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Pulmonary vasculature
Sendaway capillary NT-proBNP in pulmonary hypertension
  1. Harrison D Stubbs1,2,
  2. John Cannon3,
  3. Emily Knightbridge3,
  4. Charlotte Durrington4,
  5. Chloe Roddis4,
  6. Wendy Gin-Sing5,
  7. Fiona Massey5,
  8. Daniel S Knight6,
  9. Ruta Virsinskaite6,
  10. James L Lordan7,
  11. Eleanor Sear7,
  12. Joy Apple-Pinguel8,9,
  13. Eleanor Morris8,9,
  14. Martin K Johnson1 and
  15. Stephen J Wort8,9
  1. 1Scottish Pulmonary Vascular Unit, Golden Jubilee National Hospital, Glasgow, UK
  2. 2School of Health and Wellbeing, University of Glasgow, Glasgow, UK
  3. 3Pulmonary Vascular Disease Unit, Papworth Hospital NHS Foundation Trust, Cambridge, UK
  4. 4Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, UK
  5. 5Pulmonary Hypertension Service, Imperial College Healthcare NHS Trust, London, UK
  6. 6Royal Free London NHS Foundation Trust, London, UK
  7. 7Pulmonary Vascular Unit, Freeman Hospital, Newcastle upon Tyne, UK
  8. 8National Pulmonary Hypertension Service, Royal Brompton Hospital, London, UK
  9. 9National Heart and Lung Institute, Imperial College London, London, UK
  1. Correspondence to Dr Harrison D Stubbs; harrison.stubbs{at}ggc.scot.nhs.uk

Abstract

Background N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac ventricular wall stress that is incorporated into pulmonary hypertension (PH) risk stratification models. Sendaway sampling may enable patients to perform NT-proBNP tests remotely. This UK-wide study aimed to assess the agreement of sendaway NT-proBNP with standard venous NT-proBNP and to assess the effect of delayed processing.

Methods Reference venous NT-proBNP was collected from PH patients. Samples for capillary and venous sendaway tests were collected contemporaneously, mailed to a reference laboratory and processed at 3 and 7 days using a Roche Cobas e411 device. Differences in paired measurements were analysed with Passing-Bablok regression, percentage difference plots and the % difference in risk strata.

Results 113 patients were included in the study. 13% of day 3 capillary samples were insufficient. Day 3 capillary samples were not equivalent to reference samples (Passing Bablok analysis slope of 0.91 (95% CI 0.88 to 0.93) and intercept of 6.0 (95% CI 0.2 to 15.9)). The relative median difference was −7% and there were acceptable limits of agreement. Day 3 capillary NT-proBNP accurately risk stratified patients in 93.5% of cases. By comparison, day 3 venous results accurately risk stratified patients in 90.1% of cases and were equivalent by Passing-Bablok regression. Delayed sampling of sendaway tests led to an unacceptable level of agreement and systematically underestimated NT-proBNP.

Conclusions Sendaway NT-proBNP sampling may provide an objective measure of right ventricular strain for virtual PH clinics. Results must be interpreted with caution in cases of delayed sampling.

  • Primary Pulmonary Hypertension

Data availability statement

Data are available on reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

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/.

https://doi.org/10.1136/bmjresp-2023-002124

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker that is released in proportion to the extent of cardiac ventricular wall stress and has become established for use in risk assessment for patients with pulmonary arterial hypertension, incorporated into all contemporary pulmonary hypertension (PH) risk stratification models. Sendaway tests, through capillary sampling, can be performed by patients at home and are sent for processing at a central laboratory with results sent either directly to the patient or the referring medical team.

    WHAT THIS STUDY ADDS

    • This UK-wide study aimed to assess the agreement of sendaway NT-proBNP with standard venous NT-proBNP and to assess the effect of delayed processing on the results. When capillary NT-proBNP was compared with standard venous NT-proBNP, there were acceptable limits of agreement and capillary NT-proBNP accurately risk stratified patients in 93.5% of cases, however, capillary results were not equivalent to standard results. Delayed sampling of sendaway tests led to an unacceptable lack of agreement and systematically underestimated NT-proBNP.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Sendaway testing may allow patients to perform an NT-proBNP blood test at home, without having to travel to a healthcare facility. This could provide an objective measure of right ventricular strain during virtual clinics. PH specialist teams could incorporate this test into a virtual clinic model.

    Background

    Pulmonary arterial hypertension (PAH) is a rare and progressive form of pulmonary hypertension (PH) which if untreated may progress to right heart failure and death.1 2 PAH and certain other aetiologies of PH are diagnosed and managed in specialist pulmonary vascular units. Dysfunction of the right ventricle (RV) is the primary driver behind the symptom burden in PH, leading to exercise intolerance, exertional dyspnoea, fatigue and RV failure as the disease progresses with fluid retention, chest pain and syncope.3 4 The assessment of right ventricular function is used to risk stratify patients at the point of diagnosis and to monitor the response to treatment.1 B-type natriuretic peptide (BNP) and N-terminal prohormone of BNP (NT-proBNP) are biomarkers that are released in proportion to the extent of cardiac ventricular wall stress.5 6 NT-proBNP has become established as a surrogate marker of RV function and is incorporated into all contemporary PAH risk stratification models.1 7–11 In current practice at UK PH centres, samples are collected as venous serum or plasma blood through venepuncture at the time of a patient’ face-to-face assessment and results are commonly available ≥24 hours. NT-proBNP has superior stability than BNP but is still prone to degradation, especially at higher temperatures.6

    Remote risk assessment in PH heralds benefits such as reducing lengthy transport to specialist centres, reducing patient exposure to nosocomial infections and allowing ad hoc assessments at home.12 The majority of PH patients in the UK have a travel time of >1 hour to attend clinic appointments, are concerned about contracting COVID-19 while in hospital and 93% would be happy for some of aspects of their PH care to be remote.13 During the COVID-19 pandemic, the role of virtual consultations rapidly expanded in PH, yet consultations were often bereft of objective data, such as NT-proBNP.14 15 It remains that NT-proBNP data are often unavailable at the time of virtual clinic appointments due to the restrictions on the use or funding for these tests within primary care networks and the lack of a global remote blood monitoring facility within the National Health Service (NHS).16 17

    Point-of-care testing (POCT) for NT-proBNP has been studied in the left heart failure population18 and in the REPEAT-PAH study in PH19 20 both with acceptable agreement to standard NT-proBNP. However, it remains that POCT requires patients to travel to a healthcare facility. Sendaway tests, through capillary sampling, can be performed by patients at home and are sent for processing at a central laboratory with results sent either directly to the patient or the referring medical team. Sendaway samples may allow PH centres to obtain NT-proBNP results in a telemedicine setting. Capillary samples are obtained through fingerpick blood draw, similar to how capillary blood glucose measurements are obtained and collected in serum microtainer bottle. Venous sendaway sampling could enable patients to have blood drawn locally, such as by a general practitioner, with the result funded and followed by a specialist team.

    This UK-wide study aimed to assess the agreement of sendaway NT-proBNP with standard venous NT-proBNP and to assess the effect of delayed processing on the results.

    Methods

    Inclusion criteria

    Participants ≥16 years old with PH (mean pulmonary artery pressure≥25 mm Hg, regardless of pulmonary vascular resistance) and from any clinical classification, were included.21 Therapy with anticoagulation or antiplatelet medication was not considered an exclusion. Participants provided informed consent.

    Study structure

    Samples were collected between April 2022 and April 2023 over seven of the adult national centres for PH in Great Britain. During a single visit (day 0), during patients’ standard care, blood was drawn in sequence, following 30 min of rest and without participant exertion between tests, as below;

    1. 1x reference venous NT-proBNP—transported by Royal Mail post to a reference laboratory and analysed on arrival.

    2. 1x local venous NT-proBNP—analysed as per standard protocol at the laboratory based at each participating site.

    3. 2x sendaway venous NT-proBNP.

    4. 2x sendaway capillary NT-proBNP—each with 600 µL of blood from different fingers.

    Sendaway samples were obtained using kits from Thriva (London, UK), sent to the Thriva lab by Royal Mail post and analysed using Thriva infrastructure at day 3 and day 7 from the day of the blood draw. Sendaway samples were analysed using a Roche Cobas e411 device (Roche, Switzerland) with a 4.2%–6.3% coefficient of variation (online supplemental table S1). In cases where one sample was insufficient, the day 3 sample was prioritised. Reference samples were performed at the Royal Brompton Hospital (London) using a Roche Cobas e411 device and Elecsys proBNP II assay. This method was chosen for the reference sample to maintain reproducibility. Postal samples were sent immediately and were not refrigerated prior to postage.

    Aims

    The primary outcome was the agreement between reference and day 3 Capillary NT-proBNP results. Secondary outcomes included the assessment of (1) agreement between reference and day 3 venous sendaway NT-proBNP results and (2) the effect of delayed processing (stability) on capillary and venous sendaway NT-proBNP results by comparing the agreement between reference and day 7 results.

    Statistical analysis

    Continuous variables are presented as mean±SD, median (IQR) or number (%). Significance was set at the p<0.05 level. Where results were reported below the analytical range, they were analysed using the value closest to the reporting limit (eg, <10 was analysed as 9).

    The Shapiro-Wilk test was used to assess the normality of the data. The relationship between the reference and study NT-proBNP was assessed in several ways: (1) median difference (IQR), (2) traditional Bland-Altman plots,22 (3) percentage difference plot (4) Passing-Bablok regression23 with (5) Spearman’s r correlation.24 Reference NT-proBNP results were assigned a risk status based on the COMPERA 2.0 thresholds7 and the proportion of patients who would have been assigned a different risk stratum based on study NT-proBNP results was calculated. The relationship between the local lab and study NT-proBNP was additionally assessed with the above analyses and the results and are included in online supplemental material. The viability of sendaway sampling was measured by assessing the number and causes of invalid samples. Analysis was performed on GraphPad Prism (V.9.3.0 for Windows, GraphPad Software, San Diego, California, USA) and MedCalc (V.22.003 for Windows, MedCalc Software, Ostend, Belgium).

    Sample size calculation

    The power requirement was based on agreement using Bland-Altman analysis. Using the criteria for NT-proBNP of a mean change of 5 pg/mL with an SD of 10 pg/mL and a maximum difference of 30 pg/mL, using a power of 0.8 and a significance level of 0.95, an estimated of 83 participants was required.18 19

    Patient and public involvement

    Patients were not directly involved in the design of this study. However, this study is designed to demonstrate the utility of remote NT-proBNP testing, which could lead to benefits for patients.

    Results

    Participant demographics

    Participant demographics are shown in table 1. 114 participants were recruited into the study with one patient with CTEPH excluded as they were unable to produce sufficient blood for either capillary or venous samples. The median NT-proBNP was 514 (IQR 167–1890). The range of NT-proBNP results from all study data sets is shown in table 2; all were non-parametrically distributed (p<0.0001; online supplemental figure S1).

    View this table:
    Table 1

    Participant demographics

    View this table:
    Table 2

    NT-proBNP dataset overview

    Invalid samples

    Valid results were obtained for all reference samples, 81% of day 3 capillary samples, 74% of day 7 capillary samples and 88% of day 3 and day 7 venous samples. Of the invalid results, 13% of day 3 capillary, 19% of day 7 capillary and 1% of day 3 venous samples were not processed due to an insufficient quantity of blood in the container. One patient with severe Raynaud’s was unable to provide any quantity of capillary blood yet was able to provide venous blood. Overall, 24 samples were delayed in the postal service, and therefore, not suitable for processing. Four samples were received by Thriva laboratories but were not processed, one sample was incorrectly labelled and two samples did not arrive to Thriva for reasons unknown. There was no significant difference in the proportion of invalid samples obtained during the summer months (April–September) when compared with the winter months (October–March).

    Sendaway capillary NT-proBNP

    As shown in figure 1, the median relative difference between reference and day 3 capillary NT-proBNP was −7% (IQR −15% to 0%; (b) Passing-Bablok regression showed an estimated slope of 0.9 (95% CI 0.88 to 0.93), intercept of 6.0 (95% CI 0.2 to 15.9) and an r of 0.99 (p<0.0001) indicating there was excellent correlation yet the measures were not equivalent and (c) Bland-Altman analysis further demonstrates that day 3 capillary results were systematically lower than reference results (bias −88.9, SD 479.6 pg/mL) with limits of agreement from −1029 to 851 pg/mL. Although the absolute differences were greater at higher values, the performance of the percentage difference was uniform across the range of values. The median absolute difference was −30 pg/mL (IQR −137 to 0 pg/mL; online supplemental figure S2). Differences between reference and day 3 capillary results led to a different assignment of risk strata in 6 of 92 (6.5%) cases, of which 5 underestimated the risk status (figure 2).

    Figure 1
    Figure 1

    Analysis comparing reference and sendaway day 3 capillary NT-proBNP (pg/mL) using (A) percentage difference plot demonstrating a median difference of −7%, (B) Passing-Bablok regression showing strong correlation (r=0.99), with a slope of 0.91 (95% CI 0.88 to 0.93) and intercept of 6.0 (95% CI 0.2 to 15.9) and (C) Bland-Altman plot showing a bias of −89.9 with limits of agreement −1029 to 851. NT-proBNP, N-terminal pro-B-type natriuretic peptide.

    Figure 2
    Figure 2

    Percentage of patients as classified by four-strata risk based on reference and study NT-proBNP results. NT-proBNP, N-terminal pro-B-type natriuretic peptide.

    Sendaway venous NT-proBNP

    As shown in figure 3, the median relative difference between reference and day 3 venous NT-proBNP was 0% (IQR −4.5% to 7.4%), (b) Passing-Bablok regression showed an estimated slope of 1.0 (95% CI 0.9 to 1.02), intercept of 0.0 (95% CI −5.4 to 6.1) and an r of 0.99 (p<0.0001) indicating measurements were equivalent and (c) Bland-Altman analysis showed day 3 venous results were systematically higher than laboratory results (mean 76.6, SD 497 pg/mL) with limits of agreement from −897.5 to 1051 pg/mL. The median absolute difference was −4 pg/mL (IQR −85 to 13; online supplemental figure 2). Differences between reference and day 3 venous results led to a different assignment of risk strata in 8 of 88 (9.1%) cases, of which 6 underestimated the risk status (figure 2).

    Figure 3
    Figure 3

    Analysis comparing reference and sendaway day 3 venous NT-proBNP (pg/mL) using (A) percentage difference plot demonstrating a median difference of 0%, (B) Passing-Bablok regression showing strong correlation (r=0.99), with a slope of 1.0 (95% CI 0.9 to 1.0) and intercept of 0.0 (95% CI −5.4 to 6.1) and (C) Bland-Altman plot showing a bias +76.6 with limits of agreement −897.5 to 1051. NT-proBNP, N-terminal pro-B-type natriuretic peptide.

    Stability of sendaway NT-proBNP

    Capillary and venous samples at day 7 had poorer agreement to the reference NT-proBNP, when compared with the day 3 results and systematically underestimated the reference NT-proBNP. There was not a significant difference in results when assessed for winter and summer months (data not shown).

    Day 7 capillary: As shown in figure 4, the median relative difference between reference and day 7 capillary NT-proBNP was −28% (IQR −37.6% to −16.9%,), (b) Passing-Bablok regression showed that results were significantly different to the reference with greater deviation when compared with day 3 capillary results and (c) Bland-Altman analysis demonstrated a mean difference of −392.4 pg/mL (SD 819) and limits of agreement −1999 to 1214 pg/mL. The median absolute difference was −122 pg/mL (IQR −483 to −28 (online supplemental figure S2). Differences between reference and day 7 capillary results led to a different assignment of risk strata in 10 of 84 (11.9%) cases, of which all 10 underestimated the risk status (figure 2).

    Figure 4
    Figure 4

    Analysis comparing reference and sendaway day 7 capillary NT-proBNP (pg/mL) using (A) percentage difference plot demonstrating a median difference of −28%, (B) Passing-Bablok regression showing strong correlation (r=0.98), with a slope of 0.75 (95% CI 0.73 to 0.79) and intercept of 0.89 (95% CI −5.2 to 7.09) and (C) Bland-Altman plot showing a bias of −392.4 with limits of agreement −1999 to 1214.

    Day 7 venous: As shown in figure 5, the median relative difference between reference and day 7 venous NT-proBNP was −18.4% (IQR −28.1% to 6.7%), (b) Passing-Bablok regression showed that results were significantly different to the reference with greater deviation when compared with day 3 venous results and (c) Bland-Altman analysis demonstrated a mean difference of −227 pg/mL (SD 643) and limits of agreement −1488 to 1034 pg/mL. The median absolute difference was −87.5 pg/mL (IQR −325.5 to −10.8 (online supplemental figure S2). Differences between reference and day 7 venous results led to a different assignment of risk strata in 12 of 88 (13.6%) cases, of which 11 underestimated the risk status (figure 2).

    Figure 5
    Figure 5

    Analysis comparing reference and sendaway day 7 venous NT-proBNP (pg/mL) using (A) percentage difference plot demonstrating a median difference of −18.4%, (B) Passing-Bablok regression showing strong correlation (r=0.98), with a slope of 0.83 (95% CI 0.78 to 0.86) and intercept of 0.24 (95% CI −9.6 to 8.0) and (C) Bland Altman plot showing a bias of −227 with limits of agreement −1488 to 1034. NT-proBNP, N-terminal pro-B-type natriuretic peptide.

    Local NT-proBNP: The agreement between the local and day 3 and day 7 venous and capillary NT-proBNP were performed and results are included in (online supplemental figure 3–6). The agreement between the local and study NT-proBNP was similar yet slightly poorer compared with analysis using the reference NT-proBNP.

    Discussion

    The study investigated the agreement of sendaway capillary NT-proBNP when compared with a standard venous NT-proBNP. The main findings were (1) sendaway day 3 capillary NT-proBNP demonstrated good agreement as assessed for proportional difference and would accurately risk stratify patients as per COMPERA 2.0 thresholds in 93.5% of cases and yet was not equivalent to standard venous NT-proBNP using Passing-Bablok analysis, whereas (2) sendaway day 3 venous results accurately risk stratified patients in 90.1% of cases and yet were equivalent by Passing-Bablok regression; (3) delayed sampling of sendaway tests led to an unacceptable level of agreement with a systematic underestimation of NT-proBNP and (4) a high proportion (13%) of day 3 capillary samples were insufficient.

    The level of agreement and agreement of risk stratification for day 3 capillary samples would likely be acceptable for a virtual clinic, although clinicians would need to take into account the unreliability of delayed samples. This is especially pertinent as patients are more likely to be misclassified into a lower risk category, and hence the situation may arise where the opportunity for a treatment escalation is missed as a patient is erroneously misclassified as low risk. Remote capillary sampling could be best used for PAH patients in lower risk strata, where remote tests are used to confirm stability, and a significant rise in NT-proBNP would prompt urgent face-to-face assessment. The systematically lower capillary NT-proBNP results are likely due to the reduced stability of NT-proBNP over time,5 6 as further shown by the poorer agreement when compared between day 3 and day 7 results.

    There was a high proportion of insufficient capillary samples (13%), with feedback from the healthcare practitioners performing the test commenting that obtaining the required 600 µL of blood could be occasionally difficult. Furthermore, 24 samples were delayed in the postal service, although it was noted that the study took place during a period of UK Royal Mail industrial action between August and December 2022.25 The high number of invalid results in a real-world setting may reduce the overall utility of sendaway capillary testing and further disruption to the postal service may jeopardise this model.

    One patient was unable to provide any capillary samples due to severe Raynaud’s. However, this study included a high proportion of patients with CTD-PAH, potentially demonstrating that some patients with poor peripheral perfusion due to scleroderma are able to perform capillary testing. However, this study did not collect data on whether patients with scleroderma subsequently experienced adverse effects, such as digital ulceration, and future work should include this.

    Previous studies have investigated the use of NT-proBNP POCT. In left heart failure, POCT has been extensively studied for use in screening, overall demonstrating acceptable agreement when samples were tested contemporaneously.16 18 26–28 The REPEAT-PAH study investigated the agreement between reference and POCT NT-proBNP in patients with PH using a Quidel Triage MeterPro device, where a capillary sample is obtained by a healthcare professional with a result available within 20 min. Between reference and POCT NT-proBNP, the intraclass correlation coefficient was 0.98 and Bland-Altman analysis demonstrated the bias increased proportional to the magnitude of reference NT-proBNP, as seen in this study.19 20 The effect of delayed processing was investigated (mean delay 2.6 days) with an ICC of 0.99 between results.

    This study was limited by the lack of a patient feedback questionnaire on the process of capillary sampling. As this was primarily an agreement study, capillary samples were obtained by healthcare professionals, not by patients, and hence the feasibility of fingerpick samples at home in this population is unknown. This is clearly relevant given the high proportion of insufficient capillary samples in the study. Furthermore, an assessment of intratest reliability was not performed as only one capillary sample was taken for day 3 and day 7 results, respectively. This study relied on the UK national postage service, and therefore, may not be applicable in all countries. Future work will focus on implementing capillary NT-proBNP sampling in a group of patients in an existing virtual clinic to assess the following (1) feasibility, (2) patient perceptions and (3) adverse effects of capillary sampling. Future work should aim to reduce the number of invalid samples by increasing patient education of how to perform the test and allowing ‘practice runs’ in order to refine the fingerpick technique.

    In conclusion, capillary sendaway NT-proBNP sampling may allow specialist PH teams to incorporate an assessment of right ventricular function into virtual clinics, without requiring patients to travel. Capillary results were within acceptable limits of agreement and accurately risk stratified patients in the majority of cases, however, they must be interpreted with caution in cases of delayed sampling. Venous sendaway NT-proBNP demonstrated superior statistical agreement with the reference values yet with similar accuracy of risk stratification, and therefore, can also be relied on. These could be obtained by patients attending their local health provider.

    Data availability statement

    Data are available on reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and the study was approved by the London–Fulham Research Ethics Committee (Ref 22/LO/0097). Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    This study would not have been possible without the support from a team of research nurses and clinicians at the investigator sites who are listed in the collaberation statement. We are indebted to Winston Banya for his aid with the statistical analyses. We thank Thriva for their dedication to this study, with special thanks to H Knight, D Flewell-Smith and A Borsatti. We thank Janssen-Cliag for their support in funding the study. Finally, we wish to thank all the patients who participated.

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    Supplementary materials

    Footnotes

    • Collaborators Scottish Pulmonary Vascular Unit: Louise Cowan, Joanna Ford, Colin Church, Melanie Brewis, Jamie Ingram, Stephanie Lua; Royal Papworth Hospital: Karen Brooks, Joe Newman, Gary Polwarth, Joanna Pepke Zaba, Karen Sheares, Dolores Taboada, Kate Bunclark, Mark Toshner; Sheffield Pulmonary Vascular Disease Unit: Stefan Roman, Jenna Ablott; Imperial College Healthcare NHS Trust: Souad Ali, Margaret Hickey, Eilish Lawlee, Chantal Torpy; Royal Free: Pratibha Varghese, Karl Salazar; Freeman Hospital: Alan Greenhalgh; Royal Brompton Hospital: Laura Price, Colm McCabe, Chinthaka Samaranayake, Carl Harries, Eva Moriarty, Stuart Craig, Eleanor Morris, Thomas Mason.

    • Contributors HS: methodology, patient recruitment, formal analysis, investigation, data curation, writing–original draft, conceptualisation, project administration; MJ: methodology, supervision, writing–review and editing; SW: methodology, patient recruitment, investigation, conceptualisation, supervision, writing–reviewing and editing, project administration, approval of the final draft for submission. All other authors: patient recruitment, writing–review and editing. SW: responsible for the overall content as guarantor.

    • Funding This work was supported by funding from Janssen-Cilag. Dr DS Knight is supported by a British Heart Foundation (BHF) Clinical Research Leave Fellowship (FS/CRLF/20/23004).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • 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.