The Impact of Hydroxyurea on Career and Employment of Patients ...

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The Impact of Hydroxyurea on Career and Employment of Patients With Sickle Cell Anemia Samir K. Ballas, MD; Robert L. Bauserman, PhD; William F. McCarthy, PhD; Myron A. Waclawiw, PhD; and the Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia

Funding/Support: This study was funded by National Heart, Lung, and Blood Institute contracts NO1-HB-67129 and UO1HL45696. The purpose of this study was to determine the association between hydroxyurea treatment and changes in employment status, if any, among patients with sickle cell anemia enrolled in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH). To that end, we compared the employment status among treatment responders, treatment nonresponders, and placebo groups of patients enrolled in MSH during the clinical trial and follow-up periods. Treatment with hydroxyurea did not significantly (p > .05) affect employment status, but there was a trend for more consistent employment in the hydroxyurea group. Given the fact that patients enrolled in MSH had moderate to severe disease with irreversible complications such as avascular necrosis, it would be attractive to hypothesize that future treatment of young patients with hydroxyurea could prevent or mitigate the incidence of complications of sickle cell anemia and, hence, improve the employment status of treated patients. Keywords: sickle cell anemia n hydroxyurea J Natl Med Assoc. 2010;102:993-999 Author Affiliations: Cardeza Foundation, Department of Medicine Thomas Jefferson University, Philadelphia, Pennsylvania (Dr Ballas); Maryland Medical Research Institute, Baltimore, Maryland (Drs McCarthy and Bauserman); National Heart, Lung, and Blood Institute, Bethesda, Maryland (Dr Waclawiw). Correspondence: Samir K. Ballas, MD, FACP, Professor of Medicine and Pediatrics, Director, Sickle Cell Center, Cardeza Foundation for Hematologic Research, Jefferson Medical College, 1015 Walnut St, Philadelphia, PA 19107 ([email protected]).

Introduction

S

ickle cell disease (SCD) has been observed to have a negative impact on education, career development, employment, and work history. Despite anecdotal reports of exceptional success stories such as patients who become scientists or physicians,1 most of those affected are dependent on medical assistance and social security.2 The literature contains sparse data about JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION

career and employment in SCD.3,4 Patients with SCD are disadvantaged regarding employment. Aviation authorities, for example, exclude persons with SCD from flight deck duties.3,5 Factors such as physical stress, extremes in temperature, hypoxia, and dehydration can precipitate acute painful episodes.6 Chronic complications of SCD exert a negative impact on employment. Persistent leg ulcers can interfere with regular work attendance.6 Avascular necrosis of the femoral heads may restrict lifting and climbing, and such restriction has been recommended for patients with hip replacement for this complication.7 Reduced visual acuity due to retinopathy, strokes with residual weakness, and progressive organ damage with age may negatively affect work and limit employment opportunities.6,8 Brandon4 reported that young adults with SCD were fearful that their health would not allow them to participate in normal adult activities. Among 100 patients with SCD interviewed, 98 indicated that their health interrupted their college education and prevented them from finding and maintaining a full time job.4 A major fear among patients with SCD is the probable loss of their job due to frequent absenteeism caused by recurrent crises. This fear constitutes a major stressor in precipitating painful episodes and interrupting coping skills. In an effort to determine the pattern of employment among patients with SCD, Abrams et al9 interviewed 30 patients living in North Carolina. Fifteen patients (8 men and 7 women) reported employment in occupations, including teaching, nursing, secretarial, sales, social work, managerial, postal work, public safety, machine operation, assembly work, construction, and general labor. Of the 15 unemployed patients, 13 reported past employment. The total group had a mean of 14.5 years of employment (range, 1 month to 38 years). Twenty patients reported an annual income less than $15 000. However, this study was limited by a very small sample size. Obviously, more data are needed about the pattern of work history among patients with SCD. The purpose of the present study is to report on employment and changes in employment status among patients with SCD who enrolled in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH).10 VOL. 102, NO. 11, NOVEMBER 2010 993

Hydroxyurea and With Sickle Cell Anemia

Specifically, we examine: (a) employment status of all MSH patients at time of enrollment and at later intervals as available; and (b) compare employment status among treatment responder, treatment nonresponder, and placebo groups.

Methods Design and Results of Multicenter Study of Hydroxyurea in Sickle Cell Anemia

MSH was a randomized, double-blind placebo-controlled multicenter study to test whether hydroxyurea could reduce the rate of painful crises in adult patients. The design of the study has been described in detail elsewhere.10,11 The study was approved by the institutional review board of each center and all patients signed a consent form to be enrolled in the study. Briefly, to be eligible for the study, patients had to be at least 18 years old and have sickle cell anemia (SS). They also had to have at least 3 reported painful crises in the year prior to entry into the study. Frequency of painful crises (defined as medical facility visits with no apparent cause other than acute sickling-related pain, lasting for more than 4 hours, for which the patient was treated with narcotic or nonsteroidal anti-inflammatory drugs) was the primary endpoint. During the study, patients assigned to hydroxyurea had lower annual rates of painful crises than those given a placebo.10 Although originally intended to last 24 months for all participants, the clinical trial was stopped early because of the beneficial effects observed, with a mean duration of 21 months across patients. The MSH patients’ follow-up was an observational study of participants in the original MSH trial that began in 1996 and continued through 2002. During the followup period, patients, in consultation with their physicians, were free to continue, start, or stop treatment with hydroxyurea. Patients were seen annually for purposes of the follow-up study, although most were seen more often for purposes of medical care. Following the termination of the follow-up study, an additional observational study was initiated, with data collection beginning in 2003 and continuing through 2007.

Treatment Assignment and Treatment Response All analyses using treatment assignment are based on randomized assignment at the time of the clinical trial (to either hydroxyurea treatment or placebo). In addition, hydroxyurea patients were divided into responder and nonresponder groups, based on their fetal hemoglobin (Hb F) levels at baseline and at approximately 18 months after initiation of treatment. A responder was defined as any hydroxyurea recipient whose baseline percentage of Hb F was less than 15%, but whose follow-up level was greater than or equal to 15%. This definition was based 994 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION

on previous research and reviews suggesting that 15% fetal hemoglobin is a level expected to produce clinical benefits,12,13 a level also defined by National Heart, Lung, and Blood Institute treatment guidelines as a desired treatment outcome for sickle cell patients.14 Thus, an increase in Hb F from a lower baseline to a level greater than or equal to 15% could reasonably be expected to produce clinically meaningful benefits. Extensive crossover from the placebo trial arm to hydroxyurea treatment occurred once the trial was terminated, so that no true “placebo” group remained after that point. Similarly, no data were available for fetal hemoglobin response for placebo patients who had crossed over to hydroxyurea treatment in the follow-up period. However, carrying over treatment assignment and treatment response groups from the trial period to analyses that included follow-up years ensured that group comparisons were made on the basis of which patients had the earliest sustained exposure to hydroxyurea and which patients had the strongest responses to this earlier exposure.

Demographics and Health Behaviors A total of 299 patients were enrolled from 21 sites (20 in the United States and 1 in Canada). There were no significant differences between the hydroxyurea and placebo groups in terms of sex, race, age, or blood counts.10 The sample included 146 males and 153 females, 95% of whom identified as black, with a mean age of 30.2 years at baseline (ranging from 18 to 58). Nearly all had completed high school (81%) and almost half (49%) had some college experience. However, both personal and household income were low; almost three-fourths of the participants reported personal income of less than $10 000 per year, and more than half reported total household income of less than $20 000 per year. The low income levels were consistent with employment status; only 16% of participants reported that they were employed full-time, and 59% reported that they were unemployed or disabled. Data on substance use (alcohol and tobacco) were not available from the initial trial but were available from participants in the follow-up observational study (n = 227). Neither alcohol nor tobacco use was common. At the time of the first follow-up visit, only 30.4% reported any current alcohol use, and only 55.1% reported any alcohol use ever. Of the total sample, 39.7% reported only “light” use of alcohol as their highest use ever. For cumulative (total) years of alcohol use, only 23.3% reported more than 5 years of use. Tobacco use was even less frequent, with only 33.5% of participants reporting that they had ever been a regular tobacco user. The median age at first use was 18 years, and the median cumulative tobacco use was 10 pack-years. Among those who had ever been regular tobacco users, 96% reported cigarette use only. VOL. 102, NO. 11, NOVEMBER 2010


Measures Employment. Patients in the MSH trial completed demographic information forms at baseline and at approximate 1-year intervals thereafter. Because of the early termination of the original MSH trial, nearly all participants had baseline, 12-month, and 24-month demographic forms, but fewer than half completed forms for the 36-month interval. During the follow-up period, employment data were collected in years 1 through 5 and again in years 7 through 9. The proportion of patients with data regarding employment, however, was greatly reduced after year 5. We analyzed employment data in 2 ways: as shifts in employment patterns (for the clinical trial period only) and as the proportion of time the patient was employed (across all available data from both the clinical trial and the follow-up and observational studies). Employment patterns. Participants could indicate 1 of 10 categories for employment status (identical forms were used during the randomized trial and the follow-up period). These included full-time or part-time work (fulltime was defined as ≥35 hours of work per week), unemployed (currently looking for work), disabled, attending school full-time or part-time, retired, keeping house, volunteer work, or “other main activity.” Aside from the 2 employment categories—unemployment, and disability—the other 6 categories were indicated infrequently. To simplify analysis of changes in employment status, most categories were collapsed. Full-time and part-time employments were combined into a single category of “employed,” and all other categories were collapsed into “other.” Thus, “other” indicates unemployment or disability for the large majority of patients, but for approximately 10% it indicates some other nonemployed status. To that end, it should be noted that the fact that not everyone in the “other” category was looking for work is a possible limitation for purposes of this study. A variable was created to summarize changes in employment over time for the period of the randomized trial (this was anticipated to be the time when the most notable shifts in employment might take place, due to response to treatment). Employment status at baseline and at 24 months was the basis for categorization. A total of 275 patients (92% of the sample) had employment data for both time points. Four employment categories were coded: continuous unemployment (unemployed at both the baseline and 24-month measurements), continuous employment (employed either full-time or part-time at both time points), change from unemployment to employment, and change from employment to unemployment. The 4 categories of longitudinal employment status were also collapsed into 2 categories: those that were employed at 24 months (which includes those employed at both time points or those who improved their status by moving from unemployment to employment) and those who were unemployed at 24 months JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION

(including those unemployed at both times or those whose status deteriorated by moving from employment to unemployment). Cumulative employment. To examine longer-term employment history, the categorical approach described above might prove misleading for longer periods of time. With up to 8 years of follow-up data available, multiple shifts between employment and unemployment might occur, and focusing on the first and last years of data could prove misleading. Consequently, variables indicating the amount of time employed (as a proportion of available data) were created. Analyses of cumulative employment across both the trial and follow-up periods included any available data for the 36-month interval of the trial and for all available years of the follow-up. Thus, a patient could have up to 12 years of data (including baseline). Two values were calculated for proportion of years employed. First, total years of employment were summed across all years (in both the randomized trial and followup) with available data; then, total years of employment were divided by the total years of available data to get the proportion of years employed for that subject. All subjects with at least 2 years of employment data (n = 290 out of 298) were included in this analysis; as noted above, the maximum years of data available were 12 (4 from the trial and 8 from the follow-up). Examining cumulative employment as a proportion allowed subjects with widely varying years of total data to be included in the same analysis, because values for individual patients were based only on available data. The second proportion was calculated in the same way, using only the 8 years with the most complete data (0, 12, and 24 months from the trial, and years 1-5 from the follow-up). Income. Personal income and total household income were both reported; the analyses reported here are based on personal income reported by the patient to avoid any confound with changing employment status of other persons in the patient’s household. Income was reported as one of a dozen categories of increasing annual income, beginning with “less than $10 000” and increasing by $10 000 increments, up to “$150 000 or more.” In practice, a majority of patients reported the lowest level of personal income at every time point. To simplify further analysis, income was collapsed into 3 categories: the original categories of “less than $10 000” and “$10 000 to $19 999,” and a new category of $20 000 or more that combined all remaining options. Education. Educational level could be reported as 1 of 11 categories of increasing total education, ranging from none (followed by “fourth grade or lower”) up to doctorate degree. Because approximately two-thirds of patients reported high school diploma or equivalent or some college but no degree as their level of education, categories below “high school diploma” were collapsed VOL. 102, NO. 11, NOVEMBER 2010 995


into a single “less than high school diploma” category and those above “some college” were collapsed into a single “higher degree” category, for a total of 4 possible levels of education.

Statistical Methods For comparisons of categorical variables between treatment or response groups (eg, treatment assignment and employment status), c2 analyses were used. In cases where 1 or both variables have more than 2 categories, a significant overall c2 result does not identify which differences contribute the most to the overall results. In these instances, we intended to use either partitioning or correspondence analyses followed by collapse of categories to identify significant results. Two sets of c2 analyses were conducted to compare the gender composition, educational status, and income distribution (as well as the employment status) of all groups at baseline. In the first set of analyses, the placebo and hydroxyurea groups were compared; in the second, the placebo group and the 2 levels of hydroxyurea treatment response (responder and nonresponder) were compared. For the analysis of cumulative employment across the clinical trial and follow-up periods, generalized linear models (GLMs) were used to model differences in employment between the placebo and hydroxyurea groups, and among the placebo, responder, and nonresponder groups. Pairwise comparisons between specific groups were examined using least squares

mean estimates with the Tukey procedure to adjust for multiple comparisons. Mean ages at baseline were compared between groups in the same way. SAS (Cary, North Carolina) 9.1 was used for all analyses. Intention-to-treat analyses were used for all placebo and hydroxyurea group comparisons because actual treatment status was known only for the clinical trial period, not for the follow-up observational period. Statistical significance was defined as any p value < .05 (2 sided). Marginal statistical significance was defined as .05 ≤ p value (2 sided) ≤ .10. Because of the exploratory nature and relatively small number of the analyses, we did not correct for multiple comparisons.

Results Patient Demographics and Differences Between Treatment Groups

For the total MSH sample, no significant differences were found between the placebo and hydroxyurea groups for any of the demographic measures. In addition, although baseline data suggested a higher proportion of females, a higher age at baseline, and a greater income at baseline for responders than for the other 2 groups, none of these differences were statistically significant. Table 1 lists demographic characteristics of the treatment and placebo groups, and of responders and nonresponders within the treatment group, including employment status at baseline.

Table 1. Demographic Characteristics of Treatment and Treatment Response Groupsa Placebo (N = 147)

n (%)

All n (%)

Responders (n = 27) n (%)

Nonresponders (n=116) n (%)

76 (51.7) 29.8 (7.5)

77 (50.7) 30.6 (7.5)

18 (66.7) 32.1 (8.2)

56 (48.3) 30.5 (7.5)

29 53 46 19

29 43 59 21

(19.1) (28.3) (38.8) (13.8)

3 (11.1) 8 (29.6) 12 (44.4) 4 (14.8)

25 31 44 16

113 (76.9) 22 (15.0) 10 (6.8)

108 (71.1) 22 (14.5) 19 (12.5)

20 (74.1) 1 (3.7) 6 (22.2)

82 (70.7) 20 (17.2) 12 (10.3)

38 (25.9) 33 (22.5) 55 (37.4) 11 (7.5) 9 (6.1)

44 42 46 9 7

8 (29.6) 9 (33.3) 5 (18.5) 1 (3.7) 3 (11.1)

33 29 40 8 3

Group Female Age, mean, (SD) Education Less than high school High school/GED Some college Higher degreeb Income (baseline)