Penile surgery for patients with Peyronie’s disease initially treated with collagenase clostridium histolyticum or surgery: a claims database analysis

Collagenase clostridium histolyticum (CCH) is an injectable therapy targeting collagen present in penile plaques in Peyronie’s disease (PD). Data comparing CCH to penile surgery are limited, and long-term therapeutic outcomes are unknown. This retrospective analysis used a US claims database (January 2014–June 2017) to determine the percentage of men with subsequent penile surgery among those who initially received CCH (n = 1227) or surgery (index treatment; n = 620) for PD. Eligible patients were aged ≥18 years with continuous enrollment ≥6 months before and ≥12 months after index treatment date. During 12 months of post-index treatment follow-up, fewer patients with PD initially treated with CCH (4.6% [56/1227]) had subsequent penile surgery versus those initially treated with penile surgery (10.3% [64/620]; p < 0.0001). Mean ± SD time to first subsequent surgery after initial PD treatment was longer in the CCH versus surgery cohort (7.7 ± 3.0 vs 1.7 ± 3.2 months). The likelihood of subsequent surgery varied by initial surgery type: 18.2% after plaque incision or excision with grafting; 11.6% after penile implant; and 8.2% after tunical plication. Patients with PD who received CCH first were less likely to undergo subsequent surgery compared with those who received surgery first within a 12-month post-treatment follow-up.

Multidimensional Quantification of Exclusion Criteria to Reduce the Gap between Randomized Clinical Trial and Real-World Outcomes in Multiple Myeloma

Randomized clinical trials (RCTs) are considered the highest level of evidence to define the efficacy of newly developed treatments before their adoption into clinical practice. RCTs incorporate exclusion criteria that eliminate specific patient populations in order to reduce the incidence of serious adverse events and enhance the efficacy of a given anti-cancer strategy. However, exclusion criteria may lead to a significant gap between patients (pts) enrolled on RCTs and real world pt populations, which represent the ultimate stakeholders in cancer treatment. The analysis of real-world evidence to answer clinical questions has recently gained increased interest. Assessing different dimensions of this gap may help overcome barriers in trial recruitment and enhance the applicability of RCTs in daily practice. There has been significant advancement in treating multiple myeloma (MM) over the past two decades bringing multiple new mechanisms of action to the bedside. We selected ten recent RCTs: ASPIRE, TOURMALNE-MM01, ELOQUENT-2, ENDEAVOR, POLLUX and CASTOR, OCEAN, ICARIA, APOLLO and ELOQUENT-3 studies, which are pharma-sponsored landmark trials that provided the basis for FDA approval of anti-myeloma agents. Our objective was to quantify the gap in eligibility criteria between the ten RCTs and real world populations by examining these trials using a single institution database. Methods: Pts with relapsed MM that were initiated on a second (or later line) of therapy that were recognized, retrospectively. Eligibility criteria of the ten landmark RCTs was applied during the 21 day period before the index treatment date. Pts that received Len-containing regimens were tested as to be enrolled on trials with Len/Dex control arm, patients that received Bor-containing regimens were examined to be enrolled on Bor/Dex trials and subjects who had Pom-containing regimen were screened for Pom/Dex trials. Pts were then classified as "Trial eligible" or "Trial ineligible", accordingly and were monitored longitudinally from the index treatment date until death, loss to follow-up, or end of the follow up period. Ten commonly used eligibility criteria were examined (Fig. 1). Any cancer in the three years prior to the index treatment date was counted as "history of other malignancies", i.e., skin and prostate cancer were excluded. Concurrent infection was defined as use of any antibiotic other than acyclovir, ciprofloxacin or bactrim. To calculate area under the curve of the polygon graphs Shoelace algorithm was used. Results : 516 pts were studied between 2010 and 2020 and 153 were excluded due to missing values. 224, 136 and 98 pts were treated with Len-, Bor- or Pom-containing regimens, respectively. Overall, the trial-eligible cohort was more likely to have autologous stem cell transplant and to have had longer treatment-free period before index treatment date (p-value: 0.009). There was a substantial variation in the ineligibility rate for these ten RCTs among the study population (Fig. 1). The most common items that excluded a patient from a RCT were: other malignancy, current infection and renal dysfunction. Differences between trial-eligible and trial-ineligible pts stratified by trial are listed in Tables 1, 2 and 3 for trials with Len, Bor and Pom as control arms, respectively. The median follow-up for the Len, Bor and Pom cohorts was 31, 30 and 22 months, respectively. Trial-ineligible pts displayed a significantly worse OS (2-year rate 58% vs. 78%, p-value: 0.001) and 49% higher chance of death (HR 1.69, 90%, CI: 1.17-2.62) compared with trial-eligible cohort. Conclusion: Here, we assessed the multidimensional gap that exists between patient cohorts enrolled on RCTs and real world cohorts for ten landmark MM trials. We present a quantitative deviation score as a tool to calibrate the generalizability of these landmark trials against a single institution. Importantly, we show that trial-eligibility alone significantly correlates with superior OS across a variety of MM clinical trials across all ten MM RCTs. Furthermore, our results reveal that ineligibility rates were quite different among the ten trials which significantly limit cross-trial comparisons. We propose a uniform methodology to assess patient exclusion criteria and narrow the efficacy gap observed between RCTs and real world evidence. Figure 1 Figure 1. Disclosures Metheny: Pharmacosmos: Honoraria; Incyte: Speakers Bureau. Malek: Medpacto Inc.: Research Funding; Amgen: Honoraria; Janssen: Other: Advisory board ; Takeda: Honoraria; BMS: Honoraria, Research Funding; Cumberland Inc.: Research Funding; Bluespark Inc.: Research Funding; Sanofi: Other: Advisory Board.

Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome without Hematopoietic Cell Transplantation in a Real-World Population in the United States: Patient Characteristics, Prior Treatment Patterns, and Time to Diagnosis

Introduction: Sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a rare form of hepatic injury where liver veins are blocked by damaged endothelial cells (Hildebrandt GC, et al. Br J Haematol. 2020;190:508-19). It is often associated with chemotherapy and radiation therapy given before a hematopoietic cell transplantation (HCT) but may occur outside of the HCT setting (Richardson PG, et al. Expert Rev Clin Pharm. 2018;11:113-24). The most severe form of VOD/SOS is associated with multiorgan dysfunction/multiorgan failure (MOD/MOF) and has a mortality rate of &gt;80% if untreated (Coppell JA, et al. Biol Blood Marrow Transplant. 2018:53:138-45). This study describes the characteristics of VOD/SOS that occurs outside of the HCT setting (non-HCT VOD/SOS) in patients in the United States (US). Methods: This retrospective real-world evidence (RWE) study identified patient records within the TriNetX Dataworks US Network Electronic Medical Records (EMR) database, which covers 67 million patients from 44 healthcare organizations. Inclusion criteria required that patients had ≥1 record of a VOD/SOS diagnosis (ICD-10 code: K76.5) between January 1, 2016 and December 31, 2020, had received ≥1 instance of chemotherapy, antibody drug conjugates (ADC), or radiotherapy within 100 days prior to their first recorded VOD/SOS diagnosis, and had no record of HCT during the study period. Patient demographics and clinical characteristics, prior treatment regimen, and time to VOD/SOS diagnosis were characterized using descriptive statistics. Index treatment was defined as the treatment taken in the 100 days prior to VOD/SOS diagnosis, determined by the following hierarchy list of therapies: radiotherapy, gemtuzumab ozogamicin (GO)/inotuzumab ozogamicin (INO), vincristine, cytarabine, oxaliplatin-based, thioguanine, cyclophosphamide, 5-fluorouracil-based, etoposide, daunorubicin, doxorubicin, PEG-L-asparaginase, fludarabine, actinomycin-D, and other chemotherapies. Results: Of the 67 million patients available in the TriNetX database, 614 patients had documented VOD/SOS during the study period. Of those, 542 had ≥1 record in the EMR prior to the first VOD/SOS diagnosis. Among these 542 cases, 419 (77%) were non-HCT-related (did not have a record of HCT in the entire study period); the other 123 (23%) had a record of HCT (Figure 1). Of the 419 non-HCT VOD/SOS patients, 183 (44%) had ≥1 record of chemotherapy, ADC, or radiotherapy within the 100 days prior to first VOD/SOS diagnosis and comprised the study population. Among those 183 patients, 73 (40%) had a diagnosis of MOD/MOF at the same time VOD/SOS was documented; 61 (33%) were pediatric patients (≤16 years of age). Hematologic malignancies were the most common underlying condition (Table 1). A few patients had prior treatment with GO or INO (1% and 3%, respectively). The top 5 most common chemotherapies administered included cytarabine (25%), cyclophosphamide (20%), vincristine (17%), fludarabine (12%), and doxorubicin (11%). Overall, 103 (56%) non-HCT patients had a VOD/SOS diagnosis ≤21 days from index treatment. The median time from index treatment to VOD/SOS diagnosis was 13 days (interquartile range [IQR]: 1, 43 days) among all 183 patients. Among patients without MOD/MOF, median time was 18 days (IQR: 2, 44 days) and among patients with MOD/MOF, median time was 9 days (IQR: 0, 34 days). Conclusions: In this retrospective RWE study, the number of patients diagnosed with VOD/SOS outside of the HCT setting was approximately 3 times higher than those diagnosed in the HCT setting. Less than half of the patients diagnosed with non-HCT VOD/SOS had prior chemotherapy, ADC, or radiotherapy. Many of the non-HCT VOD/SOS patients were diagnosed with MOD/MOF. Among patients with non-HCT VOD/SOS, approximately half received their last dose of chemotherapy/ADC/radiotherapy &gt;21 days before VOD/SOS diagnosis. Study limitations included those inherent to a retrospective study, the absence of availability of chemotherapy dosing in the database, and inability to detect misdiagnosis or under-diagnosis of VOD/SOS (which may result in under-estimation of the true number of VOD/SOS cases). The unexpected, relatively high number of VOD/SOS cases in the non-HCT setting, compared to the post-HCT setting, demonstrates a substantial unmet need, as there is no VOD/SOS treatment currently indicated for these patients. Figure 1 Figure 1. Disclosures Wang: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Benettaib: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ni: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Jin: TriNetX: Current Employment. Kuranz: Apellis Pharmaceuticals, Inc.: Other: Payments from Apellis Pharmaceuticals to my institution TriNetX; TriNetX: Current Employment. Amber: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ben-Joseph: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

Effectiveness and safety of non-vitamin K antagonist oral anticoagulants versus warfarin among nonvalvular atrial fibrillation patients with prior bleeding events

Background Patients with non-valvular atrial fibrillation (NVAF) use oral anticoagulants such as warfarin or non-vitamin K antagonist oral anticoagulants (NOACs) for the prevention of stroke. However, the effectiveness and safety of warfarin and NOACs can be influenced by pre-existing patient comorbidities, such as a history of bleeding, and limited evidence are available to inform the choice of the most appropriate anticoagulant treatment for NVAF patients with bleeding history. Purpose This study used five United States insurance claims databases to evaluate the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) among NVAF patients with prior bleeding events who were prescribed NOACs versus warfarin. Methods This retrospective observational study used data from 5 databases (CMS Medicare and four commercial databases, covering &gt;180 million beneficiaries) to select adult NVAF patients who were treated with apixaban, dabigatran, rivaroxaban, or warfarin (01JAN2013–30JUN2019). Patients were required to have a prior bleeding event, defined as a hospitalization with a diagnosis for intracranial hemorrhage (ICH), gastrointestinal (GI) bleeding or bleeding at other key sites prior to or during the index treatment episode. In each database, three 1:1 NOAC-warfarin propensity-score-matched (PSM) cohorts were created before pooling the results. Outcome measures were time to first stroke/SE, (ischemic stroke, hemorrhagic stroke, and SE), and time to first MB (gastrointestinal bleeding, intracranial hemorrhage, and MB at other key sites), and were measured from the index treatment episode to treatment discontinuation or switch, death, health plan disenrollment, or end of study period. Hazard ratios of S/SE and MB were calculated using Cox proportional hazards models. Results Among the eligible NVAF population, 8.2% of patients had a prior bleeding event (ICH: 12.3%; GI: 60.7%; Other: 27.0%). After PSM, a total of 43,092 apixaban-warfarin, 11,295 dabigatran-warfarin, and 32,723 rivaroxaban-warfarin patient pairs with prior bleeding were selected with a mean follow-up of 8–9 months. Apixaban and rivaroxaban were associated with a lower risk of S/SE, and dabigatran was associated with a similar risk of S/SE when compared to warfarin. Apixaban and dabigatran were associated with a lower risk of MB, and rivaroxaban was associated with a similar risk of MB, compared to warfarin (Figure). Conclusion Among NVAF patients with prior bleeding events, NOACs were associated with varying risks of S/SE and MB compared to warfarin. These results can help inform healthcare providers concerning the impact of OAC treatment in NVAF patients with history of bleeding. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bristol-Myers Squibb Company and Pfizer, Inc.

Effectiveness and safety of non-vitamin K antagonist oral anticoagulants among nonvalvular atrial fibrillation patients with prior bleeding events

Background Among non-valvular atrial fibrillation (NVAF) patients with a history of bleeding, there is a reluctance to use oral anticoagulants (OACs) due to concerns about the risk of bleeding associated with OACs. However, lack of OAC treatments for NVAF patients is associated with a higher risk of stroke and mortality. Non-vitamin K antagonist OAC (NOACs) have been approved for the prevention of stroke in NVAF patients. There are limited data comparing the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) between patients prescribed NOACs and with a history of bleeding. Purpose This study used multiple United States data sources to evaluate the risk of S/SE and MB among NVAF patients with prior bleeding events who were prescribed NOACs. Methods This retrospective observational study used data from CMS Medicare and four commercial databases–covering &gt;180 million beneficiaries. The study selected adult NVAF patients who were prescribed apixaban, dabigatran, or rivaroxaban (01JAN2013–30JUN2019) and had a prior bleeding event which was defined as a hospitalization with a bleeding diagnosis (intracranial hemorrhage [ICH], gastrointestinal [GI] bleeding, or other bleeding sites) prior to or during the index treatment episode. After 1:1 propensity-score-matched (PSM) in each database between NOACs (apixaban-dabigatran, apixaban-rivaroxaban, and dabigatran-rivaroxaban), the resulting patient records were pooled. S/SE and MB (identified by inpatient claims) were captured during the follow-up period, which was defined as the time between the day after the index treatment date and treatment discontinuation or switch, death, end of study period, or end of medical and pharmacy enrollment. Hazard ratios of S/SE and MB were calculated using Cox proportional hazards models. Results Of the overall NVAF population treated with NOACs, 6.2% had a prior bleeding event (ICH: 13.5%; GI: 61.8%; Other: 24.6%). After PSM, a total of 11,106 apixaban-dabigatran, 30,665 apixaban-rivaroxaban, and 11,148 dabigatran-rivaroxaban pairs were matched. Apixaban was associated with a lower risk of S/SE compared to dabigatran and rivaroxaban, and dabigatran was associated with a similar risk of S/SE compared to rivaroxaban. Apixaban was associated with a lower risk of MB compared to dabigatran and rivaroxaban, and dabigatran was associated with a lower risk of MB compared to rivaroxaban (Figure). Conclusions In this subgroup of NVAF patients with a history of bleeding, apixaban was associated with a lower risk of S/SE and MB compared to dabigatran and rivaroxaban. Dabigatran was associated with a lower risk of MB compared to rivaroxaban. These results are informative for understanding the impact of NOAC treatment in NVAF patients with prior bleeding events. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bristol-Myers Squibb Company and Pfizer, Inc.

Switching and Discontinuation Pattern of Biologic Disease-Modifying Antirheumatic Drugs and Tofacitinib for Patients With Rheumatoid Arthritis in Taiwan

Rheumatoid arthritis (RA) is a chronic inflammatory systemic disease characterized by persistent joint synovial inflammation and swelling, leading to cartilage damage and bone erosion. This retrospective, longitudinal study is to evaluate the treatment patterns of biologic-naïve RA patients receiving index biologic disease-modifying antirheumatic drug (bDMARD) and tofacitinib by the data of Taiwan National Healthcare Insurance Claims and the Death Registry between 2012 and 2017. Drug survival and treatment patterns were determined by investigating the occurrence of switching and discontinuation from index treatment. At baseline, 70.0% of patients used tumor necrosis factor inhibitors (TNFi) bDMARD with the majority taking etanercept (27.0%) or adalimumab (26.2%). During the follow-up period, 40.0% (n = 3,464) of index users switched (n = 1,479) or discontinued (n = 1,985) the treatment with an average incidence rate of 0.18 per patient-year. Among the six index treatment groups, drug survival was the lowest for adalimumab and highest for tocilizumab. When compared with etanercept, only adalimumab had a higher cumulative probability of switching/discontinuation (adjusted HR = 1.17, 95% CI: 1.08–1.28), whereas golimumab, non-TNFi bDMARDs and tofacitinib were significantly less probable to switch or discontinue. For patients switching the index treatment, tocilizumab (31.2%) and tofacitinib (23.4%) were the main regimens being switched to. In addition, 48.2% of patients who discontinued the index treatment received further retreatment, and 63.8–77.0% of them were retreated with same agent. In conclusion, this population-based study found that TNFi were the preferred agents as the index treatments during 2012–2017. Non-TNFi and tofacitinib were more common second-line agents being switched to. Nearly half of discontinued patients received retreatment, with a majority receiving the same agent.

Clinical characteristics and treatment patterns with histrelin acetate subcutaneous implants vs. leuprolide injections in children with precocious puberty: a real-world study using a US claims database

Objectives Gonadotropin-releasing hormone analogs are the treatment of choice for central precocious puberty (CPP). This study characterizes patients treated with histrelin implant or leuprolide injection. Methods A US claims database was used to identify patients aged ≤20 years with ≥1 histrelin or leuprolide claim (index treatment) between April 2010 and November 2017 and continuous enrollment ≥3 months before and ≥12 months after the index treatment date. Results Overall, 4,217 patients (histrelin, n=1,001; leuprolide, n=3,216) were identified. The percentage of patients with CPP diagnosis was greater in the histrelin (96.5%) vs. leuprolide (68.8%; p<0.0001) cohort. In patients with CPP (histrelin, n=966; leuprolide, n=2,214), mean age at treatment initiation was similar for histrelin (9.0 ± 2.0 years) and leuprolide (9.1 ± 2.3 years), with >50% of patients aged 6–9 years. Mean treatment duration was significantly longer for histrelin (26.7 ± 14.8 months) vs. leuprolide (14.1 ± 12.1 months; p<0.0001), and was longer in younger patient groups. More patients switched from leuprolide to histrelin (12.3%) than vice versa (3.6%; p<0.0001). Median annual total treatment costs were slightly lower for the histrelin cohort ($23,071 [interquartile range, $16,833–$31,050]) than the leuprolide cohort ($27,021 [interquartile range, $18,314–$34,995]; p<0.0001). Conclusions Patients with CPP treated with histrelin had a longer duration of treatment, lower rates of index treatment discontinuation, and lower annual treatment costs vs. those treated with leuprolide.

Endovascular Treatment of Basilar Bifurcation Aneurysms With PulseRider-Assisted Coiling: 2-Dimensional Operative Video

Wide-necked bifurcation aneurysms pose technical and anatomical challenges to endovascular treatment, which make the simpler assisted (balloon or single stent) coiling techniques less effective.1 Consequently, unique endovascular solutions to treat such aneurysms have been devised.2,3 One such device is PulseRider (Cerenovus, New Brunswick, New Jersey), which is designed to provide neck support for a coil mass while protecting the bifurcation.3 The device comprises a body or stem that is deployed in the parent artery and a saddle component that sits at the aneurysm neck to keep the coil mass away from the bifurcation. There are several technical nuances involved in successful use of the device during positioning, deployment, and detachment.3 We present a surgical video detailing the steps of PulseRider-assisted coiling of unruptured basilar bifurcation (or basilar apex) aneurysms. The first case highlights index treatment at diagnosis and the second showcases treatment of a recurrent basilar apex aneurysm. Both patients provided informed consent to the procedure. We also briefly discuss the rationale for treating basilar apex aneurysms.4,5