BACKGROUND Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear. METHODS In an international trial with a two-by-two factorial design, we randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y 12 inhibitor to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events. RESULTS Enrollment included 4614 patients from 33 countries. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P = 0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group. CONCLUSIONS In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y 12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both. (Funded by Bristol-Myers Squibb and Pfizer; AUGUSTUS ClinicalTrials.gov number, NCT02415400.
Background: In AUGUSTUS (Open-Label, 2×2 Factorial, Randomized, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs Vitamin K Antagonist and Aspirin vs Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention), patients with atrial fibrillation and a recent acute coronary syndrome and those undergoing percutaneous coronary intervention had less bleeding with apixaban than vitamin K antagonist (VKA) and with placebo than aspirin. However, the number of ischemic events was numerically higher with placebo. The aim of this analysis is to assess the tradeoff of risk (bleeding) and benefit (ischemic events) over time with apixaban versus VKA and aspirin versus placebo. Methods: In AUGUSTUS, 4614 patients with atrial fibrillation and recent acute coronary syndrome or percutaneous coronary intervention on a P2Y 12 inhibitor were randomized to blinded aspirin or placebo and to open-label apixaban or VKA for 6 months. In a post hoc analysis, we compared the risk of 3 composite bleeding outcomes and 3 composite ischemic outcomes from randomization through 30 days and from 30 days to 6 months with apixaban and VKA and with aspirin and placebo. Results: Compared with VKA, apixaban had either a lower or a similar risk of bleeding and ischemic outcomes from randomization to 30 days and from 30 days to 6 months. From randomization to 30 days, aspirin caused more severe bleeding (absolute risk difference, 0.97% [95% CI, 0.23–1.70]) and fewer severe ischemic events (absolute risk difference, −0.91% [95% CI, −1.74 to −0.08]) than placebo. From 30 days to 6 months, the risk of severe bleeding was higher with aspirin than placebo (absolute risk difference, 1.25% [95% CI, 0.23–2.27]), whereas the risk of severe ischemic events was similar (absolute risk difference, −0.17% [95% CI, −1.33 to 0.98]). Conclusions: In patients with atrial fibrillation and recent acute coronary syndrome or percutaneous coronary intervention receiving a P2Y 12 inhibitor, apixaban is preferred over VKA. Use of aspirin immediately and for up to 30 days results in an equal tradeoff between an increase in severe bleeding and a reduction in severe ischemic events. After 30 days, aspirin continues to increase bleeding without significantly reducing ischemic events. These results inform shared, patient-centric decision making on the ideal duration of the use of aspirin after an acute coronary syndrome or percutaneous coronary intervention in patients with atrial fibrillation receiving oral anticoagulation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02415400.
The effect of verapamil on normal sodium (Na)-dependent and slow calcium (Ca)-dependent action potentials recorded from canine cardiac Purkinje fibers was studied. The Ca-dependent slow response was obtained in fibers exposed to solutions in which all NaCl was replaced by tetraethylammonium chloride and in which Ca ranged from 4 mM to 16.2 mM. Verapamil (0.25-2 mg/liter) had little or no effect on the upstroke of the normal action potential, but such concentrations of verapamil suppressed rhythmic activity and depressed excitability in fibers that showed Ca-dependent slow responses. Spontaneous activity and rhythmic activity evoked by long depolarizing pulses were depressed. Verapamil decreased the amplitude and the upstroke velocity and shifted the threshold potential toward zero in fibers that showed Ca-dependent slow responses. The effectiveness of verapamil varied with the level of Ca; 0.25 mg/liter of verapamil was as effective in suppressing activity in fibers exposed to 4 mM Ca as was 2 mg/liter of verapamil in fibers exposed to 16.2 mM Ca. Although verapamil did not alter the upstroke of the normal Nadependent action potential, it did depress the plateau and prolong the action potential of fibers exposed to normal Tyrode's solution.KEY WORDS calcium blocking drugs antiarrhythmic drugs AV node D-600 nodal tachycardia cardiac arrhythmias calcium and cardiac action potential reentrant arrhythmias SA node A: Action potential of a Purkinje fiber exposed to normal Tyrode's solution. B: Upstroke at a fast sweep speed of an action potential in a fiber exposed to normal Tyrode's solution. Exposure to 0.5 mgjliter of verapamil ctmnged the course of repolarization (C) witfwut clianging tlie upstroke (D). Vertical calibrations are 20 mv; horizontal calibrations are 50 msec in A and C and 0.2 msec in B and D.
The early afterdepolarization, which is an interruption of repolarization, can evoke a second upstroke or a salvo of action potentials. It is suggested that the electrophysiological characteristics of the early afterdepolarization can produce a lengthening of the QT interval and that the second upstroke and salvo of activity that may follow, it can explain many features of torsade de pointes and of certain other ventricular tachycardias. The early afterdepolarization, torsade de pointes, and repetitive monomorphic idiopathic ventricular tachycardia are all induced by bradycardia or by a preceding long RR interal. The R-on-T phenomenon is also discussed.
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