The Arabin pessary to prevent preterm birth in women with a twin pregnancy and a short cervix: the STOPPIT 2 RCT.

BACKGROUND: Preterm birth is common in twins and accounts for significant mortality and morbidity. There are no effective preventative treatments. Some studies have suggested that, in twin pregnancy complicated by a short cervix, the Arabin pessary, which fits around the cervix and can be inserted as an outpatient procedure, reduces preterm birth and prevents neonatal morbidity. OBJECTIVE: STOPPIT 2 aimed to evaluate the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix. DESIGN: STOPPIT 2 was a pragmatic, open label, multicentre randomised controlled trial with two treatment group - the Arabin pessary plus standard care (intervention) and standard care alone (control). Participants were initially recruited into the screening phase of the study, when cervical length was measured. Women with a measured cervical length of ≤ 35 mm were then recruited into the treatment phase of the study. An economic evaluation considered cost-effectiveness and a qualitative substudy explored the experiences of participants and clinicians. SETTING: Antenatal clinics in the UK and elsewhere in Europe. PARTICIPANTS: Women with twin pregnancy at < 21 weeks' gestation with known chorionicity and gestation established by scan at ≤ 16 weeks' gestation. INTERVENTIONS: Ultrasound scan to establish cervical length. Women with a cervical length of ≤ 35 mm at 18+ 0-20+ 6 weeks' gestation were randomised to standard care or Arabin pessary plus standard care. Randomisation was performed by computer and accessed through a web-based browser. MAIN OUTCOME MEASURES: Obstetric - all births before 34+ 0 weeks' gestation following the spontaneous onset of labour; and neonatal - composite of adverse outcomes, including stillbirth or neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis or proven sepsis, all measured up to 28 days after the expected date of delivery. RESULTS: A total of 2228 participants were recruited to the screening phase, of whom 2170 received a scan and 503 were randomised: 250 to Arabin pessary and 253 to standard care alone. The rate of the primary obstetric outcome was 18.4% (46/250) in the intervention group and 20.6% (52/253) in the control group (adjusted odds ratio 0.87, 95% confidence interval 0.55 to 1.38; p = 0.54). The rate of the primary neonatal outcome was 13.4% (67/500) and 15.0% (76/506) in the intervention group and control group, respectively (adjusted odds ratio 0.86, 95% confidence interval 0.54 to 1.36; p = 0.52). The pessary was largely well tolerated and clinicians found insertion and removal 'easy' or 'fairly easy' in the majority of instances. The simple costs analysis showed that pessary treatment is no more costly than standard care. LIMITATIONS: There was the possibility of a type II error around smaller than anticipated benefit. CONCLUSIONS: In this study, the Arabin pessary did not reduce preterm birth or adverse neonatal outcomes in women with a twin pregnancy and a short cervix. The pessary either is ineffective at reducing preterm birth or has an effect size of < 0.4. FUTURE WORK: Women with twin pregnancy remain at risk of preterm birth; work is required to find treatments for this. TRIAL REGISTRATION: Current Controlled Trials ISRCTN98835694 and ClinicalTrials.gov NCT02235181. 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. 25, No. 44. See the NIHR Journals Library website for further project information.

Women who are pregnant with twins have a much higher risk of going into labour early and having an early (preterm) birth than women who are pregnant with only one baby. For this reason, babies who are twins are much more likely to die or to have serious health complications in the first months of life. Although we know that women with twin pregnancy are at risk, there are no treatments that are recommended to prevent early births. Some studies have suggested that the Arabin pessary can help. The Arabin pessary is a silicone ring that fits around the cervix (neck of the womb). The pessary can be put in place in a clinic without any need for an anaesthetic. Some studies have suggested that the Arabin pessary helps and others have suggested that it does not. It appears to be most helpful when the cervix (neck of the womb) is already shortening. Shortening of the neck of the womb is a sign that early birth is even more likely. We asked women with twin pregnancy to take part in STOPPIT 2. Women who agreed had an ultrasound scan of the neck of the womb, which measured its length. Those with a short cervix were randomised to be offered the Arabin pessary (in addition to standard care) or standard care alone. This allocation was carried out 'at random' by a computer. We followed women up until the end of their pregnancy and collected information on the babies' health after birth. We found that the Arabin pessary did not reduce the risk of an early birth; nor did it reduce the risk of health complications for the baby. We conclude that the Arabin pessary should not be used for this purpose.

Cost-utility of maintained physical activity and physiotherapy in the management of distal arm pain: an economic evaluation of data from a randomized controlled trial.

BACKGROUND: Arm pain is common, costly to health services and society. Physiotherapy referral is standard management, and while awaiting treatment, advice is often given to rest, but the evidence base is weak. OBJECTIVE: To assess the cost-effectiveness of advice to remain active (AA) versus advice to rest (AR); and immediate physiotherapy (IP) versus usual care (waiting list) physiotherapy (UCP). METHODS: Twenty-six-week within-trial economic evaluation (538 participants aged ≥18 years randomized to usual care, i.e. AA (n = 178), AR (n = 182) or IP (n = 178). Regression analysis estimated differences in mean costs and Quality-Adjusted Life Years (QALYs). Incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves were generated. Primary analysis comprised the 193 patients with complete resource use (UK NHS perspective) and EQ-5D data. Sensitivity analysis investigated uncertainty. RESULTS: Baseline-adjusted cost differences were £88 [95% confidence interval (CI): -14, 201) AA versus AR; -£14 (95% CI: -87, 66) IP versus UCP. Baseline-adjusted QALY differences were 0.0095 (95% CI: -0.0140, 0.0344) AA versus AR; 0.0143 (95% CI: -0.0077, 0.0354) IP versus UCP. There was a 71 and 89% probability that AA (versus AR) and IP (versus UCP) were the most cost-effective option using a threshold of £20,000 per additional QALY.  The results were robust in the sensitivity analysis. CONCLUSION: The difference in mean costs and mean QALYs between the competing strategies was small and not statistically significant. However, decision-makers may judge that IP was not shown to be any more effective than delayed treatment, and was no more costly than delayed physiotherapy. AA is preferable to one that encourages AR, as it is more effective and more likely to be cost-effective than AR.

Pharmacist-led management of chronic pain in primary care: costs and benefits in a pilot randomised controlled trial.

OBJECTIVES: To explore differences in mean costs (from a UK National Health Service perspective) and effects of pharmacist-led management of chronic pain in primary care evaluated in a pilot randomised controlled trial (RCT), and to estimate optimal sample size for a definitive RCT. DESIGN: Regression analysis of costs and effects, using intention-to-treat and expected value of sample information analysis (EVSI). SETTING: Six general practices: Grampian (3); East Anglia (3). PARTICIPANTS: 125 patients with complete resource use and short form-six-dimension questionnaire (SF-6D) data at baseline, 3 months and 6 months. INTERVENTIONS: Patients were randomised to either pharmacist medication review with face-to-face pharmacist prescribing or pharmacist medication review with feedback to general practitioner or treatment as usual (TAU). MAIN OUTCOME MEASURES: Differences in mean total costs and effects measured as quality-adjusted life years (QALYs) at 6 months and EVSI for sample size calculation. RESULTS: Unadjusted total mean costs per patient were £452 for prescribing (SD: £466), £570 for review (SD: £527) and £668 for TAU (SD: £1333). After controlling for baseline costs, the adjusted mean cost differences per patient relative to TAU were £77 for prescribing (95% CI -82 to 237) and £54 for review (95% CI -103 to 212). Unadjusted mean QALYs were 0.3213 for prescribing (SD: 0.0659), 0.3161 for review (SD: 0.0684) and 0.3079 for TAU (SD: 0.0606). Relative to TAU, the adjusted mean differences were 0.0069 for prescribing (95% CI -0.0091 to 0.0229) and 0.0097 for review (95% CI -0.0054 to 0.0248). The EVSI suggested the optimal future trial size was between 460 and 690, and between 540 and 780 patients per arm using a threshold of £30,000 and £20,000 per QALY gained, respectively. CONCLUSIONS: Compared with TAU, pharmacist-led interventions for chronic pain appear more costly and provide similar QALYs. However, these estimates are imprecise due to the small size of the pilot trial. The EVSI indicates that a larger trial is necessary to obtain more precise estimates of differences in mean effects and costs between treatment groups. TRIAL REGISTRATION NUMBER: ISRCTN06131530.

Cost-effectiveness of etanercept in patients with severe ankylosing spondylitis in Germany.

OBJECTIVES: To estimate the cost-effectiveness of etanercept (ETN) plus usual care (including NSAIDs) compared with usual care alone (including NSAIDs) in patients with severe AS in Germany. METHODS: A mathematical model previously applied to the UK was adapted using resource use and cost data (for 2007) from the national database of the German Collaborative Arthritis Centres. Social health insurance (SHI) and societal perspectives were analysed. Assumptions on initial response and changes in health-related quality of life were based on Phase III randomized controlled trials. Initial treatment response according to British Society for Rheumatology guidelines were assumed as a conservative estimate in the German context. Long-term disease progression was based on the available literature. Incremental cost-effectiveness ratios (ICERs) were expressed as euros/quality-adjusted life year (QALY), for a cohort of 1000 patients over 25 years. Sensitivity analyses explored uncertainty in results. RESULTS: In the base case, ETN plus usual care (including NSAIDs) yielded 1475 more QALYs at an additional cost of €80,827,668 (SHI) or €32,657,590 (societal) leading to an ICER of €54,815/QALY and €22,147/QALY, respectively. Over a shorter time horizon of 10 years, the ICERs were €59,006 and €29,815 for SHI and societal viewpoints, respectively. Assumptions having the largest impact on results included withdrawal rates from ETN, quality of life, disease costs and initial response. CONCLUSIONS: Cost-effectiveness for ETN in patients with severe AS in Germany differs according to the cost perspective. Study estimates were higher than in the UK but comparable with reported cost-effectiveness of anti-TNF treatments in patients with RA in Germany.

Cost-effectiveness of immunoglobulin M-enriched immunoglobulin (Pentaglobin) in the treatment of severe sepsis and septic shock.

PURPOSE: To measure the cost-effectiveness of a specific polyclonal intravenous immune globulin preparation (Pentaglobin) in adult patients treated for severe sepsis and septic shock. MATERIALS AND METHODS: Effectiveness data from a meta-analysis of 9 randomized trials (N=435) were used to populate a decision model to estimate the cost-effectiveness of Pentaglobin and its comparator standard therapy from the hospital perspective in Germany. PRIMARY OUTCOME: all-cause morality; secondary outcome: intensive care unit (ICU) length of stay. Benefit was expressed as lives saved (LS). Published cost data were applied to assess differences in ICU treatment costs. Cost-effectiveness was calculated as incremental cost per LS. RESULTS: Pentaglobin reduced the risk of mortality (P<.001) but had no effect on ICU length of stay. A baseline risk of mortality of 0.4434 (risk ratio=0.5652; absolute risk reduction=0.1928; number-needed-to-treat=5.19) increased ICU treatment costs with Pentaglobin by 2,037 (22,711 vs 24,747) with a cost per LS of 10,565. Sensitivity analyses on baseline mortality risk (95% confidence interval 0.3293-0.5162) and risk ratio (95% confidence interval 0.4306-0.7420) yielded a cost per LS range of 5,715 to 28,443 with a 56.3% probability of cost-effectiveness of 12,000 or less. CONCLUSIONS: Pentaglobin is a promising adjuvant therapy both clinically and economically for treatment of adults with severe sepsis and septic shock.

A new concept for DRG-based reimbursement of services in German intensive care units: results of a pilot study.

OBJECTIVE: To evaluate LOS in developing a concept of borderline ICU LOS for a realistic reimbursement of intensive care. DESIGN: Retrospective analysis of LOS and cost data extracted from patients' electronic records. SETTING: Surgical ICU of the University Hospital Göttingen, Germany. PATIENTS AND PARTICIPANTS: All adult ICU admissions with LOS >24 h over a 24-month period (1 January 2000 to 31 December 2001; n=1631.) INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Cluster analysis partitioned the ICU population into three homogeneous groups based on ICU LOS and total direct costs: cluster 1 (n=1405; mean LOS=2.8; mean cost= Euro 2399); cluster 2 (n=190; mean LOS=13.4; mean cost=Euro 12,754); cluster 3 (n=36; mean LOS=34.9; mean cost= Euro 34,173). Cost distribution between cluster 1 and clusters 2 and 3 combined was 48 vs 52%. Upper 95 percentile LOS of 6.7 allowed cluster 1 to be replaced by an LOS profile population of < or = 7 days population (n=1355; 96% population and 91% total ICU cost overlap with cluster 1) representing 83% of total ICU population and 44% of total ICU costs. Stratification of >7 day population into LOS less than or >20 days (n=220; n=56) were further differentiated by mortality (11 vs 23%) and sepsis incidence (33 vs 79%). CONCLUSIONS: It may be feasible to formulate a LOS-based reimbursement scheme for ICU services in Germany based on the selection of (appropriate) patients' ICU LOS profiles.

Cost-effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in Germany.

Drotrecogin alfa (activated) (Xigris; Eli Lilly and Company, Indianapolis, IN) significantly reduced mortality in severe sepsis in the PROWESS trial. We evaluate the cost-effectiveness of drotrecogin alfa (activated) as an adjunct to standard therapy from the German healthcare payer's perspective with respect to patients with 1) severe sepsis and 2) severe sepsis and multiple organ failure the approved European indication. Hospital resource use based on PROWESS was valued using German unit costs. German life-tables and long-term survival assumptions determined life-years gained. European and German healthcare resource use data are examined in the sensitivity analysis. We assumed a unit price of euro;237.50 for drotrecogin alfa (activated). Per patient treated, drotrecogin alfa (activated) increased costs by euro;7,500, and hospital costs by euro;900 for all patients (euro;7,400 and euro;1,500 respectively for the approved indication) and survival by 0.59 life years (0.87 life years respectively for the approved indication). Thus drotrecogin alfa (activated) cost euro;14,100 (euro;17,700 discounting life years at 3%) per life year gained for all patients (euro;10,200 and euro;12,900, respectively, for the approved indication). Testing the unit cost of drotrecogin alfa (activated), pattern of resource use, and survival benefit, demonstrated that cost-effectiveness lies well within the range of other life saving interventions in Germany representing good economic value.