The philosophy of Evidence-based Medicine

Evidence-based Medicine is the application of the best evidence available in the care of individual patients, using mathematical estimates of probability and risk. Although elements of EBM have appeared centuries ago, the term Evidence-based Medicine has been used for 10 years only. The spread of EBM followed studies which had shown that in contemporary medicine a significant proportion of interventions, although they are considered as the standard of care, have not proven efficacy. The two principles of EBM are that evidence alone is not enough for clinical decision making and that there is a hierarchy of evidence. Evidence-based medicine can be practiced in up to five steps i.e. formulating answerable clinical questions, searching for the best available evidence, critically appraising the evidence, applying the evidence in clinical situations and evaluating one’s effectiveness and efficiency. One does not have to go through all steps in practicing EBM, e.g. there now exist the so called secondary publications which are systematic reviews or meta-analyses of all available studies on a clinical problem or journals entirely devoted in appraisal of original studies. Notwithstanding the “success” of EBM there is a strong current of criticism on subjects practical and philosophical alike. The strongest point against EBM however is that there is no evidence that practicing EBM improves patients’ outcomes. In our opinion, EBM is a very useful instrument with wide-ranging applications in the practice of medicine. However EBM is neither a new scientific field nor a paradigm shift in contemporary medicine. As an empirical approach to clinical problems, EBM does not produce scientific knowledge and therefore it should not be given more room than it deserves, neglecting basic or clinical research. “...between man and angel there is this difference, that an angel perceives the truth by simple apprehension, whereas man becomes acquainted with a simple truth by a process from manifold data” Thomas Aquinas, Summa Theologica

Encephalopathy in an adult with cat-scratch disease.

We report the case of a 53-year-old healthy man, presenting with confusion. The patient had been clinically diagnosed with cat-scratch disease (CSD) and prescribed a 10-day course of doxycycline orally. Approximately a week after he had completed the treatment, he was admitted to our department with confusion. Neurological examination revealed expressive dysphasia with no motor or sensory deficits. Cerebrospinal fluid (CSF) examination showed only increased content. Imaging with CT and MRI of the brain did not reveal any abnormalities, and funduscopy was normal. Serology confirmed Bartonella henselae infection. CSD-associated encephalopathy was confirmed based on the clinical manifestations, CSF findings and positive serology. The patient was treated with a combination of doxycycline and rifampin and he rapidly improved with complete neurological recovery within 7 days. Encephalopathy is an unusual manifestation of CSD in adults with excellent prognosis

Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial

Background Endotype classification may guide immunomodulatory management of patients with bacterial and viral sepsis. We aimed to identify immune endotypes and transitions associated with response to anakinra (human interleukin 1 receptor antagonist) in participants in the SAVE-MORE trial. Methods Adult patients hospitalized with radiological findings of PCR-confirmed severe pneumonia caused by SARS-CoV-2 and plasma-soluble urokinase plasminogen activator receptor levels of >= 6 ng/ml in the SAVE-MORE trial (NCT04680949) were characterized at baseline and days 4 and 7 of treatment using a previously defined 33-messenger RNA classifier to assign an immunological endotype in blood. Endpoints were changes in endotypes and progression to severe respiratory failure (SRF) associated with anakinra treatment. Results At baseline, 23.2% of 393 patients were designated as inflammopathic, 41.1% as adaptive, and 35.7% as coagulopathic. Only 23.9% were designated as the same endotype at days 4 and 7 compared to baseline, while all other patients transitioned between endotypes. Anakinra-treated patients were more likely to remain in the adaptive endotype during 7-day treatment (24.4% vs. 9.9%; p < 0.001). Anakinra also protected patients with coagulopathic endotype at day 7 against SRF compared to placebo (27.8% vs. 55.9%; p = 0.013). Conclusion We identify an association between endotypes defined using blood transcriptome and anakinra therapy for COVID-19 pneumonia, with anakinra-treated patients shifting toward endotypes associated with a better outcome, mainly the adaptive endotype. Trial registration ClinicalTrials.gov, NCT04680949, December 23, 2020

Efficacy and safety of early soluble urokinase plasminogen receptor plasma-guided anakinra treatment of COVID-19 pneumonia: a subgroup analysis of the SAVE-MORE randomised trialResearch in context

Summary: Background: The SAVE-MORE trial demonstrated that anakinra treatment in COVID-19 pneumonia with plasma soluble urokinase plasminogen activator (suPAR) levels of 6 ng/mL or more was associated with 0.36 odds for a worse outcome compared to placebo when expressed by the WHO-Clinical Progression Scale (CPS) at day 28. Herein, we report the results of subgroup analyses and long-term outcomes. Methods: This prospective, double-blind, randomised clinical trial, recruited patients with a confirmed SARS-CoV-2 infection, in need of hospitalisation, lower respiratory tract infection and plasma suPAR ≥6 ng/mL from 37 academic and community hospitals in Greece and Italy. Patients were 1:2 randomised to subcutaneous treatment with placebo or anakinra (100 mg) once daily for 10 days. Pre-defined subgroups of Charlson's comorbidity index (CCI), sex, age, level of suPAR, and time from symptom onset were analysed for the primary endpoint (overall comparison of distribution of frequencies of the scores from the WHO-CPS between treatments on day 28), by multivariable ordinal regression analysis in the intention to treat (ITT) population. This trial is registered with the EU Clinical Trials Register (2020-005828-11) and ClinicalTrials.gov (NCT04680949). Findings: Patients were enrolled between 23 December 2020 and 31 March 2021; 189 patients in the placebo arm and 405 patients in the anakinra arm were the ITT population. Multivariable analysis showed that anakinra treatment was accompanied by significantly lower odds for worse outcome compared to placebo at day 28 for all studied subgroups (CCI ≥ 2, OR: 0.34, 95% confidence intervals [CI] 0.22–0.50; CCI 9 ng/mL, OR: 0.35, 95% CI 0.19–0.66; suPAR 6–9 ng/mL, OR: 0.35, 95% CI 0.24–0.52; patients ≥65 years, OR: 0.41, 95% CI 0.25–0.66; and patients <65 years, OR: 0.29, 95% CI 0.19–0.45). The benefit was uniform, irrespective of the time from start of symptoms until the start of the study drug. At days 60 and 90, anakinra treatment had odds of 0.40 (95% CI 0.28–0.57) and 0.46 (95% CI 0.32–0.67) respectively, for a worse outcome compared to placebo. The costs of general ward stay, ICU stay, and drugs were lower with anakinra treatment. Interpretation: Anakinra represents an important therapeutic tool in the management of COVID-19 that may be administered in all subgroups of patients; benefits are maintained until day 90. Funding: Hellenic Institute for the Study of Sepsis; Swedish Orphan Biovitrum AB

Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1 alpha/beta inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR &gt;= 6 ng ml(-1), 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P &lt; 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.The SAVE-MORE phase 3 study demonstrates the efficacy of anakinra, an IL-1 alpha/beta inhibitor, in patients with COVID-19 and high serum levels of soluble plasminogen activator receptor

Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1 alpha/beta inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR &gt;= 6 ng ml(-1), 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P &lt; 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter. The SAVE-MORE phase 3 study demonstrates the efficacy of anakinra, an IL-1 alpha/beta inhibitor, in patients with COVID-19 and high serum levels of soluble plasminogen activator receptor