Hard Clinical Endpoints Research Articles

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.

Alcohol, Drinking Pattern, and Chronic Disease.

This review discusses the inconsistent recommendations on alcohol consumption and its association with chronic disease, highlighting the need for an evidence-based consensus. Alcohol is an addictive substance consumed worldwide, especially in European countries. Recommendations on alcohol consumption are controversial. On one hand, many nonrandomized studies defend that moderate consumption has a beneficial cardiovascular effect or a lower risk of all-cause mortality. On the other hand, alcohol is associated with an increased risk of cancer, neurological diseases, or injuries, among others. For years, efforts have been made to answer the question regarding the safe amount of alcohol intake, but controversies remain. Observational studies advocate moderate alcohol consumption following a Mediterranean pattern (red wine with meals avoiding binge drinking) as the best option for current drinkers. However, agencies such as the IARC recommend abstention from alcohol as it is a potent carcinogen. In this context, more randomized trial with larger sample size and hard clinical endpoints should be conducted to clarify the available evidence and provide clinicians with support for their clinical practice.

Role of Myocardial Strain Imaging in Cancer Therapy-Related Cardiac Dysfunction.

This review aims to provide a contemporary perspective on the role of myocardial strain imaging in the management of patients on cardiotoxic therapy. Risk/benefit evaluation of cardiotoxic cancer treatment remains challenging, weighing life-saving cancer therapy with fatal cardiac dysfunction potentially caused by cancer therapy. The serial change in left ventricular ejection fraction (LVEF) was conventionally used for the detection of cancer therapy-related cardiac dysfunction (CTRCD). Peak systolic global longitudinal strain (GLS) by speckle-tracking echocardiography has turned into a vital pre- and post-chemotherapy assessment for the early detection of cardiotoxicity. Complexity in cardiotoxic therapy regimen, different definition of CTRCD by LVEF, variations in GLS values, timings, and variable cutoffs make it challenging to standardize the protocol for the detection of CTRCD. GLS > 15% relative reduction from baseline has been widely used. Evidence suggests that GLS could predict early subclinical LV dysfunction, and initiation of cardioprotective therapy led to less decline of LV function. Most of the studies used an echocardiographic endpoint, and the impact of GLS on the long-term clinical outcome is not established. GLS has emerged as a reliable measure to identify early subclinical LV dysfunction by detecting myocardial deformation in patients on cardiotoxic chemotherapy. To date, a significant decline in GLS suggests the initiation of cardioprotective therapy with close monitoring. Interruption of prognostically important cardiotoxic chemotherapies requires a multidisciplinary team approach guided mainly by LVEF and other clinical factors. Further randomized control trials with hard clinical endpoints and longer follow-ups may help to determine the role of GLS in CTRCD.

Early Estimated Glomerular Filtration Rate Trajectories After Kidney Transplant Biopsy as a Surrogate Endpoint for Graft Survival in Late Antibody-Mediated Rejection.

BackgroundLate antibody-mediated rejection (ABMR) after kidney transplantation is a major cause of long-term allograft loss with currently no proven treatment strategy. Design for trials testing treatment for late ABMR poses a major challenge as hard clinical endpoints require large sample sizes. We performed a retrospective cohort study applying commonly used selection criteria to evaluate the slope of the estimated glomerular filtration rate (eGFR) within an early and short timeframe after biopsy as a surrogate of future allograft loss for clinical trials addressing late ABMR.MethodsStudy subjects were identified upon screening of the Vienna transplant biopsy database. Main inclusion criteria were (i) a solitary kidney transplant between 2000 and 2013, (ii) diagnosis of ABMR according to the Banff 2015 scheme at >12 months post-transplantation, (iii) age 15–75 years at ABMR diagnosis, (iv) an eGFR > 25 mL/min/1.73 m2 at ABMR diagnosis, and (v) a follow-up for at least 36 months after ABMR diagnosis. The primary outcome variable was death-censored graft survival. A mixed effects model with linear splines was used for eGFR slope modeling and association of graft failure and eGFR slope was assessed applying a multivariate competing risk analysis with landmarks set at 12 and 24 months after index biopsy.ResultsA total of 70 allografts from 68 patients were included. An eGFR loss of 1 ml/min/1.73 m2 per year significantly increased the risk for allograft failure, when eGFR slopes were modeled over 12 months [HR 1.1 (95% CI: 1.01–1.3), p = 0.020] or over 24 months [HR 1.3 (95% CI: 1.1–1.4), p = 0.001] after diagnosis of ABMR with landmarks set at both time points. Covariables influencing graft loss in all models were histologic evidence of glomerulonephritis concurring with ABMR as well as the administration of anti-thymocyte globulin (ATG) at the time of transplantation.ConclusionOur study supports the use of the eGFR slope modeled for at least 12 months after biopsy-proven diagnosis of late ABMR, as a surrogate parameter for future allograft loss. The simultaneous occurrence of glomerulonephritis together with ABMR at index biopsy and the use of ATG at the time of transplantation–likely representing a confounder in pre-sensitized recipients–were strongly associated with worse transplant outcomes.

Which predilatation balloons provide the best lesion preparation prior to use of drug coated balloons in de-novo lesions? Results from the PREPARE study.

There is a lack of data on the clinical outcomes following the use of different strategies for lesion preparation prior to the use of drug-coated balloons (DCB). In this study, we have explored the clinical outcomes between different types of predilatation balloons: semi-compliant (SB), non-compliant (NB) and scoring balloons (ScB) used when preparing de-novo lesions prior to the use of DCB. We retrospectively evaluated all patients who underwent treatment with DCB for de-novo lesions between 2011-2019 at 4 high-volume European centres. The measured study endpoints were cardiac-death, TV-MI, TLR and MACE. During the study period, 553 patients were treated with DCB for de-novo lesions, 327 with SB only, 172 with NB and 54 with ScB. There were some differences in the procedural characteristics between the 3 groups. Predilatation balloons were significantly larger in the ScB, and NB groups as compared to the SB (2.7 mm and 2.6 mm vs. 2.3 mm; P<0.001). The reference vessel diameter was significantly larger in the NB group as compared to the ScB and SB (2.6 mm vs. 2.2 mm and 2.3 mm; P<0.001). During the median follow-up duration of 547-days, there were no differences in the hard-clinical endpoints, however, TLR was significantly higher in the ScB as compared to SB and NB group (11% vs. 3.4% and 4.7%; P=0.02). The PREPARE study results do not suggest routine use of ScB prior to DCB in de-novo lesions.

Update on diastolic heart failure

In August 2021, an update of the European Society of Cardiology-Heart Failure Association guideline for the diagnosis and treatment of heart failure was released. To review the changes implied by current guidelines regarding the diagnosis and treatment of patients with heart failure and preserved left ventricular ejection fraction (HFpEF). The diagnosis of HFpEF requires the combined presence of clinical signs, left ventricular ejection fraction ≥ 50%, elevated natriuretic peptides, and elevated left ventricular filling pressure. If the diagnosis remains equivocal, astress test is recommended. The targeted identification and treatment of comorbid conditions is key for aholistic therapeutic approach to HFpEF. Diuretics are recommended in congested patients with HFpEF in order to alleviate signs and symptoms. The treatment of diabetic patients with heart failure should include asodium glucose co-transporter‑2 (SGLT2) inhibitor. All patients with HFpEF should be enrolled in amultidisciplinary heart failure management program aiming to improve self-care strategies and offer participation in an exercise program. It was recently shown for the first time in arandomized trial that hard clinical endpoints could be reduced in patients with HFpEF using the SGLT2 inhibitor empagliflozin. It is expected that this finding will become part of updated treatment recommendations in the near future. Although challenging, the early diagnosis of HFpEF is key to averting the poor prognosis associated with this frequent condition. Multidisciplinary care and innovative pharmacologic and non-pharmacologic therapies, however, can improve quality of life, exercise tolerance, and prognosis.

Intensive vs non-intensive statin pretreatment before percutaneous coronary intervention in Chinese patients: A meta-analysis of randomized controlled trials.

BACKGROUNDThe results of intensive statin pretreatment before percutaneous coronary intervention (PCI) is inconsistent between Chinese and Western populations, and there are no corresponding meta-analyses involving hard clinical endpoints in the available published literature.AIMTo evaluate the efficacy and safety of high-dose statin loading before PCI in Chinese patients through a meta-analysis.METHODSRelevant studies were identified by searching the electronic databases of PubMed, Embase and Cochrane’s Library to December 2019. The outcomes included an assessment of major adverse cardiovascular event (MACE), non-fatal myocardial infarction (MI), cardiac death, target vessel revascularization (TVR), myalgia /myasthenia and abnormal alanine aminotransferase (ALT) in all enrolled patients. Random effect model and fixed effect model were applied to combine the data, which were further analyzed by χ2 test and I2 test. The main outcomes were then analyzed through the use of relative risks (RR) and its 95% confidence interval (95%CI).RESULTSEleven studies involving 3123 individuals were included. Compared with patients receiving placebo or no statin treatment before surgery, intensive statin treatment was associated with a clear reduction of risk of MACE (RR = 0.44, 95%CI: 0.31-0.61, P < 0.00001). However, compared with the patients receiving moderate-intensity statin before surgery, no advantage to intensive statin treatment was seen (RR = 1.04, 95%CI: 0.82-1.31, P = 0.74). In addition, no significant difference was observed between intensive statin therapy and non-intensive statin therapy on the incidence of TVR (RR = 0.43, 95%CI: 0.18-1.02, P = 0.06) , myalgia /myasthenia (RR = 1.35, 95%CI: 0.30-5.95, P = 0.69) and abnormal alanine aminotransferase (RR = 1.47, 95%CI: 0.54-4.02, P = 0.45) except non-fatal MI (RR = 0.54, 95%CI: 0.33-0.88, P = 0.01).CONCLUSIONCompared with placebo or no statin pretreatment, intensive statin before PCI displayed reduced incidence of MACE. However, there was no significant benefit between high and moderate-intensity statin. In addition, no significant difference was observed between intensive statin therapy and non-intensive statin therapy on the incidence of TVR, myalgia/myasthenia and abnormal alanine aminotransferase except non-fatal MI.

NAD+-Increasing Strategies to Improve Cardiometabolic Health?

Depleted nicotinamide adenine dinucleotide (NAD+) is a common hallmark of metabolic disorders. Therefore, NAD+-increasing strategies have evolved as a potential therapeutic venue to combat cardiometabolic diseases. Several forms of vitamin B3, i.e., nicotinamide and nicotinamide mononucleotide, and especially nicotinamide riboside, have attracted most interest as potentially safe and efficacious candidates for NAD+ restoration. Herein, we dissected the characteristics of the latest clinical trials testing the therapeutic potential of different vitamin B3 molecules to improve cardiometabolic health, with a special focus on randomized, placebo-controlled clinical trials performed in the context of obesity or other pathologies, mainly linked to cardiovascular system and skeletal muscle functionality. The favorable outcomes via NAD+-increasing strategies found in the different studies were quite heterogeneous. NAD+-increasing interventions improved capacity to exercise, decreased blood pressure, increased the anti-inflammatory profile and insulin-stimulated glucose disposal, and reduced the fat-free mass. Except for the decreased blood pressure, the significant results did not include many hard clinical end points, such as decreases in weight, BMI, fasting glucose, or HbA1c percentage. However, the analyzed trials were short-term interventions. Overall, the accumulated clinical data can be interpreted as moderately promising. Additional and long-term studies will be needed to directly compare the doses and duration of treatments among different vitamin B3 regimes, as well as to define the type of patients, if any, that could benefit from these treatments. In this context, a major point of advancement in delineating future clinical trials would be to identify subjects with a recognized NAD+ deficiency using novel, appropriate biomarkers. Also, confirmation of gender-specific effect of NAD+-increasing treatments would be needed.

Salvage Radiotherapy versus Observation for Biochemical Recurrence following Radical Prostatectomy for Prostate Cancer: A Matched Pair Analysis.

Simple SummarySalvage radiotherapy improves oncologic outcomes in prostate cancer patients who develop biochemical recurrence after radical prostatectomy. However, the evidence on hard clinical endpoints is scarce. Within this study, we compare the long-term oncologic outcomes of patients with biochemical recurrence after prostatectomy, who were treated with either salvage radiotherapy or no radiotherapy. Our results show that patients who were treated with salvage radiotherapy after the development of biochemical recurrence following radical prostatectomy had a lower risk of developing metastasis and lower risk of death within the follow-up. These findings further underline the curative potential of salvage radiotherapy in the case of biochemical recurrence after radical prostatectomy, and should be discussed with these patients.Background: Salvage radiotherapy (SRT) improves oncologic outcomes in prostate cancer (PCa) patients who develop biochemical recurrence (BCR) after radical prostatectomy (RP). However, evidence on hard clinical endpoints is scarce. We compare long-term oncologic outcomes of SRT versus no radiotherapy (noRT) in patients with BCR after RP. Patients and methods: Within a multi-institutional database, we identified patients with BCR after RP between 1989 and 2016 for PCa. Patients with lymph node invasion, with adjuvant radiotherapy, or with additional androgen deprivation therapy at BCR were excluded. In all patients with SRT, SRT was delivered to the prostatic bed only. Propensity score matching (PSM) was performed to account for differences in pathologic tumor characteristics. Kaplan–Meier analyses and Cox regression models tested the effect of SRT versus no RT on metastasis-free (MFS) and overall survival (OS). Results: Of 1832 patients with BCR, 32.9% (n = 603) received SRT without ADT. The median follow-up was 95.9 months. Median total SRT dose was 70.2 Gy. After 1:1 PSM, at 15 years after RP, MFS and OS rates were 84.3 versus 76.9% (p < 0.001) and 85.3 versus 74.4% (p = 0.04) for SRT and noRT, respectively. In multivariable Cox regression models, SRT was an independent predictor for metastasis (HR: 0.37, p < 0.001) and OS (HR: 0.64, p = 0.03). Conclusion: This is the first matched-pair analysis investigating the impact of SRT versus observation only in post-RP recurrent PCa. After compensating for established risk factors, SRT was associated with better long-term MFS and OS. These results on clinical endpoints underline the curative potential of SRT.

Mendelian randomization analysis of vitamin D in the secondary prevention of hypertensive-diabetic subjects: role of facilitating blood pressure control

BackgroundVitamin D (Vit-D) promotes vascular repair and its deficiency is closely linked to the development of type 2 diabetes mellitus (T2DM) and hypertension. Whether genetially predicted vitamin D status (serological 25-hydroxyvitamin D [25(OH)D]) confers secondary protection against cardiovascular diseases (CVD) among high-risk hypertensive-diabetic subjects was unknown.MethodsThis is a prospective, individual-data, two-sample Mendelian randomization study. We interrogated 12 prior GWAS-detected SNPs of comprehensive Vit-D mechanistic pathways using high-throughput exome chip analyses in a derivation subcohort (n = 1460) and constructed a genetic risk score (GRS) (rs2060793, rs4588, rs7041; F-statistic = 32, P < 0.001) for causal inference of comprehensive CVD hard clinical endpoints in an independent sample of hypertensive subjects (n = 3746) with prevailing co-morbid T2DM (79%) and serological 25(OH)D deficiency [< 20 ng/mL] 45%.ResultsAfter 55.6 ± 28.9 months, 561 (15%) combined CVD events including myocardial infarction, unstable angina, ischemic stroke, congestive heart failure, peripheral vascular disease, and cardiovascular death had occurred. Kaplan-Meier analysis showed that genetically predicted reduced vitamin D status was associated with reduced event-free survival from combined CVD events (log-rank = 13.5, P = 0.001). Multivariate-adjusted per-allele increase in GRS predicted reduced combined CVD events (HR = 0.90 [0.84 to 0.96], P = 0.002). Mendelian randomization indicates that increased Vit-D exposure, leveraged through each 1 ng/mL genetically instrumented rise of serum Vit-D, protects against combined CVD events (Wald’s estimate: OR = 0.86 [95%CI 0.75 to 0.95]), and myocardial infarction (OR = 0.76 [95%CI 0.60 to 0.90]). Furthermore, genetically predicted increase in Vit-D status ameliorates risk of deviation from achieving guideline-directed hypertension control (JNC-8: systolic target < 150 mmHg) (OR = 0.89 [95%CI 0.80 to 0.96]).ConclusionsGenetically predicted increase in Vit-D status [25(OH)D] may confer secondary protection against incident combined CVD events and myocardial infarction in a hypertensive-diabetic population where serological 25(OH)D deficiency is common, through facilitating blood pressure control.

The Density of Renal Lymphatics Correlates With Clinical Outcomes in IgA Nephropathy

IntroductionIgA nephropathy (IgAN) is the most common primary glomerulonephritis (GN) worldwide. The disease course fluctuates, and the most important challenge is the considerable variation in the time lag between diagnosis and the development of a hard clinical end point, such as end-stage kidney disease (ESKD). The reaction of renal tissue to damage resembles the common wound-healing response. One part of this repair in IgAN is the expansion of lymphatic vessels known as lymphangiogenesis. The aim of this work was to establish the prognostic value of the density of lymphatic vessels in the renal biopsy at the time of diagnosis, for predicting the risk of ESKD in a Spanish cohort of patients with IgAN.MethodsWe performed a retrospective multicenter study of 76 patients with IgAN. The end point of the study was progression to ESKD. The morphometric analysis of lymphatic vessels was performed on tissue sections stained with antipodoplanin antibody.ResultsDensity of lymphatic vessels was significantly higher in patients with IgAN with mesangial hypercellularity >50%, segmental sclerosis, higher degrees of interstitial fibrosis, and tubular atrophy. Patients with more lymphatic vessels had significantly higher values of proteinuria and lower estimated glomerular filtration rate (eGFR). A density of lymphatic vessels ≥8 per mm2 was associated with a significantly higher rate of progression to ESKD at 3 years from biopsy. After adjustment for the International IgAN prediction score, at the multivariate logistic regression, high density of lymphatic vessels (≥8 per mm2) remained significantly associated with a higher rate of early progression to ESKD.ConclusionThis study contributes to the understanding of the natural history of the progression to ESKD in patients with IgAN revealing the density of lymphatics vessels may optimize the prognostic value of the International IgA predicting tool to calculate the risk of ESKD, favoring the evaluation of new targeted therapies.

Relation between the vitaminD status and the occurrence and severity of thyroid malignancy

Background. In spite of large volume of data linking vitaminD with cardiovascular morbidity, autoimmunity, cancer, and virtually every organ system, vitaminD and thyroid is a lesser-known aspect of vitaminD in clinical practice. The association between vitaminD deficiency and thyroid cancer is controversial. Some studies have demonstrated that higher serum vitaminD levels might protect against thyroid cancer, whereas others have not, or have even indicated the opposite to to be the case. This review intends to highlight the current literature on the impact of vitaminD status on thyroid cancer. Materials and methods. References for this review were identified through searches of PubMed for articles published to from 2005 to June 2021 using the terms “thyroid cancer” and “vitaminD”. Results. A large volume of medical literature is available from observational studies linking vitaminD with thyroid cancer. Data from interventional studies documenting beneficial effects of vitaminD on thyroid autoimmunity is also available, but lesser than that from observational studies. Short-term high dose oral vitaminD supplementation reduces TPOAb titers. Certain vitaminD receptor (VDR) gene polymorphism have been linked to increased occurrence of autoimmune thyroid disorders. VitaminD deficiency, decreased circulating calcitriol has been linked to increased thyroid cancer. Certain VDR gene polymorphisms have been linked with increased as well as decreased occurrence of thyroid cancer. Data is scant on use of vitaminD and its analogues for treating thyroid cancer. The results suggest that VitaminD deficiency may have value as a negative prognostic indicator in papillary thyroid cancer and that pre-operative laboratory evaluation may be less useful. This is important because VitaminD deficiency is modifiable. Conclusions. In spite of large volume of medical literature from observational studies linking vitaminD with thyroid cancer, meaningful concrete clinical data on impact of vitaminD supplementation on hard clinical end points in these disorders is lacking, and should be the primary area of research in the next decade.

Abstract 10776: Market-Level Variation in Utilization of Percutaneous Ventricular Assist Devices Utilization in the United States

Introduction: Percutaneous ventricular assist devices (PVAD) have begun to replace intra-aortic balloon pumps (IABP) for hemodynamic support during high-risk percutaneous coronary intervention (PCI) procedures even though data on effectiveness of PVAD compared to IABP for hard clinical endpoints remains limited. We examined variation in utilization of PVADs during PCI across U.S. markets and identify factors associated with PVAD utilization. Methods: Using 2013-2017 MEDPAR data, we identified all patients aged 65 years or older who underwent PCI with placement of either a PVAD or an IABP on the same date as the PCI procedure. The primary outcome was 30-day mortality. We used hospital referral region (HRR) to define regional healthcare markets with geographic contiguity. We examined variation in utilization of PVADs across HRRs and examined patient- and market-level characteristics across HRR quartiles of PVAD utilization. Using multilevel models, we examined the association of market-level factors with utilization of PVADs and whether higher utilization of PVADs was associated with lower risk of 30-day mortality at a market-level. Results: A total of 52,755 patients underwent inpatient PCI with either an IABP (36,260 [68.7%]) or PVAD (16,495 [31.3%]). There was a significant increase in the proportion of PCI procedures with PVAD (17% in 2013 to 46% in 2017), with a corresponding decrease in IABP (83% to 54%; P&lt;.0001 for both). There was large variation in PVAD utilization across markets (0% to 84%), which persisted even after adjustment for differences in patient characteristics (adjusted median OR of 2.19; 95% CI: 2.03-2.35). Markets in the highest quartile of PVAD utilization were larger with a higher number of hospitals and had more market-level competition compared to markets in the lowest quartile of PVAD utilization. Greater utilization of PVAD at the market-level was not associated with lower risk-adjusted 30-day mortality. Conclusions: Utilization of PVADs for PCI in the U.S. continues to increase with marked variation in PVAD use across U.S. healthcare markets. Although patient- and market-level factors were associated with use of PVADs at the market-level, greater market utilization of PVADs was not associated with lower 30-day mortality.

Evidence in crisis: a closer look into the quality of published systematic reviews in the cardiology literature

Abstract Background Systematic reviews are usually considered as the highest level of evidence and are increasingly used in shaping cardiology policies and guidelines. However, as the rate of publishing systematic reviews increases annually, there are rising concerns regarding their quality and reporting standards. Purpose The current analysis provides an insight into the quality of published systematic reviews in cardiology and provides recommendations for researchers, clinicians, and stakeholders in this regard. Methods Using a comprehensive Medline/PubMed search, we retrieved all systematic reviews, published between 2009 and 2019 in five general cardiology journals with the highest impact factor as per the Clarivate Analytics 2019 Journal Impact Factor List (Circulation, European Heart Journal, Journal of the American College of Cardiology, Circulation Research, and JAMA Cardiology). We assessed the methodological characteristics, eligibility criteria, reporting standards, as well as review quality scores according to the AMSTAR tool. Results Among 352 retrieved reviews, 275 (75.3%) performed direct head-to-head analysis and 164 (46.6%) included only clinical trials. The median numbers of searched databases and included studies were 3 (IQR: 2, 3) and 13 (IQR: 7, 30). The primary outcomes were often hard clinical endpoints as mortality (39.2%) and stroke (11.9%). 64 (18.2%) registered their protocol, 208 (58.4%) used validated tools for risk of bias assessment, 177 (52.3%) assessed for publication bias, and 221 (62.8%) adhered to the PRISMA checklist. Thirty-five reviews detected significant publication bias, which was significantly associated with heterogeneity of the primary outcome. The AMSTAR quality scores were low or critically low in 71% of evaluated reviews. Further, 87 (24.7%) did not report on whether they received funding or not, 33 (9.4%) reported receiving no funding, and 232 adequately reported on their funding sources [70 (19.9%) from governmental/academic sources, 120 (34.1%) from pharmaceutical companies, and 42 (11.9%) from both sources]. analysis showed that reviews with advanced statistical analysis, those that included RCTs, adhered to the PRISMA checklist, or had higher AMSTAR quality scores had significantly higher citation metrics (p&amp;lt;0.05). Conclusion Due to the widespread low quality and poor reporting in cardiovascular systematic reviews, clinicians should be educated on the value of methodological quality in interpreting systematic review findings. In addition, academic societies and guideline writing groups should implement rigorous critical appraisal and peer review policies to improve the synthesis and utilization of systematic reviews in evidence-based cardiovascular medicine. Funding Acknowledgement Type of funding sources: None.

The Utility of Circulating and Imaging Biomarkers Alone and in Combination in Heart Failure.

Clinical trials in the treatment of heart failure have relied on the use of a composite of hard clinical endpoints to evaluate the efficacy of the treatment arm. This has led to prolonged trials requiring large patient cohorts and extensive funding to reach statistical significance.In this paper, we have explored the potential of currently available circulating and imaging biomarkers associated with heart failure as a surrogate for hard clinical end points in clinical trials. This would be expected to result in shorter trials, smaller patient cohorts and limited funding required. We have subsequently theorized on combining circulating and imaging biomarkers as a surrogate for clinical end points such as hospitalization from heart failure and cardiac mortality.

Влияние обеспечения витамином D на аутоиммунное состояние щитовидной железы

Актуальность. Несмотря на большой объем данных, связывающих витамин D с сердечно-сосудистой заболеваемостью, аутоиммунитетом, раком и практически каждой системой органов, взаимосвязь между витамином D и щитовидной железой остается менее известным аспектом в клинической практике. Причиной активного влияния витамина D является тот факт, что рецепторы витамина D (VDR) размещены практически в каждой ткани и системе органов организма. Цель: осветить данные современной литературы о влиянии витамина D и его обеспечения на аутоиммунитет щитовидной железы. Материалы и методы. Источники этого обзора были определены с помощью поиска в PubMed по статьям, опубликованным с 2015 года по сентябрь 2020 года, с использованием терминов «щитовидная железа» и «витамин D». Результаты. Зарегистрирована достоверная обратная корреляция между антителами к тиреоидной пероксидазе (АТ-ТПО) и содержанием 25-гидроксивитамина D (25(OH)D) в сыворотке крови. Наличие положительных титров АТ-ТПО более распространено у лиц с дефицитом витамина D. В большом объеме медицинской литературы приводятся результаты наблюдательных исследований, связывающих витамин D с аутоиммунитетом щитовидной железы. Также приводятся данные интервенционных исследований, подтверждающих положительное влияние витамина D на аутоиммунитет щитовидной железы. Краткосрочный прием высоких доз пероральных добавок витамина D содействует уменьшению титров АТ-ТПО. Некоторые полиморфизмы гена VDR связаны с увеличением случаев аутоиммунных расстройств щитовидной железы. Данные о том, приводит ли коррекция дефицита витамина D при аутоиммунных расстройствах щитовидной железы к снижению потребности в левотироксине или карбимазоле соответственно при гипотиреозе или болезни Грейвса, отсутствуют. Выводы. Несмотря на большой объем медицинской литературы по обсервационным исследованиям, в которых связывают витамин D с аутоиммунитетом щитовидной железы, отсутствуют важные конкретные клинические данные о влиянии дополнительного назначения витамина D на основные клинические конечные точки при этих расстройствах. Это должно быть основной сферой исследований в следующем десятилетии.

Acute Coronary Syndromes (ACS)-Unravelling Biology to Identify New Therapies-The Microcirculation as a Frontier for New Therapies in ACS.

In acute coronary syndrome (ACS) patients, restoring epicardial culprit vessel patency and flow with percutaneous coronary intervention or coronary artery bypass grafting has been the mainstay of treatment for decades. However, there is an emerging understanding of the crucial role of coronary microcirculation in predicting infarct burden and subsequent left ventricular remodelling, and the prognostic significance of coronary microvascular obstruction (MVO) in mortality and morbidity. This review will elucidate the multifaceted and interconnected pathophysiological processes which underpin MVO in ACS, and the various diagnostic modalities as well as challenges, with a particular focus on the invasive but specific and reproducible index of microcirculatory resistance (IMR). Unfortunately, a multitude of purported therapeutic strategies to address this unmet need in cardiovascular care, outlined in this review, have so far been disappointing with conflicting results and a lack of hard clinical end-point benefit. There are however a number of exciting and novel future prospects in this field that will be evaluated over the coming years in large adequately powered clinical trials, and this review will briefly appraise these.

Addition of statins to the standard treatment in patients with cirrhosis: Safety and efficacy.

This review summarizes the safety and efficacy of statins in patients with cirrhosis. Due to concerns about the safety of statins in patients with impaired liver function, they have recently been investigated as a potential treatment option in cirrhosis. The most clinically significant adverse event is statin-related myopathy, and this may be related to the high serum statin concentrations in the setting of severely impaired liver function. Rhabdomyolysis is the most serious and potentially life-threatening manifestation. It has recently been demonstrated that the recommended dose of simvastatin in patients with decompensated cirrhosis would be 20 mg/d because higher values, such as 40 mg/d, are associated with many adverse events, especially muscle injury. Likewise, simvastatin should not be administered to patients with Model for End-stage Liver Disease score > 12 and/or Child-Pugh class C because of the high risk of severe muscle injury. Due to the pleiotropic effects, the focus on statins has shifted from being considered harmful to something useful. Through these effects, statins could prevent liver-related morbidity and mortality in cirrhotic patients. Observational studies in large populations of patients with cirrhosis have shown that treatment with statins to decrease high cholesterol levels was associated with a reduced risk of hepatic decompensation, hepatocellular carcinoma development and death. The few randomized controlled trials in patients with cirrhosis and portal hypertension showed that statins lower portal pressure, quite likely through a reduction in hepatic resistance. Another large randomized controlled trial in patients with variceal bleeding showed that simvastatin in addition to standard of care did not prevent rebleeding but improved survival rate. Despite these encouraging outcomes, the quality of the evidence regarding the use of statins is low or very low due to the observational characteristics of most of the studies involved. Therefore, it is advisable to perform further randomized controlled trials on a large series of patients with hard clinical endpoints, using different statin types and varying doses. The objectives would be to prevent liver-related morbidity and mortality rather than treating cirrhosis complications to take additional information that makes it possible to add statins to the standard of care of these patients.

The Full Revasc (Ffr-gUidance for compLete non-cuLprit REVASCularization) Registry-based randomized clinical trial

BackgroundComplete revascularization in ST elevation myocardial infarction (STEMI) patients with multivessel disease has resulted in reduction in composite clinical endpoints in medium sized trials. Only one trial showed an effect on hard clinical endpoints, but the revascularization procedure was guided by angiographic evaluation of stenosis severity. Consequently, it is not clear how Fractional Flow Reserve (FFR)-guided percutaneous coronary intervention (PCI) affects hard clinical endpoints in STEMI. Methods and ResultsThe Ffr-gUidance for compLete non-cuLprit REVASCularization (FULL REVASC) – is a pragmatic, multicenter, international, registry-based randomized clinical trial designed to evaluate whether a strategy of FFR-guided complete revascularization of non-culprit lesions, reduces the combined primary endpoint of total mortality, non-fatal MI and unplanned revascularization. 1,545 patients were randomized to receive FFR-guided PCI during the index hospitalization or initial conservative management of non-culprit lesions. We found that in angiographically severe non-culprit lesions of 90-99% severity, 1 in 5 of these lesions were re-classified as non-flow limiting by FFR. Considering lesions of intermediate severity (70%-89%), half were re-classified as non-flow limiting by FFR. The study is event driven for an estimated follow-up of at least 2.75 years to detect a 9.9%/year>7.425%/year difference (HR = 0.74 at 80% power (α = .05)) for the combined primary endpoint. ConclusionThis large randomized clinical trial is designed and powered to evaluate the effect of complete revascularization with FFR-guided PCI during index hospitalization on total mortality, non-fatal MI and unplanned revascularization following primary PCI in STEMI patients with multivessel disease. Enrollment completed in September 2019 and follow-up is ongoing.

The Use of Rifaximin in Patients With Cirrhosis.

Rifaximin is an oral nonsystemic antibiotic with minimal gastrointestinal absorption and broad‐spectrum antibacterial activity covering both gram‐positive and gram‐negative organisms. Rifaximin is currently used worldwide in patients with cirrhosis for preventing recurrent HE because its efficacy and safety have been proven by large randomized clinical trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut‐liver axis, which in turn can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not accepted because evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas in the second part, its clinical effects are critically discussed. It clearly emerges that, because of its potential activity on multiple pathogenic events, the efficacy of rifaximin in the prevention or management of complications other than HE deserves to be investigated extensively. The results of double‐blinded, adequately powered randomized clinical trials assessing the effect of rifaximin, alone or in combination with other drugs, on hard clinical endpoints, such as decompensation of cirrhosis, acute‐on‐chronic liver failure, and mortality, are therefore eagerly awaited.