Vaso-occlusive Crisis Events Research Articles

Association Between Vaso-Occlusive Crises and Opioid Prescriptions Among Patients with Sickle Cell Disease: A Retrospective Claims-Based Study.

Background/Objectives: Among sickle cell disease (SCD) patients, vaso-occlusive crises (VOCs) are recurrent and unpredictable attacks of acute pain. These pain crises are often treated with analgesics, including opioids, which have been associated with misuse and overdose. The aim of this study was to examine the association between VOC events and opioid use and assess the association between opioid prescriptions and health care resource utilization among SCD patients. Methods: This was a retrospective cohort study using Texas Medicaid medical and prescription claims between September 2011 and August 2016. The index date was the first SCD diagnosis. Patients (2-63 years) with at least one inpatient or two outpatient SCD diagnoses, who were continuously enrolled during 12 months postindex, were included in the study. The primary outcome was number of opioid prescriptions, while the independent variable was number of VOC events. Covariates included age, gender, nonopioid medication use, nonstudy SCD-related medication (penicillin and folic acid) use, evidence of blood transfusions, number of SCD-related complications, number of SCD-related comorbid conditions, and Charlson Comorbidity Index score. Negative binomial regression analysis was used to address study objectives. Results: Of 3368 included patients, 1978 (58.7%) had at least one opioid prescription with a mean of 4.2 (SD=7.2). Overall, 2071 (61.5%) had at least one VOC event with an average of 2.9 (SD=4.4). The results from the negative binomial regression showed that for every increase in VOC events, the number of opioid prescriptions increased by 9.5% (Incidence rate ratio=1.095, 95% CI: 1.078-1.111; P ≤ 0.0001). Other significant covariates associated with higher opioid use included age (13 and older compared to 2-12) and increase in the number of nonopioid pain medications, nonstudy SCD-related medications, and SCD-related complications. Conclusions: The majority of SCD patients had at least one VOC event and were prescribed opioids during the 12-month study period. We found that each VOC event was associated with a 9.5% increase in the use of opioids. SCD guidelines recommend opioids for the treatment of VOC-related pain. Payers and providers should be aware of opioid use in this population, consider appropriate VOC prevention measures, and provide SCD patients with access to appropriate pain management.

Pharmacological interventions for painful sickle cell vaso-occlusive crises in adults.

Pharmacological interventions for painful sickle cell vaso-occlusive crises in adults.

Real-World Clinical Burden of Sickle Cell Disease in the US Community-Practice Setting: A Single-Center Experience from the Foundation for Sickle Cell Disease Research

Background Sickle cell disease (SCD) is a progressively debilitating monogenic disease characterized by unpredictable, acute, life-threatening episodes and chronic complications such as hemolytic anemia and end-organ damage. It presents with a range of severity resulting in significant morbidity, poor quality of life, and early mortality. Real-world data on treatments and clinical outcomes for patients (pts) with SCD are limited, particularly in the community clinical care setting. The objectives of this retrospective real-world study were to characterize clinical manifestations and management of pts with SCD treated at the Foundation for Sickle Cell Disease Research (FSCDR). Methods A retrospective longitudinal analysis of an electronic health records (EHR) database from the FSCDR, which captured laboratory testing, treatments, and records on outpatient, emergency, and inpatient visits, was conducted. All unique pts with SCD assigned a medical record number in the EHR (N=172) were considered. Data from external records were manually entered into the EHR to supplement the EHR database. To address limitations of a real-world database, medical records for all pts included were manually reviewed and validation was performed on 10% of the sample. Pt demographics, clinical characteristics, hydroxyurea (HU) treatment (as captured by prescriptions and usage notes), administration of red blood cell transfusions, vaso-occlusive crisis (VOC) events and acute chest syndrome (ACS) (based on physician assessment) were described. Annual VOC rates were summarized by dividing the number of events by the total follow-up duration in years. Results In total, 122 pts with SCD were included. Twenty-three pts were excluded as they were not actively seeking care and/or had no relevant clinical data from 01/01/15-07/19/19. Data for 27 pts <22 years of age were unavailable at time of analysis (results of this cohort will be included in the presentation). Among all pts, 76 (62.3%) were female and 118 (96.7%) were Black or African American. The mean age at time of analysis was 39.1 (standard deviation [SD] 12.3) years with 9 (7.4%) 22-24 year-olds, 67 (54.9%) 25-40 year-olds, 35 (28.7%) 41-55 year-olds, and 11 (9.0%) ≥ 56 year-olds. The most common genotypes were HbSS (77.0%) and HbSC (17.2%). Over a mean follow-up period of 2.9 (interquartile range: 2.0, 4.4) years, 27 (22.1%) pts were treated with HU and 66 (54.1%) pts received transfusions, of which 1 (1.5%) pt chronically received episodic transfusions (i.e., continuous monthly transfusions for ≥ 6 months). The mean total hemoglobin (Hb) was 8.3 (SD 1.7) for HbSS pts and 10.9 (SD 1.5) for HbSC pts. Among pts who never received HU or transfusions during follow-up, mean Hb was 9.4 (SD 1.7) for HbSS pts and 11.4 (SD 1.6) for HbSC pts. Among pts who ever received HU or transfusions, mean Hb was 7.7 (SD 1.3) for HbSS pts and 10.3 (SD 1.1) for HbSC pts. Eleven (9.0%) pts had ≥ 1 ACS whereas 97 (79.5%) pts had ≥ 1 VOC event. ACS and VOC events occurred mostly in pts 25-55 years of age (ACS: 9 [81.8%] pts aged 25-40 years and 2 [18.2%] pts aged 41-55 years; VOC: 54 [55.7%] pts aged 25-40 years and 29 [29.9%] pts aged 41-55 years). Annual rates of VOC are described in Figure 1. Conclusions This is one of the first studies to describe clinical characteristics and management of pts with SCD in a community practice setting. Higher Hb levels among pts who never vs ever received HU or transfusions during follow-up may be a reflection of who were selected for treatment and additional studies to take into account timing of treatment and Hb assessments and confounding factors need to be conducted. The study found high VOC rates particularly among pts aged ≤ 40 years. Lower VOC rates among older pts do not necessarily indicate less severe disease. One potential reason for lower VOC rates among older pts with SCD is that cumulative exposure to ischemia-related tissue injury and resulting end organ damage may decrease VOC-related pain over time. Further investigation to elucidate the rate of VOC decline observed in older pts is needed, including looking at underlying health and end organ damage. While limitations are inherent in real-world studies, these findings underlie the ability to and importance of studying SCD management and clinical outcomes in community care settings. This study highlights the clinical burden of SCD and possibly higher than expected unmet need in this community setting. Disclosures Bronté-Hall: bluebird bio: Research Funding. Huynh:bluebird bio: Research Funding. Puri-Sharma:bluebird bio: Employment. Chang:bluebird bio: Research Funding. Chawla:bluebird bio: Employment. Signorovitch:bluebird bio: Research Funding.

Sickle Cell Disease Burden in North Lebanon

Background: Sickle cell disease (SCD) is one of the most prevalent hemoglobinopathies in Lebanon, where 0.1% of the population are affected by the disease, with the highest prevalence in North Lebanon. SCD burden has not been well characterized in this patient population. Moreover, there is limited understanding of the factors associated with complications of SCD. We hereby report on characteristics, complications, treatments and survival of a SCD cohort treated at a comprehensive SCD referral clinic in North Lebanon. Methods: Data were extracted from the health records and electronic registry of 335 SCD patients treated at the comprehensive SCD clinic of Nini hospital, Tripoli, North Lebanon between 2009 and 2019. The study population consisted of referred and newly diagnosed patients. Patients were considered to be newly diagnosed with SCD if there was a gap of ≤ 60 days between SCD diagnosis date and their first clinic visit date. Patients were regularly seen in the clinic at intervals ranging from every 2 months to 1 year depending on their age and disease severity. Patient characteristics, complications, treatment choices, and mortality were evaluated during follow-up. Follow-up was defined as the time between SCD diagnosis and last visit to the clinic. Complications included vaso-occlusive crisis (VOC), acute splenic sequestration (ASS), stroke, dactylitis, joint necrosis, priapism, leg ulcers, sepsis, iron overload and mortality. VOC events, defined as the composite of pain and/or acute chest syndrome (ACS), were only reported if they resulted in a hospitalization. Since history of VOC events was not well documented among referred patients, VOC events were assessed among patients newly diagnosed at the clinic. Results: The mean age of the study population at SCD diagnosis was 2.9 years (standard deviation [SD]: 4.3), with 73.1% of patients diagnosed within 3 years of age. Mean age at first visit to the clinic was 8.6 years (SD 10.0). 159 (47.5%) patients were female. The most common genotypes were Hemoglobin SS (233 [69.6%]), Hemoglobin Beta-0 Thalassemia (62 [18.5%]), and Hemoglobin Beta + thalassemia (27 [8.1%]). The mean number of follow up years between SCD diagnosis date and latest visit date to the clinic was 13.7 (SD: 10.5). 132 (39.4%) patients were newly diagnosed at the time of their first visit to the clinic. The most frequently encountered SCD clinical events were pain (189 [56.4%]) followed by ACS (135 [40.3%]), ASS (115 [34.3%]) and joint necrosis (55 [16.4%]). The incidence of stroke, pulmonary hypertension, priapism, leg ulcers and sepsis was low (3.3%, 4.2%, 6.0%, 3.0% and 3.9%). Persistent splenomegaly beyond 6 years was seen in 57 (17%) patients, 36 (63.2%) of these patients were of SS genotype. 276 (82.4%) patients required at least one hospitalization during their follow-up. Among newly diagnosed patients, 63% experienced at least one VOC event that led to a hospitalization with a mean of 0.4 (SD: 0.6) hospitalized VOC events per patient per year. 15 (4.5%) patients died during follow-up. The most common cause of death was stroke (3 [20%]). 84 (25.1%) and 76 (22.7%) patients underwent a cholecystectomy and surgical splenectomy respectively, and 30 (9.0%) patients underwent both. 236 (70.5%) patients were treated with Hydroxyurea. The mean age at introduction of Hydroxyurea was 11.5 years (SD: 10.1) and median starting dose was 15.2 mgs/kg/day. 281 (84%) patients received at least one blood transfusion during their follow-up. 37 (11.0%) patients received iron chelation during their follow up. 3 (0.9%) patients underwent bone marrow transplant and were cured of their disease. Conclusion: This first SCD study from North Lebanon demonstrates that SCD burden in North Lebanon is significant. Despite the high disease burden and the low community resources in this region, survival rate of this SCD patient population is relatively high. This can be attributed to the young age at diagnosis, the close comprehensive follow-up and the regular parent/patient education. The low rate of stroke, priapism and leg ulcers in this population warrants further investigation via disease associated markers and genetic determinants. As for priapism, it may be underreported due to social stigma in a conservative country as Lebanon. Noteworthy, Iron overload is under recognized and sub optimally treated. The association between specific risk factors and disease complications will be further addressed. Disclosures Inati: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Global Blood Therapeutics: Research Funding. Kanakamedala:Novartis: Consultancy; Genesis Research: Employment. Pilipovic:Novartis Pharma AG: Employment, Equity Ownership. Sabah:Novartis: Employment.

Pharmacokinetics of Ticagrelor in Infants and Toddlers Aged

Pharmacokinetics of Ticagrelor in Infants and Toddlers Aged <24 Months with Sickle Cell Disease

Relationship between Vaso-Occlusive Crises and Important Complications in Sickle Cell Disease Patients

Background: Sickle Cell Disease (SCD) describes a group of inherited hemolytic disorders caused by structurally abnormal variants of hemoglobin, which result in the sickle-shaped red blood cells (RBCs) that are characteristic of the disease. In patients with SCD, overexpression of adhesion molecules such as P-selectin bind sickled RBCs to endothelial cells; this contributes to hemolytic anemia and vaso-occlusive crises (VOCs), which are associated with severe acute and chronic pain. Patients with sickle cell disease often experience disease-related complications, affecting a diverse range of organs, thought to be due to the systemic impact of chronically inflamed vasculature, ongoing hemolysis and ischemic damage as a result of vaso-occlusive events. Many of these SCD-related complications are associated with significant morbidity and poor quality of life. The relationship between VOC frequency and the incidence of these complications is still being assessed. This study aimed to assess the relationship between the number of VOC experienced in the previous year and the occurrence of complications using real world evidence from the UK, specifically the Hospital Episode Statistics (HES) database. OBJECTIVE: To examine the relationship between the number of VOCs reported in the previous 12 months and the presence of SCD-related complications using a mixed modelling approach. METHODS: All patients reported with a diagnosis of SCD between 2008 and 2017 in the NHS England's HES database were identified. Detailed follow-up data on the number of vaso-occlusive crisis events and occurrence of complications was evaluated using ICD-10 diagnosis codes. Assuming no unmeasured confounding, the causal effect of VOCs, categorized into 3 groups (0, 1-2, 3+), was estimated using marginal structural models (MSM) for the complications reported in the dataset. To obtain inverse probability of treatment and censoring weights (IPTW and IPCW), the probability of being in each VOC category was estimated with a multinomial logistic model, and subsequently, the probability of being censored was estimated with a binary logistic model. The two models were adjusted for age, gender, ethnicity, and the occurrence in the previous 12 months of the 20 most common SCD complications and comorbidities in the dataset. Pooled logistic regressions were used to approximate the IPW-MSM Cox model. E-values were used to assess the minimum strength of association that an unmeasured confounder would have to have with both exposure (VOC) and outcome in order to fully explain away the observed relationship. Uncertainty in the magnitude of the E-value required to explain observed associations was explored by calculating values for both the point estimate and the lower bound of the confidence interval. RESULTS: A total of 15,076 patients were identified with a diagnosis of SCD in the HES database for this analysis. Patients had a median age of 30 and a female-male ratio of 1.7:1. A broad range of SCD related-complications were experienced by patients in the UK as shown in Table 1. Rates of some complications were observed less frequently than expected, in particular, leg ulcers, pulmonary hypertension, osteomyelitis, priapism and acute kidney injury, reported at &lt;5% (Table 1). The hazard ratio associated with experiencing 3+VOCs versus 0 VOC in the previous year was calculated for all identified complications, resulting in a HR ≥5, for: priapism, osteomyelitis and acute chest syndrome; HR ≥2 to &lt;5 for: gall stones, avascular necrosis, sepsis, cardiomegaly, pulmonary hypertension, CNS complications, leg ulcers, cellulitis, hyposplenism, liver complications and acute kidney injury. E-values (Table 1) suggest that most outcomes are robust to considerable unmeasured confounding, although large confidence intervals resulted in small lower-bound E-values for some outcomes (e.g. leg ulcers: 3.62 lower-bound: 1.00). Large E-values (&gt;= 3 based on similar research in SCD) suggest results are robust to considerable unmeasured confounding, while small values imply greater fragility. CONCLUSIONS: This analysis shows that vaso-occlusive crises are related to the occurrence of important complications of sickle cell disease. Reducing the annual incidence of VOC may significantly lessen the ongoing organ damage and morbidity but may also improve the patient's quality of life with respect to these conditions. Disclosures Bailey: Novartis: Employment. Abioye:Novartis: Employment. Morgan:HCD Economics: Employment. Burke:HCD Economics: Employment. Disher:Cornerstone Research Group: Employment. Brown:Cornerstone Research Group: Employment. Bonner:Cornerstone Research Group: Employment. Herquelot:HEVA: Employment. Lamarsalle:HEVA: Employment. Raguideau:HEVA: Employment.

A Prospective Phase II, Open-Label, Single-Arm, Multicenter Study to Assess the Efficacy and Safety of SEG101 (Crizanlizumab) in Sickle Cell Disease Patients with Priapism (SPARTAN)

Background: Sickle cell disease (SCD) is the most common single-gene disorder in African Americans and can lead to complications, including acute pain and chronic organ damage. Approximately 40% of men with SCD experience priapism, a clinical disorder characterized by prolonged, painful penile erection in the absence of sexual stimulation. Vaso-occlusion-induced ischemia is generally thought to account for SCD-associated priapism. Crizanlizumab, a humanized monoclonal antibody that binds P-selectin and blocks interaction with its ligands (including leukocyte PSGL-1). Crizanlizumab significantly decreased vaso-occlusive crises (VOCs) leading to healthcare visit vs placebo, and was well tolerated in SUSTAIN, a phase 2 study in adults with SCD. This SPARTAN study aims to evaluate the clinical efficacy of intravenous (IV) crizanlizumab 5 mg/kg in reducing priapic events in patients with SCD and a history of priapism utilizing a modern electronic reporting system. Electronic reporting tools have advantages over the paper format in regards to accuracy of and compliance in recording PROs (Stone et al, 2003). The study design and details of PRO collection methods are presented here. Study Design and Methods: This is a Phase 2, multicenter, open-label, single arm study of crizanlizumab in male patients aged ≥16 years with SCD-related priapism. The study will consist of 14 weeks prescreening, 12 weeks screening, and 52 weeks of treatment. The primary endpoint is percent reduction from baseline of priapic events frequency (unwanted/painful erection lasting &gt;60 minutes) by 26 weeks. It is expected that crizanlizumab treatment reduces priapic events by ≥ 25% in SCD patients with priapism by 26 weeks. Demonstration of significant percent reduction from baseline in priapic events will be evaluated statistically. Priapic events will be self-reported in real time via a restricted and secure study-issued smart watch and smart phone with a study-specific digital application (app). The patient records the start of a priapic event using a button on the pin code-protected app, which triggers a report in a database, creates a date/time stamp, and records the patient's identification. The patient is then prompted to complete an event reporting survey in one of three ways: using the app on the watch/phone, by a personal call with an operator, or by paper diary. Event reporting surveys will record priapic event occurrences, time and length of events, how the event was relieved, if there was a trigger, and the patient-reported pain at its worst during the event (scale of 0-10). Paper diaries are available as a back-up. Secondary endpoints include safety, as well as the following outcomes at 26 and 52 weeks: rate of priapic events, percent reduction in ≥4-hour erections requiring an ER visit, rate of VOC at 26 and 52 weeks, rate of uncomplicated VOC events, and rate of complicated crises. Approximately 56 patients are planned to be enrolled across 28 sites. Eligible patients must be ≥ 16 years old, have ≥4 events during prescreening, ≥3 during screening with 1 event occurring within 4 weeks prior to first treatment. Patients will be treated with IV crizanlizumab 5 mg/kg on the first day of Week 1, Week 3 (loading dose), Week 7, and then every 4 weeks until final treatment at Week 51. Primary analysis will be conducted after patients receive 26 weeks of treatment. Mandatory safety follow-ups will be conducted until 15 weeks after last dose. Patient feedback was considered and incorporated into the trial design. Results: This Phase 2 study (ClinicalTrials.gov Identifier: NCT03938454) has been successfully designed and approved by the institutional review board. Trial is ongoing. Conclusions: This study, which incorporates electronic PRO collection methods, has been designed to address the unmet treatment need in male patients &gt;16 years old with SCD-related priapism. Figure 1. SPARTAN Study Design Disclosures Darbari: Novartis: Membership on an entity's Board of Directors or advisory committees; Hilton Publishing: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Other: one day advisory board meeting . Paulose:Novartis Pharmaceuticals Corporation: Employment. Laine:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals: Employment. Kato:Novartis, Global Blood Therapeutics: Consultancy, Research Funding; Bayer: Research Funding.

PS1507 INCREASED VOC FREQUENCY ASSOCIATED WITH REDUCED HRQOL AMONG PATIENTS WITH SCD

Background:Sickle cell disease (SCD) is a global health concern. Each year as many as 200,000 infants are born with this disease worldwide. Despite improvements in outcomes over the last few decades, patient life expectancy remains 10 to 30 years shorter than that of the healthy population. A major cause of morbidity among patients with SCD is the occurrence of intense, recurrent, acute, severely painful episodes, known as vaso‐occlusive crisis (VOCs). As patients age and SCD progresses, an increased frequency of VOCs and other disease‐related complications is correlated with an increased risk of morbidity and mortality.Aims:The aim of the current analysis was to determine whether VOC frequency is associated with a decrease in the health‐related quality of life (HRQoL) and associated utility of patients with SCD.Methods:LEGACY was a prospective, multicenter, observational study that documented the outcomes of 181 adult patients with SCD living in the United States. Patients were assessed at baseline and every six months for 3 years, on several health outcomes, including the number of VOCs experienced and patient health as assessed by the Short Form‐36 (SF‐36) Health Survey. For the cohort of patients aged 18 years and older, the total number of VOCs experienced over the previous 12 months was determined for each administration of the SF‐36. Patients were categorized into three groups:‐ 0 VOCs in the previous 12 months‐ 1 to 2 VOCs in the previous 12 months‐ 3 or more (3+) VOCs in the previous 12 monthsThe SF‐36 scores for individual questionnaires were then mapped to the EuroQoL five‐dimension (EQ‐5D) questionnaire, which is a standardized instrument that can be used to derive a single utility value. The mapping was done using the random effects GLS mapping algorithm published by Rowan and colleagues (2009). Mean EQ‐5D scores were compared between groups using the Student's T‐test. Differences between the groups on the SF‐36 component scores and SF‐36 domains were also assessed.Results:Patients with 3+ VOC events in the previous 12 months had mapped mean EQ‐5D scores that tended to be lower (15%) than those of patients who had no VOC events (see Figure 1). Patients who had 3+ VOC events also showed decreases in both SF‐36 Physical Component Scores and Mental Component Scores compared to patients with no VOC events.Summary/Conclusion:To our knowledge, this is the first analysis to examine the relationship between VOC frequency and HRQoL in patients with SCD. The results of this analysis indicate that patients who have a higher number of VOC events experience a worse HRQoL compared to patients with no events. Additional research is required to understand the drivers of this difference in HRQoL.image

PF715 THE IMPACT OF CRIZANLIZUMAB ON VOC‐RELATED MEDICAL FACILITY VISITS

Background:A major cause of morbidity among patients with sickle cell disease (SCD) is the intense, recurrent, unpredictable attacks, known as vaso‐occlusive crises (VOCs), which are responsible for &gt;90% of hospital admissions in SCD. An important goal of pharmacological therapy is to prevent the occurrence of these painful episodes, and in turn, reduce the clinical and economic burden of the disease.In December 2018, the United States Food and Drug Administration granted crizanlizumab (SEG101) Breakthrough Therapy designation for the prevention of VOCs in patients with SCD. This designation was granted based on positive results from the Phase II SUSTAIN trial, in which 5 mg/kg crizanlizumab was associated with a 45.3% reduction in the median annual rate of VOCs leading to healthcare visits compared with placebo.Aims:The aim of the current analysis was to investigate the impact of crizanlizumab on VOC‐related medical facility visits.Methods:sing data from the SUSTAIN trial, analyses were conducted to determine the cumulative number of VOC events across all patients, medical facility visits and by medical facility type in the 5 mg/kg crizanlizumab and placebo arms. The total cumulative number of patient days in the study was considered in determining the event rate per year, which was calculated as follows:“[Total cumulative number of VOCs across all patients]/[Total number of days observed across all patients]” ∗ 365Incidence rate ratios (IRR) were derived using a Poisson regression model. Maximum likelihood parameter estimates were generated with standard errors to produce confidence intervals and p‐values. Effect modification over time by group was assessed by maximum likelihood.Results:The analyses showed a reduction in the overall rate of VOC events requiring a medical facility visit in the 5 mg/kg crizanlizumab group compared with the placebo group. Further examination of the impact of crizanlizumab on specific sites of care demonstrated a reduction in visits to outpatient care sites, largely driven by reduced visits to emergency care units and SCD crisis centers (Table 1). A trend to reduced inpatient admissions was also observed.Summary/Conclusion:Payers aim to reimburse treatments for SCD that reduce both the clinical and economic burden of the disease. In the SUSTAIN trial, patients treated with 5 mg/kg crizanlizumab experienced a 45.3% reduction in the median annual rate of VOCs leading to healthcare visits compared with those receiving placebo. The current analysis demonstrates that this reduction in VOCs leading to a healthcare visit was seen in most medical facility visits, largely driven by reduced visits to emergency care units and specialized SCD crisis centers. These findings suggest that patients treated with crizanlizumab will experience a substantial reduction in health care resource utilization and associated costs.image

Evaluation of Vaso-occlusive Crises in United States Sickle Cell Disease Patients: A Retrospective Claims-based Study.

Sickle cell disease (SCD) is a life-threatening vascular disease that burdens affected persons physically. SCD-related vaso-occlusive crises (VOCs) are one of the primary causes of morbidity and mortality. Our objective was to examine the epidemiology of pain crises and the relationship between pain crises and major acute complications among SCD patients. Using the Medicaid Analytic Extracts from 2009–2013, patients with SCD were selected and the first clinical claim indicating SCD during the identification period was defined as the index date. Patients were required to have continuous Medicaid enrollment for ≥6 months pre- and 12 months post-index period. Clinical outcomes included mortality, inpatient pain crises, and complications. Cox regressions were applied to examine the relationship between pain crises and deaths or acute complications, respectively. A total of 20 909 patients were included with a mean age of 17.9 years. The rate of VOC events in 100 person-years was 142.20 for adults and 53.91 for pediatric patients. Patients with VOCs were associated with a higher risk for death (hazard ratio=1.56; 95% confidence interval: [1.19–2.05]) or acute complications including acute chest syndrome, stroke, pulmonary embolism, splenic sequestration, and pulmonary hypertension. SCD patients have a substantial burden of disease-related complications. This study suggests that inpatient vaso-occlusive crisis is a key risk factor for acute complications.

Evaluation of Vaso-occlusive Crises in United States Sickle Cell Disease Patients: A Retrospective Claims-based Study

Sickle cell disease (SCD) is a life-threatening vascular disease that burdens affected persons physically. SCD related vaso-occlusive crises (VOCs) are one of the primary causes of morbidity and mortality. Our objective was to examine the epidemiology of pain crises and the relationship between pain crises and major acute complications among SCD patients. Using the Medicaid Analytic Extracts from 2009-2013, patients with SCD were selected and the first clinical claim indicating SCD during the identification period was defined as the index date. Patients were required to have continuous Medicaid enrollment for ≥6 months pre- and 12 months post-index period. Clinical outcomes included mortality, inpatient pain crises, and complications. Cox regressions were applied to examine the relationship between pain crises and deaths or acute complications, respectively. A total of 20 909 patients were included with a mean age of 17.9 years. The rate of VOC events in 100 person-years was 142.20 for adults and 53.91 for pediatric patients. Patients with VOCs were associated with a higher risk for death (hazard ratio=1.56; 95% confidence interval: [1.19-2.05]) or acute complications including acute chest syndrome, stroke, pulmonary embolism, splenic sequestration, and pulmonary hypertension. SCD patients have a substantial burden of disease-related complications. This study suggests that inpatient vaso-occlusive crisis is a key risk factor for acute complications.

PRO38 ASSOCIATION BETWEEN VASO-OCCLUSIVE CRISES AND OPIOID USE AMONG TEXAS MEDICAID RECIPIENTS WITH SICKLE CELL DISEASE

Among sickle cell disease (SCD) patients, vaso-occlusive crises (VOCs) are recurrent and unpredictable attacks of acute pain that are often treated with analgesics, including opioids, which have been associated with misuse and overdose. This study examined the association between VOC events and opioid use among SCD patients. This Texas Medicaid retrospective study of medical and prescription claims between 9/1/11-8/31/16 included: patients (2-63 years) with at least one inpatient or two outpatient SCD diagnoses who were continuously enrolled during 12 months post-index. The index date was the first SCD diagnosis. The primary outcome was number of opioid prescriptions, while the independent variable was number of VOC events. Covariates included age, gender, non-opioid medication use, non-study SCD-related medication (penicillin and folic acid) use, evidence of blood transfusions, number of SCD-related complications, number of SCD-related comorbid conditions, and Charlson Comorbidity Index. Negative binominal regression analysis was used to address the study objective. Of included patients (N=3,368), 1,978 (58.7%) had at least one opioid prescription with a mean±SD of 4.2±7.2. Overall, 2,071 (61.5%) had at least one VOC event with an average of 2.9±4.4. The regression showed that for every increase in VOC events, the number of opioids used increased by 9.5% (incidence rate ratio [IRR]=1.095, 95% CI 1.078–1.111; p<0.0001). Other significant covariates associated with higher opioid use included age (13-17, 18-24, 25-34, 35-44, 45 and older; reference 2-12) higher non-opioid pain medications, non-study SCD-related medications, and SCD-related complications. The majority of SCD patients were prescribed opioids and had at least one VOC event. Each VOC event was associated with a 10% increase in use of opioids. Despite the opioid epidemic, payers and providers should be aware of opioid use in the population and should consider appropriate VOC prevention measures, as well as the need for appropriate pain management.

Established Prevention of Vaso-Occlusive Crises with Crizanlizumab Is Further Improved in Patients Who Follow the Standard Treatment Regimen: Post-Hoc Analysis of the Phase II Sustain Study

Background: In the 52-week SUSTAIN study, which compared the P-selectin inhibitor crizanlizumab with placebo in patients with sickle cell disease (SCD), crizanlizumab 5.0 mg/kg significantly reduced the frequency of vaso-occlusive crises (VOCs) leading to healthcare utilization versus placebo (Ataga KI et al. N Engl J Med 2017;376:429-39). The overall incidences of adverse events and serious adverse events were similar among the patients treated with crizanlizumab and placebo.Aims: This post-hoc analysis from SUSTAIN evaluated key VOC-related endpoints in crizanlizumab 5.0 mg/kg and placebo groups in the per protocol (PP) population, as a way to assess the effect in patients who are able to follow the standard treatment regimen; data from the intention-to-treat (ITT) population will also be shown for context.Methods: The SUSTAIN study was a randomized, double-blind, placebo-controlled, Phase II study (NCT01895361) that enrolled patients aged 16-65 years with SCD who had experienced 2-10 VOC events in the previous 12 months. Patients were randomized 1:1:1 to receive crizanlizumab 5.0 mg/kg, 2.5 mg/kg or placebo 14 times intravenously over 52 weeks; here we focus on the 5.0 mg/kg dose of crizanlizumab versus placebo. The number and time of VOCs leading to healthcare utilization (e.g., hospital admission, emergency department visit) from randomization to end of treatment were measured for each individual patient. Analyses were conducted on the ITT population (i.e., all patients randomized) and PP population (i.e., all patients randomized who received at least 12/14 planned doses of treatment, and completed the study without major protocol violations that impacted the efficacy assessments).Results: In the crizanlizumab 5.0 mg/kg and placebo groups, there were 67 and 65 patients in the ITT population, and 40 and 41 patients in the PP population, respectively; the main reasons for exclusion from the PP population were associated with violations of the visit schedule. As shown previously (Ataga KI et al. N Engl J Med 2017;376:429-39), the median annual rate of VOCs was 1.63 in the crizanlizumab 5.0 mg/kg group versus 2.98 in the placebo group (stratified Wilcoxon Rank-Sum test, P=0.01; Table) in the ITT population. The median time to first on-treatment VOC was 4.07 versus 1.38 months (stratified log-rank test, P=0.001), respectively, in the crizanlizumab 5.0 mg/kg and placebo groups. Overall, 24/67 (35.8%) and 11/65 (16.9%) patients in the crizanlizumab 5.0 mg/kg and placebo groups (stratified Cochran-Mantel-Haenszel test, P=0.013), respectively, did not experience any VOCs during treatment. In the PP population, the median annual rate of VOCs was 1.04 with crizanlizumab 5.0 mg/kg versus 2.18 with placebo (P=0.02; Table). The median time to first on-treatment VOC was 6.55 months with crizanlizumab 5.0 mg/kg and 1.58 months in the placebo group (P<0.001). Overall, 15/40 (37.5%) and 5/41 (12.2%) patients in the crizanlizumab 5.0 mg/kg and placebo groups, respectively, did not experience any VOCs during treatment (P=0.008). The effect of treatment with crizanlizumab 5.0 mg/kg over placebo, as assessed by the three selected endpoints, is visible on the Figure, i.e., reduced frequency of VOCs, delayed first VOC, and increased number of patients with no VOCs during treatment.Conclusions: This post-hoc analysis of SUSTAIN shows that crizanlizumab 5.0 mg/kg provided benefit over placebo: nearly halving the median annual rate of VOCs, doubling the time to first VOC, and doubling the number of patients with no VOCs during treatment in the ITT population. The effect was even more pronounced in the PP population. This suggests that the superior VOC-related treatment outcomes of crizanlizumab 5.0 mg/kg versus placebo are further improved in patients who are able to follow the standard crizanlizumab treatment regimen. [Display omitted] DisclosuresKanter:NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Research Funding; Pfizer: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Sancilio: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kutlar:Novartis: Consultancy, Honoraria, Other: Personal fees, Research Funding; Sancilio: Other: DSMB Chair; Bluebird Bio: Other: DSMB Member. Bruederle:Novartis: Employment. Shi:Novartis: Employment, Other: Stock owner of Novartis. Campigotto:Novartis: Employment. Ataga:Pfizer: Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria; Modus Therapeutics: Honoraria; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees.

PSY63 - Association Between Hydroxyurea Medication Adherence and Vaso-Occlusive Crisis Events Among Texas Medicaid Enrollees with Sickle Cell Disease

PSY63 - Association Between Hydroxyurea Medication Adherence and Vaso-Occlusive Crisis Events Among Texas Medicaid Enrollees with Sickle Cell Disease

Association between Oxidative Stress, Genetic Factors, and Clinical Severity in Children with Sickle Cell Anemia

To investigate the associations between several sickle cell disease genetic modifiers (beta-globin haplotypes, alpha-thalassemia, and glucose-6-phosphate dehydrogenase deficiency) and the level of oxidative stress and to evaluate the association between oxidative stress and the rates of vaso-occlusive events. Steady-state oxidative and nitrosative stress markers, biological variables, genetic modulators, and vaso-occlusive crisis events requiring emergency admissions were measured during a 2-year period in 62 children with sickle cell anemia (58 SS and 4 Sβ0). Twelve ethnic-matched children without sickle cell anemia also participated as healthy controls (AA) for oxidative and nitrosative stress level measurement. Oxidative and nitrosative stress were greater in patients with sickle cell anemia compared with control patients, but the rate of vaso-occlusive crisis events in sickle cell anemia was not associated with the level of oxidative stress. The presence of alpha-thalassemia, but not glucose-6-phosphate dehydrogenase deficiency or beta-globin haplotype, modulated the level of oxidative stress in children with sickle cell anemia. Mild hemolysis in children with alpha-thalassemia may limit oxidative stress and could explain the protective role of alpha-thalassemia in hemolysis-related sickle cell complications.

Alpha-thalassaemia promotes frequent vaso-occlusive crises in children with sickle cell anaemia through haemorheological changes.

Sickle cell anaemia (SCA) is a severe hereditary haemoglobinopathy characterised by haemorheological abnormalities, which play a role in the occurrence of several acute and chronic clinical complications. While βS -haplotypes and alpha-thalassaemia modulate SCA clinical severity, their effects on blood rheology have been incompletely described. The aim of this study was to test the effects of these genetic modifiers on the haemorheological properties and clinical complication of children with SCA. Steady-state haemorheological profile, biological parameters, βS -haplotypes, alpha-globin status, vaso-occlusive crisis (VOC) and acute chest syndrome frequencies were analysed in 128 children (aged 5 to 18 years) with SCA. Patients with alpha-thalassaemia showed increased red blood cell (RBC) deformability and aggregation compared to those without. Median VOC rate was higher in patients with homozygous alpha-thalassaemia compared to those with a normal alpha genotype. Conversely, the haemorheological profile and clinical complications were not influenced by the βS -haplotypes in our study. Our results demonstrate that alpha-thalassaemia is associated with higher risk for VOC events in children with SCA, which may be due in part to its effects on RBC deformability and aggregation.

Acute Kidney Injury during Pediatric Vaso-Occlusive Crisis

Several potential risk factors are being evaluated for their impact on the development of chronic kidney disease (CKD) in patients with Sickle Cell Disease (SCD). Recent studies in animals, children and adults without SCD, have established that acute kidney injury (AKI) can lead to CKD, yet the risk of repeated AKI events during vaso-occlusive crisis (VOC) has not been defined in SCD. During VOC events, patients may be at risk for developing AKI due to the use of nephrotoxic pain medications, dehydration (poor concentrating ability), hemolysis, or inflammatory responses. Multiple gaps in our understanding of AKI in SCD patients need to be addressed.Methods: In order to improve our understanding of the incidence, risk factors, and outcomes associated with AKI, we conducted a two year IRB approved retrospective review of 234 episodes of ICD-10 defined VOC admitted from Children’s of Alabama Pediatric Emergency Department (ED). AKI was defined by KDIGO definition of an increase in serum creatinine (SCr) by ≥ 0.3 mg/dl or 50% increase in serum creatinine from baseline. Baseline labs were defined as the most recent outpatient laboratory value and within 12 months from admission. Thirty seven admissions were excluded as their baseline SCr could not be established. Variables analyzed included age, gender, SCD genotype, baseline and admission CBC (hemoglobin (Hb) value, white blood cell count (WBC), absolute neutrophil count (ANC), platelet count, and absolute reticulocyte count (ARC)), length of stay (LOS), and SCD modifying therapy. Generalized mixed effects model for binary outcome with random intercept, to accommodate repeated hospitalizations for the same subject, was fitted to assess the associations between clinical variables and AKI for all patients and severe phenotypes. Similarly, a generalized mixed Poisson effects model with random intercept was fitted to determine if AKI was independently associated with hospital length of stay.Results: Among 197 admissions for VOC, 33 (17%) were identified with AKI. Seventeen (52%) of the thirty three AKI events were first diagnosed in the ED. Compared to children without AKI, patients with AKI had a larger drop in hemoglobin from baseline at admission (0.5 vs. 1.21g/dL, p=0.005). For every 1 unit drop in Hb from baseline to admission, the odds of AKI increased by 49% (OR= 1.49, 95% CI 1.1-2.0). We identified no differences in AKI vs. no AKI by age, gender, SCD genotype, or SCD modifying therapy, change in WBC, ANC, Platelets or absolute reticulocyte count. In multivariate analysis accounting for age, gender, change in blood counts, SCD genotype or therapy, a drop in Hb remained the only significant variable (OR= 1.48, 95% CI 1.05-2.1). Patients with AKI admitted for vaso-occlusive crisis required significantly longer length of stay. The average LOS for those with AKI was 32% longer than the without AKI (OR 1.32, 95% CI 1.10-1.58).Conclusion: Seventeen percent of SCD patients with pain admitted to the hospital can present with or develop AKI. An acute drop in hemoglobin is a major risk factor for developing AKI. Patients that develop AKI require longer hospitalizations for their pain crisis, independent of potential confounders. Research should focus on pathophysiology of kidney injury in patients with SCD, the impact of nephrotoxic medications, and the role by which AKI leads to CKD in this population. DisclosuresAskenazi:AKI foundation: Consultancy, Speakers Bureau; BTG: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Baxter: Consultancy, Speakers Bureau. Lebensburger:American Society of Hematology, Scholar Award: Research Funding; National Institutes of Health: Research Funding.

Geographic Differences in Phenotype and Treatment of Children with Sickle Cell Anemia from the Multinational DOVE Study

Background: Sickle cell anemia (SCA) is characterized by significant phenotypic variability. DOVE1 was a Phase 3, double-blind, randomized, parallel-group, placebo-controlled, multinational study that investigated the efficacy and safety of prasugrel, a P2Y12 adenosine diphosphate receptor antagonist, for reduction of vaso-occlusive crises (VOCs), a composite of painful crisis or acute chest syndrome, in 2- to <18-year-olds with SCA (age cohorts: 2 to <6 years, 6 to <12 years, and 12 to <18 years) (NCT01794000).Methods: DOVE was conducted at 51 sites in 13 countries across 4 continents. A total of 341 subjects were randomized (prasugrel, n=171; placebo, n=170) and SCA genotypes (homozygous hemoglobin S; hemoglobin Sβ0 thalassemia) were included. Eligibility required ≥2 VOCs in the prior year. Baseline clinical and laboratory characteristics and study endpoints were compared by region. Since no overall treatment effect was found, data provided reflect the combined 341 subjects (Americas, N=57; sub-Saharan Africa [SSA], N=148; North Africa/Middle East, N=110; Europe, N=26).Results: Per regional enrollment, the largest proportion of subjects were 6 to <12 years in SSA (48.6% [n=72]), 12 to <18 years in the Americas (45.6% [n=26]) and North Africa/Middle East (58.2% [n=64]), but more evenly divided among the 3 age groups in Europe (30.8-34.6% [n=8-9]). Self-reported racial groupings differed by region (p<0.001): 100% white in North Africa/Middle East; 100% black in SSA; 19.2% white, 76.9% black, and 3.8% multiple in Europe; and 1.8% white, 96.4% black, and 1.8% multiple in the Americas. Mean body mass index was <17 in SSA and Europe (15.3 and 16.6 kg/m2) but >18 in North Africa/Middle East and the Americas (18.3 and 18.1 kg/m2) (p<0.001). Mean blood pressures were lowest in SSA (systolic: 99.0 vs. 105.4-108.0 mmHg, p=0.004; diastolic: 58.3 vs. 60.4-62.9 mmHg, p=0.003).The proportion of subjects with history of acute chest syndrome prior to enrollment was lower in SSA (6.1%) than other regions (18.2-66.7%, p<0.001). Mean number of VOCs in the year prior to enrollment was higher in the Americas than other regions (5.8 vs. 3.2-3.4, p=0.041).Hydroxyurea (HU) use at baseline varied by region: 91.2% in the Americas, 72.7% in North Africa/Middle East, 42.3% in Europe, and 6.8% in SSA (p<0.001). For subjects not on HU at baseline (Table 1), mean hemoglobin at baseline was lowest in SSA (7.6 g/dL); reticulocyte count was lowest in the Americas (214.8 billion/L) and highest in Europe (327.8 billion/L) (p=0.004).For all geographic regions, the most frequent serious adverse events (SAEs) were classified as blood and lymphatic system disorders, with the highest percentage reported as painful crisis. The second most frequent SAEs in SSA, North Africa/Middle East, and Europe were various infections and infestations. The second most frequent in the Americas was respiratory, thoracic, and mediastinal disorders; all were reported as acute chest syndrome.The overall rate of VOCs (events per patient-year) was 3.2 in Europe, 3.0 in the Americas, 2.6 in SSA, and 2.0 in North Africa/Middle East. The percentage of patients hospitalized for VOCs was greatest in Europe (76.9%) compared to other regions (28.4-57.9%); however, mean hospital stay per VOC was similar across regions (5.3-6.2 days). The percentage of VOCs causing hospitalization was highest in Europe (67.7%), followed by North Africa/Middle East (48.7%), the Americas (46.5%), and SSA (26.4%). In SSA, the majority of VOCs were managed as outpatient hospital visits (67.9%), whereas other regions more frequently used inpatient hospital visits (33.2-55.2%). Regardless of region, almost all VOCs were treated with analgesics (overall: 99.5%) and approximately half were treated with intravenous (IV) fluids (overall: 54.4%). In contrast, the proportion of VOC-related transfusions was greater in North Africa/Middle East and Europe (18.6% and 18.8%) than in the Americas and SSA (10.0% and 6.4%).Conclusions: In the DOVE study, management of VOCs with analgesics and IV fluids was similar across regions. However, there were regional differences in VOC-related hospitalizations and transfusions that may reflect differences in culture, utilization of resources, disease severity, or a combination of factors.

Regional- and Age-Related Differences in Pain in Children with Sickle Cell Anemia: Results from the Multinational DOVE Study

Background: Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) was a multi-national Phase 3 trial to assess the efficacy of prasugrel for the prevention of vaso-occlusive crisis (VOC) as a composite endpoint of painful crisis or acute chest syndrome in children and adolescents aged 2-18 years with sickle cell anemia (SCA). Despite a trend toward fewer VOCs in the prasugrel-treated oldest age group (12-18 years), DOVE did not meet its primary endpoint. This was the first multinational prospective study of diary-reported pain rate and intensity in children and adolescents with SCA.Aim of current study: This sub-study evaluated VOC events (as defined by DOVE), analgesic use, and the rate, intensity, and perception of pain by geographical region and age group.Data: During the DOVE study, participants who were 4 years or older used daily diaries to report pain rate and intensity, and analgesic use. Rates of pain and analgesic use were calculated for each patient by summing the number of days with any pain or analgesic use reported divided by the number of non-missing diary entries from randomization to 9 months. Mean pain intensity was calculated similarly, but days in which participants reported pain of "0" were not included. Pain rate and intensity were evaluated only for participants 7 years or older. Type of analgesic use (opioid vs non-opioid) was also evaluated in all participants. Treatment arms (prasugrel-treated and untreated patients) were combined for the current analysis, as justified by the lack of a statistically significant treatment effect. Data were analyzed by univariable and multivariable methods.Results: There was no association between baseline hematology labs or lactic dehydrogenase levels and pain rate or intensity. In multivariable analysis, older participants (aged ≥12 years) reported more frequent pain than younger participants (p=0.0320). Hydroxyurea (HU) use at baseline did not affect pain rate or pain intensity. The regions of the Americas and West Europe showed higher pain rate and intensity scores than Africa and the Middle East. (Table 1) Opioid use was much higher in the Americas compared with other regions p=0.0002. (Table 2)Conclusions: Pain rates were higher in older children, demonstrating a worsening of pain during the lifespan, which is consistent with previous literature. Pain rate and intensity were similar irrespective of HU treatment; whether this finding reflects increased baseline pain in participants on HU or other causality is unclear. Regional differences in pain rate and intensity were seen. Pain intensity and opioid use were significantly higher in the Americas than in other regions. In contrast, the lowest reported pain rates and intensities were found in Africa. These findings suggest cultural and/or regional differences in SCA pain perception and reporting that require further exploration. The relationship between pain intensity and analgesic treatment practices also needs further study. [Display omitted] DisclosuresKanter:Novartis: Consultancy. Heath:Eli Lilly and Company: Employment. Zhou:Eli Lilly and Company: Employment, Other: Minor Shareholder. Colombatti:Eli Lilly and Company: Research Funding. Dampier:Eli Lilly and Company: Consultancy, Research Funding. Hassab:Eli Lilly and Company: Research Funding. Brown:Eli Lilly and Company: Employment, Other: Minor Shareholder. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Yao:Eli Lilly and Company: Employment. Knorr:Eli Lilly and Company: Employment, Equity Ownership. Hoppe:Eli Lilly and Company: Consultancy.

Conjunctival microvascular hemodynamics following vaso-occlusive crisis in sickle cell disease.

Painful vaso-occlusive crisis (VOC) is the clinical hallmark of sickle cell disease (SCD). Microcirculatory hemodynamic changes following painful VOC may be indicative of future development of VOC events in subjects with SCD. The purpose of the present study was to determine alterations in conjunctival microvascular hemodynamics during non-crisis state in SCD subjects with a history of VOC. Conjunctival microcirculation imaging was performed to measure conjunctival diameter (D) and axial blood velocity (V) in 10 control and 30 SCD subjects. SCD subjects were categorized into two groups based on their history of VOC within a 2-year period before imaging (with or without VOC-H) and also based on whether there was progression in the rate of VOCs during a 2-year period following imaging as compared to before imaging (with or without VOC-P). Conjunctival V was significantly higher in SCD subjects with VOC-H than in both control subjects and SCD subjects without VOC-H (P≤0.03). Conjunctival V was also significantly higher in SCD subjects with VOC-P compared with control subjects and SCD subjects without VOC-P (P≤0.03). Assessment of the conjunctival microcirculation may be useful for understanding hemodynamic changes that lead to VOC events in SCD subjects.