Consultant revision hip arthroplasty volumes and new consultant volume trajectories in England, Wales, Northern Ireland, and the Isle of Man.

Aims: This study describes the variation in the annual volumes of revision hip arthroplasty (RHA) undertaken by consultant surgeons nationally, and the rate of accrual of RHA and corresponding primary hip arthroplasty (PHA) volume for new consultants entering practice. Methods: National Joint Registry (NJR) data for England, Wales, Northern Ireland, and the Isle of Man were received for 84,816 RHAs and 818,979 PHAs recorded between April 2011 and December 2019. RHA data comprised all revision procedures, including first-time revisions of PHA and any subsequent re-revisions recorded in public and private healthcare organizations. Annual procedure volumes undertaken by the responsible consultant surgeon in the 12 months prior to every index procedure were determined. We identified a cohort of 'new' HA consultants who commenced practice from 2012 and describe their rate of accrual of PHA and RHA experience. Results: The median annual consultant RHA volume, averaged across all cases, was 21 (interquartile range (IQR) 11 to 34; range 0 to 181). Of 1,695 consultants submitting RHA cases within the study period, the top 20% of surgeons by annual volume performed 74.2% of total RHA case volume. More than half of all consultants who had ever undertaken a RHA maintained an annual volume of just one or fewer RHA, however, collectively contributed less than 3% of the total RHA case volume. Consultant PHA and RHA volumes were positively correlated. Lower-volume surgeons were more likely to undertake RHA for urgent indications (such as infection) as a proportion of their practice, and to do so on weekends and public holidays. Conclusion: The majority of RHAs were undertaken by higher-volume surgeons. There was considerable variation in RHA volumes by indication, day of the week, and between consultants nationally. The rate of accrual of RHA experience by new consultants is low, and has important implications for establishing an experienced RHA consultant workforce.

Urbanisation generates multiple trait syndromes for terrestrial animal taxa worldwide.

Cities can host significant biological diversity. Yet, urbanisation leads to the loss of habitats, species, and functional groups. Understanding how multiple taxa respond to urbanisation globally is essential to promote and conserve biodiversity in cities. Using a dataset encompassing six terrestrial faunal taxa (amphibians, bats, bees, birds, carabid beetles and reptiles) across 379 cities on 6 continents, we show that urbanisation produces taxon-specific changes in trait composition, with traits related to reproductive strategy showing the strongest response. Our findings suggest that urbanisation results in four trait syndromes (mobile generalists, site specialists, central place foragers, and mobile specialists), with resources associated with reproduction and diet likely driving patterns in traits associated with mobility and body size. Functional diversity measures showed varied responses, leading to shifts in trait space likely driven by critical resource distribution and abundance, and taxon-specific trait syndromes. Maximising opportunities to support taxa with different urban trait syndromes should be pivotal in conservation and management programmes within and among cities. This will reduce the likelihood of biotic homogenisation and helps ensure that urban environments have the capacity to respond to future challenges. These actions are critical to reframe the role of cities in global biodiversity loss.

Financial analysis of revision hip surgery at a tertiary referral centre as classified using the British Hip Society Revision Hip Complexity Classification.

Aims: The burden of revision total hip arthroplasty (rTHA) continues to grow. The surgery is complex and associated with significant costs. Regional rTHA networks have been proposed to improve outcomes and to reduce re-revisions, and therefore costs. The aim of this study was to accurately quantify the cost and reimbursement for a rTHA service, and to assess the financial impact of case complexity at a tertiary referral centre within the NHS. Methods: A retrospective analysis of all revision hip procedures was performed at this centre over two consecutive financial years (2018 to 2020). Cases were classified according to the Revision Hip Complexity Classification (RHCC) and whether they were infected or non-infected. Patients with an American Society of Anesthesiologists (ASA) grade ≥ III or BMI ≥ 40 kg/m2 are considered "high risk" by the RHCC. Costs were calculated using the Patient Level Information and Costing System (PLICS), and remuneration based on Healthcare Resource Groups (HRG) data. The primary outcome was the financial difference between tariff and cost per patient episode. Results: In all, 199 revision episodes were identified in 168 patients: 25 (13%) least complex revisions (H1); 110 (55%) complex revisions (H2); and 64 (32%) most complex revisions (H3). Of the 199, 76 cases (38%) were due to infection, and 78 patients (39%) were "high risk". Median length of stay increased significantly with case complexity from four days to six to eight days (p = 0.006) and for revisions performed for infection (9 days vs 5 days; p < 0.001). Cost per episode increased significantly between complexity groups (p < 0.001) and for infected revisions (p < 0.001). All groups demonstrated a mean deficit but this significantly increased with revision complexity (£97, £1,050, and £2,887 per case; p = 0.006) and for infected failure (£2,629 vs £635; p = 0.032). The total deficit to the NHS Trust over two years was £512,202. Conclusion: Current NHS reimbursement for rTHA is inadequate and should be more closely aligned to complexity. An increase in the most complex rTHAs at major revision centres will likely place a greater financial burden on these units.

Hydrology is a major influence on amphibian abundance in a large European floodplain.

River-floodplain ecosystems play a crucial role in connecting landscape patches through hydrological connectivity, but they are among the most threatened ecosystems. Floodplains provide important habitat for amphibians by connecting aquatic and terrestrial habitats. Modifications to floodplain hydrology can impact amphibian communities, yet few studies have examined amphibian metacommunities in floodplain wetlands.In this study, we assessed patterns in amphibian breeding abundance in one of the largest floodplains of the Danube River, Hungary, relative to hydrological connectivity and multi-scale variables at 30 waterbody sites. Our aim was to determine whether these patterns aligned with the pond-permanence gradient hypothesis, where breeding amphibian abundance is predicted to be highest in ephemeral ponds without large predatory fish. We used Bayesian hierarchical modelling to estimate multi-species abundance from repeated survey (count) data collected over one breeding season.We detected the eggs and larvae of four amphibian species. The best model of abundance included covariates describing two principal component axes associated with waterbody hydrology and landscape composition within a 500-m radius of a site. There was a positive relationship between mean community abundance at a site and hydrological disconnection from the main river channel; however, the common toad (Bufo bufo) was associated with hydrologically connected waterbodies. There was a positive relationship between mean community abundance and a high proportion of forest cover and low cover of agricultural land within a 500-m radius around a site, although this relationship was clear for only two species. There was no support for models containing the number of large predatory fish species detected at a site.Although our results showed that amphibian abundance declined with hydrological connectivity, based on model selection we could not ascribe this relationship to an increased number of large predatory fish species detected in waterbodies close to the main river channel. Differences in life history and habitat requirements are likely to have explained interspecific responses to hydrological connectivity. Our results underscore the importance of addressing amphibian abundance at multiple spatial scales in floodplain wetlands, as landscape composition partly explained patterns in abundance.Application of multi-species abundance modelling allowed us to investigate environmental relationships for common and infrequently detected species. Habitat restoration programmes in floodplains should provide waterbodies disconnected from main river channels as potential amphibian breeding sites and protect or restore forest as terrestrial habitat.

Cognitive function with evolocumab in pediatric heterozygous familial hypercholesterolemia.

BACKGROUND: Evolocumab is a fully human monoclonal antibody inhibitor of PCSK9 approved for lowering low-density lipoprotein cholesterol in adults and pediatric patients with familial hypercholesterolemia (FH). The cognitive safety of evolocumab has been established in adults but has not yet been described in pediatric patients. OBJECTIVE: To determine the effects of evolocumab on cognitive function in pediatric heterozygous FH. METHODS: Cognitive function was assessed during a 24-week, randomized, double-blind, placebo-controlled study (HAUSER-RCT) evaluating the efficacy, safety, and tolerability of 24 weeks of monthly subcutaneous injections of evolocumab in pediatric patients with FH. Cognitive safety endpoints included changes from baseline to week 24 in test scores in domains of psychomotor function, attention, visual learning, and executive function. Between-group differences in age-standardized mean test score changes were analyzed using analysis of covariance models and point estimates with 95% confidence interval (CI). Magnitudes of difference between treatment groups (Cohen's d) and reliable change indices were calculated for each cognitive function test. RESULTS: At week 24, changes from baseline in age-standardized cognitive test scores were similar between the treatment groups. Differences (95% CI) between the evolocumab and placebo groups in mean test score changes for the Groton Maze Learning, One-Card Learning, Identification, and Detection tests were 0.1 (-0.2, 0.4), -0.1 (-0.5, 0.4), 0.3 (0.0, 0.7), 0.3 (-0.1, 0.8), respectively. For all tests, abnormal and clinically important cognitive decline occurred with lesser frequency in the evolocumab group. CONCLUSION: In pediatric patients with FH, 24-week treatment with evolocumab did not negatively influence cognition. FUNDING: This study was funded and designed by Amgen.

Biomarker Prediction of Complex Coronary Revascularization Procedures in the FOURIER Trial.

BACKGROUND: Biomarkers are known to predict major adverse cardiovascular events. However, the association of biomarkers with complex coronary revascularization procedures or high-risk coronary anatomy at the time of revascularization is not understood. OBJECTIVES: We examined the associations between baseline biomarkers and major coronary events (MCE) and complex revascularization procedures. METHODS: FOURIER was a randomized trial of the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab vs placebo in 27,564 patients with stable atherosclerosis. We analyzed adjusted associations among the biomarkers, MCE (coronary death, myocardial infarction, or revascularization), and complex revascularization (coronary artery bypass graft or complex percutaneous coronary intervention) using a multimarker score with 1 point assigned for each elevated biomarker (high-sensitivity C-reactive protein ≥2 mg/L; N-terminal pro-B-type natriuretic peptide ≥450 pg/mL; high-sensitivity troponin I ≥6 ng/L; growth-differentiation factor-15 ≥1,800 pg/mL). RESULTS: When patients were grouped by the number of elevated biomarkers (0 biomarkers, n = 6,444; 1-2 biomarkers, n = 12,439; ≥3 biomarkers, n = 2,761), there was a significant graded association between biomarker score and the risk of MCE (intermediate score: HRadj: 1.57 [95% CI: 1.38-1.78]; high score: HRadj: 2.90 [95% CI: 2.47-3.40]), and for complex revascularization (intermediate: HRadj: 1.33 [95% CI: 1.06-1.67]; high score: HRadj: 2.07 [95% CI: 1.52-2.83]) and its components (Ptrend <0.05 for each). The number of elevated biomarkers also correlated with the presence of left main disease, multivessel disease, or chronic total occlusion at the time of revascularization (P < 0.05 for each). CONCLUSIONS: A biomarker-based strategy identifies stable patients at risk for coronary events, including coronary artery bypass graft surgery and complex percutaneous coronary intervention, and predicts high-risk coronary anatomy at the time of revascularization. These findings provide insight into the relationships between cardiovascular biomarkers, coronary anatomical complexity, and incident clinical events. (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]; NCT01764633).

Development of the Revision Hip Complexity Classification using a modified Delphi technique.

AIMS: The aim of this modified Delphi process was to create a structured Revision Hip Complexity Classification (RHCC) which can be used as a tool to help direct multidisciplinary team (MDT) discussions of complex cases in local or regional revision networks. METHODS: The RHCC was developed with the help of a steering group and an invitation through the British Hip Society (BHS) to members to apply, forming an expert panel of 35. We ran a mixed-method modified Delphi process (three rounds of questionnaires and one virtual meeting). Round 1 consisted of identifying the factors that govern the decision-making and complexities, with weighting given to factors considered most important by experts. Participants were asked to identify classification systems where relevant. Rounds 2 and 3 focused on grouping each factor into H1, H2, or H3, creating a hierarchy of complexity. This was followed by a virtual meeting in an attempt to achieve consensus on the factors which had not achieved consensus in preceding rounds. RESULTS: The expert group achieved strong consensus in 32 out of 36 factors following the Delphi process. The RHCC used the existing Paprosky (acetabulum and femur), Unified Classification System, and American Society of Anesthesiologists (ASA) classification systems. Patients with ASA grade III/IV are recognized with a qualifier of an asterisk added to the final classification. The classification has good intraobserver and interobserver reliability with Kappa values of 0.88 to 0.92 and 0.77 to 0.85, respectively. CONCLUSION: The RHCC has been developed through a modified Delphi technique. RHCC will provide a framework to allow discussion of complex cases as part of a local or regional hip revision MDT. We believe that adoption of the RHCC will provide a comprehensive and reproducible method to describe each patient's case with regard to surgical complexity, in addition to medical comorbidities that may influence their management. Cite this article: Bone Jt Open 2022;3(5):423-431.

Effect of Evolocumab in Patients With Prior Percutaneous Coronary Intervention.

BACKGROUND: Patients with prior percutaneous coronary intervention (PCI) are at high residual risk for multiple types of coronary events within and beyond the stented lesion. This risk might be mitigated by more intensive LDL-C (low-density lipoprotein cholesterol)-lowering beyond just with statin therapy. METHODS: FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27 564 patients with stable atherosclerotic disease on statin to the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab or placebo with a median follow-up of 2.2 years. The end points of interest were major adverse cardiovascular events (MACE; a composite of cardiovascular death, myocardial infarction, stroke, unstable angina or coronary revascularization), and major coronary events (a composite of coronary heart death, myocardial infarction, or coronary revascularization). We compared the risk of MACE and the magnitude of relative and absolute risk reductions with evolocumab in patients with and without prior PCI. RESULTS: Seventeen thousand seventy-three patients had prior PCI. In the placebo arm, those with prior PCI had higher rates of MACE (13.2% versus 8.3%; hazard ratio [HR]adj 1.61 [95% CI, 1.42-1.84]; P<0.0001) and major coronary events (11.5% versus 6.0%; HRadj, 1.72 [95% CI, 1.49-1.99]; P<0.0001). Relative risk reductions with evolocumab were similar in patients with and without prior PCI (MACE: HR, 0.84 [0.77-0.91] versus HR, 0.88 [0.77-1.01]; Pinteraction 0.51; major coronary events: HR, 0.82 [0.75-0.90] versus HR, 0.88 [0.75-1.04]; Pinteraction 0.42). Absolute risk reductions for MACE were 2.0% versus 0.9% (Pinteraction 0.14) and for major coronary events 2.0% versus 0.7% (Pinteraction 0.045). In those with prior PCI, the effect of evolocumab on coronary revascularization (HR, 0.76 [0.69-0.85]) was directionally consistent across types of revascularization procedures: coronary artery bypass grafting (HR, 0.71 [0.54-0.94]); any PCI (HR, 0.77 [0.69-0.86]); PCI for de novo lesions (HR, 0.76 [0.66-0.88]); and PCI for stent failure or graft lesions (HR, 0.76 [0.63-0.91]). CONCLUSIONS: Evolocumab reduces the risk of MACE in patients with prior PCI including the risk of coronary revascularization, with directionally consistent effects across several types of revascularization procedures, including coronary artery bypass grafting and PCI for stent or graft failure. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01764633.

Minimum 5-Year Outcomes of a Multicenter, Prospective, Randomized Control Trial Assessing Clinical and Radiological Outcomes of Patient-Specific Instrumentation in Total Knee Arthroplasty.

BACKGROUND: Patient-specific instrumentation (PSI) was developed to produce more accurate alignment of components and consequently improve clinical outcomes when used in total knee arthroplasty. We compare radiological accuracy and clinical outcomes at a minimum of 5-year follow-up between patients randomized to undergo total knee arthroplasty performed using PSI or traditional cutting block techniques. METHODS: This multicenter, randomized control trial included patients blinded to the technique 1used. Outcome measures were coronal alignment measured radiologically, Euroqol-5D, Oxford knee score, and International Knee Society Score measured at 1- and 5-year follow-up. RESULTS: At a minimum 5-year follow-up, there were 38 knees in the PSI group and 39 in the conventional instrumentation group for analysis. Baseline demographics and clinical outcome scores were matched between groups. Overall, there was no significant difference in the coronal femoral angle (P = .59), coronal tibial angle (P = .37), tibiofemoral angle (P = .99), sagittal femoral angle (P = .34), or the posterior tibia slope (P = .12) between knees implanted using PSI and those implanted with traditional cutting blocks. On the measurement of coronal alignment, intraobserver reliability tests demonstrated substantial agreement (k = 0.64). Clinical outcomes at both 1-year and 5-year follow-up demonstrated statistically significant and clinically relevant improvement in scores from baseline in both groups, but no difference could be detected between the Euroqol-5D (P = .78), Oxford knee score (P = .24), or International Knee Society Score (P = .86) between the 2 groups. CONCLUSION: This study has shown no additional benefit to PSI in terms of improved alignment or functional outcomes at minimum 5-year follow-up over traditional techniques.

Evolocumab in patients with homozygous familial hypercholesterolemia in India.

BACKGROUND: Evolocumab is a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 approved in India for treatment of homozygous familial hypercholesterolemia (HoFH) in patients aged ≥12 years. OBJECTIVE: RAMAN (NCT03403374) was a single-country, open-label, phase 4 study evaluating the safety and tolerability of evolocumab in patients with HoFH in India. METHODS: Patients ≥12 to ≤80 years of age on stable lipid-lowering therapy with fasting low-density lipoprotein cholesterol (LDL-C) >3.4 mmol/L (>130 mg/dL) received evolocumab 420 mg subcutaneously monthly (every 2 weeks if on apheresis). The primary endpoint was patient incidence of treatment-emergent adverse events. Secondary endpoints included percent changes at week 12 in LDL-C and other lipids. RESULTS: Of 30 enrolled patients, 13 were <18 years of age. Mean±SD baseline levels of LDL-C, apolipoprotein B, and lipoprotein(a) were 12.3 ± 3.5 mmol/L (473.5 ± 135.2 mg/dL), 2.8 ± 0.7 g/L (275.3 ± 69.1 mg/dL), and 201.3 ± 177.6 nmol/L, respectively. Ten patients (33%) reported treatment-emergent adverse events, with 2 (7%) serious adverse events and none leading to discontinuation; no deaths occurred during evolocumab treatment. At week 12, mean (SE) percent changes from baseline in LDL-C, apolipoprotein B, and lipoprotein(a) were -6.4% (4.2), -6.0% (3.7), and -0.2% (4.9), respectively. Reductions in LDL-C among individual patients were variable and greatest in patients ≥18 years of age and with baseline LDL-C <13 mmol/L (<500 mg/dL). CONCLUSIONS: Evolocumab was safe and well tolerated in patients with HoFH in India with smaller reductions in LDL-C and other lipids than those observed in previous studies with HoFH and different populations.

Multi-species occupancy modeling provides novel insights into amphibian metacommunity structure and wetland restoration.

A fundamental goal of community ecology is to understand species-habitat relationships and how they shape metacommunity structure. Recent advances in occupancy modeling enable habitat relationships to be assessed for both common and rare species within metacommunities using multi-species occupancy models (MSOM). These models account for imperfect species detection and offer considerable advantages over other analytical tools commonly used for community analyses under the elements of metacommunity structure (EMS) framework. Here, we demonstrate that MSOM can be used to infer habitat relationships and test metacommunity theory, using amphibians. Repeated frog surveys were undertaken at 55 wetland sites in southeastern Australia. We detected 11 frog species from three families (Limnodynastidae, Myobatrachidae, and Pelodryadidae). The rarest species was detected at only one site whereas the most common species was detected at 42 sites (naive occupancy rate 0.02-0.76). Two models were assessed representing two competing hypotheses; the best-supported model included the covariates distance to the nearest site (connectivity), wetland area, presence of the non-native eastern mosquitofish (Gambusia holbrooki), proportion cover of emergent vegetation, an interaction term between Gambusia and emergent vegetation cover, and the proportion canopy cover over a site. Hydroperiod played no detectable role in metacommunity structure. We found species-habitat relationships that fit with current metacommunity theory: occupancy increased with wetland area and connectivity. There was a strong negative relationship between occupancy and the presence of predatory Gambusia, and a positive interaction between Gambusia and emergent vegetation. The presence of canopy cover strongly increased occupancy for several tree frog species, highlighting the importance of terrestrial habitat for amphibian community structure. We demonstrated how responses by amphibians to environmental covariates at the species level can be linked to occupancy patterns at the metacommunity scale. Our results have clear management implications: wetland restoration projects for amphibians and likely other taxa should maximize wetland area and connectivity, establish partial canopy cover, and eradicate Gambusia or provide aquatic vegetation to mitigate the impact of this non-native fish. We strongly advocate the use of MSOM to elucidate the habitat drivers behind animal occupancy patterns and to derive unbiased occupancy estimates for monitoring programs.

Low-density lipoprotein cholesterol reduction and statin intensity in myocardial infarction patients and major adverse outcomes: a Swedish nationwide cohort study.

AIMS: Clinical trials have demonstrated that a reduction in low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular (CV) events. This has, however, not yet been shown in a real-world setting. We aimed to investigate the association between LDL-C changes and statin intensity with prognosis after a myocardial infarction (MI). METHODS AND RESULTS: Patients admitted with MI were followed for mortality and major CV events. Changes in LDL-C between the MI and a 6- to 10-week follow-up visit were analysed. The associations between quartiles of LDL-C change and statin intensity with outcomes were assessed using adjusted Cox regression analyses. A total of 40 607 patients were followed for a median of 3.78 years. The median change in LDL-C was a 1.20 mmol/L reduction. Patients with larger LDL-C reduction (1.85 mmol/L, 75th percentile) compared with a smaller reduction (0.36 mmol/L, 25th percentile) had lower hazard ratios (HR) for all outcomes (95% confidence interval): composite of CV mortality, MI, and ischaemic stroke 0.77 (0.70-0.84); all-cause mortality 0.71 (0.63-0.80); CV mortality 0.68 (0.57-0.81); MI 0.81 (0.73-0.91); ischaemic stroke 0.76 (0.62-0.93); heart failure hospitalization 0.73 (0.63-0.85), and coronary artery revascularization 0.86 (0.79-0.94). Patients with ≥50% LDL-C reduction using high-intensity statins at discharge had a lower incidence of all outcomes compared with those using a lower intensity statin. CONCLUSIONS: Larger early LDL-C reduction and more intensive statin therapy after MI were associated with a reduced hazard of all CV outcomes and all-cause mortality. This supports clinical trial data suggesting that earlier lowering of LDL-C after an MI confers the greatest benefit.

Review of total hip arthroplasty in patients younger than 30 years: mid- to long-term results.

BACKGROUND: Data on the outcome of THA in patients under the age of 30 years is sparse. There is a perceived reluctance to offer surgery to young patients on the basis of potential early failure of the implant. The aim of this study was to review clinical and radiological outcomes of THA in patients under the age of 30 years in a high-volume specialist arthroplasty unit. METHODS: A retrospective review of patients between 1989 and 2009 was undertaken. 95 patients (118 THAs) were identified but 17 patients were excluded for lack of clinical records or for follow-up under 5 years. Clinical records were reviewed for demographics, underlying pathology, details of operation and failures. Radiographs were reviewed for evidence of loosening and wear of the components. Functional assessment was carried out using the modified Hip disability and Osteoarthritis Outcome Score, Oxford Hip Score and EQ-5D-5L. RESULTS: Mean age was 25 (16-30) years and 65% patients were females. The most common underlying pathologies were development dysplasia of the hip (29%) and juvenile rheumatoid arthritis (25%). Mean follow-up was 12.6 (5-24) years, during which 19 patients (25%) were revised. The majority of the revisions were for aseptic loosening of the acetabular component. CONCLUSIONS: Surgeons are cautious when considering THA in very young patients despite the significant documented improvement in function and quality of life after THA. This study reports on the mid- to long-term results of THA which will be valuable when advising young patients on the prospects of revision surgery at the time of primary THA.

Effect of Evolocumab on Complex Coronary Disease Requiring Revascularization.

OBJECTIVES: This study sought to evaluate the ability of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab to reduce the risk of complex coronary atherosclerosis requiring revascularization. BACKGROUND: PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall. METHODS: FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was a randomized trial of the PCSK9 inhibitor evolocumab versus placebo in 27,564 patients with stable atherosclerotic cardiovascular disease on statin therapy followed for a median of 2.2 years. Clinical documentation of revascularization events was blindly reviewed to assess coronary anatomy and procedural characteristics. Complex revascularization was the composite of complex percutaneous coronary intervention (PCI) (as per previous analyses, ≥1 of: multivessel PCI, ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length >60 mm) or coronary artery bypass grafting surgery (CABG). RESULTS: In this study, 1,724 patients underwent coronary revascularization, including 1,482 who underwent PCI, 296 who underwent CABG, and 54 who underwent both. Complex revascularization was performed in 632 (37%) patients. Evolocumab reduced the risk of any coronary revascularization by 22% (hazard ratio [HR]: 0.78; 95% CI: 0.71 to 0.86; p < 0.001), simple PCI by 22% (HR: 0.78; 95% CI: 0.70 to 0.88; p < 0.001), complex PCI by 33% (HR: 0.67; 95% CI: 0.54 to 0.84; p < 0.001), CABG by 24% (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.019), and complex revascularization by 29% (HR: 0.71; 95% CI: 0.61 to 0.84; p < 0.001). The magnitude of the risk reduction with evolocumab in complex revascularization tended to increase over time (20%, 36%, and 41% risk reductions in the first, second, and beyond second years). CONCLUSIONS: Adding evolocumab to statin therapy significantly reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER); NCT01764633.).

Effect of denosumab on osteolytic lesion activity after total hip arthroplasty: a single-centre, randomised, double-blind, placebo-controlled, proof of concept trial.

BACKGROUND: Osteolysis causes recurrent pain and disability after total hip arthroplasty. We investigated the effect of the human monoclonal antibody denosumab on osteolytic lesion activity in patients undergoing revision total hip arthroplasty surgery to show the biological proof of concept for a non-surgical treatment for the disease. METHODS: We did a phase 2, randomised, double-blind, placebo-controlled, proof of concept superiority trial at Sheffield Teaching Hospitals, Sheffield, UK. Eligible patients aged 30 years or older and scheduled for revision surgery for symptomatic, radiographically confirmed osteolysis were randomly allocated (1:1) to subcutaneous denosumab (60 mg single-dose) or placebo by an independent pharmacist using a random number table. The primary outcome was the between-group difference in osteoclast number per mm of bone surface of biopsies taken from the osteolytic membrane-bone interface at surgery 8 weeks later, measured by quantitative histomorphometry in all patients who underwent revision surgery. Adverse events were analysed in all randomly assigned participants. This trial is registered with the EU Clinical Trials Register (EudraCT 2011-000541-20). FINDINGS: Between Dec 12, 2012, and June 24, 2018, 51 patients were assessed for eligibility, of whom 24 were randomly assigned to study treatment. Two patients had their revision surgery cancelled for unrelated reasons, leaving 22 patients (ten in the denosumab group) for analysis of the primary outcome. There were 83% fewer osteoclasts at the osteolysis membrane-bone interface in the denosumab versus the placebo group (median 0·05 per mm [IQR 0·11] vs 0·30 mm [0·40], p=0·011). No deaths or treatment-related serious adverse events occurred. Seven adverse events, including one severe adverse event, occurred in four (36%) of 11 patients in the denosumab group. In the placebo group ten adverse events, including three severe adverse events, occurred in five (38%) of 13 patients. INTERPRETATION: To our knowledge, this is the first clinical trial of an investigational drug for osteolysis that shows tissue-specific biological efficacy. These results justify the need for future trials that target earlier-stage disease to test for clinical efficacy in reducing the need for revision surgery. FUNDING: Amgen.

Evolocumab in Pediatric Heterozygous Familial Hypercholesterolemia.

BACKGROUND: Evolocumab, a fully human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9, is widely used in adult patients to lower low-density lipoprotein (LDL) cholesterol levels. Its effects in pediatric patients with heterozygous familial hypercholesterolemia are not known. METHODS: We conducted a 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia. Patients 10 to 17 years of age who had received stable lipid-lowering treatment for at least 4 weeks before screening and who had an LDL cholesterol level of 130 mg per deciliter (3.4 mmol per liter) or more and a triglyceride level of 400 mg per deciliter (4.5 mmol per liter) or less were randomly assigned in a 2:1 ratio to receive monthly subcutaneous injections of evolocumab (420 mg) or placebo. The primary end point was the percent change in LDL cholesterol level from baseline to week 24; key secondary end points were the mean percent change in LDL cholesterol level from baseline to weeks 22 and 24 and the absolute change in LDL cholesterol level from baseline to week 24. RESULTS: A total of 157 patients underwent randomization and received evolocumab (104 patients) or placebo (53 patients). At week 24, the mean percent change from baseline in LDL cholesterol level was -44.5% in the evolocumab group and -6.2% in the placebo group, for a difference of -38.3 percentage points (P<0.001). The absolute change in the LDL cholesterol level was -77.5 mg per deciliter (-2.0 mmol per liter) in the evolocumab group and -9.0 mg per deciliter (-0.2 mmol per liter) in the placebo group, for a difference of -68.6 mg per deciliter (-1.8 mmol per liter) (P<0.001). Results for all secondary lipid variables were significantly better with evolocumab than with placebo. The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups. CONCLUSIONS: In this trial involving pediatric patients with familial hypercholesterolemia, evolocumab reduced the LDL cholesterol level and other lipid variables. (Funded by Amgen; HAUSER-RCT ClinicalTrials.gov number, NCT02392559.).

Effects of evolocumab therapy and low LDL-C levels on vitamin E and steroid hormones in Chinese and global patients with type 2 diabetes.

AIMS: We assessed the change from baseline in vitamin E, steroid hormones, adrenocorticotropic hormone (ACTH), and gonadotropins, overall and by lowest achieved low-density lipoprotein-cholesterol (LDL-C) level, in patients with type 2 diabetes and dyslipidaemia after 12 weeks of treatment with evolocumab. MATERIALS AND METHODS: This was a prespecified analysis of vitamin E, cortisol, ACTH, gonadal hormones and gonadotropins in the 12-week, placebo-controlled BERSON trial of evolocumab in patients with type 2 diabetes and dyslipidaemia. In BERSON, 981 (451 in China) patients on daily atorvastatin 20 mg were randomized to placebo or one of two doses of evolocumab. We measured analyte levels at baseline and week 12 (vitamin E in all patients; steroid/gonadal hormones only in Chinese patients). RESULTS: In both the global and Chinese populations, absolute vitamin E levels decreased from baseline to week 12 by approximately 6 µmol/L (P < .0001) among evolocumab-treated patients; however, when normalized for LDL-C, apoB or non-HDL-C, we observed no decrease in vitamin E levels. In Chinese patients, levels of cortisol and ACTH as well as the cortisol:ACTH ratio did not change significantly from baseline to week 12. No patient had a cortisol:ACTH ratio <3.0 (nmol/pmol), suggestive of adrenocortical deficiency. We did not observe clinically relevant changes for gonadal hormones and gonadotropins (oestradiol and testosterone in female and male patients, respectively, luteinizing and follicle-stimulating hormones for both). CONCLUSIONS: In the BERSON study, evolocumab did not adversely affect vitamin E, steroid hormone or gonadotropin levels in the Chinese or global type 2 diabetic populations.ClinicalTrials.gov NCT02662569.

Long-Term Evolocumab in Patients With Familial Hypercholesterolemia.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitor therapy is a treatment option for patients with familial hypercholesterolemia (FH) who are unable to reach low-density lipoprotein cholesterol (LDL-C) goals. OBJECTIVES: The aim of this study was to provide long-term safety and efficacy data for evolocumab in patients with homozygous FH (HoFH) and severe heterozygous FH (HeFH). METHODS: In this open-label, single-arm study, patients with HoFH or severe HeFH ≥12 years of age and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint was the incidence of treatment-emergent adverse events; secondary endpoints were changes in LDL-C and other lipids. RESULTS: In total, 300 patients (106 with HoFH, including 14 <18 years of age at enrollment) received evolocumab for a median of 4.1 years. Adverse events occurred in 89.3% of patients, the most common of which were nasopharyngitis, influenza, upper respiratory tract infection, and headache. Mean change in LDL-C from baseline to week 12 was -21.2% (-59.8 mg/dl) in patients with HoFH and -54.9% (-104.4 mg/dl) in those with severe HeFH and was sustained over time. Of 48 patients with HoFH who were up-titrated, mean change in LDL-C improved from -19.6% at week 12 to -29.7% after 12 weeks of 420 mg every 2 weeks. The adjudicated cardiovascular event rate was 2.7% per year. Of 61 patients receiving apheresis at enrollment, 16 discontinued apheresis. CONCLUSIONS: Evolocumab was well tolerated and effectively reduced plasma LDL-C levels in patients with HoFH and severe HeFH over a median of 4.1 years.

Long-Term Efficacy and Safety of Evolocumab in Patients With Hypercholesterolemia.

BACKGROUND: Evolocumab and other anti-PCSK9 antibodies reduced adverse cardiovascular outcomes in clinical trials of high-risk patients over <3 years median treatment duration. OBJECTIVES: The OSLER-1 trial (Open Label Study of Long Term Evaluation Against LDL-C Trial) evaluated longer-term effects of evolocumab during open-label hypercholesterolemia treatment for up to 5 years. METHODS: Patients randomized to standard of care (SOC) or evolocumab 420 mg monthly (evolocumab + SOC) for year 1. After year 1, patients could enter the all-evolocumab period and receive evolocumab + SOC for an additional 4 years. The authors analyzed the persistence of lipid effects and exposure-dependent safety focusing on yearly rates of adverse events (AEs) and anti-drug antibodies over 4.951 patient-years of observation. RESULTS: A total of 1,255 patients (safety analysis population) randomized into the year 1 SOC-controlled period and received ≥1 evolocumab dose (mean ± SD age 57 ± 12 years; 53% female). A total of 1,151 patients (efficacy analysis population) progressed to the all-evolocumab period (year 2 and beyond). Evolocumab + SOC persistently lowered mean ± SE low-density lipoprotein cholesterol (LDL-C) by 56% ± 0.6% (n = 1,071), 57% ± 0.8% (n = 1,001), 56% ± 0.8% (n = 943), and 56% ± 0.8% (n = 803) after approximately 2, 3, 4, and 5 years, respectively, from randomization. Mean baseline LDL-C decreased from 140 to 61 mg/dl on treatment. Yearly serious AE rates during evolocumab + SOC ranged from 6.9% to 7.9%, comparable to the 6.8% rate in SOC patients during year 1. Evolocumab discontinuation due to AEs occurred in 5.7% of patients. Two SOC and 2 evolocumab + SOC patients developed new, transient, binding anti-drug antibodies; no neutralizing antibodies were observed. CONCLUSIONS: The OSLER-1 trial demonstrated consistently excellent LDL-C-lowering efficacy, tolerance, and safety of evolocumab, with no neutralizing antibodies detected, throughout the longest-duration study of a PCSK9 inhibitor reported to date. (Open Label Study of Long Term Evaluation Against LDL-C Trial [OSLER-1]; NCT01439880).