Encorafenib with Binimetinib for the Treatment of Patients with BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the Single Technology Appraisal process, the National Institute for Health and Care Excellence (NICE) invited Pierre Fabre to submit evidence for the clinical and cost-effectiveness of encorafenib with binimetinib (Enco + Bini) versus dabrafenib with trametinib (Dab + Tram) as a first-line treatment for advanced (unresectable or metastatic) BRAF V600 mutation-positive melanoma. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned as the Evidence Review Group (ERG). This article summarises the ERG's review of the company's evidence submission (CS), and the Appraisal Committee's (AC's) final decision. The main clinical evidence in the CS was derived from the COLUMBUS trial and focused on the efficacy of Enco + Bini (encorafenib 450 mg per day plus binimetinib 45 mg twice daily) compared to vemurafenib. The company conducted network meta-analyses (NMAs) to indirectly estimate the relative effects of progression-free survival (PFS), overall survival (OS), adverse events (AEs) and health-related quality of life (HRQoL) for Enco + Bini versus Dab + Tram. None of the results from the NMAs demonstrated a statistically significant difference between the treatment regimens for any outcomes. The ERG advised caution when interpreting the results from the company's NMAs due to limitations relating to the methods. The ERG considered that use of the OS and PFS hazard ratios (HRs) generated by the company's NMAs to model the relative effectiveness of Enco + Bini versus Dab + Tram in the company model was inappropriate as these estimates were not statistically significantly different. The ERG amended the company's economic model to include estimates of equivalent efficacy, safety and HRQoL for Enco + Bini and Dab + Tram. The ERG considered use of different estimates of relative dose intensity to be inappropriate and used the same estimate for both drug combinations. The ERG also concluded that as only the prices of drug combinations were different, a cost comparison was an appropriate method of economic analysis. Using this approach (combined with confidential discounted drug prices for Enco + Bini and Dab + Tram), treatment with Enco + Bini was more cost effective than treatment with Dab + Tram. The AC raised concerns that an absence of evidence of a difference in outcomes between Enco + Bini and Dab + Tram did not constitute evidence of absence. However, as the numerical differences in outcomes generated by the company's networks were small, the AC did not have a preferred approach and considered that both the company's and the ERG's methods of incorporating outcome estimates into the economic model were suitable for decision making. The NICE AC recommended Enco + Bini as a first-line treatment for unresectable or metastatic melanoma with a BRAF V600 mutation.

A systematic review of health state utility values for thyroid cancer.

PURPOSE: Health state utility values are commonly used to inform economic evaluations and determine the cost-effectiveness of an intervention. The aim of this systematic review is to summarise the utility values available to represent the health-related quality of life (HRQoL) of patients with thyroid cancer. METHODS: Eight electronic databases were searched from January 1999 to April 2019 for studies which included assessment of HRQoL for patients with thyroid cancer. Utility estimates derived from multiple sources (EuroQol questionnaire 5-dimension (EQ-5D), time trade-off [TTO] and standard gamble [SG] methods) were extracted. In addition, utility estimates were generated by mapping from SF-36 and EORTC QLQ-30 to the EQ-5D-3L UK value set using published mapping algorithms. RESULTS: Searches identified 33 eligible studies. Twenty-six studies reported HRQoL for patients with differentiated thyroid cancer and seven studies for patients with general thyroid cancer. We identified studies which used different methods and tools to quantify the HRQoL in patients with thyroid cancer, such as the EQ-5D-3L, SF-36, EORTC QLQ-30 and SG and TTO techniques to estimate utility values. Utility estimates range from 0.205 (patients with low-risk differentiated thyroid cancer) to utility values approximate to the average UK population (following successful thyroidectomy surgery and radioiodine treatment). Utility estimates for different health states, across thyroid cancer sub-types and interventions are presented. CONCLUSION: A catalogue of utility values is provided for use when carrying out economic modelling of thyroid cancer; by including mapped values, this approach broadens the scope of health states that can be considered within cost-effectiveness modelling.

Lead-I ECG for detecting atrial fibrillation in patients with an irregular pulse using single time point testing: a systematic review and economic evaluation.

BACKGROUND: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and is associated with an increased risk of stroke and congestive heart failure. Lead-I electrocardiogram (ECG) devices are handheld instruments that can be used to detect AF at a single time point in people who present with relevant signs or symptoms. OBJECTIVE: To assess the diagnostic test accuracy, clinical impact and cost-effectiveness of using single time point lead-I ECG devices for the detection of AF in people presenting to primary care with relevant signs or symptoms, and who have an irregular pulse compared with using manual pulse palpation (MPP) followed by a 12-lead ECG in primary or secondary care. DATA SOURCES: MEDLINE, MEDLINE Epub Ahead of Print and MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PubMed, Cochrane Databases of Systematic Reviews, Cochrane Central Database of Controlled Trials, Database of Abstracts of Reviews of Effects and the Health Technology Assessment Database. METHODS: The systematic review methods followed published guidance. Two reviewers screened the search results (database inception to April 2018), extracted data and assessed the quality of the included studies. Summary estimates of diagnostic accuracy were calculated using bivariate models. An economic model consisting of a decision tree and two cohort Markov models was developed to evaluate the cost-effectiveness of lead-I ECG devices. RESULTS: No studies were identified that evaluated the use of lead-I ECG devices for patients with signs or symptoms of AF. Therefore, the diagnostic accuracy and clinical impact results presented are derived from an asymptomatic population (used as a proxy for people with signs or symptoms of AF). The summary sensitivity of lead-I ECG devices was 93.9% [95% confidence interval (CI) 86.2% to 97.4%] and summary specificity was 96.5% (95% CI 90.4% to 98.8%). One study reported limited clinical outcome data. Acceptability of lead-I ECG devices was reported in four studies, with generally positive views. The de novo economic model yielded incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-year (QALY) gained. The results of the pairwise analysis show that all lead-I ECG devices generated ICERs per QALY gained below the £20,000-30,000 threshold. Kardia Mobile (AliveCor Ltd, Mountain View, CA, USA) is the most cost-effective option in a full incremental analysis. LIMITATIONS: No published data evaluating the diagnostic accuracy, clinical impact or cost-effectiveness of lead-I ECG devices for the population of interest are available. CONCLUSIONS: Single time point lead-I ECG devices for the detection of AF in people with signs or symptoms of AF and an irregular pulse appear to be a cost-effective use of NHS resources compared with MPP followed by a 12-lead ECG in primary or secondary care, given the assumptions used in the base-case model. FUTURE WORK: Studies assessing how the use of lead-I ECG devices in this population affects the number of people diagnosed with AF when compared with current practice would be useful. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018090375. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Atrial fibrillation (AF) is the most common type of abnormal heart rhythm. People with AF are more likely to have a serious stroke or die than people without the condition. Many people go to their general practitioner (GP) with the signs or symptoms commonly linked to AF, such as feeling dizzy, being short of breath, feeling tired and having heart palpitations. GPs check for AF by taking the patient's pulse by hand. If the GP thinks that the patient might have AF, a 12-lead electrocardiogram (ECG) test is arranged. Lead-I (i.e. one lead) ECGs are handheld electronic devices that could detect AF more accurately than a manual pulse check. If GPs were to routinely use lead-I ECG devices, people with suspected AF could receive treatment while waiting for the AF diagnosis to be confirmed by a 12-lead ECG. This study aimed to assess whether or not the use of lead-I ECGs in GP surgeries could benefit these patients and offer good value for money to the NHS. All studies that examined how well lead-I ECGs identified people with AF were reviewed, and the economic value of using these devices was assessed. No evidence was found that examined the use of lead-I ECGs for people with signs or symptoms of AF. As an alternative, evidence for the use of lead-I ECGs for people with no symptoms of AF was searched for and these data were used to assess value for money. The study found that using a manual pulse check followed by a lead-I ECG offers value for money when compared with a manual pulse check followed by a 12-lead ECG. This is mostly because patients with AF can begin treatment earlier when a GP has access to a lead-I ECG device.

Eribulin for Treating Locally Advanced or Metastatic Breast Cancer After One Chemotherapy Regimen: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Eribulin is a recommended treatment option for locally advanced or metastatic breast cancer (LABC/MBC) in adults whose disease has progressed after at least two chemotherapy regimens. The National Institute for Health and Care Excellence (NICE) invited the manufacturer of eribulin (Halaven®; Eisai Ltd) to submit evidence for the clinical and cost effectiveness of eribulin for treating LABC/MBC after one chemotherapy regimen in accordance with the institute's Single Technology Appraisal (STA) process. This article presents a summary of the company's evidence, Evidence Review Group (ERG) review and resulting NICE guidance (TA515), issued 28 March 2018. Clinical evidence for eribulin versus capecitabine in LABC/MBC was derived from a subgroup of 392 patients with human epidermal growth factor receptor (HER2)-negative disease which had progressed after only one prior chemotherapy regimen for LABC/MBC in the phase III, randomised, controlled Study 301 (n = 1102). Overall survival (OS) but not progression-free survival (PFS) was improved for patients treated with eribulin versus capecitabine in this subgroup. Using the discounted patient access scheme price for eribulin, the company developed a de novo economic model. In the base case, the incremental cost-effectiveness ratio (ICER) for eribulin versus capecitabine was £36,244 per quality-adjusted life year (QALY) gained. However, the ERG identified several problematic issues relating to modelling OS and PFS, drug costing and utility values, and made ten revisions to the company model. The overall impact of all ten revisions was to increase the ICER per QALY gained by £46,499. The Appraisal Committee (AC) accepted all changes made by the ERG except for the change to utility values; the AC considered that the value should be mid-way between the company's and the ERG's preferred values. A modified model was submitted by the company that included this utility value, but maintained some elements of the base case that the AC had been critical of (differential PFS between treatment arms and application of treatment cap). The new model also included a 'blended' comparator (capecitabine and vinorelbine). The AC noted there was no evidence to support a 'blended' comparator, differential PFS between treatment arms or a treatment cap. The AC therefore concluded that the most plausible ICER was likely to be £69,843 per QALY gained (derived from an ERG sensitivity analysis using the AC's preferred utility value, no differential PFS and no treatment cap). Therefore, eribulin was not recommended for treating LABC/MBC in adults who have had only one chemotherapy regimen.

A systematic review of barriers and enablers to South Asian women's attendance for asymptomatic screening of breast and cervical cancers in emigrant countries.

OBJECTIVES: The aim of this review was to identify the cultural, social, structural and behavioural factors that influence asymptomatic breast and cervical cancer screening attendance in South Asian populations, in order to improve uptake and propose priorities for further research. DESIGN: A systematic review of the literature for inductive, comparative, prospective and intervention studies. We searched the following databases: MEDLINE/In-Process, Web of Science, EMBASE, SCOPUS, CENTRAL, CDSR, CINAHL, PsycINFO and PsycARTICLES from database inception to 23 January 2018. The review included studies on the cultural, social, structural and behavioural factors that influence asymptomatic breast and cervical cancer screening attendance and cervical smear testing (Papanicolaou test) in South Asian populations and those published in the English language. The framework analysis method was used and themes were drawn out following the thematic analysis method. SETTINGS: Asymptomatic breast or cervical screening. PARTICIPANTS: South Asian women, including Bangladeshi, Indian, Pakistani, Sri Lankan, Bhutanese, Maldivian and Nepali populations. RESULTS: 51 included studies were published between 1991 and 2018. Sample sizes ranged from 25 to 38 733 and participants had a mean age of 18 to 83 years. Our review showed that South Asian women generally had lower screening rates than host country women. South Asian women had poorer knowledge of cancer and cancer prevention and experienced more barriers to screening. Cultural practices and assumptions influenced understandings of cancer and prevention, emphasising the importance of host country cultures and healthcare systems. CONCLUSIONS: High-quality research on screening attendance is required using prospective designs, where objectively validated attendance is predicted from cultural understandings, beliefs, norms and practices, thus informing policy on targeting relevant public health messages to the South Asian communities about screening for cancer. PROSPERO REGISTRATION NUMBER: CSD 42015025284.

Paclitaxel as Albumin-Bound Nanoparticles with Gemcitabine for Untreated Metastatic Pancreatic Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited Celgene Ltd to submit clinical and cost-effectiveness evidence for paclitaxel as albumin-bound nanoparticles (Nab-Pac) in combination with gemcitabine (Nab-Pac + Gem) for patients with untreated metastatic pancreatic cancer. The STA was a review of NICE's 2015 guidance (TA360) in which Nab-Pac + Gem was not recommended for patients with untreated metastatic pancreatic cancer. The review was prompted by a proposed Patient Access Scheme (PAS) discount on the price of Nab-Pac and new evidence that might lead to a change in the guidance. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group (ERG). This article summarises the ERG's review of the company's evidence submission for Nab-Pac + Gem, and the Appraisal Committee (AC) decision. The final scope issued by NICE listed three comparators: gemcitabine monotherapy (Gem), gemcitabine in combination with capecitabine (Gem + Cap), and a combination of oxaliplatin, irinotecan, leucovorin and fluorouracil (FOLFIRINOX). Clinical evidence for the comparison of Nab-Pac + Gem versus Gem was from the phase III CA046 randomized controlled trial. Analysis of progression-free survival (PFS) and overall survival (OS) showed statistically significant improvement for patients treated with Nab-Pac + Gem versus Gem. Clinical evidence for the comparison of Nab-Pac + Gem versus FOLFIRINOX and versus Gem + Cap was derived from a network meta-analysis (NMA). Results of the NMA did not indicate a statistically significant difference in OS or PFS for the comparison of Nab-Pac + Gem versus either Gem + Cap or FOLFIRINOX. The ERG's main concerns with the clinical effectiveness evidence were difficulties in identifying the patient population for whom treatment with Nab-Pac + Gem is most appropriate, and violation of the proportional hazards (PH) assumption in the CA046 trial. The ERG highlighted methodological issues in the cost-effectiveness analysis pertaining to the modelling of survival outcomes, estimation of drug costs and double counting of adverse-event disutilities. The AC accepted all the ERG's amendments to the company's cost-effectiveness model; however, these did not make important differences to the incremental cost-effectiveness ratios (ICERs). The company's base-case ICER was £46,932 per quality-adjusted life-year (QALY) gained for the comparison of Nab-Pac + Gem versus Gem. Treatment with Nab-Pac + Gem was dominated both by treatment with Gem + Cap and with FOLFIRINOX in the company's base case. The AC concluded that the most plausible ICER for treatment with Nab-Pac + Gem versus Gem was in the range of £41,000-£46,000 per QALY gained. The AC concluded that Nab-Pac + Gem was not cost effective compared with Gem + Cap or FOLFIRINOX, and accepted that treatment with Nab-Pac + Gem met the end-of-life criteria versus Gem but did not consider Nab-Pac + Gem to meet the end-of-life criteria compared with Gem + Cap or FOLFIRINOX. The AC also concluded that although patients who would receive Nab-Pac + Gem rather than FOLFIRINOX or Gem + Cap were difficult to distinguish, they were identifiable in clinical practice. The AC recommended treatment with Nab-Pac + Gem for patients with untreated metastatic pancreatic cancer for whom other combination chemotherapies were unsuitable and who would otherwise receive Gem.

Pegylated Liposomal Irinotecan Hydrochloride Trihydrate for Treating Pancreatic Cancer After Gemcitabine: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Shire Pharmaceuticals) of pegylated liposomal irinotecan hydrochloride trihydrate (liposomal irinotecan) to submit clinical and cost-effectiveness evidence for its use in combination with 5-fluorouracil (5-FU) and folic acid/leucovorin (LV) for treating patients with pancreatic cancer following prior treatment with gemcitabine as part of the institute's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company's evidence, the ERG review and the resulting NICE guidance (TA440), issued on 26 April 2017. Clinical evidence for liposomal irinotecan + 5-FU/LV versus 5-FU/LV was derived from 236 patients with metastatic pancreatic cancer in the multinational, open-label, randomised controlled NAPOLI-1 trial. Results from analyses of progression-free survival and overall survival showed statistically significant improvements for patients treated with liposomal irinotecan + 5-FU/LV compared with those treated with 5-FU/LV. However, 5-FU/LV alone is rarely used in National Health Service clinical practice for patients with metastatic pancreatic cancer previously treated with gemcitabine. The company, ERG and Appraisal Committee (AC) all agreed that oxaliplatin + 5-FU/LV is the most commonly used treatment. Oxaliplatin + 5-FU/LV was compared with 5-FU/LV in two trials identified by the company. However, the company and the ERG both considered attempts to compare the efficacy of liposomal irinotecan + 5-FU/LV with oxaliplatin + 5-FU/LV to be methodologically flawed; not only was there heterogeneity between trials and their populations but also the proportional hazards assumption required to conduct a robust indirect treatment comparison (ITC) was violated. Nonetheless, data derived from an ITC were used to inform the company's economic model. Using the discounted patient access scheme price for liposomal irinotecan + 5-FU/LV, the company reported an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £54,412 for the comparison with oxaliplatin + 5-FU/LV. The ERG considered that the company's base-case cost-effectiveness results for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV were underestimates and should be interpreted with extreme caution. Following implementation of a number of model amendments, the ERG's modified exploratory ICER for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV was £106,898 per QALY gained. The AC accepted the majority of the ERG's amendments to the model, and also highlighted that the total QALYs for oxaliplatin + 5-FU/LV were lower than for 5-FU/LV in the company's model, which the AC considered to be clinically implausible. The AC therefore considered results from exploratory analyses, undertaken by the ERG, which included altering the QALY difference between liposomal irinotecan + 5-FU/LV and oxaliplatin + 5-FU/LV by ± 10%. These analyses resulted in ICERs for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV of between £201,019 per QALY gained to liposomal irinotecan + 5-FU/LV being dominated by oxaliplatin + 5-FU/LV. Therefore, despite uncertainty around the clinical-effectiveness evidence and cost-effectiveness results, the AC was confident that the ICER was in excess of £50,000 per QALY gained. The final guidance issued by NICE is that liposomal irinotecan + 5-FU/LV is not recommended within its marketing authorisation for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy.

Talimogene Laherparepvec for Treating Metastatic Melanoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Amgen) of talimogene laherparepvec (T-VEC) to submit clinical and cost-effectiveness evidence for previously untreated advanced (unresectable or metastatic) melanoma as part of the Institute's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company's submission of T-VEC, the ERG review and the resulting NICE guidance (TA410), issued in September 2016. T-VEC is an oncolytic virus therapy granted a marketing authorisation by the European Commission for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (stage IIIB, IIIC and IVM1a) with no bone, brain, lung or other visceral disease. Clinical evidence for T-VEC versus granulocyte-macrophage colony-stimulating factor (GM-CSF) was derived from the multinational, open-label randomised controlled OPTiM trial [Oncovex (GM-CSF) Pivotal Trial in Melanoma]. In accordance with T-VEC's marketing authorisation, the company's submission focused primarily on 249 patients with stage IIIB to stage IV/M1a disease who constituted 57% of the overall trial population (T-VEC, n = 163 and GM-CSF, n = 86). Results from analyses of durable response rate, objective response rate, time to treatment failure and overall survival all showed marked and statistically significant improvements for patients treated with T-VEC compared with those treated with GM-CSF. However, GM-CSF is not used to treat melanoma in clinical practice. It was not possible to compare treatment with T-VEC with an appropriate comparator using conventionally accepted methods due to the absence of comparative head-to-head data or trials with sufficient common comparators. Therefore, the company compared T-VEC with ipilimumab using what it described as modified Korn and two-step Korn methods. Results from these analyses suggested that treatment with T-VEC was at least as effective as treatment with ipilimumab. Using the discounted patient access scheme (PAS) price for T-VEC and list price for ipilimumab, the company reported incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-year (QALY) gained. For the comparison of treatment with T-VEC versus ipilimumab, the ICER per QALY gained was -£16,367 using the modified Korn method and -£60,271 using the two-step Korn method. The NICE Appraisal Committee (AC) agreed with the ERG that the company's methods for estimating clinical effectiveness of T-VEC versus ipilimumab were flawed and therefore produced unreliable results for modelling progression in stage IIIB to stage IVM1a melanoma. The AC concluded that the clinical and cost effectiveness of treatment with T-VEC compared with ipilimumab is unknown in patients with stage IIIB to stage IV/M1a disease. However, the AC considered that T-VEC may be a reasonable option for treating patients who are unsuitable for treatment with systemically administered immunotherapies (such as ipilimumab). T-VEC was therefore recommended by NICE as a treatment option for adults with unresectable, regionally or distantly metastatic (stage IIIB to stage IVM1a) melanoma that has not spread to bone, brain, lung or other internal organs, only if treatment with systemically administered immunotherapies is not suitable and the company provides T-VEC at the agreed discounted PAS price.

The clinical effectiveness and cost-effectiveness of heated humidified high-flow nasal cannula compared with usual care for preterm infants: systematic review and economic evaluation.

BACKGROUND: Respiratory problems are one of the most common causes of morbidity in preterm infants and may be treated with several modalities for respiratory support such as nasal continuous positive airway pressure (NCPAP) or nasal intermittent positive-pressure ventilation. The heated humidified high-flow nasal cannula (HHHFNC) is gaining popularity in clinical practice. OBJECTIVES: To address the clinical effectiveness of HHHFNC compared with usual care for preterm infants we systematically reviewed the evidence of HHHFNC with usual care following ventilation (the primary analysis) and with no prior ventilation (the secondary analysis). The primary outcome was treatment failure defined as the need for reintubation (primary analysis) or intubation (secondary analysis). We also aimed to assess the cost-effectiveness of HHHFNC compared with usual care if evidence permitted. DATA SOURCES: The following databases were searched: MEDLINE (2000 to 12 January 2015), EMBASE (2000 to 12 January 2015), The Cochrane Library (issue 1, 2015), ISI Web of Science (2000 to 12 January 2015), PubMed (1 March 2014 to 12 January 2015) and seven trial and research registers. Bibliographies of retrieved citations were also examined. REVIEW METHODS: Two reviewers independently screened all titles and abstracts to identify potentially relevant studies for inclusion in the review. Full-text copies were assessed independently. Data were extracted and assessed for risk of bias. Summary statistics were extracted for each outcome and, when possible, data were pooled. A meta-analysis was only conducted for the primary analysis, using fixed-effects models. An economic evaluation was planned. RESULTS: Clinical evidence was derived from seven randomised controlled trials (RCTs): four RCTs for the primary analysis and three RCTs for the secondary analysis. Meta-analysis found that only for nasal trauma leading to a change of treatment was there a statistically significant difference, favouring HHHFNC over NCPAP [risk ratio (RR) 0.21, 95% confidence interval (CI) 0.10 to 0.42]. For the following outcomes, there were no statistically significant differences between arms: treatment failure (reintubation < 7 days; RR 0.76, 95% CI 0.54 to 1.09), bronchopulmonary dysplasia (RR 0.92, 95% CI 0.72 to 1.17), death (RR 0.56, 95% CI 0.22 to 1.44), pneumothorax (RR 0.33, 95% CI 0.03 to 3.12), intraventricular haemorrhage (grade ≥ 3; RR 0.41, 95% CI 0.15 to 1.15), necrotising enterocolitis (RR 0.41, 95% CI 0.15 to 1.14), apnoea (RR 1.08, 95% CI 0.74 to 1.57) and acidosis (RR 1.16, 95% CI 0.38 to 3.58). With no evidence to support the superiority of HHHFNC over NCPAP, a cost-minimisation analysis was undertaken, the results suggesting HHHFNC to be less costly than NCPAP. However, this finding is sensitive to the lifespan of equipment and the cost differential of consumables. LIMITATIONS: There is a lack of published RCTs of relatively large-sized populations comparing HHHFNC with usual care; this is particularly true for preterm infants who had received no prior ventilation. CONCLUSIONS: There is a lack of convincing evidence suggesting that HHHFNC is superior or inferior to usual care, in particular NCPAP. There is also uncertainty regarding whether or not HHHFNC can be considered cost-effective. Further evidence comparing HHHFNC with usual care is required. STUDY REGISTRATION: This review is registered as PROSPERO CRD42015015978. FUNDING: The National Institute for Health Research Health Technology Assessment programme.