Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19.

BACKGROUND: Many COVID-19 patients develop a hyperinflammatory response which activates blood coagulation and may contribute to the occurrence of thromboembolic complications. Blockade of interleukin-6, a key cytokine in COVID-19 pathogenesis, may improve the hypercoagulable state induced by inflammation. The aim of this study was to evaluate the effects of subcutaneous tocilizumab, a recombinant humanized monoclonal antibody against the interleukin-6 receptor on coagulation parameters. METHODS: Hospitalized adult patients with laboratory-confirmed moderate to critical COVID-19 pneumonia and hyperinflammation, who received a single 324 mg subcutaneous dose of tocilizumab on top of standard of care were enrolled in this analysis. Coagulation parameters were measured before tocilizumab and at day 1, 3, and 7 after treatment. All patients were followed-up for 35 days after admission or until death. RESULTS: 70 patients (mean age 60 years, interquartile range 52-75) were included. Treatment with tocilizumab was associated with a reduction in D-dimer levels (-56%; 95% confidence interval [CI], -68% to -44%), fibrinogen (-48%; 95%CI, -60% to -35%), C-reactive protein (-93%; 95%CI, -99% to -87%), prothrombin time (-4%; 95%CI,-9% to 0.8%), and activated thromboplastin time (-4%; 95%CI,-8.7% to 0.8%), and an increase in platelet count (34%; 95%CI, 23% to 45%). These changes occurred already one day after treatment with sustained reductions throughout day 7. The improvement in coagulation was consistently observed in patients receiving prophylactic or therapeutic dose anticoagulants, and was paralleled by a rapid improvement in respiratory function. CONCLUSIONS: Subcutaneous tocilizumab was associated with significant improvement of blood coagulation parameters independently of thromboprophylaxis dose.

Low-dose subcutaneous tocilizumab to prevent disease progression in patients with moderate COVID-19 pneumonia and hyperinflammation.

AIM: This study aimed to evaluate the safety and efficacy profile of low-dose tocilizumab (TCZ), to prevent disease progression, subcutaneously administered to patients with moderate COVID-19 pneumonia and hyperinflammation. METHODS: Clinical characteristics and outcomes were retrospectively analysed of patients - with laboratory-confirmed bilateral COVID-19 pneumonia, hyperinflammation (C-reactive protein (CRP) ≥20 mg/dL), no hypoxaemia (oxygen saturation >90%), and no contraindications to TCZ - who were treated with subcutaneous TCZ (324 mg) administered within 48 h from hospitalization on top of standard of care (SOC). They were compared with matched controls treated with SOC only before TCZ was available at the institution. Clinical data were available for all patients until death or until day 35 for those discharged from hospital. FINDINGS: Ten consecutive patients (six males, median age 55 years) treated with TCZ on top of SOC, and ten patients (six males, median age 56 years) treated with SOC only were included. TCZ was well-tolerated with no clinically relevant adverse events. TCZ was associated with a reduction in CRP at day 1 (-50%, IQR -28 to -80) and day 3 (-89%, IQR -79 to -96; p = 0.005 for within-group), whereas there was no significant change in CRP values in the SOC group (p < 0.001 for between-group comparisons at both time points). TCZ resulted in a parallel improvement in oxygenation, as assessed by the ratio of partial pressure of oxygen to fraction of inspired oxygen (P/F) ratio, which increased at day 1 (+11%, IQR +6 to +16; p = 0.005 for within-group and p = 0.006 for between-group comparisons), and day 3 (+23%, IQR +16 to +34; p = 0.005 for within-group and p = 0.003 for between-group comparisons). None of the TCZ-treated patients had disease progression, defined as requirement of oxygen therapy or mechanical ventilation, whereas progression occurred in five (50%) patients among the SOC group. CONCLUSIONS: Low-dose subcutaneous TCZ may be a safe and promising therapeutic option administered on top of SOC to prevent disease progression in hospitalised patients with moderate COVID-19 and hyperinflammation.

FDG-PET/CT Assessment of Pulmonary Sarcoidosis: A Guide for Internists.

BACKGROUND: 18F-fluorodeoxyglucose positron emission tomography integrated with computed tomography (18-F-FDG-PET/CT) is getting wide consensus in the diagnosis and staging of neoplastic disorders and represents a useful tool in the assessment of various inflammatory conditions. DISCUSSION: Sarcoidosis is an uncommon disease characterized by the systemic formation of noncaseating granulomas. Lungs are the sites most often affected, and investigation with high resolution computed tomography and biopsy is essential to achieve a correct diagnosis. 18-F-FDGPET/ CT is effective in the assessment of pulmonary sarcoidosis by demonstrating pulmonary and extrathoracic involvement and findings correlate well with pulmonary function in patients affected. CONCLUSION: This review would illustrate the usefulness and limits of 18-F-FDG-PET/CT in the assessment of pulmonary sarcoidosis.

Morning Blood Pressure Surge, Dipping, and Risk of Coronary Events in Elderly Treated Hypertensive Patients.

BACKGROUND: The independent prognostic significance of morning surge (MS) of blood pressure (BP) is not yet clear. We investigated the association between MS of systolic BP and risk of coronary events in elderly treated hypertensive patients. METHODS: The occurrence of coronary events was evaluated in 1,191 elderly treated hypertensive patients (age range 60-90 years). Subjects were divided according to tertiles of MS of systolic BP of the population as a whole, by dipping status and by group-specific tertiles of MS of systolic BP in dippers and nondippers. RESULTS: During the follow-up (9.1 ± 4.9 years, range 0.4-20 years), 120 coronary events occurred. In the population as a whole, coronary event risk was not significantly associated with tertiles of MS of systolic BP, whereas nondippers were at higher risk than dippers. When nondippers and dippers were analyzed separately, by group-specific tertiles of MS of systolic BP, coronary event risk was associated with MS of systolic BP in dippers but not in nondippers. After adjustment for various covariates, Cox regression analysis showed that dippers in the third tertile (>23 mm Hg) of MS of systolic BP (hazard ratio 1.912, 95% confidence interval 1.048-3.488, P = 0.03) and nondippers (hazard ratio 1.739, 95% confidence interval 1.074-2.815, P = 0.02) were at higher coronary event risk than dippers with MS of systolic BP <23 mm Hg . CONCLUSIONS: In elderly treated hypertensive patients, high MS of systolic BP predicts coronary events in dippers but not in nondippers. Nondippers, however, show higher risk of coronary events independently of MS in systolic BP.

Metabolic Syndrome and Cardiovascular Risk in Elderly Treated Hypertensive Patients.

BACKGROUND: The independent prognostic significance of the metabolic syndrome (MetS) in the elderly is not yet clear. We investigated the association between MetS and cardiovascular risk (composite endpoint of stroke and coronary events) in elderly treated hypertensive patients. METHODS: Cardiovascular outcome was evaluated in 1,191 elderly treated hypertensive patients (≥60 years). Among them, 578 (48.5%) had MetS according to a modified joint interim statement definition (body mass index in place of waist circumference). RESULTS: During the follow-up (9.1±4.9 years, range 0.4-20 years), 139 strokes and 120 coronary events occurred. In univariate analysis, patients with MetS had higher risk of the composite endpoint (hazard ratio (HR) 1.322, 95% confidence interval (CI) 1.035-1.688, P < 0.05). Among the single components of MetS, only blood pressure (BP) level and impaired fasting glucose/diabetes were significantly associated with increased cardiovascular risk. After adjustment for age, previous events, estimated glomerular filtration rate (eGFR), left ventricular (LV) hypertrophy and left atrial (LA) enlargement, the prognostic relevance of MetS was attenuated (HR 1.245, 95% CI 0.974-1.591, P = 0.08). After further adjustment for the above-mentioned variables and ambulatory BP parameters and impaired fasting glucose/diabetes, Cox regression analysis showed that MetS was not independently associated with increased cardiovascular risk (HR 1.090, 95% CI 0.805-1.475, P = 0.58). CONCLUSIONS: In elderly treated hypertensive patients, MetS is associated with increased cardiovascular risk, but not independently of BP and glucose levels and of organ damage.

Left atrial enlargement and risk of ischemic stroke in elderly treated hypertensive patients.

BACKGROUND: The independent prognostic significance of left atrial enlargement is not yet completely clear. We investigated the association between left atrial enlargement and risk of ischemic stroke in elderly treated hypertensive patients. METHODS: The occurrence of ischemic stroke was evaluated in 1,191 elderly treated hypertensive patients (age range = 60-90 years). Left atrium diameter (cm) was indexed by body surface area (m(2)) and subjects were divided into those with normal or enlarged (≥2.4cm/m(2)) left atrium. RESULTS: During the follow-up (9.1±4.9 years; range = 0.4-20 years), 139 ischemic strokes occurred. The event rate per 100 patient-years was 1.28. There were 86 strokes in patients with normal (= 928) left atrium and 53 strokes in patients with enlarged (= 263) left atrium, respectively. Stroke-free survival curves were significantly different between the groups (P < 0.01). After adjustment for various covariables, including clinical variables, left ventricular hypertrophy, and ambulatory blood pressure parameters, Cox regression analysis showed that left atrial enlargement was significantly associated with increased risk of ischemic stroke (hazard ratio = 1.54; 95% confidence interval = 1.05-2.27; P = 0.03). CONCLUSIONS: In elderly treated hypertensive patients, left atrial enlargement is an independent predictor of ischemic stroke.

Prediction of carotid plaques in hypertensive patients by risk factors, left ventricular hypertrophy, and epicardial adipose tissue thickness.

Hypertension and other risk factors (RFs) predispose to carotid plaques (CPs). An association between left ventricular hypertrophy (LVH) or epicardial adipose tissue (EAT) and CPs has also been reported. The aim of the study was to evaluate whether the assessment of LVH and EAT thickness, beyond RFs, would be of additive value in predicting CPs in hypertensive subjects. We studied 548 hypertensive patients aged ≥ 50 years without carotid bruit. LVH and CPs were evaluated and defined according to standard criteria. EAT was measured by echocardiography above the free wall of the right ventricle at end diastole. The presence of LVH and EAT thickness above the median value (3.9 mm) together significantly increased prevalence of CPs in subjects with 0-1 risk factor, but not in those with ≥ 2 RFs who showed high prevalence of CPs independently of LVH and/or EAT. Receiver operating characteristic curve analysis showed that the addition of LVH and higher EAT thickness together significantly improved prediction of CPs in patients with 0-1 risk factor. Indeed, the area under the curve improved from 0.63 (0.56-0.69) to 0.73 (0.67-0.79), which was significantly higher (p < 0.05). In patients with ≥ 2 RFs, the addition of LVH and EAT did not significantly improve prediction of CPs. This study shows that the presence of LVH and higher EAT thickness together improves prediction of CPs in hypertensive patients with 0-1 risk factor and that those with ≥ 2 RFs show high prevalence of CPs independently of LVH and/or EAT.

Cardiac events in hypertensive patients with renal artery stenosis treated with renal angioplasty or drug therapy: meta-analysis of randomized trials.

BACKGROUND: Cardiac outcome in patients with atherosclerotic renal artery stenosis (ARAS) undergoing percutaneous transluminal renal angioplasty (PTRA) or medical therapy is not yet completely clear. The aim of this study was to perform a meta-analysis of randomized controlled trials to compare the effect of PTRA and medical therapy on nonfatal myocardial infarction in patients with ARAS. METHODS: We searched for articles reporting cardiovascular outcome, including nonfatal myocardial infarction, in patients with renal artery stenosis randomized to PTRA with/without stenting or medical therapy. RESULTS: Five studies were identified. The pooled population consisted of 1,159 subjects who experienced 56 nonfatal myocardial infarctions. When compared with medical therapy, the overall relative risk (RR) was 0.85 (95% confidence interval (CI) 0.51-1.42), P = 0.55, for PTRA. There was no significant difference between PTRA and medical therapy according to procedural characteristics (with/without stent placement), mean serum creatinine at follow-up (higher or lower than 2.0 mg/dl), and maximum follow-up length (> or <2 years). CONCLUSIONS: In patients with ARAS and hypertension, there is a lack of evidence supporting the superiority of PTRA over medical therapy in prevention of nonfatal myocardial infarction. Awaiting for results of ongoing trials, our data and previous data suggest that PTRA and drug therapy have a similar impact on cardiovascular risk reduction in patients with renal artery stenosis and hypertension.

Prognostic relevance of metabolic syndrome in hypertensive patients at low-to-medium risk.

BACKGROUND: The prognostic impact of metabolic syndrome (MetS) in the hypertensive population at low-medium risk is unknown. In this study, we evaluated the prognostic relevance of MetS in hypertensive patients at low-medium risk. METHODS: The occurrence of nonfatal and fatal cardiac and cerebrovascular events was evaluated in 802 patients with mild to moderate essential hypertension at low-medium risk according to the 2003 World Health Organization/International Society of Hypertension statement on the management of hypertension. Among these patients, 218 (27.2%) had MetS according to a modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) definition (body mass index in place of waist circumference). RESULTS: During follow-up (6.9 +/- 3.1 years; range, 0.5 to 13.1 years, mean +/- SD), 58 first cardiovascular events occurred. The event rates per 100 patient-years in patients without and with MetS were 0.87 and 1.51, respectively. Event-free survival was significantly different between groups (P = .03). After adjustment for several covariates, Cox regression analysis showed that cardiovascular risk was significantly higher in patients with than in patients without MetS (relative risk, 2.64; 95% confidence interval, 1.52 to 4.58; P = .001). Other independent predictors of outcome were age, smoking habit, 24-h systolic BP, and LDL cholesterol. CONCLUSIONS: Hypertensive patients at low-medium risk with MetS are at higher cardiovascular risk than those without MetS. Metabolic syndrome may be a useful tool for clinicians to identify subjects who are at increased risk when traditional assessment may indicate low-medium risk.

Cardiovascular risk in patients receiving double therapy with false and true nonresponder hypertension.

OBJECTIVE: The aim of this study was to evaluate cardiovascular risk in hypertensive patients receiving double therapy with false and true nonresponder hypertension. METHODS: The occurrence of fatal and nonfatal cardiovascular events was evaluated in 730 patients receiving double therapy with uncontrolled clinic blood pressure. Two hundred and seventy had false nonresponder hypertension (clinic blood pressure > or =140 or 90 mmHg and daytime blood pressure <135/85 mmHg) and 460 had true nonresponder hypertension (clinic blood pressure > or =140 or 90 mmHg and daytime blood pressure > or =135 or 85 mmHg). RESULTS: During the follow-up (4.77+/-2.9 years, range 0.2-11.7 years), 55 cardiovascular events occurred. The event rates per 100 patient-years in patients with false and true nonresponder hypertension were 1.03 and 1.9, respectively. Event-free survival was significantly different between the groups (P<0.05). After adjustment for several covariates, including clinic blood pressure (forced into the model), Cox regression analysis showed that cardiovascular risk was significantly higher in true than in false nonresponder hypertension (relative risk 2.33, 95% confidence interval 1.14-4.77, P=0.02). CONCLUSIONS: This study shows that, among treated hypertensive patients receiving double therapy with uncontrolled clinic blood pressure those with true nonresponder hypertension are at higher cardiovascular risk. Ambulatory blood pressure monitoring should be performed in this population to achieve a better prognostic stratification.

Blood pressure variability and cardiovascular risk in treated hypertensive patients.

BACKGROUND: The independent prognostic value of blood pressure (BP) variability in treated hypertension is not yet clear. We investigated the relationship between BP variability, evaluated by noninvasive monitoring, and cardiovascular outcome in treated hypertensive patients. METHODS: The occurrence of fatal and nonfatal cardiovascular events was evaluated in 1472 treated patients. Subjects with the standard deviation of daytime or night-time systolic BP below or above the median of the population were classified as having low or high BP variability. Specifically, 738 and 734 patients had low and high daytime BP variability, respectively, and 739 and 733 subjects had low and high night-time BP variability, respectively. RESULTS: During follow-up (4.88 +/- 2.9 years, range 0.2-11.6 years) there were 119 events. The event rates per 100 patient-years in subjects with low and high BP variability according to daytime BP were 1.18 and 2.01, respectively, and in those with low and high BP variability according to night-time BP were 1.2 and 2.05, respectively. Event-free survival was significantly different between the low and high BP variability groups (P = .006 for both daytime and night-time BP). However, after adjustment for other covariates in a Cox multivariate analysis, the adverse prognostic relevance of high BP variability was no longer detectable, whereas age, smoking habit, LDL cholesterol, diabetes, previous events, LV hypertrophy, and daytime or night-time systolic BP resulted independent predictors of risk. CONCLUSIONS: Increased BP variability is associated with higher incidence of cardiovascular events, but also with other relevant prognostic factors. Indeed, in multivariate analysis the possible adverse prognostic impact of BP variability is no longer evident. Thus, in treated hypertension, BP variability evaluated by noninvasive monitoring is not an independent predictor of outcome.