Implications of the antiplatelet therapy gap left with discontinuation of prasugrel in Canada

Background The current Canadian Cardiovascular Society antiplatelet therapy guidelines recommend the use of ticagrelor or prasugrel over clopidogrel as first-line platelet P2Y12 receptor antagonists for treatment of moderate- to high-risk acute coronary syndromes. Recently, Effient (prasugrel [Eli Lilly Canada Inc, Toronto, Canada]) was discontinued by its distributor in Canada. Methods Five members of the Canadian Cardiovascular Society antiplatelet therapy 2018 guidelines committee undertook an independent, evidence-based review to outline patients for whom prasugrel should be the optimal P2Y12 agent and discuss alternative strategies to consider without prasugrel. Results Several clinical scenarios where prasugrel should be indicated are identified and discussed. Considerations to be undertaken for alternative therapies are summarized, including a review of national and international guidelines for de-escalation of P2Y12 receptor antagonists. Conclusions The discontinuation of prasugrel poses a challenge for clinicians. Clinicians must consider key factors in determining the best alternate therapy.Introduction Dans ses lignes directrices actuelles sur la thérapie antiplaquettaire, la Société canadienne de cardiologie recommande l’utilisation du ticagrélor ou du prasugrel plutôt que l’utilisation du clopidogrel comme antagonistes des récepteurs plaquettaires P2Y12 de première intention dans le traitement des patients qui présentent un risque modéré à élevé de syndromes coronariens aigus. Depuis peu, le distributeur a cessé la distribution d’Effient (prasugrel) au Canada. Méthodes Cinq membres du comité des lignes directrices 2018 sur la thérapie antiplaquettaire de la Société canadienne de cardiologie ont entrepris une revue indépendante fondée sur les données probantes pour dresser le profil des patients pour lesquels le prasugrel devrait être la meilleure option parmi les antagonistes des récepteurs P2Y12 et se pencher sur les traitements alternatifs en l'absence de prasugrel. Résultats Plusieurs scénarios cliniques où le prasugrel devrait être indiqué sont recensés et abordés. Les réflexions sur les solutions de rechange au traitement, notamment une revue des lignes directrices nationales et internationales en matière de désescalade des antagonistes des récepteurs P2Y12, sont présentées. Conclusions La cessation de la distribution du prasugrel pose problème aux cliniciens. Les cliniciens doivent tenir compte des facteurs clés pour déterminer le meilleur traitement de remplacement

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Merging Qualitative Constraint Networks in a Piecewise Fashion

International audienceWe address the problem of merging qualitative constraints networks (QCNs). We point out a merging algorithm which computes a consistent QCN representing a global view of the input set of (possibly conflicting) QCNs. This algorithm is generic in the sense that it does not depend on a specific qualitative formalism. The efficiency of our method comes from the fact that it merges locally the constraints of the input QCNs bearing on the same pairs of variables. We define several constraint merging operators in a way to ensure that the induced QCNs merging operator satisfies some expected properties from a logical standpoint

Utiliser la logique propositionnelle pour la fusion de réseaux de contraintes qualitatives

National audienceDans cet article nous nous intéressons au problème de la fusion de réseaux de contraintes qualitatives (RCQ). Nous proposons une méthode de fusion de RCQ en caractérisant et en utilisant d?une part des traductions de ces réseaux en formules propositionnelles, et d?autre part en exploitant les travaux effectués sur la fusion de bases de formules propositionnelles

Fusion de réseaux de contraintes qualitatives définis sur différents formalismes qualitatifs

National audienceDans cet article nous nous intéressons au problème de la fusion de réseaux de contraintes qualitatives (RCQ) définis sur différents formalismes qualitatifs. Nous nous restreignons aux formalismes dans lesquels les relations entre les entités considérées sont définies sur le même domaine. Cette méthode est une étape préliminaire aux approches précédentes qui considèrent un ensemble de RCQ définis sur le même formalisme. La solution proposée consiste à traduire les RCQ dans un formalisme commun approprié. Deux approches sont proposées : dans la première, chacun des RCQ est traduit en un RCQ équivalent; dans la seconde, les RCQ sont traduits en approximations. Ces approches utilisent deux notions duales que nous introduisons, celles de raffinement et d'abstraction entre formalismes qualitatifs

Merging Qualitative Constraints Networks Defined on Different Qualitative Formalisms

International audienceThis paper address the problem of merging qualitative constraints networks (QCNs) defined on different qualitative formalisms. Our model is restricted to formalisms where the entities and the relationships between these entities are defined on the same domain. The method is an upstream step to a previous framework dealing with a set of QCNs defined on the same formalism. It consists of translating the input QCNs into a well-chosen common formalism. Two approaches are investigated: in the first one, each input QCN is translated to an equivalent QCN; in the second one, the QCNs are translated to approximations. These approaches take advantage of two dual notions that we introduce, the ones of refinement and abstraction between qualitative formalisms

A Syntactical Approach to Qualitative Constraint Networks Merging

International audienceWe address the problem of merging qualitative constraint networks (QCNs) representing agents local preferences or beliefs on the relative position of spatial or temporal entities. Two classes of merging operators which, given a set of input QCNs defined on the same qualitative formalism, return a set of qualitative configurations representing a global view of these QCNs, are pointed out. These operators are based on local distances and aggregation functions. In contrast to QCN merging operators recently proposed in the literature, they take account for each constraint from the input QCNs within the merging process. Doing so, inconsistent QCNs do not need to be discarded at start, hence agents reporting locally consistent, yet globally inconsistent pieces of information (due to limited rationality) can be taken into consideration

Fusion majoritaire : des espaces booléens aux espaces affines

National audienceCet article s'intéresse au problème de la fusion d'informations émanant de différentes sources éventuellement conflictuelles. Bien que ce problème ait donné lieu à une large étude dans le cadre de la logique propositionnelle, le langage propositionnel n'est pas suffisamment expressif pour un certain nombre d'applications, en particulier lorsque l'on doit gérer de l'information spatiale. Afin de combler ce manque, nous considérons une classe particulière d'interprétations d'un fragment de la logique du premier ordre, suffisamment expressive pour pouvoir raisonner à propos d'informations exprimées sous la forme de demi-espaces d'espaces affines normés. Dans ce cadre, nous définissons une famille d'opérateurs de fusion majoritaire à base de distances qui inclut l'opérateur de fusion majoritaire propositionnel $Delta^{d_H, sum}$. Nous identifions une sous-classe d'interprétations de notre langage de représentation pour laquelle le résultat du processus de fusion peut être calculé de manière analytique et exprimé sous la forme d'une formule