Significant Relative Risk Reduction Research Articles

Efficacy and safety of bempedoic acid among patients with and without diabetes: prespecified analysis of the CLEAR Outcomes randomised trial

Statins reduce LDL cholesterol and cardiovascular events among those with or without diabetes but have been reported to increase new-onset diabetes. The CLEAR Outcomes trial demonstrated that bempedoic acid reduced the risk of major adverse cardiovascular events among statin-intolerant patients at high cardiovascular risk. In this prespecified analysis, our dual aims were to evaluate the cardiovascular benefits of bempedoic acid, an ATP-citrate lyase inhibitor, in individuals with diabetes, and to evaluate the risk of new-onset diabetes and HbA1c among those without diabetes in the CLEAR Outcomes trial. CLEAR Outcomes was a randomised, double-blind, placebo-controlled trial conducted across 1250 primary care and outpatient sites in 32 countries. Patients with or without cardiovascular disease who were unwilling or unable to take guideline-recommended doses of statins and an LDL cholesterol of 2·59 mmol/L or more were randomly assigned (1:1) in a double-blinded manner to either bempedoic acid 180 mg once per day or placebo. In this prespecified analysis, the efficacy endpoint was a time-to-event analysis of four-component major adverse cardiovascular event (MACE-4), which is the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularisation, using the intention-to-treat population stratified by baseline glycaemia status. The prespecified analysis of risk of new-onset diabetes and HbA1c increase was evaluated in patients without diabetes at baseline. The CLEAR Outcomes trial was completed on Nov 7, 2022, and is registered with ClinicalTrials.gov (NCT02993406). Between Dec 22, 2016, and Nov 7, 2022, 13 970 patients were screened and randomly assigned; 6373 (45·6%) with diabetes, 5796 (41·5%) with prediabetes, and 1801 (12·9%) with normoglycaemia. Over a median of 3·4 years follow up, patients with diabetes had significant relative and absolute cardiovascular risk reductions in MACE-4 endpoints with bempedoic acid (HR 0·83; 95% CI 0·72-0·95; absolute risk reduction of 2·4%) compared to placebo, with no statistical evidence of effect modification across glycaemic strata (interaction p=0·42). The proportion of patients who developed new-onset diabetes were similar between the bempedoic acid and placebo groups, with 429 of 3848 (11·1%) with bempedoic acid versus 433 of 3749 (11·5%) with placebo (HR 0·95; 95% CI 0·83-1·09). HbA1c concentrations at month 12 and the end of the study were similar between randomised groups in patients who had prediabetes and normoglycaemia. Placebo-corrected LDL cholesterol concentrations and high-sensitivity C-reactive protein at 6 months were reduced in each glycaemic stratum (diabetes, prediabtes, and normoglycaemia) for patients randomly assigned to bempedoic acid (all p<0·001). Among patients with diabetes, bempedoic acid reduces LDL cholesterol and high-sensitivity C-reactive protein and risk of cardiovascular events. Patients without diabetes had no increase in new-onset diabetes or worsening HbA1c with bempedoic acid. The efficacy and cardiometabolic safety profile of bempedoic acid makes it a clinical option for those with and without diabetes. Esperion Therapeutics.

Persistence of significant secondary mitral regurgitation post-cardiac resynchronization therapy and survival: a systematic review and meta-analysis : Mitral regurgitation and mortality post-CRT.

Cardiac resynchronization therapy (CRT) significantly reduces secondary mitral regurgitation (MR) in patients with severe left ventricular systolic dysfunction. However, uncertainty remains as to whether improvement in secondary MR correlates with improvement with mortality seen in CRT. We conducted a meta-analysis to determine the association of persistent unimproved significant secondary MR (defined as moderate or moderate-to-severe or severe MR) compared to improved MR (no MR or mild MR) post-CRT with all-cause mortality, cardiovascular mortality, and heart failure hospitalization. A systematic search of PubMed, EMBASE, and Cochrane Library databases till July 31, 2022 identified studies reporting clinical outcomes by post-CRT secondary MR status. In 12 prospective studies of 4954 patients (weighted mean age 66.8years, men 77.8%), the median duration of follow-up post-CRT at which patients were re-evaluated for significant secondary MR was 6months and showed significant relative risk reduction of 30% compared to pre-CRT. The median duration of follow-up post-CRT for ascertainment of main clinical outcomes was 38months. The random effects pooled hazard ratio (95% confidence interval) of all-cause mortality in patients with unimproved secondary MR compared to improved secondary MR was 2.00 (1.57-2.55); p < 0.001). There was insufficient data to evaluate secondary outcomes in a meta-analysis, but limited data that examined the relationship showed significant association of unimproved secondary MR with increased cardiovascular mortality and heart failure hospitalization. The findings of this meta-analysis suggest that lack of improvement in secondary MR post-CRT is associated with significantly elevated risk of all-cause mortality and possibly cardiovascular mortality and heart failure hospitalization. Future studies may investigate approaches to address persistent secondary MR post-CRT to help improved outcome in this population.

SAT658 Tirzepatide Reduces The Predicted Risk Of Developing Atherosclerotic Cardiovascular Disease: A Post-hoc Analysis Of The Surmount-1 Trial

Abstract Disclosure: E.R. Hankosky: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. H. Wang: Other; Self; Eli Lilly &amp; Company. N.M. Lisa: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. H. Kan: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. F. Wang: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. N.N. Ahmad: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. A. Stefanski: Grant Recipient; Self; Eli Lilly &amp; Company. Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. W. Garvey: Consulting Fee; Self; Eli Lilly &amp; Company, Novo Nordisk, Boehringer Ingelheim, Pfizer, Inc., Fractyl Laboratories, Merck. Grant Recipient; Self; Eli Lilly &amp; Company, Novo Nordisk, Pfizer, Inc. Background: Tirzepatide (TZP) resulted in substantial and sustained body weight reduction among participants with obesity or overweight in SURMOUNT-1, a phase 3 randomized clinical trial. Using predictive modelling, the current study assessed the impact of TZP treatment on the 10-year risk of developing atherosclerotic cardiovascular disease (ASCVD) among SURMOUNT-1 participants. Methods: The American College of Cardiology/American Heart Association (ACC/AHA) risk engine was applied to data from SURMOUNT-1 participants free of ASCVD at baseline. ASCVD risk scores were calculated at baseline, 24, and 72 weeks. The model inputs were age, total cholesterol, high density lipoprotein, systolic blood pressure, hypertension treatment, diabetes, and smoking status. Mean percent change in the 10-year risk score from baseline to week 72 was compared between TZP groups and placebo (PBO) using Mixed Model for Repeated Measures (MMRM), adjusted for baseline risk scores and country; risk scores were analyzed on log-scale. Since the risk score was low in the overall SURMOUNT-1 population, a subgroup analysis was conducted in participants with higher ASCVD risk at baseline (score≥7.5%, ACC/AHA intermediate-to-high risk). Results: A total of 2461 participants (TZP 5 mg, n=614; 10 mg, n=616; 15 mg, n=609; PBO, n=622) were included (mean age=45 years; female=68%; White=70%). At baseline, the median 10-year predicted risk score ranged from 1.5%–1.6% and did not differ across treatment groups. Median absolute risk scores for TZP 5/10/15 mg and PBO groups were 1.4%, 1.2%, 1.3%, and 1.6% at week 24, and 1.3%, 1.2%, 1.1%, and 1.7% at week 72, respectively. At week 72, MMRM-estimated relative change in risk from baseline was -16.4%, -23.5%, -22.4%, and 12.7% for TZP 5/10/15mg and PBO, leading to significantly greater reduction for TZP groups compared to PBO (TZP 5 mg: -25.8%; 10 mg: -32.1%; 15 mg: -31.1%; p≤0.001). Among 272 participants (TZP 5 mg, n=83; 10 mg, n=66; 15 mg, n=55; PBO, n=68) with intermediate-to-high baseline ASCVD risk, median risk scores for TZP 5/10/15 mg and PBO groups were: baseline: 11.3%, 10.5%, 10.9%, 10.1%; week 72: 11.3%, 9.0%, 10.3%, 11.7%, respectively. MMRM-estimated relative risk reduction at week 72 was -10.3%, -20.6%, -16.1%, and 6.4% for TZP 5/10/15 mg and PBO groups, respectively. Consistent with the primary analysis, relative risk reduction was significantly greater in TZP groups compared to PBO (TZP 5 mg = -15.7%; 10 mg = -25.3%; 15 mg = -21.1%; p≤0.01). Conclusion: TZP treatment significantly reduced the 10-year predicted risk of developing ASCVD compared to PBO, though the magnitude of reduction in absolute risk scores was small due to low baseline risk in the overall population. Among participants with higher ASCVD risk at baseline, TZP treatment resulted in larger absolute reductions in risk along with significant relative risk reduction consistent with the primary analysis. Presentation: Saturday, June 17, 2023

Post Mastectomy Radiation Therapy Impact on Clinical Outcomes of Male Breast Cancer: A Meta-Analysis of Comparative Studies

Male breast cancer accounts for less than 1 percent of all cancer diagnoses in men. Because it is rare, it does not lend itself to large, randomized trials. In general, the approach to the treatment of early, non-metastatic male breast cancer has largely been extrapolated from female breast cancer trials though it is deemed to be a different disease. Data on early-stage post mastectomy radiation therapy (PMRT) is limited, and its benefits remain unclear. We conducted this meta-analysis to determine the impact of PMRT on recurrence patterns and survival outcomes using the available male breast cancer data. A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of invasive non-metastatic male breast cancer (MBC), comparative studies of PMRT versus none, and studies that reported the incidence of local and distant recurrences as well as survival data in the compared arms. A meta-analysis using the Mantel-Haenszel method for calculating the weighted pooled relative risk (RR) under the fixed effects model was conducted. Subsequently, the heterogeneity statistic was incorporated to calculate the summary RR under the random effects model. Ten retrospective comparative studies with 3912 patients were included and analyzed. Eight studies reported survival data. Six and three studies reported local and distant recurrence incidence, respectively. PMRT did not have an impact on overall survival or distant recurrences. However, PMRT significantly lowered the RR of locoregional recurrences (RR = 0.53, 95% CI 0.31-0.92). In addition, when survival was analyzed by TNM stage and N status, PMRT was found to have a significant reduction in RR of death in stage III (RR = 0.85, 95% CI 0.75-0.97), N1 (RR = 0.77, 95% CI 0.61-0.98), and N2 (RR = 0.61, 95% CI 0.49-0.78) disease. This is the first meta-analysis to show that PMRT is associated with a lower relative risk of death in stage III MBC as well as N1 and N2 disease. It also demonstrates a significant reduction in RR of locoregional recurrences. In the absence of randomized clinical trials, it represents the most compelling data supporting the use of PMRT in this MBC patient population using MBC data.

Aspirin in primary cardiovascular prevention: the two faces of the coin and the importance of the Number Needed to Treat: a systematic review and meta-analysis.

Aspirin has been an essential treatment for the primary preven-tion of cardiovascular diseases (CVD). Several randomized controlled studies do not support the routine use of aspirin, mainly due to its association with bleed-ing risk. This systematic review aims to advocate aspirin prescription based on the Number Needed to Treat (NNT) and the Number Needed to Harm (NNH). This combination provides a good measure of the effort to avoid an unfavor-able outcome, weighed against possible associated risks. A search of random-ized studies on aspirin treatment was conducted in two separate periods. Four studies from 1988-1998 and six from 2001-2018 were included in the analysis (157,060 participants). The primary endpoint was a composite outcome of Non-fatal Myocardial Infarction (NFMI), Non-fatal Ischemic Stroke (NFIS), and CV mortality. Major bleeding was a safety endpoint. We calculated the Absolute Risk Reduction (ARR%), NNT, and NNH, alongside the Relative Risk (RR) and 95% CI of each primary endpoint. The results of all included studies (10) showed a net benefit with aspirin treatment for NFMI (NNT= 259) and the composite outcome (NNT=292) with a significant relative risk reduction of 20% (p=0.003; I2= 0%) and 10% (p&lt;0.001; I2= 0%), respectively. There was a relevant 60% in-crease in the bleeding risk (p&lt;0.0001, NNH=208; I2= 3%). The NNT and NNH may constitute measures of efficacy and risk in clinical shared decision-making. However, it is essential to consistently establish that patients’ benefit-risk should be individualized and not represent a clinical guide for everyone.

The efficacy of combined arginine and probiotics as an add-on to 1450 ppm fluoride toothpaste to prevent and control dental caries in children – A randomized controlled trial

ObjectivesTo determine how daily consumption of a lozenge combining arginine and two probiotic strains affects the Relative Risk Reduction (RRR) in children regarding dental caries transitions and lesion activity at tooth surface level during 10–12 months. MethodsA total of 21,888 tooth surfaces in 288 children were examined. The intervention group (n = 141) received a lozenge containing 2% arginine, Lacticaseibacillus rhamnosus, LGG® (DSM33156), and Lactobacillus paracasei subsp. paracasei, L. CASEI 431® (DSM33451). The placebo group (n = 147) received a placebo lozenge. Both groups received 1,450 ppm F- toothpaste. Primary canines, molars, and first permanent molars were examined clinically (ICDAS0–6) and radiographically (R0–6) at baseline and follow-up. Sealed, filled, and missing surfaces were also included. Caries activity was computed as a sum of each caries lesion's location, color, texture, cavitation, and gingival bleeding. RRRs were computed with cluster effect on surface level. ICH-GCP was followed, including external monitoring. ResultsA total of 19,950 surfaces were analyzed after excluding 1,938 tooth surfaces. No statistically significant differences were found between the groups. The RRRs showed less caries progression (13.6%, p = 0.20), more regression (0.3%, p = 0.44), and fewer active caries lesions (15.3%, p = 0.15) in the intervention group. ConclusionDaily consumption of a lozenge combining arginine and probiotics for 10–12 months given to 5–9-years-old children characterized being with low caries risk demonstrated a marked, though not statistically significant RRR for caries progression, regression, and number of active lesions in the intervention group compared to the placebo-group. ClinicalTrials.gov (NCT03928587). Clinical significanceSince all the RRRs were in favor of the intervention group and the PF of combined arginine and probiotics is high (81.6%) compared to fluoride toothpaste (24.9%) and arginine-fluoride toothpaste alone (19.6%) the combined pre-and probiotics approach may be a future additional tool regarding caries prevention and control.

Dual antiplatelet Use for extended period taRgeted to AcuTe ischemic stroke with presumed atherosclerotic OrigiN (DURATION) trial: Rationale and design.

The optimal duration of dual antiplatelet therapy (DAPT) with clopidogrel-aspirin for the large artery atherosclerotic (LAA) stroke subtype has been debated. To determine whether the 1-year risk of recurrent vascular events could be reduced by a longer duration of DAPT in patients with the LAA stroke subtype. A total of 4806 participants will be recruited to detect a statistically significant relative risk reduction of 22% with 80% power and a two-sided alpha error of 0.05, including a 10% loss to follow-up. This is a registry-based, multicenter, prospective, randomized, open-label, blinded end point study designed to evaluate the efficacy and safety of a 12-month duration of DAPT compared with a 3-month duration of DAPT in the LAA stroke subtype. Patients will be randomized (1:1) to either DAPT for 12 months or DAPT for 3 months, followed by monotherapy (either aspirin or clopidogrel) for the remaining 9 months. The primary efficacy outcome of the study is a composite of stroke (ischemic or hemorrhagic), myocardial infarction, and all-cause mortality for 1 year after the index stroke. The secondary efficacy outcomes are (1) stroke, (2) ischemic stroke or transient ischemic attack, (3) hemorrhagic stroke, and (4) all-cause mortality. The primary safety outcome is major bleeding. This study will help stroke physicians determine the appropriate duration of dual therapy with clopidogrel-aspirin for patients with the LAA stroke subtype. URL: https://cris.nih.go.kr/cris. CRIS Registration Number: KCT0004407.

Abstract PD6-10: PD6-10 The impact of post mastectomy radiation therapy on clinical outcomes of male breast cancer: A meta-analysis of comparative studies

Abstract Background/Rationale: Male breast cancer accounts for less than 1 percent of all cancer diagnoses in men. Because it is rare, it does not lend itself to large, randomized trials. In general, the approach to the treatment of early, non-metastatic male breast cancer has largely been extrapolated from female breast cancer trials. Specifically, the data on early-stage post mastectomy radiation therapy (PMRT) is limited, and its benefits remain unclear. Objectives: We conducted this meta-analysis to determine the impact of PMRT on clinical outcomes of men with breast cancer. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of invasive non-metastatic male breast cancer (MBC), comparative studies of PMRT versus none, and studies that reported the incidence of local and distant recurrences as well as survival data in the compared arms. A meta-analysis using the Mantel-Haenszel method for calculating the weighted pooled relative risk (RR) under the fixed effects model. Subsequently, the heterogeneity statistic gets incorporated to calculate the summary RR under the random effects model. Results: Ten retrospective comparative studies with 3912 patients were included and analyzed. Eight studies reported survival data. Six and three studies reported local and distant recurrence incidence, respectively. PMRT did not have an impact on overall survival or distant recurrences. However, PMRT significantly lowered the RR of locoregional recurrences (RR=0.53, 95%CI 0.31-0.92). In addition, when survival was analyzed by TNM stage and N status, PMRT was found to have a significant reduction in RR of death in stage III (RR=0.85, 95%CI 0.75-0.97), N1 (RR=0.77, 95%CI 0.61-0.98), and N2 (RR=0.61, 95%CI 0.49-0.78) disease. Conclusions: This is the first meta-analysis to show that PMRT is associated with a lower relative risk of death in stage III MBC as well as N1 and N2 disease. It also demonstrates a significant reduction in RR of locoregional recurrences. In the absence of randomized clinical trials, it represents the most compelling data supporting the use of PMRT in this MBC patient population. Citation Format: Philip A. Haddad, Usman Zaheer. PD6-10 The impact of post mastectomy radiation therapy on clinical outcomes of male breast cancer: A meta-analysis of comparative studies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD6-10.

Reduced risk of serious pneumococcal infections up to 10years after a dose of pneumococcal conjugate vaccine in established arthritis.

To examine rates of serious pneumococcal infections up to 10years after vaccination with 7-valent conjugated pneumococcal vaccine (PCV7) in patients with arthritis compared to non-vaccinated arthritis patients. In total, 595 adult arthritis patients (rheumatoid arthritis; RA=342, 80% women and spondylarthropathy; SpA=253, 45% women) received one dose of PCV7. Mean age/disease duration were 62/16 and 51/14years, respectively. For each patient, 4 matched reference subjects were identified. At vaccination, 420 patients received bDMARDs (anti-TNF=330, tocilizumab=15, abatacept=18, anakinra=1, rituximab=56). Methotrexate was given as monotherapy (n=86) or in combination with bDMARD (n=220). 89 SpA patients received NSAIDs without DMARD. The Skåne Healthcare Register was searched for ICD-10 diagnostic codes for pneumococcal infections (pneumonia, lower respiratory tract infection, septicemia, meningitis, septic arthritis) between January 2000 and December 2018. Frequency of infections after vs before vaccination were calculated (relative risks). Relative risk ratio (RRR) and relative risk reduction (1-RRR) were calculated comparing patients vs non-vaccinated references. Kaplan-Meier and Cox regression were used to investigate time to first event and predictors of infections. Among vaccinated RA and SpA patients, there was a significant relative risk reduction of pneumonia and all serious infections; 53% and 46%, respectively. There was no significant difference in time to first pneumonia or all serious infections after vaccination between patients and references. Higher age, RA diagnosis and concomitant prednisolone were associated with infections. One dose of pneumococcal conjugate vaccine may decrease risk of serious pneumococcal infection up to 10years in patients with arthritis receiving immunomodulating treatment.

1918. Impact of the SARS-CoV-2–Neutralizing Antibody Combination AZD7442 (Tixagevimab/Cilgavimab) on the Severity and Progression of COVID-19 Symptoms in the Phase 3 TACKLE Trial

Abstract Background Outpatient treatment with SARS-CoV-2–neutralizing antibody combination AZD7442 (tixagevimab/cilgavimab) in adults with mild to moderate COVID-19 significantly reduced progression to severe disease or death through Day 29 and was well-tolerated in the Phase 3 TACKLE study (NCT04723394). We report a post hoc analysis of the impact of AZD7442 in reducing self-reported COVID-19 symptom severity and time to symptom resolution through Day 29 in TACKLE. Methods In TACKLE, non-hospitalized adults with mild to moderate COVID-19 were randomized 1:1 and dosed ≤7 days from symptom onset with a single 600mg AZD7442 dose (2 consecutive intramuscular (IM) injections, 300 mg of each antibody; n=452) or placebo (n=451). Symptom occurrence and severity were self-reported daily by participants through study Day 29. Participants rated each symptom as not experienced, mild, moderate, severe, or emergency room (ER) or hospital visit. Symptom progression was compared between AZD7442 and placebo using a stratified Cochran-Mantel-Haenszel test. Change from baseline in symptom severity was compared using a mixed model for repeated measures. Time to symptom resolution was compared using Kaplan-Meier and Cox proportional hazards methods. Missing symptom data for those who were hospitalized or died were imputed as either failures or as severity scores of ER or hospital visit. Results Progression of ≥1 symptoms to a worse severity score occurred in 170 (55.7%) AZD7442- versus 204 (63.4%) placebo-treated participants, translating to a nominally significant relative risk reduction of 12.5% (95% confidence interval 0.5–23.0; P=0.041). Over 29 days, the overall mean improvement from baseline in severity of body aches, chills, cough, diarrhea, fatigue, headache, muscle aches, nausea, and runny nose was significantly greater with AZD7442 versus placebo (Figure). The greatest improvements were observed with cough, fatigue, and muscle aches. Significant differences were observed for most symptoms within 1 and 2 weeks post AZD7442 dosing. Figure. Forest plot for LS difference in severity of COVID-19 symptoms between AZD7442 and placebo through Day 29 CI, confidence interval; LS, least squares. The overall P value is calculated using a mixed model for repeated measures, including terms for symptom severity baseline value, time from symptom onset (≤5 vs &amp;gt;5 days), risk of progression to severe COVID-19 (high vs low), treatment, visit, and treatment by visit interaction. Conclusion For the treatment of mild to moderate COVID-19, a single IM 600-mg AZD7442 dose was associated with reductions in progression of COVID-19 symptom severity and may hasten symptom improvement through Day 29. Disclosures Jesus Abraham Simón Campos, MD, AstraZeneca: Board Member|AstraZeneca: Speaker|Eli Lilly: Board Member|Pfizer: Board Member|Roche: Board Member|Roche: Speaker Douglas Arbetter, MPH, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Hugh Montgomery, MD, AstraZeneca: Advisor/Consultant|Millfield Medical Ltd: Advisor/Consultant|UK National Institute for Health Research's Comprehensive Biomedical Research Centre at University College London Hospitals: Grant/Research Support F.D. Richard Hobbs, FMedSci, AstraZeneca: Grant/Research Support|AstraZeneca: Principal investigator|NIHR Applied Research Collaboration, Oxford Thames Valley: Director|Oxford BRC and NIHR MedTech: Investigator|UKRI and NIHR: Grant/Research Support Francisco Padilla, MD, Amgen: Grant/Research Support|Amgen: Personal fees|AstraZeneca: Grant/Research Support|AstraZeneca: Personal fees|Boehringer Ingelheim: Grant/Research Support|Boehringer Ingelheim: Personal fees|Ferrer: Grant/Research Support|Ferrer: Personal fees|Kowa: Grant/Research Support|Kowa: Personal fees|Medix: Grant/Research Support|Medix: Personal fees|Merck Sharp and Dohme: Grant/Research Support|Merck Sharp and Dohme: Personal fees|Novartis: Grant/Research Support|Novartis: Personal fees|Pfizer: Grant/Research Support|Pfizer: Personal fees|Sanofi: Grant/Research Support|Sanofi: Personal fees|Servier: Grant/Research Support|Servier: Personal fees|Silanes: Grant/Research Support|Silanes: Personal fees Kenneth Kim, MD, Adagio: Funding|Eli Lilly: Funding|Merck: Funding|Pfizer: Funding|Regeneron: Speaker|Regeneron: Funding Katie Streicher, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Alison Templeton, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Rolando M. Viani, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Mark T. Esser, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds.

Real-world comparative effectiveness of ARNI versus ACEi/ARB in HF with reduced or mildly reduced ejection fraction

AimsSacubitril/valsartan is a first-in-class angiotensin receptor–neprilysin inhibitor (ARNI) with a class-1 guideline recommendation. We assessed the real-world effectiveness of ARNI versus angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB) on all-cause and cardiovascular (CV)-related mortality and hospitalizations in heart failure (HF) with reduced or mildly reduced ejection fraction (EF).MethodsPatient-level clinical, laboratory, drug dispensation, hospitalization, and mortality data were derived from the Swedish Heart Failure Registry (SwedeHF) and interlinked databases (1 April 2016–31 December 2020). Eligible ARNI:ACEi/ARB patients (n = 7275:24,604) had a left ventricular EF < 50%. Mortality and hospitalizations with ARNI (≤ 3 months pre-/post-1 April 2016 index [SwedeHF]; n = 1506) versus ACEi/ARB (≤ 3 months post-index; n = 17,108) were assessed using propensity score matching (1:1 ratio) with clinical variables, and sensitivity analysis (1:2/1:3 with, and 1:2 without clinical variables).ResultsARNI induced a 23% reduction in all-cause mortality versus ACEi/ARB (1:1 hazard ratio [HR; 95% confidence interval (CI)]: 0.77 [0.63–0.95], p = 0.013), and a non-significant 23% relative risk reduction in CV-related mortality (0.77 [0.54–1.09], p = 0.13), but no difference in all-cause or CV-related hospitalization (1.02 [0.91–1.13]; p = 0.76; 1.01 [0.91–1.15]; p = 0.84, respectively). Sensitivity analyses confirmed all-cause mortality was reduced for ARNI versus ACEi/ARB (HR 0.90 [95% CI 0.82–0.99], p = 0.026), but not CV-related mortality (HR 1.04 [95% CI 0.89–1.22], p = 0.63).ConclusionsIn this nationwide real-world study including a population of patients with HF with reduced or mildly reduced EF, ARNI as part of guideline-led Swedish clinical practice was associated with a statistically significant relative risk reduction in all-cause mortality compared with ACEi/ARB.

Efficacy of Non-Soy Isoflavone (Pueraria phaseoloides) on The Symptoms Severity Scoring by Kupperman Index in Menopausal Women

Introduction: Menopause is defined by a decline in estrogen levels, which causes various symptoms. Treatments based on foods or supplements enriched in phytoestrogens, notably isoflavones, plant-derived compounds with estrogenic effects, have recently become quite popular. This study aims to see how effective non-soy isoflavone supplementation is for menopausal symptoms in women. Methods: 26 menopausal women were given 67.5 mg of non-soy isoflavone, and 25 menopausal women were given a placebo daily for 12 weeks in an analytical double-blind, randomized clinical trial (RCT). Inclusion criteria were (1) RCT, (2) perimenopausal or postmenopausal women experiencing menopausal symptoms, (3) intervention with an oral non-soy isoflavone. Symptoms Severity Score (SSS) based on the Kupperman index (KI) questionnaire was administered to the patients before starting and at the end of the study. The Statistical Package for Social Sciences (SPSS) software was used to analyze the responses. Results: The difference in SSS scores between the treatment and control groups was significant (p = 0.000). Women receiving 67.5 mg of non-soy isoflavone daily, reduced myalgia, fatigue, and hot flushes by 92.3%, 77%, and 53.8%, respectively. For clinical significance rating, relative risk reduction (RRR) is used. A significant RRR value resulted from myalgia symptoms (76.6%), fatigue (55.7%), hot flushes (39.2%), and SSS (68.7%). Conclusion: Isoflavones did not bring a significant change in Kupperman Index compared to placebo but provided significantly improved Symptoms Severity Scoring in menopausal women.

Abstract 10209: The Effect of the Dual SGLT1 and 2 Inhibitor Sotagliflozin on Cardiovascular Mortality and Hospital Readmission Rates for Heart Failure at 30 and 90 Days Post Discharge in Patients With Type 2 Diabetes Hospitalized for Worsening Heart Failure in the SOLOIST-WHF Trial

Introduction: SGLT inhibitors demonstrate reductions in CV mortality and HHF in patients with diabetes and chronic HF. Despite therapy, patients hospitalized for worsening HF (WHF) are at high risk of death or readmission. Hypothesis: The SOLOIST-WHF trial admitted patients for their index WHF event and initiated randomized therapy during hospitalization. This study evaluated the effect of the SGLT1 and 2 inhibitor sotagliflozin on 30- and 90-day CV death and HF readmission rates after discharge. Methods: Of 1222 randomized patients with T2D, 86% were admitted for their index WHF event. Of them, 46% (n = 563) started study drug prior to or at discharge. In post hoc exploratory analyses, CV death and HF readmission (HHF or urgent visits for HF) rates were determined 30- or 90-days post discharge. Comparisons were done by Cochran-Mantel-Haenszel test stratified by region and baseline LVEF (&lt;50%, ≥50%). Results: Treatment with sotagliflozin showed significant relative risk reduction of &gt;50% for readmission for non-fatal HF-related events or the composite of CV death and readmission for HF-related events within 30 or 90 days of discharge vs placebo (Table 1). The sotagliflozin safety profile in those windows was generally consistent with the overall study duration. Incidence of adverse events (AEs) and serious AEs was similar between groups. Increased incidence of diarrhea and volume-related AEs was noted with sotagliflozin. No appreciable eGFR change from baseline occurred at 30 days, but there was lower incidence of AEs linked to acute kidney injury with sotagliflozin. Conclusions: Sotagliflozin, given to patients with T2D prior to or at hospital discharge after an episode of WHF, was well tolerated and resulted in a significant &gt;50% reduction in CV mortality or readmission for a HF event at 30 and 90 days post-discharge.

Effects of Hydroxychloroquine on Progression of Diabetic Retinopathy in Subjects with Rheumatoid Arthritis and Type 2 Diabetes Mellitus.

The study was conducted to investigate the effects of hydroxychloroquine, an anti-inflammatory drug, which was recently approved and used as an add on oral antidiabetic drug for uncontrolled Type 2 Diabetes Mellitus (DM) on an adequate dose of sulfonylurea and metformin on the progression of diabetic retinopathy (DR) in subjects with Rheumatoid Arthritis and Type 2 Diabetes Mellitus. The primary objective was to evaluate the effect of hydroxychloroquine on the onset of Diabetic Retinopathy (DR) and progression of the disease. Best-corrected visual acuity (BCVA) charts with 3 or more lines worsening of visual acuity and the development of clinically significant macular edema (CSME) were added as secondary objectives as described in the Early Treatment Diabetic Retinopathy Study (ETDRS). This retrospective analysis was done from medical records of all Rheumatoid Arthritis (RA) patients who also had T2DM and were treated with hydroxychloroquine (HCQ) 400 mg OD or 200 mg BID (N=65) and received ophthalmologic care at an endocrinology clinic in India up to a mean follow-up of 3.5±0.5 years and matched subjects taking any other disease-modifying antirheumatic drugs (DMARD) and pioglitazone (N=34). Baseline characteristics were similar in both the groups, with matched glycated haemoglobin (9.1 % and 9.2 % respectively, p=0.127). In both groups, over 3.5 years, HbA1c was reduced significantly. No new cases of DR were detected in the HCQ group, whereas 2 patients had developed DR in the pioglitazone group. At the base line visit, mild non-proliferative Diabetic Retinopathy (NPDR) was present in 18 eyes and 14 eyes in the HCQ and pioglitazone groups, respectively. Progression to moderate NPDR over 3.5 years occurred in 2 out of 18 (11 %) eyes in the HCQ group and 8 out of 14 (57 %) eyes in the pioglitazone group, respectively, representing a significant relative risk reduction (p=.001). No patients had progressed from mild NPDR to severe NPDR in the HCQ group, whereas 2 eyes had progressed from mild NPDR to severe NPDR in the pioglitazone group. None of the patients in either arm developed diabetic macular oedema. Progression of DR from mild to moderate NPDR or severe NPDR may be delayed by HCQ. Large scale randomised prospective clinical trial is required to establish the risk-benefit profiles of HCQ in T2DM.ct.

Effect on mortality and hospitalization of real-world implementation of transitional care heart failure programmes in patients with heart failure: a population-based study in 77,554 patients

Abstract Background The efficacy of heart failure programs has been demonstrated in clinical trials but their applicability in the real-world practice setting is more controversial. Purpose This study evaluates the efficacy of a comprehensive, transitional-care nurse-based HF programme integrating hospital and primary care resources in a healthcare area covering a population of 209,255 (implementation area). Methods We designed a pragmatic, population-based evaluation of the implementation of the program conducting a natural experiment. Study periods were: pre-implementation period (years 2015 and 2016), transition period (year 2017) and consolidation of implementation period (years 2018 and 2019). For the purposes of this study, we included all individuals consecutively admitted to hospital with at least one ICD-9-CM code for HF as the primary diagnosis and discharged alive in Catalonia between January, the 1st, 2015 and December, the 31st of 2019. Efficacy of the implementation of the program was measured at two levels: first, comparing the outcomes of patients exposed to the HF program between periods of implementation taking 2015–2016 as the reference period and, second, comparing outcomes between patients of the implementation area with patients of the remaining areas of the Catalonia at each predefined period. Results We included 77,554 patients in the study: 3,396 exposed to the implementation area and 74,158 exposed to the rest of healthcare areas in Catalonia. During the period of the study, 55,886 (72.1%) patients experienced at least one major adverse event. Death occurred in 37,469 (48.3%), clinically related hospitalisation in 41,709 (53.8%) and HF readmission in 29,755 (38.4%). As shown in Table 1, multivariate Cox proportional hazards models adjusted for age, gender, previous hospitalisation, co-morbidities, socioeconomic status, and time since HF diagnosis showed there was a significant (all p-values &amp;lt;0.001) relative risk reduction of the risk of all-cause death (5%), clinically related hospitalisation (13%) and HF hospitalisation (14%) in the consolidation period (2018–2019) compared to the pre-programme period (2015–2016). Similarly, as shown in Table 1 and Figure 1, while in the pre-programme period (2015–2016) the risk of adverse outcomes was significantly higher in patients exposed to the implementation area compared to the rest of Catalonia, this association was inverted during the consolidation period (2018–2019) where the risk of mortality, clinically-related readmission and HF re-hospitalisation was significantly reduced (all p-values &amp;lt;0.025) by 19%, 11% and 16%, respectively, among patients exposed to the implementation area compared with patients of the remaining areas of Catalonia. Conclusions The implementation of multidisciplinary transitional-care nurse-based heart failure programmes integrating hospital and primary care reduce mortality and hospitalisation in vulnerable patients with heart-failure. Funding Acknowledgement Type of funding sources: None.

The potential of glucagon-like peptide-1 receptor agonists in heart failure.

Heart failure (HF) remains one of the cardiovascular diseases (CVDs) associated with a high unmet medical need due to high morbidity and mortality rates and lack of efficacious interventions. HF is closely related to cardiometabolic diseases such as diabetes, obesity and chronic kidney disease, and strategies that address most or all these intertwined conditions are desirable. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are approved for type 2 diabetes (T2D), and some are also indicated for reduction of the risk of atherosclerotic CVD in T2D and for weight management. As we summarise in this concise review, preliminary evidence suggests that the cardioprotective benefits of GLP-1 RAs may also extend to HF. The most robust clinical evidence arguably originates from the large cardiovascular outcomes trials (CVOTs) completed for most GLP-1 RAs, of which the latest showed a significant relative risk reduction (RRR) of 39% (HR) with once-weekly efpeglenatide on HF requiring hospitalisation, corroborating a meta-analysis which found a significant RRR across eight GLP-1 RA CVOTs of 11%. Further, although incompletely described, multiple studies are available to provide insights into the mechanistic underpinnings, which appear to be associated mostly with indirect cardioprotective benefits owing to the ability of GLP-1 RAs to address hyperglycaemia, and reduce body weight, and, amongst others, inflammation. In sum, current evidence positions GLP-1 RAs as a potential cardioprotective strategy in HF, with HF with preserved ejection fraction emerging as the clinically most relevant phenotype for the drug class, especially when occurring in people with obesity with and without diabetes.

Effectiveness of nonpharmacological therapeutic interventions on pain and physical function in adults with rib fractures during acute care: A systematic review and meta-analysis.

BackgroundRib fractures are a common thoracic injury and notable source of chest pain. Chest pain may lead to compromised respiratory and physical function.ObjectivesOur study aimed to synthesise the evidence on the effectiveness of nonpharmacological therapeutic interventions on pain and physical function in adults admitted with rib fractures to acute care settings. Secondary outcomes included length of stay (LOS), respiratory complications, respiratory function and mortality rate.MethodA systematic literature search of English articles in nine databases was conducted. The Joanna Briggs Institute’s System for the Unified Management, Assessment and Review of Information (SUMARI) was used to conduct our study. Articles written from January 2000 to December 2017 were considered and a search update was completed in 2021. Meta-analysis was conducted for pre- versus post-bundle of care implementation for LOS, pneumonia incidence and mortality rate. Certainty of evidence was appraised using the grading of recommendations, assessment, development and evaluation (GRADE) approach.ResultsSixteen studies were included (n = 2034). Certain interventions were shown to improve respiratory function and reduce pain, pulmonary complications, LOS and mortality rate. No interventions were identified which objectively improved physical function. Meta-analysis showed a statistically significant reduction in relative risk of developing pneumonia (p = 0.00) by 63% following bundled care implementation. Certainty of evidence for this outcome was rated as very low following GRADE appraisal.ConclusionNonpharmacological therapeutic interventions used in combination with pharmacological management are viable treatment options to reduce pain, improve respiratory function and reduce the incidence of respiratory complications following acute rib fractures.Clinical implicationsAcupuncture, transcutaneous electrical nerve stimulation (TENS), noninvasive ventilation (NIV) modalities, physiotherapy techniques and multidisciplinary pathways used alongside pharmacological interventions are effective modalities for use in the treatment of acute rib fractures. Multidisciplinary care pathways are important management strategies and reduce the risk of developing pneumonia.

Prevention of Cardiovascular Events and Mortality With Icosapent Ethyl in Patients With Prior Myocardial Infarction

BackgroundREDUCE-IT was a double-blind trial that randomized 8,179 statin-treated patients with controlled low-density lipoprotein cholesterol and moderately elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in the primary endpoint, including death from cardiovascular (CV) causes. The specific impact of IPE among patients with prior myocardial infarction (MI) was unknown. ObjectivesOur goal was to examine the benefit of IPE on ischemic events among patients with prior MI in REDUCE-IT. MethodsWe performed post hoc analyses of patients with prior MI. The primary endpoint was CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary endpoint was CV death, MI, or stroke. ResultsA total of 3,693 patients had a history of prior MI. The primary endpoint was reduced from 26.1% to 20.2% with IPE vs placebo; HR: 0.74 (95% CI: 0.65-0.85; P = 0.00001). The key secondary endpoint was reduced from 18.0% to 13.3%; HR: 0.71 (95% CI: 0.61-0.84; P = 0.00006). There was also a significant 35% relative risk reduction in total ischemic events (P = 0.0000001), a 34% reduction in MI (P = 0.00009), a 30% reduction in CV death (P = 0.01), and a 20% lower rate of all-cause mortality (P = 0.054), although there was a slight increase in atrial fibrillation. Sudden cardiac death and cardiac arrest were also significantly reduced by 40% and 56%, respectively. ConclusionsPatients with a history of prior MI in REDUCE-IT treated with IPE demonstrated large and significant relative and absolute risk reductions in ischemic events, including CV death. (A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. [REDUCE-IT]; NCT01492361)

Emergency medical services evaluations for chest pain during first COVID-19 lockdown in Hollands-Midden, the Netherlands.

ObjectiveTo assess whether the COVID-19 lockdown in 2020 had negative indirect health effects, as people seem to have been reluctant to seek medical care.MethodsAll emergency medical services (EMS) transports for chest pain or out-of-hospital cardiac arrest (OHCA) in the Dutch region Hollands-Midden (population served > 800,000) were evaluated during the initial 6 weeks of the COVID-19 lockdown and during the same time period in 2019. The primary endpoint was the number of evaluated chest pain patients in both cohorts. In addition, the number of EMS evaluations of ST-elevation myocardial infarction (STEMI) and OHCA were assessed.ResultsDuring the COVID-19 lockdown period, the EMS evaluated 927 chest pain patients (49% male, age 62 ± 17 years) compared with 1041 patients (51% male, 63 ± 17 years) in the same period in 2019, which corresponded with a significant relative risk (RR) reduction of 0.88 (95% confidence interval (CI) 0.81–0.96). Similarly, there was a significant reduction in the number of STEMI patients (RR 0.52, 95% CI 0.32–0.85), the incidence of OHCA remained unchanged (RR 1.23, 95% CI 0.83–1.83).ConclusionDuring the first COVID-19 lockdown, there was a significant reduction in the number of patients with chest pain or STEMI evaluated by the EMS, while the incidence of OHCA remained similar. Although the reason for the decrease in chest pain and STEMI consultations is not entirely clear, more attention should be paid to the importance of contacting the EMS in case of suspected cardiac symptoms in possible future lockdowns.Supplementary InformationThe online version of this article (10.1007/s12471-021-01545-y) contains supplementary material, which is available to authorized users.

An update on dapagliflozin for the treatment of heart failure.

Heart failure (HF) is a substantial source of morbidity and mortality. Several clinical trials have reported a significant HF benefit of sodium/glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes. In 2019, the Food and Drug Administration (FDA) approved dapagliflozin to reduce hospitalization risk for HF in adults with type 2 diabetes and established cardiovascular disease or risk factors. Regardless of the presence of diabetes, the recent DAPA-HF study reported a significant relative risk (RR) reduction with dapagliflozin in the composite primary outcome of worsening HF or death from cardiovascular causes in patients with New York Heart Association (NYHA) class II, III or IV HF and an ejection fraction of 40%. There was a 30% RR reduction in hospitalizations for HF, 57% RR reduction in urgent HF visits, and 18% RR reduction in cardiovascular death. These results led the FDA to approve dapagliflozin in 2020 for the treatment of HF with reduced ejection fraction (NYHA class II-IV) in adults with and without type 2 diabetes. This article summarizes HF outcomes from large clinical trials of SGLT2 inhibitors and focuses on dapagliflozin's HF benefits. The review also covers potential mechanisms of HF benefit and the safety profile of dapagliflozin in patients with HF.