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Background— Patients with acute coronary syndromes and history of stroke or transient ischemic attack (TIA) have an increased rate of recurrent cardiac events and intracranial hemorrhages. Methods and Results— We evaluated treatment effects of ticagrelor versus clopidogrel in patients with acute coronary syndrome with and without a history of prior stroke or TIA in the PLATelet inhibition and patient Outcomes (PLATO) trial. Of the 18 624 randomized patients, 1152 (6.2%) had a history of stroke or TIA. Such patients had higher rates of myocardial infarction (11.5% versus 6.0%), death (10.5% versus 4.9%), stroke (3.4% versus 1.2%), and intracranial bleeding (0.8% versus 0.2%) than patients without prior stroke or TIA. Among patients with a history of stroke or TIA, the reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus clopidogrel was consistent with the overall trial results: 19.0% versus 20.8% (hazard ratio, 0.87; 95% confidence interval, 0.66–1.13; interaction P =0.84) and 7.9% versus 13.0% (hazard ratio, 0.62; 95% confidence interval, 0.42–0.91). The overall PLATO-defined bleeding rates were similar: 14.6% versus 14.9% (hazard ratio, 0.99; 95% confidence interval, 0.71–1.37), and intracranial bleeding occurred infrequently (4 versus 4 cases, respectively). Conclusions— Patients with acute coronary syndrome with a prior history of ischemic stroke or TIA had higher rates of clinical outcomes than patients without prior stroke or TIA. However, the efficacy and bleeding results of ticagrelor in these high-risk patients were consistent with the overall trial population, with a favorable clinical net benefit and associated impact on mortality. Clinical Trial Registration— URL: http://www.clinicatrials.gov . Unique identifier: NCT00391872.

Background: In Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE), apixaban (vs. warfarin) significantly reduced stroke, death, and major bleeding in 18,201 patients with atrial fibrillation (AF). We assessed the cost-effectiveness of apixaban vs. warfarin from the perspective of the US health care system. Methods: Resource use (service dates, intensive care days, days on drug) was obtained from ARISTOTLE case report forms. Unit costs for components of hospital-based care of AF patients were estimated with generalized linear models using the national Premier database. Daily cost of anticoagulants was based on current acquisition cost (apixaban=$9.49; warfarin=$0.09) for 10 years, after which time apixaban was valued at projected costs of generic substitutes ($1.89). Physician services and anticoagulant monitoring were valued using Medicare fees. Within-trial costs were estimated using inverse probability weighting for differential follow-up. Survival was modeled with patient-level ARISTOTLE data using a two stage approach that combined a time-based Cox model for the within-trial period and an age-based Cox model for extrapolation. Uncertainty surrounding estimates of cost, life expectancy and cost/per life year gained was characterized with bootstraps and sensitivity analyses. Results: After 2 years, costs in the US cohort (n=3417) excluding study drug and monitoring averaged $306 less with apixaban than warfarin ($6257 vs. $6563). This difference was more than offset by higher apixaban anticoagulation costs ($6160 vs. $1181), resulting in an overall increase of $4673/patient. Over a lifetime, gains in life expectancy with apixaban (9.92 vs. 9.69; p Conclusions: Reductions in mortality, stroke, and bleeding observed in ARISTOTLE translate to significant increases in life expectancy. At an estimated ICER of $76,365/life year gained, apixaban is a cost-effective alternative to warfarin.

Abstract An antiplatelet effect of magnesium has been demonstrated in vitro and ex vivo, and this effect may be advantageous in patients with acute myocardial infarction to inhibit reocclusion after coronary angioplasty or thrombolysis. We investigated the antithrombotic in vivo effect of intravenous magnesium in a placebo-controlled, blinded study in 46 male Wistar rats. Thrombus formation was induced by standardized arteriotomy of the femoral artery and partial inversion of the vessel wall to produce a thrombogenic area. The vessel was transilluminated and visualized dynamically by in vivo microscopy. Thrombus area was measured every minute for 30 minutes after removal of the vessel clamp by image analysis techniques, and the number of visible emboli was registered. Animals were randomized into three groups: groups 1 and 2 received saline (control group, n=15) or MgSO 4 (Mg-early group, n=15), respectively, during the entire infusion period. In group 3 intravenous saline was given during preparation of the arteriotomy followed by infusion of MgSO 4 (Mg-late group, n=16) from 10 minutes after removal of the vessel clamp. Thrombus area was significantly reduced by 75% in the Mg-early group ( P 4 significantly reduced thrombus formation in vivo but only when it was given before reperfusion. The antithrombotic effect of magnesium may be utilized in patients with acute myocardial infarction to reduce the rate of reocclusion. Magnesium infusion may also be of value in elective arterial angioplasty, but this option has not been investigated in clinical trials. However, correct timing of magnesium administration is critical to obtain an efficient antithrombotic effect.

Human detrusor strips were obtained from patients undergoing reimplantation of ureters because of reflux, transvesical prostatectomy, or cysto-urethrectomy en bloc because of bladder malignancy. The strips were electrically stimulated. A frequency-dependent contractant response was obtained that was potentiated by physostigmine and abolished by tetrodotoxin. The maximum response approximately equaled that of acetylcholine in a maximum concentration. In most bladder preparations from patients without known functional bladder disturbances, atropine (0.01 to 0.1 microM) had a marked inhibitory effect, and at concentrations exceeding 1 microM the blockade was complete. In strips obtained from patients undergoing transvesical prostatectomy, and who also had a cystometrically verified unstable bladder, there was a varying degree of atropine resistance, with some preparations showing a 50 per cent resistance to atropine. Prazosin, phentolamine, yohimbine, guanethidine, clonidine, and noradrenaline had no consistent effects on the electrically induced bladder contraction. Nifedipine and nimodipine caused a maximum of 65 per cent inhibition of the response. Addition of nimodipine to atropine-resistant strips when maximum atropine inhibition had been reached abolished the contractions. Omitting calcium from the bath solution rapidly abolished the electrically induced contraction. It is suggested that in the normal human bladder the contraction induced by electrical stimulation is mainly atropine sensitive. However, in the functionally disturbed bladder, part of the bladder contraction is atropine resistant, a finding that may have clinical implications.