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Background. Although an uncommon disease, male breast cancer (MBC) will be responsible for 300 deaths in 1993 in the United States. Because of the high rate of estrogen receptor positivity in males, adjuvant hormonal therapy with tamoxifen in the adjuvant setting has been used widely. Little is known about the side effects of this estrogen receptor blocker in males. Methods. The authors evaluated the side effects of adjuvant tamoxifen treatment in 24 patients (19 of whom were estrogen receptor positive) treated at the authors' institution between 1990 and 1993. Results. Fifteen (62.5%) patients reported at least one side effect. The most common side effect was a decrease in libido, which occurred in 7 (29.2%) patients; followed by weight gain, which occurred in 6 (25%) patients; hot flashes, which occurred in (5 20.8%); mood alterations, which occurred in 5 (20.8%); depression, which occurred in 4 (16.6%); insomnia, which occurred in 3 (12.5%); and deep venous thrombosis, which occurred in 1 (4.2%). Five (20.8%) patients terminated treatment with tamoxifen in less than 1 year because of these side effects. Two of these patients had decreased libido, two had hot flashes, and one suffered deep venous thrombosis. Conclusions. In contrast to female breast cancer patients, who have a 4% attrition rate to adjuvant tamoxifen treatment, MBC patients have a 20.8% attrition rate related to side effects of tamoxifen treatment.

Background and Purpose: It is unknown when to start anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF). Early anticoagulation may prevent recurrent infarctions but may provoke hemorrhagic transformation as AF strokes are typically larger and hemorrhagic transformation-prone. Later anticoagulation may prevent hemorrhagic transformation but increases risk of secondary stroke in this time frame. Our aim was to compare early anticoagulation with apixaban in AF patients with stroke or transient ischemic attack (TIA) versus warfarin administration at later intervals. Methods: AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) was an open-label, randomized controlled trial comparing the safety of early use of apixaban at day 0 to 3 for TIA, day 3 to 5 for small-sized AIS (<1.5 cm), and day 7 to 9 for medium-sized AIS (≥1.5 cm, excluding full cortical territory), to warfarin, in a 1:1 ratio at 1 week post-TIA, or 2 weeks post-AIS. Results: Although AREST ended prematurely after a national guideline focused update recommended direct oral anticoagulants over warfarin for AF, it revealed that apixaban had statistically similar yet generally numerically lower rates of recurrent strokes/TIA (14.6% versus 19.2%, P =0.78), death (4.9% versus 8.5%, P =0.68), fatal strokes (2.4% versus 8.5%, P =0.37), symptomatic hemorrhages (0% versus 2.1%), and the primary composite outcome of fatal stroke, recurrent ischemic stroke, or TIA (17.1% versus 25.5%, P =0.44). One symptomatic intracerebral hemorrhage occurred on warfarin, none on apixaban. Five asymptomatic hemorrhagic transformation occurred in each arm. Conclusions: Early initiation of anticoagulation after TIA, small-, or medium-sized AIS from AF does not appear to compromise patient safety. Potential efficacy of early initiation of anticoagulation remains to be determined from larger pivotal trials. REGISTRATION: URL: https://www.clinicaltrials.gov/ ; Unique identifier: NCT02283294.

In clinical practice, reducing the burden of persistent atrial fibrillation by pharmacological means is challenging. We explored if blocking the background and the acetylcholine-activated inward rectifier potassium currents (IK1 and IKACh) could be antiarrhythmic in persistent atrial fibrillation. We thus tested the hypothesis that blocking IK1 and IKACh with chloroquine decreases the burden of persistent atrial fibrillation. We used patch clamp to determine the IC50 of IK1 and IKACh block by chloroquine and molecular modeling to simulate the interaction between chloroquine and Kir2.1 and Kir3.1, the molecular correlates of IK1 and IKACh. We then tested, as a proof of concept, if oral chloroquine administration to a patient with persistent atrial fibrillation can decrease the arrhythmia burden. We also simulated the effects of chloroquine in a 3D model of human atria with persistent atrial fibrillation. In patch clamp the IC50 of IK1 block by chloroquine was similar to that of IKACh. A 14-day regimen of oral chloroquine significantly decreased the burden of persistent atrial fibrillation in a patient. Mathematical simulations of persistent atrial fibrillation in a 3D model of human atria suggested that chloroquine prolonged the action potential duration, leading to failure of reentrant excitation, and the subsequent termination of the arrhythmia. The combined block of IK1 and IKACh can be a targeted therapeutic strategy for persistent atrial fibrillation.

Background: Optimal timing to initiate anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF) is currently unknown. Compared to other stroke etiologies, AF typically provokes larger infarct volumes and greater concern of hemorrhagic transformation, so seminal randomized trials waited weeks to months to begin anticoagulation after initial stroke. Subsequent data are limited and non-randomized. Guidelines suggest anticoagulation initiation windows between 3 and 14 days post-stroke, with Class IIa recommendations, and level of evidence B in the USA and C in Europe.Aims: This open-label, parallel-group, multi-center, randomized controlled trial AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) is designed to evaluate the safety and efficacy of early anticoagulation, based on stroke size, secondary prevention of ischemic stroke, and risks of subsequent hemorrhagic transformation.Methods: Subjects are randomly assigned in a 1:1 ratio to receive early apixaban at day 0–3 for transient ischemic attack (TIA), 3–5 for small-sized AIS (<1.5 cm), and 7–9 for medium-sized AIS (1.5 cm or greater but less than a full cortical territory), or warfarin at 1 week post-TIA or 2 weeks post-stroke. Large AISs are excluded.Study Outcomes: Primary: recurrent ischemic stroke, TIA, and fatal stroke; secondary: intracranial hemorrhage (ICH); hemorrhagic transformation (HT) of ischemic stroke; cerebral microbleeds (CMBs); neurologic disability [e.g., modified Rankin Scores (mRS), National Institutes of Health Stroke Scale (NIHSS), Stroke Specific Quality of Life scale (SS-QOL)]; and cardiac biomarkers [e.g., AF burden, transthoracic echo (TTE)/transesophageal echo (TEE) abnormalities].Sample Size Estimates: Enrollment goal was 120 for 80% power (two-sided type I error rate of 0.05) to detect an absolute risk reduction of 16.5% postulated to occur with apixaban in the primary composite outcome of fatal stroke/recurrent ischemic stroke/TIA within 180 days. Enrollment was suspended at 91 subjects in 2019 after a focused guideline update recommended direct oral anticoagulants (DOACs) over warfarin in AF, excepting valvular disease (Class I, level of evidence A).Discussion: AREST will offer randomized controlled trial data about timeliness and safety of anticoagulation in AIS patients with AF.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02283294.