[Management of oral anticoagulation related intracerebral hemorrhage]. / Management von intrazerebralen Blutungen unter oraler Antikoagulation.

The incidence of intracerebral hemorrhage (ICH) in patients using oral anticoagulation (OAC) will continue to increase with the demographic change of an aging population. As compared to primary spontaneous ICH, OAC-ICH is characterized by larger hematoma volumes, more frequent hematoma enlargement and intraventricular hemorrhage resulting in an even worse prognosis. Specific treatment should focus on immediate reversal of anticoagulation in addition to the basic acute management of ICH. In ICH patients using vitamin K antagonists (VKA), complete anticoagulant reversal with an international normalized ratio (INR) <1.3 should be achieved as quickly as possible using prothrombin complex concentrate (PCC) with additional substitution of vitamin K. Patients with ICH under dabigatran treatment should receive idarucizumab. In ICH patients using factor-Xa inhibitors, andexanet should be administered as soon as approved in Europe or within clinical studies and if unavailable alternatively high-dose PCC administration. Regarding OAC resumption, results from randomized trials are pending. In comprehensive observational studies and meta-analyses ICH patients resuming OAC showed a reduced incidence of thromboembolic events and mortality without significantly increased rates of hemorrhagic complications. Non-vitamin K dependent oral anticoagulants (NOAC) might further increase the safety of OAC resumption, which should be initiated after 4-8 weeks for patients with atrial fibrillation. In contrast, VKA resumption in patients with mechanical heart valves should not take place earlier than 1 week after ICH. Generally, safety of OAC resumption appears to be affected by ICH localization along with the presence of cerebral microbleeding, cortical superficial siderosis and cortical/convexity subarachnoid hemorrhage, making it crucial to weigh up the individual patient risk with respect to thromboembolic versus hemorrhagic events.

Anticoagulation in atrial fibrillation : Current evidence and guideline recommendations.

Atrial fibrillation (AF) is the most frequently encountered sustained arrhythmia with a prevalence of 0.5-10%, depending predominantly on age. The arrhythmia is associated with significant morbidity and mortality, mainly due to thromboembolic events including stroke and systemic embolisms. These complications can be effectively prevented with anticoagulation therapy either with vitamin K antagonists (VKA) or with non-vitamin K antagonists (NOAC). VKA therapy is effective in preventing strokes but these medications are difficult to use, are associated with significant bleeding risk, and have pharmacokinetic/dynamic properties that make their use cumbersome. NOACs-either factor II or factor Xa inhibitors-have been developed over the past two decades and have been tested against VKA in large randomized controlled trials. This trial evidence was complemented more recently by increasing real-world data comprising several 100,000 patients. Finally, NOACs have been examined for their use in specific clinical situations, for example, in patients undergoing cardioversion, catheter ablation, or coronary interventions. In all of these clinical scenarios, NOACs have been similarly effective or-in many instances-even superior to treatment with VKA. Recent guidelines, therefore, recommend NOAC therapy for stroke prevention in AF as first-line therapy.

[Implantable sensors for outpatient assessment of ventricular filling pressure in advanced heart failure : Which telemonitoring design is optimal?] / Implantierbare Sensoren zur ambulanten Beurteilung des ventrikulären Füllungsdrucks bei fortgeschrittener Herzinsuffizienz : Welches Telemonitoring-Design ist optimal?

INTRODUCTION: Patients with advanced heart failure suffer from frequent hospitalizations. Non-invasive hemodynamic telemonitoring for assessment of ventricular filling pressure has been shown to reduce hospitalizations. We report on the right ventricular (RVP), the pulmonary artery (PAP) and the left atrial pressure (LAP) sensor for non-invasive assessment of the ventricular filling pressure. METHODS: A literature search concerning the available implantable pressure sensors for noninvasive haemodynamic telemonitoring in patients with advanced heart failure was performed. RESULTS: Until now, only implantation of the PAP-sensor was able to reduce hospitalizations for cardiac decompensation and to improve quality of life. The right ventricular pressure sensor missed the primary endpoint of a significant reduction of hospitalizations, clinical data using the left atrial pressure sensor are still pending. CONCLUSION: The implantation of a pressure sensor for assessment of pulmonary artery filling pressure is suitable for reducing hospitalizations for heart failure and for improving quality of life in patients with advanced heart failure.

[Treatment safety of non-vitamin K oral anticoagulants in patients with atrial fibrillation]. / Therapiesicherheit bei Verwendung nicht Vitamin-K-abhängiger oraler Antikoagulanzien bei Patienten mit Vorhofflimmern.

Non-vitamin K oral anticoagulants (NOAC) have now become established for stroke prevention in atrial fibrillation. The efficacy is at least as good if not better than that of vitamin K antagonists (VKA). The risk for major bleeding is less for NOAC than for VKA, with a particular superiority concerning the avoidance of intracerebral hemorrhage. The outcome after major bleeding is more favorable in patients receiving NOAC compared to those treated with VKA. Specific reversal agents for NOAC are currently being tested which neutralize the effects of NOAC within minutes and the clinical introduction of the first one for the thrombin inhibitor dabigatran is imminent. Such specific antidotes will further improve the safety profile of NAOC.

Dabigatran for stroke prevention in atrial fibrillation.

Dabigatran is a novel direct thrombin inhibitor that has recently been approved for primary and secondary stroke prevention and prevention of systemic embolism in patients with atrial fibrillation. In the pivotal RE-LY study, dabigatran 110 mg BID was demonstrated to be associated with a stroke rate similar to that observed with warfarin (INR target 2.0 to 3.0), but with a lower rate of major haemorrhage. Dabigatran administered at a dose of 150 mg BID was significantly more effective in stroke prevention than warfarin and showed a similar rate of major hemorrhages. Of note, both dosages resulted in an approximately 60-70% relative risk reduction of haemorrhagic stroke. The dosage of 110 mg BID should be preferably used in patients aged 75-80 years or older as the rate of extracranial bleeding events tends to increase with dabigatran 150 mg BID above this age limit. In RE-LY, myocardial infarcts occurred at a very low incidence. There were numerically more myocardial infarcts in dabigatran-treated patients than in warfarin patients; however, other myocardial ischaemic events were similar in the three treatment arms.

[Clinical profile of the new antiarrhythmic drug dronedarone]. / Klinisches Profil des neuen Antiarrhythmikums Dronedaron.

The new antiarrhythmic drug dronedarone (SR 33 589) is a benzofuran derivative structurally similar to amiodarone, however is noniodinated. The additional methansulfonylgroup renders it less lipophilic, with a substantially shorter half-life, compared to the parent compound. The electrophysiological properties of both agents are similar with inhibition of Na+, K+, and Ca++ currents (all Vaughan-Williams classes). The agent has been evaluated in a large clinical study program. The daily dose of dronedarone 800 mg has been shown (DAFNE) to be effective and well tolerated. In two design-identical randomised clinical trials (EURIDIS and ADONIS trial) the efficacy of dronedarone to maintain sinus rhythm in patients with chronic atrial fibrillation/flutter was shown to be clearly superior to placebo. The ERATO study showed the rate control properties of dronedarone. In the ATHENA morbidity/mortality study, the combined endpoint death or hospitalisation due to cardiovascular events occurred significantly less often in the dronedarone group compared to the placebo group. Particularly due to its beneficial effects on clinical outcomes such as cardiovascular hospitalizations and death in the context of high tolerability dronedarone appears to be a promising new antiarrhythmic compound.

[Clinical pharmacology and electrophysiological properties of dronedarone]. / Klinisch-pharmakologisches und elektrophysiologisches Profil von Dronedaron.

Dronedarone is a benzofuran derivative structurally similar to amiodarone but non-iodinated. The agent was systematically developed with the aim to maintain the antiarrhythmic potency of amiodarone while reducing the extracardiac side effects of the drug. Dronedarone is less lipophilic compared to the mother compound, which manifests in a substantial lower time to steady state (4-8 days compared to 1-3 weeks with amiodarone), and a more rapid elimination (half life 25-30 hours). Dronedarone has antiarrhythmic properties of all Vaughan-Williams classes. Among other channel blocking effects, It blocks sodium ion channels at higher stimulation frequency, prolongs the cardiac action potential, and has properties of a calcium channel blocker. Further, dronedarone has non-competitive antiadrenegic effects. No reverse use dependence has been documented at higher heart rate. These effects explain the antiarrhythmic and rate control properties of dronedarone in patients with atrial fibrillation.

Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events.

BACKGROUND: Atrial fibrillation (AF) is the most frequently occurring cardiac arrhythmia with often serious clinical consequences. Many patients have contraindications to anticoagulation, and it is often underused in clinical practice. The addition of clopidogrel to aspirin (ASA) has been shown to reduce vascular events in a number of high-risk populations. Irbesartan is an angiotensin receptor-blocking agent that reduces blood pressure and has other vascular protective effects. METHODS AND RESULTS: ACTIVE W is a noninferiority trial of clopidogrel plus ASA versus oral anticoagulation in patients with AF and at least 1 risk factor for stroke. ACTIVE A is a double-blind, placebo-controlled trial of clopidogrel in patients with AF and with at least 1 risk factor for stroke who receive ASA because they have a contraindication for oral anticoagulation or because they are unwilling to take an oral anticoagulant. ACTIVE I is a partial factorial, double-blind, placebo-controlled trial of irbesartan in patients participating in ACTIVE A or ACTIVE W. The primary outcomes of these studies are composites of vascular events. A total of 14000 patients will be enrolled in these trials. CONCLUSIONS: ACTIVE is the largest trial yet conducted in AF. Its results will lead to a new understanding of the role of combined antiplatelet therapy and the role of blood pressure lowering with an angiotensin II receptor blocker in patients with AF.

Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial.

BACKGROUND: Oral anticoagulation therapy reduces risk of vascular events in patients with atrial fibrillation. However, long-term monitoring is necessary and many patients cannot achieve optimum anticoagulation. We assessed whether clopidogrel plus aspirin was non-inferior to oral anticoagulation therapy for prevention of vascular events. METHODS: Patients were enrolled if they had atrial fibrillation plus one or more risk factor for stroke, and were randomly allocated to receive oral anticoagulation therapy (target international normalised ratio of 2.0-3.0; n=3371) or clopidogrel (75 mg per day) plus aspirin (75-100 mg per day recommended; n=3335). Outcome events were adjudicated by a blinded committee. Primary outcome was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. Analyses were by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00243178. RESULTS: The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. There were 165 primary events in patients on oral anticoagulation therapy (annual risk 3.93%) and 234 in those on clopidogrel plus aspirin (annual risk 5.60%; relative risk 1.44 (1.18-1.76; p=0.0003). Patients on oral anticoagulation therapy who were already receiving this treatment at study entry had a trend towards a greater reduction in vascular events (relative risk 1.50, 95% CI 1.19-1.89) and a significantly (p=0.03 for interaction) lower risk of major bleeding with oral anticoagulation therapy (1.30; 0.94-1.79) than patients not on this treatment at study entry (1.27, 0.85-1.89 and 0.59, 0.32-1.08, respectively). CONCLUSION: Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy.

[Pharmacological therapy for ventricular arrhythmias: evidence for current treatment strategies and perspectives for the future]. / Pharmakotherapie der ventrikulären Rhythmusstörungen : Was kommt, was bleibt, was geht?

This review summarizes the current status of pharmacological therapy for ventricular arrhythmias in symptomatic patients. The selection of specific drugs for this indication is highly dependent on the underlying heart disease. In primary prevention of sudden death, antiarrhythmic agents do not play a role--except betareceptor antagonists. Similarly, in patients treated for secondary prevention of cardiac arrest or hemodynamically symptomatic ventricular tachycardia, the implantable defibrillator constitutes the therapy of choice with hardly any role left for antiarrhythmic drugs. An emerging role for antiarrhythmic drug therapy is represented by the concomitant pharmacological treatment in ICD recipients who experience shocks from their devices (hybrid therapy). Several randomized clinical trials have recently evaluated this issue and permit an evidence-based treatment strategy. Currently, most patients receive sotalol or amiodarone for hybrid therapy with azimilide as a potential new class III antiarrhythmic drug for this treatment indication.

[Pharmacological cardioversion of atrial fibrillation]. / Medikamentöse Kardioversion von Vorhofflimmern.

Atrial fibrillation is a very common rhythm disorder that can be therapeutically reverted into sinus rhythm by means of pharmacological or electrical cardioversion. This article reviews options for drug therapy and tries to elucidate the mechanisms of AF termination by antiarrhythmics. We will explain the clinical basis of different therapeutic approaches and review the efficacy of selected substances according to recent clinical studies. Finally, we will focus on some important aspects of anticoagulation in the setting of pharmacological cardioversion.

Prediction of early recurrence of atrial fibrillation after external cardioversion by means of P wave signal-averaged electrocardiogram.

BACKGROUND: Therapy of atrial fibrillation by electrical cardioversion (CV) is limited by the high rate of recurrences. Early recurrence of atrial fibrillation (ERAF) occurs in a subgroup of patients whose characteristics are poorly defined. This prospective study was performed to evaluate if the P wave signal-averaged ECG (PSAECG) is able to identify patients with an increased risk of ERAF after CV. METHODS: Patients with an indication for elective external CV were enrolled. After successful CV, PSAECGs were recorded at 0.5, 1, 24 h and 1 week. The ability of PSAECG parameters (signal-averaged P wave duration, PWD; root-mean-square of the voltage of the terminal 20, 30, and 40 ms of the signal-averaged P wave; RMS20, RMS30, RMS40) to predict ERAF (prospectively defined as AF recurrence within 4 h after CV) was assessed. RESULTS: Of 111 consecutive patients, 7 experienced ERAF, 30 patients had AF recurrence later during the 1-week follow-up. Patients with ERAF had a significantly prolonged signal-averaged PWD compared to patients who remained in SR (194+/-16 ms vs 139+/-3 ms at 0.5 h, p<0.001). As ROC analysis revealed, a PWD >/=154 ms at 30 min after CV had the highest predictive accuracy for ERAF (sensitivity 100%, specificity 82%, positive predictive value 33%, negative predictive value 100%). Other parameters of the PSAECG did not reveal significant differences between patients with and without ERAF. CONCLUSIONS: The PSAECG provides a sensitive noninvasive tool for detection of patients at risk of ERAF. Thus identified, tailored pharmacological therapy is conceivable to prevent ERAF.

T-wave alternans negative coronary patients with low ejection and benefit from defibrillator implantation.

In a trial of prophylactic implantation of a defibrillator, a mortality benefit was seen among patients with previous myocardial infarction and a left-ventricular ejection fraction of 0.30 or less. We identified 129 similar patients from two previously published clinical trials in which microvolt T-wave alternans testing was prospectively assessed. At 24 months of follow-up, no sudden cardiac death or cardiac arrest was seen among patients who tested T-wave alternans negative, compared with an event rate of 15.6% among the remaining patients. Testing of T-wave alternans seems to identify patients who are at low risk of ventricular tachyarrhythmic event and who may not benefit from defibrillator therapy.

Relationship between clinical and echocardiography-derived parameters and atrial activation as measured by the P-wave signal-averaged electrocardiogram.

UNLABELLED: P-wave signal averaging is used in an attempt to detect patients at risk of atrial arrhythmias, particularly atrial fibrillation. Although many studies utilized this method, data on the relationship between clinical and echocardiographic variables and signal averaged P-wave parameters are sparse. Thus, we performed a prospective study to evaluate the influence of important clinical and echocardiographic variables on P-wave parameters. The study included 100 probands without demonstrable cardiac disease. P-wave signal averaging was performed after echocardiographic examination in all subjects. Overall P-wave duration averaged 122 +/- 16 ms and correlated significantly with age, left atrial and left ventricular end-diastolic diameter on univariate analysis (r = 0.287, 0.393 and 0.375; p = 0.004, < 0.0001 and < 0.0001, respectively). On multivariate analysis, however, age was the only independent factor affecting signal averaged P-wave duration (p = 0.02). There were statistically significant differences in left atrial size and P-wave duration if probands were grouped according to their age. CONCLUSION: There is a significant relationship between signal averaged P-wave duration and age. This may be due to increased atrial fibrosis in elderly subjects. These data should be considered when signal-averaged P wave duration is used as a risk stratifier in patients prone to atrial fibrillation.