Hard Endpoints Research Articles

Association between plasma desmosine, a marker of elastin degradation, and total atherosclerotic burden measured by whole body magnetic resonance angiography

Abstract Background Elastin degradation has been implicated in the pathophysiology of vulnerable atherosclerotic plaque. Desmosine is the cross-link component in the elastin molecule and is exclusively released from mature elastin breakdown, thus has the potential to be a physiologically relevant biomarker of atherosclerosis. Objectives The aim of the present study was: 1. To investigate whether patients with known cardiovascular disease (CVD) have higher elastin degradation as indicated by plasma desmosine (pDES); 2. to determine the relationship between pDES and total atherosclerotic burden. Methods We measured pDES by a validated stable isotope dilution LC-MS/MS method1 in a total of 146 subjects from the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) study2. (62% male, mean age 64±8 (SD) years). This included 62 patients with prior clinical diagnosis of CVD (including coronary artery disease (CAD), cerebrovascular disease and/or lower extremity arterial disease (LEAD)), and 84 patients without a clinical diagnosis of CVD. Total atherosclerotic burden was measured by whole body magnetic resonance angiography (WB-MRA). The WB-MRA data was divided into 31 anatomical arterial segments with each segment scored according to degree of luminal narrowing: 0 = no stenosis, 1 = <50% stenosis, 2 = 51–70% stenosis, 3 = 71–99% stenosis, 4 = vessel occlusion. The segment scores were summed and from this, a standardized atheroma score (SAS) was calculated by summing each individual segment's stenosis score, and divided by the number of diagnostic segments before dividing by 4 which is the maximum potential score. Relationship between SAS and pDES levels was investigated using multiple linear regression models Results pDES levels were significantly greater in patients with established clinical CVD compared to patients with no CVD (CVD patients, 0.56 (0.45–0.67) ng/mL; patients with no CVD, 0.47 (0.41–0.54)ng/mL; p=0.001). Median SAS for the study population was 4 (2–10). Overall pDES levels showed a strong correlation with SAS (r=0.44, p≤0.001). Univariable analysis suggested a significant association between pDES and whole-body atheroma score as measured by SAS. (β 29.31, p<0.001). This association persisted in the multivariable regression model adjusting for traditional cardiovascular risk factors including age, gender, BMI, systolic blood pressure, diabetes, smoking status and LDL. (adjusted β 18.75, p=0.004) Conclusion pDES levels are elevated in patients with clinical CVD when compared to those with no clinical history of CVD. pDES is also strongly associated with global atheroma burden. Overall, these findings support the role of pDES as a potential biomarker for atherosclerosis. Funding Acknowledgement Type of funding sources: None.

Impact of Clinical and Lesion Features on Outcomes After Percutaneous Coronary Intervention in Bifurcation Lesions.

Bifurcation percutaneous coronary intervention (PCI) is associated with higher risk of clinical events. This study aimed to determine clinical and lesion features that predict adverse outcomes, and to evaluate the differential prognostic impact of these features in patients undergoing PCI for bifurcation lesions. We analyzed 5,537 patients from the BIFURCAT (comBined Insights From the Unified RAIN and COBIS bifurcAtion regisTries) registry. The primary outcome was major adverse cardiac events (MACE) at 2-year follow-up; secondary outcomes included hard endpoints (all-cause death, myocardial infarction) and lesion-oriented clinical outcomes (LOCO) (target-vessel myocardial infarction, target lesion revascularization). The least absolute shrinkage andselection operator (LASSO) model was used for feature selection. During the 2-year follow-up period, MACE occurred in 492 patients (8.9%). The LASSO model identified 5clinical features (old age, chronic renal disease, diabetes mellitus, current smoking, and left ventricular dysfunction) and 4 lesion features (left main disease, proximal main branch disease, side branch disease, and a small main branch diameter) as significant features that predict MACE. A combination of all 9 features improved the predictive value for MACE compared with clinical and lesion features (area under the receiver-operating characteristics curve: 0.657 vs 0.636 vs 0.581; P< 0.001). For secondary endpoints, the clinical features had a higher impact than lesion features on hard endpoints, whereas lesion features had a higher impact than clinical features on LOCO. In bifurcation PCI, 9 features were associated with MACE. Clinical features were predominant predictors for hard endpoints, and lesion features were predominant for predicting LOCO. Clinical and lesion features have distinct values, and both should be considered in bifurcation PCI.

Is Electrocardiogram Helpful in Predicting a Rise in Troponin I as a Marker of Anthracycline Cardiotoxicity?

Screening patients on anthracycline-based chemotherapy regimens for the development of cardiotoxicity can be resource intensive. We therefore studied various traditional electrocardiogram (ECG) parameters to correlate and possibly predict the development of elevated Troponin I as a surrogate marker of anthracycline-induced cardiotoxicity. This was a single-centre prospective cohort study done between January 2014 to January 2016. Baseline ECG was compared with ECG performed after chemotherapy and different parameters were compared. Patients were divided into Troponin I positive and negative groups based on the test performed at the end of chemotherapy, using a cut-off of 0.06 ng/dL. Of the 160 patients studied, 131 (81.9%) were Troponin I negative (TnI-) and 29 (18.1%) were positive (TnI+). Breast cancer accounted for 79% of all cancers in this study. Many ECG parameters were compared between the TnI- and TnI+ groups. Of them, TP segment and TP/QT showed a significant decrease in the TnI+ group. The mean (95% confidence interval) TP in the TnI- group was 162.9 ms (145.4, 180.4) and in TnI+ groups was 117.9 ms (89, 146.8) (p = 0.03). Corresponding values for TP/QT were 0.47 (0.42, 0.51) and 0.35 (0.27, 0.42) (p = 0.02). These changes were not significant in multivariate analysis and likely reflected the different mean heart rates (HR) in both the groups, as suggested by partial correlation which was run with HR as a confounder. ECG parameters, such as QTcH, TP and TP/QT do not helpful predicting Troponin I elevations in patients on anthracycline-based chemotherapy. Further studies based on hard endpoints, for example, clinical systolic dysfunction occurring at one year, would give better information on their utility.

Immune activating and inhibiting effects of calcitriol on γδ T cells and NK cells

The immune modulatory effects of vitamin D and the impact of vitamin D deficiency on various diseases are a subject of current scientific research. However, there are few data directly linking vitamin D to hard endpoints in clinical studies, apart from its well-known effects on bone health. It is therefore of interest, that the effectiveness of the therapeutic antibody rituximab is connected to the vitamin D serum level of patients with B cell lymphomas. Rituximab exerts its effect via antibody dependent cell mediated cytotoxicity (ADCC), with NK cells and γδ T cells acting as effector cells. Here we evaluated and compared how γδ T cells and NK cells are modified by long-term in vitro cultivation with calcitriol, the active metabolite of vitamin D.Peripheral blood mononuclear cells from healthy donors were stimulated in vitro with a combination of zoledronic acid (Zol) and interleukin-2 (IL-2) or with sole IL-2 and different concentrations of calcitriol were added to culture for up to 10 days.Our results confirmed the earlier reports of immune suppressive effects of calcitriol on immune cell proliferation and interferon-γ production. Under certain conditions, in vitro incubation with calcitriol led to an inhibited rituximab-mediated ADCC of Zol/IL-2 stimulated γδ T cells, but to an increased cytotoxic activity of IL-2 stimulated NK cells.This study directly shows immune modulatory activity of calcitriol on the cellular level and links vitamin D to anti-tumoral effects of NK and γδ T cells.

Causal analysis identifies small HDL particles and physical activity as key determinants of longevity of older adults.

SummaryBackgroundThe hard endpoint of death is one of the most significant outcomes in both clinical practice and research settings. Our goal was to discover direct causes of longevity from medically accessible data.MethodsUsing a framework that combines local causal discovery algorithms with discovery of maximally predictive and compact feature sets (the “Markov boundaries” of the response) and equivalence classes, we examined 186 variables and their relationships with survival over 27 years in 1507 participants, aged ≥71 years, of the longitudinal, community-based D-EPESE study.FindingsAs few as 8-15 variables predicted longevity at 2-, 5- and 10-years with predictive performance (area under receiver operator characteristic curve) of 0·76 (95% CIs 0·69, 0·83), 0·76 (0·72, 0·81) and 0·66 (0·61, 0·71), respectively. Numbers of small high-density lipoprotein particles, younger age, and fewer pack years of cigarette smoking were the strongest determinants of longevity at 2-, 5- and 10-years, respectively. Physical function was a prominent predictor of longevity at all time horizons. Age and cognitive function contributed to predictions at 5 and 10 years. Age was not among the local 2-year prediction variables (although significant in univariable analysis), thus establishing that age is not a direct cause of 2-year longevity in the context of measured factors in our data that determine longevity.InterpretationThe discoveries in this study proceed from causal data science analyses of deep clinical and molecular phenotyping data in a community-based cohort of older adults with known lifespan.FundingNIH/NIA R01AG054840, R01AG12765, and P30-AG028716, NIH/NIA Contract N01-AG-12102 and NCRR 1UL1TR002494-01.

Effect of repeat catheter ablation vs. antiarrhythmic drug therapy among patients with recurrent atrial tachycardia/atrial fibrillation after atrial fibrillation catheter ablation: data from CHINA-AF registry.

Although several studies have proved that repeat catheter ablation is beneficial to recurrent atrial tachycardia (AT)/atrial fibrillation (AF) after AF catheter ablation, the hard endpoints of the effect of catheter ablation on recurrent AT/AF patients after AF catheter ablation remains unclear. Our study aims to compare the effect of catheter ablation and drug therapy on recurrent AT/AF patients after AF catheter ablation. Four thousand nine hundred and thirteen consecutive patients with recurrent AT/AF after catheter ablation from the China-AF registry were enrolled. The patients were divided into two study groups: the repeat catheter ablation group and the medical therapy group. The primary endpoint is a composite of cardiovascular mortality or ischaemic stroke or major bleeding events. Secondary endpoints were each component of the primary endpoints and AF recurrence rate. Landmark analysis and Cox regression were used in the statistical analysis. We chose landmark 36 months as the primary landmark date. Over a median follow-up period of 40 ± 24 months, 4913 patients were divided into either the repeat ablation group or the medical therapy group. The cumulative incidence of the composite primary outcome was significantly lower in the repeat ablation group than the medical therapy group (adjusted hazard ratio = 0.56; 95% confidence interval: 0.35-0.89; P = 0.015) of landmark 36 months (2359 patients were included in medical therapy group and 704 patients were included in repeat ablation group at landmark 36 months). However, all secondary endpoints were not statistically different in the two groups, including cardiovascular mortality, ischaemic stroke, major bleeding events, and AF recurrence rate. Based on this research, in recurrent AT/AF patients after a catheter ablation procedure, compared with medical therapy, repeat catheter ablation may significantly reduce the risk of the endpoint of composite cardiovascular mortality, ischaemic stroke, and major bleeding events.

The role of surgery for loco-regional and advanced urological cancers.

There is a general misconception that surgery is the antithesis of palliation. However, symptom mitigation, the basic tenet of palliative interventions, can be achieved by invasive procedures. Surgical care, thus, plays an important role in palliative oncology, alongside radiation and systemic therapy. There is global movement to improve palliation in oncology, and thus it is timely to evaluate the role of surgical interventions can play in this setting. Many of the surgical interventions done with palliative intent were first established as curative options. Most studies looked at interventions for local control of primary tumour including extirpative surgeries, while some studies studied pain relief for bone metastases. Results show that patients have an acceptable survival outcome and complication rate comparable to those done in the curative setting. However, not all studies report functional outcomes and symptom-relief consistently, highlighting an unmet need. More studies are needed to further define the role of surgery in palliative care. Randomized controlled trials studying surgical intervention in the palliative setting will be challenging because of lack of equipoise, inherent bias in patient and disease characteristics in those who undergo surgery. Nonetheless, studies should endeavour to study symptom-free survival and PROMs as meaningful endpoints of interventions performed in a palliative setting rather than solely focus on hard oncological endpoints of survival.

Comparison of laparoscopic ureterolithotomy and retrograde lithotripsy in the treatment of proximal ureteral stones

The current approach in the surgical treatment of ureteral calculi involves the use of endourological procedures such as retrograde ureteroscopy with lithotripsy or percutaneous antegrade lithotripsy in the proximal ureter. Ureterolithotomy as a treatment method is of an auxiliary nature and is used when endourological intervention is impossible or in case of intraoperative collisions during access conversion. However, there are several comparative studies on lithotripsy and lithotomy.The aim. Comparative analysis of the outcomes of laparoscopic lithotomy and retrograde lithotripsy in the surgical treatment of proximal ureteral calculi, as well as the search for predictors of prolonged disability.Materials and methods. A prospective randomized multicenter study included 53 patients with an established diagnosis of ureterolithiasis who were treated in the period 2018–2021 in urological hospitals in Irkutsk. All patients were divided into two comparison groups: Lithotomy group (group 1; n = 30) and Lithotripsy group (group 2; n = 23).Results. When analyzing the results of the study, it was found that the level of complications of class II–III according to Clavien – Dindo was statistically comparable in both groups (p &gt; 0.05). However, in absolute and relative terms, the prevalence of this indicator was noted during retrograde ureterolithotripsy. According to hard endpoints (reoperation, presence of residual stones or migration during the operation), 29 (96.6 %) patients of group 1 and 17 (73.4 %) patients of group 2 (p = 0.514) were successfully operated on.Conclusion. Laparoscopic ureterolithotomy may be offered to patients with large proximal ureteral stones as an alternative treatment option with better residual stone freedom but generally similar overall outcomes and complication rates.

Long-Term Clinical Outcomes and Its Predictors Between the 1- and 2-Stent Strategy in Coronary Bifurcation Lesions - A Baseline Clinical and Lesion Characteristic-Matched Analysis.

Differences in the impact of the 1- or 2-stent strategy in similar coronary bifurcation lesion conditions are not well understood. This study investigated the clinical outcomes and its predictors between 1 or 2 stents in propensity score-matched (PSM) complex bifurcation lesions.Methods and Results: We analyzed the data of patients with bifurcation lesions, obtained from a multicenter registry of 2,648 patients (median follow up, 53 months). The patients were treated by second generation drug-eluting stents (DESs). The primary outcome was target lesion failure (TLF), composite of cardiac death, target vessel myocardial infarction (TVMI), and ischemia-driven target lesion revascularization (TLR). PSM was performed to balance baseline clinical and angiographic discrepancies between 1 and 2 stents. After PSM (N=333 from each group), the 2-stent group had more TLRs (hazard ratio [HR] 3.14, 95% confidence interval [CI] 1.42-6.97, P=0.005) and fewer hard endpoints (composite of cardiac death and TVMI; HR 0.44, 95% CI 0.19-1.01, P=0.054), which resulted in a similar TLF rate (HR 1.40, 95% CI 0.83-2.37, P=0.209) compared to the 1-stent group. Compared with 1-stent, the 2-stent technique was more frequently associated with less TLF in the presence of main vessel (pinteraction=0.008) and side branch calcification (pinteraction=0.010). The 2-stent strategy should be considered to reduce hard clinical endpoints in complex bifurcation lesions, particularly those with calcifications.

The comparison of cardiovascular disease risk prediction scores and evaluation of subclinical atherosclerosis in rheumatoid arthritis: a cross-sectional study.

Primary objectives estimated prevalence of traditional cardiovascular disease (CVD) risk factors and compared different CVD risk prediction algorithms in an Indian rheumatoid arthritis (RA) population. Secondary objectives evaluated associations between carotid intima-media thickness (CIMT) and subclinical atherosclerosis (SCA) with CVD risk factors and CVD risk scores. The presence of CVD risk factors were recorded, and 10-year CVD risk was predicted using Framingham risk scoring (FRS) using lipids (FRS-Lipids), FRS using body mass index (FRS-BMI), QRISK-2, SCORE, and the algorithm recommended by ACC/AHA (ASCVD). CIMT was measured on the far-wall of the common carotid artery. Subclinical atherosclerosis was defined as CIMT > 0.9mm or the presence of carotid plaque. A total of 332 patents were enrolled, 12% had diabetes mellitus, 21.4% hypertension, and 6.9% were current/past smokers. Proportions of RA with predicted 10-year CVD risk > 10% varied from 16.2 to 41.9% between scores. Highest magnitude of risk was predicted by FRS-BMI. Agreement between scores in predicting risk was moderate in general. Mean CIMT was 0.70 ± 0.15mm. Age, male sex, and extra-articular manifestations associated with greater CIMT. All risk scores except SCORE moderately correlated with CIMT. About one-seventh had SCA defined as CIMT > 0.9mm or the presence of carotid plaques, associated with increasing age, male gender, or higher ratio of total cholesterol to high-density lipoprotein cholesterol. ASCVD and QRISK-2 scores had maximum area under curve for distinguishing SCA. Individual CVD risk scores predict 10-year CVD risk differently in Indian patients with RA, and require validation for predicting hard end points (CVD events, mortality). Key Points • Diabetes mellitus and hypertension are the most prevalent cardiovascular disease risk factors in Indian patients with RA. • Individual cardiovascular risk prediction scores predict risk differently in Indian patients with RA, highest risk being predicted by the FRS-BMI. • Carotid intima-media thickness in RA associated with increasing age, male sex and extra-articular manifestations. • 14% RA had subclinical atherosclerosis, associated with increasing age, male sex, and higher total cholesterol to HDL-C ratio, best distinguished by ASCVD and QRISK-2 scores.

Treatment of secondary hyperparathyroidism in non-dialysis CKD: an appraisal 2022s.

The situation of secondary hyperparathyroidism (SHPT) in chronic kidney disease patients not on dialysis (ND-CKD) is probably best characterised by the Kidney Disease: Improving Global Outcomes Chronic Kidney Disease-Mineral and Bone Disorder Update 2017 guideline 4.2.1 stating that the optimal parathyroid hormone levels are not known in these stages. Furthermore, new caution became recommended with regard to the routine use of active vitamin D analogues in early CKD stages and moderate SHPT phenotypes, due to their potential risks for hypercalcaemia and hyperphosphataemia aggravation. Nevertheless, there is still a substantial clinical need to prevent the development of parathyroid gland autonomy, with its associated consequences of bone and vascular damage, including fracture risks and cardiovascular events. Therefore we now attempt to review the current guideline-based and clinical practice management of SHPT in ND-CKD, including their strengths and weaknesses, favouring individualised approaches respecting calcium and phosphate homeostasis. We further comment on extended-release calcifediol (ERC) as a new differential therapeutic option now also available in Europe and on a potentially novel understanding of a required vitamin D saturation in more advanced CKD stages. There is no doubt, however, that knowledge gaps will remain unless powerful randomised controlled trials with hard and meaningful endpoints are performed.

Aspirin: 1A @ 125.

On 10 August 1897, Dr Felix Hoffmann (1868–1946) described a simple chemical reaction for synthesizing acetylsalicylic acid in a pure, stable form by heating the natural compound, salicylic acid, with acetic anhydride for 3 h. This new chemical entity was rapidly developed as an analgesic, antipyretic, and anti-inflammatory drug and marketed by the Bayer Company with the trade name ‘aspirin’. The drug was first-in-class, and its pharmacological activities provided a template for the synthesis of over 20 non-steroidal anti-inflammatory drugs (NSAIDs) during the second half of the twentieth century. Asymmetrical commercial pressures eventually displaced aspirin from the NSAID market, in favour of indomethacin, ibuprofen, diclofenac, naproxen, and others, thought by the medical community to be more effective and/or safer, in the absence of head-to-head comparisons with hard endpoints of gastrointestinal (GI) safety.1 In fact, the first regulatory approval of an NSAID with improved GI safety came about 100 years...

Atherosclerosis associated with HIV - Is it a result of treatment or inflammation?

Background and Aims : Cardiovascular disease has emerged as an important cause of death in patients with HIV, as illustrated by clinical studies evaluating such hard endpoints as stroke or myocardial infarctions. Many studies have demonstrated an increased prevalence of subclinical atherosclerosis in individuals with HIV compared to those without. Such measurements include intima media thickness and intraluminal arterial plaque as assessed by ultrasound and evaluation of coronary artery calcification and plaque by computed tomography.

Diffusion of Percutaneous Ventricular Assist Devices in US Markets.

Percutaneous ventricular assist devices (PVADs) have been replacing intra-aortic balloon pumps for hemodynamic support during percutaneous coronary intervention (PCI), even though data supporting a benefit for hard clinical end points remain limited. We evaluated diffusion of PVADs across US markets and examined the association of market utilization of PVAD with mortality and cost. Using the 2013 to 2019 Medicare data, we identified all patients aged ≥65 years who underwent PCI with either a PVAD or intra-aortic balloon pump. We used hospital referral region to define regional health care markets and categorized them in quartiles based on the proportional use of PVADs during PCI. Multilevel models were constructed to determine the association of patient, hospital, and market factors with utilization of PVADs and the association of PVAD utilization with 30-day mortality and cost. A total of 79 176 patients underwent PCI with either intra-aortic balloon pump (47 514 [60.0%]) or PVAD (31 662 [40.0%]). The proportion of PCI procedures with PVAD increased over time (17% in 2013 to 57% in 2019; P for trend, <0.001), such that PVADs overtook intra-aortic balloon pump for hemodynamic support during PCI in 2018. There was a large variation in PVAD utilization across markets (range, 0%-85%), which remained unchanged after adjustment of patient characteristics (median odds ratio, 2.05 [95% CI, 1.91-2.17]). The presence of acute myocardial infarction, cardiogenic shock, and emergent status was associated with a 45% to 50% lower odds of PVAD use suggesting that PVADs were less likely to be used in the sickest patients. Greater utilization of PVAD at the market level was not associated with lower risk mortality but was associated with higher cost. Although utilization of PVADs for PCI continues to increase, there is large variation in PVAD utilization across markets. Greater market utilization of PVADs was not associated with lower mortality but was associated with higher cost.

New Strategies for Volume Control in Patients with Diabetes Mellitus, a Narrative Review.

Sodium is reabsorbed all along the renal tubules. The positive impacts of sodium-glucose cotransporter-2 inhibitors (SGLT2i), angiotensin receptor neprilysin inhibitor (ARNI) and mineralocorticoid receptor antagonists (MRA) on hard renal and/or cardiac endpoints calls for the role of diuretics in nephroprotection and cardioprotection in patients with diabetes mellitus to be reviewed. Here, we review: (a) the mechanisms of action of the available natriuretics; (b) the physiological adaptations to chronic loop diuretic usage that lead to increased sodium reabsorption in the proximal and distal convoluted tubules; (c) the physiology of sodium retention in patients with diabetes mellitus; and (d) the mechanisms of aldosterone breakthrough. We show the rationale for combined diuretics to target not only the loop of Henle, but also the proximal and distal convoluted tubules. Indeed, higher residual proteinuria in patients treated with renin-angiotensin-aldosterone system (RAAS) blockers portends poorer renal and cardiovascular outcomes. Diuretics are known to optimize the reduction of proteinuria, in addition to RAAS blockers, but may favor aldosterone breakthrough in the absence of MRA. The aim of our study is to support a combined diuretics strategy to improve the management of patients with diabetes mellitus and chronic kidney disease or heart failure.

Chlorthalidone and Advanced Chronic Kidney Disease.

Chlorthalidone and Advanced Chronic Kidney Disease.

Research studies on screening tests.

Screening tests are done to diagnose asymptomatic disease in apparently healthy people with the aim to reduce mortality and morbidity from the disease. Certain criteria need to be fulfilled before we adopt population-level screening for any disease. Several biases exist in evaluating screening studies, and the ideal study design would be a randomized trial with hard endpoints such as mortality and morbidity.

Treatment of three-vessel disease in light of the results of the FAME-3 study

Previous randomized clinical studies have shown the superiority of coronary artery bypass grafting over percutaneous coronary intervention in the treatment of severe multivessel disease mainly because of a reduced need for repeat revascularization but, in some, a mortality benefit and reduced rate of myocardial infarction were shown among those undergoing surgery. The late breaker multicentric, randomized FAME (Fractional Flow Reserve Versus Angiography in Multivessel Evaluation)-3 study, involving 1500 patients, sought to determine whether fractional flow reserve guided percutaneous coronary intervention with implantation of new-generation drug-eluting stents was non -inferior to present-day coronary bypass surgery with respect to the composite of all-cause death, myocardial infarction, stroke and repeat revascularization at one year. The authors who were particularly active in the FAME-3 trial describe the study setting, the characteristics of the patient population, the procedures, and the results. The FAME-3 study failed to show the non-inferiority of percutaneous coronary intervention to bypass surgery in the treatment of three vessel disease using the predetermined margin. The authors present a detailed analysis of the possible reasons and some important secondary results. These include a lack of significant difference between the two arms with respect to `hard end points' and the significantly higher perioperative morbidity of the surgical group. Albeit our clinical practice should be based on the analysis of the primary end point, informing patients and shared decision making must include these secondary results when individual revascularization strategies are planned.

META-ANALYSIS ASSESSING THE IMPACT OF PRIOR HEART FAILURE AND CHRONIC KIDNEY DISEASE ON THE CARDIOVASCULAR EFFICACY OF GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS

Objective: Chronic kidney disease (CKD) and heart failure (HF) represent common co-morbidities in patients with type 2 diabetes mellitus (T2DM), constituting an additional burden that boosts overall morbidity and mortality. Therefore, we sought to determine whether history of HF or CKD affects the cardiovascular efficacy of GLP-1RAs, also utilizing data from the recently published FREEDOM Cardiovascular Outcomes Trial, which evaluated the cardiovascular safety of delivering a continuous subcutaneous infusion of the GLP-1RA exenatide (ITCA 650) in T2DM. Design and method: We searched the relevant, hallmark, cardiovascular outcome trials of GLP-1RAs in T2DM. We set as primary efficacy outcome the effect of GLP-1RAs versus placebo on the risk for a major adverse cardiovascular event (MACE) according to the prior history of HF, while we also assessed as a secondary efficacy outcome the effect of GLP-1RAs on the risk for MACE according to a prior diagnosis of CKD. Results: We finally pooled data from 4 trials for a total of 26,272 enrolled participants with T2DM. Regarding the primary efficacy outcome, we demonstrated that GLP-1RAs versus placebo resulted in a significant decrease by 14% (RR = 0.86, 95% CI; 0.76 – 0.97, I2 = 50%), regardless of history of HF (p-value for subgroup differences = 0.88). Concerning the secondary efficacy outcome, we showed that GLP-1RA treatment was superior to placebo in reducing the risk for a MACE (RR = 0.87, 95% CI; 0.75 – 1.02, I2 = 70%), while prior status of CKD did not affect the generated results (p-value for subgroup differences = 1.00). Conclusions: GLP-1RAs seem to constitute a safe and efficacious treatment option in patients with T2DM and established or at high risk for atherosclerotic cardiovascular disease, while HF or CKD status at baseline do not substantially affect the observed cardio-protective effect against hard cardiovascular endpoints.

Familiäre Krebserkrankungen

About 30% of all breast and ovarian cancer patients have a familial predisposition. In about one quarter of the women a mutation in a previously known risk gene is identified. The polygenic risk score (PRS) and nongenetic risk factors are also included in the individualized risk calculation. In the centers of the German Consortium (GC), only those genes for which there is sufficiently good evidence regarding an increased risk are examined and their results communicated in clinical care. For this purpose, these genes have been sufficiently tested with respect to the clinical validity, however, this is not sufficient for offering preventive measures in the context of standard care. For this there must be a clinical benefit, i.e. for the hard endpoints of mortality, morbidity and quality of life, there must be an advantage in utilizing the preventive measures. For all genes, except BRCA1 and BRCA2, the efficacy of risk-adapted preventive measures, such as intensified screening and prophylactic surgery, has not yet been sufficiently proven. As these data cannot usually be collected in prospective randomized trials the GC has introduced a concept for knowledge-generating care in the field of risk-adapted prevention. The aim is that the evidence-based prevention concept is offered and constantly evaluated in order to continuously adapt the concept, if necessary. For this purpose, progress monitoring and documentation within the prevention program is an indispensable prerequisite, e.g. in the database HerediCaRe. Another core concern of GC is to strengthen health literacy.