Ocrelizumab treatment in multiple sclerosis: A Danish population-based cohort study.

BACKGROUND AND PURPOSE: Real-world evidence regarding the effectiveness and safety of ocrelizumab for the treatment of multiple sclerosis (MS) is limited. The aim was to evaluate the effectiveness and safety of ocrelizumab treatment for MS in a real-world setting. METHODS: A nationwide population-based cohort study was conducted where clinical and magnetic resonance imaging data of MS patients enrolled prospectively in the Danish Multiple Sclerosis Registry who initiated ocrelizumab treatment between January 2018 and November 2020 were analyzed. RESULTS: A total of 1104 patients (85.7% relapsing-remitting MS [RRMS], 8.8% secondary progressive MS [SPMS], 5.5% primary progressive MS [PPMS]) were included, with a median follow-up period of 1.3 years. At baseline, the mean age was 41.4 years in the RRMS group, 44.5 years in the PPMS group and 50.3 years in the SPMS group. Median Expanded Disability Status Scale score was 2.5, 3.5 and 5.5, respectively. Most RRMS and SPMS patients had received previous disease-modifying therapies (87.5% and 91.8%, respectively), whereas PPMS patients were mostly treatment naïve (78.7%). After ocrelizumab initiation, 9.3% of the patients experienced a relapse and 8.7% a 24 weeks confirmed disability worsening. Conversely, 16.7% showed a 24 weeks confirmed disability improvement. After ~1 year of treatment, most patients (94.5%) were free of magnetic resonance imaging activity. Ocrelizumab was generally well tolerated, as side effects were only reported for 10% of patients, mostly consisting of infusion-related reactions and infections. CONCLUSIONS: It is shown that most MS patients treated with ocrelizumab are clinically stabilized and with an adverse event profile consistent with the experience from the pivotal clinical trials.

Existing fluid responsiveness studies using the mini-fluid challenge may be misleading: Methodological considerations and simulations.

BACKGROUND: The mini-fluid challenge (MFC) is a clinical concept of predicting fluid responsiveness by rapidly infusing a small amount of intravenous fluids, typically 100 ml, and systematically assessing its haemodynamic effect. The MFC method is meant to predict if a patient will respond to a subsequent, larger fluid challenge, typically another 400 ml, with a significant increase in stroke volume. METHODS: We critically evaluated the general methodology of MFC studies, with statistical considerations, secondary analysis of an existing study and simulations. RESULTS: Secondary analysis of an existing study showed that the MFC could predict the total fluid response (MFC + 400 ml) with an area under the receiver operator characteristic curve (AUROC) of 0.92, but that the prediction was worse than random for the response to the remaining 400 ml (AUROC = 0.33). In a null simulation with no response to both the MFC and the subsequent fluid challenge, the commonly used analysis could predict fluid responsiveness with an AUROC of 0.73. CONCLUSION: Many existing MFC studies are likely overestimating the classification accuracy of the MFC. This should be considered before adopting the MFC into clinical practice. A better study design includes a second, independent measurement of stroke volume after the MFC. This measurement serves as reference for the response to the subsequent fluid challenge.

Changes in arterial blood pressure characteristics following an extrasystolic beat or a fast 50 ml fluid challenge do not predict fluid responsiveness during cardiac surgery.

Prediction of fluid responsiveness is essential in perioperative goal directed therapy, but dynamic tests of fluid responsiveness are not applicable during open-chest surgery. We hypothesised that two methods could predict fluid responsiveness during cardiac surgery based on their ability to alter preload and thereby induce changes in arterial blood pressure characteristics: (1) the change caused by extrasystolic beats and (2) the change caused by a fast infusion of 50 ml crystalloid (micro-fluid challenge). Arterial blood pressure and electrocardiogram waveforms were collected during surgical preparation of the left internal mammary artery in patients undergoing coronary artery bypass surgery. Patients received a fluid challenge (5 ml/kg ideal body weight). The first 50 ml were infused in 10 s and comprised the micro-fluid challenge. Predictor variables were defined as post-ectopic beat changes (compared with sinus beats preceding ectopy) in arterial blood pressure characteristics, such as pulse pressure and systolic pressure, or micro-fluid challenge induced changes in the same blood pressure characteristics. Patients were considered fluid responsive if stroke volume index increased by 15% or more after the full fluid challenge. Diagnostic accuracy was calculated by the area under the receiver operating characteristics curve (AUC). Fifty-six patients were included for statistical analysis. Thirty-one had extrasystoles. The maximal AUC was found for the extrasystolic change in pulse pressure and was 0.70 (CI [0.35 to 1.00]). The micro-fluid challenge method generally produced lower AUC point estimates. Extrasystoles did not predict fluid responsiveness with convincing accuracy in patients undergoing cardiac surgery and changes in arterial waveform indices following a micro-fluid challenge could not predict fluid responsiveness. Given a low number of fluid responders and inherently reduced statistical power, our data does not support firm conclusions about the utility of the extrasystolic method. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT02903316. https://clinicaltrials.gov/ct2/show/NCT02903316?cond=NCT02903316&rank=1 .

Using extra systoles and the micro-fluid challenge to predict fluid responsiveness during cardiac surgery.

Fluid responsiveness prediction is difficult during cardiac surgery. The micro-fluid challenge (micro-FC; rapid central infusion of 50 ml) and the extrasystolic method utilising post-extrasystolic preload increases may predict fluid responsiveness. Two study windows during coronary artery bypass graft surgery were defined, 1: After anaesthesia induction until surgical incision, 2: Left internal mammarian artery surgical preparation period. Each window consisted of 10-15 min observation for extrasystoles before a micro-FC was performed, after which a traditional fluid challenge (FC) was performed (5 ml/kg). Extrasystolic and micro-FC induced changes in hemodynamic variables were derived as predictors of fluid responsiveness defined as stroke volume increasing > 10% following FC. 61 patients were studied. Post-ectopic changes in pulse pressure (PP) predicted fluid responsiveness with receiver operating characteristic area (AUC) of 0.69 [CI 0.40;0.97] in the first study window and 0.64 [0.44;0.86] in the second window. Other post-ectopic predictors such as pre-ejection period (PEP) and systolic blood pressure (SBP) had similar or lower AUCs. Heart rate was 52.9 (SD ±8.4) min- 1 and 53.6 (± 8.8) min- 1 in the two study windows. Micro-FC induced changes in PEP had AUC of 0.74 [0.57;0.90] in the first window and 0.60 [0.40;0.76] in the second window. Correcting micro-FC induced changes in PEP for the micro-FC induced changes in heart rate had AUCs of 0.84 [0.70;0.97] in the first window and 0.63 [0.47;0.79] in the second window. The investigated methods revealed insufficient validity during cardiac surgery. RR interval corrected changes during a micro-FC should be investigated further. Trial registration Clinicaltrials.gov: NCT03002129.