Absolute Benefit Research Articles

Intensity of and adherence to lipid-lowering therapy as predictors of goal attainment and major adverse cardiovascular events in primary prevention

The effectiveness of lipid-lowering therapy (LLT) for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in routine care may depend on treatment intensity and adherence. Observational study of adults with newly initiated LLT for primary prevention of ASCVD in Stockholm, Sweden, during 2017-2021. Study exposures were LLT adherence [proportion of days covered (PDC)], LLT intensity (expected reduction of LDL cholesterol), and the combined measure of adherence and intensity. At each LLT fill, adherence and intensity were calculated during the previous 12 months, and the patients estimated ASCVD risk was categorized. Study outcomes were major adverse cardiovascular events (MACE) and LDL-C goal attainment. Thirty-six thousand two hundred eighty-three individuals (mean age 63 years, 47% women, median follow-up 2 years), with a baseline low-moderate (40%), high (49%), and very-high (11%) ASCVD risk started LLT. Increases in LLT adherence, intensity, or adherence-adjusted intensity of 10% over 1 year were associated with lower risks of MACE (with hazard ratios of 0.95 [95% CI, 0.93-0.98]; 0.93 [0.86-1.00]; and 0.90 [0.85-0.95], respectively) and higher odds of attaining LDL goals. Patients with good adherence (≥80%) had similar risks of MACE and similar odds ratios for LDL-C goal attainment with low-moderate and high-intensity LLT. Treatment discontinuation was associated with increased MACE risk. The relative and absolute benefits of good adherence were greatest in patients with very high ASCVD risk. In routine-care primary prevention, better adherence to LLT was associated with a lower risk of MACE across all treatment intensities. Improving adherence is especially important among patients with very high ASCVD risk.

Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the empa-kidney trial

Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce progression of chronic kidney disease and the risk of cardiovascular morbidity and mortality in a wide range of patients. However, their effects on kidney disease progression in some patients with chronic kidney disease are unclear because few clinical kidney outcomes occurred among such patients in the completed trials. In particular, some guidelines stratify their level of recommendation about who should be treated with SGLT2 inhibitors based on diabetes status and albuminuria. We aimed to assess the effects of empagliflozin on progression of chronic kidney disease both overall and among specific types of participants in the EMPA-KIDNEY trial. EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA), and included individuals aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 20 to less than 45 mL/min per 1·73 m2, or with an eGFR of 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher. We explored the effects of 10 mg oral empagliflozin once daily versus placebo on the annualised rate of change in estimated glomerular filtration rate (eGFR slope), a tertiary outcome. We studied the acute slope (from randomisation to 2 months) and chronic slope (from 2 months onwards) separately, using shared parameter models to estimate the latter. Analyses were done in all randomly assigned participants by intention to treat. EMPA-KIDNEY is registered at ClinicalTrials.gov, NCT03594110. Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and then followed up for a median of 2·0 years (IQR 1·5-2·4). Prespecified subgroups of eGFR included 2282 (34·5%) participants with an eGFR of less than 30 mL/min per 1·73 m2, 2928 (44·3%) with an eGFR of 30 to less than 45 mL/min per 1·73 m2, and 1399 (21·2%) with an eGFR 45 mL/min per 1·73 m2 or higher. Prespecified subgroups of uACR included 1328 (20·1%) with a uACR of less than 30 mg/g, 1864 (28·2%) with a uACR of 30 to 300 mg/g, and 3417 (51·7%) with a uACR of more than 300 mg/g. Overall, allocation to empagliflozin caused an acute 2·12 mL/min per 1·73 m2 (95% CI 1·83-2·41) reduction in eGFR, equivalent to a 6% (5-6) dip in the first 2 months. After this, it halved the chronic slope from -2·75 to -1·37 mL/min per 1·73 m2 per year (relative difference 50%, 95% CI 42-58). The absolute and relative benefits of empagliflozin on the magnitude of the chronic slope varied significantly depending on diabetes status and baseline levels of eGFR and uACR. In particular, the absolute difference in chronic slopes was lower in patients with lower baseline uACR, but because this group progressed more slowly than those with higher uACR, this translated to a larger relative difference in chronic slopes in this group (86% [36-136] reduction in the chronic slope among those with baseline uACR <30 mg/g compared with a 29% [19-38] reduction for those with baseline uACR ≥2000 mg/g; ptrend<0·0001). Empagliflozin slowed the rate of progression of chronic kidney disease among all types of participant in the EMPA-KIDNEY trial, including those with little albuminuria. Albuminuria alone should not be used to determine whether to treat with an SGLT2 inhibitor. Boehringer Ingelheim and Eli Lilly.

Interpreting trial results in an era of disease‐modifying therapies: Efficacy of approved anti‐amyloid drugs in the context of the long‐term Alzheimer’s trajectory

AbstractBackgroundEarly‐stage Alzheimer’s disease (AD) typically presents with slow progression of clinical symptoms. Approved high‐potency anti‐amyloid‐β (Aβ) therapies have demonstrated changes in the disease trajectory in these early stages and offer potential benefits beyond the period for which they have been studied in trials.MethodsBased on published results, the time‐slowing of disease progression based on change in CDR sum of boxes (CDR‐SB) was approximated. Disease progression modeling using long‐term cohort data was used to estimate the natural history trajectory of CDR‐SB in AD from the preclinical stages to severe dementia. Modeling of trial inclusion criteria was used to estimate the interval of the natural history trajectory of AD that were included in trials and different scenarios for long‐term treatment effects were explored.ResultsIn positive phase 3 studies, the high‐potency anti‐Aβ therapies appeared to slow disease progression 20‐30% resulting in a 4‐6‐month delay of progression during the 18‐month study period. Included patient populations were found to differ substantially, with the EMERGE and ENGAGE studies including an earlier group of patients than CLARITY‐AD. Consistent with trial subgroup analyses, natural‐history modeling suggested that more progressed patients would see an apparent greater absolute benefit during 18 months, but less absolute benefit over longer durations. Under an assumption of continued slowing beyond the study period, a treatment slowing disease progression by 30% (5.4 months delay in disease progression after 18 months) would lead to treatment differences on CDR‐SB of ‐0.42 and ‐0.72 points for typical MCI and mild dementia patients. With continued slowing beyond the length of the trial, typical MCI patients would have a treatment effect of ‐0.96 points once reaching the same disease stage as the mild dementia patients. Five‐year treatment differences would be approximately ‐2.5 and ‐3.2 points, well beyond all estimates of clinically meaningful differences. Even in the most conservative disease‐modifying scenario assuming no increased time delay after 18 months, observed treatment differences would still increase beyond 18 months due to the nonlinear trajectory of CDR‐SB.ConclusionDisease‐modifying effects of the magnitude observed in recent trials can potentially translate into clearly meaningful differences over a longer duration.

Is antibiotic prophylaxis generally safe and effective in surgical and nonsurgical scenarios? Evidence from an umbrella review of randomized controlled trials.

The authors aimed to comprehensively evaluate the efficacy and safety of antibiotic prophylaxis through surgical and nonsurgical scenarios and assess the strength of evidence. The authors performed an umbrella review of meta-analyses of randomized controlled trials (RCTs). An evidence map was created to summarize the absolute benefits of antibiotic prophylaxis in each scenario and certainty of evidence. Seventy-five meta-analyses proved eligible with 725 RCTs and 78 clinical scenarios in surgical and medical prophylaxis. Of 119 health outcomes, 67 (56.3%) showed statistically significant benefits, 34 of which were supported by convincing or highly suggestive evidence from RCTs. For surgeries, antibiotic prophylaxis may minimize infection occurrences in most surgeries except Mohs surgery, simple hand surgery, herniorrhaphy surgery, hepatectomy, thyroid surgery, rhinoplasty, stented distal hypospadias repair, midurethral sling placement, endoscopic sinus surgery, and transurethral resection of bladder tumors with only low to very low certainty evidence. For nonsurgery invasive procedures, only low to very low certainty evidence showed benefits of antibiotic prophylaxis for cystoscopy, postoperative urinary catheterization, and urodynamic study. For medical prophylaxis, antibiotic prophylaxis showed greater benefits in nonemergency scenarios, in which patients were mainly with weakened immune systems, or at risk of recurrent chronic infections. Antibiotics prophylaxis may increase antibiotic resistance or other adverse events in most scenarios and reached significance in cystoscopy, afebrile neutropenia following chemotherapy and hematopoietic stem cell transplantation. Antibiotic prophylaxis in surgical and nonsurgical scenarios is generally effective and seems independent of surgical cleanliness and urgency of diseases. Its safety is not well determined due to lack of available data. Nevertheless, the low quality of current evidence limits the external validity of these findings, necessitating clinicians to judiciously assess indications, balancing low infection rates with antibiotic-related side effects.

Optimal Screening for Predicting and Preventing the Risk of Heart Failure Among Adults With Diabetes Without Atherosclerotic Cardiovascular Disease: A Pooled Cohort Analysis.

The optimal approach to identify individuals with diabetes who are at a high risk for developing heart failure (HF) to inform implementation of preventive therapies is unknown, especially in those without atherosclerotic cardiovascular disease (ASCVD). Adults with diabetes and no HF at baseline from 7 community-based cohorts were included. Participants without ASCVD who were at high risk for developing HF were identified using 1-step screening strategies: risk score (WATCH-DM [Weight, Age, Hypertension, Creatinine, HDL-C, Diabetes Control, QRS Duration, MI, and CABG] ≥12), NT-proBNP (N-terminal pro-B-type natriuretic peptide ≥125 pg/mL), hs-cTn (high-sensitivity cardiac troponin T ≥14 ng/L; hs-cTnI ≥31 ng/L), and echocardiography-based diabetic cardiomyopathy (echo-DbCM; left atrial enlargement, left ventricular hypertrophy, or diastolic dysfunction). High-risk participants were also identified using 2-step screening strategies with a second test to identify residual risk among those deemed low risk by the first test: WATCH-DM/NT-proBNP, NT-proBNP/hs-cTn, NT-proBNP/echo-DbCM. Across screening strategies, the proportion of HF events identified, 5-year number needed to treat and number needed to screen to prevent 1 HF event with an SGLT2i (sodium-glucose cotransporter 2 inhibitor) among high-risk participants, and cost of screening were estimated. The initial study cohort included 6293 participants (48.2% women), of whom 77.7% without prevalent ASCVD were evaluated with different HF screening strategies. At 5-year follow-up, 6.2% of participants without ASCVD developed incident HF. The 5-year number needed to treat to prevent 1 HF event with an SGLT2i among participants without ASCVD was 43 (95% CI, 29-72). In the cohort without ASCVD, high-risk participants identified using 1-step screening strategies had a low 5-year number needed to treat (22 for NT-proBNP to 37 for echo-DbCM). However, a substantial proportion of HF events occurred among participants identified as low risk using 1-step screening approaches (29% for echo-DbCM to 47% for hs-cTn). Two-step screening strategies captured most HF events (75-89%) in the high-risk subgroup with a comparable 5-year number needed to treat as the 1-step screening approaches (30-32). The 5-year number needed to screen to prevent 1 HF event was similar across 2-step screening strategies (45-61). However, the number of tests and associated costs were lowest for WATCH-DM/NT-proBNP ($1061) compared with other 2-step screening strategies (NT-proBNP/hs-cTn: $2894; NT-proBNP/echo-DbCM: $16 358). Selective NT-proBNP testing based on the WATCH-DM score efficiently identified a high-risk primary prevention population with diabetes expected to derive marked absolute benefits from SGLT2i to prevent HF.

Influence of background therapy on efficacy of dapagliflozin in patients with heart failure and improved ejection fraction

Abstract Introduction Heart failure with improved ejection fraction (HFimpEF), defined as prior reduced left ventricular EF (LVEF) ≤40% with a subsequent measurement LVEF &amp;gt;40%, is growing in prevalence, in part because of effective guideline directed medical therapy (GDMT) initiated when LVEF was ≤40%. These patients have been largely excluded from major HF clinical trials. The DELIVER trial demonstrated dapagliflozin to be beneficial in patients with symptomatic HFimpEF; whether this benefit differs by background medical therapy is unclear. Purpose We investigated the efficacy and safety of dapagliflozin in patients with HFimpEF by background HF GDMT (beta-blocker [BB], mineralocorticoid receptor antagonist [MRA], and ACEi/ARB/ARNI at baseline). Methods The DELIVER trial randomized patients with symptomatic heart failure and LVEF&amp;gt;40% to dapagliflozin or placebo. Treatment effects on the primary endpoint, worsening heart failure or cardiovascular (CV) death, and its components were assessed by a GDMT composite score. We assigned 1 point each for baseline use of ACEi/ARB, evidence-based BB, or MRA, and 2 points for sacubitril/valsartan. The composite GDMT score could range from 0 (no GDMT) to 4 (triple therapy inclusive of sacubitril/valsartan). Results Among the 6,263 patients randomized, 1,151 (18%) had HFimpEF. Of those, 2% of patients were on no GDMT, 14% were on 1 GDMT, 47% were on 2 GDMT therapies, and 37% were on triple therapy at baseline (Figure 1). Patients treated with triple therapy, compared to those on less than 3 therapies, were younger, more likely male, have a history of myocardial infarction, less likely to have diabetes, had a lower baseline LVEF and systolic blood pressure, and higher eGFR. During 2.2 years of median follow-up, the incidence rate was 9.8 per 100 person-years among those on 1 or no medications at baseline compared with 8.6 per 100 person-years among those on 2 or 3 therapies. Relative benefits of dapagliflozin on the primary outcome were not significantly modified by baseline GDMT score (Pinteraction = 0.11), but absolute benefits appeared more pronounced in those receiving 1 or no medications at baseline (Figure 2). Serious adverse events were well-balanced between treatment arms in the HFimpEF cohort, including among those already treated with triple therapy. Conclusions In patients with HFimpEF, the benefits of dapagliflozin are similar irrespective of background GDMT. Dapagliflozin was safe and did not lead to higher risk of adverse events among those with HFimpEF, including those already treated with triple therapy.Figure 1Figure 2

Physical activity and cause-specific mortality among 150,000 participants in the Mexico city prospective study

Abstract Background Previous studies of high-income populations have found that physical activity is associated with reduced mortality risk. We investigated the association of recreational physical activity intensity with cause-specific mortality at ages 35-74 in a Mexican population with high levels of adiposity and diabetes. Methods Between 1998 and 2004, 150,000 adults (age ≥35 years) were recruited into the Mexico City Prospective Study, and followed for median 19 years. Cox regression was used to assess the association of baseline-reported intensity of recreational physical activity (none, &amp;lt;30 minutes, ≥30 to &amp;lt;60 minutes, or ≥60 minutes per activity session) with death before age 75 years. Analyses were adjusted for age at risk, sex, residential district, education, smoking and alcohol consumption. They excluded those who at recruitment were aged ≥75 years, had incomplete data, or had vascular disease or any other chronic condition (except diabetes) recorded. Results Among the 45,291 men and 93,627 women aged 35-74 years, 70% of men and 81% of women reported taking no regular recreational physical activity, mean (SD) body mass index was 29.1 (4.9) kg/m2 and 13% had previously-diagnosed diabetes. There were 12,605 deaths from any cause at ages 35-74 years, including 3368 from vascular causes. Physical activity at recruitment was associated with lower all-cause mortality risk in a dose-dependent manner. Compared with those reporting no regular physical activity, those exercising ≥60 minutes per activity session had 28% lower all-cause mortality at ages 35-74 years (HR=0.72; 95% CI 0.67-0.78), including 22% lower vascular mortality (RR 0.78, 0.68-0.90). Associations were similar for the different types of vascular mortality and were similar in those with and without diabetes, so the absolute benefits of physical activity were larger in those with diabetes. Those who exercised for the longest durations per activity session had lower baseline blood pressure and a more favourable lipid profile than those who reported doing no regular recreational physical activity. Conclusions In this Mexican cohort, higher recreational physical activity was associated with a lower risk of premature death, with particularly high absolute benefits in those with diabetes.

Risk and benefits of baseline antiplatelet therapy in 58,598 patients with atrial fibrillation randomized to NOACs vs warfarin

Abstract Background The efficacy and safety of NOAC versus warfarin (W) may differ in AF pts receiving antiplatelet therapy (APT) at baseline. Moreover, prior individual trial-specific analyses examining the treatment effect of NOAC vs. W as a function of APT are underpowered for interaction testing. Purpose We evaluated outcomes by randomized anticoagulant stratified by baseline APT in a pooled individual pt-level meta-analysis of 4 pivotal RCTs of NOAC vs. W in AF: RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48. Methods Pts were stratified by use of APT vs. no APT at baseline. Pts randomized to low-dose NOAC not globally approved (edoxaban 30/15 mg or dabigatran 110 mg) were excluded. The primary efficacy and safety outcomes were stroke/systemic embolic events (S/SEE) and major bleeding, respectively; ischemic stroke (IS), intracranial hemorrhage (ICH), major GI bleeding and all-cause mortality (ACM) were secondary outcomes. Each outcome was assessed by randomized treatment using a Cox model stratified by trial with adjustment for age, sex, weight, CrCl, smoking status, HTN, DM, CAD, prior MI, PAD, and prior stroke. Interaction testing was performed by APT at baseline. Results Of 58,598 pts, 19,774 (34%) were on APT at baseline (92% aspirin only, 5% P2Y12 only, 3% DAPT). Pts treated with APT had greater prevalence of CAD (41% vs. 24%), prior MI (22% vs. 11%), and PAD (6% vs. 4%) (p&amp;lt;0.001 for each). Reflective of these baseline differences, the annualized event rate for each outcome was higher in the APT vs. no APT group (Figure). The treatment effect (HR) of NOAC vs. W for all 6 clinical outcomes was consistent irrespective of baseline APT (p-interaction [aHR] for each = NS; Figure). However, the absolute risk reduction (ARR) for NOAC vs. W differed for ICH and major GI bleeding as a function of baseline APT (Figure). Specifically, for ICH, a greater absolute benefit was seen with NOAC vs. W in those on APT at baseline (ARR 0.6% vs. 0.3%; p-int = 0.007). Conversely, for major GI bleeding, NOAC vs. W was associated with greater absolute risk in those on APT (ARR -0.6% vs. -0.2%; p-int = 0.04). Conclusions The treatment effect of NOAC vs. W is consistent irrespective of APT at baseline for S/SEE, major bleeding, and ACM. Given higher rates of bleeding in AF pts treated with both APT and anticoagulation, concomitant APT should be avoided when possible. In pts requiring concomitant APT, NOAC instead of W should be considered owing to greater absolute safety benefit for ICH, which should be weighed against individual patient-specific risk factors for GI bleeding.

Effects of icosapent ethyl on residual cardiovascular risk according to predicted baseline risk: results from REDUCE-IT

Abstract Background Icosapent ethyl is recommended by the ESC CVD Prevention Guidelines as one of the intensified prevention strategies to be considered in patients with established CVD and a high residual risk.[1] Treatment effects of icosapent ethyl may vary between individual patients. This study aimed to determine the relative and absolute treatment effects of icosapent ethyl according to baseline CVD risk. Methods Participants from the REDUCE-IT trial with established CVD were included (n = 5,785).[2] Baseline 5-year risk of major adverse cardiovascular events (MACE), defined here as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke was estimated using the ESC guideline-recommended SMART2 risk score.[3] Modification of the relative treatment effect of icosapent ethyl by baseline risk was assessed using a Cox proportional hazards model including a treatment-by-risk interaction. Next, relative treatment effects were derived stratified by quartiles of baseline risk. The observed 5-year absolute risk reduction (ARR) with icosapent ethyl within each risk quartile was assessed based on Kaplan-Meier estimates of the cumulative incidence of MACE. Results During a median follow-up of 4.8 years (interquartile range 3.2-5.3), 361 MACE events occurred in the icosapent ethyl group vs 489 in the placebo group (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.63-0.82). Mean predicted vs observed 5-year risk of MACE was 9.1% vs 10.2% in the first quartile (range 3.6-11.4%), 13.8% vs 14.6% in the second quartile (range 11.5-16.0%), 19.2% vs 19.5% in the third quartile (range 16.1-23.4%), and 33.4% vs 32.2% in the fourth quartile (range 23.5-83.0%). Icosapent ethyl significantly reduced MACE in all risk quartiles, with an HR (95% CI) of 0.62 (0.43-0.88), 0.66 (0.48-0.92), 0.69 (0.53-0.90), and 0.78 (0.63-0.96) respectively (p for treatment-by-risk interaction = 0.06). The 5-year ARR (95% CI) with icosapent ethyl increased across risk quartiles, i.e. was 5.3% (1.8-8.7%), 5.6% (1.9-9.4%), 7.4% (3.0-11.8%), and 10.8% (5.3-16.2%) respectively (Figure). This translates to a number needed to treat (NNT; 95% CI) of 19 (11-54), 18 (11-52), 14 (8-34), and 9 (6-19). Conclusions Among CVD patients with elevated triglyceride levels, icosapent ethyl significantly reduces the risk of MACE in individuals with a low, moderate, and high baseline risk. Absolute treatment benefits are largest for patients at the highest risk, as reflected by the twofold increase in ARR and decrease in NNT in the highest as compared to the lowest risk quartile.Icosapent ethyl effect in risk quartiles

Individual risk prediction of anticoagulation in atrial fibrillation patients with cirrhosis

Abstract Background We aimed to assess absolute risk and benefit from OAC therapies in individual AF patients with liver cirrhosis (LC), and to develop the optimal dose selecting risk calculator for each patient. Methods We derived and validated a prediction model for major bleeding (MB) and stroke/systemic thromboembolism (SSTE) in AF patients with LC from two-center observational cohort (n=420 in derivation cohort, n=180 in validation cohort) with 4 treatment options (standard-, low-dose NOACs, warfarin, and no OACs). Readily available clinical variables were included in machine learning-based ensembled risk calculation models. Results Model calibration and discrimination was adequate with c-statistics of 0.77[0.66-0.87] for MB and 0.74[0.74-0.84] for SSTE. Three-year absolute risk increases (ARIs) for MB with standard-dose NOACs ranged from &amp;lt;10% in 37% of patients to &amp;gt;30% in 18% of patients, with low-dose NOACs ranged from &amp;lt;10% in 47% of patients to &amp;gt;30% in 12% of patients compared without OACs. Three-year absolute risk reductions (ARRs) for SSTE with standard-dose NOACs ranged from &amp;lt;7% in 48% of patients to &amp;gt;15% in 22% of patients, with low-dose NOACs ranged from &amp;lt;7% in 57% of patients to &amp;gt;15% in 17% of patients compared without OACs. The ARI cutoff for MB and ARR cutoff for SSTE with OAC were shown as &amp;gt;2.4%/year and &amp;gt;1.2%/year (c-statistics 0.81[0.78-0.83], 0.75[0.72-0.79]). Conclusions Artificial intelligence combining clinical variables was found to predict individual patient’s bleeding and stroke/systemic embolism risks well and it can also guide each patient’s appropriate OAC dose in AF patients with LC (web-calculator can be accessed as: https://riskcalc.shinyapps.io/AFLC/).

Effects of once-weekly semaglutide on major adverse cardiovascular events in patients with type 2 diabetes and polyvascular disease: a post hoc analysis of the SUSTAIN 6 trial

Abstract Background The presence of polyvascular disease (defined as atherosclerosis involving ≥2 distinct vascular territories) is a strong, independent predictor of subsequent cardiovascular (CV) events in patients with type 2 diabetes (T2D). In the SUSTAIN 6 trial, the glucagon-like peptide-1 receptor agonist once-weekly (OW) subcutaneous semaglutide reduced major adverse cardiovascular events (MACE; a composite of death from CV causes, non-fatal myocardial infarction and non-fatal stroke) in patients with T2D at high CV risk. Purpose This analysis of SUSTAIN 6 assessed the effect of OW semaglutide on MACE in patients with T2D, stratified by the number of atherosclerotic vascular territories at baseline. Methods Patients in SUSTAIN 6 were randomised to receive 0.5 or 1.0 mg OW subcutaneous semaglutide or placebo. The median follow-up was 2.1 years. In this post hoc analysis, the SUSTAIN 6 population was stratified according to documented atherosclerosis: polyvascular disease (≥2 vascular territories), single vascular disease (1 vascular territory) or no atherosclerotic cardiovascular disease (ASCVD). Time to first MACE was analysed using a stratified Cox proportional hazards model, with pooled treatment by vascular risk group as fixed factors. Results In SUSTAIN 6, 640 patients (19.4%) had polyvascular disease, 1821 patients (55.2%) had vascular disease in one arterial bed and 836 patients (25.4%) had no ASCVD at baseline. Demographic and clinical characteristics at baseline are presented in the Table. In the total population, the presence of polyvascular disease and single vascular disease was associated with a greater risk of MACE, compared with no ASCVD (hazard ratio [HR]: 2.25 [95% confidence interval – CI: 1.47;3.52] and HR: 1.64 [95% CI: 1.11;2.48], respectively). In the SUSTAIN 6 trial, OW semaglutide significantly reduced the risk of MACE vs placebo (HR: 0.74 [95% CI: 0.58;0.95]). In this analysis, the risk of MACE was consistently lower with OW semaglutide vs placebo across those with polyvascular disease, single vascular disease and no ASCVD (pinteraction=0.98) (Figure). The absolute risk reductions for OW semaglutide vs placebo at 2 years were 3.37% [95% CI: –1.28;8.02] (number needed to treat [NNT] 30) in patients with polyvascular disease, 2.02% [95% CI: –0.30;4.34] (NNT 50) in patients with single vascular disease and 0.78% [95% CI: –1.96;3.52] (NNT 128) in patients with no ASCVD. Conclusion Patients with polyvascular disease in the SUSTAIN 6 trial population are at over two times greater risk of MACE than those without ASCVD. The MACE risk reduction with OW semaglutide vs placebo is consistent across people with T2D and polyvascular disease, single vascular disease or no ASCVD. However, patients with T2D and polyvascular disease may derive greater absolute benefit from semaglutide treatment owing to their higher risk.

Abstract 16761: Preprocedural Frailty is Associated With Lower Cardiac Rehabilitation Use Despite Greater Benefit

Introduction: Increased frailty before cardiovascular procedures is associated with poorer outcomes. While underutilized, cardiac rehabilitation (CR) is guideline-recommended for patients undergoing cardiovascular procedures and may help mitigate frailty through individualized, monitored exercise and risk factor reduction. Research Question/Hypothesis: Evaluate the relationship between preprocedural frailty, CR use, and one-year mortality. Methods: Medicare fee-for-service claims data were queried for patients who underwent inpatient percutaneous or surgical revascularization or aortic valve replacement between July 2016 and December 2018. Patients were stratified into quartiles (Q1 through Q4) using the validated claims-based frailty index. CR use was defined as attending any CR session within one year of discharge. Unadjusted and adjusted logistic regression was used to compare CR use across increasing frailty quartiles, and inverse probability treatment weighting was used to evaluate the effect of CR on one-year mortality across frailty quartiles. Results: Overall CR enrollment among the 570,851 beneficiaries was 35.3%; increasing frailty was associated with decreased CR use (unadjusted: frailty Q1: 48.3% vs Q4: 20.6%, p&lt;0.001; adjusted OR: 0.61, p&lt;0.001). Unadjusted one-year mortality was lower among CR users as opposed to non-users (2.7% vs 14.6%). After weighted adjustment, the absolute reduction in mortality associated with CR use was greater among frailer patients (Q4: -12.2%) relative to less frail patients (Q1: -2.9%) (Figure). Significant interaction effects between CR use and frailty quartiles indicated stronger associations of CR on mortality among more frail patients. Conclusions: Preprocedural frailty was associated with lower CR use despite greater absolute benefits on one-year mortality. Increasing CR enrollment in frail patients may enhance outcomes after cardiac interventions.

Limitations in the Application of Clinicopathologic Factors Alone in Predicting Radiation Benefit for Women with Low-Risk DCIS after Breast Conserving Surgery: The Impact of a 7-Gene Biosignature Based on 10-Year Ipsilateral Breast Recurrence (IBR) Rates

Most women diagnosed with ductal carcinoma in situ (DCIS) receive radiotherapy (RT) after breast conserving surgery (BCS); however, clinical trials show that over 70% of women with BCS alone will not have a recurrence and therefore not benefit from RT. Traditionally, clinicopathologic (CP) factors have been used to select for whom to de-escalate treatment, but prospective trials have failed to identify a low risk CP group that did not benefit from RT with respect to local control. This study assessed the re-classification of patients with low-risk CP into Risk groups defined by the 7-gene biosignature and compared to 10-yr IBR rates. Women (n = 926) from four international DCIS cohorts treated with BCS had formalin-fixed paraffin embedded tissue samples analyzed at a CLIA lab (Laguna Hills, CA). CP low-risk patients were identified using a) RTOG-9804-like criteria [Nuclear Grade 1 or 2 & Size ≤2.5 cm & non-Palpable & Screen Detected & margin negative (no-ink on tumor)] and b) MSKCC-like criteria [low-risk score<220, determined using nomogram weighted factors (excluding: number of re-excisions and RT treatment), and using no-ink-on-tumor instead of close margin]. The 7-gene DCIS biosignature combined biomarkers with CP factors (age, size, palpability, and margin status) using an algorithm reporting a Decision Score (DS) and Residual Risk subtype (RRt). Women with low-risk CP were classified into biosignature Low Risk (DS≤2.8, no RRt) or High Risk (DS>2.8 +/- RRt) groups. 10yr in-breast event (IBR) rates with and without RT were assessed by Kaplan-Meier rates and Cox proportional hazard analyses. Overall, 37% of all women were classified into the biosignature Low Risk group, while 51% and 34% were classified into CP low-risk groups (RTOG-9804-like, MSKCC-like, respectively). The biosignature Low Risk group (n = 338) had a 10-yr IBR risk of 5.6% after BCS and no significant RT benefit (absolute RT benefit = 0.8%, p = 0.70), 99% negative predictive value (NPV) for RT benefit. CP low-risk groups had 10-yr IBR rates of 12% and 8% after BCS without RT with absolute 6% (p = 0.04) and 4% (p = 0.1) IBR rate reductions with RT. The biosignature reclassified 51% and 63% of CP low-risk patients into the biosignature High Risk group. Importantly, these patients had higher IBR rates without RT (20% and 12%) and significant 13% (p = 0.005) and 8% (p = 0.01) absolute IBR rate reductions from RT. CP low-risk patients with concordant biosignature Low Risk demonstrated no significant RT benefit. The 7-gene predictive biosignature more reliably identified patients with low 10-yr IBR rates and no significant RT benefit than the traditional CP low-risk criteria (RTOG-9804-like, MSKCC-like). Importantly, those CP low-risk patients who were re-classified as biosignature High Risk had increased 10-year IBR rates and significant RT benefit.

Androgen Deprivation Therapy Use among Intermediate Risk Prostate Cancer Patients Undergoing Radiation Therapy across a Statewide Radiation Oncology Quality Consortium

For men with intermediate (INT) risk prostate cancer, the addition of androgen deprivation therapy (ADT) reduces risk of PSA failure, distant metastasis, and cancer-related mortality. Moreover, the relative reduction in cancer-related adverse outcomes with ADT use appears consistent across all INT risk subgroups. The absolute benefit of ADT, however, varies by baseline risk. In contemporary practice, it is unknown which clinical factors are most strongly associated with intended ADT use. Therefore, we sought to identify such factors within the diverse practices of the Michigan Radiation Oncology Quality Consortium (MROQC). Patients with localized prostate cancer undergoing definitive radiation therapy were enrolled from 6/9/20 to 11/4/22 (n = 599). Standardized patient, physician, and physicist forms were used to collect baseline and follow-up information. Intended ADT use, defined by the treating physician, was prospectively collected and is the primary outcome of this analysis. Univariable (UVA) and multivariable analyses (MVA) associations with patient (age, race, comorbidities), tumor (T stage, Gleason, percent cores positive, and PSA), and practice-related (academic vs private) factors were performed. In addition, advanced modality testing (PET, MRI, and genomic classifiers) was available as of March 2021, and subgroup analysis were performed where appropriate. A total 351 patients across 26 centers were enrolled with INT risk disease. ADT use was intended for 46% of men (n = 162/351) which differed by men with NCCN favorable INT (21%, n = 22/105) vs unfavorable INT risk disease (57%, n = 140/246), p<0.001. Sixty two percent (n = 100/162) had an intended ADT duration of 4-6 months and 21% (n = 34/162) had ≥12 months. Older age was associated with ADT use (70 vs 67, p < 0.01); there were no significant differences by race or comorbidities number. MVA showed Gleason 4+3 (OR 4.61 [2.91 - 7.42]) and > = 50% positive cores (2.56 [1.52 - 4.37]) were significantly associated with ADT use. No significant differences were noted based on practice setting. Pelvic MRI was obtained for 71% of men (n = 197/279), genomic classifiers in 47% (n = 130/279), and PET in 2% (n = 6/282). In the subset with MRI (n = 197), adverse features (ECE, SVI, or equivocal LNs) were associated with intended ADT use (OR 3.0 [1.4 - 7.1]) after adjustment for NCCN favorable/unfavorable INT risk classification. Within a state-wide consortium, intended ADT use for intermediate prostate cancer is most strongly associated with Gleason score, ≥50% positive cores, NCCN unfavorable intermediate risk classification, and adverse features on MRI. Nearly half of men had genomic classifier testing underscoring the importance ongoing trials such as NRG/GU 010.

Comparative Cardiovascular Effectiveness and Safety of SGLT-2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors According to Frailty in Type 2 Diabetes.

To evaluate the comparative cardiovascular effectiveness and safety of sodium-glucose cotransporter 2 inhibitors (SGLT-2is), glucagon-like peptide 1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 inhibitors (DPP-4is) in older adults with type 2 diabetes (T2D) across different frailty strata. We performed three 1:1 propensity score-matched cohort studies, each stratified by three frailty strata, using data from Medicare beneficiaries (2013-2019) with T2D who initiated SGLT-2is, GLP-1RAs, or DPP-4is. In time-to-event analyses, we assessed the primary cardiovascular effectiveness composite outcome of acute myocardial infarction, ischemic stroke, hospitalization for heart failure, and all-cause mortality. The primary safety outcome was a composite of severe adverse events that have been linked to SGLT-2i or GLP-1RA use. Compared with DPP-4is, the overall hazard ratio (HR) for the primary effectiveness outcome associated with SGLT-2is (n = 120,202 matched pairs) was 0.72 (95% CI 0.69-0.75), corresponding to an incidence rate difference (IRD) of -13.35 (95% CI -15.06 to -11.64). IRD ranged from -6.74 (95% CI -8.61 to -4.87) in nonfrail to -27.24 (95% CI -41.64 to -12.84) in frail people (P for interaction < 0.01). Consistent benefits were observed for GLP-1RAs compared with DPP-4is (n = 113,864), with an overall HR of 0.74 (95% CI 0.71-0.77) and an IRD of -15.49 (95% CI -17.46 to -13.52). IRD in the lowest frailty stratum was -7.02 (95% CI -9.23 to -4.81) and -25.88 (95% CI -38.30 to -13.46) in the highest (P for interaction < 0.01). Results for SGLT-2is versus GLP-1RAs (n = 89,865) were comparable. Severe adverse events were not more frequent with SGLT-2is or GLP-1RAs than DPP-4is. SGLT-2is and GLP-1RAs safely improved cardiovascular outcomes and all-cause mortality, with the largest absolute benefits among frail people.

Impact of pathological nodal staging and tumour differentiation on survival and postoperative radiotherapy in completely resected stage IIIA Non-small-cell lung cancer

BackgroundTumour differentiation is an important index for adjuvant therapy in many cancers; however, non-small cell lung cancer (NSCLC) is an exception. Furthermore, postoperative radiotherapy (PORT) is controversial in patients with NSCLC with N0-1 and N2 disease. We aimed to evaluate the impact of tumour-related factors on overall survival (OS), cancer-specific survival (CSS), and distant control (DC) in patients with completely resected stage IIIA NSCLC. Materials and MethodsPatients with stage IIIA non-metastatic NSCLC who underwent complete resection and adjuvant chemotherapy were identified from the Taiwan Cancer Registry (January 2007–December 2017). Logistic regression analysis was performed to determine the factors associated with PORT. Survival and relapse outcomes were compared using log-rank tests and Cox regression analysis. Sensitivity analysis was performed using propensity score-matched pairs. ResultsIn total, 1,897 patients were included and stratified according to PORT use (PORT vs. non-PORT). After adjusting for covariates, PORT was not found to be associated with improved survival outcomes. In patients with poorly differentiated tumours and N2 disease, absolute benefits for OS (adjusted hazard ratio [aHR] 0.76), CSS (aHR 0.80), and DC (aHR 0.74) were observed. Multivariable hazard models of propensity score-matched pN2 disease and poorly differentiated tumour subgroups also showed significant survival benefit with PORT treatment. ConclusionsPatients with poorly differentiated tumours and receiving PORT for pN2 disease showed a lower risk of distant recurrence and more favourable survival outcomes in stage IIIA NSCLC with R0 resection.

Underutilization of Mineralocorticoid Antagonists in Patients With Heart Failure With Reduced Ejection Fraction

BackgroundIt is unknown how the efficacy and safety of mineralocorticoid receptor antagonists vary according to duration of heart failure with reduced ejection fraction (HFrEF). ObjectivesIn this study, we sought to evaluate the safety and efficacy of eplerenone according to duration of HFrEF. MethodsIn the EMPHASIS-HF trial, 3 patient groups were created according to HFrEF duration: <1 year, 1 to <5 years, and ≥5 years. The primary outcome was the composite of heart failure (HF) hospitalization or cardiovascular death. Outcomes were adjusted for prespecified prognostic variables and examined with the use of Cox regression models. ResultsThe numbers of patients in each group were: 975, <1 year; 769, 1 to <5 years; and 988, ≥5 years. Patients with longer-standing HF were older and more frequently had cardiovascular and noncardiovascular comorbidities. The rate of the primary outcome (per 100 person-years) increased with HFrEF duration: 9.8 (95% CI: 8.4-11.4) for <1 year, 13.5 (95% CI: 11.6-15.7) for 1 to <5 years, and 17.6 (95% CI: 15.6-19.8) for ≥5 years. The benefits of eplerenone were consistent across HF duration: HRs for the primary outcome were 0.57 (95% CI: 0.42-0.79) for <1 year, 0.81 (95% CI: 0.60-1.10) for 1 to <5 years, and 0.61 (95% CI: 0.48-0.78) for ≥5 years; Pinteraction = 0.24. The absolute benefit was greatest in the longest-duration group: the number needed to treat for the primary outcome was 14 for <1 year, 13 for 1 to <5 years, and 10 for ≥5 years duration. ConclusionsPatients with longer-standing HFrEF had worse clinical status and a higher rate of events, but the benefit of eplerenone was consistent regardless of HFrEF duration. (A Comparison of Outcomes in Patients in NYHA Class II Heart Failure When Treated With Eplerenone or Placebo in Addition to Standard Heart Failure Medicines [EMPHASIS-HF]; NCT00232180)

Animal model of polytrauma for surgical training

Introduction: The aim of this study was to develop a training program for surgeons that would enable them to improve their practical skills using an animal model of polytrauma. Methods: Injury to the stomach, small and large bowel as well as spleen and liver injury were caused laparoscopically, and tension pneumothorax was induced thoracoscopically, in 60 laboratory pigs. A thus obtained polytrauma model was then used for the training of examination processes according to ATLS (advanced trauma life support) principles and of the treatment protocol according to DCS (damage control surgery) principles. Less experienced surgeons (N=10) completed a total of 4 training sessions, and experienced surgeons with postgraduate certification in surgery (N=10) performed 2 treatments. The relative training benefit was subsequently assessed by comparing the first and the last attempt. Furthermore, the absolute benefit of training for the beginners (novice trainees) was evaluated by comparing their last attempt with the first attempt of experienced surgeons. Results: The beginners (less experienced surgeons) showed an improvement (first vs fourth attempt) in all parameters except bowel injury management and laparotomy closure time. Based on the comparison of the experienced surgeons’ first attempt and the beginners’ first attempt, the beginners performed significantly worse in all parameters except the two mentioned above. Average total blood loss was also higher in the beginners’ group – 2531 (±661.1) g vs 1189 (±509.5) g in the experienced surgeons’ group (p&lt;0.001). Conclusion: A novel animal model of polytrauma that can be used for the training of life threatening injury management was developed and validated in the study. The beginners improved significantly in all parameters after the training. However, longer training would be required to achieve results comparable to those of experienced surgeons.

Whole blood hydroxychloroquine: Does genetic polymorphism of cytochrome P450 enzymes have a role?

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide range of clinical manifestations and multifactorial etiologies ranging from environmental to genetic. SLE is associated with dysregulated immunological reactions, with increased immune complex formation leading to end-organ damages such as lupus nephritis, cutaneous lupus, and musculoskeletal disorders. Lupus treatment aims to reduce disease activity, prevent organ damage, and improve long-term patient survival and quality of life. Antimalarial, hydroxychloroquine (HCQ) is used as a first-line systemic treatment for lupus. It has shown profound efficacy in lupus and its associated conditions. However, wide variation in terms of clinical response to this drug has been observed among this group of patients. This variability has limited the potential of HCQ to achieve absolute clinical benefits. Several factors, including genetic polymorphisms of cytochrome P450 enzymes, have been stipulated as key entities leading to this inter-individual variation. Thus, there is a need for more studies to understand the role of genetic polymorphisms in CYP450 enzymes in the clinical response to HCQ. Focusing on the role of genetic polymorphism on whole blood HCQ in lupus disorder, this review aims to highlight up-to-date pathophysiology of SLE, the mechanism of action of HCQ, and finally the role of genetic polymorphism of CYP450 enzymes on whole blood HCQ level as well as clinical response in lupus.

Individual lifetime benefit from low-dose colchicine in patients with chronic coronary artery disease.

Low-dose colchicine reduces cardiovascular risk in patients with coronary artery disease (CAD), but absolute benefits may vary between individuals. This study aimed to assess the range of individual absolute benefits from low-dose colchicine according to patient risk profile. The European Society of Cardiology (ESC) guideline-recommended SMART-REACH model was combined with the relative treatment effect of low-dose colchicine and applied to patients with CAD from the Low-Dose Colchicine 2 (LoDoCo2) trial and the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease (UCC-SMART) study (n = 10 830). Individual treatment benefits were expressed as 10-year absolute risk reductions (ARRs) for myocardial infarction, stroke, or cardiovascular death (MACE), and MACE-free life-years gained. Predictions were also performed for MACE plus coronary revascularization (MACE+), using a new lifetime model derived in the REduction of Atherothrombosis for Continued Health (REACH) registry. Colchicine was compared with other ESC guideline-recommended intensified (Step 2) prevention strategies, i.e. LDL cholesterol (LDL-c) reduction to 1.4 mmol/L and systolic blood pressure (SBP) reduction to 130 mmHg. The generalizability to other populations was assessed in patients with CAD from REACH North America and Western Europe (n = 25 812). The median 10-year ARR from low-dose colchicine was 4.6% [interquartile range (IQR) 3.6-6.0%] for MACE and 8.6% (IQR 7.6-9.8%) for MACE+. Lifetime benefit was 2.0 (IQR 1.6-2.5) MACE-free years, and 3.4 (IQR 2.6-4.2) MACE+-free life-years gained. For LDL-c and SBP reduction, respectively, the median 10-year ARR for MACE was 3.0% (IQR 1.5-5.1%) and 1.7% (IQR 0.0-5.7%), and the lifetime benefit was 1.2 (IQR 0.6-2.1) and 0.7 (IQR 0.0-2.3) MACE-free life-years gained. Similar results were obtained for MACE+ and in American and European patients from REACH. The absolute benefits of low-dose colchicine vary between individual patients with chronic CAD. They may be expected to be of at least similar magnitude to those of intensified LDL-c and SBP reduction in a majority of patients already on conventional lipid-lowering and blood pressure-lowering therapy.