944291621153HaemophiliaHaemophilia : the official journal of the World Federation of Hemophilia1351-82161365-251621371197313462610.1111/j.1365-2516.2011.02501.xNIHMS266316ArticleAtherosclerotic Heart Disease: Prevalence and Risk Factors in Hospitalized Men with Hemophilia ARagniMargaret V.MD, MPH1MooreCharity G.PhD, MSPH2Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Pittsburgh PADepartment of Medicine, Division of General Internal Medicine, and Center for Research on Health Care Data Center, University of Pittsburgh PAReprint Requests Margaret V. Ragni, MD, MPH Professor of Medicine Division Hematology/Oncology, University of Pittsburgh Medical Center Director, Hemophilia Center of Western Pennsylvania 3636 Boulevard of the Allies Pittsburgh, PA 15213-4306 Phone: 412-209-7288; Fax: 412-209-7281 ragni@dom.pitt.edu24220114320111120111112012176867871SummaryBackground

Atherosclerotic heart disease (ASHD) is a common cause of morbidity and mortality in Western society. Few studies have determined prevalence and predictors of ASHD in hemophilia (HA), a population whose survival is improving with safer blood products and effective treatments for AIDS and hepatitis C.

Objectives

The purpose of this study was to determine prevalence and factors associated with ASHD in hemophilia A patients in Pennsylvania.

Methods

The prevalence of ASHD (myocardial infarction, angina, coronary disease), cardiac catheterization, coronary angiography, co-morbidities, and in-hospital mortality were assessed on statewide ASHD discharge data, 2001–2006, from the Pennsylvania Health Care Cost Containment Council (PHC4).

Results

The prevalence of hemophilia ASHD admissions fluctuated between 6.5% and 10.5% for 2001 to 2006, p=0.62. Compared to HA without ASHD, HA with ASHD were older and more likely to be hypertensive, hyperlipidemic, and diabetic, all p<0.0001, with greater severity of illness, p=0.013. By contrast, HA and non-HA with ASHD had similar rates of hypertension, diabetes, and ICD-9 specified ischemic heart disease, including acute myocardial infarction (MI), p=0.39, old MI, p=0.47, and angina, p=0.63. Rates of catheterization and angiography, p=0.06 and p=0.07, were marginally lower, but primary circulatory system admitting diagnoses, p=0.29, were similar between HA and non-HA ASHD groups, as was length of stay, p=0.14, severity of illness, p=0.64, and in-hospital deaths, p=0.75.

Conclusions

Hemophilia patients with ASHD have similar cardiovascular risk factors, admitting diagnoses, severity of illness, and in-hospital mortality as the general population. These findings suggest cardiovascular prevention measures should be promoted in hemophilia.

atherosclerosisheart diseasehemophiliaprevalencerisk factorsUL1 RR024153-04 ||RRNational Center for Research Resources : NCRR
Introduction

Atherosclerotic heart disease (ASHD) is the most common cause of morbidity and mortality in Western society. Among individuals with hemophilia, there is increasing interest in defining the scope of ASHD, now that their survival is approaching that of the normal population with the availability of safer clotting factor concentrates and effective treatment for blood-borne pathogens HIV and hepatitis C [13]. A CDC study reported that as many as 15% of hemophilic men over 60 years of age have clinical ASHD [4]. While their mortality is 2.7-fold higher than the general population, due to hepatitis C and AIDS, the mortality from ischemic heart disease is 60% lower [3, 57]. Elevated circulating factor VIII [8], fibrinogen [9], and von Willebrand factor [10] levels are known risk factors for cardiovascular disease, but whether low factor VIII or IX, i.e. hypocoagulability, protects against ASHD remains an area of debate. In a recent case-control study we found that risk factors for ischemic heart disease (hypertension, smoking, diabetes, hyperlipidemia) and degree of intraluminal coronary stenosis at autopsy in hemophilic men are similar to those in the general population [11]. This suggests that while risk for cardiovascular disease is similar, the risk for cardiovascular mortality is lower in individuals with hemophilia than the general population, despite improving lifespan, and this may be related to hypocoagulability [11, 12]. Few data, however, exist on the prevalence and predictors of ASHD in hospitalized hemophilia patients as compared with the general population. While some studies describe a lower frequency of lipid elevation in those with hemophilia than controls [13], others studies report no difference [14, 15], suggesting differences in age, viral infection, obesity, or other confounders between these groups [16]. We, therefore, reviewed statewide inpatient ASHD discharge data for ASHD from the Pennsylvania Health Care Cost Containment Council (PHC4) to determine the prevalence and characteristics of ASHD in hospitalized hemophilia patients in Pennsylvania.

Methods

De-identified discharge data for the five-year period 2001–2006 were obtained from the Pennsylvania Health Care Cost Containment Council (PHC4). This independent agency collects inpatient hospital discharge data and outpatient procedure records from hospitals and ambulatory surgery centers in the state of Pennsylvania to monitor health care cost [17]. Data for analysis were limited to Pennsylvania residents hospitalized between 2001 and 2006, excluding female patients. Discharges were analyzed by age, race, year, severity of illness, length of stay, and vital status including in-hospital deaths [17, 18]. Coronary disease data were classified by diagnostic ICD-9 codes [19] for atherosclerotic heart disease (ICD-9 414), myocardial infarction (ICD-9 412), angina (ICD-9 413), and other ischemic heart disease (ICD-9 411). Cardiac diagnostic procedure codes were classified by procedure codes, including cardiac catheterization, EKG, angiography, and nuclear procedures. Co-morbidities were also assessed, including hypertension (ICD-9 401–405), hyperlipidemia (ICD-9 272.4); diabetes (ICD-9 250), obesity (ICD-9 278), and HIV (ICD-9 042). Primary admission diagnoses were classified as circulatory system (ICD-9 390–460), blood-forming organs (ICD-9 280–290), respiratory system (ICD-9 460–520), digestive system (ICD-9 520–580), and injury/trauma (ICD-9 800–999). Three groups of hospitalized patients were identified for comparisons: 1) individuals with hemophilia A and ASHD; 2) those with hemophilia A and no ASHD; and 3) individuals without hemophilia A but with ASHD, based on the presence or absence of these two diseases in the primary or secondary diagnoses (admissions categorization). The study was approved by the University of Pittsburgh Institutional Review Board (IRB) by exempt review.

Analysis

The annual prevalence of ASHD among hemophilia A admissions was estimated by dividing the number of admissions with ASHD and hemophilia A diagnosis by the total number of hemophilia admissions per year. Primary comparisons for analyses were carried out 1) to determine how hemophilia patients with ASHD compare to their non-hemophilia counterparts with ASHD; and 2) to determine how hemophilia patients with ASHD compared to their hemophilia counterparts without ASHD. We limited analysis to the first admission per patient once the admission categorization was determined to decrease the influence of multiple correlated admissions from the same patient on group comparisons. We compared continuous data (e.g. age, length of stay) was by Student t-test, and categorical data (e.g.race, co-morbidities, procedures) using Chi-square tests.

ResultsPrevalence of ASHD among hospitalizations in men with hemophilia A

The prevalence of ASHD admissions among individuals with hemophilia (HA) fluctuated between 6.5% and 10.5% during the time period 2001 to 2006, p=0.62 (Figure 1). The age-specific prevalence of ASHD was consistently higher in older-age compared to younger-age categories, for all admissions and by year, p<0.0001, with 1.28% (n=941) for those ≤50 years, 10.9% (n=156) for 51–64 years, 33.6% (n=110) for 65–74 years, and 31.8% (n=173) for ≥75 years of age.

Comparison of Hemophilia A patients with ASHD and without ASHD

As compared with hemophilia inpatients without ASHD, hemophilia inpatients with ASHD were older, 73 vs. 39 yr, and more likely to have hypertension, 52.7% vs. 21.1%, hyperlipidemia, 9.5% vs. 1.3%, and diabetes, 28.4% vs. 9.4%, all p<0.0001. Hemophilia inpatients with ASHD were less likely to be admitted for injury or trauma, p<0.0001, but had a greater severity of illness than those without ASHD, p=0.013. The two groups had a similar length of stay, 5.9 vs. 5.0 days, p=0.30, and a similar proportion of in-hospital deaths, 4.1% vs. 2.3%, p=0.41.

Comparison of ASHD patients with hemophilia and without hemophilia

Hospitalized hemophilic ASHD patients were as likely as non-hemophilic ASHD patients to be hypertensive, 52.7% vs. 56.2%, p=0.54, diabetic, 28.4% vs. 27.1%, p=0.80, and obese, 4.1% vs. 4.6%, p=1.00. Hyperlipidemia was significantly less common in hemophilic than nonhemophilic ASHD inpatients, 9.5% vs. 22.9%, p=0.006, even after adjustment for age, p=0.007, although no differences were noted in rates of obesity between the groups, p=1.00. Unfortunately, neither cholesterol levels nor body-mass index measures were available to quantify these findings. As expected, HIV infection was more common among ASHD inpatients with hemophilia than in those without hemophilia, 2.7% vs. 0.1%, p=0.002; as was HCV infection, 12.2% vs. 0.6%, p<0.0001. Hemophilic ASHD inpatients were just as likely as their non-hemophilic counterparts to have circulatory system disease as a primary admission diagnosis, 52.7% vs. 58.7%, p=0.29.

These two groups also had similar rates of ICD-9 specified ischemic heart disease, including acute myocardial infarction (MI), p=0.39, old MI, p=0.47, and angina, p=0.63. Hemophilic ASHD inpatients underwent somewhat fewer coronary catheterization procedures than nonhemophilic ASHD inpatients, 16.2% vs. 25.8%, and somewhat fewer coronary angiography procedures, 16.2% vs. 25.5%, p=0.06 and p=0.07, respectively.

Although length of stay was longer among hemophilic than non-hemophilic patients with ASHD, 5.9 vs 4.9 days, this did not reach significance, p=0.13. There were also no differences in severity of illness scores, p=0.64, or in-hospital deaths, 4.1% vs. 3.6%, p=0.75, between groups.

Discussion

As the hemophilia population is now aging, a number of studies have established that while cardiovascular mortality is three times more common as a cause of death [20], cardiovascular disease [3, 6, 7, 12, 21, 22], pathologic coronary artery atherosclerosis [11], and endothelial dysfunction [14] do not differ between individuals with hemophilia and the general population. Further, the prevalence of ASHD is not uncommon in older individuals in normal, nonhemophilia groups. However, there is controversy regarding whether those with hemophilia have similar cardiovascular risk factors to those in the general population. Some of the difficulties with studies to date include small cohort size, few cardiovascular events, and differing age, decade of study, and proportion HIV infected or on antiretroviral therapy.

This study utilized hospital discharge data to establish that, as compared with non-hemophilic men with ASHD, hemophilic men with ASHD have similar cardiovascular risk factors with the exception of hyperlipidemia, and they also have similar primary admitting (non-hemophilic) diagnoses. Further, they have similar cardiovascular ICD-9 codes for myocardial infarction and angina pectoris, a similar severity of illness, and a similar proportion who undergo cardiovascular diagnostic procedures. It is of note that the trend to fewer undergoing coronary angiography, although not significant, is possibly related to fear of bleeding, not only by persons with hemophilia, but by the cardiologists caring for them.

The findings of this study suggest that cardiovascular procedures should be part of standard medical care for individuals with hemophilia, just as for the general population. There are, however, important caveats to consider in this approach. Anticoagulation or anti-platelet therapy, whether for myocardial infarction or surgical procedures, e.g. coronary stent placement, may increase the risk of life-threatening bleeding in the individual with hemophilia. Further, the risk of bleeding may be even greater in the presence of other concomitant coagulation defects, e.g. thrombocytopenia or Vitamin K deficiency, not uncommon in hemophilic men with chronic hepatitis C liver disease. Thus, before initiating anticoagulation or platelet inhibitor therapy in the individual with hemophilia, careful coagulation assessment before and during anticoagulation or anti-platelet therapy is critical to avoid unforeseen bleeding. It is of note that no safety recommendations or evidence-based guidelines exist to guide anticoagulation or anti-platelet therapy in hemophilic men. This is, in part, because potential bleeding risk excludes hemophilic men them from participation in cardiovascular prevention trials. In the absence of evidence, wide-ranging approaches to anticoagulation and anti-platelet therapy for cardiovascular disease and/or procedures have been proposed, including short-term anticoagulation anti-platelet therapy only with concomitant factor infusion, low dose anticoagulation or anti-platelet therapy, or avoidance of such agents altogether [23]. The lack of hemophilia-specific guidelines for anticoagulation management of ischemic cardiovascular disease suggests the need for prospective clinical trials, which would likely require international collaboration for sufficient sample size to achieve significant findings.

There are several limitations of this study. First, the use of a hospital discharge database may miss healthier outpatients not requiring admission; however, traditionally patients with acute myocardial infarction and angina pectoris, the ICD-9 codes we reviewed, are hospitalized, and, thus, we believe few potential subjects were missed. Further, an advantage of an inpatient database is the availability of severity of illness and in-hospital mortality data, not previously reported in hemophilic men. Secondly, because these are administrative data collected for another purpose, it is not possible to verify that all patients with an ICD-9 for hemophilia actually had hemophilia, nor is it possible to establish hemophilia severity, although previous studies suggest no difference in ASHD risk by hemophilia severity [11]. Further, these data do not include clinical history of smoking, laboratory values,, e.g. lipid levels, or treatment medications for hypertension or hyperlipidemia, which may result in identification of fewer individuals with hyperlipidemia or at risk for cardiovascular disease. Thirdly, these data are limited to the state of Pennsylvania which, although unlikely, may not be representative of the nation and miss geographic differences. Fourthly, as expected, HIV infection was more common among ASHD inpatients with hemophilia than in those without hemophilia, yet the prevalence was low, in only 2.7% of patients with hemophilia. The reason for this is not known, but it is possible this reflects the advanced age of the patient population, and/or limitations of hospital discharge coding.

To summarize, the presence of atherosclerotic heart disease among adult men with hemophilia is not rare (6–10% of admissions). Cardiovascular risk factors, severity of illness and in-hospital mortality are similar in hemophilia men with ASHD compared to the general population of men with ASHD. These findings are consistent with the previous demonstration that pathologic coronary atherosclerosis [11] and endothelial dysfunction [14] in those with hemophilia are similar to the general population, and underscore the importance of a cardiovascular risk prevention strategy in adults with hemophilia, similar to that in the general population. Such a strategy will require ongoing clinical studies to define the safety of anticoagulation and anti-platelet therapy in this group.

Acknowledgements

We acknowledge Ms. Diane Comer from the Center for Research on Health Care at the University of Pittsburgh for her contribution in management and analysis of the large database. We acknowledge the expertise, dedication, and work of Pennsylvania Health Care Containment Council (PHC4) staff, including Ms. Judith Good and Ms. Rachel Anspach, data analysts. The study was supported by HHS Federal Region III Hemophilia Treatment Centers, Grant #1-H-30-MC-00038-01, Center for Diseases Control Prevention of Complications of Hemophilia Grant U10DD000193, and the Pennsylvania Department of Health State SAP #04100000330; and CTRC/CTSI grant: NIH/NCRR/CTSA UL-1 RR024153.

Disclosure The authors declare no conflicts or competing financial interests.

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The bar graph illustrates the prevalence of all ASHD admissions among admissions/hospitalizations in men with hemophilia A in the state of Pennsylvania. The mean annual percent is indicated above each bar.

Characteristics of Hemophilia and ASHD, Non-ASHD, and Non-Hemophilic ASHD Admissions in Pennsylvania

Group 1 Hemophilia ASHDGroup 2 Hemophilia No ASHDGroup 3 Non-Hemophilia ASHDp value Group 1 vs. Group 2p value Group 1 vs. Group 3
No. of Admissions N = 196N = 1,623N = 2,270,318
No. of Patients N = 74N = 531N = 483,782
Age (median, years)733970p<0.0001p=0.889
Race Non Hispanic white89.6%77.9%90.9%p=0.132p=0.703
 Non Hispanic Black9.0%14.4%6.4%
 Hispanic1.5%6.1%1.6%
 Non-Hispanic Other0.0%1.6%1.1%
Risk Factors
 Hypertension52.7%21.1%56.2%p<0.0001p=0.543
 Hyperlipidemia9.5%1.3%22.9%p<0.0001p=0.006
 Diabetes28.4%9.4%27.1%p<0.0001p=0.805
 Obesity4.1%1.5%4.6%p=0.141p=1.000
 HIV Infection2.7%5.6%0.1%p=0.409p=0.002
 HCV Infection12.2%24.3%0.6%p=0.0198p<0.0001
Altas Severity of Illness
 None14.8%34.1%18.8%p=0.013p=0.637
 Minimal42.6%38.7%40.2%
 Moderate26.2%17.0%28.2%
 Severe16.4%8.8%11.7%
 Maximal0.0%1.4%1.1%
Atlas Severity of Illness, Dichotomized
 None/Minimal/Moderate83.6%89.8%87.2%p=0.151p=0.405
 Severe/Maximal16.4%10.2%12.8%
Primary Admission Diagnosis
 Circulatory System52.7%7.2%58.7%p<0.0001p=0.293
 Blood-Forming Organs14.9%18.6%0.5%p=0.430p<0.0001
 Respiratory System1.4%6.0%7.0%p=0.165p=0.064
 Digestive System10.8%11.9%5.8%p=0.792p=0.063
 Injury, Trauma4.1%18.3%4.4%p=0.001p=1.000
ICD-9 Codes
 ICD-9 410 (AMI*)14.9%0.0%18.7%-p=0.393
 ICD-9 411 (Other IHD)16.2%0.0%11.6%-p=0.214
 ICD-9 412 (Old MI)13.5%0.0%16.6%-p=0.470
 ICD-9 413 (Angina pectoris)4.1%0.0%6.0%-p=0.629
 ICD-9 414 (ASHD, other)85.1%0.0%86.7%-p=0.688
Cardiac Diagnostic Procedures
 Cardiac catheterization16.2%0.4%25.8%-p=0.060
 Cardiac echocardiogram5.4%1.1%3.4%-p=0.325
 Coronary angiography16.2%0.6%25.5%-p=0.067
 Transesophageal echogram5.4%0.9%3.4%-p=0.323
 Intravascular Imaging0.0%0.0%0.1%-p=1.000
Length of Stay (mean days)5.95.04.9p=0.300p=0.135
 Discharged on Admit Day4.1%2.1%1.8%p=0.397p=0.147
In-Hospital Death 4.1%2.3%3.6%p=0.412p=0.752
 Died on Admit Day33.3%0.0%19.5%p=0.214p=0.478

AMI is acute myocardial infarction.

IHD is ischemic heart disease.

ASHD is atherosclerotic heart disease.