Current trends in vasopressor use to the operating room : a pharmacoepidemiologic study in French teaching and military hospitals

Objectives: Phenylephrine, ephedrine and norepinephrine are the vasopressors most commonly used in the operating room to treat anaesthesia-induced hypotension. Two new diluted forms of phenylephrine were released in 2011 (500 μg/10 mL and 500 μg/5 mL). We initiated a study to evaluate trends in the use of vasopressors in the operating room in French hospitals over the period 2011–2014. Methods: We conducted a longitudinal, retrospective, observational study between 2011 and 2014 in French teaching and military hospitals. A questionnaire was sent in February 2015 to hospital pharmacists of each centre to retrospectively collect the consumption of each type of vasopressor. Yearly numbers of vasopressor ampoules were divided by the yearly numbers of anaesthetics recorded. For each vasopressor, we calculated the number of ampoules per 100 anaesthetics recorded (/100A). Results: Thirty-two hospitals (82%) completed the questionnaire. One hundred per cent of hospitals had registered the diluted form of phenylephrine (61% had chosen the dilution 500 μg/10 mL), whereas concentrated ampoules were available in 68% of hospitals. Over the period, an exponential increase in the use of diluted phenylephrine was observed (from 1.0 ampoule/100A in 2012 to 31.7 in 2014), the use of ephedrine remained stable (26 ampoules and 17 prefilled syringe/100A), and use of norepinephrine trended upwards (from 6.7 to 8.2 ampoules/100A). Conclusions: The use of diluted phenylephrine has exponentially increased without reducing consumption of other vasopressors. This trend might be secondary to practice changes in hypotension treatment following the release of French guidelines in 2013 related to fluid management, the restriction of indications of hydroxylethyl-starch solutions in 2013, and a better knowledge of the benefit of blood pressure optimisation to reduce postoperative morbidity

Comparison of transcatheter versus surgical aortic valve implantation in high-risk patients : a nationwide study in France

Objective To compare the clinical outcomes and direct costs at 5 years between transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) using real-world evidence. Methods We performed a nationwide longitudinal study using data from the French Hospital Information System from 2009 to 2015. We matched, inside hospitals, 2 cohorts of adults who underwent TAVI or SAVR during 2010 on propensity score based on patient characteristics. Outcomes analysis included mortality, morbidity, and total costs and with a maximum 60-month follow-up. Clinical outcomes were compared between cohorts using hazard ratios (HRs) estimated from a Cox proportional hazards model for all-cause death, and from Fine and Gray's competing risk model for morbidity. Results Based on a cohort of 1598 patients (799 in each group) from 27 centers, a higher risk of death was observed after 1 year with TAVI compared with SAVR (16.8% vs 12.8%, respectively; HR, 1.33; 95% confidence interval [CI], 1.02-1.72) and was sustained up to 5 years (52.4% vs 37.2%; HR, 1.56; 95% CI, 1.33-1.84). At 5 years, the risk of stroke was increased (HR, 1.64; 95% CI, 1.07-2.54) as was myocardial infarction (HR, 2.30; 95% CI, 1.12-4.69) and pacemaker implantation (HR, 2.40; 95% CI, 1.81-3.17) after TAVI. The hospitalization costs per patient at 5 years were €69,083 after TAVI and €55,687 after SAVR (P < .001). Conclusions In our study, high-risk patients harbored a greater risk of mortality and morbidity at 5 years after TAVI compared with those who underwent SAVR and higher hospitalizations costs. Those results should encourage caution before expanding the indications of TAVI

Ixazomib for relapsed or refractory multiple myeloma : review from an evidence review group on a NICE single technology appraisal

Ixazomib is an oral proteasome inhibitor used in combination with lenalidomide plus dexamethasone (IXA-LEN-DEX) and licensed for relapsed or refractory multiple myeloma. As part of a single technology appraisal (ID807) undertaken by the National Institute of Health and Care Excellence, the Evidence Review Group, Warwick Evidence was invited to independently review the evidence submitted by the manufacturer of ixazomib, Takeda UK Ltd. The main source of clinical effectiveness data about IXA-LEN-DEX came from the Tourmaline-MM1 randomized controlled trial in which 771 patients with relapsed or refractory multiple myeloma received either IXA-LEN-DEX or placebo-LEN-DEX as their second-, third-, or fourth-line treatment. Takeda estimated the cost effectiveness of IXA-LEN-DEX using a de-novo partitioned-survival model with three health states (pre-progression, post-progression, and dead). In their first submission, this model was used to estimate the cost effectiveness of IXA-LEN-DEX vs. bortezomib plus dexamethasone (BORT-DEX) in second-line treatment, and of IXA-LEN-DEX vs. LEN-DEX in third-line treatment. To estimate the relative clinical performance of IXA-LEN-DEX vs. BORT-DEX, Takeda conducted network meta-analyses for important outcomes. The network meta-analysis for overall survival was found to be flawed in several respects, but mainly because a hazard ratio input for one of the studies in the network had been inverted, resulting in a large inflation of the claimed superiority of IXA-LEN-DEX over BORT-DEX and a considerable overestimation of its cost effectiveness. In subsequent submissions, Takeda withdrew second-line treatment as an option for IXA-LEN-DEX. The manufacturer’s first submission comparing IXA-LEN-DEX with LEN-DEX for third-line therapy employed Tourmaline-MM1 data from third- and fourth-line patients as proxy for a third-line population. The appraisal committee did not consider this reasonable because randomization in Tourmaline-MM1 was stratified according to one previous treatment and two or more previous treatments. A further deficiency was considered to be the manufacturer’s use of interim survival data rather than the most mature data available. A second submission from the company focussed on IXA-LEN-DEX vs. LEN-DEX as third- or fourth-line treatment (the two or more previous lines population) and a new patient access scheme was introduced. Covariate modeling of survival outcomes was proposed using the most mature survival data. The Evidence Review Group’s main criticisms of the new evidence included: the utility associated with the pre-progression health state was overestimated, treatment costs of ixazomib were underestimated, survival models were still associated with great uncertainty, leading to clinically implausible anomalies and highly variable incremental cost-effectiveness ratio estimates, and the company had not explored a strong assumption that the survival benefit of IXA-LEN-DEX over LEN-DEX would be fully maintained for a further 22 years beyond the observed data, which encompassed only approximately 2.5 years of observation. The appraisal committee remained unconvinced that ixazomib represented a cost-effective use of National Health Service resources. Takeda’s third submission offered new base-case parametric models for survival outcomes, a new analysis of utilities, and proposed a commercial access agreement. In a brief critique of the third submission, the Evidence Review Group agreed that the selection of appropriate survival models was problematic and at the request of the National Institute for Health Care and Excellence investigated external sources of evidence regarding survival outcomes. The Evidence Review Group considered that some cost and utility estimates in the submission may have remained biased in favor of ixazomib. As a result of their third appraisal meeting, the committee judged that for the two to three prior therapies population, and at the price agreed in a commercial access agreement, ixazomib had the potential to be cost effective. It was referred to the Cancer Drugs Fund so that further data could accrue with the aim of diminishing the clinical uncertainties

The woven endoBridge (WEB) for endovascular therapy of intracranial aneurysms : update of a systematic review with meta-analysis.

Endovascular treatment of wide-neck intracranial aneurysms (IAs) is challenging, especially in bifurcation location. The intra-saccular flow-disruptor Woven EndoBridge (WEB) offers a new concept of endovascular therapy for wide-neck IAs. We performed an update of a systematic review aimed to report the feasibility, effectiveness and safety of WEB device therapy. A systematic review was conducted using several electronic databases (including PUBMED and EMBASE), searching for studies published between October 2015 and December 2017 (those published between January 2010 and September 2015 were included in our initial systematic review). Outcomes were: success of implantation, peri-procedural complications, mortality, and adequate occlusion (complete occlusion or neck remnant). In total (initial review + update), 12 uncontrolled case-series studies were included, reporting outcomes for 940 patients (68.6% female; mean age, 57 years) harboring 962 IAs. Most IAs were wide-neck bifurcation aneurysms (75%-100%), mainly at middle cerebral artery (37%) and anterior communicating artery (24.6%). Feasibility was 97% (95% confidence interval [CI], 95%-99%), and 9% (95%CI, 5%-14%) of cases required additional treatment. There were 14% (95%CI, 9%-19%) peri-procedural complications. After a median clinical follow-up of 7 months, mortality was 5% (95%CI, 1%-10%) and was higher in series with larger proportions of ruptured IAs. At last angiographic follow-up (median, 7 months; range, 3-27.9 months), adequate occlusion rate was 81% (95%CI, 73%-88%). Although WEB showed high rates of adequate aneurysm occlusion at mid-term, procedure-related complications and mortality rates were not negligible. Future studies should compare the WEB device with other treatment options. [Abstract copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Comparison of health technology assessment for new medicines in France and England : an example based on ixazomib for patients with relapsed or refractory multiple myeloma

Introduction: The appraisal of medicines is often a complex and iterative process. We compared the health technology assessment (HTA) process in England and France taking as a case study the example of ixazomib for multiple myeloma. Methods: We undertook an analysis of eight relevant published documents identifed from the websites of the French and English HTA bodies (HAS and NICE, respectively). We analyse patients’ availability of ixazomib resulting in the different stages of the appraisal process. Results: We identified differences in the assessment, one of these being the use of an appraisal scope in England allowing the differentiation of populations and comparators according to previously approved treatments. Ixazomib became available earlier in France as part of an early access programme, but the availability was soon discontinued for newly eligible patients following an HAS determination that Ixazomib yielded no additional benefit. This opinion resulted in long pricing discussions. In England, despite the absence of an early access programme and following a process that included cost-effectiveness evaluation combined with pricing discussions, the medicine was fairly rapidly recommended for use. Conclusions: Differences in the HTA process may result in appreciable differences in time from marketing authorisation to health service adoption of newly licensed drug

Digital clinical communication for families and caregivers of children or young people with short- or long-term conditions : rapid review

Background The communication relationship between parents of children or young people with health conditions and health professionals is an important part of treatment, but it is unclear how far the use of digital clinical communication tools may affect this relationship. Objective The objective of our study was to describe, assess the feasibility of, and explore the impact of digital clinical communication between families or caregivers and health professionals. Methods We searched the literature using 5 electronic databases. We considered all types of study design published in the English language from January 2009 to August 2015. The population of interest included families and caregivers of children and young people aged less than 26 years with any type of health condition. The intervention was any technology permitting 2-way communication. Results We included 31 articles. The main designs were randomized controlled trials (RCTs; n=10), cross-sectional studies (n=9), pre- and postintervention uncontrolled (pre/post) studies (n=7), and qualitative interview studies (n=2); 6 had mixed-methods designs. In the majority of cases, we considered the quality rating to be fair. Many different types of health condition were represented. A breadth of digital communication tools were included: videoconferencing or videoconsultation (n=14), and Web messaging or emails (n=12). Health care professionals were mainly therapists or cognitive behavioral therapists (n=10), physicians (n=8), and nurses (n=6). Studies were very heterogeneous in terms of outcomes. Interventions were mainly evaluated using satisfaction or acceptance, or outcomes relating to feasibility. Clinical outcomes were rarely used. The RCTs showed that digital clinical communication had no impact in comparison with standard care. Uncontrolled pre/post studies showed good rates of satisfaction or acceptance. Some economic studies suggested that digital clinical communication may save costs. Conclusions This rapid review showed an emerging body of literature on the use of digital clinical communication to improve families’ and caregivers’ involvement in the health management of children or young people. Further research with appropriate study designs and longer-term outcome measures should be encouraged. Trial Registration: PROSPERO CRD42016035467; http://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD 42016 035467(Archived by WebCite at http://www.webcitation.org/6vpgZU1FU

Treatment of intracranial dural fistulas with Onyx : a prospective cohort, systematic review, and meta-analysis

BACKGROUND Onyx is important embolic material in the endovascular treatment of intracranial dural arteriovenous fistula (DAVF). However, its impact on DAVF occlusion rates, morbidity, mortality, and complication rates is not fully examined. OBJECTIVE To improve understanding of safety and effectiveness profiles associated with transarterial endovascular treatment using Onyx for intracranial DAVF METHODS We analyzed data from our prospective clinical registry and conducted a systematic review of all previous transarterial embolization studies using Onyx published between January 2005 and December 2015 in MEDLINE and EMBASE. RESULTS In the prospective study, 41 transarterial procedures were performed in 33 consecutive patients harboring 36 DAVFs. Complete initial exclusion was obtained in 32 of 36 (88.9%) fistulas; 31 fistulas were followed up showing 4 (12.9%) recurrences. Procedure-related morbidity and mortality were 3% and 0%, respectively. The literature review identified 19 studies involving a total of 425 patients with 463 DAVFs. Meta-analysis, including our registry data, showed an initial complete occlusion rate of 82% (95% confidence interval [CI]: 74%, 88%; I2, 70.6%), and recurrence rate at midterm of 2% (95% CI: 0%, 5%; I2, 21.5%). Pooled postoperative neurological deficit, procedure-related morbidity, and mortality rates were 4% (95% CI: 2%, 6%; I2, 0%), 3% (95% CI: 1%, 5%; I2, 0%), and 0%, respectively. CONCLUSION This meta-analysis suggests that transarterial embolization with Onyx is a safe treatment modality for DAVFs. Although Onyx showed a low recurrence rate at midterm, the long-term risk is poorly addressed in our study and should warrant a longer follow-up

Extracorporeal life support for primary graft dysfunction after heart transplantation

OBJECTIVES Survival after heart transplantation is steadily improving but primary graft dysfunction (PGD) is still a leading cause of death. Medical management seems useful in mild or moderate PGD, whereas extracorporeal life support (ECLS) could be suggested for severe PGD refractory to conventional treatment. Our aim is to present the results of ECLS for PGD after heart transplantation at a single-centre experience. METHODS We performed an observational analysis of our local database. According to the International Society for Heart and Lung Transplantation classification, patients were divided into a left and biventricular failure (PGD-LV) or isolated right ventricular failure (PGD-RV) group. The primary end point was survival to hospital discharge. RESULTS Between January 2010 and December 2016, 38 patients presented with PGD (PGD-LV n = 22, 58%; PGD-RV n = 16, 42%) requiring ECLS support. The mean age was 50.8 ± 12.4 years and 79% were males. Baseline characteristics were comparable between the 2 groups. PGD-LV patients displayed a significantly higher mortality rate on ECLS support as opposed to PGD-RV patients (46% vs 13%, P = 0.033). The rate of complications during ECLS support was comparable between the 2 groups. Twenty-three (61%) patients were successfully weaned from ECLS (PGD-LV = 50% vs PGD-RV = 75%, P = 0.111) after a mean support of 9.0 ± 6.4 days. Seventeen (45%) patients survived to hospital discharge (PGD-LV = 41% vs PGD-RV = 50%, P = 0.410). CONCLUSIONS In case of severe PGD with various manifestations of ventricular failure refractory to conventional treatment, ECLS can be considered as a feasible option with satisfactory survival in this critically ill population

Autologous chondrocyte implantation with chondrosphere for treating articular cartilage defects in the knee : an evidence review group perspective of a NICE single technology appraisal

Chondrosphere (Spherox) is a form of autologous chondrocyte implantation (ACI). It is licensed for repair of symptomatic articular cartilage defects of the femoral condyle and the patella of the knee with defect sizes up to 10 cm in adults. In a single technology appraisal (STA) [TA508] undertaken by the National Institute of Health and Care Excellence (NICE), Warwick Evidence was the Evidence Review Group (ERG) invited to independently review the evidence submitted by the manufacturer, Co.Don. The clinical effectiveness data came from their COWISI randomised controlled trial (RCT), which compared Chondrosphere with microfracture (MF). The timing of this appraisal was unfortunate given that MF was no longer the most relevant comparator because NICE had contemporaneously published guidance approving ACI in place of MF. Moreover, the COWISI RCT enrolled mostly patients with small defect sizes. Evidence of clinical effectiveness for Chondrosphere used in people with larger defect size came from another RCT, which compared three doses of Chondrosphere and that by design could not provide evidence comparing Chondrosphere to any other forms of ACI. To estimate the relative clinical performance of Chondrosphere versus other ACI, Co.Don conducted an indirect treatment comparison by network meta-analyses (NMA). The NMA was flawed in that the distribution of population characteristics that are effect modifiers greatly differed across the treatment comparisons of the network. The ERG questioned both the appropriateness of the NMA and the validity of the resulting estimates. Co.Don estimated the cost-effectiveness of Chondrosphere using a lifetime Markov model with all patients receiving the first repair during the first cycle of the model then moving into one of three health states: success, no further repair (NFR), or a second repair, if necessary. Subsequent to the first cycle, those who were a success either remained a success or moved to second repair. All those in NFR remained in NFR. The cost-effectiveness of Chondrosphere compared to other ACI forms relied on the clinical effectiveness estimates of success and failure rates obtained from the company's indirect comparisons, the validity of which the ERG questioned. The company revised cost-effectiveness estimates for Chondrosphere versus MF and for Chondrosphere versus matrix-applied characterised autologous cultured chondrocyte implant (MACI) were £4360 and around £18,000 per quality-adjusted life year gained, respectively. NICE recommended ACI using Chondrosphere for treating symptomatic articular cartilage defects of the femoral condyle and patella of the knee in adults only if certain requirements were met

EMA and NICE appraisal processes for cancer drugs : current status and uncertainties

The Evidence Review Group members that contributed to this editorial are funded by the UK NIHR HTA Programme. The views and opinions expressed are those of the authors and do not necessarily reflect those of the UK Department of Health and the NIHR.Peer reviewedPublisher PD