The proportion of patients who required IOP-lowering medications was similar between both groups. In the non-ripasudil group, some patients required three to four IOP-lowering medications to control the IOP. In the ripasudil group, however, all patients required only one to two IOP-lowering medications to control the IOP.

There were several limitations in the present study. First, there was only a very small sample size for the analysis due to the number of patients who dropped out of the study. Thus, the statistical power of the study was limited by the small sample size. In order to obtain more definitive evidence and data, large-scale trials will need to be undertaken in the future. Second, ripasudil was administered two times a day for only 3 months. Therefore, additional investigations are needed to determine the most appropriate dose of ripasudil for preventing conjunctival scarring, such as the number of installations per day and the duration of the administrations. Third, ripasudil’s instillation effect will need to be compared with another application method, namely subconjunctival injection. However, the most convenient method of administering ripasudil clinically seems to be the method that was used in the present study. Thus, topical application of ripasudil appears to be a viable method for improving glaucoma surgery outcomes. Fourth, it should also be noted that this study had an open-label design instead of employing a placebo in the non-ripasudil group, which was due to a lack of research funding.

Conclusion

The results of the present study demonstrate that the administration of the ROCK inhibitor, ripasudil, after trabeculectomy with MMC does not improve surgical outcomes in terms of the IOP. However, the number of IOP-lowering medications from the second to third year after the trabeculectomy with MMC may be reduced after the addition of ripasudil.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Ethics statements

Patient consent for publication

Ethics approval

This prospective, multicentre, randomised, open-label clinical study was registered as UMIN000019017 in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR). The study protocol was approved by the Institutional Review Board of the Hiroshima University (C-43). Participants gave informed consent to participate in the study before taking part.

Acknowledgments

To my dear coauthors, a heartfelt thank you for your invaluable contribution.

References

Supplementary material

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Footnotes

  • Contributors Guarantor: KH. Acquisition of data: HO, EN, TB, MT, YM, SN. Statistical analysis: AM and AN. Conception: YK. Planning: HO. Interpretation of data: KH and YK. Data analysis: AM and AN. Reviewing/finalizing the manuscript: KH and YK.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.