Survival and mortality among users and non-users of hydroxyurea with sickle cell disease

OBJECTIVE: to estimate survival, mortality and cause of death among users or not of hydroxyurea with sickle cell disease. METHOD: cohort study with retrospective data collection, from 1980 to 2010 of patients receiving inpatient treatment in two Brazilian public hospitals. The survival probability was determined using the Kaplan-Meier estimator, survival calculations (SPSS version 10.0), comparison between survival curves, using the log rank method. The level of significance was p=0.05. RESULTS: of 63 patients, 87% had sickle cell anemia, with 39 using hydroxyurea, with a mean time of use of the drug of 20.0±10.0 years and a mean dose of 17.37±5.4 to 20.94±7.2 mg/kg/day, raising the fetal hemoglobin. In the comparison between those using hydroxyurea and those not, the survival curve was greater among the users (p=0.014). A total of 10 deaths occurred, with a mean age of 28.1 years old, and with Acute Respiratory Failure as the main cause. CONCLUSION: the survival curve is greater among the users of hydroxyurea. The results indicate the importance of the nurse incorporating therapeutic advances of hydroxyurea in her care actions.


Introduction
Sickle cell disease (SCD) is a generic term attributed to a group of hereditary diseases with a predominance of hemoglobin S, and is among the most frequentlyfound genetic diseases in the human population (1) .
The clinical presentation is characterized by two key physiopathological processes of sickle cell anemia: hemolysis and vaso-occlusion (2) . These processes occur from the first year of life onward and, over the years, due to the chronic nature of the disease, the severity worsens, injuring various tissues and organs (3) .
Currently, advances in the treatment of, and studies on the survival of, sickle cell patients demonstrate that life expectancy has considerably improved (4) . Among the therapeutic options available, besides bone marrow transplant and chronic transfusion, one can highlight hydroxyurea (HU) (5) , whose action can increase the levels of fetal hemoglobin, improving the clinical severity and the hematological parameters, as well as reducing the rates of the disease's morbidity and mortality, with an increase in survival (6)(7) .
In this regard, emphasis is placed on a study undertaken in the United States and in Canada with patients participating in the MSH study (The Multicenter Study of Hydroxyurea in Sickle Cell Anemia), which made it possible to analyze the impact of the use of HU on mortality, with a 40% reduction in mortality being recorded by the researchers (p=0.04) among the users of this medication over nine years of monitoring (8) .
In the light of the seriousness of SCD, and bearing in mind the lack of nursing publications on this issue (3)(4)(5)(6)(7)(8)(9) , in particular with HU, it falls to the nurse to be familiar with the advances of this therapy, which have contributed to the reduction of mortality and to the consequent increase in survival in this clientele. Published evidence has demonstrated that the principal therapeutic approach in sickle cell anemia is to try to alter the production of hemoglobin S to fetal hemoglobin. This results in a lesser degree of severe hemolytic anemia, and fewer symptoms (11) .
This study's contribution is to bring support to the nurse for her work in health surveillance for the patient with sickle cell disease, ranging from guidance on medication through to the monitoring of the strategy of self-administration of HU by the patient. Thus, this study's objective was to calculate the survival, mortality and cause of death among users or not of hydroxyurea with sickle cell disease.

Method
This is a cohort study with retrospective data collection, involving patients diagnosed with sickle cell disease attended in two public hospitals in the

Results
The 63 patients with SCD included in this cohort, were monitored over 30 years, from 1980 to 2010. The accumulated probability of survival was calculated based on the total of patients studied (n=63), among whom 48 were being monitored in the service (76.2%), 10 died (15.8%) and five discontinued treatment in the institution (8%). Time zero (initial) was considered to be the moment of diagnosis, while the closure was the patient's death or discontinuation of treatment. Table 1 describes the data found for global survival, organized by sex, and establishes whether there was or was not difference between the two groups.
In establishing global survival by sex, one can observe a slightly greater survival curve in the women in the first two years, which following that is inverted until closure ( Figure 1).  Table 2). In Figure 2, one can note greater survival among the users of the medication.   when compared with the males (53.0 years) (15) .
In the present study, the statistically significant difference attributed to the comparison of the group of users and non-users of HU indicates a survival curve which is greater for those who used the medication.
The sample observed shows the exposure to HU over a mean of six years. These results evidence the benefits expected through its action, among which one finds a reduction in acute episodes, and the number of blood transfusions and episodes of inpatient treatment, resulting in greater survival and improvement of wellbeing and quality of life (6) . The probability of 10 years of survival was 86% and 65% for patients using HU and not using HU, respectively (16) .
One study with children and young adults, undertaken the period prior to the treatment (55%) (17) .
In the comparison of the time of use of HU between the sexes in the present study, there was no statistical significance. This result is similar to that of a retrospective study undertaken in Georgia (United States of America), in which sex did not influence the survival of the 226 patients using HU (7) .
In the present study, the results showed the recording of 87.3% of the patients with Hb SS; 12.7% with Hb SC; and deaths in the young age range. These findings confirm those described in the literature, emphasizing that sickle cell anemia (Hb SS), the homozygous state for hemoglobin S, represents the most common genotype, with the most serious clinical presentation of the disease (18) . In this case, it is appropriate to emphasize a Dutch study which, in analyzing the causes of death among patients with sickle cell disease in the period 1985 -2007, detected that, among 298 children, 189 (63%) were Hb SS (19) . The present study ascertained the occurrence of mortality in the second decade of life. These findings are similar to those of a study undertaken in Minas Gerais (N=151 patients) in the period 1998 -2007, in which, in the 11 deaths, the mean age was 33.5 years old, suggesting that in Brazil, patients with sickle cell disease die early; and that, therefore, the existence of an older adult population of those with the disease is not to be expected (20) . In this regard, it is worth emphasizing that approximately 88.9% (56) were between five and 40 years old, with the exception of one patient aged 63 years old.
In this investigation, however, attention is called to the absence of deaths in patients with SCD in the age range of five to 12 years old, which differs from the literature (5,21) . One possible limiting factor of the present study is the fact that it is retrospective, being based in of survival in patients with sickle cell disease, which observed that those with phenotype SC survived for longer in comparison with those of phenotype SS. The survival of patients with Hb SS was 42 to 48 years old, and, in patients with Hb SC, from 60 to 68 years old (4) .
Another aspect to be considered in this study is that the majority (60%) of the 10 deaths occurred among patients who were not using HU and among those who had been using it for less than five years. In one randomized study of the MSH, 87.1% of the 31 deaths occurred in patients in the categories "never exposed to HU" and "with less than five years of use" (12) .
Regarding the causes of death, Acute Respiratory Failure was responsible for four of the 10 deaths, as a consequence of pneumonia. Multiple Organ Failure occurred in two, related to infection/sepsis; and septic shock was responsible for one, due to sepsis. It follows that infection was the principal complication for the deaths in this study, a result similar to that of other findings on mortality in sickle cell disease (20)(21) . Among the 10 deaths recorded in this study, cardiogenic shock was the cause of two, due to Congestive Heart Failure (CHF); and CVA was responsible for one.
These complications directly compromise the function of vital organs and their associated with risk to life, with a predominance of, or being limited to, one age range. CHF is a typical late manifestation, requiring a long devolution of the tissue injury to be manifested, while a CVA may be evidenced in a much younger age range (25) .
In this study, one of the deaths related to Cardiogenic Shock occurred at the age of 17 years old, while the other, caused by a CVA, occurred at the age of 26 years old. These findings differ from the study on morbidity and mortality in sickle cell disease which, in analyzing the causes of death, recorded one case of death from Cardiogenic Shock at the age of 34 years old, and one CVA at six years of age (20) . These differences in results are confirmed by the literature, which mentioned that the mechanisms underlying age predominance are not always present (25) . In this study, there were limiting factors for the analysis of some variables, resulting from the observational character of the study, however, without prejudice to the objectives established.

Conclusion
This study demonstrated the effectiveness of the use of HU in a cohort with retrospective data collection, with a mean of six years' exposure to the medication.
In the comparison of the group of users of and nonusers, the survival curve is greater for those using the medication, there being no association between time of use and survival between the sexes.
The comparison of the group of users and nonusers of HU shows the occurrence of 10 cases of deaths, with eight among women (five using HU) and two among men (one using HU). Of the total of deaths, seven are Hb SS, in the age range between 17 and 28 years old.
The most frequent cause of death was ARF, followed by Multiple Organ Failure and Cardiogenic Shock.
This study is relevant in that it raises scientific evidence regarding the advances of therapy with HU in SCD, which should be incorporated by the nurse into her care practice. These actions may facilitate this clientele's access to the different levels of care, as well as to medications -specifically hydroxyurea -aiming for a reduction in mortality and an increase in the survival of the patient with sickle cell disease.