Has Arthroscopic Meniscectomy Use Changed in Response to the Evidence? A Large-database Study From Spain.

BACKGROUND: Several randomized clinical trials on the treatment of meniscal tears have shown that surgery is not superior to nonoperative treatment in middle-aged and older adults. However, clinical practice has not changed consistently worldwide in response to this evidence, and arthroscopic meniscectomy remains one of the most frequently performed operations. QUESTIONS/PURPOSES: (1) How has the use of arthroscopic meniscectomy changed in Spain between 2003 and 2018, particularly in middle-aged (35 to 59 years) and older patients (over 60 years) relative to younger patients? (2) How have surgical volumes changed across different healthcare areas in the same health system? (3) How has the proportion of outpatient versus inpatient arthroscopic procedures changed over time? METHODS: Data on all 420,228 arthroscopic meniscectomies performed in Spain between 2003 and 2018 were obtained through the Atlas of Variations in Medical Practice project (these years were chosen because data in that atlas for 2002 and 2019 were incomplete). This database has been promoted by the Spanish Health Ministry since 2002, and it collects basic information on all admissions to public and public-private partnership hospitals. The Spanish population of 2003 was used to calculate age- and sex-standardized rates of interventions per 10,000 inhabitants and year. To assess the change in standardized rates among the age groups over the study period, a linear regression analysis was used. Standard small-area variation statistics were used to analyze variation among healthcare areas. Data on outpatient surgery and length of stay for inpatient procedures were also included. RESULTS: The standardized rate of arthroscopic meniscectomy in Spain in 2003 was 4.8 procedures per 10,000 population (95% CI 3.9 to 5.6), while in 2018, there were 6.3 procedures per 10,000 population (95% CI 5.4 to 7.3), which represents an increase of 33%. Standardized rates increased slightly in the age group < 35 years (0.06 interventions per 10,000 inhabitants per year [95% CI 0.05 to 0.08]), whereas they increased more markedly in the age groups of 35 to 59 years (0.14 interventions per 10,000 inhabitants per year [95% CI 0.11 to 0.17]) and in those 60 years and older (0.13 interventions per 10,000 inhabitants per year [95% CI 0.09 to 0.17]). The variability among healthcare areas in the meniscectomy rate progressively decreased from 2003 to 2018. In 2003, 32% (6544 of 20,384) of knee arthroscopies were performed on an outpatient basis, while in 2018, these accounted for 67% (19,573 of 29,430). CONCLUSION: We observed a progressive increase in arthroscopic meniscectomies in Spain; this procedure was more prevalent in older patients presumed to have degenerative pathologic findings. This increase occurred despite increasing high-level evidence of a lack of the additional benefit of meniscectomy over other less-invasive treatments in middle-aged and older people. Our study highlights the need for action in health systems with the use of financial, regulatory, or incentive strategies to reduce the use of low-value procedures, as well as interventions to disseminate the available evidence to clinicians and patients. Research is needed to identify the barriers that are preventing the reversal of interventions that high-quality evidence shows are ineffective. LEVEL OF EVIDENCE: Level III, therapeutic study.

Revisiting systematic geographical variations in tonsils surgery in children in the Spanish National Health System: spatiotemporal ecological study on hospital administrative data.

OBJECTIVE: To provide new evidence on how tonsils surgery in children has geographically varied over time in the context of the Spanish National Health System. DESIGN: Observational ecological spatiotemporal study on geographical variations in medical practice, using linked administrative datasets, including virtually all surgeries performed from 2003 to 2015. SETTING: The Spanish National Health System, a quasi-federal structure with 17 autonomous communities (ACs), and 203 healthcare areas (HCAs). PARTICIPANTS: Patients aged 19 and younger residing in the HCAs and ACs. INTERVENTIONS: Tonsillectomy with adenoidectomy (T&A); and tonsillectomies alone (T). MAIN ENDPOINTS: (1) Evolution of T&A and T rates; (2) spatiotemporal variation in the risk of receiving T&A or T surgery at regional level (ACs) and HCAs; and (3) the fraction of the variation (FV) attributed to each of the components of variation-ACs, HCAs, year and interaction ACs year. RESULTS: T&A age-sex standardised rates increased over the period of analysis from 15.2 to 20.9 (5.7 points per 10 000 inhabitants). T alone remained relatively lower than T&A rates, evolving from 3.6 in 2003 to 3.9 in 2015 (0.3 points per 10 000 inhabitants). Most of the risk variation was captured at the HCAs level in both procedures (FV: 55.3% in T&A and 72.5% in T). The ACs level explained 27.6% of the FV in the risk in T&A versus 8% in T. The interaction ACs year was similar in both procedures (FV: 15.5% in T&A and 17.5% in T). The average trend hardly explained 1.46% and 1.83% of the variation, respectively. CONCLUSION: Our study showed wide persistent variations with a steady increase in rates and risk of T&A and a stagnation of T alone, where most of the variation risk was explained at HCA level.

Real-world patterns of opioid therapy initiation in Spain, 2012-2018: A population-based, retrospective cohort study with 957,080 patients and 1,509,488 initiations.

Introduction: Europe has seen a steady increase in the use of prescription opioids, especially in non-cancer indications. Epidemiological data on the patterns of use of opioids is required to optimize prescription. We aim to describe the patterns of opioid therapy initiation for non-cancer pain and characteristics of patients treated in a region with five million inhabitants in the period 2012 to 2018. Methods: Population-based retrospective cohort study of all adult patients initiating opioid therapy for non-cancer pain in the region of Valencia. We described patient characteristics at baseline and the characteristics of baseline and subsequent treatment initiation. We used multinominal regression models to identify individual factors associated with initiation. Results: A total of 957,080 patients initiated 1,509,488 opioid treatments (957,080 baseline initiations, 552,408 subsequent initiations). For baseline initiations, 738,749 were with tramadol (77.19%), 157,098 with codeine (16.41%) 58,436 (6.11%) with long-acting opioids, 1,518 (0.16%) with short-acting opioids and 1,279 (0.13%) with ultrafast drugs. When compared to tramadol, patients initiating with short-acting, long-acting and ultrafast opioids were more likely to be older and had more comorbidities, whereas initiators with codeine were more prone to be healthier and younger. Treatments lasting less than 7 days accounted for 41.82% of initiations, and 11.89% lasted more than 30 days. 19.55% of initiators with ultrafast fentanyl received more than 120 daily Morphine Milligram Equivalents (MME), and 16.12% of patients initiating with long-acting opioids were prescribed more than 90 daily MME (p < 0.001). Musculoskeletal indications accounted for 65.05% of opioid use. Overlap with benzodiazepines was observed in 24.73% of initiations, overlap with gabapentinoids was present in 11.04% of initiations with long-acting opioids and 28.39% of initiators with short-acting opioids used antipsychotics concomitantly. In subsequent initiations, 55.48% of treatments included three or more prescriptions (vs. 17.60% in baseline initiations) and risk of overlap was also increased. Conclusion: Opioids are initiated for a vast array of non-oncological indications, and, despite clinical guidelines, short-acting opioids are used marginally, and a significant number of patients is exposed to potentially high-risk patterns of initiation, such as treatments lasting more than 14 days, treatments surpassing 50 daily MMEs, initiating with long-acting opioids, or hazardous overlapping with other therapies.

SARS-CoV-2 Omicron BA.1 variant breakthrough infections in nursing home residents after an homologous third dose of the Comirnaty® COVID-19 vaccine: Looking for correlates of protection.

We investigated whether peripheral blood levels of SARS-CoV-2 Spike (S) receptor binding domain antibodies (anti-RBD), neutralizing antibodies (NtAb) targeting Omicron S, and S-reactive-interferon (IFN)-γ-producing CD4+ and CD8+ T cells measured after a homologous booster dose (3D) with the Comirnaty® vaccine was associated with the likelihood of subsequent breakthrough infections due to the Omicron variant. An observational study including 146 nursing home residents (median age, 80 years; range, 66-99; 109 female) evaluated for an immunological response after 3D (at a median of 16 days). Anti-RBD total antibodies were measured by chemiluminescent immunoassay. NtAb were quantified by an Omicron S pseudotyped virus neutralization assay. SARS-CoV-2-S specific-IFNγ-producing CD4+ and CD8+ T cells were enumerated by whole-blood flow cytometry for intracellular cytokine staining. In total, 33/146 participants contracted breakthrough Omicron infection (symptomatic in 30/33) within 4 months after 3D. Anti-RBD antibody levels were comparable in infected and uninfected participants (21 123 vs. 24 723 BAU/ml; p = 0.34). Likewise, NtAb titers (reciprocal IC50 titer, 157 vs. 95; p = 0.32) and frequency of virus-reactive CD4+ (p = 0.82) and CD8+ (p = 0.91) T cells were similar across participants in both groups. anti-RBD antibody levels and NtAb titers estimated at around the time of infection were also comparable (3445 vs. 4345 BAU/ml; p = 0.59 and 188.5 vs. 88.9; p = 0.70, respectively). Having detectable NtAb against Omicron or SARS-CoV-2-S-reactive-IFNγ-producing CD4+ or CD8+ T cells after 3D was not correlated with increased protection from breakthrough infection (OR, 1.50; p = 0.54; OR, 0.0; p = 0.99 and OR 3.70; p = 0.23, respectively). None of the immune parameters evaluated herein, including NtAb titers against the Omicron variant, may reliably predict at the individual level the risk of contracting COVID-19 due to the Omicron variant in nursing home residents.

Impact of Three Safety Interventions Targeting Off-Label Use of Immediate-Release Fentanyl on Prescription Trends: Interrupted Time Series Analysis.

Background: The Spanish health authorities are concerned by the off-label use of immediate-release formulations of fentanyl (IRF) in noncancer pain and cancer pain in patients with no chronic pain therapy. Aim: To evaluate the impact of different interventions to improve appropriateness of IRF prescription on off-label prescription. Patients and methods: We used interrupted time series (ITS) to estimate immediate and trend changes of IRF prescription for noncancer pain (NCP) and breakthrough cancer pain (BCP) in patients with and without chronic cancer pain therapy associated with two medication reviews (I1 and I2) and the issue of a safety warning letter (I3) with data from a Spanish region with 5 million inhabitants, from 2015 to 2018. Results: The use of IRF for NCP in the region Valencia was reduced from about 1,800 prescriptions per week to around 1,400. The first medication review was followed by an immediate level change of -192.66 prescriptions per week (p < 0.001) and a downward trend change of -6.75 prescriptions/week (p < 0.001), resulting in a post-intervention trend of -1.99 (p < 0.001). I2 was associated with a trend change of -23.07 (p < 0.001) prescriptions/week. After I3, the trend changed markedly to 27.23 additional prescriptions/week, for a final post-intervention trend of 2.17 (p < 0.001). Controlled-ITS provided comparable results. For potentially inappropriate BCP use, the second medication review was followed by a downward, immediate level change of -10.10 prescriptions/week (p = 0.011) and a trend change of 2.31 additional prescriptions/week (p < 0.001) and the issue of the safety warning (I3) was followed by a downward trend change of -2.09 prescriptions/week (p = 0.007). Conclusion: Despite IRF prescription for NCP decreased, the interventions showed modest and temporary effect on off-label prescription. Our results call for a review of the design and implementation of safety interventions addressing inappropriate opioid use.

Association of Vitamin K and Non-Vitamin K Oral Anticoagulant Use and Cancer Incidence in Atrial Fibrillation Patients.

The association between the use of vitamin K antagonists (VKAs) and cancer risk reduction remains unclear. We aimed to assess the association between the use of VKAs or direct oral anticoagulants (DOACs) and the incidence of cancer in a large cohort of patients with atrial fibrillation (AF) by means of a population-based, propensity-weighted cohort study using population-wide databases including patients diagnosed with nonvalvular AF (NVAF) followed for up of 5 years (median 2.94 years). We created two cohorts based on the initiation therapy (VKA or DOAC). Initiation with VKA or DOAC was defined as filling a prescription with no previous exposure in the preceding 12 months. Cancer diagnoses of any type and for specific tumors (lung, colon, prostate, bladder, and breast). We included 39,989 patients, 31,200 (78.0%) in the VKA cohort. Incidence rate for any cancer was 12.45 per 1,000 person-year in the DOAC cohort vs. 14.55 in the VKA cohort (adjusted hazard ratio (HR): 1.16, 95% confidence interval (CI): 1.02-1.32). In secondary outcomes, no differences were found for specific types of cancer, such as lung (HR: 1.28, CI: 0.89-1.83), colon (HR: 0.84, CI: 0.62-1.13), prostate (HR: 1.40, CI: 0.94-2.10), bladder (HR: 1.07, CI: 0.76-1.52), and breast (HR: 1.05, CI: 0.66-1.69). Sensitivity analyses yielded similar results. Subgroup analyses also produced consistent findings, except for men, for whom VKA was associated with a lower risk of colon cancer (HR: 0.68, 95% CI: 0.48-0.96). Our results do not confirm a chemoprotective effect of VKA when compared with DOAC in a large, real-world cohort of patients with NVAF followed for up to 5 years.

Laparoscopic Versus Open Incisional Hernia Repair: Long-Term Follow-up Results of a Randomized Clinical Trial.

PURPOSE: Long-term extension of a previous randomized controlled clinical trial comparing open (OVHR) vs. laparoscopic (LVHR) ventral hernia repair, assessing recurrence, reoperation, mesh-related complications and self-reported quality of life with 10 years of follow-up. METHODS: Eighty-five patients were followed up to assess recurrence (main endpoint), reoperation, mesh complications and death, from the date of index until recurrence, death or study completion, whichever was first. Recurrence, reoperation rates and death were estimated by intention to treat. Mesh-related complications were only assessed in the LVHR group, excluding conversions (intraperitoneal onlay; n = 40). Quality of life, using the European Hernia Society Quality of Life score, was assessed in surviving non-reoperated patients (n = 47). RESULTS: The incidence rates with 10 person-years of follow-up were 21.01% (CI 13.24-33.36) for recurrence, 11.92% (CI: 6.60-21.53) for reoperation and 24.88% (CI 16.81-36.82) for death. Sixty-two percent of recurrences occurred within the first 2 years of follow-up. No significant differences between arms were found in any of the outcomes analyzed. Incidence rate of intraperitoneal mesh complications with 10 person-years of follow-up was 6.15% (CI 1.99-19.09). The mean EuraHS-QoL score with 13.8 years of mean follow-up for living non-reoperated patients was 6.63 (CI 4.50-8.78) over 90 possible points with no significant differences between arms. CONCLUSION: In incisional ventral hernias with wall defects up to 15 cm wide, laparoscopic repair seems to be as safe and effective as open techniques, with no long-term differences in recurrence and reoperation rates or global quality of life, although lack of statistical power does not allow definitive conclusions on equivalence between alternatives. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov (NCT04192838).

A noninvasive postoperative clinical score to identify patients at risk for postoperative pulmonary complications: the Air-Test Score.

BACKGROUND: Postoperative pulmonary complications (PPCs) negatively affect morbidity, healthcare costs and postsurgical survival. Preoperative and intraoperative peripheral oxyhemoglobin saturation (SpO2) levels are independent risk factors for postoperative pulmonary complications (PPCs). The air-test assesses the value of SpO2 while breathing room-air. We aimed at building a clinical score that includes the air-test for predicting the risk for PPCs. METHODS: This is a development and validation study in patients -randomly divided into two cohorts- from a large randomized clinical trial (iPROVE) that enrolled 964 intermediate-to-high risk patients scheduled for abdominal surgery. Arterial oxygenation was assessed on room-air in the preoperative period (preoperative air-test) and 3h after admission to the postoperative care unit (postoperative air-test). The air-test was defined as positive or negative if SpO2 was ≤96% or >96%, respectively. Positive air-tests were stratified into weak (93-96%) or strong (<93%). The primary outcome was a composite of moderate-to-severe PPCs during the first seven postoperative days. RESULTS: A total of 902 patients were included in the final analysis (542 in the development cohort and 360 in the validation cohort). Regression analysis identified five independent risk factors for PPC: age, type of surgery, pre- and postoperative air-test, and atelectasis. The area under the receiver operating characteristic curve (AUC) was 0.79 (95% CI: 0.75-0.82) when including these five independent predictors. We built a simplified score termed "air-test score" by using only the pre- and postoperative SpO2, resulting in an AUC of 0.72 (95% CI: 0.67-0.76) for the derivation and 0.72 (95% CI: 0.66-0.78) for the validation cohort, respectively. The air-test score stratified patients into four levels of risk, with PPCs ranging from <15% to >75%. CONCLUSIONS: The simple, non-invasive and inexpensive bedside air-test score, evaluating pre- and postoperatively SpO2 measured on room-air, helps to predict the risk for PPCs.

Effects of oxygen on post-surgical infections during an individualised perioperative open-lung ventilatory strategy: a randomised controlled trial.

BACKGROUND: We aimed to examine whether using a high fraction of inspired oxygen (FIO2) in the context of an individualised intra- and postoperative open-lung ventilation approach could decrease surgical site infection (SSI) in patients scheduled for abdominal surgery. METHODS: We performed a multicentre, randomised controlled clinical trial in a network of 21 university hospitals from June 6, 2017 to July 19, 2018. Patients undergoing abdominal surgery were randomly assigned to receive a high (0.80) or conventional (0.3) FIO2 during the intraoperative period and during the first 3 postoperative hours. All patients were mechanically ventilated with an open-lung strategy, which included recruitment manoeuvres and individualised positive end-expiratory pressure for the best respiratory-system compliance, and individualised continuous postoperative airway pressure for adequate peripheral oxyhaemoglobin saturation. The primary outcome was the prevalence of SSI within the first 7 postoperative days. The secondary outcomes were composites of systemic complications, length of intensive care and hospital stay, and 6-month mortality. RESULTS: We enrolled 740 subjects: 371 in the high FIO2 group and 369 in the low FIO2 group. Data from 717 subjects were available for final analysis. The rate of SSI during the first postoperative week did not differ between high (8.9%) and low (9.4%) FIO2 groups (relative risk [RR]: 0.94; 95% confidence interval [CI]: 0.59-1.50; P=0.90]). Secondary outcomes, such as atelectasis (7.7% vs 9.8%; RR: 0.77; 95% CI: 0.48-1.25; P=0.38) and myocardial ischaemia (0.6% [n=2] vs 0% [n=0]; P=0.47) did not differ between groups. CONCLUSIONS: An oxygenation strategy using high FIO2 compared with conventional FIO2 did not reduce postoperative SSIs in abdominal surgery. No differences in secondary outcomes or adverse events were found. CLINICAL TRIAL REGISTRATION: NCT02776046.

Impact of Drug Safety Warnings and Cost-Sharing Policies on Osteoporosis Drug Utilization in Spain: A Major Reduction But With the Persistence of Over and Underuse. Data From the ESOSVAL Cohort From 2009 to 2015.

Background: Recent studies in several countries show a significant decrease in the consumption of osteoporosis drugs from a peak around 2009, mainly attributed to bisphosphonate safety warnings issued by regulatory agencies on jaw osteonecrosis, atypical fractures, and esophageal cancer, but no studies have assessed the impact of these warnings by risk of fracture strata. Aim: The aim of this work is to assess changes in the utilization of osteoporosis drugs in the region of Valencia (Spain) after safety warnings from regulatory agencies and cost-sharing changes, according to patient socio-demographic and risk of fracture characteristics. Patients and Methods: We constructed a monthly series of osteoporosis drug consumption for 2009-2015 from the ESOSVAL cohort (n = 11,035; women: 48%; mean age: 65 years old) and used interrupted time series and segmented linear regression models to assess changes in osteoporosis drug utilization while controlling for previous levels and trends after three natural intervention dates: the issue of the Spanish Agency for Drugs and Medical Products (AEMPS) Osteonecrosis Jaw Warning (Sept 2009), the AEMPS Atypical femur Fracture Warning (Apr 2011), and the modification of the cost-sharing scheme (Jul 2012). Results: The AEMPS Osteonecrosis Jaw Warning was not associated with a decline in the consumption of osteoporosis drugs, while the warning on atypical fracture (a downward trend of 0.11% fewer people treated each month) and the increase in the cost-sharing scheme (immediate change level of -1.07% in the proportion of people treated) were associated with a strong decline in the proportion of patients treated, so that by the end of 2015 osteoporosis drug consumption was around half that of 2009. The relative decline was similar in people with both a high and low risk of fracture. Conclusion: The AEMPS Atypical femur Fracture Warning of Apr 2010 was associated with a significant decrease in the number of people treated, reinforced by the increase in the pharmaceutical cost-sharing in 2012. Decreases in treatment affected patients both at a low and higher risk of fracture.

Pinocchio testing in the forensic analysis of waiting lists: using public waiting list data from Finland and Spain for testing Newcomb-Benford's Law.

OBJECTIVE: Newcomb-Benford's Law (NBL) proposes a regular distribution for first digits, second digits and digit combinations applicable to many different naturally occurring sources of data. Testing deviations from NBL is used in many datasets as a screening tool for identifying data trustworthiness problems. This study aims to compare public available waiting lists (WL) data from Finland and Spain for testing NBL as an instrument to flag up potential manipulation in WLs. DESIGN: Analysis of the frequency of Finnish and Spanish WLs first digits to determine if their distribution is similar to the pattern documented by NBL. Deviations from the expected first digit frequency were analysed using Pearson's χ2, mean absolute deviation and Kuiper tests. SETTING/PARTICIPANTS: Publicly available WL data from Finland and Spain, two countries with universal health insurance and National Health Systems but characterised by different levels of transparency and good governance standards. MAIN OUTCOME MEASURES: Adjustment of the observed distribution of the numbers reported in Finnish and Spanish WL data to the expected distribution according to NBL. RESULTS: WL data reported by the Finnish health system fits first digit NBL according to all statistical tests used (p=0.6519 in χ2 test). For Spanish data, this hypothesis was rejected in all tests (p<0.0001 in χ2 test). CONCLUSIONS: Testing deviations from NBL distribution can be a useful tool to identify problems with WL data trustworthiness and signalling the need for further testing.

Primary Nonadherence to Oral Anticoagulants in Patients with Atrial Fibrillation: Real-World Data from a Population-Based Cohort.

BACKGROUND: Primary nonadherence (not filling a first prescription) is an important yet unstudied aspect of adherence to oral anticoagulant (OAC) therapy. OBJECTIVE: To estimate the rates of primary nonadherence to OACs and determine associated factors in real-world practice. METHODS: This population-based retrospective cohort study set in the Valencia region of Spain (about 5 million inhabitants) included all patients with atrial fibrillation who were newly prescribed OACs during 2011-2014 (N = 18,715). Primary nonadherence was obtained by linking electronic prescription and dispensing data and assessed by type of OAC-vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs). Covariates were obtained from diverse databases, including electronic medical records. Multivariate logistic regression models were used to assess characteristics associated with primary nonadherence, adjusting for a propensity score to minimize confounding by indication. RESULTS: Primary nonadherence to OACs was 5.62% (VKA 4.29% vs. NOAC 10.81%; P < 0.001), with varying rates among specific drugs (acenocoumarol 4.2%, warfarin 10.9%, apixaban 5.0%, dabigatran 7.9%, and rivaroxaban 15.5%). After adjusting for potential confounders, the likelihood of not filling the first prescription was higher for NOAC patients than for VKA patients (OR = 2.76, 95% CI = 2.41-3.15). High coinsurance in the older groups (OR = 2.63, 95% CI = 1.47-4.69 for patients aged 66-75 years and OR = 3.02, 95% CI = 1.58-5.76 for patients aged > 75 years); being a non-Spanish European (OR = 1.49, 95% CI = 1.12-1.99); and having dementia (OR = 1.72, 95% CI = 1.37-2.16) were positively associated with primary nonadherence. Electronic transmission of prescriptions (OR = 0.85, 95% CI = 0.74-0.96); liver disease (OR = 0.73, 95% CI = 0.54-0.99); and polypharmacy (OR = 0.59, 95% CI = 0.50-0.70) were inversely associated with primary nonadherence. CONCLUSIONS: Overall, primary nonadherence to OACs was relatively low (5%). However, important differences were found between VKAs and NOACs. After adjustment, patients prescribed NOACs nearly tripled the likelihood of nonadherence compared with patients prescribed VKAs, which could negatively affect their effectiveness in clinical practice. Identified correlates were similar to those shown in the limited evidence for other medications. DISCLOSURES: This work was partially supported by the 2013 Collaboration Agreement between the Fundación para el Fomento de la Investigación Sanitaria y Biomédica (FISABIO) from the Valencia Ministry of Health and Boehringer Ingelheim, a nonconditioned program to conduct independent research in chronic health care, pharmacoepidemiology, and medical practice variation. Rodriguez-Bernal was funded by the Instituto de Salud Carlos III, Spanish Ministry of Health, and cofinanced by the European Regional Development Fund (grant number RD12/0001/0005). The views presented here are those of the authors and not necessarily those of the FISABIO Foundation, the Valencia Ministry of Health, or the study sponsors. The funding sources had no access to study data and did not participate in any way in the design or conduct of the study, data analysis, decisions regarding the dissemination of findings, the development of the manuscript, or its publication. Peiró has received fees for participation in scientific meetings and courses sponsored by Novartis and Ferrer International. In 2014, Sanfélix-Gimeno participated in an advisory meeting of Boehringer Ingelheim. García-Sempere is a former employee of Boehringer Ingelheim. Rodriguez-Bernal and Hurtado have no relationships relevant to the contents of this article to disclose. This work was previously submitted as an abstract (podium presentation) at the 31st International Society of Pharmacoepidemiology (ISPE) Annual Conference; August 22-26, 2015; Boston, Massachusetts.

Individualised perioperative open-lung approach versus standard protective ventilation in abdominal surgery (iPROVE): a randomised controlled trial.

BACKGROUND: The effects of individualised perioperative lung-protective ventilation (based on the open-lung approach [OLA]) on postoperative complications is unknown. We aimed to investigate the effects of intraoperative and postoperative ventilatory management in patients scheduled for abdominal surgery, compared with standard protective ventilation. METHODS: We did this prospective, multicentre, randomised controlled trial in 21 teaching hospitals in Spain. We enrolled patients who were aged 18 years or older, were scheduled to have abdominal surgery with an expected time of longer than 2 h, had intermediate-to-high-risk of developing postoperative pulmonary complications, and who had a body-mass index less than 35 kg/m2. Patients were randomly assigned (1:1:1:1) online to receive one of four lung-protective ventilation strategies using low tidal volume plus positive end-expiratory pressure (PEEP): open-lung approach (OLA)-iCPAP (individualised intraoperative ventilation [individualised PEEP after a lung recruitment manoeuvre] plus individualised postoperative continuous positive airway pressure [CPAP]), OLA-CPAP (intraoperative individualised ventilation plus postoperative CPAP), STD-CPAP (standard intraoperative ventilation plus postoperative CPAP), or STD-O2 (standard intraoperative ventilation plus standard postoperative oxygen therapy). Patients were masked to treatment allocation. Investigators were not masked in the operating and postoperative rooms; after 24 h, data were given to a second investigator who was masked to allocations. The primary outcome was a composite of pulmonary and systemic complications during the first 7 postoperative days. We did the primary analysis using the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02158923. FINDINGS: Between Jan 2, 2015, and May 18, 2016, we enrolled 1012 eligible patients. Data were available for 967 patients, whom we included in the final analysis. Risk of pulmonary and systemic complications did not differ for patients in OLA-iCPAP (110 [46%] of 241, relative risk 0·89 [95% CI 0·74-1·07; p=0·25]), OLA-CPAP (111 [47%] of 238, 0·91 [0·76-1·09; p=0·35]), or STD-CPAP groups (118 [48%] of 244, 0·95 [0·80-1·14; p=0·65]) when compared with patients in the STD-O2 group (125 [51%] of 244). Intraoperatively, PEEP was increased in 69 (14%) of patients in the standard perioperative ventilation groups because of hypoxaemia, and no patients from either of the OLA groups required rescue manoeuvres. INTERPRETATION: In patients who have major abdominal surgery, the different perioperative open lung approaches tested in this study did not reduce the risk of postoperative complications when compared with standard lung-protective mechanical ventilation. FUNDING: Instituto de Salud Carlos III of the Spanish Ministry of Economy and Competitiveness, and Grants Programme of the European Society of Anaesthesiology.

Rationale and study design for an individualised perioperative open-lung ventilatory strategy with a high versus conventional inspiratory oxygen fraction (iPROVE-O2) and its effects on surgical site infection: study protocol for a randomised controlled trial.

INTRODUCTION: Surgical site infection (SSI) is a serious postoperative complication that increases morbidity and healthcare costs. SSIs tend to increase as the partial pressure of tissue oxygen decreases: previous trials have focused on trying to reduce them by comparing high versus conventional inspiratory oxygen fractions (FIO2) in the perioperative period but did not use a protocolised ventilatory strategy. The open-lung ventilatory approach restores functional lung volume and improves gas exchange, and therefore it may increase the partial pressure of tissue oxygen for a given FIO2. The trial presented here aims to compare the efficacy of high versus conventional FIO2 in reducing the overall incidence of SSIs in patients by implementing a protocolised and individualised global approach to perioperative open-lung ventilation. METHODS AND ANALYSIS: This is a comparative, prospective, multicentre, randomised and controlled two-arm trial that will include 756 patients scheduled for abdominal surgery. The patients will be randomised into two groups: (1) a high FIO2 group (80% oxygen; FIO2 of 0.80) and (2) a conventional FIO2 group (30% oxygen; FIO2 of 0.30). Each group will be assessed intra- and postoperatively. The primary outcome is the appearance of postoperative SSI complications. Secondary outcomes are the appearance of systemic and pulmonary complications. ETHICS AND DISSEMINATION: The iPROVE-O2 trial has been approved by the Ethics Review Board at the reference centre (the Hospital Clínico Universitario in Valencia). Informed consent will be obtained from all patients before their participation. If the approach using high FIO2 during individualised open-lung ventilation decreases SSIs, use of this method will become standard practice for patients scheduled for future abdominal surgery. Publication of the results is anticipated in early 2019. TRIAL REGISTRATION NUMBER: NCT02776046; Pre-results.

Applying spatio-temporal models to assess variations across health care areas and regions: Lessons from the decentralized Spanish National Health System.

OBJECTIVE: To illustrate the ability of hierarchical Bayesian spatio-temporal models in capturing different geo-temporal structures in order to explain hospital risk variations using three different conditions: Percutaneous Coronary Intervention (PCI), Colectomy in Colorectal Cancer (CCC) and Chronic Obstructive Pulmonary Disease (COPD). RESEARCH DESIGN: This is an observational population-based spatio-temporal study, from 2002 to 2013, with a two-level geographical structure, Autonomous Communities (AC) and Health Care Areas (HA). SETTING: The Spanish National Health System, a quasi-federal structure with 17 regional governments (AC) with full responsibility in planning and financing, and 203 HA providing hospital and primary care to a defined population. METHODS: A poisson-log normal mixed model in the Bayesian framework was fitted using the INLA efficient estimation procedure. MEASURES: The spatio-temporal hospitalization relative risks, the evolution of their variation, and the relative contribution (fraction of variation) of each of the model components (AC, HA, year and interaction AC-year). RESULTS: Following PCI-CCC-CODP order, the three conditions show differences in the initial hospitalization rates (from 4 to 21 per 10,000 person-years) and in their trends (upward, inverted V shape, downward). Most of the risk variation is captured by phenomena occurring at the HA level (fraction variance: 51.6, 54.7 and 56.9%). At AC level, the risk of PCI hospitalization follow a heterogeneous ascending dynamic (interaction AC-year: 17.7%), whereas in COPD the AC role is more homogenous and important (37%). CONCLUSIONS: In a system where the decisions loci are differentiated, the spatio-temporal modeling allows to assess the dynamic relative role of different levels of decision and their influence on health outcomes.

Rationale and study design for an individualized perioperative open lung ventilatory strategy (iPROVE): study protocol for a randomized controlled trial.

BACKGROUND: Postoperative pulmonary and non-pulmonary complications are common problems that increase morbidity and mortality in surgical patients, even though the incidence has decreased with the increased use of protective lung ventilation strategies. Previous trials have focused on standard strategies in the intraoperative or postoperative period, but without personalizing these strategies to suit the needs of each individual patient and without considering both these periods as a global perioperative lung-protective approach. The trial presented here aims at comparing postoperative complications when using an individualized ventilatory management strategy in the intraoperative and immediate postoperative periods with those when using a standard protective ventilation strategy in patients scheduled for major abdominal surgery. METHODS: This is a comparative, prospective, multicenter, randomized, and controlled, four-arm trial that will include 1012 patients with an intermediate or high risk for postoperative pulmonary complications. The patients will be divided into four groups: (1) individualized perioperative group: intra- and postoperative individualized strategy; (2) intraoperative individualized strategy + postoperative continuous positive airway pressure (CPAP); (3) intraoperative standard ventilation + postoperative CPAP; (4) intra- and postoperative standard strategy (conventional strategy). The primary outcome is a composite analysis of postoperative complications. DISCUSSION: The Individualized Perioperative Open-lung Ventilatory Strategy (iPROVE) is the first multicenter, randomized, and controlled trial to investigate whether an individualized perioperative approach prevents postoperative pulmonary complications. TRIAL REGISTRATION: Registered on 5 June 2014 with identification no. NCT02158923 .

[C-section rate in low-risk women: a useful indicator to compare hospitals attending deliveries with different risks]. / Porcentaje de cesáreas en mujeres de bajo riesgo: un indicador útil para comparar hospitales que atienden partos con riesgos diferentes.

BACKGROUND: the C-section rate has been criticized as a performance indicator for not considering that different hospitals manage deliveries with diverse risks. In this work we explore the characteristics of a new indicator restricted to low C-section risk deliveries. METHODS: retrospective cohort of all births (n=214,611) in all public hospitals during 2005-2010 in the Valencia Region, Spain (source: minimum basic dataset). A low-risk subpopulation consisting of women under-35, no history of c-section, between 37 and 41 gestational weeks, and with a single fetus, with cephalic presentation and normal weight (2500-3999 g) was constructed. We analyzed variability in the new indicator, its correlation with the crude indicator and, using multilevel logistic regression models, the presence of residual risks. RESULTS: a total of 117 589 births (58.4% of the whole deliveries) were identified as low C-section risk. The c-section rate in these women was 11.9% (24.4% for all deliveries) ranging between hospitals from 7.0% to 28.9%. The c-section rate in low-risk and total deliveries correlated strongly (r=0.88). The remaining risks in the population of low risk did not alter the hospital effect on the c-section rate. CONCLUSION: the percentage of C-section in low risk women include a high volume of deliveries, correlated with the crude indicator and residual risks are not differentially influenced by hospitals, being a useful indicator for monitoring the quality of obstetric care in the National Health System.

[Barriers for introducing a health technology assessment organization to inform health care decision-making in the Spanish National Health System]. / Barreras a la introducción de una agencia evaluadora para informar la financiación o la desinversión de prestaciones sanitarias del Sistema Nacional de Salud.

BACKGROUND: To identify difficulties, obstacles and limitations to establish an organizational structure devoted to the evaluation of healthcare technologies for incorporation, maintenance or removal from the services portfolio of the Spanish National Health System (sNHS). METHODS: Panel of 14 experts, structured according to processes adapted from brainstorming, nominal group, and Rand consensus method techniques. RESULTS: The panel proposed 77 items as potential obstacles to the establishment of an official and independent "agency" able to inform on sNHS healthcare benefits funding or selective disinvestment. These items were focused on: 1) lack of political motivation to introduce the cost-effectiveness analysis from the state and regional governments and lack of independence and transparency of the evaluation processes, 2) the tension between a decentralized health system and evaluation activities with significant scale economies, 3) technical difficulties of the evaluation processes, including their ability to influence decision making and 4) social and professional refusal to the exclusion of healthcare benefits when it is perceived as indiscriminate. CONCLUSION: Although there is a different number and type of obstacles for developing the capacity of the sNHS to include or exclude healthcare benefits based on the evaluation of their effectiveness and efficiency, experts place in the political arena (political motivation, transparency, governance) the main difficulties to advance in this field.