Number Of Serious Adverse Events Research Articles

Risk versus Benefit of Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma: ASystematic Review and Meta-Analysis of Randomized Controlled Trials.

Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.

SIOG2023-4-P-293 - The correlation between CARG score and the number of serious adverse events in Japanese patients

SIOG2023-4-P-293 - The correlation between CARG score and the number of serious adverse events in Japanese patients

Remote Ischemic Conditioning for Acute Stroke

Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke. To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke. This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023). The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants. The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke. Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group. RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke. ClinicalTrials.gov Identifier: NCT03481777.

Medical Cannabis Is Not Associated with a Decrease in Activities of Daily Living in Older Adults.

The proportion of older adults using medical cannabis is rising. Therefore, we aimed to assess the effects of herbal medical cannabis on the functional status of older adults. We conducted a prospective observational study of patients aged 65 years or older that initiated cannabis treatment for different indications, mostly chronic non-cancer pain, during 2018-2020 in a specialized geriatric clinic. The outcomes assessed were activities of daily living (ADL), instrumental activities of daily living (IADL), pain intensity, geriatric depression scale, chronic medication use, and adverse events at six months. A cohort of 119 patients began cannabis treatment: the mean age was 79.3 ± 8.5 and 74 (62.2%) were female. Of the cohort, 43 (36.1%) experienced adverse effects due to cannabis use and 2 (1.7%) required medical attention. The mean ADL scores before and after treatment were 4.4 ± 1.8 and 4.5 ± 1.8, respectively (p = 0.27), and the mean IADL scores before and after treatment were 4.1 ± 2.6 and 4.7 ± 3, respectively (p = 0.02). We concluded that medical cannabis in older adults has a number of serious adverse events, but was not associated with a decrease in functional status, as illustrated by ADL and IADL scores after six months of continuous treatment.

Effect of semaglutide on major adverse cardiovascular events by baseline kidney parameters in participants with type 2 diabetes and at high risk of cardiovascular disease: SUSTAIN 6 and PIONEER 6 post hoc pooled analysis

BackgroundSemaglutide is a glucose-lowering treatment for type 2 diabetes (T2D) with demonstrated cardiovascular benefits; semaglutide may also have kidney-protective effects. This post hoc analysis investigated the association between major adverse cardiovascular events (MACE) and baseline kidney parameters and whether the effect of semaglutide on MACE risk was impacted by baseline kidney parameters in people with T2D at high cardiovascular risk.MethodsParticipants from the SUSTAIN 6 and PIONEER 6 trials, receiving semaglutide or placebo, were categorised according to baseline kidney function (estimated glomerular filtration rate [eGFR] < 45 and ≥ 45–<60 versus ≥ 60 mL/min/1.73 m2) or damage (urine albumin:creatinine ratio [UACR] ≥ 30–≤300 and > 300 versus < 30 mg/g). Relative risk of first MACE by baseline kidney parameters was evaluated using a Cox proportional hazards model. The same model, adjusted with inverse probability weighting, and a quadratic spline regression were applied to evaluate the effect of semaglutide on risk and event rate of first MACE across subgroups. The semaglutide effects on glycated haemoglobin (HbA1c), body weight (BW) and serious adverse events (SAEs) across subgroups were also evaluated.ResultsIndependently of treatment, participants with reduced kidney function (eGFR ≥ 45–<60 and < 45 mL/min/1.73 m2: hazard ratio [95% confidence interval]; 1.36 [1.04;1.76] and 1.52 [1.15;1.99]) and increased albuminuria (UACR ≥ 30–≤300 and > 300 mg/g: 1.53 [1.14;2.04] and 2.52 [1.84;3.42]) had an increased MACE risk versus those without. Semaglutide consistently reduced MACE risk versus placebo across all eGFR and UACR subgroups (interaction p value [pINT] > 0.05). Semaglutide reduced HbA1c regardless of baseline eGFR and UACR (pINT>0.05); reductions in BW were affected by baseline eGFR (pINT<0.001) but not UACR (pINT>0.05). More participants in the lower eGFR or higher UACR subgroups experienced SAEs versus participants in reference groups; the number of SAEs was similar between semaglutide and placebo arms in each subgroup.ConclusionsMACE risk was greater for participants with kidney impairment or damage than for those without. Semaglutide consistently reduced MACE risk across eGFR and UACR subgroups, indicating that semaglutide provides cardiovascular benefits in people with T2D and at high cardiovascular risk across a broad spectrum of kidney function and damage.Trial registrationsNCT01720446; NCT02692716.

Superior antibody immunogenicity of a viral-vectored RH5 blood-stage malaria vaccine in Tanzanian infants as compared to adults

RH5 is a leading blood-stage candidate antigen for a Plasmodium falciparum vaccine; however, its safety and immunogenicity in malaria-endemic populations are unknown. A phase 1b, single-center, dose-escalation, age-de-escalation, double-blind, randomized, controlled trial was conducted in Bagamoyo, Tanzania (NCT03435874). Between 12th April and 25th October 2018, 63 healthy adults (18-35 years), young children (1-6 years), and infants (6-11months) received a priming dose of viral-vectored ChAd63 RH5 or rabies control vaccine. Sixty participants were boosted with modified vaccinia virus Ankara (MVA) RH5 or rabies control vaccine 8weeks later and completed 6months of follow-up post priming. Primary outcomes were the number of solicited and unsolicited adverse events post vaccination and the number of serious adverse events over the study period. Secondary outcomes included measures of the anti-RH5 immune response. Vaccinations were well tolerated, with profiles comparable across groups. No serious adverse events were reported. Vaccination induced RH5-specific cellular and humoral responses. Higher anti-RH5 serum immunoglobulin G (IgG) responses were observed post boost in young children and infants compared to adults. Vaccine-induced antibodies showed growth inhibition activity (GIA) invitro against P.falciparum blood-stage parasites; their highest levels were observed in infants. The ChAd63-MVA RH5 vaccine shows acceptable safety and reactogenicity and encouraging immunogenicity in children and infants residing in a malaria-endemic area. The levels of functional GIA observed in RH5-vaccinated infants are the highest reported to date following human vaccination. These data support onward clinical development of RH5-based blood-stage vaccines to protect against clinical malaria in young African infants. Medical Research Council, London, UK.

Quality of reporting of adverse events in clinical trials of covid-19 drugs: systematic review

ObjectiveTo assess the quality of reporting of adverse events in clinical trials of covid-19 drugs based on the CONSORT (Consolidated Standards of Reporting Trials) harms extension and according to clinical...

Prehospital Tranexamic Acid for Severe Trauma

BackgroundWhether prehospital administration of tranexamic acid increases the likelihood of survival with a favorable functional outcome among patients with major trauma and suspected trauma-induced coagulopathy who are being treated in advanced trauma systems is uncertain.MethodsWe randomly assigned adults with major trauma who were at risk for trauma-induced coagulopathy to receive tranexamic acid (administered intravenously as a bolus dose of 1 g before hospital admission, followed by a 1-g infusion over a period of 8 hours after arrival at the hospital) or matched placebo. The primary outcome was survival with a favorable functional outcome at 6 months after injury, as assessed with the use of the Glasgow Outcome Scale–Extended (GOS-E). Levels on the GOS-E range from 1 (death) to 8 (“upper good recovery” [no injury-related problems]). We defined survival with a favorable functional outcome as a GOS-E level of 5 (“lower moderate disability”) or higher. Secondary outcomes included death from any cause within 28 days and within 6 months after injury.ResultsA total of 1310 patients were recruited by 15 emergency medical services in Australia, New Zealand, and Germany. Of these patients, 661 were assigned to receive tranexamic acid, and 646 were assigned to receive placebo; the trial-group assignment was unknown for 3 patients. Survival with a favorable functional outcome at 6 months occurred in 307 of 572 patients (53.7%) in the tranexamic acid group and in 299 of 559 (53.5%) in the placebo group (risk ratio, 1.00; 95% confidence interval [CI], 0.90 to 1.12; P=0.95). At 28 days after injury, 113 of 653 patients (17.3%) in the tranexamic acid group and 139 of 637 (21.8%) in the placebo group had died (risk ratio, 0.79; 95% CI, 0.63 to 0.99). By 6 months, 123 of 648 patients (19.0%) in the tranexamic acid group and 144 of 629 (22.9%) in the placebo group had died (risk ratio, 0.83; 95% CI, 0.67 to 1.03). The number of serious adverse events, including vascular occlusive events, did not differ meaningfully between the groups.ConclusionsAmong adults with major trauma and suspected trauma-induced coagulopathy who were being treated in advanced trauma systems, prehospital administration of tranexamic acid followed by an infusion over 8 hours did not result in a greater number of patients surviving with a favorable functional outcome at 6 months than placebo. (Funded by the Australian National Health and Medical Research Council and others; PATCH-Trauma ClinicalTrials.gov number, NCT02187120.)

Transplantation Outcomes with Donor Hearts after Circulatory Death

BackgroundData showing the efficacy and safety of the transplantation of hearts obtained from donors after circulatory death as compared with hearts obtained from donors after brain death are limited.MethodsWe conducted a randomized, noninferiority trial in which adult candidates for heart transplantation were assigned in a 3:1 ratio to receive a heart after the circulatory death of the donor or a heart from a donor after brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group). The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart graft at 30 days after transplantation.ResultsA total of 180 patients underwent transplantation; 90 (assigned to the circulatory-death group) received a heart donated after circulatory death and 90 (regardless of group assignment) received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor). The risk-adjusted 6-month survival in the as-treated population was 94% (95% confidence interval [CI], 88 to 99) among recipients of a heart from a circulatory-death donor, as compared with 90% (95% CI, 84 to 97) among recipients of a heart from a brain-death donor (least-squares mean difference, −3 percentage points; 90% CI, −10 to 3; P<0.001 for noninferiority [margin, 20 percentage points]). There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation.ConclusionsIn this trial, risk-adjusted survival at 6 months after transplantation with a donor heart that had been reanimated and assessed with the use of extracorporeal nonischemic perfusion after circulatory death was not inferior to that after standard-care transplantation with a donor heart that had been preserved with the use of cold storage after brain death. (Funded by TransMedics; ClinicalTrials.gov number, NCT03831048.)

Comparing the risk of anaphylaxis requiring epinephrine in oral immunotherapy and subcutaneous immunotherapy: Areview of recent Canadian real-world literature.

The safety of pediatric food oral immunotherapy (Ped-OIT) has been depicted by some as less favorable than subcutaneous immunotherapy (SCIT) owing to the increased number of serious adverse events requiring epinephrine. Areview of real-world data comparing Ped-OIT and SCIT safety is necessary to guide shared decision making. Our aim was to compare the safety and adverse event profiles of peanut Ped-OIT and SCIT using Canadian real-word literature. We performed a retrospective review of recent Canadian real-world literature on peanut Ped-OIT and SCIT safety and adverse events. The incidences of systemic reactions requiring epinephrine were 11 in 270 patients (4.07%) and 12 in 41,020 doses (0.029%) in a multicenter study in British Columbia, Alberta, Manitoba, and Nova Scotia studying 270 preschool-age children treated with peanut OIT. Similarly, a multicenter study in South-Western Ontario examining 160 patients between the ages of 1 and 17 years who were treated with peanut OIT showed that the incidences of systemic reactions requiring epinephrine were 5 in 160 patients (3.1%) and 8 in 52,751 doses (0.015%). Asingle-center retrospective review of 380 patients receiving aeroallergen SCIT showed that the incidences of systemic reactions requiring epinephrine were 28 in 380 patients (7.4%) and 1 in 1047 injection visits (0.095%). These findings are comparable to those of a review of 860 patients in Ontario who received either aeroallergen or venom SCIT, in which the incidence of systemic reaction requiring epinephrine was 10 in 4242 injections (0.24%). Despite differences in the OIT protocols used and age groups studied, recent real-world data suggest that the safety of preschool peanut OIT or peanut OIT using a slower buildup schedule is comparable to that of SCIT.

Effects of Dapagliflozin in Chronic Kidney Disease, With and Without Other Cardiovascular Medications: DAPA-CKD Trial.

Background The DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial (NCT03036150) demonstrated that dapagliflozin reduced the risk of kidney and cardiovascular events in patients with chronic kidney disease and albuminuria with and without type 2 diabetes. We aimed to determine whether baseline cardiovascular medication use modified the dapagliflozin treatment effect. Methods and Results We randomized 4304 adults with baseline estimated glomerular filtration rate 25 to 75 mL/min per 1.73 m2 and urinary albumin:creatinine ratio 200 to 5000 mg/g to dapagliflozin 10 mg or placebo once daily. The primary end point was a composite of ≥50% estimated glomerular filtration rate decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary end points included a kidney composite end point (primary composite end point without cardiovascular death), a cardiovascular composite end point (hospitalized heart failure or cardiovascular death), and all-cause mortality. We categorized patients according to baseline cardiovascular medication use/nonuse. Patients were required by protocol to receive a stable (and maximally tolerated) dose of a renin-angiotensin-aldosterone system inhibitor. We observed consistent benefits of dapagliflozin relative to placebo, irrespective of baseline use/nonuse of renin-angiotensin-aldosterone system inhibitors (98.1%), calcium channel blockers (50.7%), β-adrenergic antagonists (39.0%), diuretics (43.7%), and antithrombotic (47.4%), and lipid-lowering (15.0%) agents. Use of these drugs in combination with dapagliflozin did not increase the number of serious adverse events. Conclusions The safety profile and efficacy of dapagliflozin on kidney and cardiovascular end points in patients with chronic kidney disease were consistent among patients treated and not treated at baseline with a range of cardiovascular medications. Registration Information clinicaltrials.gov. Identifier: NCT03036150.

An obituary on DAV-132—authors’ viewpoint on the current limits of pivotal trials in clinical microbiome research

There is an urgent need for novel approaches to reduce the spread and clinical impact of infections with MDR bacteria. Da Volterra (Paris, France) is a biopharmaceutical company specializing in the development of microbiota-protective therapies. In 2010, they introduced DAV-132, an active charcoal preparation designed to protect the gut microbiota from antibiotic selection pressure, without affecting antibiotic pharmacokinetics, at the Superbugs and Superdrugs Conference in London, UK.1 In 2016, Da Volterra joined the EU Innovative Medicines Initiative (IMI) to further develop this promising product in close cooperation with academic partners. Phase I and II trials were completed successfully, confirming the protective effect of DAV-132 on the human gut microbiota.2,3 Consequently, a Phase III trial—MICROCARE—was planned and initiated. On 2 December 2022, however, the company Da Volterra was declared bankrupt. Given the significant clinical potential of DAV-132, this turn of events can be considered tragic. Could it have been avoided? The authors of this letter were closely involved in the design and conduct of the Phase III trial necessary for registration of DAV-132, which was classified as a medical device by the competent authorities. Many hurdles had to be overcome to design and implement a trial that would be feasible to execute. To meet EMA and FDA registration criteria, it was necessary to show that DAV-132 could confer a health benefit. Protecting the microbiota is a very useful property, but is not considered a health benefit per se and is not recognized as a surrogate endpoint. Therefore, an alternative clinical endpoint had to be identified. The evidence on potential health benefits associated with a balanced human microbiota seems to be growing exponentially.4 At the same time, very little of that evidence is quantifiable and directly relatable to endpoints recognized by regulators. For the Phase III trial, we needed patients with considerable antibiotic exposure. These would have to experience a measurable clinical outcome associated with their antibiotic exposure. In addition, the frequency of this outcome to occur would need to be high enough to result in a feasible sample size. The only indication that seemed to fit these criteria was the prevention of Clostridioides difficile infections (CDI). Even though CDI is considered the most frequent healthcare-associated infectious cause of diarrhoea, its overall incidence is declining. Predicting which individual patient might develop CDI remains a major challenge, despite the identification of age and intense antibiotic exposure as key risk factors for CDI.5,6 In patients undergoing induction chemotherapy for AML or high-risk myelodysplastic syndrome the frequent co-occurrence of the latter risk factors results in a relatively high cumulative incidence of CDI, ranging from 9.4% to 23.8% within the first 120 days after initiation of induction chemotherapy.7–10 Even in this selected population, a sample size of 900 was deemed necessary to show the prophylactic efficacy of DAV-132, while assuming a clinical efficacy of DAV-132 of 50% reduction in CDI cases. At the same time, selecting such a seriously ill patient population involves risks. Chemotherapy-associated side effects can significantly impair patient compliance with trial protocols, and an increased number of serious adverse events is to be expected in this population. However, given that the sample sizes calculated for all other populations were not within a realistic range, we were left with the choice of no trial versus a trial with a considerable risk of failure.

Nylon ring with titanium clip assists endoscopic cyanoacrylate injection for the treatment of GOV1-type gastric varices.

There is an estimated approximately 20 % chance of having gastric varices in patients with portal hypertension [1]. Gastric varices bleed less frequently than esophageal varices but are much more severe when they do occur. Therefore, effective treatment of such bleeding or prevention of rebleeding is vital. According to the Baveno VI Consensus Symposium, endoscopic injection of cyanoacrylate is the recommended treatment for hemostasis and prevention of rebleeding from gastric varices [2] (de Franchis and Baveno 2015). However, a number of serious adverse events has been reported including ectopic embolism, especially in bleeding patients with gastric varices and gastrorenal shunts (GOV2 or IGV1 varices) [3] [4]. As an alternative to endoscopic therapy guided by endoscopic ultrasound (EUS) and balloon-occluded retrograde transvenous obliteration, we hope to provide a new simple and effective method for the treatment of GOV1 gastric varices. By using nylon rings and clips we attempted to completely block blood flow to the gastric varices before injecting cyanoacrylate into the gastric varices. This method can effectively reduce the risk of ectopic embolism in GOV1 gastric varices and reduce the dosage of cyanoacrylate.

Effects of maternal antenatal treatment with two doses of azithromycin added to monthly sulfadoxine-pyrimethamine for the prevention of low birth weight in Burkina Faso: an open-label randomized controlled trial

BackgroundExposure during pregnancy to malaria and sexually-transmitted infections is associated with adverse birth outcomes including low birth weight (LBW). This study aimed at assessing if the adjunction of two doses of azithromycin to sulfadoxine-pyrimethamine for the intermittent preventive treatment of malaria in pregnancy can reduce LBW.MethodsA two parallel-groups, open-label randomized controlled trial involving pregnant women (16 to 35 years of age and 12 to 24 weeks of gestation as confirmed by last menstrual period or fundal height) was conducted in rural Burkina Faso. Women were assigned in a 1:1 ratio either to use azithromycin (1 g daily for 2 days) during the second and third trimesters of pregnancy plus monthly sulfadoxine-pyrimethamine (1500/75 mg) (SPAZ) (intervention) or to continue using a monthly sulfadoxine-pyrimethamine (1500/75 mg) (SP) (control). Primary outcome was a LBW (birth weight measured within 24 h after birth < 2500 g). Secondary outcomes including stillbirth, preterm birth or miscarriage are reported together with safety data.ResultsA total of 992 pregnant women underwent randomization (496 per group) and 898 (90.5%) valid birth weights were available (450 in SPAZ and 448 in SP). LBW incidence was 8.7% (39/450) in SPAZ and 9.4% (42/448) in controls (p-value = 0.79). Compared with controls, pregnant women with SPAZ showed a risk ratio (RR) of 1.16 (95% confidence interval (CI 0.64–2.08]) for preterm births, 0.75 (95% CI 0.17–3.35) for miscarriage and 0.64 (95% CI 0.25–1.64) for stillbirths. No treatment-related serious adverse events (SAEs) have been observed, and there was no significant difference in the number of SAEs (13.5% [67/496] in SPAZ, 16.7% [83/496] in SP, p-value = 0.18) or AEs (17.1% [85/496] in SPAZ, 18.8% [93/496] in SP, p-value = 0.56).ConclusionAdequate prevention regimen with monthly sulfadoxine-pyrimethamine given to all pregnant women has been proved to reduce the risk of LBW in malaria endemic areas. Adding azithromycin to the regimen does not offer further benefits, as far as women receive a malaria prevention regimen early enough during pregnancy.Trial registration Pan African Clinical Trial Registry (https://pactr.samrc.ac.za/Search.aspx): PACTR201808177464681. Registered 21 August 2018.

Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest

BackgroundExtracorporeal cardiopulmonary resuscitation (CPR) restores perfusion and oxygenation in a patient who does not have spontaneous circulation. The evidence with regard to the effect of extracorporeal CPR on survival with a favorable neurologic outcome in refractory out-of-hospital cardiac arrest is inconclusive.MethodsIn this multicenter, randomized, controlled trial conducted in the Netherlands, we assigned patients with an out-of-hospital cardiac arrest to receive extracorporeal CPR or conventional CPR (standard advanced cardiac life support). Eligible patients were between 18 and 70 years of age, had received bystander CPR, had an initial ventricular arrhythmia, and did not have a return of spontaneous circulation within 15 minutes after CPR had been initiated. The primary outcome was survival with a favorable neurologic outcome, defined as a Cerebral Performance Category score of 1 or 2 (range, 1 to 5, with higher scores indicating more severe disability) at 30 days. Analyses were performed on an intention-to-treat basis.ResultsOf the 160 patients who underwent randomization, 70 were assigned to receive extracorporeal CPR and 64 to receive conventional CPR; 26 patients who did not meet the inclusion criteria at hospital admission were excluded. At 30 days, 14 patients (20%) in the extracorporeal-CPR group were alive with a favorable neurologic outcome, as compared with 10 patients (16%) in the conventional-CPR group (odds ratio, 1.4; 95% confidence interval, 0.5 to 3.5; P=0.52). The number of serious adverse events per patient was similar in the two groups.ConclusionsIn patients with refractory out-of-hospital cardiac arrest, extracorporeal CPR and conventional CPR had similar effects on survival with a favorable neurologic outcome. (Funded by the Netherlands Organization for Health Research and Development and Maquet Cardiopulmonary [Getinge]; INCEPTION ClinicalTrials.gov number, NCT03101787.)

A Randomized Trial of Autologous Chondrocyte Implantation Versus Alternative Forms of Surgical Cartilage Management in Patients With a Failed Primary Treatment for Chondral or Osteochondral Defects in the Knee

Background: There are limited randomized controlled trials with long-term outcomes comparing autologous chondrocyte implantation (ACI) versus alternative forms of surgical cartilage management within the knee. Purpose: To determine at 5 years after surgery whether ACI was superior to alternative forms of cartilage management in patients after a failed previous treatment for chondral or osteochondral defects in the knee. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: In total, 390 participants were randomly assigned to receive either ACI or alternative management. Patients aged 18 to 55 years with one or two symptomatic cartilage defects who had failed 1 previous therapeutic surgical procedure in excess of 6 months prior were included. Dual primary outcome measures were used: (1) patient-completed Lysholm knee score and (2) time from surgery to cessation of treatment benefit. Secondary outcome measures included International Knee Documentation Committee and Cincinnati Knee Rating System scores, as well as number of serious adverse events. Analysis was performed on an intention-to-treat basis. Results: Lysholm scores were improved by 1 year in both groups (15.4 points [95% CI, 11.9 to 18.8] and 15.2 points [95% CI, 11.6 to 18.9]) for ACI and alternative, with this improvement sustained over the duration of the trial. However, no evidence of a difference was found between the groups at 5 years (2.9 points; 95% CI, −1.8 to 7.5; P = .46). Approximately half of the participants (55%; 95% CI, 47% to 64% with ACI) were still experiencing benefit at 5 years, with time to cessation of treatment benefit similar in both groups (hazard ratio, 0.97; 95% CI, 0.72 to 1.32; P > .99). There was a differential effect on Lysholm scores in patients without previous marrow stimulation compared with those with marrow stimulation (P = .03; 6.4 points in favor of ACI; 95% CI, −0.4 to 13.1). More participants experienced a serious adverse event with ACI (P = .02). Conclusion: Over 5 years, there was no evidence of a difference in Lysholm scores between ACI and alternative management in patients who had previously failed treatment. Previous marrow stimulation had a detrimental effect on the outcome of ACI. Registration: International Standard Randomised Controlled Trial Number: 48911177

Hybrid Ablation Versus Repeated Catheter Ablation in Persistent Atrial Fibrillation: A Randomized Controlled Trial

BackgroundAlthough catheter ablation (CA) is successful for the treatment of paroxysmal atrial fibrillation (AF), results are less satisfactory in persistent AF. Hybrid ablation (HA) results in better outcomes in patients with persistent atrial fibrillation (persAF), as it combines a thoracoscopic epicardial and transvenous endocardial approach in a single procedure. ObjectivesThe purpose of this study was to compare the effectiveness and safety of HA with CA in a prospective, superiority, unblinded, randomized controlled trial. MethodsForty-one ablation-naive patients with (long-standing)-persAF were randomized to HA (n = 19) or CA (n = 22) and received pulmonary vein isolation, posterior left atrial wall isolation and, if needed, a cavotricuspid isthmus ablation. The primary efficacy endpoint was freedom from any atrial tachyarrhythmia >5 minutes off antiarrhythmic drugs after 12 months. The primary and secondary safety endpoints included major and minor complications and the total number of serious adverse events. ResultsAfter 12 months, the freedom of atrial tachyarrhythmias off antiarrhythmic drugs was higher in the HA group compared with the CA group (89% vs 41%, P = 0.002). There was 1 pericarditis requiring pericardiocentesis and 1 femoral arteriovenous-fistula in the HA group. In the CA arm, 1 bleeding from the femoral artery occurred. There were no deaths, strokes, need for pacemaker implantation, or conversions to sternotomy, and the number of (serious) adverse events was comparable between groups (21% vs 14%, P = 0.685). ConclusionsHybrid AF ablation is an efficacious and safe procedure and results in better outcomes than catheter ablation for the treatment of patients with persistent AF. (Hybrid Versus Catheter Ablation in Persistent AF [HARTCAP-AF]; NCT02441738)

HTA160 A Systematic Review and Meta-Analysis of the Janus Kinase Inhibitors Safety Profile in Relation to the Risks of Secondary Bacterial Infections

Evaluation of the safety of drugs for preventive pathogenetic therapy of a newcoronavirus infection COVID-19 with the of Janus kinase inhibitors. A systematic review with a meta-analysis was conducted based on search queries in international databases. Search strategy included queries for controlled studies on the use of baricitinib and tofacitinib recommended for use as a preventive therapy for mild and moderate cases of a new coronavirus infection. Data were obtained from three randomized clinical trials. A meta-analysis of the results regarding the total number of serious adverse events (AEs) and adverse events belonging to the class "Infections and infestations" showed statistically significant evidence on the greater safety of baricitinib and tofacitinib in relation to the risks of these events compared with standard therapy: the risk ratio (RR) of serious adverse events in the comparison groups was 0.82 [95%, CI 0.69; 0.96] (p=0.02), the risk ratio of "Infections and invasions" was 0.78 [95% CI 0.63; 0.97] (p=0.03). In both cases RR was in favor of the use of Janus kinase inhibitors. The results of the meta-analysis demonstrated a favorable safety profile of baricitinib and tofacitinib when used in patients with COVID-19 in relation to the risks of developing serious AEs, as well as infections. Conducting studies of various designs in a wider patient population will allow more accurate assessment of the risks of developing secondary bacterial infections against the background of short-term use of Janus kinase inhibitors as part of their use as a preventive pathogenetic therapy during the COVID-19 pandemic.

Reporting of the safety from allergic rhinitis trials registered on ClinicalTrials.gov and in publications: An observational study

BackgroundIncomplete and inconsistent reporting of adverse events (AEs) through multiple sources can distort impressions of the overall safety of the medical interventions examined as well as the benefit-risk relationship. We aimed to assess completed allergic rhinitis (AR) trials registered in ClinicalTrials.gov for completeness and consistency of AEs reporting comparing ClinicalTrials.gov and corresponding publications.MethodsWe retrospectively examined completed randomised controlled trials on AR registered in ClinicalTrials.gov on or after 9/27/2009 to trials updated with results on or before 12/31/2021 along with any corresponding publications. Complete reporting of AEs in ClinicalTrials.gov were summarised in tables describing AE information, and complete reporting in publications was an explicit statement of serious AE, death or other AE. Difference in completeness, number, or description of AEs between ClinicalTrials.gov and publication was classified as inconsistent reporting of AEs.ResultsThere were 99 registered trials with 45 (45.5%) available publications. All published trials completely reported AEs in ClinicalTrials.gov, and 21 (46.7%) in publications (P < .001). In 43 (95.6%) publications, there was at least one inconsistency in the reporting of AEs (P < .001). 8 (17.8%) publications had different number of serious AEs (P = .003), 36 (80.0%) of other AEs (P < .001) while deaths reporting was inconsistent in 8 (57.1%) publications (P = .127).ConclusionThe reporting of AEs from AR trials is complete in ClinicalTrials.gov and incomplete and inconsistent in corresponding publications. There is a need to improve the reporting of AEs from AR trials in corresponding publications, and thus to improve patient safety.

Trial of Erythropoietin for Hypoxic–Ischemic Encephalopathy in Newborns

BackgroundNeonatal hypoxic–ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic–ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown.MethodsIn a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic–ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.ResultsOf 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P=0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57).ConclusionsThe administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic–ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.)