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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 437-442
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Mortality among males with hemophilia: relations with source of
medical care
J. Michael Soucie,
Rachelle Nuss,
Bruce Evatt,
Abdou Abdelhak,
Linda Cowan,
Holly Hill,
Marcia Kolakoski,
Nancy Wilber, and
the Hemophilia Surveillance System Project Investigators
From the Hematologic Diseases Branch, Division of AIDS, STD, and TB
Laboratory Research, National Center for Infectious Diseases, Centers
for Disease Control and Prevention, Atlanta, GA; Mountain States
Regional Hemophilia Center, Aurora, CO; Tulane University Medical
School, New Orleans, LA; Oklahoma University Health Sciences Center,
Oklahoma City, OK; Emory University School of Public Health, Atlanta,
GA; New York State Department of Health, Albany, NY; and the
Massachusetts Department of Public Health, Boston, MA.
 |
Abstract |
Although persons with hemophilia are known to be at increased risk
of death, no studies have examined the source of medical care and other
personal characteristics for associations with mortality. To determine
death rates and to identify causes of death and predictors of
mortality, we studied a cohort comprised of all hemophilic males
identified by a six-state surveillance system. Data were obtained by
medical record review of contacts with physicians, hemophilia treatment
centers (HTCs), and other sources of care during 1993-1995 and from
death certificates. Factors examined included age, race, state of
residence, health insurance type, medical care source, hemophilia
type/severity, presence of inhibitor, liver disease, HIV infection, and
AIDS. A total of 2950 subjects were followed for an average of 2.6 years. Their median age was 22 years; 73% were white, 79% had
hemophilia A, 42% had severe disease, and 67% had visited an HTC.
During 7575 person years (PYs) of observation, 236 persons died an
age-adjusted mortality rate of 40.4 deaths/1000 PYs; 65% of deaths
were HIV related. In addition to age, factors independently associated with increased risk of death (relative risk, P value) were the following: AIDS (33.5, <.001); HIV infection (4.7, <.001); liver disease (2.4, <.001); and Medicare/Medicaid insurance (1.4, .01). Those persons who had received care in an HTC had a significantly decreased risk of death (0.6, .002). Although HIV infection and the
presence of severe liver disease remain strong predictors of mortality,
survival is significantly greater among hemophilics who receive medical
care in HTCs.
(Blood. 2000;96:437-442)
© 2000 by The American Society of Hematology.
| |
Introduction |
Hemophilia A and hemophilia B are hereditary
deficiencies of factor VIII and factor IX, respectively, two
glycoproteins required for normal blood clotting. Among affected
persons, spontaneous bleeding or bleeding at the site of an injury is
common and, if uncorrected, can lead to severe disability or death.
These complications can be prevented by appropriate clinical management
and treatment with preparations of factor VIII or factor IX
concentrates, therapeutic clotting agents that have been available
since the late 1960s.
From 1970 until the early 1980s, mortality among persons with
hemophilia declined substantially.1-4 The two primary
reasons usually suggested for this decline are (a) increased
availability of clotting factor replacement products for treating
life-threatening bleeding episodes and (b) in the United
States, improved medical management provided by specialized hemophilia
treatment centers (HTCs) that were established in the
mid-1970s.1,5 The role of the former in reducing mortality
is obvious; however, little or no data are available concerning the
contribution made by HTCs toward reducing mortality among persons with hemophilia.
Because hemophilia is rare, previous studies of mortality have
frequently been limited either to a relatively small number of
individuals recruited from HTC populations or to analyses of national
mortality data that lack individual risk factor information. No studies
have directly examined the associations between mortality and factors
related to medical management, such as care received in HTCs. Current
economic pressures to reduce costs for medical care discourage the use
of expensive, specialized care for persons with rare diseases, such as
hemophilia, unless justified by demonstrated superior clinical
outcomes. Thus, the extent to which HTCs contribute to the successful
clinical management of individuals with hemophilia has become an
important issue for health care planners.
In 1995, the Centers for Disease Control and Prevention (CDC), in
collaboration with the health departments in six states, began active
surveillance for all persons with hemophilia residing in those states.
Data were collected on the health status and health care of persons
receiving care both inside and outside of HTCs. We used data collected
during the first 3 years of this surveillance project to examine the
rates and causes of death among a large cohort of affected individuals.
This report examines the effect of several factors, including source of
care, on mortality among this population.
| |
Materials and methods |
The surveillance system, case-finding methods, and data collection
procedures have been described in detail elsewhere.6 The
Hemophilia Surveillance System (HSS) is a cooperative project between
CDC and the health departments of Colorado, Georgia, Louisiana, Massachusetts, New York, and Oklahoma, designed to identify and collect
demographic and health information on all persons with hemophilia
residing in these states. The case-finding methods used, including the
use of lists obtained from physicians, clinical laboratories,
hospitals, HTCs, and other sources, have previously been shown to
enable identification of virtually all residents with
hemophilia.6
Persons were considered to have hemophilia A or B based on a
physician's diagnosis. Persons with acquired inhibitors of factor VIII
or IX in the absence of a genetic deficiency, persons with von
Willebrand disease, and symptomatic carriers of the hemophilia gene
were excluded. The level of hemophilia severity was categorized as
mild, if the patient's clotting factor activity was from 6%-30%; moderate, if from 1%-5%; and severe, if <1% of normal. Clotting factor activity was documented in 98% of cases.
Data collection
From 1995 through 1997, trained data abstractors collected
standardized demographic, clinical, treatment, and outcome data on
persons with hemophilia from medical records obtained from HTCs,
physicians' offices, laboratories, pharmacies, hospitals, emergency
rooms, and outpatient clinics for the period January 1993 through
December 1995. Pertinent to this analysis, detailed information was
collected on (a) demographic and clinical characteristics; (b) the primary source of hemophilia care and reimbursement;
(c) the results of laboratory testing; and (d) if
applicable, causes of death. Information was aggregated from all
settings in which patients received medical care.
Patients who were identified at any time during the 3-year interval
were eligible for inclusion in the system. Information collected during
the first year for which a medical record was available was used to
determine the patient's date of birth, race, state of residence, and
type of health insurance at baseline. Health insurance was categorized
as private insurance/health maintenance organization (HMO),
Medicare/Medicaid, or other/none.
HTCs provide integrated, multidisciplinary, comprehensive care to
patients with hemophilia according to a set of published guidelines7 and serve as a primary source of consultative
and treatment advice for enrolled patients and their physicians, even when these patients receive care in other health care settings. Although HTCs routinely schedule patient visits at least once per year,
visits often occur less frequently. For this analysis, patients who had
received care at an HTC any time during the study period were
considered HTC users.
Persons with a peak inhibitor titer of  1.0 Bethesda unit during the
first year of follow-up were classified as having an inhibitor; persons
with liver disease-related signs and symptoms (eg, hepatomegaly,
jaundice, dark urine, and clay-colored stools) were considered to have
severe liver disease at baseline. HIV seropositivity was determined on
the basis of a prior positive test for HIV-1 antibody. When no evidence
of HIV testing could be found, patients were categorized as having an
unknown HIV serostatus. Persons were classified as having AIDS if their
medical records indicated conditions that met the CDC surveillance case
definition for AIDS.8
Patient death data were obtained from medical records or death
certificates. Deaths were categorized according to the ninth revision
of the International Classification of Diseases, Injuries, and
Causes of Death (ICD-9),9 using the final diagnoses by attending physicians. Up to four causes, categorized as immediate, underlying, and contributing causes, were recorded. Cause-specific analyses used the multiple-cause-of-death classification, which allows
for mortality statistics based on more than one cause. A death was
considered to be HIV-related if the medical record or death certificate
listed at least one of the following diseases (ICD-9 codes) as
the immediate or underlying cause of death: (a) HIV infection
with specified conditions or other infections (042.0-044.9), (b) Pneumocystis carinii pneumonia (136.3),
(c) immune deficiency (279.1, 279.3, 279.9), or (d)
serologic or culture findings indicative of HIV infection (795.8).
Categorization of other causes of death followed the scheme used by
Chorba et al.5
Data analysis
Follow-up was from January 1 of the year of patient identification
until the date of death, or until January 1 of the year during which a
patient was lost to follow-up, or December 31, 1995, whichever came first.
A crude mortality rate was calculated for each demographic (age,
race/ethnicity, state of residence, insurance type, and hemophilia care
source) or clinical (hemophilia type and severity, inhibitor, severe
liver disease, HIV serostatus, and AIDS) characteristic. This rate was
expressed as the number of deaths among persons in a category of the
characteristic divided by the number of years of follow-up of such
persons multiplied by 1000 [deaths per 1000 person years (PYs)]. The
relative risk of death between persons in different categories of the
characteristic was assessed by using the ratio of these
rates.10 We also calculated an age-adjusted mortality rate
based on direct standardization to the U.S. male population in 1990.
Estimates of survival times and comparisons between groups of
individuals were made using the survival distribution function calculated by the actuarial method.11,12 The statistical
significance of differences in survival between groups was evaluated
with the use of a log-rank test.13 Abridged life tables for
the cohort were created with 5-year age intervals (0-4, 5-9, ..., 85+)
by using the method described by Elandt-Johnson and
Johnson.14 Two tables, one that included and one that
excluded HIV-infected individuals, were constructed and used to
estimate the life expectancy at birth and median age at death for these
populations.15
Cause-specific mortality in the cohort was compared with that in the
U.S. male population overall by using the ratio of the observed-to-expected mortality, or standardized mortality ratio (SMR).
The number of expected deaths was calculated by multiplying the number
of PYs of follow-up for each 5-year age category of the cohort by the
corresponding cause-specific mortality rates in the general male
population16 and summing the products over the age groups.
Confidence intervals for the SMRs were calculated, based on the Poisson
distribution.17
To determine characteristics independently associated with mortality,
we used proportional hazards regression.18 Prior to multivariable modeling, potential predictors to be included in the
model were examined for conformity with the proportionality assumption
by visual examination of plots of the log of the negative log of the
survival function against the log of follow-up time.13 We
used a model that included all of the factors so that we could assess
the simultaneous influence of all characteristics on mortality. All
hypothesis testing was two-tailed, with a significance level of .05.
| |
Results |
Detailed demographic analyses of this population have been published
previously.6 The characteristics and mortality rates of
2950 males with hemophilia A and B identified during the 3-year study
period are shown in Table 1. Overall, 67%
of identified patients received care in HTCs during the period. Of the
remainder, 13% had received care primarily from private physicians or
hematologists, 4% primarily from hospital- and nonhospital-based
clinics, 8% received care only in hospitals or emergency rooms, and
the rest received care from a variety of other sources. One half of the study population had private medical insurance or HMO coverage, whereas
the remainder either were insured by Medicare/Medicaid or had no
insurance. At baseline, 5% of patients had inhibitors to factor, 2%
had signs or symptoms of severe liver disease, 26% were HIV infected,
and 7% had AIDS (Table 1).
Univariate analysis
During the study period, 236 (8%) persons with hemophilia died,
corresponding to an age-adjusted mortality rate of 40.4 deaths per 1000 PYs. Mortality rates were similar among racial/ethnic groups and among
residents of the six states (Table 1). Persons who received care at an
HTC during follow-up were 30% less likely to die than were those who
did not receive HTC care. Compared with persons with private insurance
or HMO coverage, persons with Medicare or Medicaid coverage had nearly
a twofold risk of death. The risk of death for persons with hemophilia
B was half that for those with hemophilia A. Individuals with severe
disease were more than twice as likely to die compared with those with
mild disease, regardless of hemophilia type. Although no excess
mortality risk was observed according to the presence of factor
inhibitors, the risk of death was significantly increased for persons
with severe liver disease, HIV infection, or AIDS (Table 1). The 3-year survival was 21% lower (P < .001) among HIV-infected
individuals compared with noninfected persons.
AIDS/HIV infection was the immediate cause of death for 124 (52.5%)
persons (Table 2) and an underlying cause
in 29 (12%) others. Among persons between the ages of 10 and 59 years
who died, HIV infection was listed as an immediate or underlying cause of death for 50% in every 10-year age group, and it accounted for
84% of deaths among those in the 30-39 year age group (Figure 1). Liver disease was responsible for an
additional 8% of all deaths. According to mortality rates in US
males, the number of deaths from acute myocardial infarction, cancer,
liver disease, and renal disease among persons in the cohort was
greater than expected (Table 2).
View this table:
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Table 2.
Causes of death and selected standardized mortality
ratios (SMR)* among 2950 males with hemophilia in six US
states, 1993-1995
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View larger version (22K):
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| Fig 1.
Distribution by age of 236 deaths and relations with
cause among 2950 men with hemophilia in six US states, 1993-1995.
Deaths were considered to be HIV related when according to death
records the immediate, underlying, or contributing cause of death was
infection with HIV.
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Multivariate analysis
After adjusting for the effects of all of the studied
characteristics in a multivariate analysis, medical care provided by HTCs was even more strongly associated with reduced mortality; persons
who had received care in HTCs during the study period were 40%
less likely to die than those who had not (Table
3). In contrast, several factors were
associated with increased risk of death. Mortality risk increased by
60% with each additional decade of age. Persons with severe liver
disease had 2.4 times the risk of death, those persons with
HIV-infection but without AIDS had nearly 5 times the risk, and persons
with AIDS had 33 times the risk compared with persons without these
conditions.
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Table 3.
Associations between characteristics and death among
2950 males with hemophilia in six US states, 1993-1995
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For the entire cohort, the life expectancy at birth was 38.7 years,
and the median age at death was 35 years. However, when HIV-infected persons were excluded from the cohort, the life expectancy rose to 64.1 years, and the median age at death nearly doubled to 67 years.
| |
Discussion |
The finding that HTCs have a significant effect on reducing
mortality in patients with hemophilia supports the effectiveness of
such centers in providing specialized preventive care. The national HTC
program was initiated in 1975 to provide comprehensive, specialized
care to persons with bleeding disorders. Beginning in 1983, additional
CDC funding was provided to improve health outcomes among this
population by increasing the emphasis on risk-reduction practices.
Today, approximately 130 HTCs provide a range of comprehensive services, including diagnosis, clinical management, orthopedic and
dental care, along with patient education, training, and counseling, throughout the United States and its territories.
In addition to providing expertise in coagulation disorders, the HTCs
also provide individual treatment plans for persons with hemophilia and
place a premium on preventive medicine because the complications are
extremely difficult and expensive to treat. The design of the HTC
provides each patient with access to multiple medical disciplines, each
of which has specific experience in hemophilia care. This integration
of services maximizes both the effectiveness and the efficiency of the
health care program.
The substantial socioeconomic benefits of these services for
the hemophilic population, including lower cost of care, decreased health care resource utilization, and increased employment, have been
documented.19,20 However, before our analyses, no outcome comparisons between patients who do and do not receive care in HTCs
have been available. The 40% reduction in risk of death that we observed among persons using HTCs is even more remarkable
because HTCs provide health care services to a higher proportion of
severely affected patients as well as to a disproportionate share of
patients with severe liver disease, HIV infection, and AIDSthe
primary risk factors for mortality in this population (Table
4).
View this table:
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Table 4.
Distribution of clinical characteristics by source of
care among 2950 males with hemophilia in six US states, 1993-1995
|
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Several possible explanations are available for lower
mortality rates from HIV-related and liver diseases among persons
receiving HTC care. First, clinical management assistance by infectious and hepatic disease specialists is easily accessed and integrated into
the comprehensive, team approach that is a central component of the HTC
standard of care. Second, because patients with hemophilia were
excluded from participation in HIV treatment trials, HTCs using federal
funding obtained by the National Hemophilia Foundation (NHF)
were able to enroll HIV-infected hemophiliacs in special HTC-based AIDS
Clinical Trials Units. Finally, in addition to the expertise provided
by the HTC's infectious and liver disease specialists, a
unique information center maintained by the NHF with federal
support provides HTC staff with the latest treatment and prevention
information by distributing medical bulletins and compendia of
scientific articles and bibliographic citations related to HIV disease,
hepatitis, and liver disease.
HTCs may also influence mortality through the establishment and
promotion of home factor-infusion programs. Home therapy facilitates early treatment of bleeding episodes, but it requires intensive patient
training and close monitoring by the health care
professional. The practice was far more common among persons in our
cohort who received HTC care compared with those who did not (61%
versus 25%, P < .001). Other potential contributors to the
effectiveness of HTCs include extensive patient and family education
and expert consultation from HTC staff during periods of hemostatic
stress. Further study will be required to assess the contribution of
each of these factors in reducing the risk of death among
persons receiving HTC care as well as to explore reasons for the
geographic differences in mortality that we observed.
Compared with persons in other health insurance categories, those with
Medicare/Medicaid were more likely to die; this finding did
not change after adjustment for differences in the distributions of age
and other risk factors. Increased mortality among individuals with
Medicare/Medicaid coverage has been observed in the general US
population and is attributed to selection for these programs on the
basis of existing health problems or low socioeconomic status
and, once enrolled, to differences in access to medical care.21 Among persons in our cohort who were 18 years
old, 22% were either unemployed or disabled; moreover, mortality rates were 2 and 4 times higher, respectively, among individuals in these
categories compared with those who were employed (results not shown).
The unemployed and disabled comprised 29% of persons with
Medicare/Medicaid compared with only 4% of those with
private insurance or HMO coverage. Some of this observed effect of
government insurance on mortality may have been mediated by
poverty, but no socioeconomic data were available for study of this
issue. Conversely, access to HTC care appeared not to have been a
factor because the proportion of persons with and without
Medicare/ Medicaid who received HTC care was similar (69% versus
63%, respectively).
Overall, the median age at death of 35 years was substantially lower
than previous estimates of 49.1 and 40 years that were based on
mortality rates during the 1980s.5,22 This finding suggests
that the impact of AIDS on mortality among persons with hemophilia
continued to increase during the first half of the 1990s. When
HIV-infected individuals (those with and without AIDS) were excluded
from the analysis, both life expectancy and median age at death nearly
doubled. Because viral inactivation procedures have eliminated the
threat of new HIV transmissions through receipt of plasma-derived
factor concentrates, our estimate of 64.1 years, based on exclusion of
HIV-infected individuals, more accurately approximates the current life
expectancy of males presently born with hemophilia. Our figure is
similar to the estimate of 64.9 years obtained by Stafford et
al,23 which was based on mortality in the hemophilia
population during the decade prior to the beginning of the AIDS
epidemic, but it still is substantially less than the overall 72.3-year
life expectancy for US males in 1994.24
The impact of HIV infection and liver disease on mortality in this
cohort was not unexpected and is consistent with other published
findings.22,25,26 Complications associated with HIV
infection were the immediate or underlying cause of 65% of all deaths
that occurred during 1993-1995. The age-adjusted mortality rate of 40.4 deaths per 1000 PYs was more than 4 times that of the US male population.
Our findings have important implications for future medical care for
persons with hemophilia. On the basis of our surveillance data, one
third of the hemophilia population receives no care from HTCs. The
barriers to HTC utilization among persons with hemophilia have not been
formally studied, but possibilities include a lack of awareness of the
potential benefits of HTC care, socioeconomic factors, cultural
barriers, transportation and other logistical problems, and cost
concerns related to referral or reimbursement for HTC services. Formal
studies of knowledge, attitudes, and beliefs among users and nonusers
of HTCs, currently in the planning stages, will help to identify these
barriers and may suggest strategies to increase access to this vital
source of medical care.
| |
Acknowledgments |
The Hemophilia Surveillance System comprises the following persons and
institutions: Centers for Disease Control and Prevention (B. Cicatello,
B. Evatt, D. Jackson, J. M. Soucie); Colorado Department of Health (R. Hoffman, S. Michael, F. Nocera); Mountain States Regional Hemophilia
Center (M. Manco-Johnson, R. Nuss, B. Riske, J. Stultz); Georgia
Division of Public Health (N. Stroup); Emory University School of
Public Health (E. Brockman, H. Hill, B. McDowell, T. Poindexter, K. Smith, S. Stein); Louisiana State Department of Health (C. Myers);
Louisiana Comprehensive Hemophilia Care Center (A. Abdou, B. Bates, J. Bunting, C. Leissinger, V. Shea, K. Wulff); Massachusetts Department of
Public Health (L. Livens, J. Su, D. Walker, N. Wilber); Boston
Hemophilia Center (B. Ewenstein, F. Ross); New England Hemophilia
Center (D. Brettler, A. Forsberg, P. Geary, D. Thibeault); New York
State Department of Health (M. Arrington, J. Bartholomew, B. Connelly,
B. Cushman, B. Kearney, M. Kolakoski, J. Lima, J. Linden, E. Villegas);
Mt. Sinai Medical Center (E. Aulov, S. Gaynor); Oklahoma State
Department of Health (S. Kinney); Oklahoma Hemophilia Treatment Center
(H. Huszti, F. Kiplinger, C. Sexauer); and University of Oklahoma
Health Sciences Center (N. Asal, L. Cowan, B. Erickson, L. Hudson, C. Smith-Edwards, S. Warner, M. Young).
| |
Footnotes |
Submitted December 21, 1999; accepted March 8, 2000.
Reprints: J. Michael Soucie, Centers for Disease Control and
Prevention, 1600 Clifton Road, MS E64, Atlanta, GA 30333; e-mail:
msoucie{at}cdc.gov.
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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R. K. Pruthi
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M. Silva and J. V. Luck Jr.
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R. C. James and C. A. Mustard
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P. M. Mannucci and E. G.D. Tuddenham
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Top
Abstract
Introduction