Search

IMPORTANCE: Data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with atrial fibrillation (AF) and recent acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). OBJECTIVE: Determine the efficacy and safety of apixaban or vitamin K antagonists (VKA) and aspirin or placebo according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE). DESIGN, SETTING, AND PARTICIPANTS: In this prospective, multicenter, 2-by-2 factorial, randomized clinical trial, post hoc parallel analyses were performed to compare randomized treatment regimens according to presence or absence of prior stroke/TIA/TE using Cox proportional hazards models. Patients with AF, recent ACS or PCI, and planned use of P2Y12 inhibitors for 6 months or longer were included; 33 patients with missing data about prior stroke/TIA/TE were excluded. INTERVENTIONS: Apixaban (5 mg or 2.5 mg twice daily) or VKA and aspirin or placebo. MAIN OUTCOMES AND MEASURES: Major or clinically relevant nonmajor (CRNM) bleeding. RESULTS: Of 4581 patients included, 633 (13.8%) had prior stroke/TIA/TE. Patients with vs without prior stroke/TIA/TE were older; had higher CHA2DS2-VASC and HAS-BLED scores; and more frequently had prior bleeding, heart failure, diabetes, and prior oral anticoagulant use. Apixaban was associated with lower rates of major or CRNM bleeding and death or hospitalization than VKA in patients with (hazard ratio [HR], 0.69; 95% CI, 0.46-1.03) and without (HR, 0.68; 95% CI, 0.57-0.82) prior stroke/TIA/TE. Patients without prior stroke/TIA/TE receiving aspirin vs placebo had higher rates of bleeding; this difference appeared less substantial among patients with prior stroke/TIA/TE (P = .01 for interaction). Aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with (HR, 0.71; 95% CI, 0.42-1.20) and without (HR, 0.93; 95% CI, 0.72-1.21) prior stroke/TIA/TE (not statistically significant). CONCLUSIONS AND RELEVANCE: The safety and efficacy of apixaban compared with VKA was consistent with the AUGUSTUS findings, irrespective of prior stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. Although aspirin may have some benefit in patients with prior stroke, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02415400

BELONGING TO AN IMPATIENT culture promising instant answers, often poorly equipped and overwhelmed, most people struggle to piece together their fragments of faith, knowledge, and experience as best they can. [...]

Supplemental Digital Content is available in the text.

Normally I do not respond to reviews, but since I respect Monthly Review so highly - indeed I have published in it - I must say a few words in [...]

The “burden” of atrial fibrillation (AF) detected by screening likely influences stroke risk, but the distribution of burden is not well described.

THE PROPHET ARMED: Trotsky 1879-1921. By Isaac Deutscher. Verso. 496 pp. Paper $20. THE PROPHET UNARMED: Trotsky 1921-1929. By Isaac Deutscher. Verso. 444 pp. Paper $20. THE PROPHET OUTCAST: Trotsky [...]

Presents several letters to the editor on socialism. Discussion on the enlightenment project of human equality in the United States; Effect of revolutions on socialism; Comparison of socialism with Marxism.

The article points out that U.S. atheists, agnostics and secularists could be a significant influence in the 2008 U.S. presidential election if they are able to become organized. U.S. Democratic candidate Barack Obama is courting the evangelical and Catholic vote, and is mentioning religion in his speeches. According to the author, Democrats have learned the importance of appealing to devout voters and have ignored secular voters. The author suggests that secularists need to get mobilized.

Society without God: What the Least Religious Nations Can Tell Us about Contentment By Phil Zuckerman (New York University Press, 2008) 227 pp.; $35.00 AS THE TIDE OF secular self-awareness [...]

1984 AND BEYOND: HOPE TODAY Is there reason to hope today? I first asked this--rhetorically, I thought--in 1975 in the aftermath of two watershed events, one personal with its political [...]

The Nation picks up its 'First Principles' series this week with a contribution from Ronald Aronson, who argues that the left should build a movement based on the values of [...]

Background:In AUGUSTUS, apixaban led to lower rates of bleeding and hospitalization than VKA, and aspirin caused more bleeding than placebo, in patients with AF and ACS and/or PCI treated with a P2Y12 inhibitor. We evaluated the safety and efficacy of different antithrombotic strategies by age in this population.Methods:Patients were stratified into 3 age groups: <65, 65-74, and ≥75 years. Outcomes of interest were adjudicated ISTH major or clinically relevant nonmajor (CRNM) bleeding, ISTH major bleeding, death or rehospitalization, and death or ischemic events. The treatment effects of apixaban vs. VKA and aspirin vs. placebo were assessed across age categories using Cox models.Results:Of 4614 patients, 1267 (27.5%) were <65, 1802 (39.0%) were 65-74, and 1545 (33.5%) were ≥75 years. All events, including bleeding, rehospitalization, and ischemic events, were more common with older age. Compared with VKA, apixaban was associated with lower rates of ISTH major or CRNM bleeding, ISTH major bleeding, and death or hospitalization, regardless of age (Fig). Apixaban was associated with greater absolute reduction in ISTH major bleeding than VKA in the older age groups, reflecting the higher bleeding risk in these groups. No differences were observed in rates of death or ischemic events between apixaban and VKA according to age. Patients who received aspirin had higher rates of bleeding than those receiving placebo in all age groups. Rates of death or rehospitalization and death or ischemic events were similar among patients receiving aspirin or placebo in different age categories.Conclusions:The safety and efficacy of apixaban compared with VKA was consistent with the overall trial findings, irrespective of age. Aspirin compared with placebo increased ISTH major or CRNM bleeding in all age groups. Our findings support the use of apixaban plus a P2Y12 inhibitor without aspirin as the standard therapy for this patient population, regardless of age.Figure:Outcomes by Age

The article explores the history of socialism. The first true democracy in the world, socialism would abolish classes, domination, and exploitation. Originated in the industrial revolution, the new society of plenty would eliminate the division of labor and permit the fullest possible individual development.

This article examines the resurgence of religion in the United States. It discusses comedian and talk show host Bill Maher's views about religion and the evangelicals, and Clarence Darrow and John Lennon's secular perspective. The article also comments on secularism, agnosticism, and atheism. It also explores the movement away from religion which reflected the Enlightenment conviction that humans could, and increasingly would, live on their own.

The unresolved conflict between Camus and Sartre over terrorism, violence and colonialism reflects some of today’s arguments over similar issues. Above all, the two men disagreed over how to overcome the structural violence of imperialism and colonialism and whether terrorism can ever be justified. The starting terms for the discussion appear in my Camus and Sartre: The Story of a Friendship and the Conflict That Ended It(Aronson 2004); this article goes on to explore the half-truth and half-blindness characteristic of each man on these issues. Today we might bring their insights together only by insisting on a coherent analysis that includes understanding both structural or systemic violence and revolutionary violence and terrorism. I appeal for judging all sides in contemporary conflicts by a single standard.

Several letters to the letter are presented in response to the article entitled "New Atheists," by Ronald Aronson, which appeared in the June 25, 2007 issue.

Presents letters to the editor of "The Nation" regarding articles found in previous issues of the journal. Response to the article "The Avenging Angel," regarding John Brown; Discussion of the article "The Other 1905 Revolution," regarding Joshua Foer's review of the reissue of the Born-Einstein letters; Response to a review of the book "Courting Conflict: The Israeli Military Court System in the West Bank and Gaza," by Lisa Hajjar; Discussion of the article "Tangled Up in Bob," regarding singer Bob Dylan; Discussion of the article "The Impermanent Revolution," regarding a biography of Leon Trotsky; Others.

Examines the current situation in South Africa. The release of Nelson Mandela from prison; The African National Congress (ANC) no longer banned; Legal, organized events of the ANC; F.W. De Klerk's dealings with the ANC; Optimism at Mandela's release giving way to bitterness; De Klerk and the Afrikaners; Prospects for creating a democratic culture; Socialism in South Africa; More.

Triggered activity induced by delayed afterdepolarizations has been suggested as a cellular mechanism for some arrhythmias. The development of triggered activity should be favored by conditions that increase myoplasmic Ca2and increase membrane resistance. A solution which could create these conditions was devised. After perfusion with normal Tyrode's solution, 24 trabeculae were exposed to the experimental solution. All preparations developed triggered activity after exposure to the experimental solution, 83 developed delayed afterdepolarizations before the onset of triggered activity, and triggered activity stopped in all trabeculae after reperfusion with normal Tyrode's solution. The interaction of ouabain, lidocaine, and three Ca2channel blockers with triggered activity induced by the experimental solution is described. Verapamil inhibited triggered activity but not underlying voltage oscillations, whereas nisoldipine and Mn2inhibited both triggered activity and voltage oscillations. Lidocaine did not inhibit afterdepolarizations or triggered activity. Exposure to ouabain for 10 min caused delayed afterdepolarizations but not triggered activity. Our results show that the experimental solution induced triggered activity, which was highly reliable and readily reversible. The high reproducibility of this activity enables the study of interactions of pharmacological agents with this triggered activity. This may contribute to the further understanding of the mechanism underlying some arrhythmias.

Canine cardiac Purkinje fibers exposed to Na-free solution containing 128 mM tetraethylammonium chloride and 16.2 mM Ca range from being spontaneously active to being quiescent and almost inexcitable according to the level of the resting potential. Quiescent fibers can become “spontaneously” active during the passage of a long depolarizing pulse and the rate of activity is increased with increased depolarization. Fibers already active show increased frequency of activity during passage of depolarizing pulses and show inhibition of activity when hyperpolarized. Fibers exposed to normal Tyrode's solution containing 0.125 mg/L of ouabain show two types of spontaneous activity. When the resting potential is about -90 mV ouabain-poisoned fibers show diastolic depolarization and rhythmicity of the kind characteristic of normal Purkinje fibers. If the resting potential is about -50 mV spontaneous activity also is seen, the action potentials have, however, very slow upstrokes and occur wholly in the range in which the rapid Na-dependent upstroke is inactivated. Current pulses can switch the fiber from either form of activity to the other.

Abstract: The effects of amrinone on conduction in the intact canine heart were studied. Intracardiac His‐electrode catheter recordings were used to measure the functional refractory period (FRP) of the AV node and conduction time through the AV node (A2H2interval) and in the His‐Purkinje system (H2V2interval). Amrinone (2.5 to 10 mg/kg) shortened the FRP and A2H2in a dose‐dependent manner but had no significant effect on H2V2. In hearts where AV conduction was depressed by treatment with verapamil, propranolol, or ouabain, amrinone partially reversed this depression. Amrinone also shortened the recovery time of spontaneous sinoatrial (SA) node activity following a train of rapid atrial stimulation. This effect was also observed after depression of SA nodal recovery with verapamil, propranolol, or ouabain. These results indicate that amrinone enhances AV conduction and SA nodal activity in the normal heart and may favorably influence depressed AV conduction and SA nodal activity induced by a variety of cardioactive agents.

The present study explored the possibility that an alteration in the transmembrane calcium current (I_Ca), through its ability to modulate Ca²⁺ release from the sarcoplasmic reticulum, could contribute to the depressed peak [Ca²⁺]_i we previously observed in hypertrophied failing myocardium. Whole-cell patch clamp was used to measure I_Ca in single guinea pig ventricular myocytes isolated from hearts of normal guinea pigs and from guinea pig hearts in which hypertrophy and failure were induced by gradually developing left ventricular pressure overload subsequent to ascending aortic banding of young animals. Membrane capacitance (C_m) was significantly greater, and I_Ca, normalized for C_m was significantly lower in myocytes from hypertrophied failing hearts. Myocytes from hypertrophied failing hearts did not differ significantly from normal myocytes in terms of the voltage-dependence of the activation variable (d) of I_Ca (except at - 30 mV), the time course of removal of inactivation of I_Ca, and the time constant of decay of I_Ca. Measurement of the voltage dependence of the inactivation variable (f) of ICa showed that significantly more steady-state inactivation was present at 0, -10, and -20 mV in myocytes from hypertrophied failing hearts. Multiple regression analysis of all data indicated that I_Ca density decreased with increasing myocyte membrane area (as reflected by Cm) irrespective of any specific effects of hypertrophy and heart failure. We conclude that I_Ca, normalized for C_m, is significantly reduced in myocytes isolated from hypertrophied failing hearts, probably by a process associated with increased cell size, per se. Copyright 1994, 1999 Academic Press

It is suggested that torsades de pointes may be only one of a group of arrhythmias that are characterized by being pause induced or bradycardia induced. A distinction is made between the cause of the “twisting of the points” and the cause of the action potentials that initiate and sustain the tachycardia. It is pointed out that torsades de pointes and other pause-induced arrhythmias share many features with rhythmic activity arising from early afterdepolarizations. Both are seen after pauses or at low rates, both are seen in quinidine intoxication, and both are seen in hypokalemia. The short-long-short sequence that is seen in torsades de pointes and certain other pauseor bradycardia-induced arrhythmias can be fully explained by the behavior of rhythmic activity initiated and sustained by early afterdepolarizations, as can the abrupt onset and termination of pause-induced arrhythmias and their tendency to show initial warming up and terminal slowing down.

Propagated action potentials can be obtained in canine cardiac Purkinje fibers exposed to Na-free solutions containing no inorganic cation other than Ca and K. Essentially similar action potentials are obtained if Na is replaced by tetraethylammonium (TEA), tetramethylammonium (TMA), or choline. In a solution containing 128 mM TEA and 16.2 mM Ca the characteristics of these electrical responses were: maximum diastolic potential, -59 ± 3.3 mV; overshoot, 20 ± 6.8 mV; maximum upstroke velocity, 3.7 ± 2.3 V/s; conduction velocity, 0.1 m/s; and action potential duration, 360 ± 45 ms. The magnitude of the overshoot varied with log Cao with a slope of about 30 mV/10-fold concentration change. The upstroke velocity was an approximately linear function of Cao. The active response was greatly diminished or abolished by Mn and D-600 but was unaffected by tetrodotoxin. These Ca-dependent responses appeared in a region of transmembrane potential (about -50 mV) at which the rapid Na-dependent upstroke is abolished even when Na is present.

Discusses the friendship between French philosophers Albert Camus and Jean-Paul Sartre. Reaction of Camus to a book review which appeared in Sartre's 'Les Temps modernes' journal; Basis of their friendship; Camus' disavowal of the existentialism and the variety of revolutionary politics championed by Sartre; Contemporary works which illuminate their friendship,which ended in the early 1950s; Their respective views on the Algerian question; How their work may be considered in the 21st century.

The author discusses the writings, achievements, and revolutionary actions of writer Jean-Paul Sartre. He is critical that Sartre's period of alignment with communism and attitude towards violence are among the two specific features of his writings. He also explores Sartre's embrace of revolutionary and progressive violence aligned with the French Communist Party and the Soviet Union.

Chronic hypophosphataemia is associated with reversible depression in myocardial performance of the intact heart. To define the basis for this, we studied the mechanical and electrical properties of isolated left ventricular papillary muscles from rats with 6 weeks of phosphorus depletion (P6), 6 weeks of phosphorus repletion and age-matched controls (C). Muscles were perfused with Tyrodes solution (Ca2+ = 2.4 mmol·litre–1, K+ = 4.0 mmol·litre–1, dextrose = 5.5 mmol·litre–1) and driven at 0.1 Hz. P6 muscles had slowed isometric relaxation (T1/2R), depressed velocity of shortening and relaxation and prolongation of the transmembrane action potential to 75% of complete repolarisation. These results suggest that the slow relaxation phase may be the result of the prolonged APD₇₅ and that the depressed myocardial performance in the intact heart may be based on impaired relaxation and reduced the velocity of shortening associated with hypophosphataemia. This view is supported by our finding that these alterations are reversible with phosphate repletion.