Crohn’s disease management involves a step-up approach, in which steroids, anti-metabolites and TNF antagonists are used sequentially. However, this is thought to delay effective therapy and expose patients to extended periods of corticosteroids. The TOP-DOWN and SONIC trials showed superiority of early combined immunosuppression (ECI) compared to conventional management. This study, the REACT trial, was an open cluster randomized trial that involved 1982 patients, greater than 18 years of age, with documented Crohn’s regardless of Crohn’s activity or existing Crohn’s disease treatments in 41 community gastroenterology practice in Belgium and Canada randomized to ECI or conventional management. The primary outcome was corticosteroid-free remission at 12 months. Of the 41 practices, 22 were assigned to ECI and 19 to conventional management. At ECI practices, patients with continuing disease activity defined as Harvey-Bradshaw Index [HBI] score>4, received combination therapy with TNF antagonist (usually adalimumab) and an anti-metabolite of choice after initiation with corticosteroids. Presence of active disease as measured by HBI ≥7 resulted in intensification of TNF antagonist. In the conventional management practices, the physicians were unaware of the ECI-algorithm and managed patients according to usual practice. At the ECI practices, the corticosteroid-free remission at 12 months was 66.0% (SD 14) vs 61.9% (SD 16.9) at conventional management practices. Adjusted difference was 2.5%, 95% CI [-5.2, 10.2], p=0.5169. At 24 months, remission rates were 73.1% (SD 7.1) at ECI practices vs 65.1% (17.4) at conventional management practices. Adjusted differences were 6.4%, 95% CI[–0.9, 13.6], p=0.0829. Adverse outcomes, defined as surgery, hospital admission or serious disease related complications, were lower at ECI practices compared with conventional management practices. (27.7% vs 35.1%, hazard ratio [HR]: 0.73, 95% CI [0.62,0.86], p=0.0003) This study had two important limitations. The first was a lack of ileocolonoscopies to objectively assess disease activity and the second was lack of blinding due to the complex nature of the ECI algorithm. This study showed that although ECI was not more effective in controlling Crohn’s symptoms, it did have lower rates of major adverse events compared to that in conventional practice.
Almost 1 million people worldwide receive transvenous cardiac pacemakers with active-fixation leads for the treatment of bradycardia and heartblock. However, these pacemakers are associated with complication in 1 of 10 cases. The LEADLESS trial demonstrated the feasibility of the leadless cardiac pacemaker in humans. This study, an interim analysis, of the prospective LEADLESS II trial aims to investigate the safety and efficacy of implanting this pacemaker in patients requiring permanent ventricular pacing. This study was an observational non-randomized multicenter study involving 300 patients who were followed for 6 months after implantation of a leadless pacemaker. The primary efficacy endpoint was a therapeutically acceptable pacing threshold (≤2.0 V at 0.4 msec) and a therapeutically acceptable sensing amplitude (R wave ≥5.0 mV, or a value equal to or greater than the value at implantation). The primary safety endpoint was freedom from adverse events during the first 6 months after implantation. The rate of successful implantation was 95.8%, and the efficacy goals for pacing and sensing were met in 90% of the total cohort, CI [86.0%,93.2%]. The mean pacing threshold and sensing values were similar to those observed in conventional leads at 6 months. The primary safety endpoint was met in 280 of 300 patients, CI [89.9%,95.9%]. Device related complications arose in 6.7% of the cohort, including device dislodgement in 1.7%, cardiac perforation in 1.3%, elevated pacing thresholds requiring device retrieval and reimplantation in 1.3%, and vascular complications in 1.3%. In comparison, conventional ventricular pacemakers are associated with complications in 3.2% of patients, including pneumothorax in 1.1%, lead dislodgement in 0.8%, and infection in 0.5%. This study showed that the leadless pacemaker met the pacing and sensing requirement in the majority of patients, with device related adverse events in 1 of 15 patients. However, this trial was an observational study which did not compare the leadless cardiac pacemaker with conventional pacemakers. This limits the ability to make comparisons between the two. Secondly, the mean-follow up was only 6 months which limits inferences of long term effects. Lastly, the leadless pacemaker is only a single-chamber ventricular pacemaker which accounts for only a minority of those implanted in the US.
Mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone, when added to renin-angiotensin (RAS) blockers reduce proteinuria in patients with CKD but are associated with increased risk of hyperkalemia. This study examined the effect of finerenone, a novel non-steroidal MRA, on the urine albumin-creatinine ratio (UACR) at 90 days. The primary safety endpoint was serum potassium and estimated glomerular filtration rate (eGFR). The study was randomized, double-blind, placebo-controlled study that involved 1501 patients, with 823 patients in the final randomized group. 94 patients received a placebo and the 729 who received finerenone were stratified into 7 groups by dosage (2.5mg-20mg). Eligibility criteria included history of type 2 diabetes, UACR ≥30 mg/g, eGFR> 30 mL/min/1.73 m2, serum potassium ≤4.8 mmol/L. The study found significant reduction in UACR, ranging from 21-38% in the finerenone dosage groups of 7.5-20mg/day vs that in the placebo group. Specifically, finerenone demonstrated a dose-dependent reduction in UACR for doses ≥7.5mg/day. The corrected mean ratios of UACR were 0.79 [90% CI, 0.68-0.91] for 7.5mg/d; 0.76 [90% CI, 0.65-0.88] for 10 mg/d; 0.67 [90% CI, 0.58-0.77] for 15 mg/d; 0.62 [90% CI, 0.54-0.72] for 20 mg/d. Furthermore, the incidences of a serum potassium level ≥5.6 mmol/L were low (2.7%, 5.4%, 4.1%, and 6.3%) in the finerenone 1.25-, 7.5-, 15-, and 20-mg/d groups, respectively. Lastly, the incidence of an eGFR decrease of at least 40% was similar in the placebo and in the 1.25-, 7.5-, 10-, 15-, and 20-mg/d finerenone groups. The main drawbacks of the study included the lack of an active control group, inclusion of patients (60%) with eGFR 60 mL/min/1.73 m2 (meaning those who were less likely to develop hyperkalemia at baseline) and lack of long-term follow up for the intervention group. Overall, this study showed reduction in the corrected UACR at day 90 in a dose-dependent manner, with low incidences of hyperkalemia and comparable reductions in GFR with finerenone compared with placebo.
Myeloproliferative neoplasm-associated myelofibrosis has limited treatment options. Allogenic stem cell transplantation is associated with serious complications such as chronic graft vs host disease. This study examined the therapeutic activity and safety of Imetelstat, a telomerase inhibitor, in patients with advanced myelofibrosis. This was a single center, prospective study involving 33 patients who had myelofibrosis scored as high or intermediate risk disease per DIPSS system, a platelet count of at least 50×10^9/L, ANC>1×10^9/L, AST/ALT >2.5 of upper normal, bilirubin up to 3mg/dL and creatinine up to 3 mg/dL. The primary end point was the overall response rate during the first nine cycles of treatment with secondary endpoints being adverse events, spleen response and independence from red-cell transfusions. Complete or partial response occurred in 7 (21%) patients. Bone marrow fibrosis was reversed in all 4 patients who had a complete response. However, by the data-cutoff date, treatment had to be discontinued in 25 (76%) patients, primarily due to insufficient response. The most clinically significant side effects of Imetelstat included myelosupression, Grade 4 thrombocytopenia, neutropenia and anemia. Although, this study does not explore mechanisms of action or effectively address concerns about drug toxicity, as a pilot study, it shows promise as it demonstrates significant activity in patients despite having high incidences of serious myelosupression.
Dysphagia in post-stroke patients is an important risk factor for development of pneumonia. Prophylactic antibiotics are thought to decrease post-stroke pneumonia mortality and disability. This study, STROKE-NF, was a prospective, cluster-randomized, controlled clinical trial involving 1224 patients across 48 British stroke units. The primary endpoint was post-stroke pneumonia at 14 days as determined by 1) a CDC based hierarchical algorithm and 2) by physician diagnosis. 24 units were assigned to the prophylactic antibiotics group and 24 units to the standard of care group. Post stroke pneumonia was diagnosed by algorithm in 123 (11%) of 1088 patients and 192 (16%) of 1217 patients by physician diagnosis, Kappa 0.22, 95% CI[0.14,0.29]. In the algorithm-diagnosed method, no differences were noted between the two treatment groups even with adjustment for patient, stroke and center characteristics. Marginal adjusted OR was 1.21, 95% CI[.71,2.08], p=0.489. Similar results were found with the physician diagnosis method. OR 1.01, 95% CI[0.61,1.68],p=0.957. The incidence of adverse events, most commonly UTIs, was low in both groups, although the prophylactic antibiotics group did show significantly reduced non-post-stroke pneumonia, especially urosepsis (p=0.02). However, antibiotic use was associated with longer hospital stays compared with control. In conclusion, this study showed that prophylactic antibiotics did not reduce-post stroke pneumonia or mortality. The routine use of antibiotics for pneumonia prophylaxis in post-stroke patients should not be recommended.
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