BACKGROUND Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications. METHODS This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. FINDINGS Between March 12, 2013, and May 10, 2016, we ; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043). INTERPRETATION Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding. FUNDING Bayer AG. Methods This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, i...

Morphology (PREDICTION) Study were to determine the role of local hemodynamic and vascular characteristics in coronary plaque progression and to relate plaque changes to clinical events. Methods and Results-Vascular profiling, using coronary angiography and intravascular ultrasound, was used to reconstruct each artery and calculate endothelial shear stress and plaque/remodeling characteristics in vivo. Three-vessel vascular profiling (2.7 arteries per patient) was performed at baseline in 506 patients with an acute coronary syndrome treated with a percutaneous coronary intervention and in a subset of 374 (74%) consecutive patients 6 to 10 months later to assess plaque natural history. Each reconstructed artery was divided into sequential 3-mm segments for serial analysis. One-year clinical follow-up was completed in 99.2%. Symptomatic clinical events were infrequent: only 1 (0.2%) cardiac death; 4 (0.8%) patients with new acute coronary syndrome in nonstented segments; and 15 (3.0%) patients hospitalized for stable angina. Increase in plaque area (primary end point) was predicted by baseline large plaque burden; decrease in lumen area (secondary end point) was independently predicted by baseline large plaque burden and low endothelial shear stress. Large plaque size and low endothelial shear stress independently predicted the exploratory end points of increased plaque burden and worsening of clinically relevant luminal obstructions treated with a percutaneous coronary intervention at follow-up. The combination of independent baseline predictors had a 41% positive and 92% negative predictive value to predict progression of an obstruction treated with a percutaneous coronary intervention. Conclusions-Large plaque burden and low local endothelial shear stress provide independent and additive prediction to identify plaques that develop progressive enlargement and lumen narrowing. Clinical Trial Registration-URL: http:www.//clinicaltrials.gov. Unique Identifier: NCT01316159. (Circulation. 2012;126:172-181.) Key Words: atherosclerosis Ⅲ endothelium Ⅲ natural history Ⅲ shear stress A therosclerosis is a systemic disease with focal and eccentric manifestations. 1 In a patient with coronary artery disease (CAD) and systemic risk factors, each coronary lesion progresses, regresses, or remains quiescent in an independent manner, 2 indicating that local vascular factors must be a major determinant responsible for the behavior of individual plaques. Editorial see p 161 Clinical Perspective on p 181The vascular endothelium is in a unique and pivotal position to respond to the extremely dynamic forces acting on the vessel wall because of the complex 3-dimensional (3D) Received January 27, 2012; accepted May 16, 2012. Identification of an early coronary atherosclerotic plaque likely to acquire high-risk characteristics and precipitate a new coronary event may allow for development of preemptive strategies to avert adverse events. The recent Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PR...

Candesartan therapy significantly reduces cardiovascular events and mortality in patients on chronic maintenance haemodialysis and therefore improves the prognosis of these patients.

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We propose a new methodology for the valuation problem of financial contingent claims when the underlying asset prices follow a general class of continuous Itô processes. Our method can be applied to a wide range of valuation problems including complicated contingent claims associated with the term structure of interest rates. We illustrate our method by giving two examples: the valuation problems of swaptions and average (Asian) options for interest rates. Our method gives some explicit formulas for solutions, which are sufficiently numerically accurate for practical purposes in most cases. The continuous stochastic processes for spot interest rates and forward interest rates are not necessarily Markovian nor diffusion processes in the usual sense; nevertheless our approach can be rigorously justified by the Malliavin-Watanabe Calculus in stochastic analysis.

limited ability to modify the deep calcification that reduces vessel compliance and restricts vessel expansion during stent implantation. 5,6 Periprocedural complication rates, including perforation, slow flow, and periprocedural myocardial infarction (MI), are significantly higher with atherectomy than with balloon-based therapies. 7-11 Additionally, major adverse cardiac event (MACE) rates with atherectomy are suboptimal, ranging from 10.4% to 15.0% at 30 days and from 16.9% to 24.2% between 9 and 12 months. 7,12,13 C alcified coronary lesions are increasingly prevalent in patients with advancing age, diabetes mellitus, and chronic kidney disease. 1 Between 38% and 73% of coronary lesions display calcification on angiography and intravascular ultrasound, respectively. 2 Coronary artery calcification is associated with inferior clinical outcomes in the general population, 3 as well as in patients undergoing percutaneous revascularization. 4 Adjunctive therapies, such as atherectomy, are often used in an attempt to promote stent expansion in the presence of heavy calcium, yet suffer from limitations. Rotational and orbital atherectomy selectively ablate superficial calcium, which facilitates stent delivery, but both techniques have Editorial p 834

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This paper derives asymptotic expansion formulas for option prices and implied volatilities as well as the density of the underlying asset price in multi-dimensional stochastic volatility models. In particular, the integration-byparts formula in Malliavin calculus and the push-down of Malliavin weights are effectively applied. We provide an expansion formula for generalized Wiener functionals and closed-form approximation formulas in stochastic volatility environment. In addition, we present applications of the general formula to expansions of option prices for the shifted log-normal model with stochastic volatility. Moreover, with some results of Malliavin calculus in jump-type models, we derive an approximation formula for the jump-diffusion model in stochastic volatility environment. Some numerical examples are also shown.