Double-Dose Versus Standard-Dose Clopidogrel According to Smoking Status Among Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention

Background: Prior Studies have suggested better outcomes in smokers compared with nonsmokers receiving clopidogrel (“smoker's paradox”). The impact of a more intensive clopidogrel regimen on ischemic and bleeding risks in smokers with acute coronary syndromes requiring percutaneous coronary interventions remains unclear. Methods and Results: We analyzed 17 263 acute coronary syndrome patients undergoing percutaneous coronary intervention from the CURRENT‐OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Symptoms) trial, which compared double‐dose (600 mg day 1;150 mg days 2–7; then 75 mg daily) versus standard‐dose (300 mg day 1; then 75 mg daily) clopidogrel in acute coronary syndrome patients. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Interactions between treatment allocation and smoking status (current smokers versus nonsmokers) were evaluated. Overall, 6394 patients (37.0%) were current smokers. For the comparison of double‐ versus standard‐dose clopidogrel, there were significant interactions in smokers and nonsmokers for the primary outcome (P=0.031) and major bleeding (P=0.002). Double‐ versus standard‐dose clopidogrel reduced the primary outcome among smokers by 34% (hazard ratio [HR] 0.66, 95% confidence interval [CI], 0.50–0.87, P=0.003), whereas in nonsmokers, there was no apparent benefit (HR 0.96, 95% CI, 0.80–1.14, P=0.61). For major bleeding, there was no difference between the groups in smokers (HR 0.77, 95% CI, 0.48–1.24, P=0.28), whereas in nonsmokers, the double‐dose clopidogrel regimen increased bleeding (HR 1.89, 95% CI, 1.37–2.60, P<0.0001). Double‐dose clopidogrel reduced the incidence of definite stent thrombosis in smokers (HR 0.41, 95% CI, 0.24–0.71) and nonsmokers (HR 0.63, 95% CI, 0.42–0.93; P for interaction=0.19). Conclusions: In smokers, a double‐dose clopidogrel regimen reduced major cardiovascular events and stent thrombosis after percutaneous coronary intervention, with no increase in major bleeding. This suggests that clopidogrel dosing in patients with acute coronary syndromes should be personalized, taking into consideration both ischemic and bleeding risk. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00335452

Efficacy and Safety of Fondaparinux Versus Enoxaparin in Patients With Acute Coronary Syndromes Treated With Glycoprotein IIb/IIIa Inhibitors or Thienopyridines Results From the OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) Trial

ObjectivesThis study sought to evaluate the relative safety and efficacy of fondaparinux and enoxaparin in patients with acute coronary syndromes (ACS) treated with glycoprotein (GP) IIb/IIIa inhibitors or thienopyridines.BackgroundThe OASIS 5 (Fifth Organization to Assess Strategies in Ischemic Syndromes) trial showed that fondaparinux reduced major bleeding by 50% compared with enoxaparin while preserving similar efficacy. Whether this benefit is consistent in the presence or absence of concurrent antiplatelet therapy with clopidogrel and GP IIb/IIIa inhibitors is unknown.MethodsPatients with ACS (n =20,078) were randomized as a part of the OASIS 5 trial to receive either fondaparinux or enoxaparin. The use of GP IIb/IIIa inhibitors or thienopyridines was at the discretion of the treating physician. A Cox proportional hazard model was used to compare outcomes.ResultsOf the 20,078 patients randomized, 3,630 patients received GP IIb/IIIa and 13,531 received thienopyridines. There was a 40% reduction in major bleeding with fondaparinux compared with enoxaparin in those treated with GP IIb/IIIa (5.2% vs. 8.3%, hazard ratio [HR]: 0.61, p < 0.001). A similar reduction was found in those treated with thienopyridines (3.4% vs. 5.4%, HR: 0.62, p < 0.001). Ischemic events were similar between the groups, resulting in a superior net clinical outcome (death, myocardial infarction, refractory ischemia, or major bleeding) favoring fondaparinux (GP IIb/IIIa subgroup 14.8% vs. 18.9%, HR: 0.77, p = 0.001 and thienopyridines subgroup 11.0% vs. 13.2%, HR: 0.82, p < 0.001).ConclusionsIn patients receiving GP IIb/IIIa inhibitors or thienopyridines, fondaparinux reduces major bleeding and improves net clinical outcome compared with enoxaparin

Can we predict Λ\Lambda for the Non-SUSY sector of the Landscape ?

We propose a new selection criteria for predicting the most probable wavefunction of the universe that propagates on the string landscape background, by studying its dynamics from a quantum cosmology view. Previously we applied this proposal to the $SUSY$ sector of the landscape. In this work the dynamic selection criterion is applied to the investigation of the non-$SUSY$ sector.In the absence of detailed information about its structure, it is assumed that this sector has a stochastic distribution of vacua energies.The calculation of a distribution probability for the cosmological constants $\Lambda_{eff}$, obtained from the density of states $\rho$, indicates that the most probable wavefunction is peaked around universes with zero $\Lambda_{eff}$. In contrast to the {\it extended wavefunction} solutions found for the $SUSY$ sector with $N$-vacua and peaked around $\Lambda_{eff}\simeq \frac{1}{N^2}$, wavefunctions residing on the non-$SUSY$ sector exhibit {\it Anderson localization}.Although minisuperspace is a limited approach it presently provides a dynamical quantum selection rule for the most probable vacua solution from the landscape.Comment: 6 pages, 1 figur

RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome

AIMS: To establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS). METHODS: In a 26-week, multi-centre, double-blind, randomized, parallel-group study, 1279 patients with recent high-risk non-ST-segment or ST-segment elevation ACS received one of six darexaban regimens: 5 mg b.i.d., 10 mg o.d., 15 mg b.i.d., 30 mg o.d., 30 mg b.i.d., or 60 mg o.d. or placebo, on top of dual antiplatelet treatment. Primary outcome was incidence of major or clinically relevant non-major bleeding events. The main efficacy outcome was a composite of death, stroke, myocardial infarction, systemic thromboembolism, and severe recurrent ischaemia. RESULTS: Bleeding rates were numerically higher in all darexaban arms vs. placebo (pooled HR: 2.275; 95% CI: 1.13–4.60, P = 0.022). Using placebo as reference (bleeding rate 3.1%), there was a dose–response relationship (P = 0.009) for increased bleeding with increasing darexaban dose (6.2, 6.5, and 9.3% for 10, 30, and 60 mg daily, respectively), which was statistically significant for 30 mg b.i.d. (P = 0.002). There was no decrease (indeed a numerical increase in the 30 and 60 mg dose arms) in efficacy event rates with darexaban, but the study was underpowered for efficacy. Darexaban showed good tolerability without signs of liver toxicity. CONCLUSIONS: Darexaban when added to dual antiplatelet therapy after ACS produces an expected dose-related two- to four-fold increase in bleeding, with no other safety concerns but no signal of efficacy. Establishing the potential of low-dose darexaban in preventing major cardiac events after ACS requires a large phase III trial. ClinicalTrials.gov Identifier: NCT0099429

Patient assessment:Preparing for a predictable aesthetic outcome

The flux of patients seeking to make changes to the appearance of their smile zone appears to be on a pathway of continual increase. This is possibly due to an increase in awareness towards oral health, and perhaps social, peer and media pressures, respectively. Cohorts of dental practitioners have thus responded to the latter demands by attending a plethora of educational courses, often focusing on either restorative techniques or other disciplines, notably orthodontics and clear aligners in particular. Consequently, treatment planning and thus treatment provision may carry the risk of being biased or indeed ‘outcome driven’, whereby the skills and knowledge of any clinician towards a particular faculty may significantly influence the ultimate treatment plan, with the unfortunate tendency sometimes to overlook the role of the interdisciplinary approach of concomitant restorative and contemporary techniques. The role of orthodontics to facilitate the provision of such treatment, along with predictable enamel bonding, has the distinct advantage of providing an acceptable aesthetic result with minimal biological intervention. However, to achieve an optimal result in such cases requires meticulous treatment planning and patient selection to avoid pitfalls with regards to long-term stability and function. This article suggests a standardized approach to patient assessment, with an interdisciplinary perspective in mind. Clinical Relevance: With the growth of patient demand for improving the appearance of the smile, a meticulous assessment protocol is required along with effective interdisciplinary communication. This enables a comprehensive treatment plan to be developed with the correct priorities. </jats:p

Class II resin composites:Restorative options

Tooth-coloured, resin composite restorations are amongst the most frequently prescribed forms of dental restoration to manage defects in posterior teeth. The attainment of a desirable outcome when placing posterior resin composite restorations requires the clinician to have a good understanding of the benefits (as well as the limitations) posed by this material, together with a sound knowledge of placement technique. Numerous protocols and materials have evolved to assist the dental operator with this type of demanding posterior restoration. With the use of case examples, four techniques available are reported here. CPD/Clinical Relevance: This article explores varying techniques for the restoration of Class II cavities using resin composite. </jats:p

Aesthetic resin onlay restorations: 'rationale and methods'

Resin composite restorations have gained increasing popularity over the past two decades. This has been largely driven by a patient-orientated demand for the use of aesthetic restorative materials. It has occurred concomitantly with an improvement in the mechanical properties of available materials, and advances in our knowledge of resin bonding. Onlay restorations are advocated for a plethora of clinical applications. This paper considers the role of adhesive onlay restorations fabricated in resin composite in contemporary restorative practice, including the presentation of two case reports. Clinical Relevance: This case report describes a minimally invasive, aesthetic solution to provide cuspal coverage by means of either a direct or indirect resin composite onlay restoration, respectively. </jats:p

Aesthetic composite veneers for an adult patient with amelogenesis imperfecta:a case report

This case has been presented as part of the continual assessment requirement for the MSc in Aesthetic Dentistry, King's College Dental Institute. Amelogenesis imperfecta (AI) is a hereditary disorder of enamel formation, affecting both the permanent and deciduous dentitions. It can be classified into hypoplastic, hypomaturation and hypocalcified types and presents with different hereditary patterns. The aim of this article is to provide an overview of amelogenesis imperfecta, including a detailed case report for an aesthetically concerned adult patient presenting in general practice with a Witkop's Type IA defect managed with the placement of direct, layered resin composite veneers. Clinical Relevance: Amelogenesis imperfecta patients are susceptible to the restorative cycle of replacement restorations like any other patient, but start with a distinct disadvantage. This case report demonstrates a minimally invasive, relatively simple and cost-effective option for the aesthetic correction of a case of hypoplastic amelogenesis imperfecta with layered composite veneers. </jats:p