Efficacy and Safety of Ticagrelor Monotherapy in Patients Undergoing Percutaneous Coronary Intervention: A Meta-Analysis

Dual antiplatelet therapy (DAPT) and subsequent P2Y12 inhibitor monotherapy, particularly ticagrelor, is an emerging treatment strategy in patients undergoing percutaneous coronary intervention (PCI). This meta-analysis was designed to investigate whether short-term DAPT followed by ticagrelor monotherapy is associated with a favorable outcome as compared with standard DAPT (1–3 months of DAPT was termed “short-term” DAPT, 6–12 months DAPT was termed “standard” DAPT). The primary outcome was the composite of major adverse cardiovascular events (MACE) comprising myocardial infarction, stroke, and cardiovascular death. Secondary outcomes included all-cause mortality and net adverse clinical events (NACE; myocardial infarction, stroke, all-cause death, stent thrombosis, and major bleeding). The primary safety outcome was major bleeding. Three studies comprising 26,143 patients were included. The risk of MACE was similar between the two treatment groups (risk ratio (RR) 0.86, 95% confidence interval (CI), 0.72–1.02, P = 0.08, I2 = 22%). Short-term DAPT followed by ticagrelor monotherapy resulted in a 20% relative risk reduction of all-cause mortality (RR 0.80, 95% CI, 0.65–0.98, P = 0.03, I2 = 0%) and an 18% relative risk reduction of NACE (RR 0.82, 95% CI, 0.71–0.94, P = 0.005, I2 = 33%) as compared with standard DAPT. Short-term DAPT followed by ticagrelor monotherapy significantly decreased the risk of major bleeding (RR 0.67, 95% CI, 0.49–0.92, P = 0.01, I2 = 65%). In patients with acute coronary syndrome, short-term DAPT followed by ticagrelor monotherapy resulted in an unchanged ischemic risk but a significantly lower bleeding risk compared with standard DAPT. Short-term DAPT followed by ticagrelor monotherapy compared with standard DAPT resulted in a favorable safety and efficacy profile. Direct comparisons of aspirin vs. ticagrelor monotherapy following PCI are needed

Targeted temperature management after cardiac arrest is associated with reduced metabolism of pantoprazole - a probe drug of CYP2C19 metabolism

OBJECTIVE\nMETHODS\nRESULTS\nCONCLUSION\nTargeted temperature management (TTM) is part of standard post-resuscitation care. TTM may downregulate cytochrome enzyme activity and thus impact drug metabolism. This study compared the pharmacokinetics (PK) of pantoprazole, a probe drug of CYP2C19-dependent metabolism, at different stages of TTM following cardiac arrest.\nThis prospective controlled study was performed at the Medical University of Vienna and enrolled 16 patients following cardiac arrest. The patients completed up to three study periods (each lasting 24 h) in which plasma concentrations of pantoprazole were quantified: (P1) hypothermia (33 °C) after admission, (P2) normothermia after rewarming (36 °C, intensive care), and (P3) normothermia during recovery (normal ward, control group). PK was analysed using non-compartmental analysis and nonlinear mixed-effects modelling.\n16 patients completed periods P1 and P2; ten completed P3. The median half-life of pantoprazole was 2.4 h (quartiles: 1.8-4.8 h) in P1, 2.8 h (2.1-6.8 h, p = 0.046 vs. P1, p = 0.005 vs. P3) in P2 and 1.2 h (0.9 - 2.3 h, p = 0.007 vs. P1) in P3. A two-compartment model described the PK data best. Typical values for clearance were estimated separately for each study period, indicating 40% and 29% reductions during P1 and P2, respectively, compared to P3. The central volume of distribution was estimated separately for P2, indicating a 64% increase compared to P1 and P3.\nCYP2C19-dependent drug metabolism is downregulated during TTM following cardiac arrest. These results may influence drug choice and dosing of similarly metabolized drugs and may be helpful for designing studies in similar clinical situations.Pharmacolog

Endpoints for randomized controlled clinical trials for COVID-19 treatments

Background: Endpoint choice for randomized controlled trials of treatments for novel coronavirus-induced disease (COVID-19) is complex. Trials must start rapidly to identify treatments that can be used as part of the outbreak response, in the midst of considerable uncertainty and limited information. COVID-19 presentation is heterogeneous, ranging from mild disease that improves within days to critical disease that can last weeks to over a month and can end in death. While improvement in mortality would provide unquestionable evidence about the clinical significance of a treatment, sample sizes for a study evaluating mortality are large and may be impractical, particularly given a multitude of putative therapies to evaluate. Furthermore, patient states in between “cure” and “death” represent meaningful distinctions. Clinical severity scores have been proposed as an alternative. However, the appropriate summary measure for severity scores has been the subject of debate, particularly given the variable time course of COVID-19. Outcomes measured at fixed time points, such as a comparison of severity scores between treatment and control at day 14, may risk missing the time of clinical benefit. An endpoint such as time to improvement (or recovery) avoids the timing problem. However, some have argued that power losses will result from reducing the ordinal scale to a binary state of “recovered” versus “not recovered.” Methods: We evaluate statistical power for possible trial endpoints for COVID-19 treatment trials using simulation models and data from two recent COVID-19 treatment trials. Results: Power for fixed time-point methods depends heavily on the time selected for evaluation. Time-to-event approaches have reasonable statistical power, even when compared with a fixed time-point method evaluated at the optimal time. Discussion: Time-to-event analysis methods have advantages in the COVID-19 setting, unless the optimal time for evaluating treatment effect is known in advance. Even when the optimal time is known, a time-to-event approach may increase power for interim analyses. © The Author(s) 2020

Camostat Mesylate Versus Lopinavir/Ritonavir in Hospitalized Patients With COVID-19—Results From a Randomized, Controlled, Open Label, Platform Trial (ACOVACT)

Background: To date, no oral antiviral drug has proven to be beneficial in hospitalized patients with COVID-19.Methods: In this randomized, controlled, open-label, platform trial, we randomly assigned patients ≥18 years hospitalized with COVID-19 pneumonia to receive either camostat mesylate (CM) (considered standard-of-care) or lopinavir/ritonavir (LPV/RTV). The primary endpoint was time to sustained clinical improvement (≥48 h) of at least one point on the 7-category WHO scale. Secondary endpoints included length of stay (LOS), need for mechanical ventilation (MV) or death, and 29-day mortality.Results: 201 patients were included in the study (101 CM and 100 LPV/RTV) between 20 April 2020 and 14 May 2021. Mean age was 58.7 years, and 67% were male. The median time from symptom onset to randomization was 7 days (IQR 5–9). Patients in the CM group had a significantly shorter time to sustained clinical improvement (HR = 0.67, 95%-CI 0.49–0.90; 9 vs. 11 days, p = 0.008) and demonstrated less progression to MV or death [6/101 (5.9%) vs. 15/100 (15%), p = 0.036] and a shorter LOS (12 vs. 14 days, p = 0.023). A statistically nonsignificant trend toward a lower 29-day mortality in the CM group than the LPV/RTV group [2/101 (2%) vs. 7/100 (7%), p = 0.089] was observed.Conclusion: In patients hospitalized for COVID-19, the use of CM was associated with shorter time to clinical improvement, reduced need for MV or death, and shorter LOS than the use of LPV/RTV. Furthermore, research is needed to confirm the efficacy of CM in larger placebo-controlled trials.Systematic Review Registration: [https://clinicaltrials.gov/ct2/show/NCT04351724, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001302-30/AT], identifier [NCT04351724, EUDRACT-NR: 2020–001302-30]

Dexamethasone inhibits endotoxin-induced coagulopathy in human lungs

Background: Activation of local and systemic coagulation is a common finding in patients with pneumonia. There is evidence that glucocorticoids have procoagulant activity in the circulation, particularly in the context of inflammation. The effects of glucocorticoids on local pulmonary coagulation have not yet been investigated. Objective: To use a human model of lung inflammation based on the local instillation of endotoxin in order to investigate whether glucocorticoids alter pulmonary coagulation. Methods: Twenty-four healthy volunteers were randomized to receive either dexamethasone or placebo in a double-blind trial. Endotoxin was instilled via bronchoscope into right or left lung segments, followed by saline into the contralateral site. Six hours later, a bilateral bronchoalveolar lavage (BAL) was performed and coagulation parameters were measured. Results: Endotoxin induced activation of coagulation in the bronchoalveolar compartment: the level of prothrombin fragment 1 + 2 (F1 + 2) was increased three-fold (248 pmol L-1, 95% confidence interval [CI] 43-454 versus 743 pmol L-1, 95% CI 437-1050) and the level of thrombin-antithrombin complex (TATc) was increased by similar to 50% (31 mu g L-1 , 95% CI 18-45 versus 49 mu g L-1, 95% CI 36-61) as compared with saline-challenged segments. Dexamethasone reduced F1 + 2 (284 pmol L-1, 95% CI 34-534) and TATc (9 mu g L-1, 95% CI 0.7-17) levels almost to those measured in BAL fluid from the saline-instilled segments in the placebo group. Dexamethasone even profoundly reduced F1 + 2 levels (80%) in saline-instilled lung segments (50 pmol L-1, 95% CI 12-87). In contrast, dexamethasone had no effect on systemic F1 + 2 levels. Conclusions: Dexamethasone inhibits endotoxin-induced coagulopathy in lungs. This trial is the first to provide insights into the effects of glucocorticoids on pulmonary coagulation in response to endotoxin.F 5404-B21(VLID)311287

A Randomized, First-in-Human, Healthy Volunteer Trial of sutimlimab, a Humanized Antibody for the Specific Inhibition of the Classical Complement Pathway

Aberrant activation of the classical complement pathway is the common underlying pathophysiology of orphan diseases such as bullous pemphigoid, antibodymediated rejection of organ transplants, cold agglutinin disease, and warm autoimmune hemolytic anemia. Therapeutic options for these complementmediated disorders are limited and sutimlimab, a humanized monoclonal antibody directed against complement factor C1s, may be potentially useful for inhibition of the classical complement pathway. A phase I, firstinhuman, doubleblind, randomized, placebocontrolled, doseescalation trial of single and multiple doses of sutimlimab or placebo was conducted in 64 volunteers to evaluate safety, tolerability, pharmacokinetic, and pharmacodynamic profiles. Single and multiple infusions of sutimlimab were well tolerated without any safety concerns. sutimlimab exhibited a steep concentrationeffect relationship with a Hill coefficient of 2.4, and an IC90 of 15.5 g/mL. This study establishes the foundation for using sutimlimab as a highly selective inhibitor of the classical complement pathway in different diseases.(VLID)340103