Duration Of Therapy In Patients Research Articles

Risk score guided dual antiplatelet therapy duration in patients with acute coronary syndrome: insights from the FORCE-ACS registry

Abstract Background The use of risk scores to guide the duration of dual antiplatelet therapy(DAPT) in patients with acute coronary syndrome(ACS) is recommended in current guidelines, however clinical data on the impact of its prospective use is lacking. Purpose To compare risk-score guided DAPT duration to standard of care in ACS patients. Methods Since 2015, patients with ACS are enrolled in the prospective FORCE-ACS registry. In 2018, we implemented a risk score-guided approach for DAPT duration. In this analysis, we compared patients in which DAPT duration was guided by bleeding and ischemic risk assessment using PRECISE-DAPT-scores and DAPT-scores to a standard treatment group in a 1:4 ratio. In risk score-guided patients, high bleeding risk patients(HBR) were advised short DAPT(≤6 months); patients without HBR or high ischemic risk(HIR) were advised 12 months DAPT; and patients without HBR but with HIR were advised prolonged DAPT(≥30 months). In the standard treatment group DAPT duration was left at the discretion of the treating physician. Exclusion criteria included no DAPT or oral anticoagulation at discharge or implanted bio-vascular stents. Primary outcome was a composite of all-cause mortality, myocardial infarction(MI), stent thrombosis(ST), stroke and Bleeding Academic Research Consortium(BARC) 3 or 5 bleeding; a secondary composite ischemic outcome consisted of cardiovascular mortality, MI, ST and ischemic stroke. Kaplan-Meier plots with log-rank testing and Cox proportional hazard regression after adjustment of potential confounders were performed for the primary outcome. Sensitivity analyses were performed for patients included after implementation of the risk score-guided approach and for censoring events within the first six months. Results Between 2015 and 2020 8,009 patients were enrolled in the FORCE-ACS registry, of which 5,518 patients were included for analysis. The risk-score guided group(n=1,200) more often presented with ST-elevation MI, percutaneous coronary intervention or optimal medical therapy, while standard treatment patients(n=4,318) were older, more often had prior MI, prior revascularization, received coronary artery bypass grafting or conservative management. In the risk-score guided group, 15.7% had HBR, 46.4% were without HBR or HIR, and 37.9% showed HIR without HBR. The primary outcome was 6.3%(n=75) in risk score-guided patients versus 14.8%(n=637) in the standard treatment group (adjusted hazard ratio(HR) 0.47 [95%CI 0.36–0.61], p<0.001). These results remained consistent after sensitivity analyses (fig 1B). Both the composite ischemic outcome(HR 0.54 [95%CI 0.41–0.72] p<0.001) and BARC 3 or 5 bleeding (HR 0.23 [95%CI 0.08-0.63], p=0.004) were significantly lower in risk score-guided patients compared to the standard treatment group. Conclusion In this prospective analysis, risk-score guided DAPT duration showed a significant reduction of both ischemic and bleeding events compared to standard treatment.

Epidemiology and Duration of Therapy in Patients with Gram-negative Bloodstream Infections: Retrospective Analysis

Background: Longer courses of antibiotics can be associated with antimicrobial resistance and adverse effects. Randomized clinical trials support treating gram-negative bloodstream infections (GN-BSI) for a shorter duration with a consensus that a seven-day course of antibiotics is appropriate for uncomplicated GN-BSI. Prior to the implementation of a GN-BSI treatment guideline at our institution, we aimed to evaluate the characteristics of patients with GN-BSI and the duration of antibiotic therapy (DOT). Method: We retrospectively reviewed adult inpatients who had a blood culture with at least 1 gram-negative organism within 6 months (November 2022 to April 2023). Patients were excluded if they had a concomitant gram-positive bloodstream infection or if they were transitioned to comfort-focused care within 48 hours of their first positive blood culture. Complicated GN-BSI was defined as exhibiting any of the following: involvement of bone, joint, endovascular system, or foreign body, an inability to achieve source control, immunocompromised status, or failure to demonstrate clinical improvement or culture clearance within 72 hours. The primary outcome of this study was the mean DOT in patients with GN-BSI. Result: 100 patients met the inclusion criteria. Escherichia coli, identified in 54 cases, emerged as the most frequent organism. Urine (41) was the predominant source of bacteremia. Cefepime (48) was the most common empiric agent used. Of the 91 patients with available ceftriaxone susceptibility results, 84% had a susceptible organism. Amongst the 51 patients classified as having a complicated GN-BSI, the leading reason was immunosuppression. Table 1 presents a comparative analysis of complicated vs. uncomplicated GN-BSI. The average DOT for complicated GN-BSI was longer than the uncomplicated infections (20 vs. 11 days, P < 0 .005). Additionally, fewer patients transitioned to oral therapy in the complicated group (33% vs. 67%, P < 0 .005). Conclusion: At our institution, patients with uncomplicated GN-BSI have a shorter DOT and are more likely to transition to oral therapy than those with complicated GN-BSI. However, the mean DOT for uncomplicated infections remained longer than seven days and a large number of uncomplicated GN-BSI patients did not transition to oral therapy, indicating room for improvement in local practice through antimicrobial stewardship initiatives.

Patterns of vancomycin use in high-risk febrile neutropenia.

e23224 Background: Febrile neutropenia (FN) is a common complication in patients with hematologic malignancy. ASCO guidelines on the management of FN endorse empiric anti-Pseudomonas coverage while reserving the use of agents targeting gram-positive organisms and methicillin-resistant Staphylococcus aureus (MRSA) for select criteria-defined patients such as those with severe mucositis, hemodynamic instability, radiographic pneumonia, or history of MRSA colonization among others. We sought to examine our institutional management of FN, hypothesizing that local use of empiric vancomycin for high-risk FN will deviate from ASCO guidelines reflected in institutional policy. Methods: Case data from 1/1/2016 – 6/1/2023 was collected retrospectively, comprising patients admitted to the general medical floor with known leukemia, lymphoma, or multiple myeloma meeting ASCO criteria for FN. Patients admitted to intensive care at time of FN or for less than 48-hours were excluded. For each patient, use of vancomycin at time of FN diagnosis (t0) and 48-hours later (t48) was evaluated for congruence with society guidelines. Results: 91 patients were reviewed with a median age of 68 years old (IQR 59-74, 15). Median length of stay (LOS) was 20 days (IQR 7-29, 22) with FN occurring on day seven of hospitalization on average. Most patients receiving vancomycin were admitted to the hematology specialty unit at time of diagnosis (63%). Acute leukemia was the most common malignancy represented (62.8%), while high grade lymphoma comprised 23.1%. 98.9% of patients were on active chemotherapy at time of FN. 81 patients (89%) received vancomycin as empiric treatment for FN with 76 (93.8%) receiving vancomycin at t0. Of this latter cohort, 29.7% of patients received vancomycin at t0 without indication. At t48, vancomycin was discontinued in 28.4% of patients, 44.4% received vancomycin with true indication, and 27.2% were continued on vancomycin without indication. The median duration of therapy for patients receiving vancomycin incongruently at t48 was 4 days. Of those meeting criteria for vancomycin use at t48, severe mucositis and soft tissue infection were each cited in 22.2% of cases, followed by pneumonia, persistent fever, and hemodynamic instability. Notably, the presence of any grade mucositis was significantly associated with the continued use of empiric vancomycin at t48 (p = .025). Admission to hematology specialty unit did not significantly affect adherence to FN management guidelines. Conclusions: These data suggest that the use of vancomycin for FN at our institution deviates from society guidelines including on specialized hematology wards. This study was underpowered to assess adverse outcomes seen with vancomycin use such as renal injury, prolonged LOS and greater cost of care. Given the high complexity of this patient population, detailed provider education is indicated to promote safe, evidence-based care and broader antimicrobial stewardship.

Impact of Ibrutinib Dose Reduction on Duration of Therapy in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Background : Ibrutinib (Ibr) has demonstrated a significant progression-free survival and overall survival benefit compared to chemotherapy in multiple phase 3 studies in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients with CLL/SLL who continue treatment with single-agent Ibr experience better survival outcomes than those who discontinue treatment within the first 2 years. Adverse events (AEs) may be managed, and treatment outcomes are optimized through Ibr dose reduction (DR). Recent real-world data have shown that patients with a DR after an AE had longer time to next treatment (TTNT) than those without a DR and that this trend was consistent among patients with cardiac and noncardiac AEs (Shadman et al, EHA 2023). Here we continue to evaluate the impact of DR on real-world outcomes using data from electronic medical records (EMRs). Aims: This study estimates the real-world impact of DR following an AE among patients with CLL/SLL. Methods : Previously untreated adults diagnosed with CLL/SLL on or after February 12, 2013), who were treated with 420 mg single-agent Ibr on or after Feb 12, 2014 (Ibr approval date) were analyzed using EMRs from the ConcertAI database (February 12, 2013−May 1, 2022). Patients were included if they had a cardiac or noncardiac AE after single-agent Ibr initiation at 420 mg per day without any DRs/escalations prior to first AE occurrence (index date). Patients were excluded if they received an antineoplastic agent ≤6 months prior to starting first-line (1L) Ibr, an antineoplastic agent or combination therapy within 28 days of Ibr use, second-line therapy within 30 days of index, hematopoietic stem cell transplant, CYP3A inhibitor during 1L Ibr or before start of the second-line, an experimental therapy in clinical trials, or were diagnosed with other malignancies for which Ibr is indicated within 6 months prior to Ibr initiation. Demographics, clinical characteristics, and TTNT were described following AE occurrence among patients with and without DRs. A DR was defined as a dose lower than 420 mg per day on or after the date of first AE post-Ibr initiation, per pharmacy records. Cardiac AEs included atrial fibrillation, ischemic heart disease, heart failure, hypertension, and cardiomyopathy. Noncardiac AEs included febrile neutropenia, anemia, neutropenia, pancytopenia, thrombocytopenia, diarrhea, abdominal pain, musculoskeletal pain, rash, and pneumonia. TTNT sensitivity analyses requiring next-line treatment to occur ≥180 days after 1L initiation or considering a switch to another BTKi or death as censoring events were also conducted. Results : Overall, 522 patients were included in the analysis; 420 patients (80%) without a DR and 102 patients (20%) with a DR. Patients with a DR were slightly older than those without (median age: 74.5 vs 70 years); a lower proportion of women had a DR compared with men (43% vs 57%). Among patients with and without a DR, the median time to the first incident AE was 42 days and 65 days, respectively. Among patients with a DR, 68 (67%) were able to resume the full 420 mg per day Ibr dose after DR. Mean time between Ibr initiation and end of 1L Ibr treatment was significantly longer in patients with a DR compared with those without (553 days vs 464 days; P = 0.012). Fewer patients with DR had a next treatment (47%) than those without a DR (55%). Median TTNT was significantly longer in patients with DR (27 months, 95% CI: 21, 44) compared with those without (18 months, 95% CI: 15, 20) ( P = 0.007) (Figure). TTNT results were similar in each sensitivity analysis. Summary/Conclusion : Among patients with CLL/SLL treated with 1L Ibr, those with doses reduced after experiencing an AE remained on 1L Ibr longer compared with those who did not have the dose reduced. Ibr dose adjustments may support patients with CLL/SLL remaining on 1L Ibr longer.

TCT-638 New Insights Into Long- Versus Short-Term Dual Antiplatelet Therapy Duration in Patients After Stenting for Left Main Coronary Artery Disease: Findings From a Prospective Observational Study

TCT-638 New Insights Into Long- Versus Short-Term Dual Antiplatelet Therapy Duration in Patients After Stenting for Left Main Coronary Artery Disease: Findings From a Prospective Observational Study

КЛИНИКО-ФАРМАКОЛОГИЧЕСКИЕ ОСОБЕННОСТИ ПРИМЕНЕНИЯ ПРЕПАРАТОВ НОРМАЛЬНОГО ИММУНОГЛОБУЛИНА ЧЕЛОВЕКА В ПРАКТИКЕ ВРАЧА

Immunostimulating (immunomodulatory) drugs belong to the group of immunotropic drugs, the therapeutic effect of which is associated with a predominant effect on the human immune system. Medicines based on human normal immunoglobulin are immunostimulatory drugs of natural origin. In the practice of a doctor, immunoglobulins are made from human plasma and are more often used in the form for intravenous and subcutaneous administration. Immunoglobulins differ in the ratio of various subclasses of immunoglobulins G (IgG), as well as immunoglobulin class A (IgA), individual immunoglobulins are enriched with antibodies of the IgM classes, and specific immunoglobulins contain a significantly larger amount of IgG class antibodies against certain pathogens than standard immunoglobulins. Approaches to the classification of immunoglobulins, the mechanism of action, indications, contraindications, as well as clinical and pharmacological features of the use of human normal immunoglobulin, drugs available on the market in the Republic of Belarus are described, recommendations are given for their use in clinical practice. The possibilities of using immunoglobulins as a replacement (for immunodeficiency states, agammaglobulinemia) and immunomodulatory (for autoimmune diseases) therapy are presented. The possibility of using intravenous immunoglobulin for the treatment of Kawasaki syndrome, idiopathic thrombocytopenic purpura, Guillain-Barré syndrome, autoimmune polyneuropathy, diseases arising in oncological, surgical and obstetric practice, as well as for complex therapy of sepsis, including in newborns, is considered. Timely appointment of immunoglobulins in optimal doses will reduce the duration of therapy in patients with immunosuppression of various origins, reduce bleeding in immune thrombocytopenia.

Three versus 12-month dual antiplatelet therapy duration in patients with acute coronary syndrome undergoing percutaneous coronary intervention: A meta-analysis of randomized controlled trials.

The American Heart Association/American College of Cardiology guidelines on dual antiplatelet therapy (DAPT) recommend at least 12 months of a P2Y12 inhibitor and low dose aspirin in patients with an acute coronary syndrome (ACS) treated with a stent. Since that recommendation, several randomized controlled trials (RCTs) have studied an abbreviated duration of DAPT in ACS. Therefore, we sought to perform a meta-analysis of RCTs comparing 3- versus 12-month DAPT in patients presenting with ACS undergoing percutaneous coronary intervention (PCI). PubMed, Embase, and Cochrane Central databases were searched until July 31, 2022, for RCTs comparing 3- versus 12-month DAPT in patients with ACS undergoing PCI. Outcomes assessed were major adverse cardiovascular events (MACE), cardiovascular mortality, all-cause mortality, myocardial infarction (MI), stent thrombosis (ST) and bleeding. A random-effects model was used to calculate pooled relative risk (RR) and 95% confidence intervals (CI). We included 5 trials comprising 16,781 patients with an ACS that underwent PCI. There was no significant difference in MACE (RR: 0.92; 95% CI: 0.76-1.11), cardiovascular mortality (RR: 1.26; 95% CI: 0.38-4.17), or all-cause mortality (RR: 0.92; 95% CI: 0.48-1.77) between the 2 groups. In addition, there was no difference in rates of MI (RR: 0.98; 95% CI: 0.74-1.30), or ST (RR: 1.30; 95% CI: 0.55-3.05) between 3- and 12-month DAPT. However, compared with 12-month DAPT, 3-month DAPT significantly reduced risk of major bleeding (RR: 0.53; 95% CI: 0.43-0.64). In patients with ACS undergoing PCI, 3-month DAPT reduced risk of bleeding without evidence of harm.

Survival analysis of patients with advanced metastatic differentiated thyroid cancer

Introduction. Current treatment of differentiated thyroid cancer includes surgical resection of the thyroid gland, radioiodine therapy (RIT) followed by hormone therapy with levothyroxine. If a patient has distant metastases, radioiodine therapy gains vital importance, becoming a non-competitive method of treatment. However, with incomplete expressed or lost ability of tumor cells to absorb radioactive iodine (131I), the effect of RIT occurs to be limited or completely lost. Radioactive iodine refractivity develops, in which the disease progresses despite ongoing therapy. Therapy with tyrosine kinase inhibitors for the progressive radioiodine-refractory thyroid cancer is currently the only recognized effective treatment. Based on the results of the SELECT study, in an indirect comparison with the data obtained earlier in the DECISION study, lenvatinib was found to be the most effective drug.The study objective is to provide a comparative analysis of response to treatment and overall survival in two groups of patients with progressive metastatic differentiated thyroid cancer. In group 1, treatment was based on continuing radioiodine therapy in combination with suppressive hormone therapy with levothyroxine; in group 2, with the development of radioiodine refractivity, lenvatinib was prescribed.Materials and methods. The study included two groups of patients treated at different times in the A.f. Tsyb medical Radiology Research Center - branch of the National medical Research Center of Radiology, ministry of Health of Russia. group 1 included patients who continued radioiodine therapy, despite disease progression on treatment (historical control group). This group (n = 191) consisted of patients with differentiated thyroid cancer who received radioiodine therapy until January 2015, when the criteria for radioactive iodine refractivity had not yet been established and there was no unified approach to such patients and no possibility of targeted therapy with tyrosine kinase inhibitors. group 2 (n =71) consisted of patients receiving lenvatinib in the 1st line targeted therapy from January 2015 to march 2022, from the time of radiographically confirmed tumor progression according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) and establishing the fact of radioactive iodine refractivity.Results. In the historical control group (n = 19) 18 (9.4 %) patients are alive to date. It should be specifically noted that all of them had a miliary dissemination in the lungs. None of the 191 patients had a complete or partial response to treatment. All patients had either disease stabilization (83 (43.45 %) patients), or disease progression (108 (56.54 %) patients). The number of RIT courses varied from 9 to 27, 13 ± 3.4 on average. The total dose for the entire treatment period varied from 21 to 75 GBq, 39.3 ± 10 on average. Overall survival averaged 80 ± 20.3 months (min 54 months, max 162 months). patients with slow disease progression had the longest overall survival. In the lenvatinib group the median duration of therapy in patients who discontinued treatment reached 26.3 months (1-52 months). Tumor response to treatment was evaluated in 71 patients. According to the RECIST 1.1 criteria, the maximum response was regarded as complete in 1 (1.41 %) patient, as partial - in 30 (42.45 %) patients, as stable disease - in 23 (32.39 %) patients, as disease progression - in 13 (18.31 %) cases. The median time to evaluate the first response to treatment was 4 (2-8) months. PFS was 17.3 months (95 % confidence interval 15.1-19.4 months). The median PFS in the subgroup of patients who responded to lenvatinib therapy (with a complete and partial response) was 32.5 months (95 % confidence interval 30.7-37.7). The median overall survival at the time of data analysis was not reached.Conclusion. A comparative analysis showed that the approach to the treatment of patients with progressive radioyod-refracted differentiated thyroid cancer based on continued radioiodine therapy is wrong. It was the only impelled option when tyrosine kinase inhibitors therapy for differentiated thyroid cancer was unavailable. Currently, the majority of patients with progressive radioyodrefracted differentiated thyroid cancer receive lenvatinib in the first line targeted therapy. The role of this therapy in the treatment of patients with radioyodrefracted differentiated thyroid cancer is currently increasing. The promising prospects for the synthesis of new targeted drugs are becoming obvious, such as the need for further research and comparison of drugs already in use as well.

New Insights Into Long- Versus Short-Term Dual Antiplatelet Therapy Duration in Patients After Stenting for Left Main Coronary Artery Disease: Findings From a Prospective Observational Study.

The appropriate duration of dual antiplatelet therapy (DAPT) and risk-benefit ratio for long-term DAPT in patients with left main (LM) disease undergoing percutaneous coronary intervention remains uncertain. Four thousand five hundred sixty-one consecutive patients with stenting of LM disease at a single center from January 2004 to December 2016 were enrolled. Decision to discontinue or remain on DAPT after 12 months was left to an individualized decision-making based on treating physicians by weighing the patient's risks of ischemia versus bleeding and considering patient preference. The primary outcome was a composite of death, myocardial infarction, stent thrombosis, or stroke at 3 years. Key safety outcome was 3-year rate of Bleeding Academic Research Consortium 2, 3, or 5 bleeding. Of 3865 patients free of ischemic and bleeding events at 12 months, 1727 (44.7%) remained on DAPT (mostly clopidogrel based [97.7%]) beyond 12 months after LM percutaneous coronary intervention. DAPT>12-month versus ≤12-month DAPT was associated with a significant reduced risk of 3-year primary outcome (2.6% versus 4.6%; adjusted hazard ratio: 0.59 [95% CI, 0.41-0.84]). The same trend was found for other ischemic end points: death (0.9% versus 3.0%; Plog-rank<0.001), cardiovascular death (0.5% versus 1.7%; Plog-rank=0.001), myocardial infarction (0.8% versus 1.9%; Plog-rank=0.005), and stent thrombosis (0.4% versus 1.1%; Plog-rank=0.017). The key safety end point was not significantly different between 2 regimens (1.8% versus 1.6%; adjusted hazard ratio: 1.07 [95% CI, 0.65-1.74]). The effect of DAPT>12 month on primary and key safety outcomes was consistent across clinical presentations, high bleeding risk, P2Y12 inhibitor, and LM bifurcation percutaneous coronary intervention approach. In a large cohort of patients free from clinical events during the first year after LM percutaneous coronary intervention and at low apparent future bleeding risk, an individualized patient-tailored approach to longer duration (>12 month) of DAPT with aspirin plus a P2Y12 inhibitor (mostly clopidogrel) improved both composite and individual efficacy outcomes by reducing ischemic risk, without a concomitant increase in clinically relevant bleeding.

P09 The use of ESR and pain scores to determine the duration of antibiotic therapy in patients with necrotizing otitis externa

BackgroundDiagnosis of necrotizing otitis externa is often delayed despite patients having severe pain disproportionate to the clinical findings as well as cranial nerve palsies. The incidence is increasing in elderly, diabetic or immunocompromised patients and can be fatal without ‘appropriate’ antibiotic therapy.1,2ObjectivesCT, MRI, and technetium 99 bone scans are often performed but poorly correlate to the clinical response to empirical treatment.3 This novel study evaluated the use of erythrocyte sedimentation rate (ESR) and pain scores as measures of response to determine the dose and duration of antibiotic therapy in patients diagnosed with NOE over a 4 year period from November 2015.MethodsPatients diagnosed with NOE were evaluated using pain scores (0–10/10 where 0 = no pain and 10 = worst pain) and ESR at presentation and then at subsequent outpatient visits. Patients received 6 weeks of IV antibiotics (most receiving piperacillin/tazobactam 13.5 g daily via a 24 h infusion pump administered through a ‘mid-line’ as an outpatient when they were clinically well to go home) followed by oral ciprofloxacin. Initially ciprofloxacin was prescribed at 750 to 500 mg twice daily and the dose and duration of treatment was personalized according to pain scores and ESR. No ethical approval was required since this was an observational study of standard management of this condition at the Trust.ResultsTwelve patients (10 males; 2 females) aged 49 to 91 years (median 74.5 years) were treated. Five had diabetes mellitus and three had been treated for a malignancy. The time of first symptoms to diagnosis ranged from 3 weeks to 32 months (median 3 months). Six had developed facial nerve palsies; three of whom had additional cranial nerve involvement. All had swabs positive for Pseudomonas aeruginosa which in four patients was resistant to gentamicin and in two of these patients also to ciprofloxacin. At presentation pain score was 10/10 in all but three patients (5/10 in one patient and 8/10 in two patients) and ESR values ranged from 31 to 82 (median 66). Both values fell within 1–2 weeks of commencing IV antibiotics and after 6 weeks pain scores were 0/10 in eight patients, 3/10 in the others. ESR at this stage fell to 10–33 (median 15). One patient developed diarrhoea and stopped ciprofloxacin after only 2 weeks remaining well at 6 months follow-up. Eight patients required 3 to 12 months ciprofloxacin. Four patients required restarting or increasing ciprofloxacin dose to control rising pain scores which reflected an increase in their ESR values but in one of these patients having grown Pseudomonas resistant to ciprofloxacin, two further 6 week courses of piperacillin/tazobactam were required. Three patients currently remain on ciprofloxacin at the lowest dose to keep their pain scores and ESR under controlConclusionsPain scores with ESR values are invaluable in determining the activity of NOE thereby personalizing the antibiotic dose and duration in patients with this life-threatening infection.

Atypical Femur Fracture in the Setting of Long-Term Bisphosphonate use for Osteogenesis Imperfecta: A Case Report

Bisphosphonate (BP) therapy for moderate to severe osteogenesis imperfecta (OI) has become a mainstay of treatment in the last three decades. Given the significant improvements in bone mineral density and theoretical reductions in fracture risk, many patients are treated with bisphosphonates for prolonged periods of time. There currently lacks consensus in the optimal duration of BP therapy for patients with OI, and patients are often treated on a case-by-case basis. Long-term BP therapy has been associated with atypical femur fractures in adult patients treated for osteoporosis. The American Society for Bone and Mineral Research concluded that the median duration of BP therapy in patients with atypical femur fractures was 7 years. The role of long-term BP therapy in OI patients with atypical femur fractures remains unclear. Here, a case report is presented of an adolescent patient with type V OI that sustained a subtrochanteric femur fracture with features of an atypical pattern following treatment with intravenous pamidronate for 10.5 years. At the time of injury, the contralateral femur was also found to have atypical features suggestive of an impending fracture. The completed fracture was treated with closed reduction and cephalomedullary nail fixation. The impending fracture was prophylactically stabilized using the same technique. Prior to the injury, limb-length radiographs obtained to evaluate lower extremity alignment demonstrated features of an impending fracture but went unnoticed. Further studies are needed to clarify the role of long-term BP therapy in patients with OI suffering from atypical femur fractures.

How to use new antibiotics in the therapy of ventilator-associated pneumonia.

Ventilator-associated pneumonia (VAP) is a common nosocomial infection in critically ill patients requiring endotracheal intubation and mechanical ventilation. Recently, the emergence of multidrug-resistant Gram-negative bacteria, including carbapenem-resistant Enterobacterales, multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species, has complicated the selection of appropriate antimicrobials and contributed to treatment failure. Although novel antimicrobials are crucial to treating VAP caused by these multidrug-resistant organisms, knowledge of how to optimize their efficacy while minimizing the development of resistance should be a requirement for their use. Several studies have assessed the efficacy of novel antimicrobials against multidrug-resistant organisms, but high-quality studies focusing on optimal dosing, infusion time and duration of therapy in patients with VAP are still lacking. Antimicrobial and diagnostic stewardship should be combined to optimize the use of these novel agents. Improvements in diagnostic tests, stewardship practices and a better understanding of dosing, infusion time, duration of treatment and the effects of combining various antimicrobials should help optimize the use of novel antimicrobials for VAP and maximize clinical outcomes while minimizing the development of resistance.

111. Duration of Antibiotic Therapy after Debridement and Implant Retention in Patients with Periprosthetic Joint Infections

BackgroundDebridement, antibiotics, and implant retention (DAIR) is appropriate for select acute postoperative and hematogenous periprosthetic joint infections (PJIs). However, the optimal duration of antimicrobial therapy in patients treated with DAIR has not been defined. Therefore, we aimed to identify the ideal duration of parenteral and oral antibiotics after DAIR. MethodsWe performed a retrospective study of patients >18 years of age with hip or knee PJI managed with DAIR between January 1, 2008, and December 31, 2018, at Mayo Clinic. PJI was defined using criteria adapted from the International Consensus Meeting on PJI. The outcome was defined as either PJI recurrence or unplanned reoperation due to infection. Joint-stratified Cox proportional hazards regression models with time-dependent covariates were used to assess nonlinear effects of antibiotic duration. Hazard ratios were computed based on prespecified time points for comparison, whereas p-values represented the overall effect across the entire range of durations.ResultsThere were 247 unique episodes of PJI in 237 patients during the study period. Parenteral antibiotics were given in 99.2% of cases (n=245). This was followed by chronic oral antibiotic suppression in 92.2% (n=226) with a median duration of 2.2 years (1.0-4.1).DAIR failed in 65 cases over a median follow-up of 4.4 years, with a 5-year cumulative incidence of 28.1%. After adjustment for risk factors, there was no significant association between duration of parenteral antibiotics and treatment failure (p=0.203), with no difference between four versus six weeks (HR 1.11; 95% CI 0.71-1.75) (Figure 1). However, both use and longer duration of oral antibiotic therapy was associated with a lower risk of failure (p=0.006). To account for the possibility that this association was driven by results during early follow-up, conditional analyses at one- and two-year follow-up were performed. Both showed a significantly lower risk for a longer duration of antibiotics (Figure 2). Figure 1. Time-Dependent Analysis of Parenteral Antibiotic Duration Figure 2. Time-Dependent Analysis of Oral Antibiotic Suppression Duration ConclusionAfter DAIR, efficacy from four weeks of parenteral antibiotics was no different from six weeks when followed by chronic oral antibiotic suppression. Our results could not establish an optimal duration but suggested that continuing suppression portends a lower risk of failure of DAIR. Disclosures Elie Berbari, MD, Uptodate.com (Other Financial or Material Support, Honorary unrelated to this work) Matthew P. Abdel, MD, Stryker and AAOS Board of Directors (Board Member, Other Financial or Material Support, Royalties) Aaron J. Tande, MD, UpToDate.com (Other Financial or Material Support, Honoraria for medical writing)

Abstract 9914: Three Months vs 12-Months Dual Antiplatelet Therapy Duration in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

Introduction: Recent American Heart Association/American College of Cardiology guidelines on duration of dual antiplatelet therapy (DAPT) recommend DAPT for 12 months in patients presenting with an acute coronary syndrome (ACS) who underwent percutaneous intervention (PCI) (grade IIb recommendation). With the advent of newer generation stents, multiple randomized controlled trials (RCTs) have studied the role of short term -3 months DAPT compared to the guideline-indicated12 months DAPT. We aim to assess the evidence using a meta-analytic approach. Methods: PubMed, Embase and Cochrane Central databases were searched from inception until May 31, 2021. RCTs comparing short term (3 months) vs extended (12 months) DAPT in patients with ACS undergoing PCI were included. Outcomes assessed were MACE, cardiovascular mortality, all-cause mortality, myocardial infarction, stent thrombosis and bleeding events. A random-effects model was used to calculate pooled relative risk (RR) and 95% confidence intervals (CI). Results: We included 5 trials comprising 16,781 patients with an acute coronary syndrome that underwent percutaneous intervention. There was no significant difference in MACE (RR 0.92; 95% CI, 0.76-1.11), cardiovascular mortality (RR 1.26; 95% CI, 0.38-4.17), or all-cause mortality (RR 0.92; 95% CI, 0.48-1.77) between the 2 groups. In addition, there was no difference in rates of myocardial infarction (RR 0.98; 95% CI, 0.74-1.30), or stent thrombosis (RR 1.30; 95% CI, 0.55-3.05) between short-term and extended DAPT. However, compared with extended DAPT, 3-month DAPT showed significantly reduced risk of major bleeding (RR 0.53; 95% CI, 0.43-0.64). Conclusions: In patients with acute coronary syndrome undergoing PCI, short term DAPT may be reasonable for some patients, while extended DAPT may be appropriate for select others. An individualized approach on optimal DAPT duration should be used considering the risks of ischemic events and bleeding.

Treatment Pattern for Advanced Gastric Cancer in Japan and Factors Associated with Sequential Treatment: A Retrospective Administrative Claims Database Study.

IntroductionClinical trials have proven the efficacy and safety of new therapies for advanced gastric cancer (AGC), but how those therapies are used in the real world is poorly described. Real-world treatment patterns of antitumor therapies and factors associated with overall therapy duration in patients with AGC in Japan were investigated.MethodsThis retrospective cohort study used a Japanese administrative claims database (June 2014 to September 2019). Patients with AGC who started the guideline-recommended first-line combination regimens with platinum and fluoropyrimidine agents between June 2015 and July 2019 were included. Cox regression analysis was performed to identify factors associated with overall therapy duration (first line to last administration of guideline-listed agent).ResultsOf the 10,581 patients included, the most common first-line combination regimen without trastuzumab was S-1 plus oxaliplatin (4327/9069 patients; 47.7%) and with trastuzumab was capecitabine plus cisplatin (608/1512 patients; 40.2%). Most common second- and third-line regimens were ramucirumab plus taxane (3650/5358 patients; 68.1%) and nivolumab (1229/2390 patients; 51.4%), respectively. Factors positively associated with longer overall therapy duration were: oral fluoropyrimidine in first line (hazard ratio [95% confidence interval]: 0.63 [0.57–0.69]); trastuzumab in any line (0.73 [0.68–0.78]); treatment at a designated cancer hospital (0.89 [0.84–0.94]); dietary consultation within 1 month before/after start of first line (0.92 [0.86–0.98]); and treatment at a surgical department (0.94 [0.89–0.99]). Negatively associated factors were: edema (1.21 [1.07–1.37]); physical therapy (1.21 [1.12–1.31]); nutritional intervention (1.21 [1.14–1.28]) within 1 month before/after start of first line; thrombosis (1.13 [1.04–1.23]); renal disease (1.11 [1.02–1.21]); age (1.07 [1.02–1.13]); and peritoneal metastasis/ascites (1.06 [1.01–1.13]).ConclusionsIn real-world treatment practice for AGC in Japan, therapy choice after the recommended first-line chemotherapy was consistent with guidelines. Factors associated with overall therapy duration were identified, which may assist in optimizing treatment sequence.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01931-3.

Phase 2 study of DRD2 antagonist/ClpP agonist ONC201 in neuroendocrine tumors.

3002 Background: ONC201, an imipridone with specificity for the dopamine-like DRD2 receptor and the mitochondrial protease ClpP, imparts anti-cancer effects via up-regulation of TRAIL/DR5, dual AKT/ERK pathway inhibition, and promotion of an integrated stress response. Select neuroendocrine tumors are known to secrete dopamine and harbor elevated DRD2 expression, which is most pronounced in pheochromocytoma-paraganglioma (PC-PG). Methods: This investigator-initiated single center trial (NCT03034200) enrolled 10 patients with metastatic PC-PG to cohort A and 12 patients with other neuroendocrine tumors to cohort B. The primary endpoint was response using MRI or CT, PET-CT and/or PET-MRI imaging defined as CR + PR + SD &gt; 3 months by RECIST criteria assessed by investigator. Secondary endpoints included progression-free survival, overall survival and safety. ONC201 was administered at 625 mg by oral capsules once each week. CT scans and tumor markers (plasma chromogranin and metanephrines) were followed at 6 weeks, 3 months and then every 3 months. Patients with clinical benefit could receive stereotactic body radiotherapy (SBRT) for non-indicator (e.g. bone) metastases. The data cutoff for this analysis is December 1, 2020. Results: In Arm A (n = 10; all paraganglioma) 5 patients exhibited a PR and 2 additional patients exhibited SD &gt; 3 months. Median duration of therapy for patients was 9 months (range: 1.5-33) with 5 patients &gt; 1 year. In Arm B (n = 12) there were 1 PR and 2 SD &gt; 3 months. Median duration of therapy was 3 months (range: 1-33). The partial response occurred in a patient with desmoplastic small round cell tumor who remains on treatment for &gt; 2 years. There was no instance of dose modification or discontinuation due to treatment-related adverse events. Conclusions: ONC201 is well tolerated at 625mg weekly in adults with advanced neuroendocrine tumors and is associated with clinical benefit that includes tumor response, particularly in paraganglioma patients. A more intense schedule of 2 daily doses each week is under evaluation, in addition to other neuroendocrine tumors. Clinical trial information: NCT03034200.

De-escalation of five years adjuvant endocrine therapy duration in patients with ER-low positive (immunohistochemical 1% to 10%) early-stage breast cancer: A propensity-matched analysis from the prospectively maintained database.

538 Background: There are limited data on endocrine therapy benefits for patients with estrogen receptor (ER)-low positive breast cancer (staining 1% to 10% of tumor nuclei by immunohistology). We aimed to compare the effect of short-term 2-3 years versus standard 5 years of adjuvant endocrine therapy on survival outcomes in patients with ER-low positive early breast cancer. Methods: We used data from the prospectively maintained Breast Surgery Database of Fudan University Shanghai Cancer Center for this propensity-matched analysis. Women with ER-low positive, operable, and unilateral early-stage invasive ductal breast cancer were enrolled in this study. Patients with advanced disease, having received neoadjuvant chemotherapy or ovarian function suppression, or with unknown duration or longer than 5 years of adjuvant endocrine therapy were excluded. Enrolled patients were divided into three groups: received no endocrine therapy; received 2-3 years of endocrine therapy; and received approximately 5 years of endocrine therapy. The primary endpoint was disease-free survival (DFS). Multivariate Cox regression analysis and propensity score matching were performed to minimize bias. Hazard ratios (HR) with 95% CIs were calculated. Results: From 2012 to 2017, 634 patients with ER-low positive breast cancer in the database met the inclusion criteria. At a median follow-up of 60 months (interquartile range, 46-74), the 5-year DFS of the whole cohort was 84.9%, with 77.6% for patients who received no endocrine therapy (N = 89), 83.7% for patients who received 2-3 years endocrine treatment (N = 185), and 87.5% for patients who received 5 years endocrine therapy (N = 360). When compared with those receiving no endocrine therapy, patients receiving 5 years treatment was associated with a significantly improved DFS (HR, 0.55; 95% CI 0.32-0.95; P = 0.03); however, there was no significant difference in DFS between patients receiving 2-3 years and 5 years endocrine therapy (HR, 0.79; 95% CI, 0.48-1.28; P = 0.33). In the multivariate Cox regression analysis of the propensity score-matched samples of 360 patients, the DFS was not significantly better for patients who received 5 years of endocrine therapy than 2-3 years treatment (HR, 0.74; 95% CI 0.41-1.34; P = 0.32). An exploratory analysis of re-biopsy of the recurrence lesions indicated more than half of relapsed disease displayed ER-negative, and less than 5% lesions were proved to be ER ≥10% positive. Conclusions: Our data did not support the necessity of 5 years duration of endocrine therapy for patients with ER-low positive breast cancer. Short-term 2-3 years duration might be an alternative option. Further translational research on identifying endocrine-sensitive cases within ER-low positive patients is needed.

Factors for Sustaining Molecular Remission after Discontinuation of Tyrosine Kinase Inhibitors Therapy in Chronic Myeloid Leukemia: Results of Non-Randomized Prospective Clinical Trial

Aim. To study the impact of different clinical and biological factors on sustaining molecular remission after discontinuation of tyrosine kinase inhibitors (TKI) therapy in chronic myeloid leukemia (CML) patients with a stable deep molecular response (MR). Materials &amp; Methods. The prospective multi-center trial on molecular remission sustainability after TKIs withdrawal, held from 2015 to 2019, enrolled 98 CML patients. The trial included patients with chronic phase CML treated with TKIs at least during 3 years and having a stable deep MR (&lt; МО4; BCR-ABL &lt; 0.01 %) during at least 2 years. Molecular monitoring was carried out every month during first 6 months after TKIs withdrawal, every 2 months during 0.5-1 year, and every 3 months after 1-year follow-up. In case of the loss of major MR (BCR-ABL &gt; 0.1 %) therapy was reinitiated. Results. Three-year molecular relapse-free survival was 51 % (95% confidence interval 41-61 %) in all patients, 25 % in patients with the failure of prior treatment discontinuation, and 53 % in patients who discontinued TKI therapy for the first time. According to univariate analysis, the following factors proved to be significant: persistance of deep MR, duration of therapy, and depth of MR. It was shown that TKI therapy duration, but not deep MR persistance, has independent prognostic value for the Russian population of CML patients. No significant differences were identified in 3-year molecular relapse-free survival in the groups of patients treated only with imatinib (55 %) compared with patients who received 2nd generation TKI (TKI2) as first-line (70 %; p = 0.26) and second-line (39 %; p = 0.09) therapy. However, duration of therapy in patients treated with TKI2 as first-line therapy was more than twice as short as in patients treated with imatinib as first-line therapy (median 41.5 vs. 96.4 months, respectively; p &lt; 0.0001). Conclusion. Longer therapy duration and MR depth (&lt; M04.5) before TKI withdrawal raise the probability of sustaining off-treatment remission. The study showed that molecular relapse-free survival does not significantly increase with the use of TKI2 as first-line treatment compared to imatinib. Nevertheless, TKI2 as first-line treatment enables to halve the duration of therapy needed to achieve comparable molecular relapse-free survival, as compared with imatinib.

Phase 2 Study of Tagraxofusp Therapy for BPDCN Patients Post-Autologous or Post-Allogeneic Hematopoietic Cell Transplantation

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with historical overall survival (OS) of 8-14 months from diagnosis. Tagraxofusp is a targeted therapy directed to CD123. The US FDA has approved tagraxofusp for the treatment of BPDCN in adult and pediatric patients 2 years and older. CD123 is ubiquitously expressed at high levels on plasmacytoid dendritic cells (pDCs), the cell of origin of BPDCN, and targeting of CD123 with tagraxofusp resulted in high response rates, durable remissions, and a significant proportion of patients bridged to hematopoietic cell transplant (HCT) in first remission (45%). While HCT has the potential to prolong remission of patients with hematologic cancers, relapses after transplantation still occur in patients with certain risk factors including minimal residual disease (MRD). This study is designed to assess the safety and efficacy of tagraxofusp monotherapy as a maintenance treatment in patients with BPDCN post-HCT. The study is open for enrollment and expected to recruit approximately 20 patients. NCT04317781 Rationale: Available data suggest long-term remission can be expected in approximately 50% of patients with BPDCN that undergo allo-HCT. Accordingly, strategies are needed to further reduce the risk of relapse post-HCT. Methods: The study is a Phase 2, single-center, open-label, single-arm clinical trial of tagraxofusp in patients with BPDCN that have undergone HCT. Planned enrollment is 20 patients. Treatment with tagraxofusp will be initiated between day 45 and 120 post-HCT, and dosed days 1-3 in cycles 1-4, and days 1-2 in cycles 5 and beyond. Each treatment cycle is 28 days. Duration of therapy for patients in complete response (CR) or clinical CR (CRc) post-transplant is 24 cycles, with patients who are MRD-positive or remain at high risk of relapse, eligible for continued treatment for as long as they derive benefit. In patients whose post-HCT disease status is either CR with incomplete blood count recovery (CRi) or partial response (PR), treatment will continue until disease progression or unacceptable toxicity. Major Inclusion/Exclusion Criteria : Age ≥18; &amp;gt;30 days post-transplant without active or chronic infections; Karnofsky PS ≥60%; Lansky ≥60; adequate organ function including LVEF ≥ lower limit of normal (LLN); creatinine ≤1.5 mg/dL; albumin ≥3.2 g/dL; bilirubin ≤1.5 upper limit of normal (ULN); AST/ALT ≤2.5 times ULN; and ANC ≥1000. For allo-HCT, no ≥ grade 2 visceral (gut or liver) acute graft versus host disease (GVHD) and no ≥ grade 3 or any other acute GVHD (chronic GVHD allowed at investigator discretion). Key exclusions: Persistent clinically significant non-hematologic toxicities ≥ grade 2; CNS involvement; receiving chemotherapy, radiotherapy, or other anti-cancer therapy within 14 days of first dose of study drug; uncontrolled infection; HIV/Hepatitis B and/or C; and clinically significant cardiopulmonary disease. Endpoints: Primary endpoints include safety and tolerability of tagraxofusp in patients with BPDCN post-HCT, with survival as secondary outcomes. Disclosures Bashir: Amgen: Other: Advisory Board; Purdue: Other: Advisory Board; Acrotech: Research Funding; StemLine: Research Funding; KITE: Other: Advisory Board; Takeda: Other: Advisory Board, Research Funding; Celgene: Research Funding. Shpall:Magenta: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Licensing Agreement; Zelluna: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Popat:Bayer: Research Funding; Novartis: Research Funding. Pemmaraju:Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Roche Diagnostics: Honoraria; Pacylex Pharmaceuticals: Consultancy; Blueprint Medicines: Honoraria; Samus Therapeutics: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Plexxikon: Research Funding; Affymetrix: Other: Grant Support, Research Funding; AbbVie: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; MustangBio: Honoraria; Cellectis: Research Funding; Incyte Corporation: Honoraria. Champlin:Takeda: Patents &amp; Royalties; Actinium: Consultancy; Omeros: Consultancy; Genzyme: Speakers Bureau; DKMS America: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Consultancy; Cytonus: Consultancy. Qazilbash:Bioline: Research Funding; Bioclinica: Consultancy; Amgen: Research Funding; Angiocrine: Research Funding; Janssen: Research Funding.

Impact of ischemic risk factors on long-term outcomes in patients with and without high bleeding risk

BackgroundThe current guidelines have recommended to shorten the dual antiplatelet therapy duration in patients at high bleeding risk (HBR) to minimize the bleeding complications. The impact of ischemic risk factors (IRF) on long-term ischemic events in patients with and without HBR after percutaneous coronary intervention remains unclear.MethodsThe study population comprised 1219 patients who were treated with everolimus-eluting stents between 2010 and 2011. The mean follow-up period was 2996 ± 433 days. HBR was defined as set by the Academic Research Consortium. IRF was defined as high-risk features of stent-driven recurrent ischemic events endorsed in the 2017 European Society of Cardiology Guidelines. Major bleeding was defined as the occurrence of Bleeding Academic Research Consortium type 3 or 5 bleeding. Primary ischemic events included myocardial infarction, definite stent thrombosis, and cardiac death.ResultsThe 1219 patients were divided into two groups: 614 patients at HBR (HBR group) and 605 patients at no HBR (non-HBR group). The rate of IRF patients was significantly higher in the HBR group than in the non-HBR group (81.4% versus 47.6%, P < 0.001). The cumulative rate of ischemic events in the HBR group was significantly higher in IRF patients than in non-IRF patients (21.0% versus 7.0%, log rank P < 0.001), whereas that in the non-HBR group was not significantly different between IRF and non-IRF patients (10.1% versus 6.3%, log rank P = 0.09).ConclusionsMore than 80% of HBR patients treated with everolimus-eluting stents were at IRF. A combination of HBR and IRF may increase the risk of long-term ischemic events.