The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group IMPORTANCE Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.OBJECTIVE To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.DATA SOURCES Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.STUDY SELECTION Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. DATA EXTRACTION AND SYNTHESISIn this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I 2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. MAIN OUTCOMES AND MEASURESThe primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.RESULTS A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). CONCLUSIONS AND RELEVANCEIn this prospective meta-analysis of clinical trials of patients hosp...

Background Concerns have been raised about the possibility that inhibitors of the renin-angiotensin-aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19.Methods In this case-population study, we consecutively selected patients aged 18 years or older with a PCRconfirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437.Findings We collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39•0%) were female and the mean age was 69•1 years (SD 15•4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1•98, 95% CI 1•62-2•41) and risk factors (1•46, 1•23-1•73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0•94 (95% CI 0•77-1•15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0•80, 0•64-1•00) or angiotensin-receptor blockers (1•10, 0•88-1•37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0•53, 95% CI 0•34-0•80). The adjusted ORs were similar across severity degrees of COVID-19.Interpretation RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19.Funding Instituto de Salud Carlos III.

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Background In the first wave of the COVID-19 pandemic, the hypothesis that angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) increased the risk and/or severity of the disease was widely spread. Consequently, in many hospitals, these drugs were discontinued as a “precautionary measure”. We aimed to assess whether the in-hospital discontinuation of ARBs or ACEIs, in real-life conditions, was associated with a reduced risk of death as compared to their continuation and also to compare head-to-head the continuation of ARBs with the continuation of ACEIs. Methods Adult patients with a PCR-confirmed diagnosis of COVID-19 requiring admission during March 2020 were consecutively selected from 7 hospitals in Madrid, Spain. Among them, we identified outpatient users of ACEIs/ARBs and divided them in two cohorts depending on treatment discontinuation/continuation at admission. Then, they were followed-up until discharge or in-hospital death. An intention-to-treat survival analysis was carried out and hazard ratios (HRs), and their 95%CIs were computed through a Cox regression model adjusted for propensity scores of discontinuation and controlled by potential mediators. Results Out of 625 ACEI/ARB users, 340 (54.4%) discontinued treatment. The in-hospital mortality rates were 27.6% and 27.7% in discontinuation and continuation cohorts, respectively (HR=1.01; 95%CI 0.70–1.46). No difference in mortality was observed between ARB and ACEI discontinuation (28.6% vs. 27.1%, respectively), while a significantly lower mortality rate was found among patients who continued with ARBs (20.8%, N=125) as compared to those who continued with ACEIs (33.1%, N=136; p=0.03). The head-to-head comparison (ARB vs. ACEI continuation) yielded an adjusted HR of 0.52 (95%CI 0.29–0.93), being especially notorious among males (HR=0.34; 95%CI 0.12–0.93), subjects older than 74 years (HR=0.46; 95%CI 0.25–0.85), and patients with obesity (HR=0.22; 95%CI 0.05–0.94), diabetes (HR=0.36; 95%CI 0.13–0.97), and heart failure (HR=0.12; 95%CI 0.03–0.97). Conclusions The discontinuation of ACEIs/ARBs at admission did not improve the in-hospital survival. On the contrary, the continuation with ARBs was associated with a trend to a reduced mortality as compared to their discontinuation and to a significantly lower mortality risk as compared to the continuation with ACEIs, particularly in high-risk patients.

Atorvastatin, prescribed for the treatment of hypercholesterolemia, demonstrated overwhelming benefits in reducing cardiovascular morbidity and mortality. However, many patients discontinue therapy due to adverse reactions, especially myopathy. The Dutch Pharmacogenetics Working Group (DPWG) recommends an alternative agent to atorvastatin and simvastatin or a dose adjustment depending on other risk factors for statin-induced myopathy in SLCO1B1 rs4149056 CC or TC carriers. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published their guideline on simvastatin, but not on atorvastatin. In this work, we aimed to demonstrate the effect of SLCO1B1 phenotype and other variants (e.g., in CYP3A4/5, UGT enzymes or SLC transporters) on atorvastatin pharmacokinetics. For this purpose, a candidate-gene pharmacogenetic study was proposed. The study population comprised 156 healthy volunteers enrolled in atorvastatin bioequivalence clinical trials. The genotyping strategy comprised a total of 60 variants in 15 genes. Women showed higher exposure to atorvastatin compared to men (p = 0.001), however this difference disappeared after dose/weight (DW) correction. The most relevant pharmacogenetic differences were the following: AUC/DW and Cmax /DW based on (a) SLCO1B1 phenotype (p < 0.001 for both) and (b) CYP3A5*3 (p = 0.004 and 0.018, respectively). As secondary findings: SLC22A1 *2/*2 genotype was related to higher Cmax/DW (ANOVA p = 0.030) and SLC22A1 *1/*5 genotype was associated with higher Vd/F (ANOVA p = 0.032) compared to SLC22A1 *1/*1, respectively. Finally, UGT2B7 rs7439366 *1/*1 genotype was associated with higher tmax as compared with the *1/*3 genotype (ANOVA p = 0.024). Based on our results, we suggest that SLCO1B1 is the best predictor for atorvastatin pharmacokinetic variability and that prescription should be adjusted based on it. We suggest that the CPIC should include atorvastatin in their statin-SLCO1B1 guidelines. Interesting and novel results were observed based on CYP3A5 genotype, which should be confirmed with further studies.

Introduction: Thiopurine drugs are purine nucleoside analogues used for treatment of different immune-related conditions. To date, different studies highlighted the importance of thiopurine methyltransferase (TPMT) genotyping in patients who initiate treatment with thiopurines to make an adequate dose adjustment. We aimed to investigate the influence of TPMT phenotype, concomitant treatments, and demographic characteristics on the incidence of A.

The implementation of clinical pharmacogenetics in daily practice is limited for various reasons. Today, however, it is a discipline in full expansion. Accordingly, in the recent times, several initiatives promoted its implementation, mainly in the United States but also in Europe. In this document, the genotyping results since the establishment of our Pharmacogenetics Unit in 2006 are described, as well as the historical implementation process that was carried out since then. Finally, this progress justified the constitution of La Princesa University Hospital Multidisciplinary Initiative for the Implementation of Pharmacogenetics (PriME-PGx), promoted by the Clinical Pharmacology Department of Hospital Universitario de La Princesa (Madrid, Spain). Here, we present the initiative along with the two first ongoing projects: the PROFILE project, which promotes modernization of pharmacogenetic reporting (i.e., from classic gene-drug pair reporting to complete pharmacogenetic reporting or the creation of pharmacogenetic profiles specific to the Hospital’s departments) and the GENOTRIAL project, which promotes the communication of relevant pharmacogenetic findings to any healthy volunteer participating in any bioequivalence clinical trial at the Clinical Trials Unit of Hospital Universitario de La Princesa (UECHUP).