Cost-effectiveness of Diagnostic Tools to Establish the Presence of Peripheral Arterial Disease in People With Diabetes.

OBJECTIVE: To evaluate the cost-effectiveness of point-of-care duplex ultrasound (PAD-scan) and other bedside tests for the diagnosis of peripheral arterial disease (PAD) in people with diabetes. BACKGROUND: PAD is a risk factor for cardiovascular disease, diabetic foot ulceration (DFU), and amputation in diabetic patients. Diagnosis enables optimization of therapies to manage these risks. PAD-scan can be performed by frontline staff and has been shown to be the most accurate bedside test. However, its cost-effectiveness has not been investigated. METHODS: A Markov model was constructed to estimate the health outcomes and costs over 5 years of different testing strategies applied to a cohort of diabetic patients. Bedside tests investigated were PAD-scan, ankle-brachial pressure index, toe-brachial pressure index, audible and visual Doppler, transcutaneous pressure of oxygen, and pulse palpation. Health outcomes were incidence of new DFU, major cardiovascular events, amputation, death, and DFU healing rates. Sensitivity analyses were performed. RESULTS: PAD-scan was the most cost-effective bedside test with an incremental cost-effectiveness ratio of £11,391/quality-adjusted life years. PADscan had the highest probability (78.7%) of having the greatest net benefit at a willingness to pay threshold of £20,000 per quality-adjusted life years. It reduced the number of amputations by 24% and the number of cardiovascular deaths by 10% over 5 years, compared to toe-brachial pressure index (next best alternative). PAD-scans superiority in incremental cost-effectiveness ratio occurred at a PAD prevalence threshold of 0.24. DISCUSSION: PAD-scan is a cost-effective test for the detection of PAD in patients with diabetes.

Long-term Clinical and Cost-effectiveness of Early Endovenous Ablation in Venous Ulceration: A Randomized Clinical Trial.

Importance: One-year outcomes from the Early Venous Reflux Ablation (EVRA) randomized trial showed accelerated venous leg ulcer healing and greater ulcer-free time for participants who are treated with early endovenous ablation of lower extremity superficial reflux. Objective: To evaluate the clinical and cost-effectiveness of early endovenous ablation of superficial venous reflux in patients with venous leg ulceration. Design, Setting, and Participants: Between October 24, 2013, and September 27, 2016, the EVRA randomized clinical trial enrolled 450 participants (450 legs) with venous leg ulceration of less than 6 months' duration and superficial venous reflux. Initially, 6555 patients were assessed for eligibility, and 6105 were excluded for reasons including ulcer duration greater than 6 months, healed ulcer by the time of randomization, deep venous occlusive disease, and insufficient superficial venous reflux to warrant ablation therapy, among others. A total of 426 of 450 participants (94.7%) from the vascular surgery departments of 20 hospitals in the United Kingdom were included in the analysis for ulcer recurrence. Surgeons, participants, and follow-up assessors were not blinded to the treatment group. Data were analyzed from August 11 to November 4, 2019. Interventions: Patients were randomly assigned to receive compression therapy with early endovenous ablation within 2 weeks of randomization (early intervention, n = 224) or compression with deferred endovenous treatment of superficial venous reflux (deferred intervention, n = 226). Endovenous modality and strategy were left to the preference of the treating clinical team. Main Outcomes and Measures: The primary outcome for the extended phase was time to first ulcer recurrence. Secondary outcomes included ulcer recurrence rate and cost-effectiveness. Results: The early-intervention group consisted of 224 participants (mean [SD] age, 67.0 [15.5] years; 127 men [56.7%]; 206 White participants [92%]). The deferred-intervention group consisted of 226 participants (mean [SD] age, 68.9 [14.0] years; 120 men [53.1%]; 208 White participants [92%]). Of the 426 participants whose leg ulcer had healed, 121 (28.4%) experienced at least 1 recurrence during follow-up. There was no clear difference in time to first ulcer recurrence between the 2 groups (hazard ratio, 0.82; 95% CI, 0.57-1.17; P = .28). Ulcers recurred at a lower rate of 0.11 per person-year in the early-intervention group compared with 0.16 per person-year in the deferred-intervention group (incidence rate ratio, 0.658; 95% CI, 0.480-0.898; P = .003). Time to ulcer healing was shorter in the early-intervention group for primary ulcers (hazard ratio, 1.36; 95% CI, 1.12-1.64; P = .002). At 3 years, early intervention was 91.6% likely to be cost-effective at a willingness to pay of £20 000 ($26 283) per quality-adjusted life year and 90.8% likely at a threshold of £35 000 ($45 995) per quality-adjusted life year. Conclusions and Relevance: Early endovenous ablation of superficial venous reflux was highly likely to be cost-effective over a 3-year horizon compared with deferred intervention. Early intervention accelerated the healing of venous leg ulcers and reduced the overall incidence of ulcer recurrence. Trial Registration: ClinicalTrials.gov identifier: ISRCTN02335796.

Early versus deferred endovenous ablation of superficial venous reflux in patients with venous ulceration: the EVRA RCT.

BACKGROUND: Venous ulceration is a common and costly health-care issue worldwide, with poor healing rates greatly affecting patient quality of life. Compression bandaging has been shown to improve healing rates and reduce recurrence, but does not address the underlying cause, which is often superficial venous reflux. Surgical correction of the reflux reduces ulcer recurrence; however, the effect of early endovenous ablation of superficial venous reflux on ulcer healing is unclear. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of compression therapy with early endovenous ablation of superficial venous reflux compared with compression therapy with deferred endovenous ablation in patients with venous ulceration. DESIGN: A pragmatic, two-arm, multicentre, parallel-group, open randomised controlled trial with a health economic evaluation. SETTING: Secondary care vascular centres in England. PARTICIPANTS: Patients aged ≥ 18 years with a venous leg ulcer of between 6 weeks' and 6 months' duration and an ankle-brachial pressure index of ≥ 0.8 who could tolerate compression and were deemed suitable for endovenous ablation of superficial venous reflux. INTERVENTIONS: Participants were randomised 1 : 1 to either early ablation (compression therapy and superficial endovenous ablation within 2 weeks of randomisation) or deferred ablation (compression therapy followed by endovenous ablation once the ulcer had healed). MAIN OUTCOME MEASURES: The primary outcome measure was time from randomisation to ulcer healing, confirmed by blinded assessment. Secondary outcomes included 24-week ulcer healing rates, ulcer-free time, clinical success (in addition to quality of life), costs and quality-adjusted life-years (QALYs). All analyses were performed on an intention-to-treat basis. RESULTS: A total of 450 participants were recruited (224 to early and 226 to deferred superficial endovenous ablation). Baseline characteristics were similar between the two groups. Time to ulcer healing was shorter in participants randomised to early superficial endovenous ablation than in those randomised to deferred ablation [hazard ratio 1.38, 95% confidence interval (CI) 1.13 to 1.68; p = 0.001]. Median time to ulcer healing was 56 (95% CI 49 to 66) days in the early ablation group and 82 (95% CI 69 to 92) days in the deferred ablation group. The ulcer healing rate at 24 weeks was 85.6% in the early ablation group, compared with 76.3% in the deferred ablation group. Median ulcer-free time was 306 [interquartile range (IQR) 240-328] days in the early ablation group and 278 (IQR 175-324) days in the deferred endovenous ablation group (p = 0.002). The most common complications of superficial endovenous ablation were pain and deep-vein thrombosis. Differences in repeated measures of Aberdeen Varicose Vein Questionnaire scores (p < 0.001), EuroQol-5 Dimensions index values (p = 0.03) and Short Form questionnaire-36 items body pain (p = 0.05) over the follow-up period were observed, in favour of early ablation. The mean difference in total costs between the early ablation and deferred ablation groups was £163 [standard error (SE) £318; p = 0.607]; however, there was a substantial and statistically significant gain in QALY over 1 year [mean difference between groups 0.041 (SE 0.017) QALYs; p = 0.017]. The incremental cost-effectiveness ratio of early ablation at 1 year was £3976 per QALY, with a high probability (89%) of being more cost-effective than deferred ablation at conventional UK decision-making thresholds (currently £20,000 per QALY). Sensitivity analyses using alternative statistical models give qualitatively similar results. LIMITATIONS: Only 7% of screened patients were recruited, treatment regimens varied significantly and technical success was assessed only in the early ablation group. CONCLUSIONS: Early endovenous ablation of superficial venous reflux, in addition to compression therapy and wound dressings, reduces the time to healing of venous leg ulcers, increases ulcer-free time and is highly likely to be cost-effective. FUTURE WORK: Longer-term follow-up is ongoing and will determine if early ablation will affect recurrence rates in the medium and long term. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02335796. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 24. See the NIHR Journals Library website for further project information.

Venous leg ulcers are open wounds occurring on the legs of patients with venous disease. They are common, painful and distressing and reduce patient quality of life. Leg ulcers often result from valves in the leg veins not working properly. The valves normally force blood back up towards the heart; however, blood can flow backwards (reflux) when valves do not work properly, and this can cause swelling and ulceration. Compression therapy (wrapping bandages around the legs) has been shown to help ulcers heal, but it does not treat the underlying reflux problem with the veins. Newer, less invasive, techniques (known as endovenous ablation) have taken over from surgery to correct venous reflux and are more acceptable to patients as they can be performed quickly under local anaesthetic. The aim of the trial was to find out if treating patients with leg ulcers by early endovenous ablation (within 2 weeks) and standard compression therapy can increase ulcer healing compared with standard compression therapy and delayed endovenous ablation once the ulcer has healed. In total, 450 people agreed to take part in this study and were treated in 20 hospitals across England. Participants were randomly allocated to either early or delayed endovenous ablation and followed up for 12 months. The trial found that treating the veins early resulted in quicker ulcer healing than delaying treatment until the ulcer had healed. The trial also showed that participants had more time without an ulcer if the treatment was performed early rather than after ulcer healing. No safety issues with early intervention were identified. There is some evidence that quality of life was better in the early treatment group and that people in this group had less body pain. Treating ulcers early appears likely to be more cost-effective (i.e. a better use of NHS resources) than delayed treatment. Future work will focus on collecting longer-term follow-up data to find out if early endovenous ablation also reduces the chances of the ulcer coming back.

A Randomized Trial of Early Endovenous Ablation in Venous Ulceration.

BACKGROUND: Venous disease is the most common cause of leg ulceration. Although compression therapy improves venous ulcer healing, it does not treat the underlying causes of venous hypertension. Treatment of superficial venous reflux has been shown to reduce the rate of ulcer recurrence, but the effect of early endovenous ablation of superficial venous reflux on ulcer healing remains unclear. METHODS: In a trial conducted at 20 centers in the United Kingdom, we randomly assigned 450 patients with venous leg ulcers to receive compression therapy and undergo early endovenous ablation of superficial venous reflux within 2 weeks after randomization (early-intervention group) or to receive compression therapy alone, with consideration of endovenous ablation deferred until after the ulcer was healed or until 6 months after randomization if the ulcer was unhealed (deferred-intervention group). The primary outcome was the time to ulcer healing. Secondary outcomes were the rate of ulcer healing at 24 weeks, the rate of ulcer recurrence, the length of time free from ulcers (ulcer-free time) during the first year after randomization, and patient-reported health-related quality of life. RESULTS: Patient and clinical characteristics at baseline were similar in the two treatment groups. The time to ulcer healing was shorter in the early-intervention group than in the deferred-intervention group; more patients had healed ulcers with early intervention (hazard ratio for ulcer healing, 1.38; 95% confidence interval [CI], 1.13 to 1.68; P=0.001). The median time to ulcer healing was 56 days (95% CI, 49 to 66) in the early-intervention group and 82 days (95% CI, 69 to 92) in the deferred-intervention group. The rate of ulcer healing at 24 weeks was 85.6% in the early-intervention group and 76.3% in the deferred-intervention group. The median ulcer-free time during the first year after trial enrollment was 306 days (interquartile range, 240 to 328) in the early-intervention group and 278 days (interquartile range, 175 to 324) in the deferred-intervention group (P=0.002). The most common procedural complications of endovenous ablation were pain and deep-vein thrombosis. CONCLUSIONS: Early endovenous ablation of superficial venous reflux resulted in faster healing of venous leg ulcers and more time free from ulcers than deferred endovenous ablation. (Funded by the National Institute for Health Research Health Technology Assessment Program; EVRA Current Controlled Trials number, ISRCTN02335796 .).

The UK EndoVascular Aneurysm Repair (EVAR) randomised controlled trials: long-term follow-up and cost-effectiveness analysis.

BACKGROUND: Short-term survival benefits of endovascular aneurysm repair (EVAR) compared with open repair (OR) of intact abdominal aortic aneurysms have been shown in randomised trials, but this early survival benefit is soon lost. Survival benefit of EVAR was unclear at follow-up to 10 years. OBJECTIVE: To assess the long-term efficacy of EVAR against OR in patients deemed fit and suitable for both procedures (EVAR trial 1; EVAR-1); and against no intervention in patients unfit for OR (EVAR trial 2; EVAR-2). To appraise the long-term significance of type II endoleak and define criteria for intervention. DESIGN: Two national, multicentre randomised controlled trials: EVAR-1 and EVAR-2. SETTING: Patients were recruited from 37 hospitals in the UK between 1 September 1999 and 31 August 2004. PARTICIPANTS: Men and women aged ≥ 60 years with an aneurysm of ≥ 5.5 cm (as identified by computed tomography scanning), anatomically suitable and fit for OR were randomly assigned 1 : 1 to either EVAR (n = 626) or OR (n = 626) in EVAR-1 using computer-generated sequences at the trial hub. Patients considered unfit were randomly assigned to EVAR (n = 197) or no intervention (n = 207) in EVAR-2. There was no blinding. INTERVENTIONS: EVAR, OR or no intervention. MAIN OUTCOME MEASURES: The primary end points were total and aneurysm-related mortality until mid-2015 for both trials. Secondary outcomes for EVAR-1 were reinterventions, costs and cost-effectiveness. RESULTS: In EVAR-1, over a mean of 12.7 years (standard deviation 1.5 years; maximum 15.8 years), we recorded 9.3 deaths per 100 person-years in the EVAR group and 8.9 deaths per 100 person-years in the OR group [adjusted hazard ratio (HR) 1.11, 95% confidence interval (CI) 0.97 to 1.27; p = 0.14]. At 0-6 months after randomisation, patients in the EVAR group had a lower mortality (adjusted HR 0.61, 95% CI 0.37 to 1.02 for total mortality; HR 0.47, 95% CI 0.23 to 0.93 for aneurysm-related mortality; p = 0.031), but beyond 8 years of follow-up patients in the OR group had a significantly lower mortality (adjusted HR 1.25, 95% CI 1.00 to 1.56, p = 0.048 for total mortality; HR 5.82, 95% CI 1.64 to 20.65, p = 0.0064 for aneurysm-related mortality). The increased aneurysm-related mortality in the EVAR group after 8 years was mainly attributable to secondary aneurysm sac rupture, with increased cancer mortality also observed in the EVAR group. Overall, aneurysm reintervention rates were higher in the EVAR group than in the OR group, 4.1 and 1.7 per 100 person-years, respectively (p < 0.001), with reinterventions occurring throughout follow-up. The mean difference in costs over 14 years was £3798 (95% CI £2338 to £5258). Economic modelling based on the outcomes of the EVAR-1 trial showed that the cost per quality-adjusted life-year gained over the patient's lifetime exceeds conventional thresholds used in the UK. In EVAR-2, patients died at the same rate in both groups, but there was suggestion of lower aneurysm mortality in those who actually underwent EVAR. Type II endoleak itself is not associated with a higher rate of mortality. LIMITATIONS: Devices used were implanted between 1999 and 2004. Newer devices might have better results. Later follow-up imaging declined, particularly for OR patients. Methodology to capture reinterventions changed mainly to record linkage through the Hospital Episode Statistics administrative data set from 2009. CONCLUSIONS: EVAR has an early survival benefit but an inferior late survival benefit compared with OR, which needs to be addressed by lifelong surveillance of EVAR and reintervention if necessary. EVAR does not prolong life in patients unfit for OR. Type II endoleak alone is relatively benign. FUTURE WORK: To find easier ways to monitor sac expansion to trigger timely reintervention. TRIAL REGISTRATION: Current Controlled Trials ISRCTN55703451. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and the results will be published in full in Health Technology Assessment; Vol. 22, No. 5. See the NIHR Journals Library website for further project information.

Costs of an early intervention versus a conservative strategy in acute coronary syndrome.

BACKGROUND: The Randomised Intervention Treatment of unstable Angina (RITA-3) found that non-ST-elevation myocardial infarction and unstable angina patients randomised to routine early arteriography experienced a lower rate of death or myocardial infarction than patients randomised to conservative therapy over a five year period of follow up. This paper uses data from the RITA-3 trial to compare the health service costs of the two strategies. METHODS: The resource use data included initial arteriography and revascularisation procedures in the early intervention group and subsequently in both groups; in-patient days in hospital for any reason in the first year of follow-up; incidence of myocardial infarction; and cardiac medication. RESULTS: After five years, the early intervention arm accrued a total mean cost of pound sterling 11,340 (euro 15,592) and the conservative arm a mean of pound sterling 9749(euro 13,405), an additional mean cost in the intervention arm of pound sterling 1591 (95% CI pound sterling 851 to pound sterling 2276) (euro 2188; 95%CI euro 1160 to euro 3228). On average, costs increased with age and were higher in male patients and in patients with severe angina. However, the incremental cost of the intervention strategy was consistent across different patient sub-groups. CONCLUSION: Over a period of 5 years, the initial additional cost of a strategy of early intervention is only partially offset by subsequent interventions in patients managed conservatively.

Efficiency, equity, and budgetary policies: informing decisions using mathematical programming.

The standard decision rules of cost-effectiveness analysis either require the decision maker to set a threshold willingness to pay for additional health care or to set an overall fixed budget. In practice, neither are generally taken, but instead an arbitrary decision rule is followed that may not be consistent with the overall budget, lead to an allocation of resources that is less than optimal, and is unable to identify the program that should be displaced at the margin. Recent work has shown how mathematical programming can be used as a generalization of the standard decision rules. The authors extend the use of mathematical programming, first to incorporate more complex budgetary rules about when expenditure can be incurred, and show the opportunity loss, in terms of health benefit forgone, of each budgetary policy. Second, the authors demonstrate that indivisibility in a patient population can be regarded as essentially a concern for horizontal equity and represent this and other equity concerns as constraints in the program. Third, the authors estimate the different opportunity costs of a range of equity concerns applied to particular patient populations, and when imposed on all patient populations. They apply this framework of analysis to a realistic and policy-relevant problem.

Randomized trial of a brief physiotherapy intervention compared with usual physiotherapy for neck pain patients: cost-effectiveness analysis.

OBJECTIVES: To assess the cost-effectiveness of brief physiotherapy intervention versus usual physiotherapy management in patients with neck pain of musculoskeletal origin in the community setting. METHODS: A cost-effectiveness analysis was conducted alongside a multicenter pragmatic randomized controlled clinical trial. Individuals 18 years of age and older with neck pain of more than 2 weeks were recruited from physiotherapy departments with referrals from general practitioners (GPs) in the East Yorkshire and North Lincolnshire regions in the United Kingdom. A total of 139 patients were allocated to the brief intervention, and 129 to the usual physiotherapy. Resource use data were prospectively collected on the number of physiotherapy sessions, hospital stay, specialist, and GP visits. Quality-adjusted life years (QALYs) were estimated using EQ-5D data collected at baseline, 3 and 12 months from the start of the treatment. The economic evaluation was conducted from the U.K. National Health System perspective. RESULTS: On average, brief intervention produced lower costs (pounds--68; 95 percent confidence interval [CI], pounds--103 to pounds--35) and marginally lower QALYs (-0.001; 95 percent CI, -0.030 to 0.028) compared with usual physiotherapy, resulting in an incremental cost per QALY of pounds 68,000 for usual physiotherapy. These results are sensitive to patients' treatment preferences. CONCLUSIONS: Usual physiotherapy may not be good value for money for the average individual in this trial but could be a cost-effective strategy for those who are indifferent toward which treatment they receive.

Pharmacologic and pharmacokinetic assessment of anti-TGFbeta2 aptamers in rabbit plasma and aqueous humor.

PURPOSE: The aim of the study is to determine the bioactivity and effects of PEGylation on the pharmacokinetics in rabbit aqueous humor and plasma of an aptamer directed against TGFbeta2. METHODS: Pharmacological activity of anti-TGFbeta2 aptamer in rabbit ocular fluid was demonstrated using a mink lung epithelial cell proliferation assay. For pharmacokinetic analyses, concentrations of aptamers in plasma and aqueous humor were determined over time following bilateral subconjunctival administration to Dutch-belted rabbits using a hybridization-based pseudo-enzyme-linked immunosorbent assay (ELISA) assay. RESULTS: Anti-TGFbeta2 aptamer (ARC81) binds to human TGFbeta2 with a K(D) of approximately 5 nM and inhibits the activity of human TGFbeta2 in vitro in a cell-based assay with an IC(50) of approximately 100 nM. ARC81 blocks endogenously derived TGFbeta2 in rabbit aqueous humor in vitro with an IC(50) of approximately 200 nM and an IC(90) of approximately 1 microM. In vivo in rabbit, ARC81 [no polyethylene glycol (PEG)] entered systemic circulation rapidly (t(max) = 1 h in plasma) relative to aptamer conjugates ARC117 (20 kDa PEG) and ARC119 (40 kDa PEG), which showed prolonged residence in the subconjunctival space and aqueous compartment (t(max) = 6 and 12 h, respectively, in plasma). Both 20- and 40-kDa aptamer conjugates reached maximal concentrations (C(max)) in aqueous humor of 23-30 nM and remained at or above 1 nM for as long as 12 h. CONCLUSIONS: Pharmacologically active levels of anti-TGFbeta2 aptamers can be sustained in the ocular fluid and local tissue environment over a 12-h period after single administration. Daily subconjunctival administration of PEGylated anti-TGFbeta2 aptamers should allow further pharmacological evaluation of these agents in a rabbit conjunctival scarring model. Perioperative administration, via subconjunctival injection, may prove to be an effective means to deliver therapeutic quantities of TGFbeta2 aptamer conjugates in trabeculectomy procedures.