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...

Background-Permanent pacemaker (PPM) requirement is a recognized complication of transcatheter aortic valve implantation. We assessed the UK incidence of permanent pacing within 30 days of CoreValve implantation and formulated an anatomic and electrophysiological model. Methods and Results-Data from 270 patients at 10 centers in the United Kingdom were examined. Twenty-five patients (8%) had preexisting PPMs; 2 patients had incomplete data. The remaining 243 were 81.3Ϯ6.7 years of age; 50.6% were male. QRS duration increased from 105Ϯ23 to 135Ϯ29 milliseconds (PϽ0.01). Left bundle-branch block incidence was 13% at baseline and 61% after the procedure (PϽ0.001). Eighty-one patients (33.3%) required a PPM within 30 days.Rates of pacing according to preexisting ECG abnormalities were as follows: right bundle-branch block, 65.2%; left bundle-branch block, 43.75%; normal QRS, 27.6%. Among patients who required PPM implantation, the median time to insertion was 4.0 days (interquartile range, 2.0 to 7.75 days). Multivariable analysis revealed that periprocedural atrioventricular block (odds ratio, 6.29; 95% confidence interval, 3.55 to 11.15), balloon predilatation (odds ratio, 2.68; 95% confidence interval, 2.00 to 3.47), use of the larger (29 mm) CoreValve prosthesis (odds ratio, 2.50; 95% confidence interval, 1.22 to 5.11), interventricular septum diameter (odds ratio, 1.18; 95% confidence interval, 1.10 to 3.06), and prolonged QRS duration (odds ratio, 3.45; 95% confidence interval, 1.61 to 7.40) were independently associated with the need for PPM. Conclusion-One third of patients undergoing a CoreValve transcatheter aortic valve implantation procedure require a PPM within 30 days. Periprocedural atrioventricular block, balloon predilatation, use of the larger CoreValve prosthesis, increased interventricular septum diameter and prolonged QRS duration were associated with the need for PPM. (Circulation. 2011;123:951-960.)Key Words: aortic stenosis Ⅲ electrocardiography Ⅲ pacemakers Ⅲ transcatheter aortic valve Ⅲ transcatheter aortic valve implantation A ortic stenosis (AS) is the most common valvular disease in Europe, 1,2 and age is a significant factor in its natural history. 2 Severe AS occurs in 2% to 4% of adults Ͼ65 years of age. 3,4 Current guidelines recommend aortic valve replacement (AVR) surgery for these patients when they become symptomatic or develop impaired left ventricular systolic function with an ejection fraction Ͻ50%. 5,6 However, the aging population generates greater numbers of patients with severe AS and significant comorbidities, 3 prohibitively raising their perioperative risks for surgical AVR. Since the first successful implant in 2002,7 transcatheter aortic valve implantation (TAVI) has become an increasingly common technology in this cohort. The initial surveillance has been encouraging with respect to procedural success, improvement in quality of life, and short-term and medium-term mortality. 8 -10 Clinical Perspective on p 960Aortic valvular disease is itself associated with cond...

Many patients who are prescribed low-dose EC aspirin for secondary prevention of cardiovascular events have persistent uninhibited platelet COX activity. Younger and heavier patients and those with a previous MI are most likely to have an inadequate response to treatment.

Summary.  Background: Aspirin (acetylsalicylic acid) irreversibly inhibits platelet cyclooxygenase (COX)‐1, the enzyme that converts arachidonic acid (AA) to the potent platelet agonist thromboxane (TX) A2. Despite clear benefit from aspirin in patients with cardiovascular disease (CAD), evidence of heterogeneity in the way individuals respond has given rise to the concept of ‘aspirin resistance.’Aims: To evaluate the hypothesis that incomplete suppression of platelet COX as a consequence of variation in the COX‐1 gene may affect aspirin response and thus contribute to aspirin resistance. Patients and methods: Aspirin response, determined by serum TXB2 levels and AA‐induced platelet aggregation, was prospectively studied in patients (n = 144) with stable CAD taking aspirin (75–300 mg). Patients were genotyped for five single nucleotide polymorphisms in COX‐1 [A‐842G, C22T (R8W), G128A (Q41Q), C644A (G213G) and C714A (L237M)]. Haplotype frequencies and effect of haplotype on two platelet phenotypes were estimated by maximum likelihood. The four most common haplotypes were considered separately and less common haplotypes pooled. Results: COX‐1 haplotype was significantly associated with aspirin response determined by AA‐induced platelet aggregation (P = 0.004; 4 d.f.). Serum TXB2 generation was also related to genotype (P = 0.02; 4 d.f.). Conclusion: Genetic variability in COX‐1 appears to modulate both AA‐induced platelet aggregation and thromboxane generation. Heterogeneity in the way patients respond to aspirin may in part reflect variation in COX‐1 genotype.