Drug Discontinuation Rates Research Articles

Comparison of Short-Term Outcomes for Standard Versus Nonstandard Induction Dosing of Infliximab for Pediatric Inflammatory Bowel Disease.

Recent studies have emphasized the early use of infliximab (IFX) in pediatric patients with inflammatory bowel disease. Standard dosing of 5 mg/kg/dose may not be sufficient to achieve optimal clinical outcomes. The aim of our study was to compare short-term outcomes with standard dosing of IFX to higher, nonstandard dosing of IFX for induction therapy. Retrospective study of 162 pediatric patients receiving either standard (5-6 mg/kg, n = 90) or nonstandard (>6 mg/kg, n = 72) dosing of IFX during induction was performed. Patient demographics, clinical outcomes, and laboratory data were collected. Need for dose escalation during the first 6 months, combination therapy with immunomodulators, and steroid-free progression were investigated. Clinical remission rates between the 2 groups were significantly different, with patients receiving nonstandard dosing demonstrating higher rates (58% vs 78%; p = 0.012). Use of combination therapy with immunomodulators was significantly different between standard and nonstandard groups (80% vs 48%; p < 0.001). Numeric trend in need for IFX dose escalation in the first 6 months was seen between standard and nonstandard groups (54% vs 39%, respectively; p = 0.087). Post-induction IFX trough concentrations, rates of antibody development, drug discontinuation, and infusion reaction were similar. Nonstandard induction dosing of IFX was associated with higher rates of clinical remission, despite similar rates of serum IFX trough concentrations. There was a numeric trend towards the standard group requiring dose escalation within the first 6 months of therapy. Patients given nonstandard dosing may achieve superior clinical outcomes compared with those on standard dosing.

Variable Frailty Categorization Among Real-World Patient with Multiple Myeloma: A Prospective Cohort Study (MFRAIL)

Introduction Multiple Myeloma (MM) is a non-curable cancer of older adults. Frailty has emerged as one important high-risk factor which confers a poor prognosis with reduced progression free survival, increased toxicity, higher rates of drug discontinuation and worse overall survival. Several tools have emerged for evaluation of frailty in MM in recent years. These include non-cancer specific geriatric assessment tools such as the Fried frailty index or more specific MM tools such as the International Myeloma Working Group (IMWG) frailty index, simplified frailty index or the Mayo frailty index. Uptake of these measures across clinical settings has been variable, leading to a gap in knowledge about the prevalence of geriatric impairments among MM patients as well as the proportion of patients classified as frail using these different scoring systems. The MFRAIL study is an ongoing prospective, multicentre study evaluating the association of different frailty assessment tools at baseline and longitudinally over time with clinical outcomes. In this abstract we present an interim analysis after at least 50% of patients have been enrolled. We describe baseline characteristics from the initial 57 patients enrolled into the study with the specific objective of 1) to report the prevalence of geriatric impairments among MM patients prior to therapy initiation 2) characterize the proportion of patients classified as frail using different frailty assessment tools. Methods The MFRAIL is an ongoing, prospective pilot cohort study being conducted at three sites within Ontario, Canada which was initiated in August 2021. Multiple myeloma patients aged >18 initiating a new line of therapy are enrolled in the preceding six weeks. Demographic and MM-specific factors are collected at baseline and at 12 months following treatment along with MM response criteria, toxicity and health care utilization. Additional collected measures include: comorbidities, physical performance measures (NIH 4 meter walk test and grip strength), cognition, patient reported outcome of quality of life and depression. Frailty assessment tools measured include the IMWG frailty index (Palumbo et al. Blood 2015), simplified frailty index (Facon et al. Leukemia 2020), Mayo frailty index (Milani et al. AJH 2016) and the Fried frailty index (modified from Fried et al. J Gerontol A Biol Sci Med Sci 2001). Results A total of 57 patients were enrolled in the study (data cut off June 1/2022) with baseline characteristics summarized in Table 1. The median age of the patients was 71 (range 47-93) with 61% males. A total of 26% and 35% of the patients had an ECOG and CCI status of 2 or higher, respectively. Polypharmacy was common with over 50% of the patients being prescribed five or more medications at baseline. Geriatric impairments were common with over 1/3 of the patients reporting at least one deficit in ADLs or IADLs. Additionally, cognitive impairment was present in 19.3% of the patients. With regards to treatment details, 61.4% of the enrolled patients received first line treatment (ASCT eligible 34.3%, ASCT ineligible 65.7%), 26.3% second line and the remainder third line and beyond. Immunomodulatory-based treatments were the most common with 57.8% of the patients utilizing these agents. Empiric dose reduction outside the product monograph was observed in 17.5% of the patients with the majority of dose reductions (80%) done for agents other than dexamethasone alone among those patients. The prevalence of frailty in our cohort ranged from 12.3% (Fried frailty index), 17.5% (Mayo frailty index), 38.6% (IMWG frailty index) to 52.6% (simplified frailty score). Similarly, the number of patients classified as fit/robust also varied ranging from 15.8% (Mayo frailty index), 25.3% (fried frailty index), 33.3% (IMWG frailty index) and 47.3% (simplified frailty score). Conclusion Impairments in geriatric domain are common among real-world patients with MM emphasizing the need to incorporate these assessments in routine clinical practise. Additionally, prevalence of patients classified as frail versus fit varies depending upon the assessment tool utilized with no uniform definition of frailty in routine clinical practise. Further work is needed in both evaluating and standardizing frailty assessment tools in different clinical settings and with different therapeutic modalities to further optimize outcomes in this high-risk patient subgroup. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 12010: Efficacy and Safety of Dofetilide and Sotalol in Patients With Hypertrophic Cardiomyopathy

Introduction: Patients with hypertrophic cardiomyopathy (HCM) often have atrial fibrillation (AF) and ventricular arrhythmias (VA) requiring rhythm control. In the 2014 AF Guidelines, class III anti-arrhythmic drugs are not recommended in patients with left ventricular hypertrophy, but in the 2020 HCM Guidelines, sotalol (STL) and dofetilide (DOF) are deemed “reasonable” for rhythm control, both based on limited data. Methods: We conducted an observational study (2001-2021) of patients with HCM who were treated with DOF or STL for AF and/or VA. Baseline characteristics and drug-related adverse events were analyzed from the electronic medical record, and rates of discontinuation and arrhythmia recurrence at 1 year and by time of chart review were compared using Kaplan Meier curves and log rank test. Results: There were 21 DOF and 52 STL HCM patients with AF, and 18 STL patients with VA. At 1 year, AF patients on DOF or STL had no significant difference in rates of AF recurrence (42.9% vs 44.2%, p=0.664) or drug discontinuation (38.1% vs 29.4%, p=0.582). Recurrence and discontinuation rates of VA on STL were comparable (Figure). Over a median follow up of 1603 days (IQR 994, 4131), there was a trend toward greater efficacy for STL with respect to less AF recurrence (p=0.085) and less frequent discontinuation (p=0.153; Figure). On univariate analysis, only NYHA class predicted AF recurrence. Reasons for discontinuation were most often for inefficacy or mild side-effects. One patient with prior alcohol septal ablation who was on STL for AF developed complete heart block followed by non-sustained torsades de pointes in the setting of a severe influenza infection and later underwent defibrillator implantation. There were no other cases of pro-arrhythmia or sudden death related to DOF. Conclusions: DOF and STL are modestly effective for the treatment of AF and VA in HCM patients, with a low rate of serious adverse events.

Discontinuation Rates of Tadalafil Alone and in Combination with a-Blockers in the Treatment of Male Lower Urinary Tract Symptoms with or without Coexisting Erectile Dysfunction: A Systematic Review and Meta-Analysis.

We examined the discontinuation rates of tadalafil alone and in combination with a-blockers (ABs) for the treatment of male lower urinary tract symptoms (LUTS), with or without erectile dysfunction (ED). We searched the EMBASE, PubMed, Web of Science, Scopus, Cochrane Library, and ClinicalTrials.gov databases for studies published until May 15, 2022. The discontinuation rates associated with LUTS medications were subsequently analyzed by meta-analysis. Forty-four studies, including 1724 discontinued patients, were included. The combined discontinuation rate was 12.78% (95% confidence interval (CI) 9.89-15.98%), and the discontinuation rates because of adverse events and lack of efficacy were 4.56% (95% CI 3.39-5.90%) and 3.30% (95% CI 1.53-5.72%), respectively. The discontinuation rate of tadalafil alone or in combination with ABs for LUTS with or without ED was relatively low and varied according to the study type. Patients receiving monotherapy or combination therapy were similarly likely to abandon treatment. Treatment with a fixed-dose combination was associated with better persistence than with a free-dose combination. These data may help guide clinicians in selecting drug regimens when making decisions. Factors associated with treatment withdrawal need to be determined through high-quality clinical studies to reduce the drug discontinuation rate, which will ultimately reduce healthcare costs and improve patient outcomes.

Severe drug-induced liver injury (DILI) associated with benznidazole therapy for Chagas' disease.

Chagas’ disease (CD), a neglected tropical disease caused by Trypanosoma cruzi, endemic in Latin America and sporadic in many parts of the world, affects 6–7 million people.1 Although the efficacy of drug treatment of late-stage CD remains uncertain,2 it is expected to prevent severe cardiac, intestinal and/or neurological complications. Since 1970, only two drugs have been available for CD treatment: benznidazole and nifurtimox. Benznidazole is highly metabolized by the liver.3 Both drugs are associated with a high rate of drug discontinuation due to side effects, such as skin reactions, leucopenia and neuropathy. A mild elevation of transaminases is sometimes observed. Discontinuation of benznidazole due to serious toxic effects is rarely necessary, and adverse effects usually disappear when treatment is stopped.4–6 Here we describe the case of a patient treated with benznidazole for CD who developed severe liver toxicity. A 68-year-old woman who was born in El Salvador and migrated in Italy in 2010, taking levetiracetam (500 mg twice per day) for epilepsy, was diagnosed in June 2021 with chronic CD according to WHO criteria. The disease staging did not reveal organ involvement. Liver ultrasonography showed a mild hyperechogenic structure.

Who are the Best Candidate Patients with Diabetes for Tirzepatide?

Background: Tirzepatide is a dual receptor agonist of the 2 incretin hormones: Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon- Like Peptide-1 (GLP-1) which is was recently approved for treatment of type 2 diabetes. Objective: To define the most appropriate patients that may benefit from tirzepatide. Methods: Pubmed search until August 10, 2022. Search terms were GLP- 1, GIP, tirzepatide, efficacy, safety, obesity. Clinical trials and pertinent animal studies and reviews were included. Results: Tirzepatide was more effective in lowering hemoglobin A1c (HbA1c) levels and body weight than submaximal doses of semaglutide (1.0 mg once-weekly), dulaglutide (1.5 mg once-weekly), insulin degludec (mean daily dose 48.8 U) and insulin glargine (mean daily dose 43.5 U). In patients with type 2 diabetes and Non-Alcoholic Fatty Liver Disease (NAFLD), tirzepatide significantly decreased Liver Fat Content (LVC). Safety profile of tirzepatide was generally similar to that of GLP-1 agonists, but frequency of Gastrointestinal (GI) adverse effects are slightly higher with tirzepatide. Incidence of severe hypoglycemia (blood glucose &lt; 54 mg/dl) is also slightly higher with tirzepatide than semaglutide and dulaglutide, but much lower than insulin degludec and glargine. Drug discontinuation rates due to adverse effects were higher with tirzepatide compared with semaglutide, dulaglutide, and insulin. Conclusions: Tirzepatide may be most appropriate for patients with type 2 diabetes who are obese, as alternative to GLP-1 agonists or basal insulin, and in patients with NAFLD.

Dalbavancin in the treatment of acute bacterial skin and skin structure and other infections: a safety evaluation

ABSTRACT Introduction Dalbavancin is a second-generation lipoglycopeptide approved since 2014 to treat acute bacterial skin and skin-structure infections (ABSSSI). Dalbavancin is characterized by Gram-positive activity and novel pharmacokinetic properties allowing prolonged terminal half-life andonce weekly dosing . A good safety profile was reported in clinical trials . Areas covered Dalbavancin safety and tolerability from trials and post-marketing studies were reviewed. While most reports included predominantly ABSSSI, two clinical trials and recent observational studies have explored the use of dalbavancin for off-label indications, mainly including bloodstream and osteoarticular infections. Expert opinion The occurrence of drug-related adverse effects (AE) was similar between dalbavancin and comparators in clinical trials enrolling patients with ABSSSI. Most common AE included gastrointestinal symptoms, infusion reaction, and hypersensitivity. Low rates of drug discontinuation and serious AE were reported across studies. In the past 5 years, several observational studies have reported safety data on the use of dalbavancin, confirming its favorable safety profile. Nevertheless, data from dalbavancin off-label use, often derived from prolonged (>2 weeks) treatments with variable dosing regimens, were mainly retrospective and lacked comparators. Further research is required to allow a reliable analysis of short- and long-term dalbavancin-related AE in non-ABSSSI.

UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis

Thirty-to-forty percent of patients with primary biliary cholangitis inadequately respond to ursodeoxycholic acid. Our aim was to assemble national, real-world data on the effectiveness of obeticholic acid (OCA) as a second-line treatment, alongside non-licensed therapy with fibric acid derivatives (bezafibrate or fenofibrate). This was a nationwide observational cohort study conducted from August 2017 until June2021. We accrued data from 457 patients; 349 treated with OCA and 108 with fibric acid derivatives. At baseline/pre-treatment, individuals in the OCA group manifest higher risk features compared with those taking fibric acid derivatives, evidenced by more elevated alkaline phosphatase values, and a larger proportion of individuals with cirrhosis, abnormal bilirubin, prior non-response to ursodeoxycholic acid, and elastography readings >9.6kPa (P < .05 for all). Overall, 259 patients (OCA) and 80 patients (fibric acid derivatives) completed 12 months of second-line therapy, yielding a dropout rate of 25.7% and 25.9%, respectively. At 12 months, the magnitude of alkaline phosphatase reduction was 29.5% and 56.7% in OCA and fibric acid groups (P < .001). Conversely, 55.9% and 36.4% of patients normalized serum alanine transaminase and bilirubin in the OCA group (P < .001). The proportion with normal alanine transaminase or bilirubin values in the fibric acid group was no different at 12 months compared with baseline. Twelve-month biochemical response rates were 70.6% with OCA and 80% under fibric acid treatment (P= .121). Response rates between treatment groups were no different on propensity-score matching or on sub-analysis of high-risk groups defined at baseline. Across the population of patients with primary biliary cholangitis in the United Kingdom, rates of biochemical response and drug discontinuation appear similar under fibric acid and OCA treatment.

Comparison of the Total Side Effects of Injectable Disease-Modifying Drugs for the First-line Treatment of Relapsing-Remitting Multiple Sclerosis

Background: Physicians generally prescribe disease-modifying drugs (DMDs) to reduce the frequency and severity of relapses in multiple sclerosis (MS). The frequency and severity of side effects are important factors that can affect drug choice. The main purpose of this analysis was to evaluate the side effects of different types of first-line injectable DMDs and determine which drug has more complications, and which drug has the most drug discontinuation rates due to severe side effects. Methods: Four groups of injectable DMDs were compared in 386 relapsing-remitting MS (RRMS) patients in the range of 15-60 years who were controlled with these drugs for at least two years (2017-2019) and had the Expanded Disability Status Scale (EDSS) from 0 to 5 without underlying heart and liver diseases. Eventually, the frequency of side effects was determined for each group, and the collected data were compared in each treatment group. Results: In the present study, 31% of patients had no complications. Most of the reported complications (68.25%) were mild in severity, and only 15.5% of the patients discontinued their therapy. Conclusion: The findings recommend that the side effects of different DMDs used for RRMS should be studied more comprehensively in clinical and post-marketing trials. Additionally, physicians should take note of these side effects of DMDs in their prescriptions to increase patients’ adherence to therapy.

Effectiveness of TNF-inhibitors, abatacept, IL6-inhibitors and JAK-inhibitors in 31 846 patients with rheumatoid arthritis in 19 registers from the ‘JAK-pot’ collaboration

BackgroundJAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different...

Oral Selexipag versus Inhaled Treprostinil Effect on Pulmonary Arterial Hypertension

<h3>Purpose</h3> There has been increasing use of oral selexipag over inhaled treprostinil given the convenience of oral administration and the twice daily dosing. However, there is paucity of data comparing both treatments. <h3>Methods</h3> This was a retrospective, multicenter cohort study of adult patients diagnosed with pulmonary arterial hypertension (PAH) initiated on oral selexipag or inhaled treprostinil at two tertiary medical centers. The primary outcome was worsening of PAH, defined as a composite of PAH related hospitalization or initiation of a parenteral prostacyclin due to worsening symptoms. Events were analyzed up to 18 months from initiation. <h3>Results</h3> Between January 1, 2012, and June 30, 2019, 251 patients met inclusion criteria (inhaled treprostinil = 81, and oral selexipag = 170). The primary outcome occurred in 17 (20.9%) patients in the treprostinil group, and in 37 (21.7%) in the selexipag group with incidence rate 21 and 18.25 events per 100 patient-years, respectively (P = 0.64 by log-rank test). The primary outcome was adjusted for age, gender, World Health Organization Functional Class (WHO-FC), and background dual therapy (hazard ratio 1.05, 95% CI 0.57 - 1.86, P = 0.86). Drug discontinuation due to side effects was higher in the treprostinil group 19 (23.5%) compared to the selexipag group 15 (8.8%), (OR 3.2, 95% CI 1.51 - 6.62, p = 0.002). <h3>Conclusion</h3> Among patients with PAH, there was no difference in worsening of PAH between inhaled treprostinil and oral selexipag. However, the drug discontinuation rate due to side effects was significantly higher in the treprostinil group.

Association of polypill therapy with cardiovascular outcomes, mortality, and adherence: A systematic review and meta-analysis of randomized controlled trials

Prior studies have reported improvements in population-level risk factor burden and cardiovascular disease (CVD) outcomes using polypills for CVD risk reduction. However, a comprehensive assessment of the impact of polypills on CVD outcomes, mortality, adherence, and side effects across different settings has not previously been reported. We performed a systematic review and meta-analysis of randomized controlled trials examining the association between polypill therapy and CVD outcomes published before February 2021. The primary outcome of interest was the risk of major adverse CVD events (MACE). Risk ratios for dichotomous outcomes were converted to log RR and pooled using a generic inverse variance weighted random-effects model. Data for continuous outcomes were pooled using random-effects modeling and presented as mean differences with 95% CIs. Eight studies representing 25,584 patients were included for analysis. In the overall pooled analysis, the use of polypills was associated with a non-significant reduction in the risk of MACE (RR: 0.85; 95% CI: 0.70–1.02) and significant reductions in the risk of all-cause mortality (RR: 0.90; 95% CI: 0.81–1.00). The reductions in the risk of MACE with polypill use varied by baseline risk and nature of the study population (primary prevention vs. secondary prevention), with the most significant risk reduction among lower-risk cohorts, including within primary prevention populations [RR 0.70 (0.62, 0.79)]. Among measures of CVD risk factors, modest but significant reductions were observed for systolic and diastolic blood pressure [systolic: mean difference 1.99 mmHg (95% CI: −3.07 to −0.91); diastolic: mean difference 1.30 mmHg (95% CI: −2.42 to −0.19), but not for levels of total or low-density lipoprotein-cholesterol. Use of the polypill strategy significantly improved drug adherence (RR: 1.31; 95% CI: 1.11–1.55) with no association between polypill use and rates of adverse events or drug discontinuation. The use of polypill formulations is associated with significant reductions in CVD risk factors and the risk of all-cause mortality and MACE, particularly in the low-risk and primary prevention population.

Impact of sacubitril/valsartan on the indication for defibrillator and left ventricular remodeling: real life data

Introduction and objectiveThe use of sacubitril/valsartan (SV) has shown a reduction in mortality compared to enalapril, in addition to achieving an improvement in left ventricular remodeling. There is ample evidence of its use in real life. However, there are no clinical trials that show a reduction in the indication for implantable cardioverter defibrillator (ICD) after its use. MethodsProspective real-life study of patients with heart failure and reduced ejection fraction treated with SV, starting in the outpatient phase or during hospitalization. An analysis of individual and combined endpoints for efficacy and safety is carried out, including the change of indication of ICD with the use of SV. ResultsAfter 12 months, a clear reduction in the indication for ICD was achieved, an improvement in left ventricular remodeling, a reduction in natriuretic peptides, and a reduction in readmissions for heart failure. In addition, showing clear safety and a low rate of drug discontinuation (6%). ConclusionsThe results of this real-life study achieved a combined endpoint of efficacy in 88.3% of patients, demonstrating the safety of SV. On the other hand, the indication for ICD is drastically reduced, so the moment to indicate an ICD should be clarified through clinical trials.

Short-term, but not long-term, beneficial effects of concomitant benzodiazepine use on clinical course in patients with schizophrenia.

This study aims to examine possible differences in the effect on the course characteristics of the disease in cases of no use, short-term use and long-term use of benzodiazepines in patients with schizophrenia. In this retrospective observational study, the sample comprised patients with schizophrenia who were admitted to our psychiatric clinics from January 2015 to January 2019. Patients were also retrospectively tracked from the date of the first admission during the specified time until the end of the observation period (24 months) for clinical course characteristics. Data for 1710 patients with schizophrenia were included in the analyses. Patients with short-term benzodiazepines use had fewer psychiatric hospitalizations and shorter lengths of stay at psychiatric services than patients with no use or long-term use. Rates of antipsychotic drug discontinuation and suicidal behavior were also significantly lower among short-term benzodiazepines users than among those with no use or long-term use. In conclusion, our study indicates that short-term benzodiazepines use is associated with a better clinical course in patients with schizophrenia. Future studies should evaluate the effects of different benzodiazepines use patterns on disease prognosis with longer-term follow-up and prospective methodology and should concomitantly examine psychopathological variables.

Comparative efficacy and safety of mizoribine and mycophenolate mofetil for treating systemic lupus erythematosus: a retrospective cohort study.

Background:Mizoribine (MZR) is an immunosuppressive agent that selectively inhibits inosine monophosphate dehydrogenase; its actions are considerably similar to those of mycophenolate mofetil (MMF). This study aimed to clarify whether MZR can be a good treatment option for systemic lupus erythematosus (SLE) and to compare the efficacy and safety of MZR and MMF in patients with active SLE.Methods:We retrospectively compared the efficacy, continuation rate, and safety of MZR (52 patients) and MMF (31 patients) after adjusting for stabilized inverse probability of treatment weighting based on propensity scores. The efficacy endpoints were as follows: cumulative incidence of lupus low disease activity state (LLDAS) or remission attainment and flares and change in prednisolone dose over 2 years. Drug continuation rates were defined as the time from drug initiation to discontinuation for any cause, owing to the lack of efficacy, or owing to adverse events. The safety endpoint was the frequency of adverse events.Results:Overall, 25 (48.1%) and 13 (25.0%) patients in the MZR group and 18 (58.1%) and 15 (48.3%) in the MMF group achieved LLDAS and remission during the follow-up period, respectively; thus, the cumulative incidence of LLDAS and remission attainment of the two groups was similar after adjustment. Prednisolone dose was steadily reduced in both the groups, and the change in prednisolone dose was nearly identical between the two groups. Drug discontinuation rate due to adverse events and the frequency of all adverse events and infections were higher in the MMF group than in the MZR group, albeit without significance after adjustment.Conclusion:MZR is as effective as MMF in controlling SLE activity. The adverse events of MZR, whose profile differs from MMF, are comparable to or less than those of MMF. MZR may be a valuable option as an immunosuppressive agent for SLE, as well as MMF.

192. Tolerability Outcomes of Multi-drug Antibiotic Treatment for Pulmonary Nontuberculous Mycobacterial Disease due to Mycobacterium avium Complex in U.S. Medicare Beneficiaries with Bronchiectasis

BackgroundNontuberculous mycobacteria (NTM), most frequently Mycobacterium avium complex (MAC), cause increasingly common pulmonary infections. Treatment interruptions and early discontinuation are common in MAC therapy, but population-based data on treatment outcomes are severely lacking. We examined tolerability outcomes of guideline-based 3-drug therapies (GBT) targeted for pulmonary MAC infection. MethodsAmong beneficiaries with bronchiectasis (ICD-9-CM 494.0 or 494.1) in U.S. Medicare data (01/2006 – 12/2014), we identified first-time MAC GBT therapy users, excluding those with cystic fibrosis, HIV, or a history of organ transplant. MAC GBT was defined as an overlapping prescription of ≥ 28-day supply of a macrolide, ethambutol and rifamycin. Using Cox regression methods, we compared time-to-regimen change or discontinuation within 12 months of therapy start in the following groups: 1) azithromycin-ethambutol-rifamycin vs. clarithromycin-ethambutol-rifamycin; 2) macrolide-ethambutol-rifampin vs. macrolide-ethambutol-rifabutin; and 3) azithromycin-ethambutol-rifampin vs. clarithromycin-ethambutol-rifabutin.ResultsWe identified 4,626 GBT therapy users (mean 77.9 years [s.d. 6.1], female [77.7%], and non-Hispanic white [87.2%]). Overall, the rate of regimen change or discontinuation was higher in the clarithromycin-based regimens compared to azithromycin-containing regimens, and in rifabutin-containing regimens compared to rifampin-containing regimens. The rate of drug regimen change or discontinuation was 65% greater in the clarithromycin-ethambutol-rifabutin group compared to the azithromycin-ethambutol-rifampin group (adjusted hazard ratio: 1.64, 95% CI: 1.43, 1.64) (Table 1, Figure 1). ConclusionAzithromycin-based regimens and rifampin-containing regimens were less likely to be changed or discontinued within 12 months of therapy compared to clarithromycin-based regimens and rifabutin-containing regimens, respectively. More research is needed to identify factors associated with early treatment change or discontinuation. Disclosures Emily Henkle, PhD, MPH, AN2 (Consultant, Advisor or Review Panel member)Zambon (Advisor or Review Panel member) Theodore K. Marras, MD, Astra Zeneca (Speaker’s Bureau)Insmed (Scientific Research Study Investigator)Novartis (Speaker’s Bureau)RedHill (Consultant)Spero (Consultant) Kevin L. Winthrop, MD, MPH, Insmed (Consultant, Grant/Research Support)Paratek (Consultant)RedHill (Consultant)Spero (Consultant) Kevin L. Winthrop, MD, MPH, Insmed (Consultant, Research Grant or Support)Paratek (Consultant)RedHill Biopharma (Consultant)Spero (Consultant)

Real-world utilization of bempedoic acid in an academic preventive cardiology practice

Lipid management for prevention and treatment of cardiovascular disease remains insufficient for many with currently available therapies. Evaluate real-world use of bempedoic acid. Retrospective study of patients in our Center for Preventive Cardiology who were prescribed bempedoic acid between February 2020 and July 2021. Patients were managed according to clinical standards of care, with lipid assessments at months ≤3, 6, and 12 post-bempedoic acid initiation. Seventy-three patients were prescribed bempedoic acid, with 64 initiating therapy. The majority had atherosclerosis (89%), familial hypercholesterolemia (64%), and statin intolerance (74%), with baseline low-density lipoprotein cholesterol (LDL-C) 120 mg/dL. Prior authorization requests and appeals of denials were required in 90% and 19% of cases, respectively. Cost-mitigating strategies reduced median monthly drug costs from $432 pre-insurance approval to $80 post-insurance approval, to $10 after financial assistance intervention. Bempedoic acid reduced LDL-C by -36.7%, -31%, and -20.3% at ≤3, 6, and 12, respectively, with >20% achieving LDL-C <70 mg/dL. There was substantial inter-individual heterogeneity in LDL-C lowering. We observed high rates of drug discontinuation (35.9%), mostly related to treatment-emergent adverse events (TEAEs) (32.8%), primarily musculoskeletal complaints. Use of reduced dose bempedoic acid (<180 mg) was associated similar LDL-C lowering but TEAE and drug discontinuation were still common. Real-world use of bempedoic acid was limited by insurance and cost barriers requiring substantial post-prescription interventions. In patients at heightened risk for atherosclerotic events and statin intolerance, bempedoic acid was associated with clinically meaningful LDL-C lowering, but high rates of TEAEs and drug discontinuations.

Abstract 11965: Association of Ticagrelor versus Clopidogrel With Bleeding, Dyspnea, and Premature Discontinuation in Patients With Acute Coronary Syndrome

Introduction: Current clinical data have raised the issues regarding the risk of adverse events (e.g. bleeding and dyspnea) and the limited clinical benefit during ticagrelor vs. clopidogrel treatment in patients with acute coronary syndrome (ACS). Hypothesis: Association between bleeding and dyspnea during dual antiplatelet therapy (DAPT), and it would be related with drug switch or discontinuation. Methods: East Asian patients presented with ACS were undergoing percutaneous coronary intervention, and were treated with DPAT with ticagrelor (n=270) or clopidogrel (n=674). At 30-day follow-up, we evaluated platelet function with VerifyNow, and incidence of bleeding (BARC criteria) and dyspnea (MMRC scale) using the dedicated questionnaire. Results: During 30-day follow-up, ACS patients on ticagrelor showed the higher rates of bleeding (45.6% vs. 23.6%; HR, 2.71) and dyspnea (26.3% vs. 13.6%; HR, 2.25) compared with those on clopidogrel. In terms of low platelet reactivity (LPR), ticagrelor showed the lower cutoff (‘PRU≤20’) compared with clopidogrel (‘PRU≤110’). In multivariate analysis, LPR phenotype (OR, 2.70), not type of P2Y 12 inhibitor (OR, 1.34), was significantly associated with the risk of bleeding (Figure) . In addition, type of P2Y 12 inhibitor (OR, 2.14) and bleeding episode (OR, 2.83) increased the risk of dyspnea (Figure) . At 12-month follow-up, ticagrelor treatment showed a higher risk of drug discontinuation than clopidogrel treatment (27.8% vs. 4.7%; HR, 7.71). During ticagrelor administration, patients with both dyspnea and bleeding had a higher rate of drug discontinuation compared to those without both dyspnea and bleeding (adjusted HR, 3.05). Conclusions: This study suggests that incidence of bleeding and dyspnea was frequent during ticagrelor treatment in East Asian patients with ACS. A close association between bleeding and dyspnea increased the risk of drug discontinuation during ticagrelor treatment.

Epistaxis in anticoagulated patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial

Abstract Background Epistaxis is common with antithrombotic therapy yet under-investigated in cardiovascular clinical trials and observational studies. These bleeding events are often troublesome to patients and may lead to anticoagulant discontinuation. Purpose To describe the frequency, severity, and outcomes of epistaxis in patients with atrial fibrillation (AF) randomized to edoxaban vs warfarin. Methods ENGAGE AF-TIMI 48 randomized 21,105 patients with AF and CHADS2 ≥2 to a higher-dose edoxaban regimen (HDER; 60mg daily), a lower-dose edoxaban regimen (LDER; 30mg daily), or warfarin, with edoxaban doses reduced by 50% in patients meeting dose-reduction criteria. Location and severity of bleeding were adjudicated by a blinded Clinical Events Committee using ISTH criteria. Patients with intracranial hemorrhage were excluded from this analysis. Patients with more than one bleeding event were categorized according to the most severe event. The safety cohort with interval censoring during study drug interruption was analyzed. Proportions were compared using a Pearson's chi-squared test and treatment arms were compared using a Cox proportional hazards model. Results 5,247 patients with a bleeding event were included in this analysis, including 1,008 (19.2%) with epistaxis and 4,239 (80.8%) with exclusively non-epistaxis bleeding. Baseline characteristics were similar for patients with epistaxis as compared to non-epistaxis bleeding. Epistaxis events were overall less severe than non-epistaxis bleeds (ISTH major: 3.2% vs 20.7%; CRNM: 64.7% vs 60.1%; minor: 32.1% vs 19.2%; p&amp;lt;0.001; Fig. 1, Panel A). Two life-threatening and no fatal epistaxis bleeds occurred. Permanent study drug discontinuation was similar following epistaxis vs non-epistaxis bleeding in patients with major (59.4% vs 53.6%; p=0.52) or CRNM bleeding (32.5% vs 33.3%; p=0.70), but was significantly higher after minor epistaxis versus minor bleeding at other sites (33.3% vs 23.9%; p=0.001; Fig. 1, Panel B). Compared to warfarin, hazard ratios (HR) for epistaxis bleeding were: 1) major: HDER 0.47 (0.19–1.15), LDER 0.65 (0.29–1.45); 2) major/CRNM: HDER 1.00 (0.84–1.19), LDER 0.70 (0.58–0.85); 3) major/CRNM/minor: HDER 1.09 (0.95–1.26), LDER 0.73 (0.62–0.86) (Fig. 1, Panel C). Conclusion Epistaxis was frequent in patients with atrial fibrillation on anticoagulation. When compared to warfarin, LDER reduced the risk of epistaxis by 27–30% while HDER neither increased nor decreased these events. There were significantly higher rates of permanent drug discontinuation following minor epistaxis as compared to minor bleeding at other sites. These findings suggest that epistaxis is symptomatically important, may cause disproportionate interruption in antithrombotic therapy, and deserves increased attention in cardiovascular studies. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Pharma Development Figure 1

Termination Based on Event Accrual in Per Protocol Versus Intention to Treat in the ROCKET AF Trial

BackgroundIn event‐driven clinical trials, study termination is based on accrual of a target number of primary efficacy events. For noninferiority trials in which superiority is conditionally examined, the ideal cohort in which to track event accrual is unclear. We used data from the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial to determine the effect of primary efficacy‐event tracking in the per‐protocol cohort during the on‐treatment period versus the intention‐to‐treat (ITT) cohort during the ITT period.Methods and ResultsROCKET AF was terminated after accruing 429 primary efficacy events (stroke or systemic embolism) in the per‐protocol cohort during the on‐treatment period for noninferiority. We identified the date on which 429 events occurred in the ITT cohort during the ITT period. We performed noninferiority and superiority analyses based on hypothetical study termination on this date. ROCKET AF would have terminated 226 days earlier if events were tracked during the ITT period. Similar to the main trial findings, rivaroxaban would have met noninferiority versus warfarin for the primary efficacy end point (hazard ratio [HR], 0.77; 95% CI, 0.62–0.96; P<0.001). In contrast to the main trial findings, rivaroxaban would have met superiority for the primary efficacy end point (HR, 0.82; 95% CI, 0.68–0.99; P=0.038). In both termination scenarios, rivaroxaban was associated with a lower risk of intracranial hemorrhage and similar risk of other safety end points.ConclusionsClinical trial termination based on event accrual in the ITT cohort versus the per‐protocol cohort may have important implications on trial results depending on rates of study drug discontinuation and event rates off treatment.