Composite Cardiovascular Endpoint Research Articles

Role of Diuretics in Cardiovascular Events and Mortality in Systolic Blood Pressure Intervention Trial: A Post Hoc Analysis.

In a post hoc analysis, we examined whether postrandomization diuretics use can explain and/or mediate the beneficial effects of intensive systolic BP lowering on cardiovascular disease and all-cause mortality in the Systolic Blood Pressure Intervention Trial (SPRINT). SPRINT was a randomized, controlled trial of 9361 participants comparing the effects of intensive (systolic BP target <120 mm Hg) versus standard (systolic BP target <140 mm Hg) BP control on a primary composite cardiovascular end point in participants aged 50 years or older with systolic BP of 130-180 mm Hg. In time-varying multivariable Cox analyses, we assessed hazard ratios (HRs) of cardiovascular end points and all-cause mortality in participants on thiazide type, loop and/or potassium (K) sparing, or no diuretics. We also conducted mediation analysis to formally assess the role of diuretics in the effects of intensive systolic BP lowering. At baseline, diuretics were prescribed in 46% and 48% of participants in standard and intensive systolic BP-lowering groups, respectively, and in 46% and 74% in the corresponding groups during the trial. The lower risk of cardiovascular end points in the intensive group (HR, 0.75; 95% confidence interval [CI], 0.64 to 0.89) persisted after adjustment for postrandomization time-varying diuretics use (HR, 0.74; 95% CI, 0.62 to 0.89). Across the entire study population, time-varying diuretics use was not associated with cardiovascular end points (compared with no diuretics, HR for thiazide type, 0.89; 95% CI, 0.73 to 1.10, and loop/K sparing, 1.29; 95% CI, 0.97 to 1.73). However, thiazide-type diuretics were associated with lower risk of cardiovascular end points in the intensive (HR, 0.62; 95% CI, 0.46 to 0.85) but not in the standard (HR, 1.07; 95% CI, 0.82 to 1.39) group. In mediation analysis, HRs for total effect, direct effect (not mediated through diuretics use), and indirect effect (mediated through diuretics) of the intervention on cardiovascular end points were 0.66 (95% CI, 0.54 to 0.79), 0.67 (95% CI, 0.54 to 0.81), and 0.98 (95% CI, 0.88 to 1.10), respectively. The results were largely similar for all-cause mortality. The favorable effects of intensive systolic BP lowering on cardiovascular end points and all-cause mortality in SPRINT were independent of and not mediated by time-varying diuretics use. However, thiazide-type diuretics use associated with benefit if intensive systolic BP lowering was targeted.

Cardiovascular Safety of Amphetamine/Dextroamphetamine versus Methylphenidate in Older Adults

Background: Recent epidemiological data has shown a sharp increase in stimulant use among older adults, which is notable as older adults may be especially vulnerable to their cardiovascular effects. Results of recent studies have shown an increase in cardiovascular events among older adults using stimulants; however, little data exists comparing cardiovascular safety of these agents head-to-head. Objective: To determine if the incidence of serious cardiovascular events, including myocardial infarction (MI), stroke/transient ischemic attack (TIA), or arrhythmia, are different in patients taking amphetamine/dextroamphetamine compared with patients taking methylphenidate. Methods: Retrospective chart review of veterans 50 years and older at the Veterans Affairs North Texas Health Care System (VANTHCS) who were first prescribed a stimulant between 2015 and 2021. The primary outcome was the difference in composite cardiovascular events between amphetamine/dextroamphetamine and methylphenidate. Secondary outcomes were the composite cardiovascular endpoints compared individually (MI, stroke/TIA, or arrhythmia). Hazard ratios were calculated based off of a time-to-event analysis displayed using a Kaplan-Meier curve for primary and secondary outcomes. Results: 466 veterans were screened for inclusion, 30 were excluded, and 436 were included. There was no difference found in composite cardiovascular events between the 241 veterans in the amphetamine/dextroamphetamine group and the 195 veterans in the methylphenidate group with 12 (5%) vs 8 (4.1%) events respectively (P = .6635). There was also no difference in time-to-event analysis (P = .4966). Conclusion: In elderly veterans, there was no difference found in incidence of major cardiovascular events with the use of amphetamine/dextroamphetamine compared with methylphenidate.

Comparative Effectiveness of Interventional Therapy versus Exercise Rehabilitation in Stable Angina Patients with Severe Coronary Artery Stenosis.

Management strategies for stable angina include pharmacotherapy, revascularization, and exercise-based cardiac rehabilitation (CR). The optimal treatment for stable angina patients with severe coronary artery stenosis remains unclear. This study aimed to compare interventional therapy with exercise rehabilitation in this population. Fifty stable angina patients with severe coronary stenosis who underwent stent implantation were included in the optimal medical therapy (OMT) plus percutaneous coronary intervention (PCI) group, and 50 patients who did not undergo interventional treatment were included in OMT plus CR group receiving exercise rehabilitation guidance for one year. Cardiovascular composite endpoint events, cardiopulmonary fitness, and quality of life scale scores were assessed after one year. No significant difference in incidence of cardiovascular composite endpoint events was observed between OMT plus PCI group with OMT plus CR group (20.0% vs 14.6%) after one year. Cardiopulmonary fitness represented as peak VO2 (19.2±3.5 vs 17.6±3.2 mL/kg/min), peak load (120±19 vs 108±20 W), and AT (13.5±1.5 vs 12.1±1.3 mL/kg/min) were significantly higher in the rehabilitation group than the intervention group after one year. Both groups showed improvement in their quality of life, but the rehabilitation group improved in more scales. Interventional therapy did not reduce cardiovascular events compared to exercise-based rehabilitation in stable angina patients with severe coronary artery stenosis, but the rehabilitation can improve cardiovascular fitness and quality of life more.

Effects of Dapagliflozin in Chronic Kidney Disease Across the Spectrum of Age and by Sex

BackgroundThe sodium-glucose cotransporter type 2 inhibitor dapagliflozin reduces the risk of progressive kidney disease and cardiovascular events in patients with chronic kidney disease, with and without type 2 diabetes. Whether its effects are uniform across the spectrum of age and among men and women is unknown.ObjectiveWe performed a pre-specified analysis in DAPA-CKD to evaluate efficacy and safety of dapagliflozin according to baseline age and sex.DesignProspective randomized placebo-controlled trial.ParticipantsA total of 4304 adults with chronic kidney disease (estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2; urinary albumin-to-creatinine ratio 200–5000 mg/g) with and without type 2 diabetes.InterventionDapagliflozin 10 mg versus placebo once daily.Main MeasuresPrimary endpoint was a composite of ≥ 50% sustained eGFR decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary endpoints included kidney composite endpoint (same as primary composite endpoint but without cardiovascular death), cardiovascular composite endpoint (hospitalized heart failure or cardiovascular death), and all-cause mortality.Key ResultsMedian follow-up was 2.4 years. Absolute risks of cardiovascular composite endpoint and all-cause mortality were higher in older patients. Absolute risk of kidney composite endpoint was highest in patients < 50 years (10.7 and 6.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively) and lowest in patients ≥ 80 years (3.0 and 1.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively). There was no evidence of heterogeneity of the effects of dapagliflozin on the primary or secondary endpoints based on age or sex. Neither age nor sex modified the effects of dapagliflozin on total or chronic eGFR slope.ConclusionsDapagliflozin reduced the risks of mortality, cardiovascular events, and CKD progression in older patients, including in septuagenarians and octogenarians who comprised 25% of participants. Ageism and/or therapeutic nihilism should not discourage the use of dapagliflozin in older women and men who are likely to experience considerable benefit.Trial Registryclinicaltrials.govNIH Trial Registry NumberNCT03036150

Long-term outcome of patients presenting with myocardial injury or myocardial infarction.

Patients with acute or chronic myocardial injury are frequently identified in the context of suspected myocardial infarction (MI). We aimed to investigate their long-term follow-up. We prospectively enrolled 2714 patients with suspected MI and followed them for all-cause mortality and a composite cardiovascular endpoint (CVE; cardiovascular death, MI, unplanned revascularization) for a median of 5.1years. Final diagnoses were adjudicated by two cardiologists according to the Fourth Universal Definition of MI, including 143 (5.3%) ST-elevation MI, 236 (8.7%) non-ST-elevation MI (NSTEMI) Type 1 (T1), 128 (4.7%) NSTEMI T2, 86 (3.2%) acute and 677 (24.9%) with chronic myocardial injury, and 1444 (53.2%) with other reasons for chest pain (reference). Crude event rates per 1000 patient-years for all-cause mortality were highest in patients with myocardial injury (81.6 [71.7, 92.3]), and any type of MI (55.9 [46.3, 66.7]), compared to reference (12.2 [9.8, 15.1]). Upon adjustment, all diagnoses were significantly associated with all-cause mortality. Moreover, patients with acute (adj-HR 1.92 [1.08, 3.43]) or chronic (adj-HR 1.59 [1.16, 2.18]) myocardial injury, and patients with NSTEMI T1 (adj-HR 2.62 [1.85, 3.69]) and ST-elevation MI (adj-HR 3.66 [2.41, 5.57]) were at increased risk for cardiovascular events. Patients with myocardial injury are at a similar increased risk for death and cardiovascular events compared to patients with acute MI. Further studies need to determine appropriate management strategies for patients with myocardial injury. Clinicaltrials.gov (NCT02355457).

Central Blood Pressure predicts the future cardiovascular risk better than peripheral Blood Pressure: the northern shanghai study

Abstract Background Controversy exists in the comparison between central and peripheral blood pressure (BP) in predicting the future cardiovascular risk. Aim To examine whether central BP predicts cardiovascular events and mortality better than brachial BP in a large cohort of elderly Chinese. Method A total of 3048 participants enrolled in the Northern Shanghai Study, a prospective cohort study focusing on the cardiovascular risk of community-dwelling elderly Chinese living in the north of Shanghai, China between 2014 and 2019, were included. Central BP was estimated tonometrically from the redial pulse waveform. The vital status and cardiovascular events of all participants were confirmed by reviewing the regional morality record system in October 2022. Cox proportional hazards models were conducted to evaluated the predictive value of central and peripheral systolic BP (SBP) and pulse pressure (PP). Results During the median follow-up of 5.6 years, the primary composite cardiovascular endpoint was occurred in 315 participants (10.3%). When central and peripheral SBP were analyzed separately, both central and peripheral SBP significantly associated with the primary composite endpoint (Peripheral: HR 1.047, 95% CI 1.016 to 1.079; Central: HR 1.051, 95%CI 1.020 to 1.091; Per 5 mm Hg), after adjusting age, sex, BMI, current smoking, lipid, cerebrocardiovascular disease, diabetes, antihypertensive treatment, statin treatment, hypoglycemic treatment and estimated glomerular filtration rate. When central and peripheral SBP were included in the same stepwise Cox regression, only central SBP stayed in the final model (HR 1.054, 95%CI 1.024 to 1.085, per 5 mm Hg), after adjustment for covariates. Similar trends were observed on the comparison between central and peripheral PP. Conclusions Central BP predicts the future cardiovascular risk better than peripheral BP in the elderly Chinese.

Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13 970 Contemporary High-Risk Patients With Statin Intolerance.

Among patients treated with statin therapy to guideline-recommended cholesterol levels, residual inflammatory risk assessed by high-sensitivity C-reactive protein (hsCRP) is at least as strong a predictor of future cardiovascular events as is residual risk assessed by low-density lipoprotein cholesterol (LDLC). Whether these relationships are present among statin-intolerant patients with higher LDLC levels is uncertain but has implications for the choice of preventive therapies, including bempedoic acid, an agent that reduces both LDLC and hsCRP. The multinational CLEAR-Outcomes trial (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen Outcomes Trial) randomly allocated 13 970 statin-intolerant patients to 180 mg of oral bempedoic acid daily or matching placebo and followed them for a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and for all-cause mortality. Quartiles of increasing baseline hsCRP and LDLC were assessed as predictors of future adverse events after adjustment for traditional risk factors and randomized treatment assignment. Compared with placebo, bempedoic acid reduced median hsCRP by 21.6% and mean LDLC levels by 21.1% at 6 months. Baseline hsCRP was significantly associated with the primary composite end point of major cardiovascular events (highest versus lowest hsCRP quartile; hazard ratio [HR], 1.43 [95% CI, 1.24-1.65]), cardiovascular mortality (HR, 2.00 [95% CI, 1.53-2.61]), and all-cause mortality (HR, 2.21 [95% CI, 1.79-2.73]). By contrast, the relationship of baseline LDLC quartile (highest versus lowest) to future events was smaller in magnitude for the primary composite cardiovascular end point (HR, 1.19 [95% CI, 1.04-1.37]) and neutral for cardiovascular mortality (HR, 0.90 [95% CI, 0.70-1.17]) and all-cause mortality (HR, 0.95 [95% CI, 0.78-1.16]). Risks were high for those with elevated hsCRP irrespective of LDLC level. Bempedoic acid demonstrated similar efficacy in reducing cardiovascular events across all levels of hsCRP and LDLC. Among contemporary statin-intolerant patients, inflammation assessed by hsCRP predicted risk for future cardiovascular events and death more strongly than hyperlipidemia assessed by LDLC. Compared with placebo, bempedoic acid had similar efficacy for reducing cardiovascular risk across hsCRP and LDLC strata. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02993406.

From Cardiorenal Syndrome to Chronic Cardiovascular and Kidney Disorder: A Conceptual Transition.

The association between cardiac and kidney dysfunction has received attention over the past two decades. A putatively unique syndrome, the cardiorenal syndrome, distinguishing five subtypes on the basis of the chronology of cardiac and kidney events, has been widely adopted. This review discusses the methodologic and practical problems inherent to the current classification of cardiorenal syndrome. The term "disorder" is more appropriate than the term "syndrome" to describe concomitant cardiovascular and kidney dysfunction and/or damage. Indeed, the term disorder designates a disruption induced by disease states to the normal function of organs or organ systems. We apply Occam's razor to the chronology-based construct to arrive at a simple definition on the basis of the coexistence of cardiovascular disease and CKD, the chronic cardiovascular-kidney disorder (CCKD). This conceptual framework builds upon the fact that cardiovascular and CKD share common risk factors and pathophysiologic mechanisms. Biological changes set in motion by kidney dysfunction accelerate cardiovascular disease progression and vice versa . Depending on various combinations of risk factors and precipitating conditions, patients with CCKD may present initially with cardiovascular disease or with hallmarks of CKD. Treatment targeting cardiovascular or kidney dysfunction may improve the outcomes of both. The portfolio of interventions targeting the kidney-cardiovascular continuum is in an expanding phase. In the medium term, applying the new omics sciences may unravel new therapeutic targets and further improve the therapy of CCKD. Trials based on cardiovascular and kidney composite end points are an attractive and growing area. Targeting pathways common to cardiovascular and kidney diseases will help prevent the adverse health effects of CCKD.

Effect of Glucagon-like Peptide-1 Receptor Agonist on Cardiac Structure and Function in Patients with Heart Failure: A Systematic Review and Meta-analysis

Article Effect of Glucagon-like Peptide-1 Receptor Agonist on Cardiac Structure and Function in Patients with Heart Failure: A Systematic Review and Meta-analysis Xinyu Zhang 1, and Hongyuan Zhang 2, * 1 Division of Bioscience, University College London, London, UK 2 Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK * Correspondence: hongyuan.zhang-3@postgrad.manchester.ac.uk Received: 23 May 2023 Accepted: 8 August 2023 Abstract: Recent clinical trials have shown that glucagon-like peptide-1 receptor agonists (GLP-1RAs) yield positive effects on composite cardiovascular endpoints, rendering them potentially promising therapeutic agents for heart failure (HF). This study analysed the effect of GLP-1RAs on cardiac structure and function in HF patients. MethodsA comprehensive search was conducted across PubMed, Cochrane Library, Ovid Embase, Ovid Medline, and Web of Science databases, spanning from inception to August 1, 2022, to identify randomised controlled trials (RCTs) comparing alterations in cardiac structure and function in HF patients receiving GLP-1RAs or placebo. Cardiac structures were assessed through left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular mass (LVM). Systolic function was evaluated using left ventricular ejection fraction (LVEF), stroke volume (SV), and global longitudinal strain (GLS). Diastolic function was assessed via the early to late diastolic filling velocity ratio (E/A ratio) and the early transmitral filling velocity to early diastolic mitral annular velocity ratio (E/e ratio). The I2 statistic was used to test heterogeneity. Pooled relative risks were calculated using random-effects models. Potential publication bias was assessed using the Cochrane Risk of Bias 2 tool. ResultsA total of 1,417 patients from 16 randomised placebo-controlled trials were enrolled in this meta-analysis. Among all HF patients, GLP-1RAs demonstrated improvement in diastolic function as indicated by E/A (MD = -0.15; 95% CI: -0.21 to -0.09; P &lt; 0.00001; I2 = 43%) and E/e’ (MD = -0.82; 95% CI: -1.53 to -0.11; P = 0.02; I2= 62%). However, GLP-1RAs did not exhibit any improvement in cardiac structure and systolic function parameters for HF patients. ConclusionGLP-1RAs demonstrated potential for improving diastolic function in HF patients, but did not show any impact on systolic function and cardiac structure. Therefore, the application of GLP-1RAs should be based on the specific HF type and accompanying comorbidities.

Self-measured home blood pressure highlights cardiovascular risk in women: the HOMED-BP study.

No studies examined sex differences in relation to the prognostic significance of self-measured home blood pressure (HBP). We compared the predictive power for the risk of cardiovascular events in 1547 women and 1516 men with hypertension using HBP captured at treatment-free baseline and during on-treatment follow-up, based on the Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) study. To express the change in risk for the composite cardiovascular endpoint associated with a 1-SD increase in HBP at baseline or on treatment, we derived multivariable-adjusted hazard ratios (HR) based on a Cox regression model. Over a median follow-up of 7.3 years, 100 composite events occurred, including 40 events in women. In women, systolic HBP both at baseline and on-treatment showed significant risk increment (at baseline: HR per 1-SD increment, 1.62; 95% confidence interval [CI], 1.17-2.24. on-treatment: HR, 1.74; 95% CI, 1.32-2.29). However, systolic HBP at baseline did not predict cardiovascular events in men (P = 0.25). On-treatment HBP was significantly associated with cardiovascular risk (P ≤ 0.012) irrespective of sex. Nevertheless, the point estimate of HR for systolic HBP in men (1.33) was less than that in women (1.74), and the interaction of sex with 1 SD-increase in systolic HBP in cardiovascular risk was significant irrespective of baseline (P = 0.039) or follow-up (P = 0.040) measurement when they were mutually adjusted. The increase in cardiovascular risk with the systolic HBP was steeper in women than in men for both baseline and on-treatment. The current findings unveil the importance of the control of systolic HBP, especially in women. Clinical Trial Registration: UMIN Clinical Trial Registry ( http://www.umin.ac.jp/ctr ), Unique identifier: C000000137.

Adenosine Triphosphate Citrate Lyase and Fatty Acid Synthesis Inhibition

Adenosine triphosphate citrate lyase (ACLY) is a key regulatory enzyme of glucose metabolism, cholesterol and fatty acid synthesis, and the inflammatory cascade. Bempedoic acid, an ACLY inhibitor, significantly reduces atherogenic lipid markers, including low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol, and apolipoprotein B. Additional effects of ACLY inhibition include antitumor growth; reduction of triglycerides and proinflammatory molecules such as high-sensitivity C-reactive protein; less insulin resistance; reduction of hepatic lipogenesis; and weight loss. While numerous ACLY inhibitors have been identified, most of the clinical data have focused on bempedoic acid. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) program was a series of phase 3 clinical trials that evaluated its effects on lipid parameters and safety, leading to US Food and Drug Administration approval in 2020. CLEAR Outcomes was a phase 3, double-blind, randomized, placebo-controlled trial in individuals with a history of statin intolerance, serum LDL-C level of 100 mg/dL or higher, and a history of, or at high risk for, cardiovascular disease. Bempedoic acid modestly reduced the primary 4-way cardiovascular composite end point as well as the individual components of myocardial infarction and coronary revascularization but did not reduce stroke, cardiovascular death, or all-cause mortality. Rates of gout and cholelithiasis were higher with bempedoic acid, and small increases in serum creatinine, uric acid, and hepatic-enzyme levels were also observed. ACLY inhibition with bempedoic acid has been established as a safe and effective therapy in high-risk patients who require further LDL-C lowering, particularly for those with a history of statin intolerance. The recently published CLEAR Outcomes trial revealed modest reductions in cardiovascular events with bempedoic acid, proportional to its LDL-C lowering, in high-risk individuals with statin intolerance and LDL-C levels of 100 mg/dL or higher. The additional effects of ACLY inhibition have prompted a more thorough search for novel ACLY inhibitors for conditions such as cancer, hypertriglyceridemia, chronic inflammation, type 2 diabetes, fatty liver disease, obesity, and metabolic syndrome. Similarly, therapies that reduce fatty acid synthesis are being explored for their use in cardiometabolic conditions.

Cardiovascular Safety of Testosterone-Replacement Therapy

BackgroundThe cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism has not been determined.MethodsIn a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial, we enrolled 5246 men 45 to 80 years of age who had preexisting or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng per deciliter. Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel (dose adjusted to maintain testosterone levels between 350 and 750 ng per deciliter) or placebo gel. The primary cardiovascular safety end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis. A secondary cardiovascular end point was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, assessed in a time-to-event analysis. Noninferiority required an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio among patients receiving at least one dose of testosterone or placebo.ResultsThe mean (±SD) duration of treatment was 21.7±14.1 months, and the mean follow-up was 33.0±12.1 months. A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority). Similar findings were observed in sensitivity analyses in which data on events were censored at various times after discontinuation of testosterone or placebo. The incidence of secondary end-point events or of each of the events of the composite primary cardiovascular end point appeared to be similar in the two groups. A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group.ConclusionsIn men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034.)

#3669 EFFECT OF DAPAGLIFLOZIN IN PATIENTS WITH CKD ACROSS THE SPECTRUM OF AGE AND BY SEX

Abstract Background and Aims The SGLT2 inhibitor dapagliflozin reduces the risk of progressive kidney disease and cardiovascular events in patients with and without type 2 diabetes. Among patients with CKD, baseline risks of cardiovascular disease and CKD progression vary based on age and sex. Whether the effects of dapagliflozin are uniform among patients across the spectrum of age and among men and women is unknown. Therefore, we performed a pre-specified analysis from the DAPA-CKD trial to evaluate efficacy and safety of dapagliflozin according to baseline age and sex. Method We randomized 4304 adults with baseline estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio 200–5000 mg/g to dapagliflozin 10 mg or placebo once daily. The primary endpoint was a composite of ≥50% eGFR decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary endpoints included a kidney composite endpoint (primary composite endpoint without cardiovascular death), a cardiovascular composite endpoint (hospitalized heart failure or cardiovascular death), and all-cause mortality. Study participants were categorized based on decades of age (&amp;lt;50, 50-59, 60-69, 70-79, and ≥80 years). Sex was based on self-report. We conducted time-to-event analyses using a proportional hazards (Cox) regression stratified by randomization factors (diabetes status and UACR), adjusting for baseline eGFR, and analyzed the effects of dapagliflozin on total and chronic eGFR slopes using a mixed effects linear spline model. Results Median follow-up was 2.4 years. 671 (15.6%), 935 (21.7%), 1501 (34.9%), 999 (23.2%), and 198 (4.6%) participants were &amp;lt;50, 50-59, 60-69, 70-79, and ≥80 years of age, respectively; 1425 (33.1%) were women and 2879 (66.9%) were men. Racial composition varied by age and sex; older patients were more likely to be white, younger patients were more likely to be Asian, and a higher proportion of women were black. As expected, absolute risks of the cardiovascular composite endpoint and all-cause mortality were higher in older patients; absolute risks of the kidney composite endpoint were highest in patients &amp;lt;50 (10.7 and 6.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively) and lowest in patients ≥80 years (3.0 and 1.2 per 100 patient-years in the placebo and dapagliflozin groups, respectively). There was no evidence of heterogeneity of the relative effects of dapagliflozin on the primary composite or secondary endpoints based on age or sex. Neither age nor sex modified the effects of dapagliflozin on total or chronic eGFR slope (Figure 1). Conclusion Benefits of dapagliflozin were evident across the spectrum of age and among women and men. Although younger trial participants with CKD and albuminuria were more likely to experience CKD progression, dapagliflozin reduced the risks of mortality, cardiovascular events, and CKD progression in older patients, including in more than 25% septuagenarians and octogenarians. Ageism and/or therapeutic nihilism should not diminish the use of dapagliflozin in older patients who are likely to experience considerable benefit.

#2984 ACHIEVED BLOOD PRESSURE AND CARDIOVASCULAR OUTCOMES IN PATIENTS WITH ADVANCED STAGE CHRONIC KIDNEY DISEASE

Abstract Background and Aims In patients with severely decreased eGFR (stage 4-5 CKD), efficacy of treating patients to a lower blood pressure (BP) target is uncertain. The Systolic blood PRessure INtervention Trial (SPRINT) demonstrated lower rates of a composite cardiovascular (CVD) endpoint and death in the intensive treatment group with a target systolic blood pressure (SBP) of &amp;lt;120 mmHg. This study has influenced guidelines; the updated 2021 Kidney Disease Improving Global Outcomes (KDIGO) now suggest lowering the SBP to &amp;lt; 120 mmHg, if tolerated. In this study we set out to investigate the association between SBP and CVD in a large cohort of nephrology-referred patients with CKD stage 3-5. Method We included patients ≥18 years participating in the Swedish Renal Registry (SRR-CKD) who had a first registered eGFR &amp;lt;60 ml/min/1.73 m2 2006-2017 with at least one recorded BP measurement and two out-patient visits within one year. We excluded individuals with a recorded SBP &amp;lt;100 mmHg or prior kidney failure replacement treatment. After the initial one-year observation period, we followed patients until the primary or secondary outcome was attained, or until December 31, 2017. The achieved average systolic BP, measured during routine out-patient care using any standard electronic or manual blood pressure device, was categorized into a priori defined categories. To align with SPRINT, the primary endpoint was Major Cardiovascular Events (MACE) defined as the composite of first myocardial infarction (MI), non-MI acute coronary syndrome, stroke, heart failure, or death attributable to CVD. The secondary endpoints were the individual components of the primary composite endpoint, all-cause death, or a composite of the primary endpoint and death. Demographics, body mass index, underlying kidney disease, and laboratory values at the start of follow-up were obtained from the SRR-CKD. Information on comorbidity, including Charlson comorbidity index was gathered from a linkage with the National Patient Registry; medications were obtained from the National Prescribed drug register. The primary endpoint and secondary endpoints were assessed by cause-specific Cox proportional hazards regression, adjusting for age, sex, history of CVD, Charlson comorbidity, plasma albumin, phosphate, diuretics, RAASi, betablockers, eGFR, and diastolic blood pressure. Missing data were handled through multiple imputation. Results In total 15,668 patients with a median eGFR 23 ml/min/1.73 m2, mean age 71 years and 33% women were followed over a period of 2.8 years (IQR 1.4-5.0). There were 6359 patients (41%) experiencing the primary outcome; 2601 (17%) with a coronary artery event, 1427 (9%) MI, 1,345 (9%) cerebrovascular event, and 5,480 (35%) patients died. The unadjusted analysis showed a J-shaped relationship between SBP and the primary outcome, with the lowest risk of events in patients with SBP around 125 mmHg (Figure 1). In multivariable models, there was a higher risk of experiencing the primary outcome if the average SBP was &amp;gt;150 mmHg (HR 1.09;95%CI 1.0-1.19), the highest risk being in those with SBP above 160 mmHg (HR 1.40 with 95% CI 1.28-1.53) as compared to those with SBP 130-140 mmHg (Figure 2). We observed 30% lower risk of MI when the SBP was 100–120 mmHg after adjustments (HR 0.70 (95% CI 0.56–0.88) as compared to 130–140, and higher risk of MI at SBP &amp;gt;160 mmHg (1.78; 1.49–2.12) with 11% higher risk of MI with every 10 mmHg increase in SBP (HR 1.11; 1.07–1.14). The other cardiovascular endpoints, including all-cause mortality showed a similar pattern as the primary composite endpoint. Conclusion In patients with advanced stage CKD, SBP &amp;lt;120 mmHg is associated with lower risk of MI, but not with lower risk of other cardiovascular outcomes or all-cause mortality. A SBP &amp;gt;140 mmHg was associated with higher risk of most cardiovascular events including cardiovascular mortality and all-cause mortality.

#2710 SEX DIFFERENCE IN CARDIOVASCULAR RISK IN PATIENTS WITH CHRONIC KIDNEY DISEASE: A POOLED ANALYSIS OF FOUR COHORT STUDIES

Abstract Background and Aims Progression of chronic kidney disease (CKD) has proven to be faster in men than in Women [1-3]. Whether the same holds true for cardiovascular risk remains ill-defined. Method We conducted a pooled analysis of 4 cohort studies from 40 nephrology clinics in Italy including patients with CKD (estimated GFR&amp;lt;60 ml/min/1.73m2 or higher if proteinuria &amp;gt;0.15 g/day). The aim was to compare multivariable-adjusted risk (Hazard Ratio, 95% Confidence Interval) of a composite cardiovascular endpoint (cardiovascular death and non-fatal myocardial infarction, congestive heart failure, stroke, revascularization, peripheral vascular disease, and nontraumatic amputation) in women (n = 1,192) versus men (n = 1,635). Results At baseline, women had slightly higher systolic blood pressure (SBP) as compared with men (139±19 vs 138±18 mmHg, P = 0.049), lower eGFR (33.4 vs 35.7 mL/min/1.73 m2 , P = 0.001) and lower urine protein excretion (0.30 g/day vs 0.45 g/day in men, P&amp;lt;0.001). Women did not differ from men in age and prevalence of diabetes while having a lower prevalence of cardiovascular disease, left ventricular hypertrophy and smoking habit. During a median follow-up of 4.0 years, 517 fatal and non-fatal cardiovascular events were registered (199 in women and 318 in men). The adjusted risk of cardiovascular events was lower in women (0.73, 0.60-0.89, P = 0.002) than in men; however, the cardiovascular risk advantage of women progressively diminished as SBP (as continuous variable) increased (P for interaction = 0.021; Figure 1). Similar results were obtained when considering SBP categories; when compared to men, women had a lower cardiovascular risk for SBP &amp;lt;130 mmHg (0.50, 0.31-0.80; P = 0.004) and between 130–140 mmHg (0.72, 0.53-0.99; P = 0.038), while no difference was observed for SBP&amp;gt;140 mmHg (0.85, 0.64-1.11; P = 0.232). Conclusion Higher BP levels abolish the cardiovascular protection seen in female vs male patients with overt CKD. This finding supports the need for higher awareness of hypertensive burden in women with CKD.

Effects of Dapagliflozin in Chronic Kidney Disease, With and Without Other Cardiovascular Medications: DAPA-CKD Trial.

Background The DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial (NCT03036150) demonstrated that dapagliflozin reduced the risk of kidney and cardiovascular events in patients with chronic kidney disease and albuminuria with and without type 2 diabetes. We aimed to determine whether baseline cardiovascular medication use modified the dapagliflozin treatment effect. Methods and Results We randomized 4304 adults with baseline estimated glomerular filtration rate 25 to 75 mL/min per 1.73 m2 and urinary albumin:creatinine ratio 200 to 5000 mg/g to dapagliflozin 10 mg or placebo once daily. The primary end point was a composite of ≥50% estimated glomerular filtration rate decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary end points included a kidney composite end point (primary composite end point without cardiovascular death), a cardiovascular composite end point (hospitalized heart failure or cardiovascular death), and all-cause mortality. We categorized patients according to baseline cardiovascular medication use/nonuse. Patients were required by protocol to receive a stable (and maximally tolerated) dose of a renin-angiotensin-aldosterone system inhibitor. We observed consistent benefits of dapagliflozin relative to placebo, irrespective of baseline use/nonuse of renin-angiotensin-aldosterone system inhibitors (98.1%), calcium channel blockers (50.7%), β-adrenergic antagonists (39.0%), diuretics (43.7%), and antithrombotic (47.4%), and lipid-lowering (15.0%) agents. Use of these drugs in combination with dapagliflozin did not increase the number of serious adverse events. Conclusions The safety profile and efficacy of dapagliflozin on kidney and cardiovascular end points in patients with chronic kidney disease were consistent among patients treated and not treated at baseline with a range of cardiovascular medications. Registration Information clinicaltrials.gov. Identifier: NCT03036150.

Sex-differences in associations of LV structure and function measured by echocardiography with long-term risk of mortality and cardiovascular morbidity.

Three-dimensional echocardiography (3DE) measures of the left ventricle (LV) predict outcomes in high risk individuals, but their prognostic value in the general population is unknown. We aimed to establish whether 3DE was associated with mortality and morbidity in a multi-ethnic community-based sample, if associations differed by sex, and explored potential mechanisms explaining sex differences. 922 individuals (69.7 ± 6.2 years; 717 men) from the SABRE study underwent a health examination including echocardiography. Associations between 3DE LV measures (ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), LV remodeling index (LVRI) and LV sphericity index (LVSI), and all-cause mortality and a composite cardiovascular endpoint [comprising new onset (non)fatal coronary heart disease, heart failure hospitalization, new-onset arrhythmias and cardiovascular mortality] were determined using multivariable Cox regression over a median follow-up of 8 years (all-cause mortality) and 7 years (composite cardiovascular endpoint). There were 123 deaths and 151 composite cardiovascular endpoints. Lower EF, higher LV volumes and LVSI were associated with increased all-cause mortality, and higher LV volumes were associated with the composite cardiovascular endpoint independent of potential confounders. Associations between LV volumes, LVRI, LVSI, and mortality differed by sex (p interaction <0.1). In men increased LV volumes and LVSI and decreased LVRI and EF were associated with higher mortality, but associations were null or reversed in women (hazard ratios (95% CI) men vs. women: EDV 1.25 (1.05, 1.48) vs. 0.54 (0.26, 1.10); ESV, 1.36 (1.12, 1.63) vs. 0.59 (0.33, 1.04); LVRI, 0.79 (0.64, 0.96) vs. 1.70 (1.03, 2.80); LVSI, 1.27 (1.05, 1.54) vs. 0.61 (0.32, 1.15); and EF, 0.78 (0.66, 0.93) vs. 1.27 (0.69, 2.33). Similar sex differences were observed for associations with the composite cardiovascular outcome. Adjustment for LV diastolic stiffness and arterial stiffness marginally attenuated these differences. 3DE measures of LV volume and remodeling are associated with all-cause mortality and cardiovascular morbidity; however, some associations differ by sex. Sex-differences in LV remodeling patterns may influence mortality and morbidity risk in the general population.

Prevalence and Effects of High-Intensity Statins for Japanese Patients Presenting With Acute Coronary Syndrome - A Post Hoc Secondary Analysis of STOPDAPT-2 ACS.

The REAL-CAD trial, reported in 2017, demonstrated a significant reduction in cardiovascular events with high-intensity statins in patients with chronic coronary syndrome. However, data are scarce on the use of high-intensity statins in Japanese patients with acute coronary syndrome (ACS). In STOPDAPT-2 ACS, which exclusively enrolled ACS patients between March 2018 and June 2020, 1,321 (44.2%) patients received high-intensity statins at discharge, whereas of the remaining 1,667 patients, 96.0% were treated with low-dose statins. High-intensity statins were defined as the maximum approved doses of strong statins in Japan. The incidence of the cardiovascular composite endpoint (cardiovascular death, myocardial infarction, definite stent thrombosis, stroke) was significantly lower in patients with than without high-intensity statins (1.44% vs. 2.69% [log-rank P=0.025]; adjusted hazard ratio [aHR] 0.48, 95% confidence interval [CI] 0.24-0.94, P=0.03) and the effect was evident beyond 60 days after the index percutaneous coronary intervention (log-rank P=0.01; aHR 0.38, 95% CI 0.17-0.86, P=0.02). As for the bleeding endpoint, there was no significant difference between the 2 groups (0.99% vs. 0.73% [log-rank P=0.43]; aHR 0.96, 95% CI 0.35-2.60, P=0.93). The prevalence of high-intensity statins has increased substantially in Japan. The use of the higher doses of statins in ACS patients recommended in the guidelines was associated with a significantly lower risk of the primary cardiovascular composite endpoint compared with lower-dose statins.

Sex difference in cardiovascular risk in patients with chronic kidney disease: pooled analysis of four cohort studies.

Progression of chronic kidney disease (CKD) has proven to be faster in men than in women. Whether the same holds true for cardiovascular risk remains ill-defined. We conducted a pooled analysis of 4 cohort studies from 40 nephrology clinics in Italy including patients with CKD (estimated GFR<60ml/min/1.73m2 or higher if proteinuria>0.15g/day). The aim was to compare multivariable-adjusted risk (Hazard Ratio, 95% Confidence Interval) of a composite cardiovascular endpoint (cardiovascular death and non-fatal myocardial infarction, congestive heart failure, stroke, revascularization, peripheral vascular disease, and non-traumatic amputation) in women (n=1192) versus men (n=1635). At baseline, women had slightly higher systolic blood pressure (SBP) as compared with men (139±19vs 138±18mmHg, P=0.049), lower eGFR (33.4vs 35.7mL/min/1.73 m2, P=0.001) and lower urine protein excretion (0.30g/day vs 0.45g/day in men, P<0.001). Women did not differ from men in age and prevalence of diabetes while having a lower prevalence of cardiovascular disease, left ventricular hypertrophy and smoking habit. During a median follow-up of 4.0 years, 517 fatal and non-fatal cardiovascular events were registered (199 in women and 318 in men). The adjusted risk of cardiovascular events was lower in women (0.73, 0.60-0.89, P=0.002) than in men; however, the cardiovascular risk advantage of women progressively diminished as SBP (as continuous variable) increased (P for interaction=0.021). Similar results were obtained when considering SBP categories; when compared to men, women had lower cardiovascular risk for SBP <130mmHg (0.50, 0.31-0.80; P=0.004) and between 130-140mmHg (0.72, 0.53-0.99; P=0.038), while no difference was observed for SBP>140mmHg (0.85, 0.64-1.11; P=0.232). Higher BP levels abolish the cardiovascular protection seen in female vs male patients with overt CKD. This finding supports the need for higher awareness of hypertensive burden in women with CKD.

Efficacy of Dapagliflozin by Baseline Diabetes Medications: A Prespecified Analysis From the DAPA-CKD Study.

To determine whether the benefits of dapagliflozin in patients with type 2 diabetes and chronic kidney disease (CKD) in the Dapagliflozin And Prevention of Adverse Outcomes in CKD trial (DAPA-CKD) varied by background glucose-lowering therapy (GLT). We randomized 4,304 adults (including 2,906 with type 2 diabetes) with a baseline estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio of 200-5,000 mg/g to dapagliflozin 10 mg or placebo once daily (NCT03036150). The primary end point was a composite of ≥50% eGFR decline, end-stage kidney disease, and kidney or cardiovascular cause of death. Secondary end points included a kidney composite end point (primary composite end point without cardiovascular death), a cardiovascular composite end point (hospitalized heart failure or cardiovascular death), and all-cause mortality. In this prespecified analysis, we investigated the effects of dapagliflozin on these and other outcomes according to baseline GLT class or number of GLTs. The effects of dapagliflozin on the primary composite outcome were consistent across GLT classes and according to the number of GLTs (all interaction P > 0.08). Similarly, we found consistent benefit of dapagliflozin compared with placebo on the secondary end points regardless of background GLT class or number of GLTs. The same applied to the rate of decline in the eGFR rate and safety end points. Dapagliflozin reduced the initiation of insulin therapy during follow-up compared with placebo (hazard ratio 0.72; 95% CI 0.54-0.96; P = 0.025). Dapagliflozin reduced kidney and cardiovascular events in patients with type 2 diabetes and CKD across baseline GLT class or classes in combination.