Vascular risk levels affect the predictive value of platelet reactivity for the occurrence of MACE in patients on clopidogrel. Systematic review and meta-analysis of individual patient data.

Prior studies have shown an association between high on-clopidogrel platelet reactivity (PR) and the risk of major adverse cardiovascular events (MACE). However, large intervention trials on PR-tailored treatments have been neutral. The role and usefulness of PR with regard to levels of cardiovascular risk are unclear. We undertook a systematic review and meta-analysis of individual patient data on MACE outcomes (acute coronary syndromes (ACS), ischaemic strokes, and vascular deaths) in relation to PR and its interaction with cardiovascular risk levels. PR was determined using ADP-induced light transmission aggregometry with a primary concentration of 20 µM ADP. Thirteen prospective studies totaled 6,478 clopidogrel-treated patients who experienced 421 MACE (6.5 %) during a median follow-up of 12 months. The strength of the association between the risk of MACE and PR increased significantly (p=0.04) with the number of risk factors present (age> 75 years, ACS at inclusion, diabetes, and hypertension). No association was detected in patients with no risk factor (p=0.48). In patients presenting one risk factor, only high-PR was associated with an increased risk of MACE (HR 3.2, p=0.001). In patients presenting ≥ 2 risk factors, the increase of risk started from medium-PR (medium-PR: HR=2.9, p=0.0004; high-PR: HR=3.7, p=0.0003). PR allowed the reclassification of 44 % of the total population to a different risk level for the outcome of MACE, mostly in intermediate or high risk patients. In conclusion, the magnitude of the association between PR and MACE risk is strongly dependent on the level of cardiovascular risk faced by patients on clopidogrel

Qu'avons-nous appris de la pandémie de COVID-19 en Suisse latine?

Expérience de différents acteurs de la santé de cantons particulièrement exposé

Overuse and underuse of thromboprophylaxis in medical inpatients.

Background Thromboprophylaxis (TPX) prescription is recommended in medical inpatients categorized as high risk of venous thromboembolism (VTE) by validated risk assessment models (RAMs), but how various RAMs differ in categorizing patients in risk groups, and whether the choice of RAM influences estimates of appropriate TPX use is unknown. Objectives To determine the proportion of medical inpatients categorized as high or low risk according to validated RAMs, and to investigate the appropriateness of TPX prescription. Methods This is a prospective cohort study of acutely ill medical inpatients from three Swiss university hospitals. Participants were categorized as high or low risk of VTE by validated RAMs (i.e., the Padua, IMPROVE, simplified, and original Geneva score). We assessed prescription of any TPX at baseline. We considered TPX prescription in high-risk and no TPX prescription in low-risk patients as appropriate. Results Among 1352 medical inpatients, the proportion categorized as high risk ranged from 29.8% with the IMPROVE to 66.1% with the original Geneva score. Overall, 24.6% were consistently categorized as high risk, and 26.3% as low risk by all four RAMs. Depending on the RAM used, TPX prescription was appropriate in 58.7-63.3% of high-risk (i.e., 36.7-41.3% underuse) and 52.4-62.8% of low-risk patients (i.e., 37.2-47.6% overuse). Conclusion The proportion of medical inpatients considered as high or low VTE risk varied widely according to different RAMs. Only half of patients were consistently categorized in the same risk group by all RAMs. While TPX remains underused in high-risk patients, overuse in low-risk patients is even more pronounced

TRAF3 Epigenetic Regulation Is Associated With Vascular Recurrence in Patients With Ischemic Stroke

Clopidogrel is one of the most used antiplatelet drugs in patients with cardiovascular disease. However, 16% to 50% of patients have a high on-clopidogrel platelet reactivity and an increased risk of ischemic events. The pathogenesis of high on-treatment platelet reactivity in patients with stroke is only partially explained by genetic variations. This study aims to find differentially methylated sites across the genome associated with vascular recurrence in ischemic stroke patients treated with clopidogrel

Aktionsplan für die Universitäre Allgemeine Innere Medizin

Entscheidungsträger haben Mühe, die Rationale einer «Allgemeinen» Inneren Medizin (AIM) am hochspezialisierten Universitätsspital zu verstehen und monieren deren «Profilunschärfe». Zudem konzentrieren sich auf der AIM multimorbide, oft unrentable Patienten. Folgen sind die Benachteiligung in Bezug auf Priorisierung und Ressourcen. Daraus wiederum resultieren Attraktivitätsverlust, Entakademisierung und Nachwuchsschwierigkeiten. In letzter Zeit hat die universitäre AIM allerdings wieder Interesse bei den Spitalleitungen erfahren. Gründe hierfür sind der Generalisten­mangel, die «Epidemie» an multimorbiden Patienten, die spezialisierungsbedingte Fragmentierung sowie die Kompetenzabnahme der Spezialmedizin, Probleme ausserhalb ihrer Fachzone zu managen. Dies führte zum Auftrag von unimedsuisse an die Ordinarien der internistischen Universitätskliniken, einen Aktionsplan zur Stärkung der AIM in der universitären Spitalorganisation zu erarbeiten. Der Plan beinhaltet eine stärkere spitalinterne Priorisierung der AIM mit Investition in Infrastruktur und Personal, die Anerkennung fachlicher allgemeininternistischer Kompetenzressorts sowie die Schaffung von strukturierten Berufsprofilen. Diese Massnahmen sollen Prestige/Attraktivität des Fachs AIM stärken und bessere Entwicklungs­perspektiven ermöglichen mit dem Ziel, den Generalistenmangel zu bekämpfen und Gesundheitskosten zu senken

PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations.

CLINICAL QUESTION In adults with low density lipoprotein (LDL) cholesterol levels >1.8 mmol/L (>70 mg/dL) who are already taking the maximum dose of statins or are intolerant to statins, should another lipid-lowering drug be added, either a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor or ezetimibe, to reduce the risk of major cardiovascular events? If so, which drug is preferred? Having decided to use one, should we add the other lipid-lowering drug? CURRENT PRACTICE Most guidelines emphasise LDL cholesterol targets in their recommendations for prescribing PCSK9 inhibitors and/or ezetimibe in adults at high risk of experiencing a major adverse cardiovascular event. However, to achieve these goals in very high risk patients with statins alone is almost impossible, so physicians are increasingly considering other lipid-lowering drugs solely for achieving LDL cholesterol treatment goals rather than for achieving important absolute cardiovascular risk reduction. Most guidelines do not systematically assess the cardiovascular benefits of adding PCSK9 inhibitors and/or ezetimibe for all risk groups across primary and secondary prevention, nor do they report, in accordance with explicit judgments of assumed patients' values and preferences, absolute benefits and harms and potential treatment burdens. RECOMMENDATIONS The guideline panel provided mostly weak recommendations, which means we rely on shared decision making when applying these recommendations. For adults already using statins, the panel suggests adding a second lipid-lowering drug in people at very high and high cardiovascular risk but recommends against adding it in people at low cardiovascular risk. For adults who are intolerant to statins, the panel recommends using a lipid-lowering drug in people at very high and high cardiovascular risk but against adding it in those at low cardiovascular risk. When choosing to add another lipid-lowering drug, the panel suggests ezetimibe in preference to PCSK9 inhibitors. The panel suggests further adding a PCSK9 inhibitor to ezetimibe for adults already taking statins at very high risk and those at very high and high risk who are intolerant to statins. HOW THIS GUIDELINE WAS CREATED An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified four risk groups of patients (low, moderate, high, and very high cardiovascular risk) and primarily applied an individual patient perspective in moving from evidence to recommendations, though societal issues were a secondary consideration. The panel considered the balance of benefits and harms and burdens of starting a PCSK9 inhibitor and/or ezetimibe, making assumptions of adults' average values and preferences. Interactive evidence summaries and decision aids accompany multi-layered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that also allows re-use and adaptation. THE EVIDENCE A linked systematic review and network meta-analysis (14 trials including 83 660 participants) of benefits found that PCSK9 inhibitors or ezetimibe probably reduce myocardial infarctions and stroke in patients with very high and high cardiovascular risk, with no impact on mortality (moderate to high certainty evidence), but not in those with moderate and low cardiovascular risk. PCSK9 inhibitors may have similar effects to ezetimibe on reducing non-fatal myocardial infarction or stroke (low certainty evidence). These relative benefits were consistent, but their absolute magnitude varied based on cardiovascular risk in individual patients (for example, for 1000 people treated with PCSK9 inhibitors in addition to statins over five years, benefits ranged from 2 fewer strokes in the lowest risk to 21 fewer in the highest risk). Two systematic reviews on harms found no important adverse events for these drugs (moderate to high certainty evidence). PCSK9 inhibitors require injections that sometimes result in injection site reactions (best estimate 15 more per 1000 in a 5 year timeframe), representing a burden and harm that may matter to patients. The MATCH-IT decision support tool allows you to interact with the evidence and your patients across the alternative options: https://magicevidence.org/match-it/220504dist-lipid-lowering-drugs/. UNDERSTANDING THE RECOMMENDATIONS The stratification into four cardiovascular risk groups means that, to use the recommendations, physicians need to identify their patient's risk first. We therefore suggest, specific to various geographical regions, using some reliable risk calculators that estimate patients' cardiovascular risk based on a mix of known risk factors. The largely weak recommendations concerning the addition of ezetimibe or PCSK9 inhibitors reflect what the panel considered to be a close balance between small reductions in stroke and myocardial infarctions weighed against the burdens and limited harms.Because of the anticipated large variability of patients' values and preferences, well informed choices warrant shared decision making. Interactive evidence summaries and decision aids linked to the recommendations can facilitate such shared decisions. The strong recommendations against adding another drug in people at low cardiovascular risk reflect what the panel considered to be a burden without important benefits. The strong recommendation for adding either ezetimibe or PCSK9 inhibitors in people at high and very high cardiovascular risk reflect a clear benefit.The panel recognised the key uncertainty in the evidence concerning patient values and preferences, namely that what most people consider important reductions in cardiovascular risks, weighed against burdens and harms, remains unclear. Finally, availability and costs will influence decisions when healthcare systems, clinicians, or people consider adding ezetimibe or PCSK9 inhibitors

The pandemic toll and post-acute sequelae of SARS-CoV-2 in healthcare workers at a Swiss University Hospital.

Healthcare workers have potentially been among the most exposed to SARS-CoV-2 infection as well as the deleterious toll of the pandemic. This study has the objective to differentiate the pandemic toll from post-acute sequelae of SARS-CoV-2 infection in healthcare workers compared to the general population. The study was conducted between April and July 2021 at the Geneva University Hospitals, Switzerland. Eligible participants were all tested staff, and outpatient individuals tested for SARS-CoV-2 at the same hospital. The primary outcome was the prevalence of symptoms in healthcare workers compared to the general population, with measures of COVID-related symptoms and functional impairment, using prevalence estimates and multivariable logistic regression models. Healthcare workers (n=3,083) suffered mostly from fatigue (25.5%), headache (10.0%), difficulty concentrating (7.9%), exhaustion/burnout (7.1%), insomnia (6.2%), myalgia (6.7%) and arthralgia (6.3%). Regardless of SARS-CoV-2 infection, all symptoms were significantly higher in healthcare workers than the general population (n=3,556). SARS-CoV-2 infection in healthcare workers was associated with loss or change in smell, loss or change in taste, palpitations, dyspnea, difficulty concentrating, fatigue, and headache. Functional impairment was more significant in healthcare workers compared to the general population (aOR 2.28; 1.76-2.96), with a positive association with SARS-CoV-2 infection (aOR 3.81; 2.59-5.60). Symptoms and functional impairment in healthcare workers were increased compared to the general population, and potentially related to the pandemic toll as well as post-acute sequelae of SARS-CoV-2 infection. These findings are of concern, considering the essential role of healthcare workers in caring for all patients including and beyond COVID-19

Antiplatelet drugs and platelet reactivity: is it time to halt clinical research on tailored strategies?

Personalized medicine of antiplatelet drugs in cardiovascular patients has led to a significant enthusiasm. Indeed, numerous longitudinal studies showed an association between high platelet reactivity and the recurrence of ischemic events. The first small randomized trials of P2Y12 blockers tailored to each patient's platelet reactivity yielded encouraging reductions of coronary stent thrombosis in high-risk populations. The discovery of genetic variants contributing to the pharmacodynamic effect of clopidogrel has then paved the way toward a personalized antiplatelet therapy based on reliable and stable genetic tests. This enthusiasm was soon tempered by large interventional trials demonstrating that a platelet function testing-based strategy did not improve clinical outcome and that genetic variants discovered up to now only explained a small part of the pharmacodynamic effect of clopidogrel, thus limiting its clinical use. Looking back to the most recent trials, their target populations and the type of clinical setting, it seems that the one-size-fits all policy regarding antiplatelet drugs may be well acceptable for low-risk patients. On the contrary, integration of the clinical setting as well as other risk factors may help to identify subgroups of patients who could derive a benefit from a truly personalized management of antiplatelet therapy

Genetics of clopidogrel poor-response

This chapter focuses on the genetic determinants of clopidogrel response, a highly heritable phenotype. A candidate gene approach identified several polymorphisms involved in drug absorption or metabolisation but the contribution of these genetic variants to the variability of clopidogrel response is small, challenging the implementation of routine genetic testing for the personalization of antiplatelet therapy. Next generation sequencing will provide a better DNA coverage than genome wide association studies and certainly improve our understanding of the genetic basis of clopidogrel response variability