Riociguat in pulmonary hypertension and heart failure with preserved ejection fraction: the haemoDYNAMIC trial.

AIMS: The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. This study investigated the efficacy of chronic treatment with the oral soluble guanylate cyclase stimulator riociguat in patients with PH-HFpEF. METHODS AND RESULTS: The phase IIb, randomized, double-blind, placebo-controlled, parallel-group, multicentre DYNAMIC trial assessed riociguat in PH-HFpEF. Patients were recruited at five hospitals across Austria and Germany. Key eligibility criteria were mean pulmonary artery pressure ≥25 mmHg, pulmonary arterial wedge pressure >15 mmHg, and left ventricular ejection fraction ≥50%. Patients were randomized to oral treatment with riociguat or placebo (1:1). Patients started at 0.5 mg three times daily (TID) and were up-titrated to 1.5 mg TID. The primary efficacy endpoint was change from baseline to week 26 in cardiac output (CO) at rest, measured by right heart catheterization. Primary efficacy analyses were performed on the full analysis set. Fifty-eight patients received riociguat and 56 patients placebo. After 26 weeks, CO increased by 0.37 ± 1.263 L/min in the riociguat group and decreased by -0.11 ± 0.921 L/min in the placebo group (least-squares mean difference: 0.54 L/min, 95% confidence interval 0.112, 0.971; P = 0.0142). Five patients dropped out due to riociguat-related adverse events but no riociguat-related serious adverse event or death occurred. CONCLUSION: The vasodilator riociguat improved haemodynamics in PH-HFpEF. Riociguat was safe in most patients but led to more dropouts as compared to placebo and did not change clinical symptoms within the study period.

Soluble suppression of tumorigenicity 2 as outcome predictor after cardiopulmonary resuscitation: an observational prospective study.

Prognostication after cardiopulmonary resuscitation (CPR) is complex. Novel biomarkers like soluble suppression of tumorigenicity 2 (sST2) may provide an objective approach. A total of 106 post-CPR patients were included in this single-center observational prospective study. Serum sST2 levels were obtained 24 h after admission. Individuals were assigned to two groups: patients below and above the overall cohort's median sST2 concentration. Primary outcome was a combined endpoint at 6 months (death or Cerebral Performance Category > 2); secondary endpoint 30-day mortality. A uni- and multivariate logistic regression analysis were conducted. Elevated sST2-levels were associated with an increased risk for the primary outcome (OR 1.011, 95% CI 1.004-1.019, p = 0.004), yet no patients with poor neurological outcome were observed at 6 months. The optimal empirical cut-off for sST2 was 46.15 ng/ml (sensitivity 81%, specificity 53%, AUC 0.69). Levels above the median (> 53.42 ng/ml) were associated with higher odds for both endpoints (death or CPC > 2 after 6 months: 21% vs. 49%, OR 3.59, 95% CI 1.53-8.45, p = 0.003; death after 30 days: 17% vs. 43.3%, OR 3.75, 95% CI 1.52-9.21, p = 0.003). A positive correlation of serum sST2 after CPR with mortality at 30 days and 6 months after cardiac arrest could be demonstrated.

Thinking fast and slow: lactate and MELD-XI (model for end-stage liver disease excluding INR) are useful for estimating mortality after cardiopulmonary resuscitation.

BACKGROUND: Intensivists keep getting challenged with prognostication after cardiopulmonary resuscitation (CPR). The model for end-stage liver disease, excluding INR (MELD-XI) Score has proven valuable for assessing illness severity. Serum lactate is a readily available and established indicator of general stress and tissue hypoxia. We aimed to evaluate the prognostic value of MELD-XI combined with serum lactate in patients after CPR. METHODS: A retrospective analysis on 106 patients after CPR was performed. Multivariable Cox regression was performed to evaluate associations with 30-day mortality and neurological outcome by means of cerebral performance category (CPC). An optimal cut-off was calculated by means of the Youden Index. Patients were then divided into subgroups based on the optimal cut-offs for MELD-XI and serum lactate. RESULTS: MELD-XI and lactate were independently associated with mortality. The respective cut-offs were MELD-XI>12 and lactate ≥2.5 mmol/L. Patients were split into three groups: lactate <2.5 mmol/L and MELD-XI≤12 (low-risk; N.=32), lactate ≥2.5 mmol/L or MELD-XI>12 (medium-risk; N.=39), and lactate ≥2.5 mmol/L and MELD-XI >12 (high-risk; N.=33). The mortality rates were 6%, 26% and 61% in the low, medium and high-risk group. This combined model yielded in the highest predictive abilities (AUC=0.78 95%CI: 0.68-0.85; P=0.03 vs. AUC=0.66 for SOFA Score). Worse neurological outcome (CPC 3 or 4) was more common in the medium and high-risk group (6.25%, 10.3% and 9.1%). CONCLUSIONS: The combination of MELD-XI and lactate concentration at ICU admission was superior to the more complex SOFA Score for prediction of mortality after CPR.

Mortality after cardiopulmonary resuscitation on a medical ICU : A sex-specific outcome analysis.

BACKGROUND: Performing cardiopulmonary resuscitation (CPR) and postresuscitation care in the intensive care unit (ICU) are standardized procedures; however, there is evidence suggesting sex-dependent differences in clinical management and outcome variables after cardiac arrest (CA). METHODS: A prospective analysis of patients who were hospitalized at a medical ICU after CPR between December 2018 and March 2020 was conducted. Exclusion criteria were age < 18 years, hospital length of stay < 24 h and traumatic CA. The primary study endpoint was mortality after 6 months and the secondary endpoint neurological outcome assessed by cerebral performance category (CPC). Differences between groups were calculated by using U­tests and χ2-tests, for survival analysis both univariate and multivariable Cox regression were fitted. RESULTS: A total of 106 patients were included and the majority were male (71.7%). No statistically significant difference regarding 6­month mortality between sexes could be shown (hazard risk, HR 0.68, 95% confidence interval, CI 0.35-1.34; p = 0.27). Neurological outcome was also similar between both groups (CPC 1 88% in both sexes after 6 months; p = 1.000). There were no statistically significant differences regarding general characteristics, pre-existing diseases, as well as the majority of clinical and laboratory parameters or measures performed on the ICU. CONCLUSION: In a single center CPR database no statistically significant sex-specific differences regarding post-resuscitation care, survival and neurological outcome after 6 months were observed.

Successful long-term antibiotic suppressive therapy in a case of prosthetic valve endocarditis and a case of extensive aortic and subclavian graft infection.

INTRODUCTION: The indication for surgical valve replacement in cases of infective endocarditis is well defined in current guidelines. However, some patients are not fit or willing to undergo major surgical procedures. Interestingly, to the best of our knowledge, there is scarce information in the literature on how to deal with such cases and what might be the outcome. CASE REPORT: We present two complicated cases of prosthetic infective endocarditis with definite indication for replacement of involved foreign material, who were treated successfully with long-term suppressive antibiotic therapy. CONCLUSION: These two cases demonstrate that individualized long-term antibiotic suppressive therapy might be effective in selected patients with complicated PVE unfit or unwilling to undergo high-risk cardiothoracic surgical interventions.

Transcatheter aortic valve implantation in a patient with suspected hereditary von Willebrand disease and severe gastrointestinal bleeding - a case report.

INTRODUCTION: von Willebrand disease is the most common hereditary coagulopathy and is characterised by a deficiency in the quantity or quality of the von Willebrand factor. Heyde Syndrome, in contrast, is an acquired form of von Willebrand syndrome (AVWS) due to calcific aortic valve stenosis, characterised by gastrointestinal bleeding from angiodysplasia. CASE PRESENTATION: A 73-year-old patient presented with severe gastrointestinal bleeding and stated that she suffered from hereditary von Willebrand disease. Upon echocardiography, a severe aortic valve stenosis was found, and hence the suspicion of additional AVWS was raised. Since endoscopic interventions and conservative therapeutic approaches did not result in a cessation of the bleeding, transcatheter aortic valve implantation (TAVI) was performed to stop the additional shear stress on von Willebrand factor. This resulted in cessation of the bleeding. CONCLUSION: Retrospectively, this life-threatening gastrointestinal bleeding was a result of severe Heyde Syndrome, which could be alleviated by TAVI. Whether the patient had suffered from inherited von Willebrand disease in the past, remains uncertain. AVWS should be considered in patients with suspected inherited von Willebrand disease and concomitant severe aortic valve stenosis, since it constitutes a treatable cause of a potentially severe bleeding disorder.

Mechanical circulatory support with Impella versus intra-aortic balloon pump or medical treatment in cardiogenic shock-a critical appraisal of current data.

AIMS: Patients suffering from cardiogenic shock (CS) have a high mortality and morbidity. The Impella percutaneous left-ventricular assist device (LVAD) decreases LV preload, increases cardiac output, and improves coronary blood flow. We aimed to review and meta-analyze available data comparing Impella versus intra-aortic pump (IABP) counterpulsation or medical treatment in CS due to acute myocardial infarction or post-cardiac arrest. METHODS AND RESULTS: Study-level data were analyzed. Heterogeneity was assessed using the I2 statistic. Risk rates were calculated and obtained using a random-effects model (DerSimonian and Laird). Four studies were found suitable for the final analysis, including 588 patients. Primary endpoint was short-term mortality (in-hospital or 30-day mortality). In a meta-analysis of four studies comparing Impella versus control, Impella was not associated with improved short-term mortality (in-hospital or 30-day mortality; RR 0.84; 95% CI 0.57-1.24; p = 0.38; I2 55%). Stroke risk was not increased (RR 1.00; 95% CI 0.36-2.81; p = 1.00; I22 0%), but risk for major bleeding (RR 3.11 95% CI 1.50-6.44; p = 0.002; I2 0%) and peripheral ischemia complications (RR 2.58; 95% CI 1.24-5.34; p = 0.01; I2 0%) were increased in the Impella group. CONCLUSION: In patients suffering from severe CS due to AMI, the use of Impella is not associated with improved short-time survival but with higher complications rates compared to IABP and medical treatment. Better patient selection avoiding Impella implantation in futile situations or in possible lower risk CS might be necessary to elucidate possible advantages of Impella in future studies.

Two cases of serious rhabdomyolysis during linezolid treatment.

Linezolid is an oxazolidinone antibiotic with activity against gram-positive organisms, particularly methicillin-resistant Staphylococcus aureus (MRSA). To the best of our knowledge, there are only two case reports on rhabdomyolysis in patients treated with linezolid. Here, we describe two cases of serious rhabdomyolysis: one in a patient with septic community-acquired (CA)-MRSA pneumonia and a second case in a patient with suspected catheter-related blood stream infection.

Evaluation of the pharmacoDYNAMIC effects of riociguat in subjects with pulmonary hypertension and heart failure with preserved ejection fraction : Study protocol for a randomized controlled trial.

BACKGROUND: The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFPEF) resulting in substantial morbidity and mortality. So far, neither established heart failure therapies nor pulmonary vasodilators have proven to be effective for this condition. Riociguat (Adempas®, BAY 63-2521), a stimulator of soluble guanylate cyclase, is a novel pulmonary and systemic vasodilator that has been approved for the treatment of precapillary forms of PH. With regard to postcapillary PH, the DILATE-1 study was a multicenter, double-blind, randomized, placebo-controlled single-dose study in subjects with PH associated with HFPEF. Although there was no significant change in the primary outcome measure, peak decrease in mean pulmonary artery pressure with riociguat versus placebo, riociguat significantly increased stroke volume without changing heart rate, pulmonary artery wedge pressure, transpulmonary pressure gradient or pulmonary vascular resistance. The present study is designed to test the efficacy of long-term treatment with riociguat in patients with PH associated with HFPEF. METHODS/STUDY DESIGN: The DYNAMIC study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical phase IIb trial evaluating the efficacy, safety and kinetics of riociguat in PH-HFPEF patients. The drug will be given over 26 weeks to evaluate the effects of riociguat versus placebo. The primary efficacy variable will be the change from baseline in cardiac output at rest, measured by right heart catheter after 26 weeks of study drug treatment. Additional efficacy variables will be changes from baseline in further hemodynamic parameters, changes in left and right atrial area, right ventricular volume, as well as right ventricular ejection fraction measured by cardiac magnetic resonance imaging, and changes from baseline in World Health Organization (WHO) class and N­terminal prohormone B­type natriuretic peptide (NT-proBNP). The trial was registered on 25 August 2014 (EudraCT Number: 2014-003055-60; www.clinicaltrialsregister.eu ).

Global research trends in the medical therapy of pulmonary arterial hypertension 2000-2014.

BACKGROUND: Pulmonary arterial hypertension is a progressive disease of the pulmonary vasculature that affects more than 200.000 patients worldwide. Without medical treatment it leads to right heart failure and death. Extensive fundamental and clinical research has been performed throughout the globe to modify the disease and improve survival. METHODS: We performed a bibliometric study on medical treatment for pulmonary arterial hypertension to identify study characteristics, impact factors and the countries of origin of basic and clinical studies that were published between 2000 and 2014. For visualization of the obtained data density equalizing maps were prepared. RESULTS: A total of 681 studies were eligible, of these 56% were clinical studies that have included a total of 30960 patients. Most studies were performed on endothelin receptor antagonists, followed by prostacyclins and phosphodiesterase type 5 inhibitors. Impact factors did not differ between clinical and basic science studies. The United States for clinical studies, and China for basic science studies were identified as main contributors to the global scientific output. CONCLUSIONS: This first bibliometric study in the field of pulmonary arterial hypertension shows that a significant amount of scientific research was performed within the last 14 years mainly in North America, Asia and Europe. As current trends in this field of research we identified combination therapies and Asian countries being a new hatchery for emerging experimental and clinical studies.

[Use of ECMO in adult patients with cardiogenic shock: a position paper of the Austrian Society of Cardiology]. / Positionspapier der Österreichischen Kardiologischen Gesellschaft zum Einsatz der extrakorporalen Membranoxygenation (ECMO) bei Erwachsenen kardiologischen Patienten.

The use of ECMO to stabilize critically ill patients with severely depressed cardiac function and hemodynamics increased in the last years due to broader availability, better performance and easier implantation of the devices. The present guidelines of the Austrian Society of Cardiology focus on the use of ECMO in adult non-operated patients with cardiac diseases. Not only indications and contraindications are highlighted, but also the equally important issues of monitoring, complication management, measures during implantation and operation, and weaning of the devices are treated in detail. Thereby the present guidelines aim to optimize the use of ECMO in the individual centers, and aim to help current non-ECMO centers in developing a local ECMO-program or to contact ECMO-centers for discussion of individual patients.

[Use of ECMO in adult patients with cardiogenic shock: a position paper of the Austrian Society of Cardiology]. / Positionspapier der Österreichischen Kardiologischen Gesellschaft zum Einsatz der extrakorporalen Membranoxygenation (ECMO) bei Erwachsenen kardiologischen Patienten.

The use of ECMO to stabilize critically ill patients with severely depressed cardiac function and hemodynamics increased in the last years due to broader availability, better performance and easier implantation of the devices. The present guidelines of the Austrian Society of Cardiology focus on the use of ECMO in adult non-operated patients with cardiac diseases. Not only indications and contraindications are highlighted, but also the equally important issues of monitoring, complication management, measures during implantation and operation, and weaning of the devices are treated in detail. Thereby the present guidelines aim to optimize the use of ECMO in the individual centers, and aim to help current non-ECMO centers in developing a local ECMO-program or to contact ECMO-centers for discussion of individual patients.

Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study.

BACKGROUND: Deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling results from endothelial dysfunction and may underlie impaired cardiac relaxation in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) and pulmonary hypertension (PH). The acute hemodynamic effects of riociguat, a novel soluble guanylate cyclase stimulator, were characterized in patients with PH and HFpEF. METHODS: Clinically stable patients receiving standard HF therapy with a left ventricular ejection fraction > 50%, mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, and pulmonary arterial wedge pressure (PAWP) > 15 mm Hg at rest were randomized to single oral doses of placebo or riociguat (0.5, 1, or 2 mg). The primary efficacy variable was the peak decrease in mPAP from baseline up to 6 h. Secondary outcomes included hemodynamic and echocardiographic parameters, safety, and pharmacokinetics. RESULTS: There was no significant change in peak decrease in mPAP with riociguat 2 mg (n = 10) vs placebo (n = 11, P = .6). However, riociguat 2 mg significantly increased stroke volume (+9 mL [95% CI, 0.4-17]; P = .04) and decreased systolic BP (-12 mm Hg [95% CI, -22 to -1]; P = .03) and right ventricular end-diastolic area (-5.6 cm2 [95% CI, -11 to -0.3]; P = .04), without significantly changing heart rate, PAWP, transpulmonary pressure gradient, or pulmonary vascular resistance. Riociguat was well tolerated. CONCLUSIONS: In patients with HFpEF and PH, riociguat was well tolerated, had no significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01172756; URL: www.clinicaltrials.gov.