1. Selecting the appropriate macrolide antibiotic
Macrolide antibiotics have been shown to have anti-inflammatory and immunomodulatory properties, reducing pro-inflammatory cytokines critical in CRS[7, 8]. International guidelines recommend the use of low-dose long-term macrolides in selected patients with CRS but evidence is weak, and also based on roxithromycin which is not currently available in the UK[9, 10]. A survey of 158 UK ENT surgeons (2013) found that 92% prescribed antibiotics prior to ESS surgery, with 16% prescribing 12 weeks’ macrolide treatment. The UK sinonasal audit in 2000 found that 7% of CRSwNP and 18.9% of CRSsNP patients received low-dose long-term antibiotics prior to ESS.
Treatment duration has been evaluated in some low quality studies, but evidence suggests that longer courses of macrolide therapy are more effective than shorter courses in patients with CRS[13, 14] .
More recently, concerns have been raised about potential cardiovascular risks from the use of full-dose, short-term macrolides . Macrolides may cause prolongation of the QT interval which can lead to arrhythmia and myocardial infarction. However, the safety of lower doses for longer periods in such cases for CRS has yet to be investigated.
The health informatics analysis evaluated current trends in antibiotic prescribing, including treatment duration and safety. The analyses found that penicillins remain the first choice antibiotic for patients with a high likelihood of CRS, however, a recent trend towards the increased use of macrolides and tetracyclines (mainly doxycycline) was found for patients with a definitive diagnosis of CRS.
The most common treatment duration for both macrolide and penicillin prescriptions for CRS was found to be 1 week. However, macrolides were likely to be prescribed for a longer durations (over 8 weeks) than penicillins, particularly for those with a definitive CRS diagnosis.
Analysis of macrolide safety data found that there was no statistically significant short or long-term risk associated with macrolide prescription compared to penicillin for patients with CRS. A potential (non-significant) short-term risk of myocardial infarction during the first 30 days following prescription was found with macrolide antibiotics. However, no significant risks were particularly associated with clarithromycin, and there was no evidence of increased risk of cardiovascular events.
GPs described prescribing short courses of antibiotics in primary care, with limited experience of long-term antibiotic use for patients with CRS. ENT surgeons commonly described the use of clarithromycin in patients prior to sinus surgery, however, treatment durations were often less than 8 weeks, and generally for CRSwNP patients. Patients described the role of antibiotics as appropriate to treat infections and were uncertain about their use in CRS. Some expressed concerns about potential gastrointestinal side effects and antibiotic resistance, especially with longer courses of treatment.
Expert panel review:
The expert panel agreed that clarithromycin should be selected as the macrolide of choice for the MACRO trial due to its increasing use as a first and second line treatment for patients with CRS, and the perceived need to establish its role in CRS management. A 12-week course of treatment was selected as the appropriate treatment duration based on the evidence for effectiveness with longer treatment durations and no associated increased risk with longer treatment courses. To mitigate against any potential problems associated with increased cardiovascular risk with macrolide treatment, the panel agreed that patients with a prior history of ischaemic heart disease and those over 65 with diabetes will be excluded from the MACRO trial. A baseline ECG will be added to the trial screening process to identify and exclude those with prolongation of the QT interval.
2. Role of oral corticosteroids (OCS)
Short courses of oral corticosteroids (OCS) are commonly used in treating patients with chronic rhinosinusitis, either alone or in combination with other treatments. Currently international guidelines (EPOS) recommend OCS for severe CRSwNP patients. A Cochrane review suggests that a short course of OCS improves quality of life and symptom control compared to placebo or no treatment, for patients with nasal polyps, although little or no difference was noted after 3 months. Another review found that as an adjunct treatment, OCS may result in an improvement in symptom severity and reduction in nasal polyps, but the quality of evidence was low, and no data was available to assess longer term benefits . To date, no RCTs have assessed the role of OCS for CRSsNP. Prescribing of OCS for CRS has been evaluated in a number of studies. A UK survey in 2013 found that 34% of ENT surgeons sometimes or always prescribed OCS as part of maximal medical therapy for CRS . A Canadian survey in 2016 found that 79% prescribed OCS for CRSwNP, whilst 23% prescribed them for CRSsNP at least sometimes . The UK Sinonasal audit in 2000 found that 14% of CRS patients received OS prior to ESS (18% of CRSwNP compared to 6% of CRSsNP), suggesting that OCS use is not routine for all patients prior to ESS.
The health informatics data provided limited information about the prescribing of OCS for CRS. The CPRD only captures primary care prescriptions for CRS, whilst secondary care prescribing of OCS is only captured if prescription advice is sent back to the patient’s GP. Data presented to the panel meeting included combined data for intranasal corticosteroids (INCS) and OCS. Patients with polyps present and polyps unknown were both highly likely to receive a steroid prescription (INCS or OCS) both before and after sinus surgery, but no conclusions could be drawn for the individual usage of OCS.
GPs reported infrequent use of oral steroids in primary care, with some GPs expressing a lack of confidence for use in CRSwNP. ENT specialists described the use of OCS for CRSwNP prior to surgery, and for occasional rescue courses for severe cases. However, concerns were raised about the potential of a ‘pre-operative blast of steroids’ to affect surgical outcomes which could consequently affect trial results. Likewise, post-operative OCS were described as ‘muddying the waters’, resulting in an unclear picture of the effectiveness of surgery alone. A few patients had experience of oral steroid use and described rapid symptom relief especially after surgery. Whilst there were some reported concerns about side effects, patients were generally agreeable to their use if recommended by their specialist.
Expert panel review
The expert panel agreed that there was insufficient evidence to support the routine use of OCS, either in the 3-month run-up to the MACRO trial or post randomisation. Nevertheless, it was agreed that a short course of OCS could be used as a rescue medication during the trial, whereby usage would be documented and compared between treatment arms.
3. Care pathways: Polyp and non-polyp patients
Care pathways for CRSsNP and CRSwNP are uncertain, but there are like to be key similarities in patient management, especially at a primary care stage. GPs do not have access to endoscopy or CT scanning, and therefore distinguishing between patients based on polyp status is difficult unless polyps are big enough to be visible at the nostrils. It is likely, therefore, that primary care management and referral would be similar for both phenotypes. The Chronic Rhinosinusitis Epidemiology Study found that rates of antibiotics, oral steroids and nasal irrigation were not significantly different between the two main subgroups of CRSwNP and CRSsNPs, suggesting similar treatment pathways. Ultimately, it is possible that a CRSsNP patient may subsequently develop nasal polyps, and thus converge any treatment and management pathways for CRSsNP and CRSwNP.
From CPRD data, both ‘polyps present’ and ‘polyps unknown’ groups showed similar patterns of consultation in primary and secondary care. Prescribing rates were broadly comparable, however, slightly higher levels of OCS prescribing was observed in ‘polyps present’ group, whilst antibiotic prescribing was slightly increased when the polyp status was unknown. From the health economic analysis, where the highest CRS cost relates to ESS surgery, mean costs per patient were similar between both groups.
ENT surgeons and GPs described some differences in the CRS patient journey for CRSwNP and CRSsNP. Patients with nasal polyps were described as difficult to diagnose in primary care due to the lack of diagnostic facilities, but patients with visible polyps were more likely to be prescribed medical treatment (steroid drops/oral steroids) in primary care and receive an early referral for specialist opinion. In secondary care, ENT specialists reported that patients with nasal polyps were more likely to be prescribed oral steroids and listed earlier for surgery.
For patients without nasal polyps, GPs described themselves as confident in making the CRS diagnosis, and management commonly included a range of intranasal corticosteroid sprays. Onward referral was often not prioritised for non-polyp patients and patient pressure and lack of treatment response were the main drivers to secondary care referral. In secondary care, patients without nasal polyps were more likely to receive long-term antibiotics, and patient preference contributed to the decision for surgery.
Expert panel review
The expert panel considered the options of either conducting separate trials or including both phenotypes in a single trial. In light of the diagnostic difficulties in primary care and the possibility that CRS patients without polyps may subsequently develop them, the expert panel agreed that two separate studies would be less relevant to the real world setting. Including CRSwNP and CRSsNP patients in a single trial was considered to be more pragmatic, and likely to provide answers that could be generalised back to primary care, where polyp status can be uncertain. It was agreed, however, that trial analysis should include stratification for polyp status to determine whether outcomes vary by CRS phenotype.
4. MACRO Trial design
There was a mixed response to the two proposed trial designs both from clinicians and patients. Some clinicians expressed a preference for the single-stage 3 arm design (figure 1) describing it as ’simple to understand and describe to patients’, potentially easier to recruit to, and evaluated surgery earlier in the patient pathway. Likewise, patients liked the simplicity of the design, but some expressed concerns that surgery was too early in their treatment journey, without all medical treatment options being explored first. However, clinicians generally considered the two-stage 2-comparison design (figure 2) to be a ‘more conservative approach’ and more closely aligned to current practice, but was potentially more complex for patients to understand. Concerns were also raised about retention of patients for the second randomisation. Patients generally liked the two-stage 2-comparison design, describing it as allowing them to try medical treatments first, with the potential for surgery to be delayed or avoided.
Expert panel review
The panel agreed that the qualitative work highlighted barriers and facilitators to both trial designs and debated the key issues at length. The main issues arising about the single-stage 3-arm design (figure 1) concerned the use of medical treatment prior to trial entry, and the potential timing of surgery. Some patients were concerned about the possibility of being randomised to surgery before all medical treatment options had been explored. This raised the question about what was considered to be ‘appropriate medical treatment (AMT)’ before a patient was deemed a suitable candidate for surgery. Guidelines suggest that AMT should include a trial of intranasal steroids (INCS) for at least 8 weeks, with the optional adjunct of saline irrigation. For CRSsNP patients, a short course of broad-spectrum antibiotics or low-dose macrolides is appropriate, and CRSwNP patients may benefit from a short course of OCS. Health informatics data identified that most patients receive INCS and a short course of antibiotics prior in primary care, and therefore were likely to have received AMT prior to consultation in secondary care where trial recruitment will take place.
Following intense debate of the key issues, the expert panel was unable to reach consensus on the trial design during the panel meeting itself. Further exploratory work was agreed to help address the key issue surrounding AMT prior to surgery, including exploring patient views of AMT prior to surgery, and trial investigator views of patient eligibility for surgery. The following work was carried out:
· Patients who participated in the original qualitative research (n=25) were presented with a scenario of ‘being invited to participate in a 3-arm trial if their ENT specialist felt they were eligible for surgery on the basis of already receiving AMT’. In the sample of patients who responded (n=18/25), most agreed that theoretically they would consent to take part in such a trial. However, seven would not take part (four patients would prefer to choose their treatment rather than being randomised, and three expressed concerns about the risks of early surgery)
· Principal Investigators for the MACRO trial (n=10) were approached to explore their attitudes to AMT, specifically the treatments that they considered essential prior to patients being eligible for surgery (and hence the trial). In general, INCS were described as essential for both CRSwNP and CRSsNP patients. OCS were considered essential only for polyps patients. Short-term antibiotics were often used for both phenotypes but were not generally considered to be essential. Views on the importance of prior treatment with long-term antibiotics was varied for both phenotypes. Overall failed medical treatment was described as the main criteria for surgery.
These results were presented back to the expert panel who had the opportunity to consider and review the additional information and reflect on the panel discussions and opinions of the other panel members. Each panel member was then asked to vote for their preferred trial design, by emailing their decision to the programme manager, describing the reasons for their choice. The results were collated and a trial design agreed.
The final agreed trial design was a modified 3-arm design (Figure 3) where patients would be eligible if the local PI considered them to be suitable candidates for further treatment (including surgery). This modified design addressed the key issues of patient concern about timing of surgery (patients will have received AMT prior to being considered eligible for the trial) and AMT (practice is varied but most patients will have received antibiotics and INCS in primary care, although macrolide treatment is not widely used).