Towards personalized antithrombotic management with drugs and devices across the cardiovascular spectrum.

Intravascular thrombus formation and embolization are among the most frequent events leading to a number of cardiovascular conditions with high morbidity and mortality. The underlying causes are stasis of the circulating blood, genetic and acquired coagulation disorders, and reduced antithrombotic or prothrombotic properties of the vascular wall (Virchow's triad). In the venous system, intravascular thrombi can cause venous thrombosis and pulmonary and even peripheral embolism including ischaemic stroke [through a patent foramen ovale (PFO)]. Thrombi in the left atrium and its appendage or ventricle form in the context of atrial fibrillation and infarction, respectively. Furthermore, thrombi can form on native or prosthetic aortic valves, within the aorta (in particular at sites of ulcers, aortic dissection, and abdominal aneurysms), and in cerebral and peripheral arteries causing stroke and critical limb ischaemia, respectively. Finally, thrombotic occlusion may occur in arteries supplying vital organs such the heart, brain, kidney, and extremities. Thrombus formation and embolization can be managed with anticoagulants and devices depending on where they form and embolize and on patient characteristics. Vitamin K antagonists are preferred in patients with mechanical valves, while novel oral anticoagulants are first choice in most other cardiovascular conditions, in particular venous thromboembolism and atrial fibrillation. As anticoagulants are associated with a risk of bleeding, devices such as occluders of a PFO or the left atrial appendage are preferred in patients with an increased bleeding risk. Platelet inhibitors such as aspirin and/or P2Y12 antagonists are preferred in the secondary prevention of coronary artery disease, stroke, and peripheral artery disease either alone or in combination depending on the clinical condition. A differential and personalized use of anticoagulants, platelet inhibitors, and devices is recommended and reviewed in this article.

Device-detected atrial fibrillation and risk for stroke: an analysis of >10,000 patients from the SOS AF project (Stroke preventiOn Strategies based on Atrial Fibrillation information from implanted devices).

OBJECTIVE: The aim of this study was to assess the association between maximum daily atrial fibrillation (AF) burden and risk of ischaemic stroke. BACKGROUND: Cardiac implanted electronic devices (CIEDs) enhance detection of AF, providing a comprehensive measure of AF burden. DESIGN, SETTING, AND PATIENTS: A pooled analysis of individual patient data from five prospective studies was performed. Patients without permanent AF, previously implanted with CIEDs, were included if they had at least 3 months of follow-up. A total of 10 016 patients (median age 70 years) met these criteria. The risk of ischaemic stroke associated with pre-specified cut-off points of AF burden (5 min, 1, 6, 12, and 23 h, respectively) was assessed. RESULTS: During a median follow-up of 24 months, 43% of 10 016 patients experienced at least 1 day with at least 5 min of AF burden and for them the median time to the maximum AF burden was 6 months (inter-quartile range: 1.3-14). A Cox regression analysis adjusted for the CHADS2 score and anticoagulants at baseline demonstrated that AF burden was an independent predictor of ischaemic stroke. Among the thresholds of AF burden that we evaluated, 1 h was associated with the highest hazard ratio (HR) for ischaemic stroke, i.e. 2.11 (95% CI: 1.22-3.64, P = 0.008). CONCLUSIONS: Device-detected AF burden is associated with an increased risk of ischaemic stroke in a relatively unselected population of CIEDs patients. This finding may add to the basis for timely and clinically appropriate decision-making on anticoagulation treatment.

GARFIELD-AF: risk profiles, treatment patterns and 2-year outcomes in patients with atrial fibrillation in Germany, Austria and Switzerland (DACH) compared to 32 countries in other regions worldwide.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is a worldwide non-interventional study of stroke prevention in patients with non-valvular AF. METHODS AND RESULTS: 52,080 patients with newly diagnosed AF were prospectively enrolled from 2010 to 2016. 4121 (7.9%) of these patients were recruited in DACH [Germany (n = 3567), Austria (n = 465) and Switzerland (n = 89) combined], and 47,959 patients were from 32 countries in other regions worldwide (ORW). Hypertension was most prevalent in DACH and ORW (85.3% and 75.6%, respectively). Diabetes, hypercholesterolaemia, carotid occlusive disease and vascular disease were more prevalent in DACH patients vs ORW (27.6%, 49.4%, 5.8% and 29.0% vs 21.7%, 40.9%, 2.8% and 24.5%). The use of non-vitamin K antagonist oral anticoagulants (NOACs) increased more in DACH over time. Management of vitamin K antagonists was suboptimal in DACH and ORW (time in therapeutic range of INR ≥ 65% in 44.6% and 44.4% of patients or ≥ 70% in 36.9% and 36.0% of patients, respectively). Adjusted rates of cardiovascular mortality and MI/ACS were higher in DACH while non-haemorrhagic stroke/systemic embolism was lower after 2-year follow-up. CONCLUSIONS: Similarities and dissimilarities in AF management and clinical outcomes are seen in DACH and ORW. The increased use of NOAC was associated with a mismatch of risk-adapted anticoagulation (over-and-undertreatment) in DACH. Suboptimal control of INR requires educational activities in both regional groups. Higher rates of cardiovascular death in DACH may reflect the higher risk profile of these patients and lower rates of non-haemorrhagic stroke could be associated with increased NOAC use.

Methodological challenges in the coding and adjudication of sudden deaths in a large simple trial with observational follow-up: the ziprasidone observational study of cardiac outcomes (ZODIAC).

PURPOSE: The Ziprasidone Observational study of car DIAC Outcomes (ZODIAC), a large simple trial comparing ziprasidone versus olanzapine in real-world use, showed no difference in risk of sudden death. Upon the request of the US Food and Drug Administration, 205 fatal events were readjudicated applying ICD-10 coding rules for sudden death. METHODS: A readjudication committee coded three domains (witness to death, time of symptom onset to death, and most likely cause of death) for use within algorithms consistent with ICD-10 rules. Relative risks (RR) and corresponding 95%CI were calculated for persons randomized to ziprasidone versus olanzapine, comparing 1-year incidence of sudden death, using multiple definitions. RESULTS: Data on symptom onset to death and diagnosis of specific cardiac arrhythmias required by the ICD-10 rules were often lacking. Sensitivity analyses were conducted to explore the impact of cases suggestive of cardiac origin but missing data required by ICD-10 sudden death codes. Overall, the readjudicated data matched the study's initial findings, with no significant difference in 1-year mortality between ziprasidone and olanzapine for sudden death not otherwise specified and sudden cardiac death (R96.0 or R96.1 or I46.1; RR = 1.11, 95%CI 0.45- 2.77). CONCLUSIONS: After outcome readjudication, ZODIAC found no difference in the risk of sudden death among those randomized to ziprasidone versus olanzapine. However, unlike hospital-based studies, fatal events in general population studies often occur outside hospital and often lack the clinical detail needed for the exact determination of symptom onset and event. Epidemiological evaluations of sudden death need to consider the limitations of the available data.

EHRA Expert Consensus Statement on the management of cardiovascular implantable electronic devices in patients nearing end of life or requesting withdrawal of therapy.

The purpose of this Consensus Statement is to focus on implantable cardioverter-defibrillator (ICD) deactivation in patients with irreversible or terminal illness. This statement summarizes the opinions of the Task Force members, convened by the European Heart Rhythm Association (EHRA) and the Heart Rhythm Society (HRS), based on ethical and legal principles, as well as their own clinical, scientific, and technical experience. It is directed to all healthcare professionals who treat patients with implanted ICDs, nearing end of life, in order to improve the patient dying process. This statement is not intended to recommend or promote device deactivation. Rather, the ultimate judgement regarding this procedure must be made by the patient (or in special conditions by his/her legal representative) after careful communication about the deactivation's consequences, respecting his/her autonomy and clarifying that he/she has a legal and ethical right to refuse it. Obviously, the physician asked to deactivate the ICD and the industry representative asked to assist can conscientiously object to and refuse to perform device deactivation.

Effect of fish oil on ventricular tachyarrhythmia in three studies in patients with implantable cardioverter defibrillators.

AIMS: To determine the effects of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) from fish on the incidence of recurrent ventricular arrhythmia in implantable cardioverter defibrillator (ICD) patients by combining results from published trials. METHODS AND RESULTS: We searched in the Medline, EMBASE, and Cochrane databases and performed a meta-analysis on all three available trials on fish oil and ventricular arrhythmia. Furthermore, we pooled individual data of two of these randomized, double-blind, placebo-controlled trials (Raitt et al. Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial. JAMA 2005;293:2884-2891 and Brouwer et al. Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. JAMA 2006;295:2613-2619). The main outcome was time to first confirmed ventricular fibrillation (VF) or ventricular tachycardia (VT) combined with death for the meta-analysis, and time to first spontaneous confirmed VF or VT for the pooled analysis. The meta-analysis (n = 1148) showed no convincing protective effect of fish oil (RR 0.90; 95% CI 0.67-1.22). The hazard ratio for the subgroup of patients with coronary artery disease at baseline (0.79; 0.60-1.06) tended towards a protective effect. The pooled analysis (n = 722) showed that time to appropriate ICD intervention was similar for fish oil and placebo treatment (log-rank P = 0.79). CONCLUSION: These findings do not support a protective effect of omega-3 PUFAs from fish oil on cardiac arrhythmia in all patients with an ICD. Current data neither prove nor disprove a beneficial or a detrimental effect for subgroups of patients with specific underlying pathologies.

Consumer-led screening for atrial fibrillation using consumer-facing wearables, devices and apps: A survey of health care professionals by AF-SCREEN international collaboration.

AIM: A variety of consumer-facing wearables, devices and apps are marketed directly to consumers to detect atrial fibrillation (AF). However, their management is not defined. Our aim was to explore their role for AF screening via a survey. METHODS AND RESULTS: An anonymous web-based survey was undertaken by 588 health care professionals (HCPs) (response rate 23.7%). Overall, 57% HCPs currently advise wearables/apps for AF detection in their patients: this was much higher for electrophysiologists and nurses/allied health professionals (74-75%) than cardiologists (57%) or other physicians (34-38%). Approximately 46% recommended handheld (portable) single-lead dedicated ECG devices, or, less frequently, wristband ECG monitors with similar differentials between HCPs . Only 10-15% HCPs advised photoplethysmographic wristband monitors or smartphone apps. In over half of the HCP consultations for AF detected by wearables/apps, the decision to screen was entirely the patient's. About 45% of HCPs perceive a potential role for AF screening in people aged >65 years or in those with risk factors. Almost 70% of HCPs believed we are not yet ready for mass consumer-initiated screening for AF using wearable devices/apps, with patient anxiety, risk of false positives and negatives, and risk of anticoagulant-related bleeding perceived as potential disadvantages, and perceived need for appropriate management pathways. CONCLUSIONS: There is a great potential for appropriate use of consumer-facing wearables/apps for AF screening. However, it appears that there is a need to better define suitable individuals for screening and an appropriate mechanism for managing positive results before they can be recommended by HCPs.

Time-trends and treatment gaps in the antithrombotic management of patients with atrial fibrillation after percutaneous coronary intervention: Insights from the CHUM AF-STENT Registry.

BACKGROUND: The management of atrial fibrillation and flutter (AF) patients undergoing percutaneous coronary intervention (PCI) has undergone a rapid recent evolution. In 2016, the Canadian Cardiovascular Society (CCS) published expert recommendations to help guide clinicians in balancing bleeding and thrombotic risks in these patients. HYPOTHESIS: Antithrombotic regimen prescriptions for AF patients undergoing PCI evolved after the publication of the 2016 CCS AF guidelines. METHODS: A prospective cohort of AF patients undergoing PCI with placement of a coronary stent from a single tertiary academic center was analyzed for the recommended antithrombotic regimen at discharge. Prescribing behavior was compared between three time periods (Cohort A [2010-2011]; Cohort B [2014-2015]; Cohort C [2017]) using the χ2 test. In addition, antithrombotic management in Cohorts B and C were compared to guideline-recommended therapy. RESULTS: A total of 459 patients with AF undergoing PCI were identified. Clinical and procedural characteristics were similar between cohorts, with the exception of an increase in drug-eluting stent (DES) use over time (P < .01). Overall, the rate of oral anticoagulation (OAC) increased over time (P < .01), associated with an increase in nonvitamin K OAC prescription (P < .01) and a concomitant decrease in vitamin K antagonist prescription (P < .01). Despite this, the overall rate of anticoagulation remains below what would be predicted with perfect guideline compliance (75% vs 94%, P < .01). CONCLUSION: There has been a dramatic shift in clinical practice for AF patients requiring PCI, with increases in prescription of OAC even in the context of an increase in the use of DES. However, room for further practice optimization still exists.

Oral anticoagulation for subclinical atrial tachyarrhythmias detected by implantable cardiac devices: an international survey of the AF-SCREEN Group.

AIMS: At present, there is little evidence on how to treat subclinical atrial fibrillation (SCAF) or atrial high rate episodes (AHREs) detected by cardiac implantable electronic devices (CIEDs). Our aim was to assess current practice around oral anticoagulation (OAC) in such patients. METHODS: A web-based survey undertaken by 310 physicians: 59 AF-SCREEN International Collaboration members and 251 non-members. RESULTS: In patients with SCAF/AHRE and a CHA2DS2VASc ≥ 2 in males or ≥ 3 in female the amount of SCAF/AHRE triggering use of OAC was variable but <2% of respondents considered that no AHRE would require OAC. Around one third (34%) considered SCAF/AHRE duration of >5-6 min as the basis for OAC prescription, while 16% and 18% required a burden of at least 5.5 h or 24 h, respectively. The propensity to prescribe OAC for a low burden of AHREs differed according to certain respondent characteristics (greater propensity to prescribe OAC for neurologists). When the clinical scenario included a prior stroke or a prior cardioembolic stroke, stated prescription of OAC was very high. More than 96% felt that any SCAF/AHRE should be treated with OAC. CONCLUSIONS: There is substantial heterogeneity in the perception of the risk of stroke/systemic embolism associated with SCAF/AHRE of variable duration. The threshold of AHRE burden that would trigger initiation of OAC is highly variable, and differs according to the clinical scenario (lower threshold in case of previous stroke). Ongoing trials will clarify the real benefit and risk/benefit ratio of OAC in this specific clinical setting.

ESC CardioMed.

Reprinted with permission from: Eur Heart J. 2018; 19: 959-961.

Trial to evaluate the management of paroxysmal supraventricular tachycardia during an electrophysiology study with tecadenoson.

BACKGROUND: Tecadenoson is a potent selective A1-adenosine receptor agonist with a dose-dependent negative dromotropic effect on the AV node. Tecadenoson terminates induced paroxysmal supraventricular tachycardia (PSVT) without the clinically significant side effects caused by stimulation of other adenosine receptors. This trial was designed to determine a safe and effective tecadenoson bolus for termination of electrophysiologically induced PSVT. METHODS AND RESULTS: Patients with a history of symptomatic PSVT and inducible PSVT at the time of a clinically indicated electrophysiology study were randomized into a multicenter, double-blind, placebo-controlled trial. Five 2-dose tecadenoson bolus regimens were evaluated versus placebo (75/150, 150/300, 300/600, 450/900, 900 microg/900 microg). The second bolus was administered only if PSVT persisted for 1 minute after the first bolus. Each tecadenoson regimen resulted in a significant therapeutic conversion rate compared with placebo (range, 50.0% to 90.3%, analysis of all patients dosed; n=181; P<0.0005). Conversion by the first bolus was dose related (range: placebo, 3.3% to 86.7% for 900 microg/900 microg). Time to conversion was dose dependent, with a median time of <1 minute for the 3 highest dose regimens. Postconversion arrhythmias were transient, requiring no additional treatment in 4 regimens (including placebo). Transient second- and third-degree heart block occurred at higher doses (300/600, 450/900, 900 microg/900 microg) and was supported with backup pacing when needed. No effect on blood pressure was observed. Ten patients with a history of asthma or chronic obstructive pulmonary disease tolerated tecadenoson without bronchospasm. CONCLUSIONS: We identified an optimal tecadenoson regimen (300 microg/600 microg) that effectively and rapidly converted 90% (28 of 31) of PSVT patients to normal sinus rhythm with no significant adverse effects.

Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease.

Resting heart rate is associated with cardiovascular and all-cause mortality, and the mortality benefit of some cardiovascular drugs seems to be related in part to their heart rate-lowering effects. Since it is difficult to separate the benefit of heart rate lowering from other actions with currently available drugs, a 'pure' heart rate-lowering drug would be of great interest in establishing the benefit of heart rate reduction per se. Heart rate is determined by spontaneous electrical pacemaker activity in the sinoatrial node. Cardiac pacemaker cells generate the spontaneous slow diastolic depolarisation that drives the membrane voltage away from a hyperpolarised level towards the threshold level for initiating a subsequent action potential, generating rhythmic action potentials that propagate through the heart and trigger myocardial contraction. The I(f) current is an ionic current that determines the slope of the diastolic depolarisation, which in turn controls the heart beating rate. Ivabradine is the first specific heart rate-lowering agent to have completed clinical development for stable angina pectoris. Ivabradine specifically blocks cardiac pacemaker cell f-channels by entering and binding to a site in the channel pore from the intracellular side. Ivabradine is selective for the I(f) current and exerts significant inhibition of this current and heart rate reduction at concentrations that do not affect other cardiac ionic currents. This activity translates into specific heart rate reduction, which reduces myocardial oxygen demand and simultaneously improves oxygen supply, by prolonging diastole and thus allowing increased coronary flow and myocardial perfusion. Ivabradine lowers heart rate without any negative inotropic or lusitropic effect, thus preserving ventricular contractility. Ivabradine was shown to reduce resting heart rate without modifying any major electrophysiological parameters not related to heart rate. In patients with left ventricular dysfunction, ivabradine reduced resting heart rate without altering myocardial contractility. Thus, pure heart rate lowering can be achieved in the clinic as a result of specific and selective I(f) current inhibition. Two randomised clinical studies have shown that ivabradine is an effective anti-ischaemic agent that reduces heart rate and improves exercise capacity in patients with stable angina. Ivabradine was shown to be superior to placebo in improving exercise tolerance test (ETT) criteria (n = 360) and, in a 4-month, double-blind, controlled study (n = 939), ivabradine 5 and 7.5mg twice daily were shown to be at least as effective as atenolol 50 and 100mg once daily, respectively, in improving total exercise duration and other ETT criteria, and reducing the number of angina attacks. Experimental data indicate a potential role of pure heart rate lowering in other cardiovascular conditions, such as heart failure.

Validation of echocardiographic left atrial parameters in atrial fibrillation using the index beat of preceding cardiac cycles of equal duration.

BACKGROUND: The clinical assessment of left atrial function during atrial fibrillation is challenging and often inaccurate because of the beat-to-beat variability in the cycle length. The aim of this study was to validate the use of an index beat, the beat following two preceding cardiac cycles of equal duration, for the measurement of left atrial functional indices, including area, volume, and expansion index. The index beat was compared with the conventional but time-consuming method of averaging multiple consecutive cardiac cycles. METHODS: Thirty patients with persistent or permanent atrial fibrillation were studied using two-dimensional echocardiography, and left atrial indices were measured from the average of 17 consecutive cardiac cycles compared with that of an index beat taken from outside of these 17 cycles. RESULTS: The index beat showed good correlation with the averaging technique, and comparison of the two methods showed them to be interchangeable. Clinically, the differences in left atrial functional indices between the two methods were minor. CONCLUSIONS: Use of the index beat to measure dynamic left atrial function in atrial fibrillation can easily be performed and is as accurate as and less time consuming than the onerous method of averaging of multiple cardiac cycles.

Postoperative atrial fibrillation - what do we really know?

Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery, occurring in 20% to 60% of patients. Advanced age, history of atrial fibrillation (AF), heart failure, peripheral arterial disease and chronic obstructive pulmonary disease are predictors of POAF. The pathogenesis of AF seems to be multifactorial, and includes electrical and structural remodeling as well as inflammation (a systemic response caused by cardiopulmonary bypass and cardiotomy). Numerous pharmacologic agents can decrease the incidence of POAF. It is also necessary to evaluate an agent's ability to decrease stroke, mortality, length of stay and hospital costs. Currently, the use of beta-blockers with adjunctive amiodarone has been shown to reduce POAF and several of its complications. Two therapeutic choices exist in patients with POAF: rate control and rhythm control. The decision which is more important to target should be based on the symptoms of the individual patient. Unlike in patients with chronic AF, POAF is generally transient, and the risks of anticoagulation may outweigh the benefits. Surgical ablation techniques and ablation devices have progressed considerably. This made the procedures quicker and simpler, and therefore feasible in virtually all clinical contexts. In turn, this has raised the issue of post-ablation arrhythmias. Although relapsing AF is generally addressed conservatively, it may require ablation, frequently transseptal. Further research is needed to identify the predictors of POAF and the most effective pharmacological and invasive methods for the prevention and treatment of POAF.

QT-interval turbulence induced by atrial and ventricular extrastimuli in patients with ventricular tachycardia.

Atrial and ventricular premature beats (APB, VPB) cause consistent changes in the sinus-cycle length known as heart rate (HR) turbulence. HR turbulence is described by turbulence onset (TO) and turbulence slope (TS). This article investigated into whether specific QT interval changes are associated with HR turbulence and whether these can be assessed using HR turbulence quantifiers. A total of 40 patients (54 +/- 16 years, 34 men) referred for electrophysiological evaluation for ventricular tachycardia (VT) underwent a study protocol prior to programmed electrical stimulation. The protocol consisted of three consecutive series of atrial and ventricular stimulation with single extrastimuli delivered from the high right atrium and the right ventricular apex at a coupling interval decremented from 750 to 400 ms at a 50-ms step. A 20-second period of sinus rhythm was allowed between ES. Turbulence onset and TS after an APB and a VPB were calculated separately using a dedicated computer algorithm. Consistent changes in the QT interval (QT turbulence) were observed immediately after premature beats and were determined using TO. QT TO was calculated as a relative difference between the QT interval of the first sinus cycle after the induced premature beat and the mean of the QT intervals of the two sinus cycles preceding the premature beat. QT turbulence was present following both APBs and VPBs but was less pronounced after an APB. In contrast to negative VPB-induced TO of HR turbulence reflecting early acceleration of the HR, VPB-induced TO of QT turbulence was positive showing lengthening of the QT interval following a VPB. The subgroup analysis has shown that QT turbulence was significantly attenuated in patients with ischemic heart disease and a left ventricular (LV) ejection fraction (EF) 0.40 (after an APB: 0.73 +/- 0.31% vs 2.58 +/- 0.31%, respectively, P = 0.0044; after a VPB: 1.18 +/- 0.29% vs 4.40 +/- 1.38%, respectively, P = 0.0026). Neither APB nor VPB produced late QT dynamics equivalent to TS of HR turbulence. QT-interval turbulence occurs in association with HR turbulence following induced VPB and APB but QT dynamics is opposite to that of HR. It can be expressed as TO but not TS. Patients with ischemic VT and LV dysfunction exhibited significantly lower QT TO values than those with nonischemic VT and normal ventricular function.

CME Paper: Acute Myocardial Infarction in the Elderly.

Up to half of admissions with myocardial infarction are over 70 years of age. Mortality in this age group is higher than in younger age groups. However, elderly patients are less likely to be managed in an acute coronary care setting. Low dose aspirin should be given to all elderly patients with myocardial infarction. Thrombolytic agents have the greatest effect in the elderly even though they give an increased risk of hemorrhagic stroke. They are underused in the elderly with myocardial infarction for a number of reasons. Ã -Blockers reduce mortality post infarction and ACE inhibitors improve morbidity and mortality rates in those with evidence of heart failure post infarction. Amiodarone may also be of use as an antiarrhythmic in the post infarction period. (c) 2000 by CVRR, Inc.