Standard operating procedure for idarucizumab reversal of dabigatran anticoagulation in ischemic and hemorrhagic stroke.

BACKGROUND: Reversal of dabigatran anticoagulation activity using idarucizumab is indicated for individuals suffering from life-threatening or non-controlled bleeding and those in need of urgent operation or invasive intervention. Through idarucizumab application patients with acute ischemic stroke (AIS) may regain eligibility for intravenous thrombolysis (IVT) and patients with intracranial hemorrhage (ICH) may show less hematoma growth, thereby improving functional outcome in both groups. However, evidence is limited, and international guidelines contain heterogenous recommendations substantiating the need for the review of evidence and standard operating procedures (SOPs). MATERIALS AND METHODS: For our review, we searched PubMed for all published articles using idarucizumab and ischemic stroke/hemorrhagic stroke as keywords. Illustrating two clinical cases, we discuss the current literature and national guidelines. RESULTS: Our search retrieved 47 articles of which 8 case studies or series made public after 2020/2021, 28 reviews, 1 leading opinion article, 1 editorial and 10 guidelines. Summarizing the available evidence, idarucizumab application in stroke patients taking dabigatran results in decreased mortality rate and improved functional outcomes. Based on two clinical cases from our departments, we provide SOPs on how to deal with eligible patients in a time-efficient way, thereby reducing door-to-needle times in AIS and preventing early deterioration in ICH patients. CONCLUSION: Reversal of dabigatran with idarucizumab in stroke patients appears easy to manage, safe and beneficial. The SOPs aim to reassure stroke physicians to include dabigatran reversal into their daily clinical routine when dealing with patients presenting with ischemic or hemorrhagic stroke under dabigatran therapy.

Inflammatory, Metabolic, and Coagulation Effects on Medial Arterial Calcification in Patients with Peripheral Arterial Disease.

Calcium deposits in the vessel wall in the form of hydroxyapatite can accumulate in the intimal layer, as in atherosclerotic plaque, but also in the medial layer, as in medial arterial calcification (MAC) or medial Möenckeberg sclerosis. Once considered a passive, degenerative process, MAC has recently been shown to be an active process with a complex but tightly regulated pathophysiology. Atherosclerosis and MAC represent distinct clinical entities that correlate in different ways with conventional cardiovascular risk factors. As both entities coexist in the vast majority of patients, it is difficult to estimate the relative contribution of specific risk factors to their development. MAC is strongly associated with age, diabetes mellitus, and chronic kidney disease. Given the complexity of MAC pathophysiology, it is expected that a variety of different factors and signaling pathways may be involved in the development and progression of the disease. In this article, we focus on metabolic factors, primarily hyperphosphatemia and hyperglycemia, and a wide range of possible mechanisms by which they might contribute to the development and progression of MAC. In addition, we provide insight into possible mechanisms by which inflammatory and coagulation factors are involved in vascular calcification processes. A better understanding of the complexity of MAC and the mechanisms involved in its development is essential for the development of potential preventive and therapeutic strategies.

Direct oral anticoagulants for secondary stroke prevention in patients over 80 years of age: the role of geriatric functional status.

Prescribing anticoagulation therapy in very old (≥ 80-years) patients with atrial fibrillation (AF) is an emerging clinical issue, but current knowledge and recommendations are insufficient. We aimed to determine the efficacy and safety of direct oral anticoagulants (DOACs) in secondary stroke prevention in very old patients and to explore the related geriatric functional status of these patients. Three hundred fifty-three consecutive ≥ 80-year-old patients treated for transient ischemic attack (TIA) or ischemic stroke (IS) at the neurological clinic at UMC Ljubljana, who were prescribed DOACs for AF between December 2012 and May 2020, were included. Data regarding recurrent TIA/IS, major bleeds, intracranial hemorrhage (ICH) and death were collected. Data were descriptively compared with data from RCTs- including younger patients. Patients prescribed DOACs between January 2018 and May 2020 were contacted in December 2020, and their functional status was assessed using the Barthel index (BI). The efficacy of secondary stroke prevention with DOACs was comparable to RCTs for significantly younger patients. Major bleeds occurred more often, but most incidences were gastrointestinal, and the rate of ICH was comparable. Importantly, most patients were highly independent determined by BI. Overall, our real world results suggest that DOACs are as effective at preventing IS in secondary prevention in very old patients than in younger patients and that geriatric functional assessment could be a useful tool in the decision-making process.

Inflammatory and Prothrombotic Biomarkers, DNA Polymorphisms, MicroRNAs and Personalized Medicine for Patients with Peripheral Arterial Disease.

Classical risk factors play a major role in the initiation and development of atherosclerosis. However, the estimation of risk for cardiovascular events based only on risk factors is often insufficient. Efforts have been made to identify biomarkers that indicate ongoing atherosclerosis. Among important circulating biomarkers associated with peripheral arterial disease (PAD) are inflammatory markers which are determined by the expression of different genes and epigenetic processes. Among these proinflammatory molecules, interleukin-6, C-reactive protein, several adhesion molecules, CD40 ligand, osteoprotegerin and others are associated with the presence and progression of PAD. Additionally, several circulating prothrombotic markers have a predictive value in PAD. Genetic polymorphisms significantly, albeit moderately, affect risk factors for PAD via altered lipoprotein metabolism, diabetes, arterial hypertension, smoking, inflammation and thrombosis. However, most of the risk variants for PAD are located in noncoding regions of the genome and their influence on gene expression remains to be explored. MicroRNAs (miRNAs) are single-stranded, noncoding RNAs that modulate gene expression at the post-transcriptional level. Patterns of miRNA expression, to some extent, vary in different atherosclerotic cardiovascular diseases. miRNAs appear to be useful in the detection of PAD and the prediction of progression and revascularization outcomes. In conclusion, taking into account one's predisposition to PAD, i.e., DNA polymorphisms and miRNAs, together with circulating inflammatory and coagulation markers, holds promise for more accurate prediction models and personalized therapeutic options.

Revascularization outcomes following acute ischemic stroke in patients taking direct oral anticoagulants: a single hospital cohort study.

Successful revascularization therapy is of paramount importance in patients suffering acute ischemic stroke (AIS). However, there is currently only limited evidence on revascularization outcomes for patients suffering AIS while treated with direct oral anticoagulants (DOACs). The aim of our study was to determine the efficacy and safety of intravenous thrombolysis (IVT) and mechanical reperfusion (MeR) in AIS patients taking DOACs, and compare them to randomized clinical trials (RCTs), which included patients without DOAC treatment. In an observational cohort study, we analyzed clinical and radiological outcomes following AIS for all consecutive patients on DOAC therapy treated by IVT or MeR, between 2013 and 2019, at the University Medical Center Ljubljana. Patients in the IVT group were on dabigatran treatment and have received idarucizumab as a reversal agent prior to IVT. Patients in the MeR group had a large vessel occlusion. The primary outcome of the study was efficiency, defined as significant improvement after recanalization (National Institutes of Health Stroke Scale (NIHSS) score improvement of ≥8 points after 24 h and modified Rankin Scale (mRS) ≤2 after 3 months) and safety, defined as occurrence of symptomatic intracerebral hemorrhage (SICH) and mortality. Fifty-one DOAC-treated patients with AIS were included. Nineteen dabigatran-treated patients received IVT after reversal by idarucizumab. Thirty-two patients with a large vessel occlusion (12 on dabigatran, 12 on rivaroxaban, and 8 on apixaban) received MeR. Median NIHSS at admission was 9 in the IVT group and 17 in the MeR group. A significant clinical improvement, 24 h after revascularization (median improvement of NIHSS ≥8), occurred in 84% of patients treated with IVT and 25% of patients treated with MeR. A favorable functional outcome after 3 months (modified Rankin Scale (mRS) ≤2) occurred in 84 % of patients treated with IVT and 44% of patients treated with MeR. SICH occurred in one patient (5%) in the IVT group, and in two patients (6%) in the MeR group. In summary, in our observational study of DOAC-treated AIS patients, the level of IVT efficiency was substantially better than in the RCTs. At the same time, the results of MeR treatment were on the same level as in non-DOAC AIS patients included in the RCTs. The observed safety of IVT and MeR treatment was similar to the RCTs. We propose that thrombi in patients on dabigatran may have increased susceptibility to IVT, thereby allowing for better clinical results.

Re-initiation of anticoagulation after central nervous system hemorrhage during treatment with direct oral anticoagulants: a single hospital cohort study.

BACKGROUND: Central nervous system (CNS) hemorrhage is a serious complication related to direct oral anticoagulant (DOAC) therapy. Current recommendations about re-initiation of anticoagulation treatment are limited to expert opinions. For this purpose, we analyzed the data of all consecutive DOAC patients with CNS hemorrhage, in whom DOACs were reinitiated. METHODS: Over a 6-year period (2012-2018), all consecutive patients with CNS hemorrhage (subdural, subarachnoid, intracerebral, spinal), while receiving DOACs, were included in this observational single-center cohort study. DOAC therapy was reinitiated only in patients with well-controlled arterial hypertension and diabetes, as well as exclusion of vascular malformations and cerebral amyloid angiopathy. The composite primary endpoint comprised of recurrent CNS hemorrhage, ischemic stroke, and mortality; secondary endpoints were separate aforementioned outcomes. RESULTS: Of the 54 patients included, 18 died within a month of CNS hemorrhage. The average observational time was 590 days. DOACs were reinitiated in 13/36 patients (36%); of these patients, three died: none due to ischemic stroke or recurrent CNS bleeding. In 23 patients, anticoagulation was not reinitiated; of these patients, 10 died: three from recurrent CNS hemorrhage, one due to ischemic stroke, and six from causes unrelated to stroke. CONCLUSIONS: In carefully selected patients, re-initiation of DOAC therapy did not increase the rate of both endpoints. Recommendations for DOAC re-initiation, which include hypertension and diabetes control, as well as treated vascular malformations, and excluded cerebral amyloid angiopathy, appear to be valid in clinical practice.

Treating Arterial Ageing in Patients with Diabetes: From Mechanisms to Effective Drugs.

Diabetes mellitus is a major healthcare problem. It is not only characterized by hyperglycemia and chronic complications, but in longer lasting diabetes and a longer living population, it is also associated with accelerated arterial ageing, which importantly contributes to cardiovascular complications. The accelerated arterial ageing in patients with diabetes should be considered separately from arterial ageing in patients without diabetes. Basic and clinical research have allowed better insight into the mechanisms of arterial ageing. In a simplified mechanistic way, it could be considered that the three tightly connected cornerstone characteristics of arterial ageing in patients with diabetes are: phenotypic presentation as endothelial dysfunction and arterial stiffness, and the underlying basic ageing-facilitating mechanism represented as the impaired expression of genetic longevity pathways. Currently, specific drugs for preventing/treating arterial ageing are not available. Therefore, we aimed to review the capacity of available drugs, particularly antidiabetic drugs, to interfere with the arterial ageing process. In the near future, these characteristics could help to guide therapy in patients with diabetes. Overall, it appears that arterial ageing could become a new target in diabetes. The expanding knowledge regarding the capability of antidiabetic drugs and other available drugs to inhibit/delay arterial aging is therefore essential.

Molecular Mechanisms Responsible for Diastolic Dysfunction in Diabetes Mellitus Patients.

In diabetic patients, cardiomyopathy is an important cause of heart failure, but its pathophysiology has not been completely understood thus far. Myocardial hypertrophy and diastolic dysfunction have been considered the hallmarks of diabetic cardiomyopathy (DCM), while systolic function is affected in the latter stages of the disease. In this article we propose the potential pathophysiological mechanisms responsible for myocardial hypertrophy and increased myocardial stiffness leading to diastolic dysfunction in this specific entity. According to our model, increased myocardial stiffness results from both cellular and extracellular matrix stiffness as well as cell⁻matrix interactions. Increased intrinsic cardiomyocyte stiffness is probably the most important contributor to myocardial stiffness. It results from the impairment in cardiomyocyte cytoskeleton. Several other mechanisms, specifically affected by diabetes, seem to also be significantly involved in myocardial stiffening, i.e., impairment in the myocardial nitric oxide (NO) pathway, coronary microvascular dysfunction, increased inflammation and oxidative stress, and myocardial sodium glucose cotransporter-2 (SGLT-2)-mediated effects. Better understanding of the complex pathophysiology of DCM suggests the possible value of drugs targeting the listed mechanisms. Antidiabetic drugs, NO-stimulating agents, anti-inflammatory agents, and SGLT-2 inhibitors are emerging as potential treatment options for DCM.

Intravenous Thrombolysis After Idarucizumab Application in Acute Stroke Patients-A Potentially Increased Sensitivity of Thrombi to Lysis?

BACKGROUND: Rapid inactivation of dabigatran by its specific inhibitor idarucizamab allows intravenous thrombolysis (IVT) in patients suffering ischemic stroke while being treated with dabigatran. Only limited data of this approach is available and numerous questions regarding efficacy/safety remain to be answered. Herein, we present the findings from the Slovenian national cohort study. METHODS: Retrospective analysis of all stroke patients treated with idarucizumab and IVT (n = 11) in the period from July 2016 to February 2018 from Slovenian region were analyzed. RESULTS: The indication for dabigatran treatment in all 11 cases was nonvalvular atrial fibrillation. Importantly, 6 out of 11 cases were classified as severe ischemic strokes (National Institutes of Health Stroke Scale; NIHSS ≥ 10) with a median NIHSS 13. At admission, prolonged activated partial thromboplastin time was present in 9 patients indicating therapeutic anticoagulation activity. The average door-to-needle time was 156 minutes. After 3 months, 9 patients had a modified Rankin Score of less than or equal to 2 and 7 patients had mRS less than 1 whereas, 2 patients died due to symptomatic intracranial hemorrhage (sICH); 1 due to spontaneous sICH, and the other due to a large ischemic stroke with hemorrhagic transformation. No thrombotic complications were observed. CONCLUSIONS: Our data show that IVT after idarucizumab administration is a safe and effective method of treatment in ischemic stroke patients on dabigatran. We recorded a higher proportion of patients with favorable outcome as well as with sICH compared to the randomized controlled studies which could suggest a higher sensitivity of thrombi to IVT in dabigatran treated patients.

Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat "Aging-Related Disorders".

The incidence of aging-related disorders may be decreased through strategies influencing the expression of longevity genes. Although numerous approaches have been suggested, no effective, safe, and easily applicable approach is yet available. Efficacy of low-dose fluvastatin and valsartan, separately or in combination, on the expression of the longevity genes in middle-aged males, was assessed. Stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin-valsartan combination (10 and 20 mg, respectively), and placebo (control) were analyzed. They were taken before and after 30 days of treatment and, additionally, five months after treatment discontinuation. The expression of the following longevity genes was assessed: SIRT1, PRKAA, KLOTHO, NFE2L2, mTOR, and NF-κB. Treatment with fluvastatin and valsartan in combination significantly increased the expression of SIRT1 (1.8-fold; p < 0.0001), PRKAA (1.5-fold; p = 0.262) and KLOTHO (1.7-fold; p < 0.0001), but not NFE2L2, mTOR and NF-κB. Both fluvastatin and valsartan alone significantly, but to a lesser extent, increased the expression of SIRT1, and did not influence the expression of other genes. Five months after treatment discontinuation, genes expression decreased to the basal levels. In addition, analysis with previously obtained results revealed significant correlation between SIRT1 and both increased telomerase activity and improved arterial wall characteristics. We showed that low-dose fluvastatin and valsartan, separately and in combination, substantially increase expression of SIRT1, PRKAA, and KLOTHO genes, which may be attributed to their so far unreported pleiotropic beneficial effects. This approach could be used for prevention of ageing (and longevity genes)-related disorders.

Empagliflozin on top of metformin treatment improves arterial function in patients with type 1 diabetes mellitus.

BACKGROUND: Deteriorated arterial function and high incidence of cardiovascular events characterise diabetes mellitus. Metformin and recent antidiabetic drugs, SGLT2 inhibitors, reduce cardiovascular events. We explored the possible effects of empagliflozin's effect on top of metformin treatment on endothelial function and arterial stiffness parameters in type 1 diabetes mellitus (T1DM) patients. METHODS: Forty T1DM patients were randomised into three treatment groups: (1) empagliflozin (25 mg daily), (2) metformin (2000 mg daily) and (3) empagliflozin/metformin (25 mg daily and 2000 mg daily, respectively). The fourth group received placebo. Arterial function was assessed at inclusion and after 12 weeks treatment by: endothelial function [brachial artery flow-mediated dilation (FMD), reactive hyperaemia index (RHI)], arterial stiffness [pulse wave velocity (PWV) and common carotid artery stiffness (ß-stiffness)]. For statistical analysis one-way analysis of variance with Bonferroni post-test was used. RESULTS: Empagliflozin on top of metformin treatment significantly improved endothelial function as did metformin after 12 weeks of treatment: FMD [2.6-fold (P < 0.001) vs. 1.8-fold (P < 0.05)] and RHI [1.4-fold (P < 0.01) vs. 1.3-fold (P < 0.05)]. Empagliflozin on top of metformin treatment was superior to metformin in improving arterial stiffness parameters; it significantly improved PWV and ß-stiffness compared to metformin [by 15.8% (P < 0.01) and by 36.6% (P < 0.05), respectively]. Metformin alone did not influence arterial stiffness. CONCLUSION: Empagliflozin on top of metformin treatment significantly improved arterial stiffness compared to metformin in T1DM patients. Endothelial function was similarly improved in all treatment groups. Empagliflozin seems to possess a specific capacity to decrease arterial stiffness, which could support its cardioprotective effects observed in large clinical studies. Trial registration Clinical trial registration: NCT03639545.

Improving Arterial Wall Characteristics in Patients After Myocardial Infarction with a Very Low Dose of Fluvastatin and Valsartan: A Proof-of-Concept Study.

BACKGROUND We tested the concept of improving arterial wall characteristics by treatment with a very low-dose combination of fluvastatin and valsartan (low-flu/val) in stable, post-myocardial infarction (MI) patients. MATERIAL AND METHODS We enrolled 36 post-MI middle-aged males in the treatment (n=20) or control (n=16) group receiving low-flu/val (10 mg/20 mg) or placebo, respectively. The parameters of endothelial function (flow-mediated dilatation (FMD), reactive hyperemia index), and arterial stiffness (carotid-femoral pulse wave velocity (cf-PWV), local carotid PWV, and beta stiffness coefficient) were measured before and after 30 days of therapy, and 10 weeks later. RESULTS Treatment with low-flu/val improved FMD from 3.1±1.3% to 4.8±1.5% (p<0.001; by 54.8%) and cf-PWV from 7.8±1.1 to 6.7±1.5 m/s (p<0.01; by 14.1%) without affecting either lipids or blood pressure. In the treatment group, FMD and/or cf-PWV significantly improved in 17 patients, but the improvements did not correlate. The benefits obtained were still detectable 10 weeks after complete treatment cessation. No changes were obtained in the control group. No other vascular parameters changed. CONCLUSIONS Low-flu/val added "on top of" optimal therapy substantially improves endothelial function and arterial stiffness in post-MI patients. Since these improved parameters are well-known predictors of future coronary events, such treatment could decrease cardiovascular risk. Further studies are therefore warranted.

The "Rise-Peak-Fall" Pattern of Time Dependency of the Cardiovascular Pleiotropic Effects of Treatment With Low-dose Atorvastatin, Losartan, and a Combination Thereof in Rats.

Treatment with low, subtherapeutic doses of statins and sartans expresses beneficial pleiotropic effects on the arterial wall. The present study explored whether these effects depend on treatment duration. Wistar rats were randomly divided into 4 groups and received low-dose atorvastatin, low-dose losartan, their combination, or saline (control) daily. After 4, 6, 8, and 10 weeks of treatment, the animals were anesthetized, blood samples taken, and hearts and thoracic aortas isolated. Thoracic aorta endothelium-dependent relaxation and parameters of the isolated heart exposed to ischemic-reperfusion injury were assessed along with blood serum parameters and vasoactive genes expression. Low-dose atorvastatin, losartan, and especially their combination showed the characteristic time dependency of all studied parameters (thoracic aorta relaxation, isolated heart parameters, C-reactive protein values, genes encoding endothelial nitric oxide synthase, and CD40). The peak in efficacy was observed after 6 weeks of treatment and subsequently steadily declined. The peak versus control values were significant for all measured parameters. Only a combination of atorvastatin and losartan increased nitric oxide and decreased asymmetric dimethylarginine. A characteristic time-dependent "rise-peak-fall" pattern of the cardiovascular pleiotropic effects of statins and sartans in subtherapeutic low doses was revealed. Evidently, resistance to the explored treatment occurs after a certain period.

The presence of cerebral and/or systemic endothelial dysfunction in patients with leukoaraiosis--a case control pilot study.

BACKGROUND: In spite of high prevalence and clinical relevance of leukoaraiosis (LA), its pathophysiology is still incompletely understood. Theories of ischaemic genesis and a leaky blood-brain barrier are contradictory yet could share a common denominator-endothelial dysfunction (cerebral, systemic or both), which has not been studied thoroughly in LA. METHODS: Thirty patients with LA (58 years (SD 7)) and 30 gender- and age-matched controls without LA (55 years (SD 6)) were recruited. The vascular risk factors (VRF) were identical in both groups. Cerebral endothelial function was determined by cerebrovascular reactivity to L-arginine (CVR). Systemic endothelial function was determined by flow-mediated dilatation (FMD) of the brachial artery after hyperaemia. All participants underwent a brain MRI to search for radiological signs of LA that was classified according to the Fazekas score. Linear regression was used to explore the correlation between CVR and FMD in patients with LA. A 95 % confidence interval was used. For any statistical test used in the study, p ≤ 0.050 was regarded as statistically significant. RESULTS: We found a marked and significant decrease in both CVR (9.6 % (SD 3.2) vs. 15.8 % (SD 6.1), p < 0.001) and FMD (4.8 % (SD 3.1) vs. 7.4 % (SD 3.8), p = 0.004) in LA patients compared to controls. Both CVR (7.4 % (SD 3.1) vs. 12.2 % (SD 2.6), p = 0.001) and FMD (3.0 % (SD 2.2) vs. 6.4 % (SD 3.1), p = 0.011) were significantly decreased in LA subgroup Fazekas 3 compared to subgroup Fazekas 1. CVR and FMD significantly positively correlated (b = 0.192, 95 % CI = 0.031-0.354, p = 0.02). CONCLUSIONS: The results of our pilot study suggest that patients with LA have a significant impairment of both cerebral and systemic endothelial function that is larger than could be expected based on present VRF. Endothelial dysfunction increases in parallel with LA severity and correlates between cerebral and systemic arterial territory. Overall, our results suggest a so far unknown "intrinsic" generalised endothelial dysfunction in patients with LA that could be involved in LA pathophysiology. This interesting issue needs to be confirmed in larger samples since it could help better understand the mechanisms underlying LA.

A Combination of Low Doses of Fluvastatin and Valsartan Decreases Arterial Stiffness in Patients After Myocardial Infarction: A Pilot Study.

BACKGROUND: Despite optimum treatment, patients who experience myocardial infarction are still at high risk for future events. OBJECTIVE: We evaluated the effect of 30 days of treatment with combination of low, subtherapeutic doses of fluvastatin and valsartan on arterial stiffness in patients after myocardial infarction, a therapy that has not been used yet. METHODS: Fourteen male patients with a history of myocardial infarction were enrolled into a pilot double-blind randomized controlled study. They were allocated to receive 10 mg fluvastatin and 20 mg valsartan or placebo for 30 days in addition to their regular pharmacotherapy. Carotid-femoral pulse wave velocity was measured on inclusion, after 30 days, and after 3 months. RESULTS: Mean (SD) carotid-femoral pulse wave velocity decreased significantly in the treatment group after 30 days and persisted at lower values after 3 months (from 8.4 [1.5] m/sec to 7.3 [1.1] m/sec to 7.2 [0.8] m/sec; P < 0.05). The 95% CI for decrease after 30 days in the treatment group was 0.5-1.6. Only nonsignificant changes were observed in the control group. Serum lipid levels and arterial blood pressure did not change significantly in any group. CONCLUSIONS: The treatment resulted in a significant and sustained improvement of arterial stiffness in male patients with a history of myocardial infarction, which highlights the need for further study of this new approach.

Stable phase post-MI patients have elevated VEGF levels correlated with inflammation markers, but not with atherosclerotic burden.

BACKGROUND: The role of vascular endothelial growth factor (VEGF) in patients in the stable phase after myocardial infarction (MI) has not yet been explored. Therefore, we compared the values of VEGF in post-MI patients with those obtained in healthy controls. Furthermore, we investigated whether the values of VEGF correlate to either inflammation markers or the atherosclerotic burden. METHODS: 41 male patients (on average 44 years old) in the stable phase after MI (on average 20.5 months after MI) were recruited, while 25 healthy age-matched males served as controls. Plasma levels of VEGF and several markers of inflammation were measured by standard procedures. The atherosclerotic burden was determined by the angiographic severity of coronary atherosclerosis, endothelial dysfunction (measured by ultrasound measurement of the flow mediated dilation of the brachial artery), the intima-media thickness of the common carotid artery and the ankle-brachial pressure index. RESULTS: VEGF values were significantly elevated in post-MI patients compared to the controls (53.8 ± 42.7 pg/ml vs. 36.3 ± 8.9 pg/ml, p = 0.014). The elevated VEGF values significantly correlated to the (increased) values of the inflammatory molecules interleukin 6 and 8 (r = 0.37, p = 0.017; and r = 0.45, p = 0.003; respectively). In contrast, no correlation was found between VEGF and the parameters of the atherosclerotic burden, although FMD and IMT were significantly impaired in patients. CONCLUSIONS: We found that plasma levels of VEGF are increased in the stable phase after MI and correlate with inflammation cytokines, but not with the atherosclerotic burden. Thus, this suggests that increased levels of VEGF are a part of ongoing inflammatory activity. Since VEGF in these patients stimulates neovascularization of inflamed plaques and induces their destabilization, the VEGF level can have an important negative prognostic value. Clearly, further studies are needed to clarify the role of VEGF as a prognostic marker.

Coenzyme Q10 supplementation decreases statin-related mild-to-moderate muscle symptoms: a randomized clinical study.

BACKGROUND: Statin use is frequently associated with muscle-related symptoms. Coenzyme Q10 supplementation has yielded conflicting results in decreasing statin myopathy. Herein, we tested whether coenzyme Q10 supplementation could decrease statin-associated muscular pain in a specific group of patients with mild-to-moderate muscle symptoms. MATERIAL/METHODS: Fifty patients treated with statins and reporting muscle pain were recruited. The Q10 group (n=25) received coenzyme Q10 supplementation over a period of 30 days (50 mg twice daily), and the control group (n=25) received placebo. The Brief Pain Inventory (BPI) questionnaire was used and blood testing was performed at inclusion in the study and after 30 days of supplementation. RESULTS: The intensity of muscle pain, measured as the Pain Severity Score (PSS), in the Q10 group was reduced from 3.9±0.4 to 2.9±0.4 (P<0.001). The Pain Interference Score (PIS) after Q10 supplementation was reduced from 4.0±0.4 to 2.6±0.4 (P<0.001). In the placebo group, PSS and PIS did not change. Coenzyme Q10 supplementation decreased statin-related muscle symptoms in 75% of patients. The relative values of PSS and PIS significantly decreased (-33.1% and -40.3%, respectively) in the Q10 group compared to placebo group (both P<0.05). From baseline, no differences in liver and muscle enzymes or cholesterol values were found. CONCLUSIONS: The present results show that coenzyme Q10 supplementation (50 mg twice daily) effectively reduced statin-related mild-to-moderate muscular symptoms, causing lower interference of statin-related muscular symptoms with daily activities.

Andexanet Alfa: What We Have Learned from Clinical Trials and Real-World Data.

Andexanet alfa is a specific reversal agent for factor Xa inhibitors with immediate reversal of their anticoagulant effect. Andexanet alfa is currently approved for use in patients treated with rivaroxaban and apixaban who have life-threatening or uncontrolled bleeding. New data from both controlled clinical trials and real-world experience are continuously being published, providing greater insight into the clinical characteristics of the drug, such as efficacy and safety. It is worth considering that andexanet alfa could be of benefit in a variety of different clinical scenarios where patients receiving treatment with apixaban and rivaroxaban (and endoxaban) have life-threatening conditions. These different clinical scenarios, which range from pre-treatment of urgent surgery, especially neurosurgical interventions, and concomitant use of andexanet alfa and prothrombin complex concentrate to onset of bleeding more than 6 h prior to admission, should be clarified as well as the issue of "low/high" dose of andexanet alfa and the need for baseline anti-Xa inhibitor levels measured by point-of-care testing. Finally, management of patients at high risk of thrombosis or recent arterial/venous thrombotic events needs to be further explored. In this current opinion, we address these urgent questions in the light of recent literature and clinical trial data.

Idarucizumab in dabigatran-treated patients with acute stroke: a review and clinical update.

Idarucizumab is an antibody fragment specific for the immediate reversal of dabigatran anticoagulation effects. The use of idarucizumab is approved for dabigatran-treated patients suffering from life-threatening or uncontrolled bleeding and those in need of urgent surgery or invasive procedures. Data from randomized controlled clinical trials and real-world experience provide reassuring evidence about the efficacy and safety of idarucizmab use in patients with acute stroke. In this narrative review, we summarize the available real-world evidence and discuss the relevance and importance of idarucizumab treatment in acute stroke patients in everyday clinical practice. In addition, we also discuss special issues like prothrombin complex concentrate application as an alternative to idarucizumab, its application before endovascular therapy, sensitivity of thrombi to lysis, and necessary laboratory examinations.