Greater Absolute Reduction Research Articles

Aspirin Use and Incidence of Colorectal Cancer According to Lifestyle Risk

Aspirin reduces the risk of colorectal cancer (CRC). Identifying individuals more likely to benefit from regular aspirin use for CRC prevention is a high priority. To assess whether aspirin use is associated with the risk of CRC across different lifestyle risk factors. A prospective cohort study among women in the Nurses' Health Study (1980-2018) and men in the Health Professionals Follow-Up Study (1986-2018) was conducted. Data analysis was performed from October 1, 2021, to May 22, 2023. A healthy lifestyle score was calculated based on body mass index, alcohol intake, physical activity, diet, and smoking with scores ranging from 0 to 5 (higher values corresponding to a healthier lifestyle). Regular aspirin use was defined as 2 or more standard tablets (325 mg) per week. Outcomes included multivariable-adjusted 10-year cumulative incidence of CRC, absolute risk reduction (ARR), and number needed to treat associated with regular aspirin use by lifestyle score and multivariable-adjusted hazard ratios for incident CRC across lifestyle scores. The mean (SD) baseline age of the 107 655 study participants (63 957 women from the Nurses' Health Study and 43 698 men from the Health Professionals Follow-Up Study) was 49.4 (9.0) years. During 3 038 215 person-years of follow-up, 2544 incident cases of CRC were documented. The 10-year cumulative CRC incidence was 1.98% (95% CI, 1.44%-2.51%) among participants who regularly used aspirin compared with 2.95% (95% CI, 2.31%-3.58%) among those who did not use aspirin, corresponding to an ARR of 0.97%. The ARR associated with aspirin use was greatest among those with the unhealthiest lifestyle scores and progressively decreased with healthier lifestyle scores (P < .001 for additive interaction). The 10-year ARR for lifestyle scores 0 to 1 (unhealthiest) was 1.28%. In contrast, the 10-year ARR for lifestyle scores 4 to 5 (healthiest) was 0.11%. The 10-year number needed to treat with aspirin was 78 for participants with lifestyle scores 0 to 1, 164 for score 2, 154 for score 3, and 909 for scores 4 to 5. Among the components of the healthy lifestyle score, the greatest differences in ARR associated with aspirin use were observed for body mass index and smoking. In this cohort study, aspirin use was associated with a greater absolute reduction in risk of CRC among individuals with less healthy lifestyles. The findings of the study suggest that lifestyle risk factors may be useful to identify individuals who may have a more favorable risk-benefit profile for cancer prevention with aspirin.

Antithrombotic Strategies According to Age: Insights from the AUGUSTUS Trial

ObjectiveWe aimed to evaluate the safety and efficacy of antithrombotic strategies by age in patients with atrial fibrillation and acute coronary syndrome and/or percutaneous coronary intervention in AUGUSTUS. MethodsPatients were stratified into 3 age groups: <65, 65-74, and ≥75 years. Outcomes of interest were major or clinically relevant non-major bleeding, major bleeding, death or rehospitalization, and ischemic events. Treatment effects of apixaban vs. vitamin K antagonist (VKA) and aspirin vs. placebo were assessed across age groups using Cox models. ResultsOf 4614 patients, 1267 (27.5%) were <65, 1802 (39.0%) were 65-74, and 1545 (33.5%) were ≥75 years. Apixaban was associated with lower rates of major or clinically relevant non-major bleeding than VKA (<65: HR 0.69 [0.47-1.00]; 65-74: HR 0.57 [0.43-0.75]; ≥75: HR 0.81 [0.63-1.04]). Death or hospitalization occurred less often with apixaban, regardless of age. No differences were observed in rates of ischemic events between apixaban and VKA according to age. Aspirin was associated with higher rates of bleeding than placebo (<65: HR 1.67 [1.15-2.43]; 65-74: HR 2.32 [1.73-3.10]; ≥75: HR 1.69 [1.31-2.19]). Rates of death or rehospitalization and ischemic events were similar among patients receiving aspirin or placebo across age groups. ConclusionsApixaban was associated with greater absolute reduction in bleeding than VKA in older age groups, reflecting their higher hemorrhagic risk. Aspirin increased bleeding in all age groups vs. placebo. Our findings support the use of apixaban plus a purinergic receptor P2Y12(P2Y12) inhibitor without aspirin in patients with atrial fibrillation and recent acute coronary syndrome/percutaneous coronary intervention, regardless of age.

A targeted educational intervention increases oral anticoagulation rates in high-risk atrial fibrillation patients

BackgroundAnticoagulation is the cornerstone of atrial fibrillation (AF) management for stroke prevention. Recently, we showed that AF patients’ oral anticoagulation (OAC) rates in a large US multispecialty health system are above 80%. ObjectiveThis study sought to improve OAC rates in AF patients via an educational intervention targeted to primary care providers with low OAC rates. MethodsPrimary care clinicians were stratified by proportions of their AF patients at elevated stroke risk not on anticoagulation medication. Clinicians with the lowest rates of anticoagulation were assigned to a target group receiving an educational program consisting of e-mail messaging summarizing anticoagulation guidelines. All other clinicians were assigned to a comparison group. Data from a six-month lead-in phase were compared with a six-month follow-up period to determine if the proportion of AF patients treated with OACs had changed. ResultsThere were 141 primary care clinicians with patients who met the inclusion criteria, with 36 (25.53%) assigned to the educational intervention (EG) and 105 (74.47%) assigned to the comparison group (CG). At baseline there was a significant difference in percent of high-risk AF patients who were untreated in the EG (20.65%) as compared to the high-risk patients who were untreated in the CG (13.64%, p=0.001). After the educational intervention, high-risk AF patients without anticoagulation decreased in both EG (15.47% p=0.047) and CG (10.14% p=0.07) with greater absolute reduction in the EG (5.19% versus 3.50%). ConclusionA targeted education program was associated with increased anticoagulation rates for AF patients at high risk of stroke.

Seasonal use case for the RTS,S/AS01 malaria vaccine: a mathematical modelling study

A 2021 clinical trial of seasonal RTS,S/AS01E (RTS,S) vaccination showed that vaccination was non-inferior to seasonal malaria chemoprevention (SMC) in preventing clinical malaria. The combination of these two interventions provided significant additional protection against clinical and severe malaria outcomes. Projections of the effect of this novel approach to RTS,S vaccination in seasonal transmission settings for extended timeframes and across a range of epidemiological settings are needed to inform policy recommendations. We used a mathematical, individual-based model of malaria transmission that was fitted to data on the relationship between entomological inoculation rate and parasite prevalence, clinical disease, severe disease, and deaths from multiple sites across Africa. The model was validated with results from a phase 3b trial assessing the effect of SV-RTS,S in Mali and Burkina Faso. We developed three intervention efficacy models with varying degrees and durations of protection for our population-level modelling analysis to assess the potential effect of an RTS,S vaccination schedule based on age (doses were delivered to children aged 6 months, 7·5 months, and 9 months for the first three doses, and at 27 months of age for the fourth dose) or season (children aged 5-17 months at the time of first vaccination received the first three doses in the 3 months preceding the transmission season, with any subsequent doses up to five doses delivered annually) in seasonal transmission settings both in the absence and presence of SMC with sulfadoxine-pyrimethamine plus amodiaquine. This is modelled as a full therapeutic course delivered every month for four or five months of the peak in transmission season. Estimates of cases and deaths averted in a population of 100 000 children aged 0-5 years were calculated over a 15-year time period for a range of levels of malaria transmission intensity (Plasmodium falciparum parasite prevalence in children aged 2-10 years between 10% and 65%) and over two west Africa seasonality archetypes. Seasonally targeting RTS,S resulted in greater absolute reductions in malaria cases and deaths compared with an age-based strategy, averting an additional 14 000-47 000 cases per 100 000 children aged 5 years and younger over 15 years, dependent on seasonality and transmission intensity. We predicted that adding seasonally targeted RTS,S to SMC would reduce clinical incidence by up to an additional 42 000-67 000 cases per 100 000 children aged 5 years and younger over 15 years compared with SMC alone. Transmission season duration was a key determinant of intervention effect, with the advantage of adding RTS,S to SMC predicted to be smaller with shorter transmission seasons. RTS,S vaccination in seasonal settings could be a valuable additional tool to existing interventions, with seasonal delivery maximising the effect relative to an age-based approach. Decisions surrounding deployment strategies of RTS,S in such settings will need to consider the local and regional variations in seasonality, current rates of other interventions, and potential achievable RTS,S coverage. UK Medical Research Council, UK Foreign Commonwealth & Development Office, The Wellcome Trust, and The Royal society.

Corticosteroid-binding Globulin (SERPINA6) Establishes Postpubertal Sex Differences in Rat Adrenal Development.

Encoded by SerpinA6, plasma corticosteroid-binding globulin (CBG) transports glucocorticoids and regulates their access to cells. We determined how CBG influences plasma corticosterone and adrenal development in rats during the pubertal to adult transition using CRISPR/cas9 to disrupt SerpinA6 gene expression. In the absence of CBG, total plasma corticosterone levels were ∼80% lower in adult rats of both sexes, with a greater absolute reduction in females than in males. Notably, free corticosterone and adrenocorticotropic hormone were comparable between all groups. Between 30 and 90 days of age, wild-type female rats showed increases in adrenal weight and the size of the corticosterone-producing region, the zona fasciculata (zf), in tandem with increases in plasma CBG and corticosterone concentrations, whereas no such changes were observed in males. This sex difference was lost in rats without CBG, such that adrenal growth and zf expansion were similar between sexes. The sex-specific effects of CBG on adrenal morphology were accompanied by remarkable changes in gene expression: ∼40% of the adrenal transcriptome was altered in females lacking CBG, whereas almost no effect was seen in males. Over half of the adrenal genes that normally exhibit sexually dimorphic expression after puberty were similarly expressed in males and females without CBG, including those responsible for cholesterol biosynthesis and mobilization, steroidogenesis, and growth. Rat adrenal SerpinA6 transcript levels were very low or undetectable. Thus, sex differences in adrenal growth, morphology and gene expression profiles that emerge during puberty in rats are dependent on concomitant increases in plasma CBG produced by the liver.

Age at Initiation of Lower Gastrointestinal Endoscopy and Colorectal Cancer Risk Among US Women

In the past 4 years, the American Cancer Society and the US Preventive Services Task Force updated recommendations to initiate colorectal cancer (CRC) screening at 45 years of age to address the increasing incidence of CRC among adults younger than 50 years. However, empirical evidence evaluating the potential benefits of screening in younger populations is scant. To examine the association between endoscopy initiation at different ages and risk of CRC among US women. This prospective cohort study used data from the Nurses' Health Study II, which included US female health professionals followed up from 1991 through 2017. Data analysis was performed from August 2020 to June 2021. Age at initiation of sigmoidoscopy or colonoscopy for screening (routine screening or because of family history) or symptoms. Incident CRC, confirmed by medical records, pathology reports, and the National Death Index. Cumulative incidence of CRC in each group was estimated with age as the time scale, and the absolute risk reduction associated with endoscopy initiation at different ages through 60 years was calculated. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% CIs, stratified by age and calendar year of questionnaire cycle and adjusted for CRC risk factors in the multivariable models. Among 111 801 women aged 26 to 46 years (median, 36 years) at enrollment, 519 incident CRC cases were documented over 26 years, encompassing 2 509 358 person-years of follow-up. In the multivariable analysis, compared with no endoscopy, undergoing endoscopy was associated with a significantly lower risk of incident CRC for age at initiation before 45 years (HR, 0.37; 95% CI, 0.26-0.53), 45 to 49 years (HR, 0.43; 95% CI, 0.29-0.62), 50 to 54 years (HR, 0.47; 95% CI, 0.35-0.62), and 55 years or older (HR, 0.46; 95% CI, 0.30-0.69). The absolute reduction in the estimated cumulative incidence of CRC through 60 years of age was 72 per 100 000 persons for initiation of endoscopy at 45 to 49 years of age vs 50 to 54 years of age. Compared with no endoscopy, initiation of endoscopy before 50 years of age was also associated with a reduced risk of CRC diagnosed before 55 years of age (<45 years: HR, 0.45 [95% CI, 0.29-0.70]; 45-49 years: HR, 0.43 [95% CI, 0.24-0.76]). In this cohort study, compared with no endoscopy, initiation of endoscopy before 50 years of age was associated with a reduced risk of CRC, including CRC diagnosed before 55 years of age. Screening before 50 years of age was associated with greater absolute reduction in CRC risk compared with initiation of CRC screening at 50 years of age or later.

Non-fasting Changes in Blood Lipids After Three Daily Meals Within a Day in Chinese Inpatients With Cardiovascular Diseases.

BackgroundNon-fasting (i.e., postprandial) lipid detection is recommended in clinical practice. However, the change in blood lipids in Chinese patients with cardiovascular diseases after three daily meals has never been reported yet.MethodsSerum levels of blood lipids were measured or calculated in 77 inpatients (48 men and 29 women) at high or very high risk of atherosclerotic cardiovascular disease (ASCVD) in the fasting state and at 4 h after three meals within a day according to their diet habits.ResultsFemale patients showed significantly higher level of high-density lipoprotein cholesterol (HDL-C) than male patients, and the gender difference in other lipid parameters did not reach statistical significance at any time-point. Levels of triglyceride (TG) and remnant cholesterol (RC) increased, while that of low-density lipoprotein cholesterol (LDL-C) decreased significantly after three meals (p < 0.05). Levels of HDL-C, total cholesterol (TC), and non-high-density lipoprotein cholesterol (non-HDL-C) showed smaller changes after three meals. Percent reductions in the non-fasting LDL-C levels after lunch and supper were around 20%, which were greater than that after breakfast. The percent reductions in the non-fasting non-HDL-C levels after three meals were smaller than those in the non-fasting LDL-C levels. Patients with TG level ≥ 2.0 mmol/L (177 mg/dL) after lunch had significantly greater absolute reduction of LDL-C level than those with TG level < 2.0 mmol/L (177 mg/dL) after lunch [–0.69 mmol/L (–27 mg/dL) vs. –0.36 mmol/L (–14 mg/dL), p<0.01]. There was a significant and negative correlation between absolute change in LDL-C level and that in TG level (r = −0.32) or RC level (r = −0.67) after lunch (both p<0.01).ConclusionLDL-C level decreased significantly after three daily meals in Chinese patients at high or very high risk of ASCVD, especially when TG level reached its peak after lunch. Relatively, non-HDL-C level was more stable than LDL-C level postprandially. Therefore, when LDL-C level was measured in the non-fasting state, non-HDL-C level could be evaluated simultaneously to reduce the interference of related factors, such as postprandial hypertriglyceridemia, on detection.

Outcomes With Intermediate Left Main Disease: Analysis From the ISCHEMIA Trial.

Patients with significant (≥50%) left main disease (LMD) have a high risk of cardiovascular events, and guidelines recommend revascularization to improve survival. However, the impact of intermediate LMD (stenosis, 25%-49%) on outcomes is unclear. Randomized ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) participants who underwent coronary computed tomography angiography at baseline were categorized into those with (25%-49%) and without (<25%) intermediate LMD. The primary outcome was a composite of cardiovascular mortality, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. The primary quality of life outcome was the Seattle Angina Questionnaire summary score. Among the 3699 participants who satisfied the inclusion criteria, 962 (26%) had intermediate LMD. Among invasive strategy participants with intermediate LMD on coronary computed tomography angiography, 49 (7.0%) had significant (≥50% stenosis) left main stenosis on invasive angiography. Patients with intermediate LMD had a higher risk of cardiovascular events in the unadjusted but not in the fully adjusted model compared with those without intermediate LMD. An invasive strategy increased procedural MI and decreased nonprocedural MI with no significant difference for other outcomes including the primary end point. There was no meaningful heterogeneity of treatment effect based on intermediate LMD status except for nonprocedural MI for which there was a greater absolute reduction with invasive management in the intermediate LMD group (-6.4% versus -2.0%; Pinteraction=0.049). The invasive strategy improved angina-related quality of life and the benefit was durable throughout follow-up without significant heterogeneity based on intermediate LMD status. In the ISCHEMIA trial, there was no meaningful heterogeneity of treatment benefit from an invasive strategy regardless of intermediate LMD status except for a greater absolute risk reduction in nonprocedural MI with invasive management in those with intermediate LMD. An invasive strategy increased procedural MI, reduced nonprocedural MI, and improved angina-related quality of life. URL: https://www. gov; Unique identifier: NCT01471522.

A Matched Comparison of Long-Term Outcomes of Total and Unicompartmental Knee Replacements in Different Ages Based on National Databases: Analysis of Data From the National Joint Registry for England, Wales, Northern Ireland, and the Isle of Man.

The 2 main treatment options for end-stage single compartment knee arthritis are unicompartmental (UKR) or total knee replacement (TKR). We compared the long-term outcomes in different age groups. In total, 54,215 UKRs and 54,215 TKRs from the National Joint Registry and Hospital Episode Statistics database were propensity score matched and Kaplan-Meier and regression analysis used to compare revision, reoperation, mortality, and 3-month complications. UKR had higher 10-year revision rates (12% vs 5%, hazard ratio [HR] 2.31, P < .001) and 10-year reoperation rates (25% vs 21%, HR 1.12, P < .001). UKR had lower 10-year mortality rates (13.6% vs 15.5%, HR 0.86, P < .001). UKR had lower rates of medical (P < .001) and procedure related (P < .001) complications and deaths (HR 0.61, P= .02). If 100 patients had a UKR instead of a TKR then over 10 years, if they were <55 years old there would be 7 more reoperations and 1 less death; if they were 55-64 years old there would be 6 more reoperations and 2 more deaths; if they were 65-74 years old there would be 4 more reoperations and 2 less deaths; and if they were ≥75 years old there would be 3 more reoperations and 4 less deaths. UKR has higher revision and slightly higher reoperation rates but lower mortality rates than matched TKR. The decision to do a UKR should, in part, be based on the balance of these risks, which are influenced by patient age. In the elderly group (>75 years) the data suggests that UKR compared to TKR has a greater absolute reduction in mortality than the increase in reoperation rate. III.

Abstract 12512: Antithrombotic Strategies According to Age in Patients With Atrial Fibrillation and a Recent Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights From the Augustus Trial

Background: In AUGUSTUS, apixaban led to lower rates of bleeding and hospitalization than VKA, and aspirin caused more bleeding than placebo, in patients with AF and ACS and/or PCI treated with a P2Y12 inhibitor. We evaluated the safety and efficacy of different antithrombotic strategies by age in this population. Methods: Patients were stratified into 3 age groups: &lt;65, 65-74, and ≥75 years. Outcomes of interest were adjudicated ISTH major or clinically relevant nonmajor (CRNM) bleeding, ISTH major bleeding, death or rehospitalization, and death or ischemic events. The treatment effects of apixaban vs. VKA and aspirin vs. placebo were assessed across age categories using Cox models. Results: Of 4614 patients, 1267 (27.5%) were &lt;65, 1802 (39.0%) were 65-74, and 1545 (33.5%) were ≥75 years. All events, including bleeding, rehospitalization, and ischemic events, were more common with older age. Compared with VKA, apixaban was associated with lower rates of ISTH major or CRNM bleeding, ISTH major bleeding, and death or hospitalization, regardless of age (Fig). Apixaban was associated with greater absolute reduction in ISTH major bleeding than VKA in the older age groups, reflecting the higher bleeding risk in these groups. No differences were observed in rates of death or ischemic events between apixaban and VKA according to age. Patients who received aspirin had higher rates of bleeding than those receiving placebo in all age groups. Rates of death or rehospitalization and death or ischemic events were similar among patients receiving aspirin or placebo in different age categories. Conclusions: The safety and efficacy of apixaban compared with VKA was consistent with the overall trial findings, irrespective of age. Aspirin compared with placebo increased ISTH major or CRNM bleeding in all age groups. Our findings support the use of apixaban plus a P2Y12 inhibitor without aspirin as the standard therapy for this patient population, regardless of age. Figure: Outcomes by Age

Gender disparities in access to care for time-sensitive conditions during COVID-19 pandemic in Chile

BackgroundDuring the COVID-19 pandemic, reductions in healthcare utilization are reported in different contexts. Nevertheless, studies have not explored specifically gender disparities in access to healthcare in the context of COVID-19.MethodsTo evaluate gender disparities in access to medical in Chile we conducted an interrupted time series analysis using segmented regression. The outcome variable was the number of weekly confirmed cases of a set of oncologic and cardiovascular time-sensitive conditions at a national level. The series contained data from weeks 1 to 39 for 2017 to 2020. The intervention period started at week 12. We selected this period because preventive interventions, such as school closures or teleworking, were implemented at this point. We estimated the level effect using a dummy variable indicating the intervention period and slope effect using a continuous variable from weeks 12 to 39. To test heterogeneity by gender and age group, we conducted a stratified analysis.ResultsWe observed a sizable reduction in access to care with a slowly recovery for oncologic (level effect 0.323; 95% CI 0.291–0.359; slope effect 1.022; 95% CI 1.016–1.028) and cardiovascular diseases (level effect 0.586; 95% CI 0.564–0.609; slope effect 1.009; 95% CI 1.007–1.011). Greater reduction occurred in women compared to men, particularly marked on myocardial infarction (level effect 0.595; 95% CI 0.566–0.627 versus 0.532; 95% CI 0.502–0.564) and colorectal cancer (level effect 0.295; 95% CI 0.248–0.35 versus 0.19; 95% CI 0.159–0.228). Compared to men, a greater absolute reduction was observed in women for oncologic diseases, excluding sex-specific cancer, (1352; 95% CI 743–1961) and cardiovascular diseases (1268; 95% CI 946–1590).ConclusionWe confirmed a large drop in new diagnoses for time-sensitive conditions during the COVID-19 pandemic in Chile. This reduction was greater for women. Our findings should alert policy-makers about the urgent need to integrate a gender perspective into the pandemic response.

A real-world assessment of treatment patterns in patients with atherosclerotic cardiovascular disease with hypercholesterolemia: a retrospective database analysis in Germany

Abstract Background The European Society of Cardiology (ESC) guidelines suggest that greater absolute reduction in low-density lipoprotein cholesterol (LDL-C) leads to greater cardiovascular risk reduction. Several lipid-lowering treatments (LLTs) are available in Germany; however, the research on treatment patterns and LDL-C outcomes among patients (pts) receiving LLTs in real-world setting is limited. Purpose To characterize the pts characteristics, treatment patterns and LDL-C outcomes of pts with atherosclerotic cardiovascular disease (ASCVD) with hypercholesterolemia (ASCVD-H) in Germany. Methods This is a descriptive, non-interventional, retrospective cohort study of ASCVD-H pts identified from general physician (GP) practices available in the electronic medical record (EMR) database Disease Analyzer (January 1992-June 2020) in Germany. ASCVD-H pts were included if they had a recorded diagnosis, were prescribed LLTs or had LDL-C levels of ≥55 mg/dL anytime within 6 months before and 3 months after the index date (ID), as per the data recorded by the participating physician. The first encounter of ASCVD after hypercholesterolemia during the identification period (1/07/2015–30/06/2019) was considered as the ID. Persistence was measured as the duration (in days) with allowed gap of 60 days and adherence as proportion of days covered (PDC) within 12 and 24 months after ID. Results We included 147,905 pts with ASCVD-H (57.2% male; mean age: 70.6 yrs; ≥75 yrs-old: 43.3%; mean BMI: 29.0 kg/m2). Coronary artery disease was the most common index diagnosis (73.2%), followed by cerebrovascular disease (31.7%) and peripheral vascular disease (21.5%). Hypertension (83.5%) and diabetes (27.6%) were the most common comorbidities among these pts. At ID, statin monotherapy (58.6%) was the most commonly prescribed LLT, with simvastatin being the most common drug (36.4%). The use of PCSK9 inhibitors, ezetimibe and fibrates was very limited (&amp;lt;1%; Table 1). Of note, LDL-C measurements (6 months prior and 3 months post index) were available for 50.7% of pts. In pts with uncontrolled LDL-C (≥55 mg/dL), 47.9% were receiving statin monotherapy (28.6% were on simvastatin), whereas there was no LLT prescribed in 48.0% of pts. The mean (SD) persistence and adherence to statins monotherapy within 24 months follow-up was 522 (260) days and 0.721 (0.345), respectively, with 60% of pts being adherent (PDC ≥0.80) to statins monotherapy. Conclusions Pts with ASCVD-H in Germany treated by GPs are elderly pts with multiple cardiovascular comorbidities. LDL-C was measured in nearly half of the pts, and almost all had LDL-C ≥55 mg/dL at ID. Findings indicate low prescription of LLTs in GP setting, particularly non-statin LLTs. The mean adherence (PDC) to statin monotherapy was 72% within the 24-month after ID. Data suggest the need for newer therapies with potential to control LDL-C levels. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis Pharma AG, Basel, Switzerland.

Common Statin Intolerance Variants in ABCB1 and LILRB5 Show Synergistic Effects on Statin Response: An Observational Study Using Electronic Health Records.

Background: Statin intolerance impacts approximately 10% of statin users, with side effects ranging from mild myalgia to extreme intolerance resulting in myopathy and rhabdomyolysis. Statin intolerance results in poor adherence to therapy and can impact statin efficacy. Many genetic variants are associated with statin intolerance. The effect of these variants on statin efficacy has not been systematically explored.Methods: Using longitudinal electronic health records and genetic biobank data from Tayside, Scotland, we examined the effect of seven genetic variants with previously reported associations with simvastatin or atorvastatin intolerance on the outcome of statin response. Statin response was measured by the reduction achieved when comparing pre- and post-statin non-high-density lipoprotein-cholesterol (non-HDL-C). Post-treatment statin response was limited to non-HDL-C measured within 6months of therapy initiation. Univariate and multivariable linear regression models were used to assess the main and adjusted effect of the variants on statin efficacy.Results: Around 9,401 statin users met study inclusion criteria, of whom 8,843 were first prescribed simvastatin or atorvastatin. The average difference in post-treatment compared to pre-treatment non-HDL-cholesterol was 1.45 (±1.04) mmol/L. In adjusted analyses, only two variants, one in the gene ATP-binding cassette transporter B1 (ABCB1; rs1045642), and one in leukocyte immunoglobulin like receptor B5 (LILRB5; rs12975366), were associated with statin efficacy. In ABCB1, homozygous carriers of the C allele at rs1045642 had 0.06mmol/L better absolute reduction in non-HDL-cholesterol than carriers of the T allele (95% CI: 0.01, 0.1). In LILRB5 (rs12975366), carriers of the C allele had 0.04mmol/L better absolute reduction compared to those homozygous for the T allele (95% CI: 0.004, 0.08). When combined into a two-variant risk score, individuals with both the rs1045642-CC genotype and the rs12975366-TC or CC genotype had a 0.11mmol/L greater absolute reduction in non-HDL-cholesterol compared to those with rs1045642-TC or TT genotype and the rs12975366-TT genotype (95% CI: 0.05, 0.16; p<0.001).Conclusion: We report two genetic variants for statin adverse drug reactions (ADRs) that are associated with statin efficacy. While the ABCB1 variant has been shown to have an association with statin pharmacokinetics, no similar evidence for LILRB5 has been reported. These findings highlight the value of genetic testing to deliver precision therapeutics to statin users.

European trends in cervical cancer mortality in relation to national screening programs, 1985–2014

BackgroundCervical cancer is the fourth leading oncological cause of death in women. Variable trends in cervical cancer mortality have been observed across Europe, despite the widespread adoption of screening programs. This variability has previously been attributed to heterogeneity in the quality of screening programs. MethodsAge-standardized cervical cancer death rates for European countries between 1985 and 2014 were analyzed using Joinpoint regression. Countries were dichotomized based on year of implementation and population invitational coverage of national population-based cervical cancer screening programs. National cervical cancer mortality trends during the study period were compared based on this classification. ResultsDecreasing trends in mortality were observed in all European countries with the specific exceptions of Bulgaria, Greece and Latvia. The highest rates of cervical cancer mortality throughout the study period were in Romania (16.0-14.9/100,000) and the lowest rates in Italy (1.4-1.2/100,000). The greatest percentage decline in mortality was observed in the United Kingdom and the greatest absolute reduction in mortality was seen in Hungary. European countries which implemented a national population-based cervical cancer screening program prior to 2009 demonstrated greater improvements in cervical cancer mortality outcomes compared to those that did not (p = 0.016). ConclusionCervical cancer mortality is improving in most European countries; however, substantial variation remains. Trends in mortality were associated with the time of implementation of national population-based cervical screening programs.

Abstract 068: Hypertension And Longitudinal Changes In Cardiac Structure And Function In The Hispanic Community Health Study/Study Of Latinos: Echocardiographic Study Of Latinos (Echo-SOL) Ancillary Study

Introduction: Hypertension, one of the most modifiable risk factors of heart disease, induces cardiac remodeling and worsens myocardial function prior to the development of clinical symptoms. Using a comprehensive cohort of Hispanic/Latino adults, we assessed cardiac structure and function, in relation to hypertension, and the longitudinal impact of blood pressure control. Hypothesis: If baseline hypertensive adults are stratified by longitudinal blood pressure (BP) control, there will be differences in the progression of cardiac structure and function parameters. Methods: The Echo-SOL Ancillary Study provided serial comprehensive echocardiographic assessments of Hispanic adults aged 45-74 years. They were arranged into two groups based on the presence of baseline hypertension (&gt;140/90mmHg). Linear regression models were used to estimate the association between baseline BP properties and the longitudinal change in echocardiogram parameters. We then subdivided each group based on whether the they maintained BP control (&lt;140/90mmHg) on follow up and used linear regression models to test for significance among the mean longitudinal change of echocardiogram parameters. All analyses accounted for the complex sampling design of HCHS/SOL and Echo-SOL. Results: There was a total of 1818 adults at baseline, with 1643 obtaining serial echocardiograms an average of 4.3 years later, mean age of approximately 56 years. Among all adults, baseline pulse pressure was significantly associated with a longitudinal increase in left ventricular (LV) end diastolic volume (β=0.13, p=0.02), whereas the change in LV mass index longitudinally decreased with baseline diastolic BP (β=-0.14, p&lt;0.01). When isolating the subgroup defined as hypertensive at baseline, the adults who had uncontrolled BP on follow up had a greater absolute increase in the average E/E’ ratio and greater decrease in average E’ velocity, 0.95±0.08 and -0.96±0.06 respectively, compared to the adults with controlled BP 0.04±0.07 and -0.74± 0.04 respectively (p&lt;0.01). In addition, the controlled BP group had a greater absolute reduction in LV end-diastolic volume of 6.94mL than those with uncontrolled BP, 4.60mL (p&lt;0.01). Conclusions: Our study is the first to study the association of longitudinal impact of blood pressure control with cardiac structure and function in Hispanic/Latino adults. We found that higher baseline brachial BP properties were associated with reduced in LV mass index and increased LV end diastolic volumes. Among the baseline hypertensive adults, there was a significantly higher progression in diastolic dysfunction among the participants who had poor BP control, but those with controlled BP on follow up had greater LV enlargement. Despite these differences, both subgroups ultimately showed a collective progression in diastolic dysfunction and a decrease in end-diastolic volume over time.

Effects of a single-entry intake system on access to outpatient visits to specialist physicians and allied health professionals: a systematic review.

Background:Canada lags behind other countries with respect to wait times for specialist physician and allied health professional consultations. We conducted a systematic review to assess the effects of a single-entry model on waiting time, referral volume and the satisfaction of patients and health care providers.Methods:We searched MEDLINE, Embase, Cochrane CENTRAL and CINAHL databases from inception to December 2019. We included studies from countries in the Organisation for Economic Co-operation and Development that reported on the effects of a single-entry model on the time between referral to first assessment by a specialist physician or allied health professional, termed wait time 1 (WT1). Patient volume and the satisfaction of providers and patients were secondary outcomes. We conducted a narrative synthesis using descriptive statistics.Results:Of the 4637 citations identified, 17 met the eligibility criteria, and we included 10 of these in the final analysis. All of the included studies reported an absolute reduction in WT1 after implementation of the single-entry model. The average percent reduction in WT1 across specialties was greatest for surgical referrals (57%) and urgent internal medicine referrals (40%). Higher initial WT1 was associated with a greater absolute reduction in WT1 after implementation of the single-entry model (p = 0.002). Patient and provider satisfaction with the single-entry model was high in all studies. The effect estimates from all included studies were at high risk of bias.Interpretation:Single-entry models were associated with an absolute reduction in time from referral from primary care to consultation. These models represent a promising option to improve access to a range of health services, but there is a need for rigorous prospective evaluations to inform policy. PROSPERO Registration:CRD42018100395

Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment

OBJECTIVEIn observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor.RESEARCH DESIGN AND METHODSIn the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data.RESULTSAmong 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.02−1.06, P < 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85–1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment–baseline lipoprotein(a) interaction P = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03−1.12; P = 0.0002) for incident type 2 diabetes.CONCLUSIONSIn patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.

Interaction of diabetes genetic risk and successful lifestyle modification in the Diabetes Prevention Programme.

To test whether diabetes genetic risk modifies the association of successful lifestyle changes with incident diabetes. We studied 823 individuals randomized to the intensive lifestyle intervention (ILS) arm of the Diabetes Prevention Programme who were diabetes-free 1 year after enrolment. We tested additive and multiplicative interactions of a 67-variant diabetes genetic risk score (GRS) with achievement of three ILS goals at 1 year (≥7% weight loss, ≥150 min/wk of moderate leisure-time physical activity, and/or a goal for self-reported total fat intake) on the primary outcome of incident diabetes over 3 years of follow-up. A lower GRS and achieving each or all three ILS goals were each associated with lower incidence of diabetes (all P < 0.05). Additive interactions were significant between the GRS and achievement of the weight loss goal (P < 0.001), physical activity goal (P = 0.02), and all three ILS goals (P < 0.001) for diabetes risk. Achievement of all three ILS goals was associated with 1.8 (95% CI 0.3, 3.4), 3.1 (95% CI 1.5, 4.7), and 3.9 (95% CI 1.6, 6.2) fewer diabetes cases/100-person-years in the first, second and third GRS tertiles (P < 0.001 for trend). Multiplicative interactions between the GRS and ILS goal achievement were significant for the diet goal (P < 0.001), but not for weight loss (P = 0.18) or physical activity (P = 0.62) goals. Genetic risk may identify high-risk subgroups for whom successful lifestyle modification is associated with greater absolute reduction in the risk of incident diabetes.

Prophylactic Mastectomy and Breast Reconstruction in Patients at High Risk for Breast Cancer

This paper summarizes key issues pertinent to oncologic and surgical outcomes of risk-reducing mastectomy and reconstruction. Among BRCA 1/2 mutation carriers who present with initial breast cancer, risk-reducing mastectomy in patients who are young at time of initial breast cancer diagnosis have the greatest absolute reduction in contralateral breast cancer risk associated with contralateral risk-reducing mastectomy. Although retrospective studies are suggestive of a survival advantage conferred by risk-reducing mastectomy in BRCA ½ carriers, additional research in the contemporary era of magnetic resonance screening is necessary. A wide variety of reconstructive options are available after risk-reducing mastectomy. Long-term patient-reported outcomes favor autologous tissue reconstruction techniques. The decision for risk-reducing surgery and mastectomy reconstruction in patients with increased genetic propensity for breast cancer is multifaceted, with multiple factors pertinent to consideration including type of mastectomy, timing, and method of reconstruction. Shared informed decision making is critical to optimize outcomes. Appropriate patient counseling based on growing evidence regarding patient-reported outcomes should be provided in order to tailor therapeutic recommendations.

Glycemic Control after Initiating Direct-Acting Antiviral Agents in Patients with Hepatitis C Virus and Type 2 Diabetes Mellitus Using the United States Integrated Healthcare System.

Objective:Hepatitis C virus (HCV) has an increased risk of Type 2 diabetes mellitus (T2DM). Prior studies found that the eradication of HCV with direct-acting antiviral (DAA) agents led to improved glycemic control in patients with T2DM. We aimed to identify the association between HCV eradication and glycemic control in patients diagnosed with HCV and T2DM.Methods:A retrospective observational study was conducted to identify adult patients diagnosed with HCV from January 1, 2014, to August 31, 2017. Patients were included if they were initiated on one of the following DAA agents within the study period: Sofosbuvir/velpatasvir, sofosbuvir/ledispavir, elbasvir/grazopevir. Patients were also required to have the diagnosis of T2DM. The primary outcome of this study was the average change in glycosylated hemoglobin (HbA1c) pre- versus post-DAA agents.Findings:Our final cohort consisted of 996 patients diagnosed with HCV and T2DM: Patients who achieved sustained virologic response (SVR) (n = 937, 94%) and those who did not achieve SVR (n = 59, 6%). In the SVR group, there was a 0.3950% reduction in HbA1c (P < 0.0001) and in those who did not achieve SVR group, there was 0.3532% reduction in HbA1c (P = 0.0051). In the overall study population, SVR group had 0.04% more reduction in HbA1c but was not statistically significant (P = 0.7441).Conclusion:Both groups had statistically significant reductions in HbA1c when comparing the mean change in average HbA1c pre-versus post-DAA agent. Patients who achieved SVR had a greater absolute reduction in HbA1c by 0.04%; however, this was not statistically significant.