Model-Informed Precision Dosing: Background, Requirements, Validation, Implementation, and Forward Trajectory of Individualizing Drug Therapy.

Model-informed precision dosing (MIPD) has become synonymous with modern approaches for individualizing drug therapy, in which the characteristics of each patient are considered as opposed to applying a one-size-fits-all alternative. This review provides a brief account of the current knowledge, practices, and opinions on MIPD while defining an achievable vision for MIPD in clinical care based on available evidence. We begin with a historical perspective on variability in dose requirements and then discuss technical aspects of MIPD, including the need for clinical decision support tools, practical validation, and implementation of MIPD in health care. We also discuss novel ways to characterize patient variability beyond the common perceptions of genetic control. Finally, we address current debates on MIPD from the perspectives of the new drug development, health economics, and drug regulations.

[Selected novelties for hospital based internal medicine]. / Nouveautés en médecine interne hospitalière.

In this selective overview of articles, we describe new concepts, therapeutic measures and pharmacological agents that may modify current practice in clinical internal medicine. Novelties for the management of cardiovascular disease, such as heart failure, hypoxemic respiratory failure, nosocomial pneumonia and certain allergies are discussed.

À travers quelques articles et études choisis, cet article décrit de nouveaux concepts, mesures thérapeutiques et agents pharmacologiques pouvant modifier les pratiques courantes en médecine interne. Des notions concernant la gestion de maladies cardiovasculaires telles que l'insuffisance cardiaque, les décompensations respiratoires hypoxémiques, les pneumonies nosocomiales et la gestion d'allergies y figurent au premier plan.

Brain functional connectivity alterations associated with neuropsychological performance 6-9 months following SARS-CoV-2 infection.

Neuropsychological deficits and brain damage following SARS-CoV-2 infection are not well understood. Then, 116 patients, with either severe, moderate, or mild disease in the acute phase underwent neuropsychological and olfactory tests, as well as completed psychiatric and respiratory questionnaires at 223 ± 42 days postinfection. Additionally, a subgroup of 50 patients underwent functional magnetic resonance imaging. Patients in the severe group displayed poorer verbal episodic memory performances, and moderate patients had reduced mental flexibility. Neuroimaging revealed patterns of hypofunctional and hyperfunctional connectivities in severe patients, while only hyperconnectivity patterns were observed for moderate. The default mode, somatosensory, dorsal attention, subcortical, and cerebellar networks were implicated. Partial least squares correlations analysis confirmed specific association between memory, executive functions performances and brain functional connectivity. The severity of the infection in the acute phase is a predictor of neuropsychological performance 6-9 months following SARS-CoV-2 infection. SARS-CoV-2 infection causes long-term memory and executive dysfunctions, related to large-scale functional brain connectivity alterations.

[Advances in hospital based internal medicine]. / Nouveautés en médecine interne hospitalière.

Hospital based internal medicine has been strongly solicited for over two years with the SARS-CoV-2 epidemic. This epidemic continues to evolve and represents a strain for public health. Numerous studies have addressed issues concerning this epidemic, and multiple novelties concerning other frequent pathologies have also been published. Management strategies of cardiovascular, pulmonary, gastro-intestinal and metabolic diseases are discussed.

La médecine interne hospitalière a été fortement sollicitée depuis 2 ans avec l'épidémie de SARS-CoV-2. Celle-ci continue d'évoluer et reste une épreuve pour la santé publique. Une pléthore d'études a tenté de résoudre les multiples défis que représente cette épidémie, mais de multiples nouveautés concernant d'autres pathologies fréquentes sont également apparues. La prise en charge des maladies cardiovasculaires, pulmonaires, gastro-intestinales et métaboliques est évoquée.

One-year persistent symptoms and functional impairment in SARS-CoV-2 positive and negative individuals.

BACKGROUND: Persistent symptoms of SARS-CoV-2 are prevalent weeks to months following the infection. To date, it is difficult to disentangle the direct from the indirect effects of SARS-CoV-2, including lockdown, social, and economic factors. OBJECTIVE: The study aims to characterize the prevalence of symptoms, functional capacity, and quality of life at 12 months in outpatient symptomatic individuals tested positive for SARS-CoV-2 compared to individuals tested negative. METHODS: From 23 April to 27 July 2021, outpatient symptomatic individuals tested for SARS-CoV-2 at the Geneva University Hospitals were followed up 12 months after their test date. RESULTS: At 12 months, out of the 1447 participants (mean age 45.2 years, 61.2% women), 33.4% reported residual mild to moderate symptoms following SARS-CoV-2 infection compared to 6.5% in the control group. Symptoms included fatigue (16% vs. 3.1%), dyspnea (8.9% vs. 1.1%), headache (9.8% vs. 1.7%), insomnia (8.9% vs. 2.7%), and difficulty concentrating (7.4% vs. 2.5%). When compared to the control group, 30.5% of SARS-CoV-2 positive individuals reported functional impairment at 12 months versus 6.6%. SARS-CoV-2 infection was associated with the persistence of symptoms (adjusted odds ratio [aOR] 4.1; 2.60-6.83) and functional impairment (aOR 3.54; 2.16-5.80) overall, and in subgroups of women, men, individuals younger than 40 years, those between 40-59 years, and in individuals with no past medical or psychiatric history. CONCLUSION: SARS-CoV-2 infection leads to persistent symptoms over several months, including in young healthy individuals, in addition to the pandemic effects, and potentially more than other common respiratory infections. Symptoms impact functional capacity up to 12 months post infection.

Accuracy of a score predicting the presence of an atypical pathogen in hospitalized patients with moderately severe community-acquired pneumonia.

BACKGROUND: Atypical pathogens (AP), present in some patients with community-acquired pneumonia (CAP), are intrinsically resistant to betalactam drugs, the mainstay of empirical antibiotic treatment. Adding antibiotic coverage for AP increases the risk of adverse effects and antimicrobial selection pressure, while withholding such coverage may worsen the prognosis if an AP is causative. A clinical model predicting the presence of AP would allow targeting atypical coverage for patients most likely to benefit. METHODS: This is a secondary analysis of a multicentric randomized controlled trial that included 580 adults patients hospitalized for CAP. A predictive score was built using independent predictive factors for AP identified through multivariate analysis. Accuracy of the score was assessed using area under the receiver operating curve (AUROC), sensitivity, and specificity. RESULTS: Prevalence of AP was 5.3%. Age < 75 years (OR 2.7, 95% CI 1.2-6.2), heart failure (OR 2.6, 95% CI 1.1-6.1), absence of chest pain (OR 3.0, 95% CI 1.1-8.2), natremia < 135 mmol/L (OR 3.0, 95% CI 1.4-6.6) and contracting the disease in autumn (OR 2.7, 95% CI 1.3-5.9) were independently associated with AP. A predictive score using these factors had an AUROC of 0.78 (95% CI 0.71-0.85). A score of 0 or 1 (present in 33% of patients) had 100% sensitivity and 35% specificity. CONCLUSION: Use of a score built on easily obtained clinical and laboratory data would allow safe withholding of atypical antibiotic coverage in a significant number of patients, with an expected positive impact on bacterial resistance and drug adverse effects. TRIAL REGISTRATION: NCT00818610.

Development and assessment of PharmaCheck: an electronic screening tool for the prevention of twenty major adverse drug events.

BACKGROUND: Adverse drug events (ADEs) can be prevented by deploying clinical decision support systems (CDSS) that directly assist physicians, via computerized order entry systems, and clinical pharmacists performing medication reviews as part of medical rounds. However, physicians using CDSS are known to be exposed to the alert-fatigue phenomenon. Our study aimed to assess the performance of PharmaCheck-a CDSS to help clinical pharmacists detect high-risk situations with the potential to lead to ADEs-and its impact on clinical pharmacists' activities. METHODS: Twenty clinical rules, divided into four risk classes, were set for the daily screening of high-risk situations in the electronic health records of patients admitted to our General Internal Medicine Department. Alerts to clinical pharmacists encouraged them to telephone prescribers and suggest any necessary treatment adjustments. PharmaCheck's performance was assessed using the intervention's positive predictive value (PPV), which characterizes the proportion of interventions for each alert triggered. PharmaCheck's impact was assessed by considering clinical pharmacists as a filter for ruling out futile alerts and by comparing the final clinical PPV with a pharmacist (the proportion of interventions that led to a change in the medical regimen) to the final clinical PPV without a pharmacist. RESULTS: Over 132 days, 447 alerts were triggered for 383 patients, leading to 90 interventions (overall intervention PPV = 20.1%). By risk class, intervention PPVs made up 26.9% (n = 65/242) of abnormal laboratory value alerts, 3.1% (4/127) of alerts for contraindicated medications or medications to be used with caution, 28.2% (20/71) of drug-drug interaction alerts, and 14.3% (1/7) of inadequate mode of administration alerts. Clinical PPVs reached 71.0% (64/90) when pharmacists filtered alerts and 14% (64/242) if they were not doing it. CONCLUSION: PharmaCheck enabled clinical pharmacists to improve their traditional processes and broaden their coverage by focusing on 20 high-risk situations. Alert management by pharmacists seemed to be a more effective way of preventing risky situations and alert-fatigue than a model addressing alerts to physicians exclusively. Some fine-tuning could enhance PharmaCheck's performance by considering the information quality of triggers, the variability of clinical settings, and the fact that some prescription processes are already highly secured.

[Latest progress in internal medicine]. / Avancées récentes en médecine interne.

Internal medicine continues de evolve as a result of further insight and evidence for the efficacy of given interventions. Although numerous studies have addressed issues concerning the SARS-COV-2 epidemic, multiple novelties concerning other frequent pathologies have also been presented. Management strategies of cardiovascular disease, infectious diseases and venous thromboembolism are particularly concerned.

La médecine interne continue d'évoluer au fur et à mesure de nouvelles évidences d'efficacité par rapport aux diverses interventions. Une pléthore d'études a tenté de résoudre les multiples défis que représente l'épidémie au SARS-CoV-2, mais de multiples nouveautés concernant d'autres pathologies fréquentes sont également apparues. La prise en charge des maladies cardiovasculaires, de maladies infectieuses et la maladie thromboembolique sont particulièrement concernées.

Role of Intermediate Care Unit Admission and Noninvasive Respiratory Support during the COVID-19 Pandemic: A Retrospective Cohort Study.

BACKGROUND: The COVID-19 pandemic has led to shortage of intensive care unit (ICU) capacity. We developed a triage strategy including noninvasive respiratory support and admission to the intermediate care unit (IMCU). ICU admission was restricted to patients requiring invasive ventilation. OBJECTIVES: The aim of this study is to describe the characteristics and outcomes of patients admitted to the IMCU. METHOD: Retrospective cohort including consecutive patients admitted between March 28 and April 27, 2020. The primary outcome was the proportion of patients with severe hypoxemic respiratory failure avoiding ICU admission. Secondary outcomes included the rate of emergency intubation, 28-day mortality, and predictors of ICU admission. RESULTS: One hundred fifty-seven patients with COVID-19-associated pneumonia were admitted to the IMCU. Among the 85 patients admitted for worsening respiratory failure, 52/85 (61%) avoided ICU admission. In multivariate analysis, PaO2/FiO2 (OR 0.98; 95% CI: 0.96-0.99) and BMI (OR 0.88; 95% CI: 0.78-0.98) were significantly associated with ICU admission. No death or emergency intubation occurred in the IMCU. CONCLUSIONS: IMCU admission including standardized triage criteria, self-proning, and noninvasive respiratory support prevents ICU admission for a large proportion of patients with COVID-19 hypoxemic respiratory failure. In the context of the COVID-19 pandemic, IMCUs may play an important role in preserving ICU capacity by avoiding ICU admission for patients with worsening respiratory failure and allowing early discharge of ICU patients.

[Internal medicine in 2020]. / 2020 en revue par les internistes hospitaliers.

2020: annus horribilis for hospital medicine? The past year, notable because of the current pandemic, has had a profound impact on multiple aspects of medical practice. Just as all medical staff and the general population, hospital internists were put under immense strain in 2020. This year has more than ever reinforced our belief in the importance of keeping a critical and scientific eye on the mass of new studies and data produced every year. The internists of the HUG propose a critical review of selected recent publications that may influence our daily management of patients.

2020 : annus horribilis pour la médecine hospitalière ? L'année écoulée, marquée par la pandémie en cours, a eu un impact majeur sur de multiples aspects de notre pratique. Comme l'ensemble du monde médico-soignant et de la population, les internistes hospitaliers ont été mis à rude épreuve en 2020. Cette année a plus que jamais renforcé notre conviction de l'importance de porter un regard scientifique sur la masse de nouveautés qui surviennent chaque année. Les internistes hospitaliers des HUG vous proposent de partager leur vision critique de publications scientifiques récentes utiles pour notre pratique quotidienne.

Diagnostic accuracy of Augurix COVID-19 IgG serology rapid test.

AIMS: To validate the diagnostic accuracy of the Augurix SARS-CoV-2 IgM/IgG rapid immunoassay diagnostic test (RDT) for COVID-19. METHODS: In this unmatched 1:1 case-control study, blood samples from 46 real-time RT-PCR-confirmed SARS-CoV-2 hospitalized cases and 45 healthy donors (negative controls) were studied. Diagnostic accuracy of the IgG RDT was assessed against both an in-house recombinant spike-expressing immunofluorescence assay (rIFA), as an established reference method (primary endpoint), and the Euroimmun SARS-CoV-2 IgG enzyme-linked immunosorbent assays (ELISA) (secondary endpoint). RESULTS: COVID-19 patients were more likely to be male (61% vs 20%; P = .0001) and older (median 66 vs 47 years old; P < .001) than controls. Whole blood IgG-RDT results showed 86% and 93% overall Kendall concordance with rIFA and IgG ELISA, respectively. IgG RDT performances were similar between plasma and whole blood. Overall, RDT sensitivity was 88% (95% confidence interval [95%CI]: 70-96), specificity 98% (95%CI: 90-100), PPV 97% (95%CI: 80-100) and NPV 94% (95%CI: 84-98). The IgG-RDT carried out from 0 to 6 days, 7 to 14 days and > 14 days after the SARS-CoV-2 RT-PCR test displayed 30%, 73% and 100% positivity rates in the COVID-19 group, respectively. When considering samples taken >14 days after RT-PCR diagnosis, NPV was 100% (95%CI:90-100), and PPV was 100% (95%CI:72-100). CONCLUSIONS: The Augurix IgG-RDT done in whole blood displays a high diagnostic accuracy for SARS-CoV-2 IgG in high COVID-19 prevalence settings, where its use could be considered in the absence of routine diagnostic serology facilities.

Vegetarian, pescatarian and flexitarian diets: sociodemographic determinants and association with cardiovascular risk factors in a Swiss urban population.

Prevalence and trends of different vegetarian diets remain unknown, with estimates varying depending on the source. Evidence suggests that vegetarian diets are associated with a more favourable cardiovascular risk profile. The present study aimed to assess the prevalence and trends of different types of vegetarian diets in a population-based representative sample, sociodemographic characteristics of participants following such diets and the association of these diets with cardiovascular risk factors. Using repeated cross-sectional population-based surveys conducted in Geneva, Switzerland, 10 797 individuals participated in the study between 2005 and 2017. Participants were classified as vegetarians, pescatarians, flexitarians or omnivores using an FFQ. Sociodemographic and cardiovascular risk factors were evaluated through questionnaires, anthropometric measurements and blood tests. Findings show prevalence of vegetarians increased from 0·5 to 1·2 %, pescatarians from 0·3 to 1·1 % and flexitarians remained stable at 15·6 % of the population over the study period. Compared with omnivores, vegetarians were more likely to be young (OR 2·38; 95 % CI 1·01, 5·6), have higher education (OR 1·59; 95 % CI 1·01, 2·49) and lower income (OR 1·83; 95 % CI 1·04, 3·21); pescatarians and flexitarians were more likely to be women (pescatarian: OR 1·81; 95 % CI 1·10, 3·00; vegetarian: OR 1·57; 95 % CI 1·41, 1·75) and flexitarians were also more likely to have a lower income (OR 1·31; 95 % CI 1·13, 1·53). Participants who adhered to any diet excluding/reducing meat intake had lower BMI, total cholesterol and hypertension compared with omnivores. The present study shows an increase in the prevalence of vegetarians over a 13-year period and suggests that the different vegetarian diets assessed are associated with a better cardiovascular risk profile.

MicroRNA-126 is a regulator of platelet-supported thrombin generation.

Circulating microRNA (miRNA) expression profiles correlate with platelet reactivity. MiR-126 is a promising candidates in this regard. We generated a transgenic zebrafish line with thrombocyte-specific overexpression of miR-126. Laser injury of the posterior cardinal vein of 5 day-old larvae was performed with or without antithrombotic pre-treatment. Platelet-like structures (PLS) derived from human megakaryocytes transfected with miR-126 were also evaluated for procoagulant activity. Finally, we studied the correlation between miR-126 level and thrombin generation markers in a cohort of stable cardiovascular patients. Control zebrafish developed small thrombocyte-rich thrombi at the site of vessel injury, without vessel occlusion. The miR-126 transgenic line developed an occluding thrombus in 75% (95% CI: 51-91%) of larvae. Pre-treatment with the direct thrombin inhibitor argatroban, but not aspirin, prevented vessel occlusion in the transgenic line (0% occlusion, 95%CI: 0-18%). Upon activation, human PLS showed an increased procoagulant profile after miR-126 transfection compared to control. Finally, the plasma levels of miR-126, but not a control platelet-derived miRNA, correlated with markers of in vivo thrombin generation in a cohort of 185 cardiovascular patients. Our results from three complementary approaches support a key role for miR-126 in platelet-supported thrombin generation and open new avenues in the tailoring of antithrombotic treatment.

Feasibility and safety of high-intensity interval training for the rehabilitation of geriatric inpatients (HIITERGY) a pilot randomized study.

BACKGROUND: High-intensity interval training (HIIT) has been shown to be more effective than moderate-intensity continuous training (MICT) for the physical rehabilitation. However, data on its suitability for older hospitalized patients is scarce. METHODS: Randomized controlled trial in a hospital setting. Inclusion of 100 patients, ≥65 years old, hospitalized for rehabilitation after an acute medical condition, in a two-week rehabilitation program of either four HIIT or three MICT sessions per week. Completion was defined as participation in all but two planned sessions accomplishing ≥50% of each session. We assessed: upper-limb muscle strength (handgrip isometric strength test), lower-limb muscle strength (quadriceps and ankle flexion and extension tests); gait speed and spatio-temporal parameters (instrumented walkway), and exercise capacity (6-min walk test). All adverse events were recorded as safety endpoints. RESULTS: An intention-to-treat analysis showed a 44% completion rate for the HIIT group (95% CI, 30-59) and 77% for MICT (95% CI, 55-82). A modified intention-to-treat analysis restricted to patients who participated in ≥1 session showed an 88% completion rate in the HIIT group (95%CI, 69-97) and an 80% completion rate in MICT (95%CI, 65-90). The exercises most frequently undertaken were the pedal exerciser (54%) and the NuStep (32%). There were no significant differences in the various measures. No serious adverse events occurred. CONCLUSION: A HIIT rehabilitation program for this population was feasible, safe and had a high adherence rate. TRIAL REGISTRATION NUMBER: Clinicatrials.gov ID: NCT02318459. Trial registration date: November 7th, 2014. Retrospectively registered. This study adheres to the CONSORT guidelines.

[«â€ ARNI†¼ (Angiotensin Receptor-Neprilysin Inhibitor): when, for whom and how?] / «â€ ARNI†¼ (Angiotensin Receptor- Neprilysin Inhibitor)†: quand, pour qui et comment†?

The association of an angiotensin II receptor antagonist and a neprilysin inhibitor (ARNI or Angiotensin Receptor-Neprilysin Inhibitor) is a new actor in the management of heart failure with reduced left ventricular ejection fraction (LVEF). The PARADIGM-HF trial performed in outpatients with a LVEF ≤ 35-40 % demonstrated that sacubitril-valsartan was superior to enalapril in reducing cardiovascular mortality and heart failure hospitalizations. Precautions in the initiation of sacubitril-valsartan, its use as well as its place in the drug management strategy for chronic heart failure are described in the present review. Additional data in patients hospitalized with reduced LVEF, in patients with LVEF > 45 % as well as the effects on blood pressure, renal or cognitive functions are presented.

L'association d'un antagoniste des récepteurs de l'angiotensine II et d'un inhibiteur de la néprilysine (ARNI : Angiotensin Receptor-Neprilysin Inhibitor) est un acteur supplémentaire dans la prise en charge de l'insuffisance cardiaque à fraction d'éjection ventriculaire gauche (FEVG) diminuée. L'étude PARADIGM-HF, conduite chez des patients ambulatoires (FEVG ≤ 35-40 %), a montré que la combinaison sacubitril-valsartan était supérieure à l'énalapril en réduisant la mortalité cardiovasculaire et les hospitalisations pour insuffisance cardiaque. Les modalités d'introduction, certaines précautions d'emploi, ainsi que sa place dans la stratégie de prise en charge médicamenteuse, sont décrites. Les autres données chez les patients hospitalisés avec FEVG diminuée, les patients avec FEVG > 45 % ainsi que les effets sur la pression artérielle, la fonction rénale ou les troubles cognitifs sont abordés.

[Contemporary novelties in internal medicine]. / Médecine interne hospitalière en revue.

Confronted with increasingly complex and interdependent medical situations, targeted clinical answers and recommendations are -increasingly the result of a comprehensive appraisal of existing -evidence. In addition, public health and economic stakes have to be considered and integrated into the decision process, diagnosis and management of numerous clinical entities. This selective overview covers some of these entities and demonstrate the expanding overlap between inpatient and outpatient practice.

Face à des problématiques médicales de plus en plus complexes et interdépendantes, des réponses et recommandations ciblées sont aujourd'hui proposées, basées sur une revue compréhensive de la littérature. Des enjeux de santé publique et d'économie de la santé viennent s'ajouter au processus décisionnel, diagnostique, et de prise en charge dans de nombreuses pathologies. Cette revue sélective traite de certains de ces sujets et démontre l'accroissement du chevauchement entre médecines hospitalière et ambulatoire.

Low-dose computed tomography for the diagnosis of pneumonia in elderly patients: a prospective, interventional cohort study.

The diagnosis of pneumonia is challenging. Our objective was to assess whether low-dose computed tomography (LDCT) modified the probability of diagnosing pneumonia in elderly patients.We prospectively included patients aged over 65 years with a suspicion of pneumonia treated with antimicrobial therapy (AT). All patients had a chest radiograph and LDCT within 72 h of inclusion. The treating clinician assessed the probability of pneumonia before and after the LDCT scan using a Likert scale. An adjudication committee retrospectively rated the probability of pneumonia and was considered as the reference for diagnosis. The main outcome was the difference in the clinician's pneumonia probability estimates before and after LDCT and the proportion of modified diagnoses which matched the reference diagnosis (the net reclassification improvement (NRI)).A total of 200 patients with a median age of 84 years were included. After LDCT, the estimated probability of pneumonia changed in 90 patients (45%), of which 60 (30%) were downgraded and 30 (15%) were upgraded. The NRI was 8% (NRI event (-6%) + NRI non-event (14%)).LDCT modified the estimated probability of pneumonia in a substantial proportion of patients. It mostly helped to exclude a diagnosis of pneumonia and hence to reduce unnecessary AT.

Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC).

RATIONALE: The P2Y12 receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response. STUDY DESIGN: Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and genome-wide studies. RESULTS: In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate-stimulated platelet function tests included vasodilator-stimulated phosphoprotein assay, light transmittance aggregometry, and the VerifyNow P2Y12 assay. A proof-of-principle analysis based on genotype data provided by each group showed a strong and consistent association between CYP2C19*2 and platelet reactivity (P value=5.1 × 10-40). CONCLUSION: The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic approaches in a large cohort of clopidogrel-treated patients to better understand the genetic basis of on-treatment response variability.

Platelet reactivity in stable cardiovascular patients with chronic kidney disease.

The study aimed to evaluate antiplatelet drug responsiveness in stable outpatients with cardiovascular disease and chronic kidney disease (CKD) and examine whether impaired antiplatelet drug responsiveness is associated with worse clinical outcomes in this population. Stable cardiovascular patients (n = 771) were enrolled at least one month after an acute ischemic atherothrombotic event. Antiplatelet drug responsiveness was assessed with specific assays (serum TxA2 for aspirin, the VASP assay for clopidogrel) and other aggregation-based assays using different agonists. All patients were followed until the first occurrence of a major adverse cardiovascular event. The 133 CKD patients were found to have higher activity of von Willebrand factor and higher fibrinogen levels. After a median follow-up of 33 months, 88 events occurred in patients without CKD and 31 events in patients with CKD (5.0 events and 8.7 events per 100 patient years, respectively, HR = 1.75 (95% CI 1.16-2.63; p = 0.008). The prevalence of poor aspirin and clopidogrel responsiveness and high platelet reactivity as assessed with different aggregation-based assays was similar in patients with estimated GFR ≥ 60 ml/min, 45-59 ml/min, and < 45 ml/min. No significant interaction for CKD vs. non-CKD was observed for events occurrence in patients with or without high platelet reactivity on several assays, with the exception of collagen-induced aggregation. In stable cardiovascular patients, CKD is not associated with higher platelet reactivity. Decreased antiplatelet drug responsiveness is not associated with worse clinical outcomes in CKD patients.