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Patients who had received a drug-eluting stent and then dual antiplatelet therapy for 12 months were randomly assigned to 18 more months of therapy or aspirin alone. Continued therapy resulted in lower rates of stent thrombosis and major adverse cardiovascular events but more bleeding. Millions of patients worldwide undergo coronary stenting each year for the treatment of ischemic heart disease. 1 , 2 Although drug-eluting stents reduce the rate of restenosis as compared with bare-metal stents, there is concern that drug-eluting stents may be associated with a risk of stent thrombosis beyond 1 year after treatment. 3 Stent thrombosis is rare, yet it is frequently associated with myocardial infarction and may be fatal. 3 Furthermore, ischemic events, such as myocardial infarction, stroke, or death from cardiovascular causes, that are unrelated to the treated coronary lesion may also occur beyond 1 year. 4 , 5 The use of dual antiplatelet therapy . . .

In this trial, 14,264 patients with atrial fibrillation were randomly assigned to receive either rivaroxaban or warfarin. In a per-protocol, as-treated analysis, rivaroxaban was noninferior to warfarin with respect to the primary end point of stroke or systemic embolism. Atrial fibrillation is associated with an increase in the risk of ischemic stroke by a factor of four to five 1 and accounts for up to 15% of strokes in persons of all ages and 30% in persons over the age of 80 years. 2 The use of vitamin K antagonists is highly effective for stroke prevention in patients with nonvalvular atrial fibrillation and is recommended for persons at increased risk. 3 – 5 However, food and drug interactions necessitate frequent coagulation monitoring and dose adjustments, requirements that make it difficult for many patients to use such drugs in clinical practice. 6 – 8 Rivaroxaban is . . .

The risk of venous thromboembolism is high after total hip arthroplasty and could persist after hospital discharge. Our aim was to compare the use of rivaroxaban for extended thromboprophylaxis with short-term thromboprophylaxis with enoxaparin. 2509 patients scheduled to undergo elective total hip arthroplasty were randomly assigned, stratified according to centre, with a computer-generated randomisation code, to receive oral rivaroxaban 10 mg once daily for 31–39 days (with placebo injection for 10–14 days; n=1252), or enoxaparin 40 mg once daily subcutaneously for 10–14 days (with placebo tablet for 31–39 days; n=1257). The primary efficacy outcome was the composite of deep-vein thrombosis (symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism, and all-cause mortality up to day 30–42. Analyses were done in the modified intention-to-treat population, which consisted of all patients who had received at least one dose of study medication, had undergone planned surgery, and had adequate assessment of thromboembolism. This study is registered at ClinicalTrials.gov, number NCT00332020. The modified intention-to-treat population for the analysis of the primary efficacy outcome consisted of 864 patients in the rivaroxaban group and 869 in the enoxaparin group. The primary outcome occurred in 17 (2·0%) patients in the rivaroxaban group, compared with 81 (9·3%) in the enoxaparin group (absolute risk reduction 7·3%, 95% CI 5·2–9·4; p<0·0001). The incidence of any on-treatment bleeding was much the same in both groups (81 [6·6%] events in 1228 patients in the rivaroxaban safety population vs 68 [5·5%] of 1229 patients in the enoxaparin safety population; p=0·25). Extended thromboprophylaxis with rivaroxaban was significantly more effective than short-term enoxaparin plus placebo for the prevention of venous thromboembolism, including symptomatic events, in patients undergoing total hip arthroplasty. Bayer HealthCare AG, Johnson & Johnson Pharmaceutical Research and Development LLC.

In patients with acute coronary syndromes, low doses of rivaroxaban were effective in reducing the primary end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban also reduced overall mortality, although there was more bleeding. After an acute coronary syndrome, patients remain at risk for recurrent cardiovascular events despite standard medical therapy, including long-term antiplatelet therapy with aspirin and an adenosine diphosphate–receptor inhibitor. This risk may be related in part to excess thrombin generation that persists beyond the acute presentation in such patients. 1 As a result, there has been interest in evaluating the role of oral anticoagulants after an acute coronary syndrome. Improved cardiovascular outcomes were reported for patients who were treated with the anticoagulant warfarin in addition to aspirin. 2 However, widespread use of long-term warfarin in such patients has been limited by challenges associated . . .

Aims/hypothesis The aim of this work was to evaluate the efficacy and safety of canagliflozin vs placebo and sitagliptin in patients with type 2 diabetes who were being treated with background metformin. Methods This randomised, double-blind, four-arm, parallel-group, Phase 3 study was conducted at 169 centres in 22 countries between April 2010 and August 2012. Participants ( N  = 1,284) with type 2 diabetes aged ≥18 and ≤80 years who had inadequate glycaemic control (HbA 1c ≥7.0% [53 mmol/mol] and ≤10.5% [91 mmol/mol]) on metformin therapy received canagliflozin 100 mg or 300 mg, sitagliptin 100 mg, or placebo ( n  = 368, 367, 366, 183, respectively) for a 26 week, placebo- and active-controlled period followed by a 26 week, active-controlled period (placebo group switched to sitagliptin [placebo/sitagliptin]) and were included in the modified intent-to-treat analysis set. Randomisation was performed using a computer-generated schedule; participants, study centres and the sponsor were blinded to group assignment. The primary endpoint was change from baseline in HbA 1c at week 26; secondary endpoints included changes in HbA 1c (week 52) and fasting plasma glucose (FPG), body weight, and systolic blood pressure (BP; weeks 26 and 52). Adverse events (AEs) were recorded throughout the study. Results At week 26, canagliflozin 100 mg and 300 mg reduced HbA 1c vs placebo (−0.79%, –0.94%, –0.17%, respectively; p  < 0.001). At week 52, canagliflozin 100 mg and 300 mg demonstrated non-inferiority, and canagliflozin 300 mg demonstrated statistical superiority, to sitagliptin in lowering HbA 1c (−0.73%, –0.88%,–0.73%, respectively); differences (95% CI) vs sitagliptin were 0% (−0.12, 0.12) and −0.15% (−0.27, –0.03), respectively. Canagliflozin 100 mg and 300 mg reduced body weight vs placebo (week 26: –3.7%, –4.2%, –1.2%, respectively; p  < 0.001) and sitagliptin (week 52: –3.8%, –4.2%, –1.3%, respectively; p  < 0.001). Both canagliflozin doses reduced FPG and systolic BP vs placebo (week 26) and sitagliptin (week 52) ( p  < 0.001). Overall AE and AE-related discontinuation rates were generally similar across groups, but higher with canagliflozin 100 mg. Genital mycotic infection and osmotic diuresis-related AE rates were higher with canagliflozin; few led to discontinuations. Hypoglycaemia incidence was higher with canagliflozin. Conclusions/interpretation Canagliflozin improved glycaemia and reduced body weight vs placebo (week 26) and sitagliptin (week 52) and was generally well tolerated in patients with type 2 diabetes on metformin. Clinical trial registry ClinicalTrials.gov NCT01106677 Funding This study was supported by Janssen Research & Development, LLC.

Background and Objective: Rivaroxaban is an oral, direct Factor Xa inhibitor, which is at an advanced stage of clinical development for prevention and treatment of thromboembolic disorders. Two phase II studies, ODIXa-DVT and EINSTEIN DVT, assessed the efficacy and safety of oral rivaroxaban (once daily or twice daily) for treatment of acute deep-vein thrombosis (DVT). Population pharmacokinetic and pharmacodynamic analyses of rivaroxaban in patients in these two phase II studies were conducted to characterize the pharmacokinetics/pharmacodynamics of rivaroxaban and the relationship between important patient covariates and model parameters. Exposure simulations in patients with atrial fibrillation (AF) were also performed in order to predict the exposure of rivaroxaban, using modified demographic data reflecting the characteristics of a typical AF population. Methods: A population pharmacokinetic model was developed using plasma samples from these patients. Various simulations were conducted to explore the pharmacokinetics of rivaroxaban in patients with DVT and to predict exposure in those with AF. Correlations between plasma rivaroxaban concentrations and the prothrombin time, Factor Xa activity, HepTest® and activated partial thromboplastin time were also described. Results: The pharmacokinetics of rivaroxaban in patients with DVT were found to be consistent and predictable across all doses studied. The area under the plasma concentration-time curve (AUC) increased dose dependently. The same total daily doses given once daily achieved higher maximum plasma concentration (C max ) values (∼20%) and lower trough (minimum) plasma concentration (C trough ) values (∼60%) than when given twice daily; however, the 5th–95th percentile ranges for these parameters overlapped. Rivaroxaban clearance was moderately influenced by age and renal function, and the volume of distribution was influenced by age, body weight and sex; the effects were within the observed interindividual variability. Simulations in virtual patient populations with AF showed that a rivaroxaban dose of 15 mg once daily in patients with creatinine clearance of 30–49 mL/min would achieve AUC and C max values similar to those observed with 20 mg once daily in patients with normal renal function. The prothrombin time correlated almost linearly with plasma rivaroxaban concentrations (≤500 µg/L). Conclusion: Population analyses of phase II clinical data indicated that the pharmacokinetics and pharmacodynamics of all rivaroxaban doses were predictable and were affected by expected demographic factors in patients with acute DVT.

P2Y 12 inhibitors are effective in non–ST-segment elevation acute coronary syndromes, but the timing of drug dosing is unclear. In this trial, pretreatment with prasugrel, as compared with treatment after coronary angiography, did not improve outcomes and increased the risk of bleeding. Clopidogrel does not become biologically and clinically effective until several hours after administration. 1 , 2 Although a loading dose of clopidogrel is required in patients undergoing percutaneous coronary intervention (PCI), it is uncertain whether pretreatment with clopidogrel (with treatment given early enough before catheterization to be effective) is efficient when the coronary-artery anatomy in a patient with a non–ST-segment elevation (NSTE) acute coronary syndrome is not known. Pretreatment can delay a coronary-artery bypass grafting (CABG) procedure or increase unnecessarily the risk of bleeding in patients who do not need to undergo PCI. Two randomized studies, one involving patients with NSTE acute . . .

To evaluate the effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in type 2 diabetes mellitus inadequately controlled with metformin monotherapy. This was a double-blind, placebo-controlled, parallel-group, multicenter, dose-ranging study in 451 subjects randomized to canagliflozin 50, 100, 200, or 300 mg once daily (QD) or 300 mg twice daily (BID), sitagliptin 100 mg QD, or placebo. Primary end point was change in A1C from baseline through week 12. Secondary end points included change in fasting plasma glucose (FPG), body weight, and overnight urinary glucose-to-creatinine ratio. Safety and tolerability were also assessed. Canagliflozin was associated with significant reductions in A1C from baseline (7.6-8.0%) to week 12: -0.79, -0.76, -0.70, -0.92, and -0.95% for canagliflozin 50, 100, 200, 300 mg QD and 300 mg BID, respectively, versus -0.22% for placebo (all P < 0.001) and -0.74% for sitagliptin. FPG was reduced by -16 to -27 mg/dL, and body weight was reduced by -2.3 to -3.4%, with significant increases in urinary glucose-to-creatinine ratio. Adverse events were transient, mild to moderate, and balanced across arms except for a non-dose-dependent increase in symptomatic genital infections with canagliflozin (3-8%) versus placebo and sitagliptin (2%). Urinary tract infections were reported without dose dependency in 3-9% of canagliflozin, 6% of placebo, and 2% of sitagliptin arms. Overall incidence of hypoglycemia was low. Canagliflozin added onto metformin significantly improved glycemic control in type 2 diabetes and was associated with low incidence of hypoglycemia and significant weight loss. The safety/tolerability profile of canagliflozin was favorable except for increased frequency of genital infections in females.

In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA). In ROCKET AF, patients with AF who were at increased risk of stroke were randomly assigned (1:1) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin (international normalised ratio 2·0–3·0). Patients and investigators were masked to treatment allocation. Between Dec 18, 2006, and June 17, 2009, 14 264 patients from 1178 centres in 45 countries were randomly assigned. The primary endpoint was the composite of stroke or non-CNS systemic embolism. In this substudy we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA. Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population. ROCKET AF is registered with ClinicalTrials.gov, number NCT00403767. 7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2·79% rivaroxaban vs 2·96% warfarin; hazard ratio [HR] 0·94, 95% CI 0·77–1·16) and those without (1·44%vs 1·88%; 0·77, 0·58–1·01; interaction p=0·23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13·31% rivaroxaban vs 13·87% warfarin; HR 0·96, 95% CI 0·87–1·07) and those without (16·69%vs 15·19%; 1·10, 0·99–1·21; interaction p=0·08). There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF. Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare.

In this trial, bedside platelet-function monitoring to adjust antiplatelet therapy after coronary stent implantation did not reduce the rate of subsequent cardiovascular events, a finding that calls into question the clinical value of this type of testing. Clopidogrel and aspirin play a central role in the treatment of patients undergoing percutaneous coronary intervention. 1 Up to one third of patients have inadequate platelet inhibition, with an increased risk of events. 2 – 5 Platelet-function testing can determine the degree of platelet reactivity during treatment at the bedside and potentially identify patients in whom adjustment of antiplatelet therapy is warranted to minimize the risks of both ischemic and bleeding complications. 6 Cohort studies and meta-analyses have largely shown the prognostic value of high platelet reactivity during antiplatelet therapy in patients undergoing coronary stenting. 7 , 8 Randomized clinical trials have also shown that stronger . . .