“Managing the Hemophilia Patient With Comorbidities: Perspectives of a Hematologist and an Internist”

"Managing the Hemophilia Patient With Comorbidities: Perspectives of a Hematologist
and an Internist"

Miguel A. Escobar, MD and Gabriel M. Aisenberg, MD
November 29, 2012


INTRODUCTION
The number of individuals in the United States with comorbidities is growing. According to estimates from the Robert Wood Johnson Foundation (RWJF), 133 million Americans live with a chronic condition (2004 data), and 63 million Americans (21%) have more than 1 chronic condition or multiple illnesses or impairments.1, 2  These figures are expected to rise dramatically in coming years. By 2020, according to projections from RWJF, 157 million Americans will have a single chronic condition, and the number with comorbidities will increase to 81 million.1, 2 

The risk for comorbidities increases with age.2  Presently, 62% of Americans older than 65 years have coexisting conditions. According to the Institute of Medicine, 23% of Medicare beneficiaries have 5 or more chronic conditions (as cited in Vogeli et al 2007 2 ). These conditions are not without a price tag: 80% of Medicare spending is devoted to patients with 4+ chronic conditions.3 

It is difficult to coordinate care for this subgroup of patients compared to other consumers of care.2  Older patients with comorbidities use more services than other cohorts. According to RWJF data, individuals with comorbid conditions have an average of nearly 15 physician visits and fill more than 50 prescriptions annually.1  The average Medicare beneficiary sees 7 physicians in a 1-year period.1  A lack of coordinated care across providers and service settings can result in suboptimal care for patients.1 



Comorbidities in an Aging Hemophilia Population
Historically, hemophilia care was a matter of pediatrics, due to the short life expectancy of patients with the disorder (eg, 1831-1920: 11 years; 1930-1939: 7.8 years).4  Although the AIDS epidemic had a devastating impact on the hemophilia population during the 1980s and 1990s, currently the life expectancy of this cohort is on an upswing.4  Various studies report similar mortality statistics. According to a UK report, patients with severe hemophilia have a life expectancy of 63 years.5  For moderate and mild hemophilia, it is 75 years. Similarly, a Dutch study found that the life expectancy was 59 years for patients with severe hemophilia and 67 and 73 years for patients with moderate and mild hemophilia, respectively.6 

An increase in life expectancy for this patient cohort can be attributed to improvements in hemophilia care over the past 3 decades.7, 8, 9, 10  As a result of viral inactivation methods, recombinant products, therapeutic strategies, and progress in the management of liver disease, an aging patient population is emerging. Based on a study of patients with hemophilia A or B attending US HTCs, individuals 45 and older comprise 15% of the total hemophilia population and those older than 65 make up 2% of this population.10 

The disease is no longer considered solely a disease of childhood. Changes in the profile of the hemophilia patient have extended the spectrum of comprehensive care from pediatric-based therapy to
adult- and geriatric-based care.4  The emerging population of older hemophilia patients not only must manage such conditions as arthropathy and iatrogenically induced viral infections resulting from a lack of proper early treatment,11  they are at increased risk for age-related health issues previously unrecognized in this cohort, such as cardiovascular disease (CVD), complications of HIV and HCV infections, cancer, and renal disease, all of which impact patients' quality of life (Figure 1).7 , 9  Bearing out this fact, a recently conducted retrospective chart review of middle-aged and elderly hemophilia patients found that all patients in the study sample (N=63) had more than 1 comorbid condition, and 19% of those older than 65 had 3 or more comorbid conditions, such as chronic hepatitis C, hypertension, HIV, chronic arthropathy, or overweight/obesity.12 

Managing the elderly hemophilia population requires a restructuring of healthcare delivery so that patients with the disorder are offered the same preventive care as that of the general population.13  The disease state should not preclude affected individuals from tests, procedures, or surgeries to which other groups have access (Gabriel M. Aisenberg, MD, and Miguel A. Escobar, MD, oral communication, May 17, 2012). To achieve an "equality" of care, greater coordination of care is needed, with a multifaceted approach that enlists the expertise of multiple specialists on the comprehensive care team, including an internist and other specialists, as required.12, 14 



CASE 1: ROBERT L.
Robert L. is a 52-year-old male with severe hemophilia A (FVIII <1%) and a high-titer inhibitor (20 BU). A prophylactic regimen with bypassing agents has been followed for the past 5 years. He is also seropositive for hepatitis C. Although there is no history of colon cancer in his family, at his annual physical exam he is urged by his internist to undergo a colonoscopy as part of routine screening.


CASE 1: ROBERT L.
Expert Q&A with Gabriel M. Aisenberg, MD,
and Miguel A. Escobar, MD



BACKGROUND OF COMMON AGE-RELATED COMORBIDITIES IN THE HEMOPHILIA POPULATION
Cardiovascular Disease

CVD has been the leading cause of death among US males since the 1950s.15  Although the incidence of CVD in hemophilia patients is lower than that of the general population, it appears to be increasing.13  The early medical literature points to a protective effect of hemophilia against CVD, which was believed to be conferred by the hypocoagulable nature of the bleeding disorder.16, 17   However, a growing body of data suggests that hemophilia patients have a similar frequency of CVD risk factors as males without hemophilia.9, 18

In a data analysis of approximately 3400 males with hemophilia living in the United States from 1993 to 1998, Kulkarni and colleagues found that the prevalence of ischemic heart disease (IHD) was 15.2% in older individuals, similar to that of an age-matched control population of nonhemophilia subjects.18, 19  These investigators also noted that increased life expectancy was associated with increased risk for IHD, which had an age-specific prevalence of 0.05% in patients younger than 30 and 15.2% in those 60 and older.19 

Five years earlier, in a surveillance study undertaken by Soucie and colleagues to determine death rates and identify causes of death and predictors of mortality in hemophilic men (median age 22 years), similar conclusions were drawn.20  The investigators reported a standardized mortality ratio (SMR; ratio of the observed-to-expected number of deaths from a particular cause) of 3.0 for myocardial infarction (MI) among 236 men who died during 7575 person-years of observation, indicating an increased risk for MI among hemophilia patients. An SMR greater than 1 indicates a greater number of deaths than would be expected in a cohort of similarly aged men without hemophilia.20

Strengthening the argument that the bleeding disorder does not protect against the damaging effects of CVD, it appears that the same factors contributing to CVD in the general population also impact hemophilia patients.15  The recent work of Tuinenburg et al, Khleif et al, and Hofstede et al suggest that factors contributing to CVD in hemophilia patients include increasing age, hypertension, diabetes mellitus, hyperlipidemia, high cholesterol, and overweight/obesity.11,  12, 21  This body of work underscores the fact that screening for CVD risk factors should be an integral part of hemophilia care.22 



CASE 2: EDWARD B.
Edward B. is a 64-year-old male with mild hemophilia A (FVIII 30%) that was diagnosed in childhood. He experiences bleeding episodes only infrequently and treats them on demand with factor concentrate. He visits his hemophilia treatment center (HTC) regularly for checkups. He recently presented to the emergency department of a local hospital with chest pain at rest. Although there is no family history of cardiovascular disease, Edward takes irbesartan 150 mg daily for stage 1 hypertension (BP 150/95) and atorvastatin 20 mg daily for borderline high cholesterol. Based on results of a stress test, which reveals significant narrowing in the left anterior descending artery, he is scheduled for an angiography and percutaneous coronary intervention (PCI).

CASE 2: EDWARD B.
Expert Q&A with Gabriel M. Aisenberg, MD,
and Miguel A. Escobar, MD



Viral Disease

The advent of HAART (highly active antiretroviral therapy) has significantly improved the survival of HIV-infected hemophilia patients. Up to one-third of patients live 20 to 25 years with the virus.10  However, an overwhelming majority of older hemophilia patients must also contend with the comorbidity of HCV infection, which is associated with reduced HCV clearance, leading to increased hepatic inflammation and accelerated progression to cirrhosis and liver failure.10, 15  Up to 98% of patients treated with large pool plasma-derived factor concentrates pre-1985, before development of viral inactivation, are infected with HCV, and 80% of these patients developed a chronic form of the virus.8  HCV is a major cause of chronic liver disease, liver failure, liver transplantation, and other complications in hemophilia patients and a leading cause of death.8, 9  HAART, beneficial for extending the lives of HIV-infected hemophilia patients, is also a contributor to liver disease in this cohort, and its use is associated with end-stage liver disease (ESLD) in HCV/HIV—coinfected patients.10  Cirrhosis, a potential complication of HCV, develops in approximately 20% to 30% of infected patients, with a rapid rise in incidence 15 years postinfection.9  Evidence suggests that patients in this cohort are also at risk for thrombocytopenia. A landmark study conducted by Eyster et al (1985) reveals that the platelet disorder is strongly associated with liver disease, which was a leading cause of death in the study population of hemophilia patients observed for 5 or more years.23 

Cancer

With increasing age, hemophilia patients will develop malignancies. These patients have the same cancer mortality rates as the general population, with the exception of hepatocellular carcinoma, the leading cause of death in this cohort.8, 10, 18  However, survival increased from 1992 to 2004, with the greatest improvement seen in those with localized disease and in patients receiving therapy.15  Older patients with hemophilia are also at increased risk for HIV-associated non-Hodgkin lymphoma. However, use of HAART has resulted in substantial reductions in incidence and mortality rates associated with this malignancy.15 

Renal Disease

Based on results of a CDC-sponsored surveillance study, patients with hemophilia have a 50-fold increased risk of death from renal disease compared to the general population.20  Risk factors include HIV infection, hypertension, and kidney bleeding in chronic renal disease.15  HIV infection, too, is associated with a variety of acute and chronic renal diseases, such as HIV-associated nephropathy and immune complex glomerulonephritis.15  Nephrotoxicity of HAART and HCV coinfection also contribute to renal disease in HIV-positive hemophilia patients.15 



TREATMENT OF AGE-RELATED COMORBIDITIES IN THE HEMOPHILIA POPULATION
The emergence of an aging hemophilia population is a relatively recent phenomenon. Consequently, evidence-based guidelines on which to draw are lacking. Clinicians, instead, must rely on anecdotal reports of suggested treatments.18, 24  Table 1 provides recommendations for managing common comorbidities.15 

In the following Q&A discussion, Dr. Escobar, a practicing hematologist, and Dr. Aisenberg, a practicing internist, describe how they manage hemophilia patients who have comorbidities such as CVD, HIV/HCV, liver disease, cancer, and renal disease. As part of their discussion, the following topics are addressed:

  • Precautions taken when liver biopsy is required

  • Inhibitor development in the elderly

  • Cardiovascular risk management and thromboembolic prophylaxis in elderly hemophilia patients

  • Perioperative management of hemophilia patients with comorbidities

  • Preventive and/or therapeutic measures taken with hemophilia patients regarding overweight and obesity (a 2004 survey indicates that 35% of adult hemophilic patients are overweight 21 )


CASE 2: EDWARD B.
Expert Q&A with Gabriel M. Aisenberg, MD,
and Miguel A. Escobar, MD



CONCLUSION
Despite a variety of comorbidities that may be experienced by individuals with hemophilia, one guiding principle should be in place for clinicians: Treat the diseases as they would be treated in the general population, in cooperation with an experienced hematologist. Data collection in the subgroup of patients with age-related diseases should be undertaken by international registries or clinical surveillance to determine:

  • How the diseases are managed by clinicians

  • Treatment protocols

  • Outcomes

Additionally, lifestyle issues should be addressed and screening programs incorporated into management and treatment plans of these patients. Larger studies are needed to further identify how to manage and treat aging hemophilia patients with comorbidities so that they may enjoy an improved quality of life in their golden years.



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