Steven J. Edwards

Objectives: To review how statistically non-significant indirect treatment comparison (ITC) results are interpreted within National Institute for Health and Care Excellence (NICE) cost-comparison evaluations (CCEs) and develop a framework to support interpretations of these results from Bayesian network meta-analyses (NMAs). Design: A systematic review of CCEs between 2017 (first introduced) and April 2025. A framework (point-and-density plots) was developed to better interpret statistically non-significant NMA results for CCEs. Data sources: CCEs were identified through NICE website searches, references of similar reviews and communications with NICE. Eligibility criteria: NICE technology appraisals (from 2017) that followed a CCE approach ab initio, had final guidance available and used non-statistically significant ITC results were included. Data extraction and synthesis: A single reviewer performed screening and data extraction with validation by a second reviewer. Narrative syntheses were performed separately for company, External Assessment Group (EAG) and committee perspectives. Point-and-density plots combine elements of forest plots and density plots alongside reporting the probability that a treatment is non-inferior relative to a comparator. These were applied to a recent CCE (TA1019) for crovalimab for patients with paroxysmal nocturnal haemoglobinuria. Results: Among 41 CCEs, EAGs raised concerns about statistically non-significant ITC results while companies relied heavily on them. Only ∼32% of CCEs applied formal methods to explore ITC result uncertainty. For the example framework analysis, comparisons of crovalimab to eculizumab (mean difference (MD): 0.018; 95% CIs −0.22 to 0.25) and ravulizumab (MD: 0.079; 95% CIs −0.25 to 0.41) were statistically non-significant, with non-inferiority not demonstrated. However, point-and-density plots indicated a 95.9% and 86.3% probability of non-inferiority of crovalimab versus eculizumab and ravulizumab. Conclusions: Interpretations of statistically non-significant ITC results are inconsistent within individual CCEs and across appraisals. Implementation of the presented recommendations and framework would improve the consistency and robustness of CCEs. PROSPERO registration number: CRD420251034143.

Background: Cystic fibrosis is a life-limiting genetic condition that affects over 9000 people in England. Cystic fibrosis is usually diagnosed through newborn screening and causes symptoms throughout the body, including the lungs and digestive system. Around 90% of individuals with cystic fibrosis have at least one copy of the F508del mutation on the cystic fibrosis transmembrane conductance regulator gene. Objectives: To appraise the clinical effectiveness and cost-effectiveness of elexacaftor–tezacaftor–ivacaftor, tezacaftor–ivacaftor and lumacaftor–ivacaftor within their expected marketing authorisations for treating people with cystic fibrosis and at least one F508del mutation, compared with each other and with established clinical management before these treatments. Methods: A de novo systematic literature review (search date February 2023) was conducted searching electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials), bibliographies of relevant systematic literature reviews, clinical trial registers, recent conferences and evidence provided by Vertex Pharmaceuticals (Boston, MA, USA). Data on the following outcomes were summarised: acute change in per cent predicted forced expiratory volume in 1 second (change in weight-for-age z-score; and change in pulmonary exacerbation frequency requiring intravenous antibiotics. Network meta-analyses were conducted where head-to-head data were not available. Data from clinical trials and real-world evidence were examined to assess long-term effectiveness. A patient-level simulation model was developed to assess the cost-effectiveness of the three modulator treatments. The model employed a lifetime horizon and was developed from the perspective of the National Health Service. Results: Data from 19 primary studies and 7 open-label extension studies were prioritised in the systematic literature review. Elexacaftor/tezacaftor/ivacaftor was associated with a statistically significant increase in predicted forced expiratory volume in 1 second and weight-for-age z-score and a reduction in pulmonary exacerbations compared with established clinical management, lumacaftor/ivacaftor and tezacaftor/ivacaftor, and also led to a reduction in the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management, although the magnitude of this decrease was uncertain. Lumacaftor/ivacaftor and tezacaftor/ivacaftor were also associated with a statistically significant increase in predicted forced expiratory volume in 1 second and reduction in pulmonary exacerbations relative to established clinical management, but with a smaller effect size than elexacaftor/tezacaftor/ivacaftor. There was some evidence that tezacaftor/ivacaftor reduced the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management, but little evidence that lumacaftor/ivacaftor reduced the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management. The incremental cost-effectiveness ratios from the economic analysis were confidential. However, for all genotypes studied the incremental cost-effectiveness ratios were above what would be considered cost-effective based on the National Institute for Health and Care Excellence threshold of £20,000–30,000 per quality-adjusted life-year gained. Conclusions: Despite the improved clinical benefits observed, none of the cystic fibrosis transmembrane conductance regulator gene modulators assessed would be considered cost-effective based on the National Institute for Health and Care Excellence threshold of £20,000–30,000 per quality-adjusted life-year gained. This is largely driven by the high acquisition costs of cystic fibrosis transmembrane conductance regulator gene modulator treatments. Study registration: This study is registered as PROSPERO CRD42023399583. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135829) and is published in full in Health Technology Assessment; Vol. 29, No. 19. See the NIHR Funding and Awards website for further award information.

Background: Atopic dermatitis is a chronic relapsing inflammatory skin condition. One of the most common skin disorders in children, atopic dermatitis typically manifests before the age of 5 years, but it can develop at any age. Atopic dermatitis is characterised by dry, inflamed skin accompanied by intense itchiness (pruritus). Objectives: To appraise the clinical and cost effectiveness of abrocitinib, tralokinumab and upadacitinib within their marketing authorisations as alternative therapies for treating moderate -to -severe atopic dermatitis compared to systemic immunosuppressants (first -line ciclosporin A or second -line dupilumab and baricitinib). Data sources: Studies were identified from an existing systematic review (search date 2019) and update searches of electronic databases (MEDLINE, EMBASE, CENTRAL) to November 2021, from bibliographies of retrieved studies, clinical trial registers and evidence provided by the sponsoring companies of the treatments under review. Methods: A systematic review of the clinical effectiveness literature was carried out and a network meta -analysis undertaken for adults and adolescents at different steps of the treatment pathway. The primary outcome of interest was a combined response of Eczema Area and Severity Index 50 + Dermatology Life Quality Index >= 4; where this was consistently unavailable for a step in the pathway, an analysis of Eczema Area and Severity Index 75 was conducted. A de novo economic model was developed to assess cost effectiveness from the perspective of the National Health Service in England. The model structure was informed through systematic review of the economic literature and by consulting clinical experts. Effectiveness data were obtained from the network meta -analysis. Costs and utilities were obtained from the evidence provided by sponsoring companies and standard UK sources. Results: Network meta -analyses indicate that abrocitinib 200 mg and upadacitinib 30 mg may be more effective, and tralokinumab may be less effective than dupilumab and baricitinib as second -line systemic therapies. Abrocitinib 100 mg and upadacitinib 15 mg have a more similar effectiveness to dupilumab. Upadacitinib 30 and 15 mg are likely to be more effective than ciclosporin A as a first -line therapy. Upadacitinib 15 mg, abrocitinib 200 and 100 mg may be more effective than dupilumab in adolescents. The cost effectiveness of abrocitinib and upadacitinib for both doses is dependent on the subgroup of interest. Tralokinumab can be considered cost-effective as a second -line systemic therapy owing to greater cost savings per quality -adjusted life -year lost. Conclusions: The primary strength of the analysis of the three new drugs compared with current practice for each of the subpopulations is the consistent approach to the assessment of clinical and cost effectiveness. However, the conclusions are limited by the high uncertainty around the clinical effectiveness and lack of data for the primary outcome for comparisons with baricitinib and for the adolescent and adult first -line populations.

Health Technology Assessment Volume: 25, Issue: 23, Published in March 2021

Background: Cryptogenic stroke is a stroke for which no cause is identified after standard diagnostic tests. Long-term implantable cardiac monitors may be better at diagnosing atrial fibrillation and provide an opportunity to reduce the risk of stroke recurrence with anticoagulants.Objectives: The objectives were to assess the diagnostic test accuracy, clinical effectiveness and cost-effectiveness of three implantable monitors [BioMonitor 2-AF™ (Biotronik SE & Co. KG, Berlin, Germany), Confirm Rx™ (Abbott Laboratories, Lake Bluff, IL, USA) and Reveal LINQ™ (Medtronic plc, Minneapolis, MN, USA)] in patients who have had a cryptogenic stroke and for whom no atrial fibrillation is detected after 24 hours of external electrocardiographic monitoring.Data sources: MEDLINE, EMBASE, The Cochrane Library, Database of Abstracts of Reviews of Effects and Health Technology Assessment databases were searched from inception until September 2018.Review methods: A systematic review was undertaken. Two reviewers agreed on studies for inclusion and performed quality assessment using the Cochrane Risk of Bias 2.0 tool. Results were discussed narratively because there were insufficient data for synthesis. A two-stage de novo economic model was developed: (1) a short-term patient flow model to identify cryptogenic stroke patients who have had atrial fibrillation detected and been prescribed anticoagulation treatment (rather than remaining on antiplatelet treatment) and (2) a long-term Markov model that captured the lifetime costs and benefits of patients on either anticoagulation or antiplatelet treatment.Results: One randomised controlled trial, Cryptogenic Stroke and underlying Atrial Fibrillation (CRYSTAL-AF) (Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo CA,et al.Cryptogenic stroke and underlying atrial fibrillation.N Engl J Med2014;370:2478–86), was identified, and no diagnostic test accuracy study was identified. The CRYSTAL-AF trial compared the Reveal™ XT (a Reveal LINQ predecessor) (Medtronic plc) monitor with standard of care monitoring. Twenty-six single-arm observational studies for the Reveal devices were also identified. The only data for BioMonitor 2-AF or Confirm Rx were from mixed population studies supplied by the companies. Atrial fibrillation detection in the CRYSTAL-AF trial was higher with the Reveal XT than with standard monitoring at all time points. By 36 months, atrial fibrillation was detected in 19% of patients with an implantable cardiac monitor and in 2.3% of patients receiving conventional follow-up. The 26 observational studies demonstrated that, even in a cryptogenic stroke population, atrial fibrillation detection rates are highly variable and most cases are asymptomatic; therefore, they probably would not have been picked up without an implantable cardiac monitor. Device-related adverse events, such as pain and infection, were low in all studies. The de novo economic model produced incremental cost effectiveness ratios comparing implantable cardiac monitors with standard of care monitoring to detect atrial fibrillation in cryptogenic stroke patients based on data for the Reveal XT device, which can be related to Reveal LINQ. The BioMonitor 2-AF and Confirm RX were included in the analysis by making a strong assumption of equivalence with Reveal LINQ. The results indicate that implantable cardiac monitors could be considered cost-effective at a £20,000–30,000 threshold. When each device is compared incrementally, BioMonitor 2-AF dominates Reveal LINQ and Confirm RX.Limitations: The cost-effectiveness analysis for implantable cardiac monitors is based on a strong assumption of clinical equivalence and should be interpreted with caution.Conclusions: All three implantable cardiac monitors could be considered cost-effective at a £20,000–30,000 threshold, compared with standard of care monitoring, for cryptogenic stroke patients with no atrial fibrillation detected after 24 hours of external electrocardiographic monitoring; however, further clinical studies are required to confirm their efficacy in cryptogenic stroke patients.Study registration: This study is registered as PROSPERO CRD42018109216.Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 5. See the NIHR Journals Library website for further project information.

Objective: To compare the effectiveness and safety of treatments for advanced or metastatic renal cell carcinoma (amRCC) after treatment with vascular endothelial growth factor (VEGF)-targeted treatment.Design: Systematic review and network meta-analysis of randomised controlled trials (RCTs) and comparative observational studies. MEDLINE, EMBASE and Cochrane Library were searched up to January 2018.Participants: People with amRCC requiring treatment after VEGF-targeted treatment.Interventions: Axitinib, cabozantinib, everolimus, lenvatinib with everolimus, nivolumab, sorafenib and best supportive care (BSC).Outcomes: Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes were objective response rate (ORR), adverse events, and health-related quality of life (HRQoL).Results: Twelve studies were included (n=5144): five RCTs and seven observational studies. Lenvatinib with everolimus significantly increased OS and PFS over everolimus (HR 0.61, 95% Credible Interval [95%CrI]: 0.36 to 0.96 and 0.47, 95%CrI: 0.26 to 0.77, respectively) as did cabozantinib (HR 0.66, 95%CrI: 0.53 to 0.82 and 0.51, 95%CrI: 0.41 to 0.63, respectively). This remained the case when observational evidence was included. Nivolumab also significantly improved OS versus everolimus (HR 0.74, 95%CrI: 0.57 to 0.93). OS sensitivity analysis, including observational studies, indicates everolimus being more effective than axitinib and sorafenib. However, inconsistency was identified in the OS sensitivity analysis. PFS sensitivity analysis suggests axitinib is more effective than everolimus, which may be more effective than sorafenib. The results for ORR supported the OS and PFS analyses. Nivolumab is associated with fewer grade 3 or grade 4 adverse events than lenvatinib with everolimus or cabozantinib. HRQoL could not be analysed due to differences in tools used.Conclusions: Lenvatinib with everolimus, cabozantinib and nivolumab are effective in prolonging the survival for people with amRCC subsequent to VEGF-targeted treatment, but there is considerable uncertainty about how they compare to each other and how much better they are than axitinib and sorafenib.PROSPERO registrationnumber: CRD42017071540.

Skin cancer is one of the most common cancers in the UK. Patients with suspicious skin lesions are assessed clinically with/without dermoscopy, and lesions still considered suspicious are then surgically removed or have the diagnosis confirmed by a punch biopsy. To evaluate the diagnostic accuracy of the in vivo VivaScope^© reflective confocal microscopy (RCM) system, a noninvasive technology designed to provide a more accurate presurgical diagnosis, leading to fewer biopsies of benign lesions, or to provide greater accuracy for lesion margins. MEDLINE, EMBASE and the Cochrane Library were searched to identify studies evaluating dermoscopy plus RCM, or RCM alone, with histopathology as the reference test. Clinical experts were also contacted for information on unpublished studies. Eleven studies met the inclusion criteria but were too heterogeneous to be combined by meta-analysis. Results indicated that VivaScope subsequent to dermoscopy may improve diagnostic accuracy of malignant melanomas compared with dermoscopy. For margin delineation, the data suggest that mapping using VivaScope 1500 for lentigo maligna (LM) and LM melanoma may improve accuracy in terms of complete excision of lesions compared with dermoscopically determined margins. For basal cell carcinoma, the limited data show high diagnostic accuracy with both VivaScope 1500 and VivaScope 3000. Evidence on the effectiveness of VivaScope in diagnosing cutaneous squamous cell carcinomas was very limited. The use of VivaScope 1500 following dermoscopy may improve patient care and management of suspicious skin lesions, although the generalizability of these results to the UK population remains unclear.

Background: Fibrin sealants are used in different types of surgery to prevent the accumulation of post-operative fluid (seroma) or blood (haematoma) or to arrest haemorrhage (bleeding). However, there is uncertainty around the benefits and harms of fibrin sealant use.Objectives: To systematically review the evidence on the benefits and harms of fibrin sealants in non-emergency surgery in adults.Data sources: Electronic databases [MEDLINE, EMBASE and The Cochrane Library (including the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment database and the Cochrane Central Register of Controlled Trials)] were searched from inception to May 2015. The websites of regulatory bodies (the Medicines and Healthcare products Regulatory Agency, the European Medicines Agency and the Food and Drug Administration) were also searched to identify evidence of harms.Review methods: This review included randomised controlled trials (RCTs) and observational studies using any type of fibrin sealant compared with standard care in non-emergency surgery in adults. The primary outcome was risk of developing seroma and haematoma. Only RCTs were used to inform clinical effectiveness and both RCTs and observational studies were used for the assessment of harms related to the use of fibrin sealant. Two reviewers independently screened all titles and abstracts to identify potentially relevant studies. Data extraction was undertaken by one reviewer and validated by a second. The quality of included studies was assessed independently by two reviewers using the Cochrane Collaboration risk-of-bias tool for RCTs and the Centre for Reviews and Dissemination guidance for adverse events for observational studies. A fixed-effects model was used for meta-analysis.Results: We included 186 RCTs and eight observational studies across 14 surgical specialties and five reports from the regulatory bodies. Most RCTs were judged to be at an unclear risk of bias. Adverse events were inappropriately reported in observational studies. Meta-analysis across non-emergency surgical specialties did not show a statistically significant difference in the risk of seroma for fibrin sealants versus standard care in 32 RCTs analysed [n = 3472, odds ratio (OR) 0.84, 95% confidence interval (CI) 0.68 to 1.04;p = 0.13;I² = 12.7%], but a statistically significant benefit was found on haematoma development in 24 RCTs (n = 2403, OR 0.62, 95% CI 0.44 to 0.86;p = 0.01;I² = 0%). Adverse events related to fibrin sealant use were reported in 10 RCTs and eight observational studies across surgical specialties, and 22 RCTs explicitly stated that there were no adverse events. One RCT reported a single death but no other study reported mortality or any serious adverse events. Five regulatory body reports noted death from air emboli associated with fibrin sprays.Limitations: It was not possible to provide a detailed evaluation of individual RCTs in their specific contexts because of the limited resources that were available for this research. In addition, the number of RCTs that were identified made it impractical to conduct independent data extraction by two reviewers in the time available.Conclusions: The effectiveness of fibrin sealants does not appear to vary according to surgical procedures with regard to reducing the risk of seroma or haematoma. Surgeons should note the potential risk of gas embolism if spray application of fibrin sealants is used and not to exceed the recommended pressure and spraying distance. Future research should be carried out in surgery specialties for which only limited data were found, including neurological, gynaecological, oral and maxillofacial, urology, colorectal and orthopaedics surgery (for any outcome); breast surgery and upper gastrointestinal (development of haematoma); and cardiothoracic heart or lung surgery (reoperation rates). In addition, studies need to use adequate sample sizes, to blind participants and outcome assessors, and to follow reporting guidelines.Study registration: This study is registered as PROSPERO CRD42015020710.Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Skin cancer is one of the most common cancers in the UK. The main risk factor is exposure to ultraviolet radiation from sunlight or the use of sunbeds. Patients with suspicious skin lesions are first examined with a dermoscope. After examination, those with non-cancerous lesions are discharged, but lesions that are still considered clinically suspicious are surgically removed. VivaScope^®is a non-invasive technology designed to be used in conjunction with dermoscopy to provide a more accurate diagnosis, leading to fewer biopsies of benign lesions or to provide more accurate presurgical margins reducing the risk of cancer recurrence.Objectives: To evaluate the clinical effectiveness and cost-effectiveness of VivaScope^®1500 (Caliber Imaging and Diagnostics, Rochester, NY, USA; Lucid Inc., Rochester, NY, USA; or Lucid Inc., MAVIG GmbH, Munich, Germany) and VivaScope^®3000 (Caliber Imaging and Diagnostics, Rochester, NY, USA) in the diagnosis of equivocal skin lesions, and VivaScope 3000 in lesion margin delineation prior to surgical excision of lesions.Data sources: Databases (MEDLINE, EMBASE and The Cochrane Library) were searched on 14 October 2014, reference lists of included papers were assessed and clinical experts were contacted for additional information on published and unpublished studies.Methods: A systematic review was carried out to identify randomised controlled trials (RCTs) or observational studies evaluating dermoscopy plus VivaScope, or VivaScope alone, with histopathology as the reference test. A probabilistic de novo economic model was developed to synthesise the available data on costs and clinical outcomes from the UK NHS perspective. All costs were expressed as 2014 prices.Results: Sixteen studies were included in the review, but they were too heterogeneous to be combined in a meta-analysis. One of two diagnostic studies that were deemed most representative of UK clinical practice reported that dermoscopy plus VivaScope 1500 was significantly more sensitive than dermoscopy alone in the diagnosis of melanoma (97.8% vs. 94.6%;p = 0.043) and significantly more specific than dermoscopy alone in the diagnosis of non-melanoma (92.4% vs. 26.74%;p < 0.000001). The results of another study suggest 100% [95% confidence interval (CI) 86.16% to 100%] sensitivity for dermoscopy plus VivaScope 1500 versus 100% (95% CI 91.51% to 100%) for dermoscopy alone. Specificity varied from 51.77% to 80.2% depending on the analysis set used. In terms of margin delineation with VivaScope, one study found that 17 out of 29 patients with visible lentigo maligna (LM) had subclinical disease of > 5 mm beyond the dermoscopically identified margin. Using ‘optimistic’ diagnostic data, the economic model resulted in an incremental cost-effectiveness ratio (ICER) of £8877 per quality-adjusted life-year (QALY) (£9362 per QALY), while the ‘less favourable’ diagnostic data resulted in an ICER of £19,095 per QALY (£25,453 per QALY) in the diagnosis of suspected melanomas. VivaScope was also shown to be a dominant strategy when used for the diagnostic assessment of suspected basal cell carcinoma (BCC). Regarding margin delineation of LM, mapping with VivaScope was cost-effective, with an ICER of £10,241 per QALY (£11,651 per QALY). However, when VivaScope was used for diagnosis as well as mapping of LM, then the intervention cost was reduced and VivaScope became a dominant strategy.Limitations: There is an absence of UK data in the included studies and, therefore, generalisability of the results to the UK population is unclear.Conclusions: The use of VivaScope appears to be a cost-effective strategy in the diagnostic assessment of equivocal melanomas and BCCs, and in margin delineation of LM prior to surgical treatment.Future work: High-quality RCTs are required in a UK population to assess the diagnostic accuracy of VivaScope in people with equivocal lesions.Study registration: This study is registered as PROSPERO CRD42014014433.Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Typically occurring on the external genitalia, anogenital warts (AGWs) are benign epithelial skin lesions caused by human papillomavirus infection. AGWs are usually painless but can be unsightly and physically uncomfortable, and affected people might experience psychological distress. The evidence base on the clinical effectiveness and cost-effectiveness of treatments for AGWs is limited.Objectives: To systematically review the evidence on the clinical effectiveness of medical and surgical treatments for AGWs and to develop an economic model to estimate the cost-effectiveness of the treatments.Data sources: Electronic databases (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Web of Science) were searched from inception (or January 2000 for Web of Science) to September 2014. Bibliographies of relevant systematic reviews were hand-searched to identify potentially relevant studies. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were searched for ongoing and planned studies.Review methods: A systematic review of the clinical effectiveness literature was carried out according to standard methods and a mixed-treatment comparison (MTC) undertaken. The model implemented for each outcome was that with the lowest deviance information criterion. A de novo economic model was developed to assess cost-effectiveness from the perspective of the UK NHS. The model structure was informed through a systematic review of the economic literature and in consultation with clinical experts. Effectiveness data were obtained from the MTC. Costs were obtained from the literature and standard UK sources.Results: Of 4232 titles and abstracts screened for inclusion in the review of clinical effectiveness, 60 randomised controlled trials (RCTs) evaluating 19 interventions were included. Analysis by MTC indicated that ablative techniques were typically more effective than topical interventions at completely clearing AGWs at the end of treatment. Podophyllotoxin 0.5% solution (Condyline^®, Takeda Pharmaceutical Company Ltd; Warticon^®solution, Stiefel Laboratories Ltd) was found to be the most effective topical treatment evaluated. Networks for other outcomes included fewer treatments, which restrict conclusions on the comparative effectiveness of interventions. In total, 84 treatment strategies were assessed using the economic model. Podophyllotoxin 0.5% solution first line followed by carbon dioxide (CO₂) laser therapy second line if AGWs did not clear was most likely to be considered a cost-effective use of resources at a willingness to pay of £20,000–30,000 per additional quality-adjusted life-year gained. The result was robust to most sensitivity analyses conducted.Limitations: Limited reporting in identified studies of baseline characteristics for the enrolled population generates uncertainty around the comparability of the study populations and therefore the generalisability of the results to clinical practice. Subgroup analyses were planned based on type, number and size of AGWs, all of which are factors thought to influence treatment effect. Lack of data on clinical effectiveness based on these characteristics precluded analysis of the differential effects of treatments in the subgroups of interest. Despite identification of 60 studies, most comparisons in the MTC are informed by only one RCT. Additionally, lack of head-to-head RCTs comparing key treatments, together with minimal reporting of results in some studies, precluded comprehensive analysis of all treatments for AGWs.Conclusions: The results generated by the MTC are in agreement with consensus opinion that ablative techniques are clinically more effective at completely clearing AGWs after treatment. However, the evidence base informing the MTC is limited. A head-to-head RCT that evaluates the comparative effectiveness of interventions used in clinical practice would help to discern the potential advantages and disadvantages of the individual treatments. The results of the economic analysis suggest that podophyllotoxin 0.5% solution is likely to represent a cost-effective first-line treatment option. More expensive effective treatments, such as CO₂laser therapy or surgery, may represent cost-effective second-line treatment options. No treatment and podophyllin are unlikely to be considered cost-effective treatment options. There is uncertainty around the cost-effectiveness of treatment with imiquimod, trichloroacetic acid and cryotherapy.Study registration: This study is registered as PROSPERO CRD42013005457.Funding: The National Institute for Health Research Health Technology Assessment programme.