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Blood, Vol. 95 No. 10 (May 15), 2000:
pp. 3057-3064
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Center for Health Care Research and Departments of Medicine
and Pediatrics, Medical University of South Carolina, Charleston, SC.
Measurement of cerebral blood velocity (CBV) by transcranial Doppler
has been used to identify patients with sickle cell disease (SCD) who
are at high risk of ischemic stroke. This study examines outcomes of
bone marrow transplantation (BMT) and periodic blood transfusion (PBT)
as a basis for making treatment recommendations for patients who have
elevated CBV and no other indications for BMT. Decision analysis was
used to compare the number of quality-adjusted life years (QALYs)
experienced by a population of patients with SCD at high risk for
stroke who were treated with PBT or BMT. Markov models were constructed
to represent the clinical course of patients with SCD who were treated
with PBT or BMT. Medical literature and expert opinion provided risks
of stroke and death for different disease states, estimates of
transition probabilities from one clinical state to another, and
quality of life. An intention-to-treat analysis and an analysis of
treatment received were both performed on hypothetical cohorts of
100 000 patients. Patients with SCD who were managed with a strategy
of intending to provide BMT could expect 16.0 QALYs, compared with 15.7 QALYs for a strategy of intending to provide PBT; however, the
variation around these estimates was large. In the treatment received
analysis, patients compliant with PBT therapy and iron chelation could
expect the best outcomes (19.2 QALYs). From a policy perspective,
neither BMT nor PBT can be considered the "best" treatment for
children with SCD who have abnormal CBV. Abnormal CBV should not be the only criterion for selecting patients with sickle cell for BMT.
(Blood. 2000;95:3057-3064)
Sickle cell disease (SCD) is associated with the high
risk of both ischemic and hemorrhagic stroke. Patients with SCD who experience an ischemic stroke have an even higher risk of recurrent ischemic stroke.1 Several studies have demonstrated that
patients with SCD at high risk for stroke may be identified by
transcranial Doppler (TCD) measurements of blood velocity in the
internal carotid and middle cerebral arteries.2,3 The STOP
Study, a stroke prevention trial for patients with SCD at high risk of
stroke, demonstrated that periodic blood transfusion (PBT)
significantly lowers the risk of stroke in patients with cerebral blood
velocity (CBV) greater than 200 cm/s.4
Currently, patients with SCD who have had an ischemic stroke and are
thus at risk for recurrence are typically transfused for their
lifetimes. This treatment strategy stems primarily from 2 studies both
of a small series of patients in whom the stroke recurrence rate was
greater than 50% within a year after transfusions were
halted.5,6 However, follow-up studies of similar sizes have
demonstrated much more favorable results in patients whose transfusion
regimens were stopped or diminished after 3 to 9 years.7-9 Nevertheless, most practitioners still recommend that patients with SCD
who have a stroke be transfused indefinitely, as the consequences of
recurrent stroke can be devastating. The duration of transfusion
required to decrease the risk of primary stroke in patients with
abnormal TCD is unknown.
Long-term transfusion, although highly effective in preventing ischemic
stroke recurrence and other complications of SCD,4 is
associated with increased risk of iron overload, infection, and
alloimmunization. Iron overload and toxicity lead to organ dysfunction,
including early cardiac death. The consequences of iron toxicity can
only be prevented by chelation therapy, which is both inconvenient,
leading to poor compliance, and expensive. For these reasons, patients
who have had an ischemic stroke are considered candidates for bone
marrow transplantation (BMT) if they have a matched sibling
donor.10 Available data suggest that, despite significant
mortality and morbidity, BMT prevents stroke recurrence and obviates
the need for long-term transfusions.10-13
Because of the high efficacy of transfusions in preventing primary
strokes, it is currently recommended that all patients with SCD and
with high CBV be transfused for an indefinite period to keep their
sickle-cell hemoglobin (HbS) levels below 30% of total hemoglobin. In
a logical extension from secondary stroke prevention, it has been
proposed that patients with abnormal CBV also be considered candidates
for BMT.
The decision to offer BMT to patients with SCD is complicated by a
number of issues, including the uncertainty of
outcomes.10,13 To date, no study examined whether patients
with SCD and with a high risk of stroke, identified by abnormal TCD,
would have better outcomes with PBT or BMT. Although PBT may be favored
because of the relatively high mortality risk (5%-10%) associated
with BMT, some clinicians note that lifetime transfusions and iron chelation significantly diminishes quality of life, and that BMT offers
patients a chance to be "cured" of SCD and the associated pain
crises and morbidity. Thus, the factors that are thought to be of
greatest importance in this decision include the risk of death, quality
of life, and need for lifelong transfusions for patients receiving PBT.
Donor availability and compliance with iron chelation may also play an
important role in determining which strategy is preferred.
The factors involved in choosing between BMT and periodic transfusions
to manage patients at high risk for strokes are very similar to those
faced in recommending unrelated BMT for patients with chronic
myelogenous leukemia (CML). For patients with CML, the decision to
undergo unrelated BMT, complicated by the unpredictability of outcomes
and risk of slow disease progression, must be carefully weighed against
the risks of morbidity and mortality from matched unrelated donor BMT.
These issues were recently successfully addressed in a decision
analysis that found transplantation within the first year of diagnosis
of CML provided the greatest quality-adjusted expected survival, when
compared with delayed transplantation or no
transplantation.14
We report here a decision analysis study using Markov models to compare
BMT with PBT for the management of a population of patients with SCD
who have high CBV. The analysis is applicable to the population of
patients with SCD who have no indications for BMT, who would be
transplanted only because of an abnormally high CBV. Because these SCD
patients are assumed not to have multiple recurrent pain crises,
episodes of acute chest syndrome, or other abnormalities that would
make them candidates for BMT, they are likely to be healthier, in
general, than the average SCD patients.
The decision analysis model was designed to answer the following
question: "For sickle cell patients identified as high risk of
stroke by transcranial Doppler with no other indications for BMT,
should the recommended treatment be bone marrow transplantation or
periodic prophylactic blood transfusion?" The overall decision tree
diagram is shown in Figure 1.
Intention-to-treat analysis versus treatment received analysis
Markov models and risk estimates
Blood marrow transplantation model.
After undergoing BMT, the patient may have a successful outcome without
complications. However, the patient may experience chronic graft versus
host disease (cGVHD), BMT rejection, hemorrhagic stroke, ischemic
stroke, or death. The model incorporating these clinical states is
illustrated in Figure 2. Several published studies provided data on the risk of death, risk of cGVHD, and risk of
transplant rejection among patients receiving BMT. Data are reported by
Walters et al10 (n = 32), Abboud et al11
(n = 9), Vermylen et al12 (n = 50), and Bernaudin et
al13 (n = 26). Table 1
summarizes the data obtained from these studies. Of the 117 total BMT
patients, 7 (6.0%) died within 1 year, 19 (16.2%) experienced cGVHD,
and 14 (12.0%) rejected the transplant. Among the patients receiving
BMT, risk of dying is assumed to be twice that of a person without SCD
(still much lower than patients with SCD). In addition, there is a high
(6%) risk of dying during the first year after transplantation, and
this risk diminishes over the next 2 years. The risk of cGVHD
developing is assumed to be 10% within the first year and to diminish
to 0% by 5 years after BMT. The risk of an ischemic stroke after BMT
(Table 2) is assumed to be the same as the
risk of a patient with SCD who receives PBT (90% lower than it would
have been without BMT or PBT, according to results from the STOP
study). The risk of a hemorrhagic stroke in a patient with SCD is
presumed to be unchanged by BMT. The risk of BMT rejection is
approximately 9% in the first year and rapidly decreases to 0% by 5 years.
Periodic blood transfusion model.
In the PBT model (Figure 3), there are 5 states: on PBT (healthy), alloimmunization, hemorrhagic stroke,
ischemic stroke, and death. Patients with abnormal TCD receiving PBT
have a reduced risk of death when compared with patients with SCD who
do not have a high risk of stroke, as transfusions reduce the rate of complications associated with SCD.7-9 The risk of
hemorrhagic and ischemic stroke (Table 2) is the same as that for
patients who receive BMT. The risk of alloimmunization, defined as
development of 1 or, more commonly, multiple antibodies that make it
impossible to transfuse a patient safely, is assumed to be 0.2% per
year. Patients who receive PBT and who develop alloimmunization are assumed to be no longer eligible for PBT, and thus their risk of
ischemic stroke is the same as the risk for a high-risk stroke patient.
Patients compliant with transfusions and any iron-chelating therapy
that may be necessary (ie, desferoxamine) are assumed not to suffer
consequences associated with iron overload. Patients who were
noncompliant with iron chelation have an increased risk of ischemic
stroke, and the risk of death increases as iron overload develops and
then decreases slowly over time as interventions to reduce iron are
initiated (eg, intravenous desferoxamine, stopping transfusions).
Patients who were noncompliant with the transfusion regimen were
assumed to receive half as many transfusions (ie, once every 2 months),
resulting in a 5-fold increased risk of stroke, relative to the
transfused patient. Patients who refuse transfusion therapy are assumed
to have twice the risk of death and 10 times the ischemic stroke risk
of those patients who are transfused on a regular basis.
Risk of stroke The risk of hemorrhagic stroke was derived from work published by Ohene-Frempong et al.16 In this study, the risk of hemorrhagic stroke varied by age, with the highest rates among those aged 6 to 9 years old (0.25 strokes per 100 patient-years) and those aged 20 to 29 years old (0.44 strokes per 100 patient-years). These rates were applied to both the BMT patients and the PBT patients. The risk of death immediately after hemorrhagic stroke was assumed to be 33%, as data from 2 studies of stroke were combined.16,17Mortality rates Mortality rates among the average sickle cell patients were obtained from a study by Platt et al,18 whereas mortality rates for the average healthy black population were obtained using life tables derived from United States vital statistics data.19 The average SCD patient has a life expectancy of 42 years, compared with 71 years for the black population of the US. Depending on treatment and outcome, patient category-specific mortality probabilities were obtained by multiplying the Platt et al18 and life table mortality probabilities by relative risks estimated by an expert panel of clinicians. Table 3 lists the disease state classification, the respective reference group, and the relative risk of death applied in the analysis. For example, patients who undergo a successful BMT were assumed to die at a rate equal to twice that of the healthy US black population, an assumption that was based on a recent study in which mortality rates for patients surviving at least 2 years after BMT for conditions, including acute myelogenous leukemia, acute lymphoblastic leukemia, chronic mylogenous leukemia, or aplastic anemia were shown to be substantially (4 to 26 times) higher than age-, sex-, and nationality-matched general populations.20 Patients with SCD who survive BMT were not assumed to have quite the dramatic increases in risk of death as the patients with leukemia; nevertheless, patients with SCD who survive BMT probably have some increased risk of death compared with the general population. We assumed this risk of death to be 2 times that of the general population. Patients who reject a BMT were assumed to die at a rate equal to twice that of patients with SCD. The risk of death was assumed to increase as iron levels increase, and decrease slowly as the physician intervenes to reduce iron load, and the magnitude of this elevated risk of death was obtained from data published by Olivieri et al.21
Quality-adjusted life years In this study, the major outcome of interest was QALYs. In the absence of direct reports of quality of life from patients with SCD, estimates of quality of life were based on information provided by 2 physicians (M.R.A., S.M.J.) experienced in the care of patients with SCD. Perfect health was assigned a quality of life of 1, whereas death was assigned a quality of life of 0. Patients who underwent a successful BMT were assigned the highest quality of life (0.95), followed by BMT patients with cGVHD (0.85), compliant PBT patients (0.85), patients noncompliant with the transfusion regimen (0.85), transfused patients who have become alloimmunized (0.80), patients who refuse BMT and PBT (0.80), PBT patients noncompliant with iron chelation (0.75), and BMT patients who reject the transplant (0.70). In a study of stroke patients aged 18 to 57,22 quality of life values were estimated at 0.45 for major stroke, which we have adopted in our model. These quality of life values are well within the ranges of the Health and Activity Limitation Index (HALex), developed using data from the National Health Interview Survey and reported for the more common conditions, such as diabetes (median HALex = 0.63) and chronic sinusitis (median HALex = 0.92).23 Because we have accounted for the quality of life in our models, the main outcome of comparison between the 2 strategies is the number of expected QALYs.Time discount rate The value of future years of life was adjusted, based on the assumption that people value the present time more than they value future time, in a manner similar to the way a person would rather receive a dollar today than 10 years from now. The most common method of accounting for such a preference is by valuing future years of life with a declining exponential curve. If the rate of decline is 5%, then 1 year of life now is worth 0.95 years of life next year, and 0.9025 years of life in 2 years. Although discount rates vary throughout the literature, recent recommendations for cost-effectiveness analysis made by The Panel on Cost-Effectiveness in Health and Medicine include a base case discount rate of 3%,24 which has been adopted in this study.Baseline case scenario For the purposes of examining the hypothetical cohorts within this study, a baseline case scenario was developed that included the following assumptions. The patient with SCD has been identified as high risk for stroke by means of TCD, and no other indications for BMT have been identified. No assumption of gender is made, but we have assumed that the patient is 5 years old at the time the treatment decision needs to be made. Patients with SCD who receive PBT are assumed to need transfusions indefinitely (ie, for the remainder of their lives). The baseline mortality rate of these patients is equal to 80% of that of the typical sickle cell patient, with transfusions providing additional protection from death. We have assumed that 80% of patients who receive PBT will be compliant with the PBT regimen and that, of these patients, 35% will be compliant with iron-chelating therapy. Life years are assumed to be discounted at 3% per year.Sensitivity analysis Because of the uncertainty in the assumptions made in our model, sensitivity analyses were performed on variables used in the intention-to-treat analysis. This method helps identify variables that have the greatest impact on the QALYs associated with each treatment strategy. The sensitivity analyses varied the discount rate, age at transplantation, the duration of PBT, relative risk of death among those transfused, probability of noncompliance (both with the transfusion regimen and with iron chelation), refusal of PBT and BMT, probability of donor availability, 1-year mortality risk associated with BMT, and quality of life values. In addition, Monte Carlo simulations were performed (10 000 trials for each strategy) to estimate the variance around the expected QALYs of the PBT and BMT strategies.
Intention-to-treat analysis For patients with SCD at high risk of stroke, a decision to manage patients with an "intention-to-transplant" strategy would yield, on average, 15.2 discounted QALYs per patient, compared with 14.9 discounted QALYs per patients under an "intention-to-transfuse" strategy. Table 4 shows expected outcomes after 20 years in hypothetical cohorts of 100 000 patients with SCD under the 2 different intention-to-treat strategies. Although there are slightly more patients living stroke-free under the BMT strategy than under the PBT strategy, the magnitude of this difference is small (0.8%). In addition, the difference in the total number of patients alive after 20 years under each strategy is even smaller in magnitude (0.1%). Thus, a recommendation of BMT for 100 000 such patients would result in 810 more patients living stroke-free after 20 years than a recommendation of PBT; however, there would also be 111 more deaths in the group for whom BMT was recommended. Further analysis indicates that under the BMT strategy, 7.5% of patients die within 5 years, compared with 7.4% under the PBT strategy. A key reason why these 2 strategies have similar results is that only 8% of patients intended for BMT actually receive BMT, due to lack of donor availability and refusals.
Treatment received analysis Those patients actually receiving BMT could expect 18.6 discounted QALYs, whereas the average PBT patient could expect 15.7 discounted QALYs. Patients compliant with PBT and chelation had 19.2 expected discounted QALYs. Patients who are noncompliant with iron-chelating therapy could expect 14.1 discounted QALYs, whereas those noncompliant with transfusion could expect 14.8 discounted QALYs. Patients who refuse PBT could expect 12.3 discounted QALYs. Further analysis indicates that among those receiving BMT, 11.6% die within 5 years, compared with 2.6% among compliant PBT patients, 6.5% among those noncompliant with the transfusion regimen, 10.4% among those noncompliant with iron chelation, and 8.6% among those who refuse PBT and BMT. Thus, patients compliant with transfusion would do better, on average, than patients given BMT. However, the noncompliant patients would do worse, on average, than the BMT patients.
Sensitivity analyses
Discount rate.
At a discount of 0%, the decision to consider transplantation offered
only a marginal benefit over considering PBT (27.8 QALYs vs 26.8 QALYs). As the discount rate was increased to 10%, the benefit of BMT
over PBT diminished to zero (6.8 QALYs for both BMT and PBT).
Discounting had a greater impact on life years after BMT, because the
BMT cohort experienced more life years in the distant future that are
subsequently affected by discounting.
Age at transplantation.
As the age at transplantation varied from 2 to 10 years, the difference
between the 2 strategies remained constant (0.3 QALYs). In addition,
the number of QALYs associated with each strategy was not sensitive to
changes in the age at transplantation, given that for BMT, the number
of expected QALYs was 15.3 for a 2-year-old and 15.0 for a 10-year-old,
and for PBT, the number of expected QALYs was 15.0 for a 2-year-old and
14.7 for a 10-year-old.
Duration of transfusion.
As the number of years of transfusion to decrease the stroke risk was
varied from a lifetime of periodic transfusions down to 10, 5, and 3 years, the degree to which BMT was favored diminished significantly. If
only 5 years of transfusion are required to reduce the risk of stroke
in these patients, and if the percentage of patients who
refuse PBT treatment can be kept to a minimum (less than
5%), then BMT no longer offered any benefit over PBT.
Additional survival benefit due to transfusion.
As the risk of death associated with transfusions changed, there was
little change in the difference between the QALYs associated with BMT
and those associated with PBT. With transfused patients having half the
typical SCD patient's risk of death (ie, RR = 0.5), the difference
between BMT and PBT was 0.2 QALYs, as was the case when a relative risk
of 0.3 was chosen.
Noncompliance with transfusion regimen.
As the percentage of patients who are noncompliant with their regular
transfusions varied, there was little change in the difference between
the QALYs associated with considering BMT and those associated with
considering PBT. If 50% of patients receiving PBT were noncompliant
with the transfusion regimen, the decision to consider BMT would offer
15.4 QALYs versus 15.1 QALYs for considering PBT. This difference
diminished only slightly as the proportion of PBT patients who were
noncompliant decreased.
Noncompliance with iron-chelating therapy.
As compliance with iron-chelating therapy increased, PBT resulted in
greater QALYs. For example, when the proportion of patients receiving
PBT who are noncompliant with desferoxamine was reduced to 25%, the
difference in expected QALYs between the decision to consider BMT and
the decision to consider PBT was less than 0.01 QALYs. In addition,
improvement in compliance with iron chelation in combination with
improvement in compliance with the transfusions made PBT the preferred choice.
Donor availability and refusal of BMT.
Increasing donor availability and the acceptance of BMT for patients
with available donors slightly improved outcomes associated with the
intent to transplant. However, the relative change in overall QALYs was
still relatively small. For example, changing the probability of donor
availability from 0.14 to 0.30 changed the expected QALYs from 15.2 to
15.6 (a 2.6% increase). Given the degree of variability associated
with the expected QALYs, this is still not significantly greater than
outcomes associated with the intent to transfuse.
One-year mortality risk associated with BMT.
The 1-year risk of death associated with BMT was varied from 3% to
12%. Higher probability of death from BMT was associated with
diminished expected QALYs under the intent-to-transplant arm; however,
the expected QALYs were still relatively close between the 2 intention-to-treat arms, regardless of the actual value chosen for the
BMT mortality risk.
Quality of life values.
A series of 1-way sensitivity analyses on the quality-of-life utility
values (Table 7) revealed that, although the expected number of QALYs
is sensitive to changes in some disease state quality-of-life values,
the difference between the expected number of QALYs for each treatment
strategy remains relatively small across quality of life values ranging
from 0 (death) to 1 (perfect health). For example, as the quality of
life for patients receiving PBT who are noncompliant with iron
chelation varies from 0 to 1, the expected QALYs for the PBT arm range
from 9.7 to 16.7, whereas the expected QALYs for the BMT arm range from
10.4 to 16.8. The reason that the expected outcomes for the BMT arm
change when quality-of-life values associated with PBT are varied is again due to the fact that so many patients for whom BMT is intended will ultimately not receive BMT, either because of lack of donor availability or refusal of BMT. In addition, as the quality of life
assigned to cGVHD varies from 0 to 1, the expected number of QALYs for
the BMT arm varies from 15.0 to 15.3, whereas the expected
number of QALYs for the PBT arm remains constant at 14.9.
Variation of other combinations of key variables.
If all patients accepted PBT and were compliant with both the
transfusions and with iron chelation, PBT would offer more QALYs than
BMT, with or without the discounting of future years of life. Thus,
combinations that improve (1) the proportion of patients who accept
PBT, (2) the proportion of patients who are compliant with the
transfusion regimen, and (3) the proportion of patients who are
compliant with iron chelation would all make PBT the optimal choice.
For example, if we assume that 95% of patients would accept PBT, 95%
of those who accepted to be compliant with the PBT regimen, 95% of
those patients to be compliant with iron-chelating therapy, and between
3 and 5 years of transfusion, PBT would be the optimal choice. The
benefit provided by PBT would still be small (less than 1 QALY), but
the risk of short-term death would still be small in contrast to BMT.
Monte Carlo simulations.
In a series of Monte Carlo simulations, the standard deviations around
these estimates of expected QALYs were determined to be quite large
(approximately 6 QALYs). Because a large variation exists in some of
the point estimates of risk, the magnitude of the variation of the
expected QALYs under each strategy is also large.
This decision analysis provides insight into the decision to
recommend transplantation or transfusion for patients with sickle cell
whose only potential indication for BMT is the high risk of stroke.
This study incorporates results from published medical literature and
the most recent clinical knowledge of SCD. Although a decision analysis
cannot take the place of a randomized clinical trial (RCT), the models
generated allow comparisons in treatment strategies in the absence of
direct clinical trials, comparing the management strategies. The model
identifies key variables that need to be considered in the design of
any future clinical trials of BMT and PBT, including compliance with
transfusion regimen and with iron chelation, the duration of time
necessary for transfusions to sufficiently reduce the risk of stroke,
bone marrow donor availability, and BMT mortality. Such a randomized
trial of BMT and PBT might not be feasible because of limited BMT
donors, low consent rates, reluctance to enroll patients, or other
factors. In lieu of such evidence from an RCT, this study
may help inform individual decisions and assist in developing practice
policies and recommendations.
Submitted July 26, 1999; accepted January 11, 2000.
Reprints: Paul J. Nietert, Center for Health Care Research,
Medical University of South Carolina, 135 Rutledge Ave, Suite 1201, PO
Box 250550, Charleston, SC 29425.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
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Abstract
Introduction
