Assessment of knowledge and practices of patients with sickle cell anemia regarding the disease and preventive measures of its pain crisis

Abstract Abstract 1651 Background: Pain crises are the most common symptom experienced by individuals with sickle cell anemia (SCA). Frequency of pain crises varies significantly and high rate is a risk factor for higher mortality in adults with SCA. The risk factors for pain crises in children and adolescents with SCA are not completely understood. To determine factors associated with frequent severe pain crises, we analyzed the cohort of children and adolescents with SCA who were enrolled in the prospective study “The Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH)”. All children were evaluated in their steady, non-crisis state. Methods: Family-reported history of number of severe pain crises in the preceding 12 months was recorded prospectively in 365 children and adolescents with SCA. Severe pain crises were defined as painful vaso-occlusive episodes requiring evaluation in Emergency Department (ED) or in-patient hospitalization. Lifetime history of red cell transfusions, echocardiography, and laboratory studies were obtained. Clinical and laboratory characteristics of study subjects who had ≥3 severe pain crises in the preceding year were compared to subjects with < 3 severe pain crises. Results: Study subject ranged in age from 3–20 years and 175 (48%) were female. Seventy two children (20 %) had ≥3 severe pain crises in the preceding year (frequent pain crisis group); 293 (80%) children had < 3 severe pain crises (infrequent pain crisis group), including 224 (61%) subjects who had no admissions/ ED visits for pain. Associated factors for frequent pain crisis included older age (odds ratio 1.2; 95% confidence interval 1.12–1.35; P <0.001) and α-thalassemia trait (odds ratio 3.22; 95% confidence interval 1.55–6.69; P =0.002) while higher steady state serum lactate dehydrogenase (LDH) was associated with infrequent pain crisis (odds ratio 0.35; 95% confidence interval 0.13–0.98; P =0.045). In a group of patients without α-thalassemia trait, older age and low LDH were linked to frequent pain crisis. Subjects in the frequent pain crisis group had higher median hemoglobin (9.0 vs. 8.5 gm/dL; p=0.003) and higher ferritin (median 455 vs. 191 ng/mL; p=0.008). Higher ferritin in the frequent pain crisis group was mirrored by the higher percentage who reported >10 lifetime transfusions (42% vs. 22%; p=0.001). Median tricuspid regurgitation jet velocity (TRV) was higher in the frequent pain crisis group (2.41 vs. 2.31; p= 0.001) but the proportion of children with TRV>2.5 was not different (19.4% vs.11.5% in infrequent crises group; p=0.09). Hydroxyurea use was not different between the groups (51% vs. 40%; p=0.08) nor was fetal hemoglobin (10% vs. 12%; p=0.2). Conclusions: The occurrence of severe pain crisis varies among children and adolescents with SCA with a large number of children experiencing no severe painful episodes. Consistent with the Cooperative Study of Sickle Cell Disease report, the risk of severe pain crisis increases with age. Individuals with α-thalassemia trait are likely to experience more frequent pain crises possibly related to higher hemoglobin concentration and viscosity. However, even after controlling for α-thalassemia trait, children and adolescents who reported more frequent severe pain crises showed evidence of less hemolysis, consistent with a hypothetical model associating the hemolytic subphenotype of SCA with less frequent vasoocclusive pain crises. Further studies are indicated to identify the molecular mechanisms of pain in sickle cell anemia. Disclosures: No relevant conflicts of interest to declare.

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Health Care Utilization for Painful Events Is Associated with Early Mortality in a Contemporary Population of Adults with Sickle Cell Anemia

Blood ◽

10.1182/blood.v118.21.2115.2115 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2115-2115

Author(s):

Deepika S. Darbari ◽

Mariana Hildeshem ◽

Caterina Minniti ◽

Gregory J. Kato ◽

James G. Taylor

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Severe Pain ◽

Early Mortality ◽

Care Utilization ◽

Cell Disease ◽

History Of ◽

Pain Crisis ◽

Ed Visits ◽

Painful Events

Abstract Abstract 2115 Background: Painful vaso-occlusive crises are the most common symptom associated with sickle cell anemia (SCA) and show a large inter-patient variability in the frequency and severity. Historically a high rate of admissions for pain is associated with early mortality in SCA adults. Modern day management of SCA includes screening for life threatening complications such as pulmonary hypertension and disease modifying therapies such as hydroxyurea and chronic blood transfusions. It has also become clear that all acute painful events including some self reported crisis do not lead to ED visit/ hospitalization therefore use of healthcare utilization may underestimate the actual frequency of painful vaso-occlusive crises. The present study determined if ED visit/ hospitalizations for painful vaso-occlusive crises remain a marker of early mortality in the modern era. Methods: To determine the relative contribution of pain and other established risk factors for death in a contemporary adult cohort with sickle cell anemia, we analyzed data of SCA individuals who were evaluated at NIH between February 2001 and June 2007 for screening of the IRB approved protocol to study pulmonary hypertension in sickle cell disease. Self reported history of vaso-occlusive painful events requiring visit to an emergency department (ED) or in-patient hospitalization in 12 months preceding the enrollment was used to stratify study subjects into no-ED visit/ hospitalization or ED visit/hospitalization group. Characteristics between the groups were compared. Doppler echocardiography was used to estimate systolic pulmonary artery pressure through measurement of the tricuspid regurgitation velocity (TRV). Study subjects were followed prospectively and age at death was recorded. Results: One hundred and four (40%) SCA subjects reported no ED visit/ hospitalization while 160 (60%) reported at least one ED visit/ hospitalization in 12 months preceding the enrollment. Although not statistically significant, a higher proportion of study participants in the ED visit/ hospitalization group were on hydroxyurea (38 vs. 69%; P=0.4), and more likely to have received > 10 red cell transfusions (37 vs. 48%; P= 0.09). The no-ED/ hospitalization group and ED/ hospitalization groups were not different in median age (33 vs. 31; P=0.1) or fetal hemoglobin concentration (7.7 vs. 6.9%; P=0.3). Overall forty (15.1%) individuals died during the median follow-up period of 5 years. Cox proportional hazards analysis was performed to determine if severe pain crisis requiring ED visits/hospitalizations were associated with early mortality after adjusting for other known risk factors for mortality (Table 1). Risk for mortality was significantly associated with a history of severe pain crisis requiring ED visit/hospitalization in preceding year (RR 2.81, 95% CI: 1.2–6.4, P= 0.04), elevated TRV ≥ 3 m/s (RR 4.07, 95% CI: 1.3–12.8, P= 0.02) and elevated ferritin (RR 2.31, 95% CI: 1.0–5.0, P= 0.04). Conclusions: Severe painful episodes requiring health care utilization are associated with premature mortality and despite likely underestimation of actual frequency of pain, remain a marker of disease severity. Elevated TRV a marker of elevated pulmonary arterial pressure and early mortality has a cumulative effect with pain on reduced survival. Consistent with Cooperative Study of Sickle Cell Disease (CSSCD) report, higher hemoglobin (and lower LDH) was associated with reports of ED visit/ hospitalization likely related to increased viscosity. We conclude that as a group, SCA patients reporting severe pain requiring ED visits /hospitalization and elevated TRV are at the highest risk for shortened survival. Disclosures: No relevant conflicts of interest to declare.

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2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia

Blood ◽

10.1182/blood.v96.7.2379.h8002379_2379_2384 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2379-2384

Author(s):

Mabel Koshy ◽

Louise Dorn ◽

Linda Bressler ◽

Robert Molokie ◽

Donald Lavelle ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Complete Blood Count ◽

Fetal Hemoglobin ◽

Therapeutic Benefit ◽

Additional Treatment ◽

Acute Chest Syndrome ◽

F Cells ◽

Pain Crisis ◽

Globin Synthesis

Augmentation of the fetal hemoglobin (HbF) levels is of therapeutic benefit in patients with sickle cell anemia. Hydroxyurea (HU), by increasing HbF, lowers rates of pain crisis, episodes of acute chest syndrome, and requirements for blood transfusions. For patients with no HbF elevation after HU treatment, augmentation of HbF levels by 5-aza-2′-deoxycytidine (5-aza-CdR, decitabine) could serve as an alternate mode of treatment. Eight adult patients participated in a dose-escalating phase I/II study with 5-aza-CdR at doses ranging from 0.15 to 0.30 mg/kg given 5 days a week for 2 weeks. HbF, F cell, F/F cell, γ-globin synthesis ratio, complete blood count, and chemistry were measured. The average γ-globin synthesis relative to non-α-globin synthesis prior to therapy was 3.19% ± 1.43% and increased to 13.66% ± 4.35% after treatment. HbF increased from 3.55% ± 2.47% to 13.45% ± 3.69%. F cells increased from 21% ± 14.8% to 55% ± 13.5% and HbF/F cell increased from 17% to 24%. In the HU nonresponders HbF levels increased from 2.28% ± 1.61% to 2.6% ± 2.15% on HU, whereas on 5-aza-CdR HbF increased to 12.70% ± 1.81%. Total hemoglobin increased by 1 g/dL in 6 of 8 patients with only minor reversible toxicities, and all patients tolerated the drug. Maximum HbF was attained within 4 weeks of treatment and persisted for 2 weeks before falling below 90% of the maximum. Therefore 5-aza-CdR could be effective in increasing HbF in patients with sickle cell anemia who failed to increase HbF with HU. Demonstration of sustained F levels with additional treatment cycles without toxicity is currently being performed.

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Prognostic Significance of Early Vaso-Occlusive Complications in Children Who Have Sickle Cell Anemia.

Blood ◽

10.1182/blood.v106.11.3176.3176 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3176-3176

Author(s):

Charles T. Quinn ◽

Elizabeth P. Shull ◽

Naveed Ahmad ◽

Zora R. Rogers ◽

George R. Buchanan

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Strong Predictor ◽

Prognostic Significance ◽

Adverse Outcomes ◽

Acute Chest Syndrome ◽

Disease Modifying Therapy ◽

Pain Crisis ◽

Disease Modifying

Abstract Sickle cell anemia (SS) is a phenotypically variable disease whose course is difficult to predict. The Cooperative Study of Sickle Cell Disease (CSSCD) found that dactylitis in the 1st year of life predicted adverse outcomes in later childhood. We aimed to determine whether early vaso-occlusive complications, including dactylitis, were prognostic in the Dallas Newborn Cohort. We studied all cohort members with SS or sickle-β0-thalassemia who were <1 yr of age at their first clinic visit, ≥5 yrs of age at last follow-up, and who had complete records. We defined 3 potential “early” (occurring in the first 3 yrs of life) predictors: any hospitalization for (1) pain crisis (non-dactylitis), (2) dactylitis, or (3) acute chest syndrome (ACS). We studied the associations of these predictors with the following “late” (occurring on or after the 3rd birthday) outcomes: death of any cause; overt stroke; use of hydroxyurea (HU), chronic transfusion (CT), or stem cell transplantation (SCT); and mean number of hospitalizations for late pain crisis and ACS. Late pain and ACS episodes were enumerated for each patient between the 3rd birthday and the last clinical encounter or the start date of a disease-modifying therapy (HU, CT, or SCT), whichever was first. Mean number of pain and ACS events was analyzed for the late follow-up period in total and in 2-yr intervals. Outcomes up to age 20 were included. Two-sided Fisher exact and t-tests were used appropriately. There were 264 subjects (256 SS; 54.9% male). Mean age at first visit was 4.1±2.3 mos (±S.D.) and mean follow-up was 12.1±4.3 yrs. The following early hospitalizations occurred: 53 subjects (20.1%) had pain crisis; 16 (6.1%) had dactylitis, and 85 (32.9%) had ACS. There were 5 deaths and 30 overt strokes. Sixty-six subjects were treated with HU (37), CT (40), and/or SCT (1). We found that subjects who had early pain, dactylitis, or ACS (compared with those who did not) were not more likely to die (1.7 vs. 2.1%; P>0.99) or have a stroke (12.2 vs. 10.3%; P=0.69). However, the use of a disease-modifying therapy was more common among subjects who had early pain (37.7 vs. 19.9%; P=0.01) and ACS (37.6 vs. 16.2%; P<0.001), but not dactylitis (18.8 vs. 23.6%; P>0.99). This prediction held only for HU use when the treatments (HU, CT, or SCT) were analyzed separately. Subjects who experienced early pain or ACS had on average a 2.2-fold (P=0.02) or 2.1-fold (P=0.01), respectively, higher number of late pain crises between ages 3 and 11, but not beyond (all P>0.05). Dactylitis did not predict a higher number of late painful events at any age (all P>0.05). Likewise, neither early pain nor dactylitis was associated with a higher number of hospitalizations for late ACS (all P>0.05). However, subjects who had early ACS had a 1.7 to 3.6-fold higher mean number of ACS events throughout all late age groups (all P<0.05). In summary, early hospitalization for pain, dactylitis, or ACS did not predict death or stroke. Early pain and ACS were associated with use of HU in later childhood, but not CT or SCT. Early pain and ACS predicted an increased number of hospitalizations for pain until age 11, but not beyond. Early ACS was a strong predictor of recurrent ACS throughout childhood. Notably, we found that hospitalization for dactylitis had no particular prognostic significance, unlike the CSSCD. In conclusion, the prognostic significance of early vaso-occlusive complications is limited.

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Hydroxyurea Use in Sickle Cell Disease Patients in a Florida Medicaid Population.

Blood ◽

10.1182/blood.v110.11.79.79 ◽

2007 ◽

Vol 110 (11) ◽

pp. 79-79 ◽

Cited By ~ 6

Author(s):

Jane N. Ritho ◽

Dionne Y. Mayhew ◽

Abraham G. Hartzema ◽

Huazhi Liu ◽

Richard Lottenberg

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Slow Release ◽

Medication Possession Ratio ◽

Pharmacy Claim ◽

Early Therapy ◽

Number Of Patients ◽

Medicaid Population ◽

Pain Crisis ◽

Opioid Medications

Abstract Background: Efficacy of hydroxyurea (HU) was demonstrated in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) placebo-controlled randomized clinical trial with a reduction in average crisis rate (weighted mean difference −2.80; CI −4.74 to −0.86). HU was FDA-approved in 1998 for treatment of adults with sickle cell anemia experiencing recurrent painful episodes. An observational 9 year follow-up study of the MSH cohort demonstrated improved survival for patients taking HU. Purpose: To examine adoption and utilization of HU in SCD patients in a Medicaid population. Methods: A retrospective cohort study was conducted using Florida Medicaid eligibility, medical and pharmacy data for January 1, 2001 to December 31, 2005. The Medicaid database consists of medical and outpatient pharmacy utilization and reimbursement claims. SCD patients aged between 16 and 64 years with at least one inpatient or two outpatient SCD diagnosis claims (ICD-9-CM 282.6x), and meeting continuous eligibility criteria were included. HU adoption was determined by the presence of at least one HU pharmacy claim using National Drug Codes. Adherence to HU was calculated using the medication possession ratio (MPR) defined as the cumulative daily dose dispensed (excluding the last prescription refill and hospitalizations) divided by the time period between the first and last HU prescription (Rx) dispensed. Descriptive and bi-variate analyses were used to assess the relationship between patient characteristics, treatment and utilization of medical resources. Results: The mean age of the 2,301 SCD patients identified is 25 years ± 10.9(SD). Of those, the majority were female (64%) and younger than 25 years of age (60%). During the study eligibility period, 72% had at least one SCD-related emergency department visit, 88% at least one hospitalization and 53% at least one inpatient claim for SCD with pain crisis. During the study period, 33.4% of the patients had ≥ 3 hospitalizations for SCD with pain crisis in any 12 month period. Approximately one-third of patients had red blood cell transfusions (36%) but only 4.4% had a claim for iron-chelation. Of all SCD patients 26% used outpatient opioid medications with 65.4% receiving slow-release formulations. Nearly 17% of the cohort (n=384) had at least one pharmacy claim for HU. Compared to non-HU users, HU users were more likely to be males (OR 1.79; CI 1.44–2.23), aged ≥ 25 years (OR 1.35; CI 1.08–1.71), with a history of using slow-release opioid medications (OR 5.95; CI 4.65–7.59) or receiving red cell transfusions (OR 4.21; CI 3.35–5.31). Of those SCD patients eligible to receive HU according to the MSH criteria (≥ 3 hospitalizations a year for SCD crisis), only 38% received at least one HU Rx (OR 11.78, CI: 8.26–16.80). For those patients receiving at least two HU Rx, only 30.2% had a MPR of ≥ 0.60 (see Table). Conclusions: The prevalence of HU use in this Medicaid population is low. Our results suggest that only a small subset of SCD patients receive HU prescriptions consistently. Early therapy drop out and low adherence rates are common in patients prescribed HU. Interventions to promote physician adoption and prescribing of HU are needed, as are efforts to increase patient adherence. HU Possession Ratio Number of patients (%) 0 – < 0.2 69 (28.6) 0.2 – < 0.4 46 (19.1) 0.4 – < 0.6 53 (22.0) 0.6 – < 0.8 36 (14.9) > 0.8 37 (15.4) Total 241 (100)

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2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia

Blood ◽

10.1182/blood.v96.7.2379 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2379-2384 ◽

Cited By ~ 119

Author(s):

Mabel Koshy ◽

Louise Dorn ◽

Linda Bressler ◽

Robert Molokie ◽

Donald Lavelle ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Complete Blood Count ◽

Fetal Hemoglobin ◽

Therapeutic Benefit ◽

Additional Treatment ◽

Acute Chest Syndrome ◽

F Cells ◽

Pain Crisis ◽

Globin Synthesis

Abstract Augmentation of the fetal hemoglobin (HbF) levels is of therapeutic benefit in patients with sickle cell anemia. Hydroxyurea (HU), by increasing HbF, lowers rates of pain crisis, episodes of acute chest syndrome, and requirements for blood transfusions. For patients with no HbF elevation after HU treatment, augmentation of HbF levels by 5-aza-2′-deoxycytidine (5-aza-CdR, decitabine) could serve as an alternate mode of treatment. Eight adult patients participated in a dose-escalating phase I/II study with 5-aza-CdR at doses ranging from 0.15 to 0.30 mg/kg given 5 days a week for 2 weeks. HbF, F cell, F/F cell, γ-globin synthesis ratio, complete blood count, and chemistry were measured. The average γ-globin synthesis relative to non-α-globin synthesis prior to therapy was 3.19% ± 1.43% and increased to 13.66% ± 4.35% after treatment. HbF increased from 3.55% ± 2.47% to 13.45% ± 3.69%. F cells increased from 21% ± 14.8% to 55% ± 13.5% and HbF/F cell increased from 17% to 24%. In the HU nonresponders HbF levels increased from 2.28% ± 1.61% to 2.6% ± 2.15% on HU, whereas on 5-aza-CdR HbF increased to 12.70% ± 1.81%. Total hemoglobin increased by 1 g/dL in 6 of 8 patients with only minor reversible toxicities, and all patients tolerated the drug. Maximum HbF was attained within 4 weeks of treatment and persisted for 2 weeks before falling below 90% of the maximum. Therefore 5-aza-CdR could be effective in increasing HbF in patients with sickle cell anemia who failed to increase HbF with HU. Demonstration of sustained F levels with additional treatment cycles without toxicity is currently being performed.

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