Exercise therapy for chronic symptomatic peripheral artery disease.

All guidelines worldwide strongly recommend exercise as a pillar of the management of patients affected by lower extremity peripheral artery disease (PAD). Exercise therapy in this setting presents different modalities, and a structured programme provides optimal results. This clinical consensus paper is intended for clinicians to promote and assist for the set-up of comprehensive exercise programmes to best advice in patients with symptomatic chronic PAD. Different exercise training protocols specific for patients with PAD are presented. Data on patient assessment and outcome measures are narratively described based on the current best evidence. The document ends by highlighting disparities in access to supervised exercise programmes across Europe and the series of gaps for evidence requiring further research.

Rescue From Permanent Kidney Injury in Acute Thrombosis of Both Renal Veins, the Inferior Vena Cava, and Both Iliofemoral Veins by Catheter-Based Thrombectomy.

CASE: A 33-year-old man with previously diagnosed lupus membranous nephropathy presented with painful swelling in both legs. Laboratory tests revealed acute kidney injury, and imaging studies by duplex ultrasound and computed tomography scan showed acute thrombosis of both renal veins, the infrahepatic inferior vena cava, and both iliofemoral venous segments. Initially, pharmacomechanical thrombolysis led to an insufficient morphological result. The therapeutic breakthrough was achieved by catheter-based mechanical thrombectomy of the infrarenal vena cava and both renal veins, which successfully cleared all affected venous segments from thrombus, paralleled by improvement of the patient's condition. However, after 1 week, the patient experienced recurrent thrombosis of the right renal vein with hemorrhagic infarction of the right kidney. After further optimization of immunomodulatory and antithrombotic therapy, a repeated catheter-based mechanical thrombectomy resulted in sustained clinical improvement and preservation of renal venous drainage and kidney function. CONCLUSION: Extensive acute thrombosis of both renal veins, the inferior vena cava, and both iliofemoral venous segments is a rare emergency potentially threatening kidney function. Immediate effective thrombus removal is essential to preserve kidney function and can be achieved by catheter-based mechanical thrombectomy embedded in a comprehensive immunomodulatory and antithrombotic therapeutic concept. CLINICAL IMPACT: This case demonstrated the efficacy of a catheter-based therapeutic approach in patients with extensive thrombosis of the venous system. A catheter-based approach must be embedded in a comprehensive medical therapeutic concept, which is essential to achieve a sustainable result.

Exercise Therapy for Chronic Symptomatic Peripheral Artery Disease: A Clinical Consensus Document of the European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases in Collaboration With the European Society of Vascular Medicine and the European Society for Vascular Surgery.

All guidelines worldwide strongly recommend exercise as a pillar in the management of patients affected by lower extremity peripheral artery disease (PAD). Exercise therapy in this setting presents different modalities, and a structured programme provides optimal results. This clinical consensus paper is intended to promote and assist the set up of comprehensive exercise programmes and best advice for patients with symptomatic chronic PAD. Different exercise training protocols specific for patients with PAD are presented. Data on patient assessment and outcome measures are described based on the current best evidence. The document ends by highlighting supervised exercise programme access disparities across Europe and the evidence gaps requiring further research.

Capillaroscopic differences between primary Raynaud phenomenon and healthy controls indicate potential microangiopathic involvement in benign vasospasms.

BACKGROUND: For primary Raynaud phenomenon (PRP), an otherwise unexplained vasospastic disposition is assumed. To test the hypothesis of an additional involvement of distinct ultrastructural microvascular alterations, we compared the nailfold capillary pattern of patients with PRP and healthy controls. METHODS: A total of 120 patients with PRP (with a median duration of vasospastic symptoms of 60 [IQR: 3-120] months) were compared against 125 controls. In both groups, nailfold capillaroscopy was performed to record the presence of dilatations, capillary edema, tortuous capillaries, ramifications, hemorrhages, and reduced capillary density and to determine a semiquantitative rating score. Further, the capacity of finger skin rewarming was investigated by performing infrared thermography in combination with cold provocation. RESULTS: Unspecific morphologic alterations were found in both, PRP, such as controls, whereby the risk for PRP was four times as high in the presence of capillary dilations (CI: 2.3-7.6) and five times as high if capillary density was reduced (CI: 1.9-13.5). Capillary density correlated with thermoregulatory capacity in both hands in the PRP group, but not in controls. In addition, a negative correlation between the microangiopathy score and the percentage degree of rewarming in both hands was found for patients with PRP only. CONCLUSION: We found specific differences within the microvascular architecture between patients with PRP and controls. As a conclusion, PRP may not be an entirely benign vasospastic phenomenon, but might be associated with subtle microcirculatory vasculopathy. In addition, we suggest that the implementation of a scoring system might serve as guidance in the diagnostic process at least of patients with long-standing PRP.

The TOPOS study.

Background: We aimed to study the long-term safety and efficacy of oblique venous stents for post-thrombotic syndrome (PTS) with iliac vein compression. Patients and methods: In the multinational, prospective, single-arm TOPOS study, PTS patients scheduled for endovascular therapy with the sinus-Obliquus® stent and optional distal extension with the sinus-Venous® or sinus-XL Flex® stent were enrolled at eight European vascular centres between October 2016 and December 2020. The primary outcome was primary stent patency at 24 months, and secondary outcomes included the clinical course of PTS (Villalta score, revised Venous Clinical Severity Score [rVCSS], Visual Analog Scale [VAS] of pain), quality of life changes (Chronic Venous Insufficiency Quality of Life Questionnaire, CIVIQ-20), and device-related complications. Results: We enrolled 60 patients (mean age 46±15 years, 68% women, 13% active ulcers): 80% required stent extension (70% below the inguinal ligament). The primary patency rate at 24 months was 80.7% (95%CI 68.1-90.0%); it was higher in patients without vs. those with stent extension (90.9% vs. 78.3%, p=.01). Compared to baseline, the Villalta, rVCSS, pain VAS, and CIVIQ-20 decreased by a median of 8 (interquartile range (IQR): 4-11), 5 (IQR: 3-7), 3 (IQR: 2-5), and 17 (IQR: 6-22) points, respectively; p<.001 for all parameters. Overall, 9 events of acute stent occlusion, 4 symptomatic stent stenosis, and 1 pulmonary embolism occurred. We did not observe major bleeding events or contralateral thrombosis. Conclusions: Endovascular treatment with the oblique stent and optional stent extension was safe and resulted in high patency rates at 24 months. The reduction in PTS severity was substantial and persisted over 2-year follow-up.

Adverse reactions after intravascular iodinated contrast media administration and their management.

Endovascular interventions and diagnostic examinations using iodinated contrast media (ICM) are standard of care in current vascular medicine. Although ICM use is generally considered safe, it may be associated with adverse reactions, vary from minor disturbances to rare, but severe life-threatening complications. This position paper of European Society of Vascular Medicine integrates current knowledge and summarizes the key information related to the use of intravascular ICM, serving as recommendation on prevention and management of acute, late, and very late adverse reactions. It should help the health professionals in all fields of vascular medicine to make decisions in daily practice for safe use of contrast media.

Exercise therapy for chronic symptomatic peripheral artery disease.

All guidelines worldwide strongly recommend exercise as a pillar in the management of patients affected by lower extremity peripheral artery disease (PAD). Exercise therapy in this setting presents different modalities, and a structured programme provides optimal results. This clinical consensus paper is intended to promote and assist the set up of comprehensive exercise programmes and best advice for patients with symptomatic chronic PAD. Different exercise training protocols specific for patients with PAD are presented. Data on patient assessment and outcome measures are described based on the current best evidence. The document ends by highlighting supervised exercise programme access disparities across Europe and the evidence gaps requiring further research.

Preprocedural imaging modalities in patients undergoing iliocaval venous recanalization and stent placement.

PURPOSE: To determine the diagnostic accuracy of preinterventional imaging modalities in patients being evaluated for iliocaval venous recanalization and stent placement. METHODS: Consecutive patients with iliocaval postthrombotic obstructions or nonthrombotic iliac vein lesions (NIVL), who were scheduled for recanalization, underwent duplex ultrasound (DUS), magnetic resonance venography (MRV), multiplanar venography (MPV), and intravascular ultrasound (IVUS). The diagnostic accuracies of DUS, MRV, and MPV were analyzed using IVUS as reference. RESULTS: A total of 216 limbs in 108 patients (80 patients with postthrombotic obstructions, 28 patients with NIVL) were examined. In patients with postthrombotic obstructions, the diagnostic sensitivities for the detection of lesions of the common femoral vein were 81% (95% CI 71-89%) for DUS, 76% (95% CI 65-85%) for MRV, and 86% (95% CI 76-93%) for MPV. The sensitivities for detecting lesions of the iliac veins were 96% (95% CI 89-99%) for DUS, 99% (95% CI 92-100%) for MRV, and 100% (95% CI 94-100%) for MPV. Regarding the inferior vena cava, the sensitivities were 44% (95% CI 24-65%) for DUS, 52% (95% CI 31-73%) for MRV, and 70% (95% CI 47-86%) for MPV. The sensitivities for detecting NIVL were 58% (95% CI 34-79%) for DUS, 90% (95% CI 68-97%) for MRV, and 95% (95% CI 73-99%) for MPV. CONCLUSION: In patients scheduled for recanalization of iliocaval postthrombotic obstructions, the sensitivities of DUS, MRV, and MPV were similar. In patients with suspected inferior vena cava involvement and in patients with NIVL, additional imaging with MR or conventional venography is required.

Closure of Post-thrombotic Iliac Arteriovenous Fistulas by Iliac Vein Recanalization.

PURPOSE: The purpose of this study was to report the closure of iliac arteriovenous fistulas associated with a post-thrombotic iliac vein occlusion by iliac venous stent recanalization. CASE REPORT: An 80-year-old woman presented with a worsening painful swelling of her left leg after an iliofemoral deep vein thrombosis 6 months ago. Duplex ultrasound and magnetic resonance venography revealed a post-thrombotic obstruction of her iliac veins as well as several arteriovenous fistulas between branches of her left external and internal iliac arteries and adjacent diseased venous segments. In a first attempt, coil embolization did not sustainably close these iliac arteriovenous fistulas. Direct stent recanalization of the chronically diseased iliofemoral venous segment, however, resulted in an immediate closure of arteriovenous shunt flow and subsequent improvement of clinical symptoms. Six months after iliac vein stent recanalization, still no fistulas could be detected any more, venous stents were fully patent, and the patient was free of symptoms. CONCLUSION: Post-thrombotic iliofemoral obstructions might be associated with the development of arteriovenous fistulas. Direct stent recanalization of the chronically occluded veins results in closure of related arteriovenous fistulas. CLINICAL IMPACT: This case suggests that the combined occurrence of post-thrombotic venous obstructions with arteriovenous fistulas, which are related to aforementioned venous lesions, should be evaluated for primary venous stent recanalization rather than fistula embolization.

Antithrombotic therapies in aortic and peripheral arterial diseases in 2021: a consensus document from the ESC working group on aorta and peripheral vascular diseases, the ESC working group on thrombosis, and the ESC working group on cardiovascular pharmacotherapy.

The aim of this collaborative document is to provide an update for clinicians on best antithrombotic strategies in patients with aortic and/or peripheral arterial diseases. Antithrombotic therapy is a pillar of optimal medical treatment for these patients at very high cardiovascular risk. While the number of trials on antithrombotic therapies in patients with aortic or peripheral arterial diseases is substantially smaller than for those with coronary artery disease, recent evidence deserves to be incorporated into clinical practice. In the absence of specific indications for chronic oral anticoagulation due to concomitant cardiovascular disease, a single antiplatelet agent is the basis for long-term antithrombotic treatment in patients with aortic or peripheral arterial diseases. Its association with another antiplatelet agent or low-dose anticoagulants will be discussed, based on patient's ischaemic and bleeding risk as well therapeutic paths (e.g. endovascular therapy). This consensus document aims to provide a guidance for antithrombotic therapy according to arterial disease localizations and clinical presentation. However, it cannot substitute multidisciplinary team discussions, which are particularly important in patients with uncertain ischaemic/bleeding balance. Importantly, since this balance evolves over time in an individual patient, a regular reassessment of the antithrombotic therapy is of paramount importance.

Management of chronic peripheral artery disease patients with indication for endovascular revascularization.

With an increasing global burden of patients with chronic peripheral artery disease (PAD) the safe and effective provision of lower limb revascularisation is a growing medical need. Endovascular procedures for the treatment of PAD have become a crucial cornerstone of modern vascular medicine, and the first line revascularisation approach if technically feasible and taking patient choice into consideration. With the increasing age of patients with PAD and the increasing number of comorbidities open vascular surgery is also often not feasible. We outline a framework of key messages, endorsed by the board of the European Society of Vascular Medicine for pre-, peri- and post procedural management of patients requiring endovascular arterial procedures of the lower limbs. These key messages emphasize the important and increasing role of interventional vascular physicians.

Early clinical outcomes for treatment of post-thrombotic syndrome and common iliac vein compression with a hybrid Oblique self-expanding nitinol stent - the TOPOS study.

Background: Physical attributes of conventional stents used in the ilio-caval territory are often unfavorable in the presence of external compression close to the bifurcation. A hybrid oblique stent was developed for the treatment of common iliac vein compression without compromising the contralateral iliac vein inflow. Patients and methods: The ongoing international monitored TOPOS study enrolled 60 patients with post-thrombotic syndrome (PTS) treated with the sinus-Obliquus stent (optimed) and provisional distal stent extension. At 3-month follow-up, patency rates were obtained from duplex ultrasound, and clinical outcomes were assessed by the Villalta score, revised venous severity score (rVCSS), pain intensity score and chronic venous disease quality of life questionnaire (CIVIQ-20). Results: Mean age was 46.6 ± 14.9 years (68.3 % women). Mean number of implanted stents was 1.9 ± 0.6; 12 (20 %) patients received the hybrid oblique stent only. Forty-eight (80 %) patients had distal stent extension, and 42 (70 %) had stents below the inguinal ligament. Four (7 %) patients (all with stent extension) developed stent thrombosis. Primary and secondary patency rates at 3 months were 93.1 % (95 %CI 83.3-98.1 %), and 100 % (95 %CI 93.8-100 %), respectively. Improvement in Villalta, rVCSS, CIVIQ-20, and pain intensity score from baseline to 3-month follow-up was 6.9 ± 1.4 points (95 %CI 4.1-9.8; p < 0.0001), 3.4 ± 1.0 points (95 %CI 1.3-5.4 points; p < 0.01), 13.6 ± 2.7 points (95 %CI 8.2-19.0 points; p < 0.0001), and 2.4 ± 0.5 (95 %CI 1.4-3.3; p < 0.0001), respectively. At follow-up, 38 (63 %) patients were free from the PTS and none developed contralateral deep vein thrombosis. Conclusions: In patients with PTS and common iliac vein compression, treatment with the hybrid oblique stent with provisional stent extension resulted in high patency rates and improvement in PTS severity and quality of life at 3-month. Two-year results of TOPOS will assess the durability of this treatment.

Risk stratification of elderly patients with acute pulmonary embolism.

BACKGROUND: Combining high-sensitivity cardiac Troponin T (hs-cTnT), NT-pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) may improve risk stratification of patients with pulmonary embolism (PE) beyond the PESI risk score. METHODS: In the prospective multicentre SWITCO65+ study, we analysed 214 patients ≥ 65 years with a new submassive PE. Biomarkers and clinical information for the PESI risk score were ascertained within 1 day after diagnosis. Associations of hs-TnT, NT-proBNP, hs-CRP and the PESI risk score with the primary endpoint defined as 6-month mortality were assessed. The discriminative power of the PESI risk score and its combination with hs-cTnT, NT-proBNP and hs-CRP for 6-month mortality was compared using integrated discrimination improvement (IDI) index and net reclassification improvement (NRI). RESULTS: Compared with the lowest quartile, patients in the highest quartile had a higher risk of death during the first 6 months for hs-cTnT (adjusted HR 10.22; 95% CI 1.79-58.34; P = 0.009) and a trend for NT-proBNP (adjusted HR 4.3; 95% CI 0.9-20.41; P = 0.067) unlike hs-CRP (adjusted HR 1.97; 95% CI 0.48-8.05; P = 0.344). The PESI risk score (c-statistic 0.77 (95% CI 0.69-0.84) had the highest prognostic accuracy for 6-month mortality, outperforming hs-cTnT, NT-proBNP and hs-CRP (c-statistics of 0.72, 0.72, and 0.54), respectively. Combining all three biomarkers had no clinically relevant impact on risk stratification when added to the PESI risk score (IDI = 0.067; 95% CI 0.012-0.123; P = 0.018; NRI = 0.101 95% CI -0.099-0.302; P = 0.321). CONCLUSIONS: In elderly patients with PE, 6-month mortality can adequately be predicted by the PESI risk score alone.

Effects of n-3 PUFA on endothelial function in patients with peripheral arterial disease: a randomised, placebo-controlled, double-blind trial.

As only limited evidence is available for potential benefits of n-3 PUFA supplementation in patients with peripheral arterial disease (PAD), we studied the effects of 4 g n-3 PUFA on endothelial function and inflammatory markers. Seventy patients with stable PAD classified as Rutherford stage 2 or 3 and good control of cardiovascular factors were randomised to receive either 4 g n-3 PUFA or placebo daily for 3 months in a double-blind fashion. Primary endpoint was endothelial function assessed by flow-mediated vasodilation (FMD). In addition, ankle-brachial index, maximum and pain-free walking distances were determined. Lipid parameters including the omega-3 index reflecting n-3 PUFA intake as well as pro-inflammatory, endothelial and platelet activation markers were measured over the same time interval. After 3 months of treatment with 4 g n-3 PUFA daily, a significant improvement of FMD was observed compared with placebo (n-3 PUFA, median Δ 3·7 (interquartile range (IQR) -1·8, 7·1) % v. placebo, Δ -0·5 (IQR -6·5, 3·0) %, P = 0·01 between the groups). After a 3-month washout period, this benefit was not sustained (n-3 PUFA, median Δ 0·6 (IQR -2·2, 5·6) % v. placebo, Δ -0·9 (IQR -6·6, 6·7) %, P = 0·20). In response to n-3 PUFA, an improvement of lipid parameters with a pronounced increase in the omega-3 index was seen. No changes were found for other parameters. In conclusion, in patients with PAD, 4 g/d n-3 PUFA improved cardiovascular risk in PAD patients, which needs testing in large-scale trials.

Perioperative beta-blockers for preventing surgery-related mortality and morbidity in adults undergoing cardiac surgery.

BACKGROUND: Randomized controlled trials (RCTs) have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue. A previous version of this review assessing the effectiveness of perioperative beta-blockers in cardiac and non-cardiac surgery was last published in 2018. The previous review has now been split into two reviews according to type of surgery. This is an update and assesses the evidence in cardiac surgery only. OBJECTIVES: To assess the effectiveness of perioperatively administered beta-blockers for the prevention of surgery-related mortality and morbidity in adults undergoing cardiac surgery. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, Biosis Previews and Conference Proceedings Citation Index-Science on 28 June 2019. We searched clinical trials registers and grey literature, and conducted backward- and forward-citation searching of relevant articles. SELECTION CRITERIA: We included RCTs and quasi-randomized studies comparing beta-blockers with a control (placebo or standard care) administered during the perioperative period to adults undergoing cardiac surgery. We excluded studies in which all participants in the standard care control group were given a pharmacological agent that was not given to participants in the intervention group, studies in which all participants in the control group were given a beta-blocker, and studies in which beta-blockers were given with an additional agent (e.g. magnesium). We excluded studies that did not measure or report review outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE. MAIN RESULTS: We included 63 studies with 7768 participants; six studies were quasi-randomized and the remaining were RCTs. All participants were undergoing cardiac surgery, and in most studies, at least some of the participants were previously taking beta-blockers. Types of beta-blockers were: propranolol, metoprolol, sotalol, esmolol, landiolol, acebutolol, timolol, carvedilol, nadolol, and atenolol. In twelve studies, beta-blockers were titrated according to heart rate or blood pressure. Duration of administration varied between studies, as did the time at which drugs were administered; in nine studies this was before surgery, in 20 studies during surgery, and in the remaining studies beta-blockers were started postoperatively. Overall, we found that most studies did not report sufficient details for us to adequately assess risk of bias. In particular, few studies reported methods used to randomize participants to groups. In some studies, participants in the control group were given beta-blockers as rescue therapy during the study period, and all studies in which the control was standard care were at high risk of performance bias because of the open-label study design. No studies were prospectively registered with clinical trials registers, which limited the assessment of reporting bias. We judged 68% studies to be at high risk of bias in at least one domain.Study authors reported few deaths (7 per 1000 in both the intervention and control groups), and we found low-certainty evidence that beta-blockers may make little or no difference to all-cause mortality at 30 days (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.47 to 1.90; 29 studies, 4099 participants). For myocardial infarctions, we found no evidence of a difference in events (RR 1.05, 95% CI 0.72 to 1.52; 25 studies, 3946 participants; low-certainty evidence). Few study authors reported cerebrovascular events, and the evidence was uncertain (RR 1.37, 95% CI 0.51 to 3.67; 5 studies, 1471 participants; very low-certainty evidence). Based on a control risk of 54 per 1000, we found low-certainty evidence that beta-blockers may reduce episodes of ventricular arrhythmias by 32 episodes per 1000 (RR 0.40, 95% CI 0.25 to 0.63; 12 studies, 2296 participants). For atrial fibrillation or flutter, there may be 163 fewer incidences with beta-blockers, based on a control risk of 327 incidences per 1000 (RR 0.50, 95% CI 0.42 to 0.59; 40 studies, 5650 participants; low-certainty evidence). However, the evidence for bradycardia and hypotension was less certain. We found that beta-blockers may make little or no difference to bradycardia (RR 1.63, 95% CI 0.92 to 2.91; 12 studies, 1640 participants; low-certainty evidence), or hypotension (RR 1.84, 95% CI 0.89 to 3.80; 10 studies, 1538 participants; low-certainty evidence).We used GRADE to downgrade the certainty of evidence. Owing to studies at high risk of bias in at least one domain, we downgraded each outcome for study limitations. Based on effect size calculations in the previous review, we found an insufficient number of participants in all outcomes (except atrial fibrillation) and, for some outcomes, we noted a wide confidence interval; therefore, we also downgraded outcomes owing to imprecision. The evidence for atrial fibrillation and length of hospital stay had a moderate level of statistical heterogeneity which we could not explain, and we, therefore, downgraded these outcomes for inconsistency. AUTHORS' CONCLUSIONS: We found no evidence of a difference in early all-cause mortality, myocardial infarction, cerebrovascular events, hypotension and bradycardia. However, there may be a reduction in atrial fibrillation and ventricular arrhythmias when beta-blockers are used. A larger sample size is likely to increase the certainty of this evidence. Four studies awaiting classification may alter the conclusions of this review.

Perioperative beta-blockers for preventing surgery-related mortality and morbidity in adults undergoing non-cardiac surgery.

BACKGROUND: Randomized controlled trials (RCTs) have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in an unselected population remains a controversial issue. A previous version of this review assessing the effectiveness of perioperative beta-blockers in cardiac and non-cardiac surgery was last published in 2018. The previous review has now been split into two reviews according to type of surgery. This is an update, and assesses the evidence in non-cardiac surgery only. OBJECTIVES: To assess the effectiveness of perioperatively administered beta-blockers for the prevention of surgery-related mortality and morbidity in adults undergoing non-cardiac surgery. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, Biosis Previews and Conference Proceedings Citation Index-Science on 28 June 2019. We searched clinical trials registers and grey literature, and conducted backward- and forward-citation searching of relevant articles. SELECTION CRITERIA: We included RCTs and quasi-randomized studies comparing beta-blockers with a control (placebo or standard care) administered during the perioperative period to adults undergoing non-cardiac surgery. If studies included surgery with different types of anaesthesia, we included them if 70% participants, or at least 100 participants, received general anaesthesia. We excluded studies in which all participants in the standard care control group were given a pharmacological agent that was not given to participants in the intervention group, studies in which all participants in the control group were given a beta-blocker, and studies in which beta-blockers were given with an additional agent (e.g. magnesium). We excluded studies that did not measure or report review outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE. MAIN RESULTS: We included 83 RCTs with 14,967 participants; we found no quasi-randomized studies. All participants were undergoing non-cardiac surgery, and types of surgery ranged from low to high risk. Types of beta-blockers were: propranolol, metoprolol, esmolol, landiolol, nadolol, atenolol, labetalol, oxprenolol, and pindolol. In nine studies, beta-blockers were titrated according to heart rate or blood pressure. Duration of administration varied between studies, as did the time at which drugs were administered; in most studies, it was intraoperatively, but in 18 studies it was before surgery, in six postoperatively, one multi-arm study included groups of different timings, and one study did not report timing of drug administration. Overall, we found that more than half of the studies did not sufficiently report methods used for randomization. All studies in which the control was standard care were at high risk of performance bias because of the open-label study design. Only two studies were prospectively registered with clinical trials registers, which limited the assessment of reporting bias. In six studies, participants in the control group were given beta-blockers as rescue therapy during the study period.The evidence for all-cause mortality at 30 days was uncertain; based on the risk of death in the control group of 25 per 1000, the effect with beta-blockers was between two fewer and 13 more per 1000 (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.89 to 1.54; 16 studies, 11,446 participants; low-certainty evidence). Beta-blockers may reduce the incidence of myocardial infarction by 13 fewer incidences per 1000 (RR 0.72, 95% CI 0.60 to 0.87; 12 studies, 10,520 participants; low-certainty evidence). We found no evidence of a difference in cerebrovascular events (RR 1.65, 95% CI 0.97 to 2.81; 6 studies, 9460 participants; low-certainty evidence), or in ventricular arrhythmias (RR 0.72, 95% CI 0.35 to 1.47; 5 studies, 476 participants; very low-certainty evidence). Beta-blockers may reduce atrial fibrillation or flutter by 26 fewer incidences per 1000 (RR 0.41, 95% CI 0.21 to 0.79; 9 studies, 9080 participants; low-certainty evidence). However, beta-blockers may increase bradycardia by 55 more incidences per 1000 (RR 2.49, 95% CI 1.74 to 3.56; 49 studies, 12,239 participants; low-certainty evidence), and hypotension by 44 more per 1000 (RR 1.40, 95% CI 1.29 to 1.51; 49 studies, 12,304 participants; moderate-certainty evidence).We downgraded the certainty of the evidence owing to study limitations; some studies had high risks of bias, and the effects were sometimes altered when we excluded studies with a standard care control group (including only placebo-controlled trials showed an increase in early mortality and cerebrovascular events with beta-blockers). We also downgraded for inconsistency; one large, well-conducted, international study found a reduction in myocardial infarction, and an increase in cerebrovascular events and all-cause mortality, when beta-blockers were used, but other studies showed no evidence of a difference. We could not explain the reason for the inconsistency in the evidence for ventricular arrhythmias, and we also downgraded this outcome for imprecision because we found few studies with few participants. AUTHORS' CONCLUSIONS: The evidence for early all-cause mortality with perioperative beta-blockers was uncertain. We found no evidence of a difference in cerebrovascular events or ventricular arrhythmias, and the certainty of the evidence for these outcomes was low and very low. We found low-certainty evidence that beta-blockers may reduce atrial fibrillation and myocardial infarctions. However, beta-blockers may increase bradycardia (low-certainty evidence) and probably increase hypotension (moderate-certainty evidence). Further evidence from large placebo-controlled trials is likely to increase the certainty of these findings, and we recommend the assessment of impact on quality of life. We found 18 studies awaiting classification; inclusion of these studies in future updates may also increase the certainty of the evidence.

Perioperative beta-blockers for preventing surgery-related mortality and morbidity.

BACKGROUND: Randomized controlled trials have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue. OBJECTIVES: The objective of this review was to systematically analyse the effects of perioperatively administered beta-blockers for prevention of surgery-related mortality and morbidity in patients undergoing any type of surgery while under general anaesthesia. SEARCH METHODS: We identified trials by searching the following databases from the date of their inception until June 2013: MEDLINE, Embase , the Cochrane Central Register of Controlled Trials (CENTRAL), Biosis Previews, CAB Abstracts, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Derwent Drug File, Science Citation Index Expanded, Life Sciences Collection, Global Health and PASCAL. In addition, we searched online resources to identify grey literature. SELECTION CRITERIA: We included randomized controlled trials if participants were randomly assigned to a beta-blocker group or a control group (standard care or placebo). Surgery (any type) had to be performed with all or at least a significant proportion of participants under general anaesthesia. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from all studies. In cases of disagreement, we reassessed the respective studies to reach consensus. We computed summary estimates in the absence of significant clinical heterogeneity. Risk ratios (RRs) were used for dichotomous outcomes, and mean differences (MDs) were used for continuous outcomes. We performed subgroup analyses for various potential effect modifiers. MAIN RESULTS: We included 88 randomized controlled trials with 19,161 participants. Six studies (7%) met the highest methodological quality criteria (studies with overall low risk of bias: adequate sequence generation, adequate allocation concealment, double/triple-blinded design with a placebo group, intention-to-treat analysis), whereas in the remaining trials, some form of bias was present or could not be definitively excluded (studies with overall unclear or high risk of bias). Outcomes were evaluated separately for cardiac and non-cardiac surgery.CARDIAC SURGERY (53 trials)We found no clear evidence of an effect of beta-blockers on the following outcomes.• All-cause mortality: RR 0.73, 95% CI 0.35 to 1.52, 3783 participants, moderate quality evidence.• Acute myocardial infarction (AMI): RR 1.04, 95% CI 0.71 to 1.51, 3553 participants, moderate quality evidence.• Myocardial ischaemia: RR 0.51, 95% CI 0.25 to 1.05, 166 participants, low quality evidence.• Cerebrovascular events: RR 1.52, 95% CI 0.58 to 4.02, 1400 participants, low quality evidence.• Hypotension: RR 1.54, 95% CI 0.67 to 3.51, 558 participants, low quality evidence.• Bradycardia: RR 1.61, 95% CI 0.97 to 2.66, 660 participants, low quality evidence.• Congestive heart failure: RR 0.22, 95% CI 0.04 to 1.34, 311 participants, low quality evidence.Beta-blockers significantly reduced the occurrence of the following endpoints.• Ventricular arrhythmias: RR 0.37, 95% CI 0.24 to 0.58, number needed to treat for an additional beneficial outcome (NNTB) 29, 2292 participants, moderate quality evidence.• Supraventricular arrhythmias: RR 0.44, 95% CI 0.36 to 0.53, NNTB five, 6420 participants, high quality evidence.• On average, beta-blockers reduced length of hospital stay by 0.54 days (95% CI -0.90 to -0.19, 2450 participants, low quality evidence).NON-CARDIAC SURGERY (35 trials)Beta-blockers significantly increased the occurrence of the following adverse events.• All-cause mortality: RR 1.25, 95% CI 1.00 to 1.57, 11,413 participants, low quality of evidence, number needed to treat for an additional harmful outcome (NNTH) 167.• Hypotension: RR 1.50, 95% CI 1.38 to 1.64, NNTH 16, 10,947 participants, high quality evidence.• Bradycardia: RR 2.23, 95% CI 1.48 to 3.36, NNTH 21, 11,033 participants, moderate quality evidence.We found a potential increase in the occurrence of the following outcomes with the use of beta-blockers.• Cerebrovascular events: RR 1.59, 95% CI 0.93 to 2.71, 9150 participants, low quality evidence.Whereas no clear evidence of an effect was found when all studies were analysed, restricting the meta-analysis to low risk of bias studies revealed a significant increase in cerebrovascular events with the use of beta-blockers: RR 2.09, 95% CI 1.14 to 3.82, NNTH 265, 8648 participants.Beta-blockers significantly reduced the occurrence of the following endpoints.• AMI: RR 0.73, 95% CI 0.61 to 0.87, NNTB 76, 10,958 participants, high quality evidence.• Myocardial ischaemia: RR 0.51, 95% CI 0.34 to 0.77, NNTB nine, 978 participants, moderate quality evidence.• Supraventricular arrhythmias: RR 0.73, 95% CI 0.57 to 0.94, NNTB 112, 8744 participants, high quality evidence.We found no clear evidence of an effect of beta-blockers on the following outcomes.• Ventricular arrhythmias: RR 0.68, 95% CI 0.31 to 1.49, 476 participants, moderate quality evidence.• Congestive heart failure: RR 1.18, 95% CI 0.94 to 1.48, 9173 participants, moderate quality evidence.• Length of hospital stay: mean difference -0.45 days, 95% CI -1.75 to 0.84, 551 participants, low quality evidence. AUTHORS' CONCLUSIONS: According to our findings, perioperative application of beta-blockers still plays a pivotal role in cardiac surgery, as they can substantially reduce the high burden of supraventricular and ventricular arrhythmias in the aftermath of surgery. Their influence on mortality, AMI, stroke, congestive heart failure, hypotension and bradycardia in this setting remains unclear.In non-cardiac surgery, evidence shows an association of beta-blockers with increased all-cause mortality. Data from low risk of bias trials further suggests an increase in stroke rate with the use of beta-blockers. As the quality of evidence is still low to moderate, more evidence is needed before a definitive conclusion can be drawn. The substantial reduction in supraventricular arrhythmias and AMI in this setting seems to be offset by the potential increase in mortality and stroke.

Relation of Nailfold Capillaries and Autoantibodies to Mortality in Patients With Raynaud Phenomenon.

BACKGROUND: In incipient Raynaud phenomenon, nailfold capillaroscopy and autoantibody tests are obtained to screen for an emerging connective tissue disease. Whether the presence of abnormal nailfold capillaries and autoantibodies are related to mortality in patients with incipient Raynaud phenomenon is not known. METHODS AND RESULTS: In 2958 consecutive patients (78% women, median age 45 years) with incipient Raynaud phenomenon without previously known connective tissue disease, nailfold capillaroscopy and laboratory tests for antinuclear antibodies (ANA) and ANA subsets were obtained at initial presentation. During a median follow-up period of 9.3 years, 227 women (9.9% of female patients) and 129 men (20% of male patients) with Raynaud phenomenon died. In comparison with a demographically matched standard population, survival was poorer in patients with Raynaud phenomenon (log-rank test P<0.0001). In patients with Raynaud phenomenon, mortality was higher in men than in women (P<0.0001, Cox proportional hazards model). In women, the presence of abnormal nailfold capillaries, ANA, and anti-Scl-70 antibodies were related to an increase in all-cause mortality. The conjoint presence of abnormal nailfold capillaries and autoantibodies was associated with the highest mortality rates. In men, abnormal nailfold capillaries, and ANA and ANA subsets, as well, were not related to survival. In both sexes, patients' age and serum creatinine were associated with mortality. CONCLUSIONS: In Raynaud phenomenon, male sex, age, and serum creatinine are related to mortality. Abnormal nailfold capillaries and autoantibodies are associated with an increase in all-cause mortality in female patients, but not in male patients with Raynaud phenomenon.

The Fatty Liver Index (FLI) Relates to Diabetes-Specific Parameters and an Adverse Lipid Profile in a Cohort of Nondiabetic, Dyslipidemic Patients.

BACKGROUND: Patients with hyperlipidemia are at high risk for developing a fatty liver. The fatty liver index (FLI) is a noninvasive and well-established method for the estimation of a fatty liver. However, little is known about the metabolic characterization of nondiabetic treated patients with hyperlipidemia who have different risk levels for a fatty liver. METHODS: In this study, 74 nondiabetic patients with hyperlipidemia were divided into 3 groups according to their fatty liver index. A comparison of metabolic characteristics was done. These characteristics included intima media thickness (IMT) and nutritional habits, which were further divided into FLI subgroups with low, intermediate, and high risk for a fatty liver. RESULTS: Patients with hyperlipidemia, with a high risk for a fatty liver (FLI ≥ 60), had subclinical elevations in parameters of carbohydrate metabolism (insulin, fasting plasma glucose, C-peptide) including a higher insulin resistance (quantitative insulin sensitivity check index, QUICKI) compared to lower FLI groups. These patients also presented a higher risk for a metabolic syndrome (p = 0.018), as well as an adverse lipid profile (e.g., high-density lipoprotein [HDL] cholesterol, triglycerides [TG]-HDL ratio). FLI group 3 was characterized by significantly lower levels of omega-3 fatty acids (p = 0.048). CONCLUSION: The fatty liver index relates to diabetes-specific parameters and an adverse lipid profile and is an appropriate index for risk evaluation of metabolic syndrome.

SAVE-AMD: Safety of VEGF Inhibitors in Age-Related Macular Degeneration.

OBJECTIVE: To determine whether intraocular treatment with vascular endothelial growth factor (VEGF) inhibitors change systemic endothelial function (EF) in patients with neovascular age-related macular degeneration (AMD). METHODS: In this prospective, randomized, 2-center, double-masked controlled interventional trial, patients with neovascular and dry AMD were enrolled. Eligible neovascular AMD patients received 2 intravitreal loading doses of either ranibizumab 0.5 mg or bevacizumab 1.25 mg at 4-week intervals and were subsequently followed every 4 weeks and treated according to a pro re nata regime for up to 1 year. Patients with dry AMD served as controls. The primary endpoint was the change in EF assessed by flow-mediated dilatation (FMD) after 2 months of treatment with VEGF inhibitors in patients with AMD compared to patients with dry AMD. FMD was assessed with B-mode high-resolution ultrasonography of the left brachial artery. RESULTS: 24 patients with neovascular AMD and 26 patients with dry ADM were included in the trial. Treatment with VEGF inhibitors did not significantly change FMD (from 4.7 ± 2.4 to 3.9 ± 1.9% after 8 weeks, p = 0.07, and to 5.1 ± 2.0% after 1 year; p = 0.93 vs. baseline, respectively). CONCLUSIONS: EF did not significantly differ between patients with neovascular AMD treated with intravitreal VEGF inhibition and patients with dry AMD.