Risk Of All-cause Death Research Articles

Clinical effectiveness of nirmatrelvir plus ritonavir for patients with COVID-19 and preexisting psychiatric disorders

ABSTRACT Objectives This study assessed the clinical effectiveness of the combination of nirmatrelvir and ritonavir (NMV-r) in treating nonhospitalized patients with COVID-19 who have preexisting psychiatric disorders. Methods Patients diagnosed with COVID-19 and psychiatric disorders between 1 March 2020, and 1 December 2022, were included using the TriNetX network. The primary outcome was the composite outcome of all-cause emergency department (ED) visits, hospitalization, or death within 30 days. Results Propensity score matching yielded two cohorts of 20,633 patients each. The composite outcome of all-cause ED visits, hospitalization, or death within 30 days was 3.57% (737 patients) in the NMV-r cohort and 5.69% (1176) in the control cohort, resulting in a reduced risk in the NMV-r cohort (HR: 0.657; 95% confidence interval (CI): 0.599–0.720). The NMV-r cohort exhibited a lower risk of all-cause hospitalization (HR: 0.385; 95% CI: 0.328–0.451) and all-cause death (HR: 0.110; 95% CI: 0.053–0.228) compared with the control group. Conclusion NMV-r could mitigate the risk of adverse outcomes in nonhospitalized patients with COVID-19 and preexisting psychiatric disorders. However, only a limited number of patients in this population received adequate treatment, thus emphasizing the importance of promoting its appropriate use.

Association of age at diagnosis of type 2 diabetes mellitus with the risks of the morbidity of cardiovascular disease, cancer and all-cause mortality: Evidence from a real-world study with a large population-based cohort study.

To investigate the impact of diagnosis age of type 2 diabetes mellitus (T2DM) on subsequent adverse outcomes within the Chinese population. 549,959 eligible T2DM patients were included from Ningbo and Jinhua city in Zhejiang province, China. Standardized ratio was used to evaluate the risks of coronary heart disease (CHD), stroke, cancer and all-cause death in different T2DM diagnosis age groups. For all adverse outcomes, higher excess risks were observed in the youngest age group (30-39) than in the oldest age group (≥80) with T2DM. The standardized incidence ratios (SIR) were 5.93 (95 % CI: 3.46, 10.14) for CHD, 5.45 (95 % CI: 3.72, 7.99) for stroke and 1.85 (95 % CI: 1.38, 2.49) for cancer in the youngest age group, and were 1.32 (95 % CI: 1.08, 1.60) for CHD, 1.25 (95 % CI: 1.08, 1.44) for stroke, and 0.78 (95 % CI: 0.56, 1.09) for cancer, respectively, in the oldest age group. The standardized mortality ratios (SMR) for all-cause death were 3.15 (1.69, 5.84) vs. 1.12 (0.88,1.43). These excess risks decreased with increasing diagnosis age (all P value < 0.001). Consistent results were observed when individuals were stratified by sex or further excluded with the time from T2DM diagnosis to endpoints less than 1 or 2 years. The earlier the diagnosis of T2DM, the higher the risk for subsequent adverse outcomes. It is imperative to enhance the management and monitoring of early-onset patients during follow-up.

The contribution of cumulative blood pressure load to dementia, cognitive function and mortality in older adults.

Few studies evaluated the contribution of long-term elevated blood pressure (BP) towards dementia and deaths. We examined the association between cumulative BP (cBP) load and dementia, cognitive decline, all-cause and cardiovascular deaths in older Australians. We also explored whether seated versus standing BP were associated with these outcomes. The Sydney Memory and Aging Study included 1037 community-dwelling individuals aged 70-90 years, recruited from Sydney, Australia. Baseline data was collected in 2005-2007 and the cohort was followed for seven waves until 2021. cSBP load was calculated as the area under the curve (AUC) for SBP ≥140 mmHg divided by the AUC for all SBP values. Cumulative diastolic BP (cDBP) and pulse pressure (cPP) load were calculated using thresholds of 90 mmHg and 60 mmHg. Cox and mixed linear models were used to assess associations. Of 527 participants with both seated and standing BP data (47.7% men, median age 77), 152 (28.8%) developed dementia over a mean follow-up of 10.5 years. Higher cPP load was associated with a higher risk of all-cause deaths, and cSBP load was associated with a higher risk of cardiovascular deaths in multivariate models ( P for trend < 0.05). Associations between cPP load, dementia and cognitive decline lost statistical significance after adjustment for age. Differences between sitting and standing BP load were not associated with the outcomes. Long-term cPP load was associated with a higher risk of all-cause deaths and cSBP load associated with a higher risk of cardiovascular deaths in older Australians.

Impact of sex-specific thresholds for low flow in assessment of prognosis in concordantly and discordantly graded aortic valve stenosis.

Sex-specific low flow was recently defined as stroke volume index (SVi) ≤40 ml/m² in men and ≤32 ml/m² in women. We tested the prognostic association of these cut-offs in patients with aortic stenosis (AS) with concordantly and discordantly graded AS (CGASEL and DGASEL) based on pressure recovery adjusted aortic valve area (energy loss, EL). Data from 1351 patients with asymptomatic AS, peak jet velocity <4m/s and preserved left ventricular ejection fraction enrolled in the Simvastatin and Ezetimibe in AS study was used. DGASEL was defined as EL <1.0 cm² with mean aortic gradient <40 mmHg, and CGASEL as EL ≥1.0 cm² with mean aortic gradient <40mmHg. Patients were further grouped into normal and low flow. Outcome was combined all-cause death and hospitalization for heart failure. CGASEL with normal/low flow was present in 915/253 patients, and DGASEL with normal/low flow in 57/126 patients. During median 4.3 years follow-up, event-free survival was lower in patients with DGASEL irrespective of flow compared to CGASEL with normal flow (p<0.05). In Cox regression analysis, DGASEL with normal or low flow were both associated with increased risk of all-cause death and hospitalization for heart failure after adjustment for age, sex, heart rate, randomized study treatment, hypertension, aortic valve replacement and aortic valve calcification (p<0.05). No survival difference was found between patients with normal vs. low flow within groups of DGASEL or CGASEL. Identification of low flow by the proposed sex-specific thresholds of SVi needs more prognostic validation before application in clinical practice.

Sodium-glucose cotransporter-2 inhibitors in acute myocardial infarction: a systematic review and meta-analysis of randomized controlled trials.

We aimed to assess the efficacy and safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus placebo, initiated within the hospitalization period, in addition to habitual treatment, for treating adult patients with confirmed acute myocardial infarction (AMI). We also conducted subgroup analysis by diabetes mellitus (DM) status and type of AMI. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs). The primary outcome was hospitalization for heart failure (HF). The secondary outcomes were all-cause death, cardiovascular death, and serious adverse events (AEs). We pooled risk ratios (RR) with a 95% confidence interval (CI) for binary outcomes. The between-study variance was assessed using tau2 statistics. We included five RCTs, encompassing 11,211 patients. SGLT2i significantly reduced the risk of hospitalization for HF compared to placebo (RR 0.73; 95% CI [0.61, 0.88]). However, the risk of all-cause death (RR 1.05; 95% CI [0.78, 1.41]) and cardiovascular death (RR 1.04; 95% CI [0.84, 1.29]) was similar between the groups, as well as the risk of serious AEs (RR 1.01; 95% CI [0.90, 1.14]). In the subgroup analysis by DM status and type of AMI, there were no significant subgroup differences for the outcomes of hospitalization for HF and all-cause death. In patients with AMI, treatment with SGLT2i is safe and significantly reduces the risk of hospitalization for HF, but it has no impact on all-cause death and cardiovascular death compared to placebo.

Implications of renal function on adverse clinical events in patients with atrial fibrillation: a comparative analysis of VKA and NOAC therapy - Insights from the GLORIA-AF Registry Phase III

Abstract Background Renal function, as assessed by creatinine clearance (CrCl), plays a crucial role in determining the efficacy and safety of oral anticoagulant (OAC) therapy in patients with atrial fibrillation (AF). Purpose To investigate the relationships between CrCl and the risk of clinical adverse events in patients with AF receiving OAC therapy, comparing the safety profiles of vitamin K antagonists (VKA) and non-vitamin K antagonist oral anticoagulants (NOACs). Methods Anticoagulated AF patients from the prospective Global Registry on Long-Term Oral Anti-Thrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) registry Phase III were studied. CrCl was calculated for renal function, according to Cockcroft-Gault equation. Restricted cubic spline (RCS) were used to explore the nonlinear association between adverse end events and CrCl, comparing VKA and NOAC therapy. Cox regression models were used to analysis the associations between adverse end events and OAC therapy in patients with different CrCl levels, adjusted by clinical features and previous disease. Patients were followed up for the composite outcome (all-cause death, thromboembolism and major bleeding), all-cause death, cardiovascular disease (CVD), major bleeding, myocardial infarction (MI) and stroke. Results In 10,594 AF patients (mean age 70.35 ± 9.92 years; 55% male; 73% on NOAC), RCS analysis revealed decreased risks of all cause death, composite outcomes and CVD with increasing CrCl in patients with CrCl &amp;lt; 80 mL/min. Multivariate Cox models indicated that NOAC therapy associated with lower risk of all cause death (HR 0.68, 95% CI 0.58-0.78), composite outcomes (HR 0.77, 95% CI 0.68-0.86), CVD (HR 0.7, 95% CI 0.56-0.87), major bleeding (HR 0.74, 95% CI 0.61-0.91) in AF patients. For CrCl &amp;gt; 95 mL/min, a lower risk of all cause death (HR 0.56, 95% CI 0.38-0.82), composite outcomes (HR 0.68, 95% CI 0.51-0.91) and major bleeding (HR 0.54, 95% CI 0.35-0.85) were associated with NOAC therapy, vs. VKA. For CrCl &amp;lt; 30 mL/min, a lower risk of all cause death (HR 0.47, 95% CI 0.28-0.81), composite outcomes (HR 0.56, 95% CI 0.35-0.89) and CVD (HR 0.43, 95% CI 0.20-0.90) were related to NOAC therapy. No significant difference in outcomes between VKA and NOAC were found in patients with moderate CrCl. Conclusion Increasing CrCl were associated with decreased risk of adverse clinical events, including all-cause death and CVD in anticoagulated AF patients. For patients with CrCl &amp;gt;= 95 and &amp;lt; 30, NOAC therapy, was associated with lower risks of adverse outcomes.Figure 1Figure 2

One-year risk of all-cause death and major cardiovascular events in patients presenting with hypertensive crisis. A report from a global federated research health network

Abstract Background Few data are available about the clinical course of patients presenting with hypertensive crisis who are discharged alive from hospital. Purpose To assess the long-term risk of adverse events in patients with hypertensive crises. Methods Retrospective study utilizing a research health network. Based on the ICD-10-CM codes recorded between 2000 and 2022, from 85 health care associations mainly located in the United States, patients with hypertensive crisis were subdivided into hypertensive urgencies (I16.0) and hypertensive emergencies (I16.1). In those with hypertensive emergencies, the type of target organ damage was reported, ie. central nervous system (ischemic stroke, hypertensive encephalopathy, intracerebral hemorrhages), cardiovascular (CVS: myocardial infarction (MI), heart failure (HF), aorta dissection (AD)), or renal (acute kidney failure). Primary outcomes were the one-year risks of all-cause death, and major cardiovascular events (MACE: MI, stroke, cardiac arrest, AD, and HF). Secondary outcomes were the risks for each type of MACE. Cox regression analysis after propensity score matching (PSM) 1:1 was used to produce hazard ratios (HRs) and 95% Confidence Intervals (95%CIs). Results Overall, we identified 25 294 patients with hypertensive emergency (age 62.4±15.7, 46.1% females) and 21,737 patients with hypertensive urgency (age 63.5±17.2, 55.5% females). Patients with hypertensive emergency were more likely males, Black or African American origin and showed a higher prevalence of chronic hypertensive-related complications, vs. those with hypertensive urgency. After PSM, patients with hypertensive emergency showed a higher risk of all-cause death (HR, 1.34, 95%CI 1.25-1.44) and MACE (HR 4.09, 95%CI 3.87-4.33), vs. those with hypertensive urgency. Of the secondary outcomes, patients with hypertensive emergency had increased risks of MI (HR 3.33, 95%CI 3.03-3.67), stroke (HR 4.73, 95%CI 4.33-5.17), cardiac arrest (HR 1.30, 95%CI 1.07-1.58), AD (HR 5.49, 95%CI 3.90-7.73), and HF (HR 3.01, 95%CI 2.74-3.14). All the different types of organ involvement during the hypertensive emergency were each associated with similar long-term risks of adverse events (Figure 1). Conclusion Patients with hypertensive emergency have a high long-term risk of MACE and all-cause death. Preventing the onset of target organ damage in patients with hypertensive crisis is crucial to mitigate their long-term risk of adverse events.

Causes and predictors of long-term mortality in patients referred to a cardiac rehabilitation program

Abstract Introduction Cardiac rehabilitation (CR) programs have proven to reduce short-term mortality in patients with ischemic heart disease (IHD) and hospitalization rates in patients with heart failure (HF) (1-3). However, there is insufficient evidence about long-term mortality (&amp;gt;24-36 months) for patients receiving treatments based on recent clinical practice recommendations. Purpose To assess the long-term prognosis and predictors of mortality in a heterogenous group of patients referred to cardiac rehabilitation, and to obtain a detailed overview of death causes. Methods An inferential analysis of consecutive patients referred for exercise-based CR at a single site between January 2016 and January 2021 was performed. Included subjects were classified attending to four indications for referral: IHD, HF, valvular heart disease (VHD) and cancer therapy-related cardiovascular toxicity (CTR-CVT). Patients who did not initiate the CR program or were referred for other indications were excluded. The primary endpoint was all cause death. The secondary endpoint was cardiovascular (CV) death. A survival analysis was performed using Kaplan Meier estimates for each referral indication and a Cox proportional hazards model was fitted to investigate mortality predictors. The initiation of the exercise program was considered the inclusion date, and patients were followed until they met the primary endpoint or censored by January 2024. Results A total of 1180 patients were included in the analysis (81% male, mean age 61 ± 11 years), with a median follow-up of 5.3 years. Most of the patients had been referred due to IHD (87%), while the proportion for HF, VHD, and CTR-CVT was 9.9%, 1.8% and 1.4%, respectively. Seventy-eight patients (6.6%) died during follow-up, with a Kaplan-Meier estimated survival of 94.5% at 5 years (95% CI 93.2%-95.9%). Nineteen patients (24.4%) died due to a cardiovascular event, mostly sudden cardiac death (47%). The predominant non-CV causes of death were infectious disease (36%) and cancer (34%). A multivariate Cox model analysis (Table 1) showed an increased risk of all cause death for patients referred due to HF (HR 2.95, 95% CI 1.33 - 6.55), VHD (HR 5.55, 95% CI 1.19 - 25.9) and CTR-CVT (22.47, 95% IC 7.32 - 68.95) when compared to IHD (Figure 1). Other significant predictors of mortality were LVEF &amp;lt;40%, male sex, age, diabetes, peripheral vascular disease, and multivessel coronary disease. Only LVEF &amp;lt;40%, VHD, CTR-CVT and peripheral vascular disease were independent predictors of CV death. Conclusion Patients who initiated an exercise-based CR program had a low risk of all cause death at 5 years. Indications for CR other than IHD were associated with higher mortality rates after adjusting for confounder variables, likely due to a selection bias of patients in advanced stages of the disease.Table 1.Cox models for all-cause deathFigure 1.KM plot for all-cause death

Cardiovascular outcomes in acute coronary syndrome patients with cancer: a statewide population-linkage study

Abstract Background Advances in oncology treatment have led to an increase in the number of cancer survivors. As a result, the number of acute coronary syndrome (ACS) patients with cancer is increasing and the outcomes of these patients are not well described. Purpose This study aimed to examine revascularisation strategies and all cause and cardiovascular death in ACS patients with and without cancer. Methods Hospitalised patients in New South Wales, Australia, from July 2006 to December 2020 with a primary diagnosis of ACS were identified from the statewide Admitted Patient Data Collection database. Patients were stratified into those with or without a history of cancer (non-melanoma skin cancers excluded). Propensity scoring matching (PSM) for the variables of age, gender and cardiovascular risk factors was performed with each cancer patient matched to two non-cancer patients. Cox proportional hazards regression model was used to evaluate the hazard ratios of all-cause mortality between individuals with a history of cancer in the 5 years preceding their hospital admission, and those without. Additionally, Fine-Gray competing risk analysis was performed for cardiovascular death with non-cardiovascular mortality as the competing event. Results During the study period, 193,848 patients were admitted with ACS. 12,543 patients had a history of cancer and were PSM to 25,085 patients without cancer. The median age was 75 (Q1-Q3 67-82) years with 69% male and hypertension the most prevalent risk factor (55%) (Table 1). ACS patients with cancer had clinically comparable, rates of percutaneous revascularisation (36 vs 37%, p=0.07) and coronary artery bypass grafting (11 vs 13%, p&amp;lt;0.001) with ACS patients without cancer. During a median follow up of 8.6 (95% CI 8.4-8.8) years, ACS patients with a history of cancer had a significant higher risk of all cause death (HR 1.42 95% CI [1.38-1.46]) and cardiovascular death (SHR 1.14 [1.11-1.18]). The cumulative incidence function demonstrated cardiovascular death in those with a cancer history occurred in 20% by approximately 1.4 years follow up compared to 2.5 years in those without cancer (Figure 1). Conclusion ACS patients with cancer have a higher risk of all cause death and cardiovascular death compared to those without a history of cancer with clinically comparably revascularisation rates. Further studies to determine the cause of increased cardiovascular death in ACS patients with cancer are required.Figure 1

Organ perfusion pressure: a significant predictor of outcomes in cardiogenic shock

Abstract Background Cardiogenic shock (CS) is an ominous condition with a high mortality rate. The diagnosis of CS relies upon signs and/or symptoms of end-organ hypoperfusion. However, the combination of hypoperfusion and systemic congestion poses a serious risk and significantly increases mortality rates in critically ill patients. Purpose This study evaluated organ perfusion pressure (OPP), calculated as mean arterial pressure (MAP) minus central venous pressure (CVP), as a predictor of outcomes in CS. Methods All consecutive patients with CS related to acute myocardial infarction (AMI-CS) or acutely decompensated heart failure (ADHF-CS) enrolled in the multicenter Altshock-2 registry between January 2020 and November 2023 were selected. Only patients with both OPP and primary endpoint data available were included in the analysis. The primary outcome was in-hospital all-cause mortality. Results 316 patients fulfilled the inclusion criteria (mean age: 64±13 years, 62 [20%] females, mean left ventricular ejection fraction: 24%±10%, mean MAP: 71±16 mmHg, mean CVP: 12±6 mmHg). Mean OPP was 59.1±17.3 mmHg. In-hospital all-cause death occurred in 117 (37%) patients. In univariable analysis, higher OPP was associated with a significantly lower risk of in-hospital all-cause death both as a continuous variable (HR 0.981 per mmHg [95%CI 0.969-0.993], p-value=0.003) and dichotomized (HR 0.522 [95%CI 0.354-0.770], p-value=0.001) according to the optimal cut-off value of 59.5 mmHg identified by receiver operating characteristic curve analysis (specificity 66.4%, sensitivity 53.8%, area under the curve 0.61). OPP greater than 59.5 mmHg predicted significantly reduced risk of in-hospital all-cause death among ADHF-CS patients (HR 0.315 [95%CI 0.151-0.660], p-value=0.002), but not among AMI-CS patients (HR 0.628 [95%CI 0.392-1.007], p-value=0.054). After multivariable adjustment for significant clinical data available at first bedside assessment, namely age and Sequential Organ Failure Assessment score, higher OPP still predicted significantly lower risk of in-hospital all-cause death (HR 0.984 [95%CI 0.972-0.996], p-value=0.010). In univariable analysis, OPP was also associated with significantly increased long-term overall survival (p-value&amp;lt;0.001), but not with worsening renal function at 24 hours after CS onset, in-hospital length of stay or the composite of left ventricular assist device implantation or heart transplantation. Conclusions In this multicenter, observational, prospective study of patients hospitalized for CS, higher OPP on admission was associated with a significantly reduced risk of in-hospital all-cause death.

Adherence to the Atrial Fibrillation Better Care (ABC) pathway and outcomes in patients with chronic kidney disease: A report from the APHRS-AF registry

Abstract Background The Atrial Fibrillation Better Care (ABC) pathway is based on three pillars: "A" avoid stroke with oral anticoagulation, "B" better symptoms control, and "C" optimization of cardiovascular risk factors and lifestyles. This integrated approach has been associated with improved outcomes in atrial fibrillation (AF) patients, but few data are available in patients with chronic kidney disease (CKD). Purpose To investigate the correlation between chronic kidney disease, adherence to the ABC pathway, and the occurrence of adverse events in patients with AF enrolled in the Asian-Pacific Heart Rhythm Society-AF Registry. Methods Logistic regression was used to investigate factors associated with CKD, warfarin use and rhythm control strategies. Cox regression analysis adjusted for age≥75 years, paroxysmal AF, CHA2DS2VASc≥2, chronic obstructive pulmonary disease, cancer, and ABC adherence was used to calculate Hazard Ratios (HRs) and 95% Confidence Interval (CI) for the risk of primary outcomes in patients with CKD (eGFR &amp;lt;60 ml/min/1.73m2). Sensitivity analyses were performed in moderate (eGFR 59-30) and severe CKD (eGFR&amp;lt;30). Interaction analysis investigated the effect of ABC pathway based on presence or absence of CKD. Primary outcomes were the risks of all-cause death, major cardiovascular events (MACE: Cardiovascular death, acute coronary syndromes, thromboembolic events, and acute heart failure) and major bleeding. Results We included 2 578 AF patients without CKD (age 66.5±11.3 years, 32.5% females) and 1 047 AF patients with CKD (75.3±10.3 years, 40.8% females). Lower ABC pathway full adherence was observed in CKD patients (42.1% vs 29.5%, p&amp;lt;0.001), primarily due to low adherence to "A" and "C" criteria. Logistic regressions confirmed the lower likelihood of anticoagulation (Odds Ratio (OR) 0.61, 95%CI 0.44-0.83), a higher use of warfarin (OR 1.50, 95%CI 1.23-1.83) and lower use of rhythm control strategies (OR 0.79, 95%CI 0.66-0.94) in CKD patients. After one-year follow up, patients with CKD had a higher incidence of all-cause death (1.6% vs 7.2%, p&amp;lt;0.001) and MACE (3.4% vs 8.1%, p,0.001) compared to those without CKD. On Cox multivariable analysis (Figure 1, Panel A-D), CKD and ABC adherence were independently associated with the risk of all-cause death (HR 2.54, 95%CI 1.69-3.80 and HR 0.57, 95%CI 0.35-0.93, respectively) and MACE (HR 1.58, 95%CI 1.14-2.20 and HR 0.66, 95%CI 0.46-0.95, respectively). The risk of primary outcomes was the highest in those with severe CKD. No association was found with the risk of major bleeding. The interaction analysis confirmed that the beneficial effect of ABC pathway adherence on death (p int= 658) and MACE (p int= 0.568) was irrespective of CKD. Conclusion AF patients with CKD have low ABC pathway adherence and high risk of all-cause death and MACE. Efforts to improve the ABC pathway adherence in AF patients with CKD are needed to improve their long-term clinical outcomes.Figure 1.Cox regression analyses

Diabetes mellitus and adverse clinical events in patients with atrial fibrillation: implications of insulin treatment: a report from the GLORIA-AF Registry Phase III

Abstract Background Atrial Fibrillation (AF) and diabetes mellitus (DM) are both associated with adverse clinical events, but the associations has not been fully elucidated, especially in relation to insulin use. Purpose To analyze the associations between DM and the risk of clinical adverse events in patients with AF, and second, explore the impact of insulin treatment in these patients. Methods We studied patients with AF from the prospective Global Registry on Long-Term Oral Anti-Thrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) registry with 3-years follow-up. Clinical events included all-cause death, major bleeding, myocardial infarction (MI), stroke, thromboembolism (TE), and major adverse cardiovascular events (MACE). MACE was defined as a composite of stroke, MI and major bleeding. Kaplan-Meier curves were used to estimate the cumulative incidence of clinical events. Multivariable cox regression models with subgroups were used to estimate the association between DM and the risk of mortality and clinical events. Results A total of 15,861 AF patients were included (mean age 70.00 ± 10,21 years old; 55% male, 20% Asia), of which 3,666 had DM (mean age 70.04 ± 9.54 years old; 59% male, 21% Asia). Kaplan-Meier curves showed that AF patients with DM had higher cumulative hazard of all outcomes, including all-cause death (OR: 1.56, 95%CI: 1.38-1.77), CVD (OR: 1.72, 95%CI: 1.44-2.06), major bleeding (OR: 1.4, 95%CI: 1.17-1.67), stroke (OR: 1.29, 95%CI: 1.04-1.61), TE (OR: 1.26, 95%CI:1.02-1.56), MI (OR: 1.88, 95%CI: 1.48-2.39) and MACE (OR: 1.61, 95%CI: 1.41-1.84). After adjustment by prior disease and drugs, the outcomes of stroke (OR: 1.19, 95%CI: 0.95-1.49) and TE (OR: 1.22, 95%CI: 0.98-1.52) showed not significant. Subgroup analysis found that increased risks of stroke were found in female (OR: 1.43, 95%CI: 1.03-1.98, Pinteraction = 0.062) and non-Asian patients (OR: 1.39, 95%CI: 1.06-1.82, Pinteraction = 0.175) with DM. For all cause death, subgroup results were similar with overall patients. In addition, insulin use increased the risk of all cause death (OR: 1.82, 95%CI: 1.45-2.29), CVD (OR: 1.70, 95%CI: 1.22-2.37), major bleeding (OR: 1.54, 95%CI: 1.08-2.18), MI (OR: 1.72, 95%CI: 1.12-2.64), MACE (OR: 1.65, 95%CI: 1.28-2.11) in patients with AF and DM. Multivariable model showed similar result. Conclusions DM was independently associated with higher risk of all-cause death, CVD, MI, major bleeding, and MACE in patients with AF. Insulin use was associated with higher risk of all-cause death, CVD, MI, major bleeding, and MACE in patients with AF and DM.Figure 1Figure 2

Right ventricular dysfunction parameters at echocardiography in patients with acute pulmonary embolism: meta-analysis of individual participant data

Abstract Background &amp; Aim Echocardiography has a crucial role for decision making on management of patient with acute pulmonary embolism (PE) according to current international guidelines. However, the definition of right ventricle dysfunction (RVD) at echocardiography requires standardization. We performed an Individual patient data meta-analysis (IPDMA) to assess the role of individual parameters of RVD and of combinations of parameters for the prediction of short-term all-cause mortality and PE-related death. Methods A systematic search was run to identify clinical studies reporting on RVD at echocardiography and on short-term clinical outcome in patients with acute PE. Individual patient data from the original studies were pooled to perform a meta-analysis (IPDMA). The study outcomes were short-term death defined as death occurring within 30 days from PE diagnosis and PE-related death. Multiple imputation was used for the management of missing data. The odds ratio for all cause and PE related mortality were calculated using generalized linear mixed effects model. Results Individual data from 9,233 patients with acute PE from 16 studies were pooled in a unique database. All cause short-term mortality occurred in 9% of patients (95% CI 0.06-0.13, I2 93%). The IPDMA was feasible for the following parameters: tricuspid anulus systolic excursion (TAPSE), estimated pulmonary artery pressure (PAP) &amp;gt;30mmHg, right to left ventricle diameter ratio (RV/LV)&amp;gt;1, hypokinesia, paradoxical septal motion, RV diameter&amp;gt;30 mm and McConnel sign. All these parameters, except for PAP&amp;gt;30mmHg and RV diameter&amp;gt;30 mm, were predictors of short-term all cause death in the overall population and in hemodynamically patients (table). All the assessed RV findings, except for the McConnell’s sign, were predictors of PE-related death (Table). The presence of one RVD parameter only was not associated with increased risk of all cause death (OR 1.22, 95% CI 0.97-1-54), while the presence of two parameters or ≥ three parameters were (OR 1.63, 95% CI 1.24-2.15; OR 2.07 95% CI 1.59-2.69, respectively). Conclusion In patients with acute PE, the majority of RVD parameter at echocardiography are predictors of short-term death and of PE-related death. The higher the number of RVD parameters the worst the prognosis. These results claim for standardization in RVD definition to guide decision making for patient management.

Plasma levels of human growth differentiation factor 15 (GDF-15) and their effect of alirocumab on major adverse cardiovascular events and all-cause death after acute coronary syndrome

Abstract Background Human growth differentiation factor 15 (GDF-15) is a stress response cytokine of the transforming growth factor-β superfamily with roles in health and disease, cell survival and inflammation, and whose elevated plasma levels impair muscle metabolism and cause cachexia. GDF-15 also may play multiple roles in the pathophysiology of cardiovascular disease. Methods The ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab to placebo added to high-intensity or maximum-tolerated statin in patients post-acute coronary syndrome (ACS). We assessed in &amp;gt;11,000 patients for whom biobank samples were available, the relation between GDF-15 levels (Roche Diagnostics) at baseline and at 4 months with risk of major adverse cardiovascular events (MACE; primary endpoint, comprising coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischaemic stroke, unstable angina requiring hospitalization) and all-cause death, with adjustment for age and sex. Results Median GDF-15 (quartile [Q]1, Q3) at baseline was 1022 (755, 1465) pg/mL and was reduced by a placebo-adjusted median of 22 pg/mL with alirocumab (p=0.0009) at month 4. This lowering of GDF-15 by alirocumab may represent the first such report via pharmacotherapy. In the placebo group, baseline GDF-15 was significantly associated with risks of MACE (Figure Panel A) and death (Panel B). Relative risk reduction with alirocumab did not vary according to baseline GDF-15 levels for MACE (Panel C) and death (Panel D). Four-year MACE absolute risk reduction [ARR (95% CI)] with alirocumab at Q1 and Q3 of baseline GDF-15 was 2.0% (0.1%, 3.9%) and 2.6% (0.2%, 5.0%), respectively. Reduction of GDF-15 with alirocumab at month 4 was not associated with subsequent MACE (p=0.46) but was associated with death (p=0.0009), with greater reductions translating to lower risk. Conclusion In patients with recent ACS, GDF-15 is a strong predictor of both MACE and death. Reduction of GDF-15 with alirocumab at month 4 was not associated with subsequent MACE but was associated with death (p=0.0009), with greater ARR reductions translating to lower risk. Figure. Splines for baseline GDF-15 vs risk of MACE (Panel A; spline p&amp;lt;0.0001) or all-cause death (Panel B; spline p&amp;lt;00001) through 4 years in the placebo group; treatment hazard ratio for MACE (Panel C; spline p=0.52) and all-cause death (Panel D; spline p=0.78). All splines reflect adjustment for age and sexFigure

Influences of cardiovascular disease on the relationship between baseline systolic blood pressure and adverse outcomes in diabetes: insights from large population-based study

Abstract Objective To evaluate the influences of cardiovascular disease (CVD) on the relationship between baseline systolic blood pressure (SBP) and adverse outcomes in diabetes. Methods This is an observational study of 16431 community-dwelling adults with diabetes and 7.8% had CVD. The relationship between SBP (either as a categorical or continuous variable) with major adverse cardiovascular event (MACE) and all-cause death were evaluated by baseline CVD status using multivariable-adjusted Cox proportional hazard models and restricted cubic spline. Results After a median follow-up of 3.4 years, 2145 (13.1%) MACE and 1025 (6.2%) all-cause death occurred. In the overall participants there was a linear relationship between SBP and MACE (P-nonlinear=0.55) and a U-shaped relationship between SBP and all-cause death (P-nonlinear=0.002). In participants free of CVD, in reference to SBP &amp;lt; 120 mmHg group, the risks for MACE increased as SBP category (120-129, 130-139, and ≥ 140 mmHg) advanced (P-trend &amp;lt; 0.001) and there was a linear relationship (P-nonlinear=0.75; Figure 1A); while the risks for all-cause death were lower in SBP of 120-139 mmHg and 140-159 mmHg groups while higher in SBP ≥ 160 mmHg group, and there was a U-shaped relationship (P-nonlinear&amp;lt;0.001; Figure 1B). Notably, in participants with existing CVD the relationship between SBP with MACE and all-cause death did not show any specific pattern. Conclusion The relationship between baseline SBP with MACE and all-cause death varied substantially by baseline CVD status. Future studies to investigate the threshold of initiating BP-lowering treatment and the appropriate BP target in diabetes may consider applying a CVD-based stratification strategy.

Risk of death, thromboembolic events, and bleeding in elderly patients with Atrial Fibrillation and Clinical Complexity who are not taking oral anticoagulation

Abstract Background Patients with Atrial Fibrillation (AF) often exhibit Clinical Complexity (CC), defined as ≥2 features, i.e. patients aged ≥75 years plus a body mass index (BMI) &amp;lt; 23/kg/m2 and/or bleeding history and/or chronic kidney disease. No data are available about the clinical course of patients with Atrial Fibrillation (AF) and CC who are not taking oral anticoagulation (OAC). Purpose To assess the risk of thrombotic and hemorrhagic events in patients with Atrial Fibrillation (AF) and CC who are not taking OAC. Methods Retrospective study with a health care research network (TriNetX). Based on the ICD-10-CM codes entered between 2011-2022 from 85 health care organizations mainly located in the United States, AF patients ≥75 years with CC were categorized into two groups based on the use of OAC during the last year before the study period. The primary outcomes were the one-year risk of death, major cardiovascular events ([MACE]: heart failure, stroke, and myocardial infarction), and major bleeding (central nervous system, gastrointestinal, internal bleeding, and hypovolemic shock). Secondary outcomes were each component of the primary outcome and catheter ablation. Cox regression analyses were used to calculate hazard ratios (HRs) and 95% CIs following propensity score matching 1:1. Results Overall, we identified 271,402 AF CC patients not on OAC (80.1±6.8 years, 46.5% females) and 87,101 AF CC patients on OAC (79.8±6.5 years, 47.6% females). Before PSM, AF CC patients not on OAC showed no significant differences in cardiovascular and bleeding risk factors but were less treated with pharmacological treatment than AF CC patients on OAC. After PSM, no significant differences were found between the two groups, but AF CC not on OAC were at higher risk of all-cause death (HR 1.54, 95%CI 1.50-1.57), MACE (HR 1.13, 95%CI 1.11-1.16), and major bleeding (HR 1.34, 95%CI 1.31-1.38), when compared to AF CC on OAC. AF CC patients not on OAC were associated with a higher risk of each component of the primary outcome and with a lower use of catheter ablation procedures (HR 0.48, 95%CI 0.43-0.54) (Table 1). The risk of the composite outcomes was the highest in those with all the three CC components. A progressive increase in OAC prescription was observed during the follow-up period, with increasing of NOACs and lower use of warfarin being observed. There was a clear temporal relationship between increasing OAC prescription and incidence of bleeding in CC patients (Figure 1) Conclusions AF CC patients not on OAC have a high risk of all-cause death, thrombotic and hemorrhagic events. Over time, increasing NOAC use was associated with more bleeding in CC patients. New antithrombotic approaches aimed at reducing thrombotic risk without increasing bleeding risk are needed in these patients.Figure 1 OAC new prescriptions

Elevated levels of plasma inactive stromal cell derived factor-1a predict long-term adverse outcomes in diabetic patients with coronary artery disease

Abstract Background Because of the significantly increased cardiovascular risk by complicating type 2 diabetes (T2D) in patients with coronary artery disease (CAD), the appropriate risk estimation is crucial in patients with T2D following percutaneous coronary intervention (PCI). Nevertheless, there is no established biomarker which can precisely predict outcomes in this particular population. Although stromal cell derived factor-1α (SDF-1α) has been suggested to play a key role in the pathogenesis of T2D, the prognostic impact of SDF-1α in the secondary prevention of CAD is yet to be elucidated. In particular, the ability of SDF-1α isoforms in outcome prediction in this population has not been assessed. Purpose The aim of present study was to investigate the prognostic implication of three isoforms of SDF-1α, such as total, active, and inactive forms of SDF-1α in diabetic patients following PCI. Methods This single-center retrospective analysis involved consecutive patients with T2D who underwent PCI for the first time between 2008 and 2018 (n=849). Primary and secondary outcome measures were all-cause death and the composite of cardiovascular death, non-fatal myocardial infarction, and ischemic stroke (3P-MACE), respectively. For determining plasma levels of SDF-1α, we measured not only total, but also the active type of SDF-1α by ELISA. Inactive isoform of the SDF-1α was calculated by subtracting the active isoform from total SDF-1α. Participants were divided into two groups according to the median of three forms of plasma SDF-1α levels (total SDF-1α: 2270 pg/mL, active SDF-1α: 686 pg/mL, inactive SDF-1α: 1537 pg/mL) at PCI procedure and the incidence and risk of subsequent endpoints following PCI were assessed. Results Kaplan-Meier analyses revealed increased risk of both all-cause death and 3P-MACE in patients with elevated levels of inactive SDF-1α (Figure 1). Constantly, multivariate Cox hazard analyses adjusted by age, sex, body mass index (&amp;gt;25), acute coronary syndrome, and chronic kidney disease (≥ stage 3) repeatedly indicated the 1 higher log-transformed inactive SDF-1α was significantly associated with increased risk of all-cause death (hazard ratio (HR): 2.21, 95% confidence interval (CI): 1.05–4.67, p=0.04) and 3P-MACE (HR: 2.30, 95% CI: 1.01–5.09, p=0.04). However, neither of total and active SDF-1α reached statistical significance (Figure 2). Furthermore, the addition of inactive SDF-1α to baseline models in multivariate Cox proportional hazard analysis significantly enhanced both the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI) for all-cause death (NRI 0.29, p=0.009; IDI 0.007, p=0.03) and 3P-MACE (NRI 0.38, p=0.001; IDI 0.007, p=0.01) while adding total and active SDF-1α did not improve them. Conclusion In diabetic patients following PCI, elevated levels of plasma inactive SDF-1α, not total and active isoforms, might be a useful indicator of adverse outcomes.

Edoxaban dose, frailty, and outcomes in patients with atrial fibrillation: the ETNA-AF-Europe 4-year follow-up

Abstract Background Frailty is a common reason to choose non-recommended (non-rec) doses of non-vitamin-K-antagonist oral anticoagulants in patients with atrial fibrillation (AF); however, it is not known how this practice affects stroke and bleeding outcomes. Purpose To assess clinical outcomes in frail patients with AF receiving non-rec vs recommended (rec) doses of edoxaban using 4-yr follow-up data from ETNA-AF-Europe. Methods The prospective, observational ETNA-AF-Europe study followed patients with AF receiving edoxaban for up to 4 yrs. In ETNA-AF-Europe, perceived frailty was based on investigators’ own clinical binary judgement in each patient. Objective frailty was determined using a simplified adaptation of the Rockwood’s Frailty Index. For objective frailty, patients with missing index were categorised as non-frail. Patients with perceived or objective frailty were combined for this analysis. Baseline characteristics and hazard ratios (HRs) with 95% confidence intervals (CIs) assessing risk of outcomes in frail patients prescribed non-rec vs rec edoxaban doses (i.e., non-rec 60mg vs rec 30mg and non-rec 30mg vs rec 60mg) are presented. Data were adjusted for age, sex, and derived versions of the CHA2DS2-VASc and HAS-BLED scores. Net clinical benefit was defined as any stroke/systemic embolic event (SEE), transient ischaemic attack, venous thromboembolic event, major bleeding, or cardiovascular death, whichever came first. Results Of 13164 patients, 1786 were frail (13.6%; perceived frailty [n=1410], age [IQR]: 82.0 [78.0-86.0] yrs, women: 57.9%; objective frailty [n=540], age [IQR]: 77.0 [71.0-82.0] yrs, women: 31.9%; both, n=164). Baseline characteristics are reported in Table 1. Risk of all-cause death was higher in frail patients treated with non-rec 30mg vs rec 60mg (HR [95% CI]: 1.44 [1.06,1.96]). The annualised rate [CI] of any stroke/SEE was non-significantly higher (HR [95% CI]:1.60 [0.80,3.20]) with non-rec 30mg (n=169; 2.25 [1.25,4.06]) vs rec 60mg (n=622; 1.54 [1.08,2.20]). There was, however, no association between treatment received and risk (HR [95% CI]) of major bleeding (1.19 [0.58,2.43]) or net clinical benefit (1.26 [0.84,1.87]) (Figure 1). In frail patients who received non-rec 60mg (n=183) vs rec 30mg (n=695), risk of any stroke/SEE (HR [95% CI]) was higher (2.15 [1.03,4.49]), but there were no significant differences in the risk (HR [95% CI]) of major bleeding (1.03 [0.52,2.01]), net clinical benefit (1.15 [0.78,1.71]), or all-cause death (0.79 [0.59,1.05]) (Figure 1). Conclusions In this large European AF registry, the presence of frailty should not drive dosing recommendations for edoxaban. In particular, when compared with the rec 60mg dose, the non-rec 30mg (reduced) dose, was associated with more all-cause death and no benefits on major bleeding.Baseline Characteristics

Amiodarone-related thyroid dysfunction and associated outcomes in patients with heart failure - a matched case-control study

Abstract Aim The association between amiodarone-related thyroid dysfunction and the risk of worsening heart failure (HF) or death has been reported with conflicting results. Methods The study cohort was patients with HF and without a history of thyroid dysfunction (defined by medical treatment or diagnosis) who initiated treatment with amiodarone in the period 1996-2021. Within this cohort, those who developed thyroid dysfunction (cases) were identified and matched 1:3 on age, sex, calendar year, duration of HF, and time since initiation of amiodarone with patients (controls) from the same cohort and followed for the primary outcome of HF hospitalization or all-cause death at 1-year, assessed by Kaplan Meier curves and Cox regression models adjusted for ischemic heart disease, chronic kidney disease, malignancy, atrial fibrillation and ventricular tachycardia. Results The study cohort comprised 21,947 patients, of whom 4,137 (19%) developed thyroid dysfunction following initiation of amiodarone. After matching, the study population consisted of 4,063 cases (mean age 69 years, 68% men, 41.6% developed thyroid dysfunction within the first year after initiation of amiodarone) and 10,940 matched controls, (Figure 1). The index date was the date of thyroid dysfunction for cases, and for matched controls a date at a similar distance since amiodarone initiation. At 1-year follow-up, the primary outcome occurred in 1,543 (38.0%) cases and 3,681 (33.6%) matched controls (reference), adjusted hazard ratio (HR) 1.13 (95%, confidence interval CI 1.07-1.20), although this was solely driven by HF hospitalization (28.9% vs 21.8%; HR 1.32 (95% CI 1.23-1.41), whereas all-cause death was lower among cases (18.2% vs. 20.4%, HR 0.85 (95% CI 0.78-0.93), (Figure 2). Conclusions Among HF patients treated with amiodarone, the development of thyroid dysfunction was associated with an increased risk of HF hospitalization or all-cause death, but this was solely driven by the excess risk of HF hospitalization, whereas it was associated with a lower risk of all-cause death. The absence of excess mortality indicates that thyroid complications are manageable in this vulnerable population of patients with HF.Figure 1 Flowchart of the populationFigure 2 Cumulative risk

Association between reduced risk of gastrointestinal bleeding related to proton pump inhibitor use and subsequent all-cause death in patients with percutaneous coronary intervention

Abstract Background Gastrointestinal bleeding is the leading cause of post-percutaneous coronary intervention (PCI) bleeding complications which are associated with a high risk for subsequent clinical outcomes. The aim of this study was to estimate association between risk of gastrointestinal bleeding events related to proton pump inhibitor (PPI) use and subsequent clinical outcomes in patients with PCI. Methods The Clinical Deep Data Accumulation System (CLIDAS) is a database for inclusive of patient characteristics, medications, laboratory test, physiological test, cardiac catheterization and PCI treatment, all of which were aggregated from electronic medical records in 7 tertiary hospitals in Japan. Data of 6457 patients who underwent PCI between April 2014 and March 2020 and were then followed for 30 days after the index PCI, were analyzed. These patients were divided into two groups based on use of PPI; the PPI group (n=5285; 82%) and the non-PPI group (n=1172; 18%). Clinical outcomes, defined as gastrointestinal bleeding and all-cause death, were assessed using propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) models. Results Among the 6457 PCI patients, 90 (1.7%) in the PPI group and 31 (2.6%) in the non-PPI group experienced gastrointestinal bleeding events. Adjusting for baseline demographics, comorbidities, and anti-thrombotic treatments, the multivariable Cox hazard model suggested a trend towards a lower risk of gastrointestinal bleeding with PPI use (HR, 0.70; 95%CI, 0.46-1.05; p=0.087). The PSM analysis confirmed a significant association between PPI use and a lower risk of gastrointestinal bleeding (HR, 0.13; 95%CI, 0.04-0.43; p=0.001), consistent with IPTW model results (HR, 0.60; 95%CI, 0.38-0.95; p=0.031). Subgroup analysis showed that PPI use was associated with a low risk of all-cause death in patients with acute coronary syndrome (ACS) (HR, 0.58; 95%CI, 0.36-0.93; p=0.024). Causal mediation analysis indicated an indirect effect of PPI on reducing all-cause death through the suppression of gastrointestinal bleeding events. Conclusion These findings suggested that use of PPI against gastrointestinal bleeding complications might reduce the risk of subsequent all-cause death in ACS patients undergoing PCI.