[Cardiogenic shock complicating myocardial infarction]. / Infarktbedingter kardiogener Schock.

Cardiogenic shock as a complication of myocardial infarction (5-10%) increases the mortality of uncomplicated myocardial infarction from less than 10% to 40%. This is due to the development of multiple organ dysfunction syndrome triggered by the extensive shock-induced impairment of organ perfusion. Therefore, guideline-based treatment should not only be restricted to reopening of the occluded coronary artery and management of complications of the infarction: important for survival are also guideline-driven optimization of organ perfusion by inotropic and vasoactive substances and, with well-defined indications, by temporary mechanical circulatory support but not by intra-aortic counterpulsation. Equally important, however, are shock-specific intensive care measures to prevent or attenuate organ dysfunction, such as lung protective ventilation in cases where ventilation is obligatory.

Efficacy of telemedical interventional management in patients with heart failure (TIM-HF2): a randomised, controlled, parallel-group, unmasked trial.

BACKGROUND: Remote patient management in patients with heart failure might help to detect early signs and symptoms of cardiac decompensation, thus enabling a prompt initiation of the appropriate treatment and care before a full manifestation of a heart failure decompensation. We aimed to investigate the efficacy of our remote patient management intervention on mortality and morbidity in a well defined heart failure population. METHODS: The Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial was a prospective, randomised, controlled, parallel-group, unmasked (with randomisation concealment), multicentre trial with pragmatic elements introduced for data collection. The trial was done in Germany, and patients were recruited from hospitals and cardiology practices. Eligible patients had heart failure, were in New York Heart Association class II or III, had been admitted to hospital for heart failure within 12 months before randomisation, and had a left ventricular ejection fraction (LVEF) of 45% or lower (or if higher than 45%, oral diuretics were being prescribed). Patients with major depression were excluded. Patients were randomly assigned (1:1) using a secure web-based system to either remote patient management plus usual care or to usual care only and were followed up for a maximum of 393 days. The primary outcome was percentage of days lost due to unplanned cardiovascular hospital admissions or all-cause death, analysed in the full analysis set. Key secondary outcomes were all-cause and cardiovascular mortality. This study is registered with ClinicalTrials.gov, number NCT01878630, and has now been completed. FINDINGS: Between Aug 13, 2013, and May 12, 2017, 1571 patients were randomly assigned to remote patient management (n=796) or usual care (n=775). Of these 1571 patients, 765 in the remote patient management group and 773 in the usual care group started their assigned care, and were included in the full analysis set. The percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause death was 4·88% (95% CI 4·55-5·23) in the remote patient management group and 6·64% (6·19-7·13) in the usual care group (ratio 0·80, 95% CI 0·65-1·00; p=0·0460). Patients assigned to remote patient management lost a mean of 17·8 days (95% CI 16·6-19·1) per year compared with 24·2 days (22·6-26·0) per year for patients assigned to usual care. The all-cause death rate was 7·86 (95% CI 6·14-10·10) per 100 person-years of follow-up in the remote patient management group compared with 11·34 (9·21-13·95) per 100 person-years of follow-up in the usual care group (hazard ratio [HR] 0·70, 95% CI 0·50-0·96; p=0·0280). Cardiovascular mortality was not significantly different between the two groups (HR 0·671, 95% CI 0·45-1·01; p=0·0560). INTERPRETATION: The TIM-HF2 trial suggests that a structured remote patient management intervention, when used in a well defined heart failure population, could reduce the percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause mortality. FUNDING: German Federal Ministry of Education and Research.

Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome.

BACKGROUND: Cardiogenic shock (CS) and low cardiac output syndrome (LCOS) as complications of acute myocardial infarction (AMI), heart failure (HF) or cardiac surgery are life-threatening conditions. While there is a broad body of evidence for the treatment of people with acute coronary syndrome under stable haemodynamic conditions, the treatment strategies for people who become haemodynamically unstable or develop CS remain less clear. We have therefore summarised here the evidence on the treatment of people with CS or LCOS with different inotropic agents and vasodilative drugs. This is the first update of a Cochrane review originally published in 2014. OBJECTIVES: To assess efficacy and safety of cardiac care with positive inotropic agents and vasodilator strategies in people with CS or LCOS due to AMI, HF or cardiac surgery. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and CPCI-S Web of Science in June 2017. We also searched four registers of ongoing trials and scanned reference lists and contacted experts in the field to obtain further information. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials in people with myocardial infarction, heart failure or cardiac surgery complicated by cardiogenic shock or LCOS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified 13 eligible studies with 2001 participants (mean or median age range 58 to 73 years) and two ongoing studies. We categorised studies into eight comparisons, all against cardiac care and additional other active drugs or placebo. These comparisons investigated the efficacy of levosimendan versus dobutamine, enoximone or placebo, epinephrine versus norepinephrine-dobutamine, amrinone versus dobutamine, dopexamine versus dopamine, enoximone versus dopamine and nitric oxide versus placebo.All trials were published in peer-reviewed journals, and analysis was done by the intention-to-treat (ITT) principle. Twelve of 13 trials were small with few included participants. Acknowledgement of funding by the pharmaceutical industry or missing conflict of interest statements emerged in five of 13 trials. In general, confidence in the results of analysed studies was reduced due to serious study limitations, very serious imprecision or indirectness. Domains of concern, which show a high risk of more than 50%, include performance bias (blinding of participants and personnel) and bias affecting the quality of evidence on adverse events.Levosimendan may reduce short-term mortality compared to a therapy with dobutamine (RR 0.60, 95% CI 0.37 to 0.95; 6 studies; 1776 participants; low-quality evidence; NNT: 16 (patients with moderate risk), NNT: 5 (patients with CS)). This initial short-term survival benefit with levosimendan vs. dobutamine is not confirmed on long-term follow up. There is uncertainty (due to lack of statistical power) as to the effect of levosimendan compared to therapy with placebo (RR 0.48, 95% CI 0.12 to 1.94; 2 studies; 55 participants, very low-quality evidence) or enoximone (RR 0.50, 95% CI 0.22 to 1.14; 1 study; 32 participants, very low-quality evidence).All comparisons comparing other positive inotropic, inodilative or vasodilative drugs presented uncertainty on their effect on short-term mortality with very low-quality evidence and based on only one RCT. These single studies compared epinephrine with norepinephrine-dobutamine (RR 1.25, 95% CI 0.41 to 3.77; 30 participants), amrinone with dobutamine (RR 0.33, 95% CI 0.04 to 2.85; 30 participants), dopexamine with dopamine (no in-hospital deaths from 70 participants), enoximone with dobutamine (two deaths from 40 participants) and nitric oxide with placebo (one death from three participants). AUTHORS' CONCLUSIONS: Apart from low quality of evidence data suggesting a short-term mortality benefit of levosimendan compared with dobutamine, at present there are no robust and convincing data to support a distinct inotropic or vasodilator drug-based therapy as a superior solution to reduce mortality in haemodynamically unstable people with cardiogenic shock or LCOS.Considering the limited evidence derived from the present data due to a generally high risk of bias and imprecision, it should be emphasised that there remains a great need for large, well-designed randomised trials on this topic to close the gap between daily practice in critical care medicine and the available evidence. It seems to be useful to apply the concept of 'early goal-directed therapy' in cardiogenic shock and LCOS with early haemodynamic stabilisation within predefined timelines. Future clinical trials should therefore investigate whether such a therapeutic concept would influence survival rates much more than looking for the 'best' drug for haemodynamic support.

Effect of inflammatory mediators on cardiovascular function.

PURPOSE OF REVIEW: Inflammatory mediators can interfere with cardiovascular system. This article describes some recent findings in this field. RECENT FINDINGS: In septic cardiomyopathy, direct and indirect interactions of endotoxin with the pacemaker current contribute to cardiac autonomic dysfunction and inadequately high heart rate, worsening prognosis. In myocardial infarction, inflammatory blood cells correlate with impaired coronary microvascular reperfusion. In cardiogenic shock, systemic inflammation and development of multiorgan dysfunction syndrome have a major impact on mortality. Shock patients have low levels of activated protein C and high levels of the endogenous danger signal molecule peroxiredoxin 1; both conditions might represent further therapeutic targets. As major cause of cytopathic hypoxia, mitochondrial dysfunction has also been identified in mitochondria from peripheral blood mononuclear cells in paediatric septic shock. Transcatheter aortic valve endocarditis, a new endocarditis entity after transcatheter aortic valve implantation in old and very old patients, needs our special attention, because immunosenescence may modify the clinical course in a negative sense. Systemic spreading of endocarditis to septic shock adds to the local valve infection the problem of septic shock. SUMMARY: Not only in septic shock, but also in classic heart diseases like cardiogenic shock and endocarditis, the detrimental role of inflammatory mediators becomes more and more evident, whereas effective anti-inflammatory treatment concepts are still missing.

Intra-aortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock.

BACKGROUND: Intra-aortic balloon pump counterpulsation (IABP) is currently the most commonly used mechanical assist device for patients with cardiogenic shock due to acute myocardial infarction. Although there has been only limited evidence from randomised controlled trials, the previous guidelines of the American Heart Association/American College of Cardiology (AHA/ACC) and the European Society of Cardiology (ESC) strongly recommended the use of the IABP in patients with infarction-related cardiogenic shock on the basis of pathophysiological considerations, non-randomised trials and registry data. The recent guidelines downgraded the recommendation based on a meta-analysis which could only include non-randomised trials showing conflicting results. Up to now, there have been no guideline recommendations and no actual meta-analysis including the results of the large randomised multicentre IABP-SHOCK II Trial which showed no survival benefit with IABP support. This systematic review is an update of the review published in 2011. OBJECTIVES: To evaluate, in terms of efficacy and safety, the effect of IABP versus non-IABP or other assist devices guideline compliant standard therapy on mortality and morbidity in patients with acute myocardial infarction complicated by cardiogenic shock. SEARCH METHODS: Searches of CENTRAL, MEDLINE (Ovid) and EMBASE (Ovid), LILACS, IndMed and KoreaMed, registers of ongoing trials and proceedings of conferences were updated in October 2013. Reference lists were scanned and experts in the field contacted to obtain further information. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials on patients with acute myocardial infarction complicated by cardiogenic shock. DATA COLLECTION AND ANALYSIS: Data collection and analysis were performed according to the published protocol. Individual patient data were provided for six trials and merged with aggregate data. Summary statistics for the primary endpoints were hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs). MAIN RESULTS: Seven eligible studies were identified from a total of 2314 references. One new study with 600 patients was added to the original review. Four trials compared IABP to standard treatment and three to other percutaneous left assist devices (LVAD). Data from a total of 790 patients with acute myocardial infarction and cardiogenic shock were included in the updated meta-analysis: 406 patients were treated with IABP and 384 patients served as controls; 339 patients were treated without assisting devices and 45 patients with other LVAD. The HR for all-cause 30-day mortality of 0.95 (95% CI 0.76 to 1.19) provided no evidence for a survival benefit. Different non-fatal cardiovascular events were reported in five trials. During hospitalisation, 11 and 4 out of 364 patients from the intervention groups suffered from reinfarction or stroke, respectively. Altogether 5 out of 363 patients from the control group suffered from reinfarction or stroke. Reocclusion was treated with subsequent re-revascularization in 6 out of 352 patients from the intervention group and 13 out of 353 patients of the control group. The high incidence of complications such as moderate and severe bleeding or infection in the control groups has to be attributed to interventions with other LVAD. Possible reasons for bias were more frequent in small studies with high cross-over rates, early stopping and the inclusion of patients with IABP at randomisation. AUTHORS' CONCLUSIONS: Available evidence suggests that IABP may have a beneficial effect on some haemodynamic parameters. However, this did not result in survival benefits so there is no convincing randomised data to support the use of IABP in infarct-related cardiogenic shock.

Inotropic agents and vasodilator strategies for acute myocardial infarction complicated by cardiogenic shock or low cardiac output syndrome.

BACKGROUND: The recently published German-Austrian S3 Guideline for the treatment of infarct related cardiogenic shock (CS) revealed a lack of evidence for all recommended therapeutic measures. OBJECTIVES: To determine the effects in terms of efficacy, efficiency and safety of cardiac care with inotropic agents and vasodilator strategies versus placebo or against each other for haemodynamic stabilisation following surgical treatment, interventional therapy (angioplasty, stent implantation) and conservative treatment (that is no revascularization) on mortality and morbidity in patients with acute myocardial infarction (AMI) complicated by CS or low cardiac output syndrome (LCOS). SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), EMBASE (Ovid) and ISI Web of Science, registers of ongoing trials and proceedings of conferences in January 2013. Reference lists were scanned and experts in the field were contacted to obtain further information. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials in patients with AMI complicated by CS or LCOS. DATA COLLECTION AND ANALYSIS: Data collection and analysis were performed according to the published protocol. All trials were analysed individually. Hazard ratios (HRs) and odds ratios with 95% confidence intervals (CI) were extracted but not pooled because of high heterogeneity between the control group interventions. MAIN RESULTS: Four eligible, very small studies were identified from a total of 4065 references. Three trials with high overall risk of bias compared levosimendan to standard treatment (enoximone or dobutamine) or placebo. Data from a total of 63 participants were included in our comparisons, 31 were treated with levosimendan and 32 served as controls. Levosimendan showed an imprecise survival benefit in comparison with enoximone based on a very small trial with 32 participants (HR 0.33; 95% CI 0.11 to 0.97). Results from the other similarly small trials were too imprecise to provide any meaningful information about the effect of levosimendan in comparison with dobutamine or placebo. Only small differences in haemodynamics, length of hospital stay and the frequency of major adverse cardiac events or adverse events overall were found between study groups.Only one small randomised controlled trial with three participants was found for vasodilator strategies (nitric oxide gas versus placebo) in AMI complicated by CS or LCOS. This study was too small to draw any conclusions on the effects on our key outcomes. AUTHORS' CONCLUSIONS: At present there are no robust and convincing data to support a distinct inotropic or vasodilator drug based therapy as a superior solution to reduce mortality in haemodynamically unstable patients with CS or low cardiac output complicating AMI.

Intra-aortic balloon counterpulsation in the treatment of infarction-related cardiogenic shock--review of the current evidence.

The European ST-elevated myocardial infarction (STEMI) guideline suggested the intra-aortic balloon pump (IABP) with a recommendation level I and a level of evidence C as an effective measure in combination with balloon angioplasty in patients with cardiogenic shock (CS), stent implantation, and inotropic and vasopressor support. Similarly, upon mechanical complication due to myocardial infarction (MI), the guideline suggests that in patients with a ventricular septal defect or in most patients with acute mitral regurgitation, preoperative IABP implantation is indicated for circulatory support. The American College of Cardiology/American Heart Association STEMI guideline recommends the use of the IABP with a recommendation level I and a level of evidence B if CS does not respond rapidly to pharmacological treatment. The guideline notes that the IABP is a stabilizing measure for angiography and early revascularization. Even in MI complications, the use of preoperative IABP is recommended before surgery. Within this overview, we summarize the current evidence on IABP use in patients with CS complicated by MI. From our Cochrane data analysis, we conclude that in CS due to acute MI (AMI) treated with adjuvant systemic fibrinolysis, the IABP should be implanted. In patients with CS following AMI, treated with primary percutaneous coronary intervention (PCI), the IABP can be implanted, although data are not distinctive (i.e., indicating positive and negative effects). In the future, randomized controlled trials are needed to determine the use of IABP in CS patients treated with PCI. When patients with CS are transferred to a PCI center with or without thrombolysis, patients should receive mechanical support with an IABP. To treat mechanical MI complications-in particular ventricular septal defect-patients should be treated with an IABP to stabilize their hemodynamic situation prior to cardiac surgery. Similar recommendations are given in the German Austrian guidelines on treatment of infarction-related CS patients (http://www.awmf.org/leitlinien/detail/ll/019-013.html).

Transcoronary pacing in an animal model : Second coated guidewire versus cutaneous patch as indifferent electrodes.

BACKGROUND: Transcoronary pacing is a seldom used treatment option for unheralded bradycardias in the setting of percutaneous coronary interventions (PCI). In the present study we compared a coated guidewire inserted proximally into a coronary artery with a cutaneous patch electrode as indifferent electrodes for transcoronary pacing in a porcine model. METHODS: Transcoronary pacing was investigated in 7 adult pigs in an animal catheterization laboratory. A standard guidewire insulated by a monorail-balloon was advanced into the periphery of a coronary artery serving as the cathode. As the indifferent anode, a special guidewire with electrical insulated by a polytetrafluoroethylene (PTFE) coating was positioned into the proximal part of the same coronary vessel. Transcoronary pacing parameters (threshold and impedance data and the magnitude of the epicardial electrogram) were compared with unipolar transcoronary pacing using a cutaneous patch electrode. RESULTS: Transcoronary pacing was successful against both indifferent electrodes. Pacing thresholds obtained with the coated guidewire technique (1.8 ± 1.3 V) were similar to those obtained by standard unipolar transcoronary pacing with a cutaneous patch electrode (1.8 ± 1.5 V). The impedance with the additional coated guidewire was 419 ± 144 Ω and thereby slightly higher compared to 320 ± 103 Ω obtained by pacing against the patch electrode (p < 0.05). Both settings yielded comparable R­wave amplitudes (8.0 ± 5.1 mV vs. 7.1 ± 3.6 mV). CONCLUSIONS: A second coated guidewire is as effective as a cutaneous patch electrode when added as an indifferent electrode in transcoronary pacing. This transcoronary pacing technique could replace temporary transvenous pacing in emergency situations during PCI, especially when using the radial approach.

Intra-aortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock.

BACKGROUND: Intra-aortic balloon pump counterpulsation (IABP) is currently the most commonly used mechanical assist device for patients with cardiogenic shock due to acute myocardial infarction.Although there is only limited evidence by randomised controlled trials, the current guidelines of the American Heart Association/American College of Cardiology and the European Society of Cardiology strongly recommend the use of the intra-aortic balloon counterpulsation in patients with infarction-related cardiogenic shock on the basis of pathophysiological considerations as also non-randomised trials and registry data.    OBJECTIVES: To determine the effect of IABP versus non-IABP or other assist devices guideline compliant standard therapy, in terms of efficacy and safety, on mortality and morbidity in patients with acute myocardial infarction complicated by cardiogenic shock. SEARCH STRATEGY: Searches of CENTRAL, MEDLINE and EMBASE, LILACS, IndMed and KoreaMed, registers of ongoing trials and proceedings of conferences were conducted in January 2010, unrestricted by date. Reference lists were scanned and experts in the field contacted to obtain further information. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials on patients with myocardial infarction complicated by cardiogenic shock. DATA COLLECTION AND ANALYSIS: Data collection and analysis were performed according to a published protocol. Individual patient data were provided for five trials and merged with aggregate data. Summary statistics for the primary endpoints were hazard ratios (HR's) and odds ratios with 95% confidence intervals (CI). MAIN RESULTS: Six eligible and two ongoing studies were identified from a total of 1410 references. Three compared IABP to standard treatment and three to percutaneous left assist devices (LVAD). Data from a total of 190 patients with acute myocardial infarction and cardiogenic shock were included in the meta-analysis: 105 patients were treated with IABP and 85 patients served as controls. 40 patients were treated without assisting devices and 45 patients with LVAD. HR's for all-cause 30-day mortality of 1.04 (95% CI 0.62 to 1.73) provides no evidence for a survival benefit. While differences in survival were comparable in patients treated with IABP, with and without LVAD, haemodynamics and incidences of device related complications show heterogeneous results. AUTHORS' CONCLUSIONS: Available evidence suggests that IABP may have a beneficial effect on the haemodynamics, however there is no convincing randomised data to support the use of IABP in infarct related cardiogenic shock.

Intracoronary compared with intravenous bolus abciximab application during primary percutaneous coronary intervention: design and rationale of the Abciximab Intracoronary versus intravenously Drug Application in ST-Elevation Myocardial Infarction (AIDA STEMI) trial.

BACKGROUND: Intravenous abciximab reduces major adverse cardiac events in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Intracoronary abciximab bolus application during PCI results in high local drug concentration, improved perfusion, reduction of infarct size, and less microvascular obstruction. The hypothesis of this trial is that abciximab bolus intracoronary in comparison to standard intravenous application will improve the outcome of patients undergoing primary PCI in STEMI. STUDY DESIGN: The Abciximab Intracoronary versus intravenously Drug Application in STEMI (AIDA STEMI) study is a 1,912-patient, prospective, multicenter, randomized, open-label, controlled trial. The study is designed to compare the efficacy and safety of intracoronary versus intravenous bolus abciximab administration during primary PCI with subsequent intravenous infusion for 12 hours. Patients will be randomized in a 1:1 fashion to 1 of the 2 treatments. The primary efficacy end point of AIDA STEMI is the composite of all-cause mortality, recurrent MI, or new congestive heart failure within 90 days of randomization. The primary safety outcome assessment will be major bleeding. CONCLUSIONS: The AIDA STEMI study addresses important questions regarding the efficacy and safety of intracoronary abciximab bolus administration during primary PCI in patients with STEMI, potentially optimizing the route of administration of glycoprotein IIb/IIIa inhibitors in the catheterization laboratory.

Intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized IABP SHOCK Trial for attenuation of multiorgan dysfunction syndrome.

OBJECTIVE: Patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction with cardiogenic shock (CS) are often treated with intra-aortic balloon pump counterpulsation (IABP), even though the evidence to support this is limited. We determined whether IABP as an addition to PCI-centered therapy ameliorates multiorgan dysfunction syndrome (MODS) in patients with acute myocardial infarction complicated by CS. DESIGN: A prospective, randomized, controlled, open-label clinical trial recruiting patients between March 2003 and June 2004 (ClinicalTrials.gov ID NCT00469248). SETTING: Tertiary care university hospital. PATIENTS AND INTERVENTIONS: Forty-five consecutive patients with AMI and CS undergoing PCI were randomized to treatment with or without IABP. MEASUREMENTS AND MAIN RESULTS: Acute Physiology and Chronic Health Evaluation (APACHE) II scores (primary outcome measure), hemodynamic values, inflammatory markers, and plasma brain natriuretic peptide (BNP) levels (secondary outcomes) were collected over 4 days from randomization. The prospective hypothesis was that adding IABP therapy to "standard care" would improve CS-triggered MODS. The addition of IABP to standard therapy did not result in a significant improvement in MODS (measured by serial APACHE II scoring over 4 days). IABP use had no significant effect on cardiac index or systemic inflammatory activation, although BNP levels were significantly lower in IABP-treated patients. Initial and serial APACHE II scoring correlated with mortality better than cardiac index, systemic inflammatory state, and BNP levels in this group of patients. Nonsurvivors had significantly higher initial APACHE II scores (29.9 +/- 2.88) than survivors (18.1 +/- 1.66, p < .05). Nevertheless, discrepancies among patients within the groups cannot be ruled out and might interfere with our results. CONCLUSIONS: In this randomized trial addressing addition of IABP in CS patients, mechanical support was associated only with modest effects on reduction of APACHE II score as a marker of severity of disease, improvement of cardiac index, reduction of inflammatory state, or reduction of BNP biomarker status compared with medical therapy alone. However, the limitations of our present trial preclude any definitive conclusion, but request for a larger prospective, randomized, multicentered trial with mortality as primary end point.

Use, Persistence, Efficacy, and Safety of Apixaban in Patients with Non-Valvular Atrial Fibrillation in Unselected Patients in Germany. Results of the Prospective Apixaban in Atrial Fibrillation (APAF) Registry.

INTRODUCTION: Apixaban has been shown to be superior to warfarin in patients with non-valvular atrial fibrillation in the randomized ARISTOTLE trial and its use is recommended in current guidelines. There are only scarce data about its use, efficacy, and safety in unselected patients in Germany. METHODS AND RESULTS: The APAF registry is a prospective non-interventional study enrolling 5015 patients with non-valvular atrial fibrillation. Of these, 1349 (26.9%) patients were initially treated with apixaban and followed up at 3 and 12 months. The dose of apixaban used was 1 × 2.5 mg in 1.6%, 2 × 2.5 mg in 30.4%, and 2 × 5 mg daily in 68.0% of patients, respectively. Inappropriate underdosing of apixaban was observed in 22.3%, mostly in elderly patients with higher HAS-BLED Score and a history of bleeding. Persistence to apixaban after 1 year was 88.6%, while the dose was changed in 3.7% of patients. Switching to other NOACs or VKAs occurred in 5.1%. After 12 months, all-cause mortality was 5.0%, non-fatal stroke occurred in 0.4%, non-fatal myocardial infarction in 0.6%, ISTH major bleeding in 0.8%, moderate or minor bleeding in 4.3% of patients, respectively. CONCLUSIONS: In this prospective experience in unselected patients with atrial fibrillation, persistence to apixaban was high, and efficacy and safety were comparable to the results in clinical trials, supporting its use in clinical practice.

Mortality and morbidity 1 year after stopping a remote patient management intervention: extended follow-up results from the telemedical interventional management in patients with heart failure II (TIM-HF2) randomised trial.

BACKGROUND: The Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial showed that, compared with usual care, a structured remote patient management (RPM) intervention done over 12-months reduced the percentage of days lost due to unplanned cardiovascular hospitalisations and all-cause death. The aim of the study was to evaluate whether this clinical benefit seen for the RPM group during the initial 12 month follow-up of the TIM-HF2 trial would be sustained 1 year after stopping the RPM intervention. METHODS: TIM-HF2 was a prospective, randomised, multicentre trial done in 43 hospitals, 60 cardiology practices, and 87 general practitioners in Germany. Patients with heart failure, New York Heart Association functional class II or III, and who had been hospitalised for heart failure within 12 months before randomisation were randomly assigned to either the RPM intervention or usual care. At the final study visit (main trial), the RPM intervention was stopped and the 1 year extended follow-up period started, which lasted 1 year. The primary outcome was percentage of days lost due to unplanned cardiovascular hospitalisations and all-cause mortality. Analyses were done using the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01878630. FINDINGS: Between Aug 13, 2013, and May 12, 2017, 1538 patients were enrolled (765 to the remote patient management group and 773 to the usual care group) in the main trial. 671 of 765 patients in the remote patient management group and 673 of 773 in the usual care group completed the main trial and started the extended follow-up period up to 1 year later. In the extended follow-up period, the percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause mortality did not differ significantly between groups weighted mean 5·95% [95% CI 4·59-7·31] in the RPM group vs 6·64% [95% CI 5·19-8·08] in the usual care group [rate ratio 0·79; 95% CI 0·78-1·21]). However, when data from the main trial and the extended follow-up period were combined, the percentage of days lost due to unplanned cardiovascular hospitalisation or all-cause death was significantly less in patients allocated to the RPM group (382 [50%] of 765; weighted mean 9·28%; 95% CI 7·76-10·81) than in the UC group (398 [51%] of 773; 11·78%; 95% CI 10·08-13·49; ratio of weighted average 0·79; 95% CI 0·62-1·00; p=0·0486). INTERPRETATION: The positive effect of our RPM intervention on morbidity and mortality over the course of the main trial was no longer observed 1 year after stopping the RPM intervention. However, because the TIM-HF2 trial was not powered to show significance during the extended follow-up period, our results are exploratory and require further research. FUNDING: German Federal Ministry of Education and Research.

Right ventricular function in myocardial infarction complicated by cardiogenic shock: Improvement with levosimendan.

OBJECTIVES: Levosimendan improves left ventricular hemodynamic function in patients with cardiogenic shock. However, its impact on right ventricular performance has not been determined. We compared the hemodynamic effects of levosimendan on left and right ventricular function in patients with intractable cardiogenic shock following myocardial infarction. DESIGN: Observational hemodynamic study. SETTING: Tertiary care center university hospital. PATIENTS: Fifty-six patients with cardiogenic shock secondary to myocardial infarction were treated with percutaneous revascularization (including intra-aortic balloon pump when appropriate) and commenced on conventional inotropic therapy. INTERVENTION: Twenty-five consecutive patients with cardiogenic shock due to myocardial infarction who had not improved sufficiently with conventional therapy (including dobutamine and norepinephrine) received levosimendan (as a bolus of 12 microg/kg per minute for 10 mins then 0.1 microg/kg per minute--0.2 mug/kg per minute) as "bail-out" therapy for 24 hrs while invasive hemodynamic parameters were recorded. MEASUREMENTS AND MAIN RESULTS: Levosimendan therapy was associated with a significant increase in cardiac index from 2.1 +/- 0.1 to 3.0 +/- 0.2 L x min x m (p < .01). In addition, levosimendan enhanced right ventricular cardiac power index (0.14 +/- 0.19 to 0.18W +/- 0.12, p < .001), while pulmonary vascular resistance fell from 227.7 +/- 94.5 to 178.1 +/- 62.3 dyne x s x cm (p = .002). No significant change in central venous pressure or mean pulmonary artery pressure was observed. The observed hemodynamic improvement was sustained after the levosimendan infusion was stopped. CONCLUSIONS: Levosimendan infusion for cardiogenic shock following acute myocardial infarction improved hemodynamic parameters of right ventricular performance. Furthermore, we describe the use of right ventricular cardiac power index as a hemodynamic parameter of right ventricular performance.

Autonomic dysfunction predicts both 1- and 2-month mortality in middle-aged patients with multiple organ dysfunction syndrome.

OBJECTIVE: Multiple organ dysfunction syndrome (MODS) is a disease entity that carries a high mortality rate. It is characterized by a sequential failure of several organ systems after a trigger event, most commonly sepsis. There is increasing evidence that autonomic dysfunction may substantially contribute to the development of MODS. We recently characterized the spectrum of autonomic dysfunction by using heart rate variability in critically ill MODS patients and were able to show that autonomic dysfunction predicts 28-day mortality in MODS. The aim of the present study was evaluate whether autonomic dysfunction is also a predictor of 180-day and 365-day mortalities. DESIGN: Prospective cohort study. SETTING: Twelve-bed medical intensive care unit in a university center. PATIENTS: Ninety consecutively admitted score-defined MODS patients. INTERVENTIONS: We assessed heart rate variability as a marker of autonomic dysfunction. The patients were followed for 180- and 365-day mortalities. MEASUREMENTS AND MAIN RESULTS: We prospectively used the heart rate variability variable lnVLF, which predicted 28-day mortality best in the entire cohort of patients, for analysis of longer term mortality. The variable lnVLF was found to be useful for risk prediction for about 60 days, and then the survival curves became nearly parallel. CONCLUSIONS: Autonomic function of critically ill MODS patients is blunted, and this attenuation has prognostic implications not merely concerning 28-day mortality but also concerning longer term (about 2-month) mortality.

Pharmacokinetic comparison of oral and intravenous etoposide in patients treated with the CHOEP-regimen for malignant lymphomas.

BACKGROUND: The addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome in patients with aggressive non-Hodgkin's lymphoma. The intravenous administration of etoposide on three consecutive days represents a logistic problem and needs resources particular in the outpatient setting. This could be avoided by using etoposide capsules on days 2 and 3. However, the oral administration of cytotoxic agents is often affected by variable absorption and drug interactions. PATIENTS AND METHODS: We investigated the pharmacokinetic equivalency of oral and intravenous etoposide in ten patients (male, n=7; female, n=3; median age 56 years) with aggressive lymphomas. Treatment consisted of standard CHOP plus etoposide 100 mg/m2 given intravenously on day 1, and 200 mg/m2 orally on days 3 and 4. Samples from blood and urine were taken on days 1 (i.v. study) and 3 (p.o. study) before and after etoposide administration. Etoposide levels were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated with the TOPFIT computer program. RESULTS: Mean peak plasma level after intravenous etoposide was significantly higher compared to oral administration (16.3+/-3.7 vs. 12.0+/-4.2 microg/ml; P=0.015). The mean bioavailability of oral etoposide was 58+/-15% with an interpatient variability of 26%. Significant differences of bioavailability of oral etoposide between the used dose levels (350, 400 and 450 mg) were not observed. Mean AUC after a 100 mg/m2 intravenous and a 200 mg/m2 oral dose of etoposide were 74.0+/-18.3 and 84.9+/-29.6 microg h/ml (P=0.481). Interpatient variability of AUC was 25% for the intravenous route and 35% after oral intake. Urinary etoposide excretion as percentage of administered dose was 39.4+/-10.6% after intravenous infusion versus 35.4+/-9.4% after oral intake (P=0.422). Renal clearance was also very similar with intravenous and oral route (18.5+/-7.4 vs. 16.7+/-6.6 ml/min; P=0.546). CONCLUSION: The equivalency of AUC after 200 mg/m2 of oral and 100 mg/m2 of intravenous etoposide support the use of the oral preparation in patients treated with the CHOEP regimen, which makes the chemotherapy more convenient for the patients and help to reduce costs.

Optimal course of treatment in acute cardiogenic shock complicating myocardial infarction.

INTRODUCTION: About 5% of patients with myocardial infarction suffer from cardiogenic shock as a complication, with a mortality of ≥30%. Primary percutaneous coronary intervention as soon as possible is the most successful therapeutic approach. Prognosis depends not only on the extent of infarction, but also - and even more - on organ hypoperfusion with consequent development of multiple organ dysfunction syndrome. Areas covered: This review covers diagnostic, monitoring and treatment concepts relevant for caring patients with cardiogenic shock complicating myocardial infarction. All major clinical trials have been selected for review of the recent data. Expert commentary: For optimal care, not only primary percutaneous intervention of the occluded coronary artery is necessary, but also best intensive care medicine avoiding the development of multiple organ dysfunction syndrome and finally death. On contrary, intra-aortic balloon pump - though used for decades - is unable to reduce mortality of patients with cardiogenic shock complicating myocardial infarction.

Proteome analysis of myocardial tissue following ischemia and reperfusion--effects of complement inhibition.

Myocardial ischemia-reperfusion injury can be related to complement activation with generation of chemotactic mediators, release of cytokines, leukocyte accumulation, and subsequent severe tissue injury. In this regard, activation of transcription factors (i.e., NFkappaB) and de novo protein synthesis or inflammatory protein degradation seems to play an important role. In the present study, we analyzed the cardiac protein expression following myocardial ischemia (60 min) and reperfusion (180 min) in a rabbit model utilizing two-dimensional electrophoresis and nanoHPLC/ESI-MS/MS for biochemical protein identification. To achieve cardioprotective effects, we used a novel highly selective small molecule C1s inhibitor administered 5 min prior to reperfusion. The reduction of myocardial injury was observed as diminished plasma creatine kinase activity in C1s-INH-248-treated animals (65.2+/-3 vs. 38.5+/-3 U/g protein after 3 h of reperfusion, P<0.05). With proteome analysis we were able to detect 509+/-21 protein spots on the gels of the 3 groups. A pattern of 480 spots with identical positions was found on every gel of myocardial tissue of sham animals, vehicle and C1s-INH-248-treated animals. We analyzed 11 spots, which were identified by mass spectrometry: Superoxide dismutase, alpha-crystallin-chain-B, mitochondrial stress protein, Mn SOD, ATP synthase A chain heart isoform, creatine kinase, and troponin T. All of these proteins were significantly decreased in the vehicle group when we compared to sham-treated animals. Treatment with C1s-INH-248 preserved levels of these proteins. Thus, blocking the classical complement pathway with a highly specific and potent synthetic inhibitor of the activated C1 complex archives cardio-protection by altering and preserving different anti-inflammatory and cytoprotective cascades.

Attenuated autonomic function in multiple organ dysfunction syndrome across three age groups.

Multiple organ dysfunction syndrome (MODS) is the failure of several organs after a trigger event. The mortality is high, at up to 70%. We hypothesize that autonomic dysfunction may substantially contribute to the development of MODS and speculate that there is an age dependence of autonomic dysfunction in MODS. A total of 90 consecutively admitted MODS patients were assigned to this study. Three variables of autonomic function were analyzed: heart rate variability (HRV), baroreflex sensitivity (BRS) and chemoreflex sensitivity (CRS). The patient cohort was divided into three age groups. The main finding was that BRS, CRS and almost all indices of HRV were attenuated in comparison to normal range data and there was no age dependence for HRV indices or CRS, but there was for BRS. In conclusion, autonomic function in MODS is attenuated. The influence of MODS on autonomic function overwhelms the age dependence of autonomic function observed in healthy subjects.

[Update cardiogenic shock]. / Update kardiogener Schock.

Although IABP support induces left ventricular unloading, these beneficial effect does not lead to improved microcirculation and survival. The use of percutaneous extracorporeal support systems (ECLS, ECMO) as well as left ventricular assist devices (pVAD) for adjunctive treatment of STEMI has increased during the recent years, but without sufficient evidence for a survival benefit. The PCI-access via the radial artery may lead to improved outcomes, especially in regard to survival. A liberal transfusion regimen for red cell packages in the perioperative phase of cardiac surgery seems to improve outcomes in regard to lower incidence of cardiogenic shock postoperatively.