The harm of anticoagulation in patients with low-risk by CHADS2 and reclassified as high-risk by CHA2DS2VASc: inferences from TRAF cohort.

OBJECTIVE: There is a gap in the knowledge concerning oral anticoagulation (OAC) in atrial fibrillation (AF) patients with a non-high risk of stroke. CHA2DS2VASc and CHADS2 scores generated imprecise risk estimates for low risk patients. We aimed to assess OAC in patients with low risk by CHADS2 and reclassified as high-risk by CHA2DS2VASc. PATIENTS AND METHODS: In this study, retrospective nationwide population-based study, data were obtained from the Turkish claims and utilization management system. Patients with non-valvular AF (n=451,113) between 2007 and 2012 sub-divided into those with a CHA2DS2VASc≥1 and CHADS2=0 (n=41,273) who were off-warfarin (n=29,448) and on-warfarin (n=11,825). Stroke and systemic embolism, major bleeding, all-cause mortality, net clinical benefit (NCB) and ultimate NCB (UNCB) were assessed. RESULTS: Of the total cohort (mean age 66.1 ± 14.1 years, 56.1% female), CHA2DS2VASc improved the net reclassification index of observed 5-year composite thromboembolic endpoint by 6.9% (p<0.05). CHA2DS2VASc reclassified 9.7% low risk patients as high risk. Among reclassified-high-risk category (patients with a CHA2DS2VASc score of ≥1 and CHADS2 score of 0), major bleeding for that prescribed warfarin was 3% and higher than the rate of thromboembolism among those off-warfarin. NCB (-0.035) and UNCB (-0.021) were negative. Death and hospitalization at 1 year were significantly higher for on-warfarin group. CONCLUSIONS: Clinical outcomes, net clinical benefit indices are negative; rates of death and hospitalization were significantly higher for OAC in reclassified category. This emphasizes the importance of greater attention to balancing the risks and benefits of OAC in patients with low risk by CHADS2 and reclassified as high-risk by CHA2DS2VASc.

En pacientes con fibrilación auricular es preferible tratar con anticoagulantes que con ácido acetilsalicílico-clopidogrel / Clopidogrel plus aspirin versus oral anticoagulation for atrial fi brillation inthe Atrial fi brillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial

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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.

[Minimizing the risks associated with QTc prolongation in people with schizophrenia. A consensus statement by the Cardiac Safety in Schizophrenia Group]. / Comment minimiser les risques associés à un allongement significatif de l'intervalle QTc chez les personnes souffrant de schizophrénie. Recommandations consensuelles du Cardiac Safety in Schizophrenia Group.

Schizophrenia is one of the most debilitating mental illnesses, complicated by an increased incidence of suicide amongst patients compared with the general population. A recent report has also demonstrated a 33% increase in -relative risk of death associated with circulatory disease, indicating that the latter may be a more critical factor than either suicide or accidental death in this population. Indeed, the average life expectancy of a person with schizophrenia is currently approximately a decade less than that of the general population. Additionally, it has been shown that in over 50% of people with schizophrenia, there is a reduction in their chance of reaching psychosocial goals. Since the arrival of the first antipsychotic drugs in the middle of the last century, the outlook for patients with schizophrenia has improved markedly. In particular, the introduction of the new generation (atypical) class of antipsychotic agents in the 1980s and 90s has resulted in a significant reduction in the incidence of violent and aggressive episodes in treated patients. A better side-effect profile of these drugs, especially reduced extra pyramidal symptoms (EPS), has resulted in improved patient outcomes and the possibility of good long-term control of the disorder. However, while the introduction of antipsychotic agents has undoubtedly revolutionised the prognosis for patients with schizophrenia, these medications are not without their own problems. One of the concerns to emerge over the last fifteen years is unpredictable, sudden and unexplained death in patients taking antipsychotic drugs. The cause of sudden death in this population is controversial and the role of drugs is not clear. People with schizophrenia also appear to be at higher risk of cardiovascular disease compared with the general population. Many factors may play a role in this including a higher prevalence of smoking, poorer diet, more sedentary lifestyle and a greater likelihood of alcoholism and substance abuse. However, it is possible that the impact of adverse effects on the cardiovascular system related to certain antipsychotic drug use may well increase the prevalence of mortality and morbidity due to cardiovascular events and may also play a significant role in the reduced life expectancy of the patient with schizophrenia. The range of mechanisms whereby antipsychotic drugs can influence cardiovascular function is very broad and includes: receptor blockade; conduction disturbance (eg bundle branch block); delayed ventricular repolarisation (prolonged QTc interval); left ventricular dysfunction; sinus node abnormalities; myocarditis; postural hypotension; polydipsia-hyponatremia syndrome; weight gain; glucose intolerance. Of these, QTc interval prolongation, with the risk of progression to the potentially fatal ventricular tachyarrhythmia Torsades de Pointes (TdP), is of particular concern as this arrhythmia is unpredictable and difficult to manage. Coupled with these clinical concerns are regulatory issues regarding several compounds that have received warnings or been withdrawn from the market. Recently, there has been no clear guidance for psychiatrists regarding QTc interval prolongation and TdP. This document seeks: 1) to explore drug-induced ventricular arrhythmias with particular emphasis on QTc interval prolongation as a warning of increased vulnerability, 2) to provide guidelines on the therapeutic management of the patient with schizophrenia to minimize the risk of iatrogenic cardiotoxicity. Several guidance documents have previously been published in this area including the report published by the UK Working Group of the Royal College of Psychiatrists' Psychopharmacology Sub-Group in 1997, and the policy document on the potential for QTc prolongation and proarrhythmia by non-antiarrhythmic drugs published in June 1999 under the auspices of the European Society of Cardiology. This document seeks to supplement currently published guidelines.

Task Force on Sudden Cardiac Death, European Society of Cardiology.

The European Society of Cardiology has convened a Task Force on Sudden Cardiac Death in order to provide a comprehensive, educational document on this important topic. The main document has been published in the European Heart Journal in August 2001. The Task Force has now summarized the most important clinical issues on sudden cardiac death and provided tables with recommendations for risk stratification and for prophylaxis of sudden cardiac death. The present recommendations are specifically intended to encourage the development and revision of national guidelines on prevention of sudden cardiac death. The common challenge for cardiologists, physicians of other medical specialties and health professionals throughout Europe is to realize the potential for sudden cardiac death prevention and to contribute to public health efforts to reduce its burden.

The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy.

OBJECTIVES: We sought to assess the impact of intermittent atrial fibrillation (AF) on health-related quality of life (QoL). BACKGROUND: Intermittent AF is a common condition with little data on health-related QoL questionnaires to guide investigational therapies. METHODS: Outpatients from four centers, with documented AF (n = 152), completed validated QoL questionnaires (Medical Outcomes Study Short Form 36 [SF-36], Specific Activity, Symptom Checklist, Illness Intrusiveness and University of Toronto AF Severity Scales). Comparison groups were made up of healthy individuals (n = 47) and four cardiac control groups: published (n = 78) and created for study (n = 69) percutaneous transluminal coronary angioplasty (PTCA); published heart failure (n = 216) and published postmyocardial infarction (MI) (n = 107). RESULTS: Across all domains of the SF-36, AF patients reported substantially worse QoL than healthy controls (1.3 to 2.0 standard deviation units), with scores of 24%, 23%, 16% and 30% lower than healthy individuals on measures of physical and social functioning, mental and general health, respectively (all p < 0.001). Patients with AF were either significantly worse (p < 0.05, published controls) or as impaired (study controls) as either PTCA or post-MI patients on all domains of the SF-36 and the same as heart failure controls on SF-36 psychological subscales. Patients with AF were as impaired or worse than study PTCA controls on measures of illness intrusiveness, activity limitations and symptoms. Associations between objective disease indexes and subjective QoL measures had poor correlations and accounted for <6% of the total variability in QoL scores. CONCLUSIONS: Quality of life is as impaired in patients with intermittent AF as in patients with significant structural heart disease. Patients' perception of QoL is not dependent on the objective measures of disease severity that are usually employed.

Spontaneous episodes of atrial fibrillation after implantation of the Metrix Atrioverter: observations on treated and nontreated episodes. Metrix Investigators.

OBJECTIVES: We sought to evaluate the number and duration of device-treated and self-terminating, nontreated episodes of atrial fibrillation (AF) after implantation of the Metrix Atrioverter. BACKGROUND: A recent study has shown that the Atrioverter can rapidly restore sinus rhythm in patients with AF; however, the effect of the device on the clinical course of the arrhythmia in these patients is unknown. METHODS: The Atrioverter was implanted in 51 patients with symptomatic, recurrent, drug-refractory AF. The device was programmed to periodically monitor the cardiac rhythm. Defibrillation of AF episodes was performed under physician observation. RESULTS: During a mean follow-up of 260 +/- 144 days, 1,161 episodes of AF were observed during valid monitoring periods in 45 of 51 patients. Forty-one patients experienced 231 episodes for which they sought defibrillation therapy. The average duration of the treated episodes during valid monitoring periods (190 of 231 episodes in 39 of 41 patients) was significantly longer than that of the nontreated episodes (38 +/- 44 vs. 10 +/- 8 h; p < 0.05). The time between episodes requiring Atrioverter therapy increased, and the risk of having an episode requiring treatment decreased. No changes were observed in the number and duration of the short-lasting, nontreated episodes as time since implantation of the device increased. CONCLUSIONS: In patients with symptomatic, recurrent, drug-refractory AF, the frequency of long-lasting episodes, which were treated under observation with repeated defibrillation using the Atrioverter, decreased. The number and duration of short-lasting, nontreated episodes did not change during the 20-month study period. The effect of ambulatory use of the device on the recurrence of short-lasting episodes needs to be evaluated.

Classification of atrial fibrillation.

Atrial fibrillation (AF) is the subject of several overlapping schemes of classification in which the subgroups are often poorly defined. New methods of classification have been applied to accommodate new information and new concepts. These are often appropriate only in limited circumstances and may lead to confusion if applied out of context. We will describe the principal schemes used to classify AF and discuss the limitations of each.

The prognostic value of the QT interval and QT interval dispersion in all-cause and cardiac mortality and morbidity in a population of Danish citizens.

AIMS: To evaluate the prognostic value of the QT interval and QT interval dispersion in total and in cardiovascular mortality, as well as in cardiac morbidity, in a general population. METHODS AND RESULTS: The QT interval was measured in all leads from a standard 12-lead ECG in a random sample of 1658 women and 1797 men aged 30-60 years. QT interval dispersion was calculated from the maximal difference between QT intervals in any two leads. All cause mortality over 13 years, and cardiovascular mortality as well as cardiac morbidity over 11 years, were the main outcome parameters. Subjects with a prolonged QT interval (430 ms or more) or prolonged QT interval dispersion (80 ms or more) were at higher risk of cardiovascular death and cardiac morbidity than subjects whose QT interval was less than 360 ms, or whose QT interval dispersion was less than 30 ms. Cardiovascular death relative risk ratios, adjusted for age, gender, myocardial infarct, angina pectoris, diabetes mellitus, arterial hypertension, smoking habits, serum cholesterol level, and heart rate were 2.9 for the QT interval (95% confidence interval 1.1-7.8) and 4.4 for QT interval dispersion (95% confidence interval 1.0-19-1). Fatal and non-fatal cardiac morbidity relative risk ratios were similar, at 2.7 (95% confidence interval 1.4-5.5) for the QT interval and 2.2 (95% confidence interval 1.1-4.0) for QT interval dispersion. CONCLUSION: Prolongation of the QT interval and QT interval dispersion independently affected the prognosis of cardiovascular mortality and cardiac fatal and non-fatal morbidity in a general population over 11 years.

Species distributions, land values, and efficient conservation

Efforts at species conservation in the United States have tended to be opportunistic and uncoordinated. Recently, however, ecologists and economists have begun to develop more systematic approaches. Here, the problem of efficiently allocating scarce conservation resources in the selection of sites for biological reserves is addressed. With the use of county-level data on land prices and the incidence of endangered species, it is shown that accounting for heterogeneity in land prices results in a substantial increase in efficiency in terms of either the cost of achieving a fixed coverage of species or the coverage attained from a fixed budget.

Tachycardia-induced atrial myopathy: an important mechanism in the pathophysiology of atrial fibrillation?

The atrial myocardium of patients with chronic atrial fibrillation (AF) is often abnormal in its histologic features and in its electrophysiologic properties. These abnormalities have been interpreted in some cases as the cause of AF and in others as a consequence of AF. We believe that both are the case. We will review the features of this atrial myopathy and discuss the likely mechanisms and consequences of the process.

Acute hemodynamic effects of intravenous ibutilide in patients with or without reduced left ventricular function.

Many antiarrhythmic agents have adverse hemodynamic effects which limit their use in patients with impaired ventricular function or during tachyarrhythmias. Ibutilide is an intravenous, selective class III antiarrhythmic agent that is effective for conversion of atrial fibrillation or flutter. This multicenter, randomized, placebo-controlled, dose-ranging study evaluated the effects of intravenous ibutilide on hemodynamic parameters during invasive monitoring in 47 patients with or without reduced left ventricular ejection fraction (LVEF) > 35% or < or = 35%. Patients received either placebo or ibutilide as a 10-minute loading and a 30-minute maintenance infusion using 1 of the following dosing regimens: placebo then placebo (n = 12); 0.01 then 0.002 mg/kg (n = 12); 0.02 then 0.004 mg/kg (n = 12); or 0.03 then 0.006 mg/kg (n = 11). Ibutilide significantly increased QT and QTc intervals in a dose-related manner with mean increases ranging from 51 to 99 ms, but did not alter the PR interval or QRS duration. During ibutilide infusion, a few small but statistically significant changes from baseline in several hemodynamic variables were present. However, the changes in cardiac output, pulmonary artery or capillary wedge pressures, blood pressure, or heart rate in patients receiving ibutilide were not significantly different from the changes in patients receiving placebo. Thus, ibutilide did not cause clinically important adverse hemodynamic effects, even in patients with depressed ventricular function. One patient developed 2 episodes of nonsustained torsades de pointes during ibutilide. These results demonstrate that with careful monitoring for proarrhythmia, ibutilide can be used safely from a hemodynamic standpoint in the acute treatment of arrhythmias, even in patients with reduced ventricular function.

Patency of infarct-related artery. Effect of restoration of anterograde flow on vagal reflexes. ATRAMI (Automatic Tone and Reflexes After Myocardial Infarction) Investigators.

BACKGROUND: In post-myocardial infarction (MI) patients, the restoration of anterograde flow in the infarct-related artery (IRA) significantly improves survival. Limitation of infarct size and increased electrical stability of the myocardium are likely operating mechanisms for this beneficial effect. We tested the hypothesis that patency of the IRA may enhance vagal reflexes, a factor known to affect electrical stability of the infarcted myocardium. METHODS AND RESULTS: Analysis of angiographic data was performed in 359 of 1284 post-MI patients enrolled in a multicenter prospective study within 8 weeks after the index MI. All the patients underwent baroreflex sensitivity (BRS) assessment by the phenylephrine method. The BRS of the entire population averaged 8.2+/-5.5 ms/mm Hg and was significantly related to age but not to ejection fraction (EF). One-, two-, and three-vessel disease was present in 138, 96, and 99 patients, respectively, while no coronary stenosis was observed in 26. IRA patency was documented in 234 patients (65%), while in the remaining 125 (35%), the artery remained occluded. Patients with occluded IRAs had more extensive coronary disease (2 to 3 vessels, 71% versus 46%, P<.01) and more depressed left ventricular (LV) function (LVEF, 48+/-13% versus 53+/-12%, P<.001). Patency of the IRA was associated with higher BRS values (BRS, 8.9+/-5.8 versus 7.1+/-4.7 ms/mm Hg, P<.005) and with a lower incidence (9% versus 18% P<.02) of markedly depressed BRS (<3 ms/mm Hg), a condition suggested by preliminary studies to be associated with an increased risk of post-MI mortality. The association between IRA patency and BRS was more evident in anterior than in inferior MI. Multivariate regression analysis showed that age of the patient and patency of the IRA were the major independent determinants of BRS, while LVEF was weakly related to BRS and only when analyzed as a categorized variable. CONCLUSIONS: The presence of an open IRA is associated with higher baroreflex sensitivity, and this effect is largely independent of limitation of infarct size by IRA patency. These data offer new insights into the mechanisms by which coronary artery patency may affect cardiac electrical stability and survival.

Examination of a resin-modified glass-ionomer material as a pit and fissure sealant.

The purpose of this in vitro study was to examine the effect of various powder-liquid ratios of an experimental resin-modified glass-ionomer polymer cement on dye penetration when the cement was used as a pit and fissure sealant. Eighty extracted human third molars were randomly assigned to one of four pit and fissure sealant conditions: a resin-based sealant or one of three variations in powder-liquid ratios (1.4:1.0, 1.8:1.0, and 2.0:1.0) of an experimental, light-activated, resin-modified glass-ionomer cement. After sealant placement, the teeth were thermocycled and immersed in methylene blue dye. The teeth were sectioned, and the extent of dye penetration along the sealant-enamel interface was measured linearly. The resin-sealed occlusal fissures showed statistically significantly less dye penetration than did the three powder-liquid ratios of the experimental resin-modified glass-ionomer-cement sealant.