Men with hemophilia were initially thought to be protected from cardiovascular disease (CVD), but it is now clear that atherothrombotic events occur. The primary objective of the CVD in Hemophilia ...study was to determine the prevalence of CVD and CVD risk factors in US older men with moderate and severe hemophilia and to compare findings with those reported in age-comparable men in the Atherosclerosis Risk in Communities (ARIC) cohort. We hypothesized if lower factor levels are protective from CVD, we would see a difference in CVD rates between more severely affected and unaffected men. Beginning in October 2012, 200 patients with moderate or severe hemophilia A or B (factor VIII or IX level ≤ 5%), aged 54 to 73 years, were enrolled at 19 US hemophilia treatment centers. Data were collected from patient interview and medical records. A fasting blood sample and electrocardiogram (ECG) were obtained and assayed and read centrally. CVD was defined as any angina, any myocardial infarction by ECG or physician diagnosis, any self-reported nonhemorrhagic stroke or transient ischemic attack verified by physicians, or any history of coronary bypass graft surgery or coronary artery angioplasty. CVD risk factors were common in the population. Compared with men of similar age in the ARIC cohort, patients with hemophilia had significantly less CVD (15% vs 25.8%; P < .001). However, on an individual patient level, CVD events occur and efforts to prevent cardiovascular events are warranted. Few men were receiving secondary prophylaxis with low-dose aspirin, despite published opinion that it can be used safely in this patient population.
•CV risk factors are common in older men with hemophilia.•Although older men with hemophilia have less CV disease than comparable unaffected men, CV events do occur and require treatment.
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Introduction: Over a three-year period, U.S. men with hemophilia were found to be 50 times more likely to die from renal disease than the general population (SMR 50; 95% CI 26.8-92.8) (Soucie et al., ...Blood 2000). Despite this finding, data regarding chronic kidney disease (CKD) and its risk factors in patients with hemophilia remain limited. The objective of this study is to determine the prevalence of CKD and CKD risk factors among older men with moderate and severe hemophilia.
Methods: This CKD cohort study is an extension of a U.S. national study sponsored by the American Thrombosis and Hemostasis Network (ATHN). The study, entitled ATHN 1: A Cross-Sectional Analysis of Cardiovascular Disease (CVD) in the Hemophilia Population, began enrollment in 10/2012. Inclusion criteria are men with moderate or severe congenital hemophilia A or B (FVIII or IX level ≤ 5%), age 54-73. Men with an additional bleeding disorder (besides liver dysfunction) were excluded. In this extension study, CKD risk factors, historical creatinine levels, and history of renal events were obtained from patient interview and chart review after obtaining informed consent. Glomerular filtration rate (GFR) values were calculated using the CKD-EPI equation and compared to values in the general population using the NHANES dataset (Coresh et al., JAMA 2007). CKD is defined as the presence of either kidney damage or decreased kidney function with GFR < 60 ml/min/1.73 m2 for ≥ 3 months, irrespective of cause.
Results: As of 6/30/2018, 134/200 planned subjects have been enrolled and interim analysis on 134 subjects from 18 U.S. hemophilia treatment centers (HTCs) is presented here. The majority were white (119; 88.8%) or African-American (13; 9.7%). Mean age was 64 years (SD: 5; range: 56-77). Most used factor on demand, with only 38.8% (52/134) on prophylaxis, defined as ≥2 doses of FVIII or ≥ 1 dose FIX/week. Four (3.0%) had a current inhibitor. Viral infection was common; 28.4% currently had hepatitis C, and 19.4% HIV. Hypertension (HTN) was reported in 51.5% of subjects, 14.9% diabetes mellitus (DM); and average BMI was 28.2 kg/m2 (36.6% obese). 11.6% (16/134) were found to have CVD (defined as angina, MI, TIA, or ischemic or embolic stroke).
Acute kidney injury was common. Fasting blood work showed an abnormally elevated creatinine in 26.9% subjects (mean 1.1 mg/dl, SD 0.4). Mean historical maximum creatinine reported in the cohort was 1.0 (range 0.5-4.8), with mean GFR 67 (range 11-126). 11.4% (13/114) met the definition of CKD. Stages of CKD by GFR in the hemophilia cohort were similar to the NHANES general population (p=0.561). See Table 1 for subject reported history of renal events, and Table 2 for specific diagnoses of renal disease.
In our cohort, hemophilia subjects with CKD tended to have a diagnosis of intrinsic kidney disease (60.0% vs 11.6%, p=0.02), and non-significantly tended to have DM (23.1% vs 12.8%), age ≥65 years (21.1% vs 9.4%), and HTN (18.0% vs 9.8%) compared to subjects without CKD. No other significant trends were identified, including no association with CVD, HCV, HIV, BMI, or hematuria.
Conclusions: In this interim analysis of an ongoing national prospective cohort study, older men with moderate to severe hemophilia commonly report risk factors for CKD, including HTN (51.5%), DM, viral infection, and potential renal damaging medication use. Only 11.6% had CVD. Urological symptoms were also common, including hematuria and obstructive symptoms with urination.
In our cohort, 11.4% met the definition of CKD, defined as the presence of either kidney damage or GFR < 60 ml/min/1.73 m2 for ≥ 3 months. The distribution of GFR values appeared similar to the general population. As with risk factors associated with CKD in the general population, diagnosis of intrinsic kidney disease was significantly associated with CKD in hemophilia subjects, with non-significant trend for increased DM, older age, and HTN compared to subjects without CKD. It is reassuring that the prevalence of CKD does not appear to be increased in men with hemophilia compared to the general population, despite a known and unexplained high incidence of HTN in the hemophilia population. We plan to formally compare the prevalence of CKD and CKD risk factors with similarly aged men in the ARIC database once enrollment is complete, as understanding the risk factors that contribute to CKD is essential to halt its progression.
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Sood:Bayer: Research Funding. Shapiro:BioMarin: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Sangamo Biosciences: Consultancy; Octapharma: Research Funding; OPKO: Research Funding; Daiichi Sankyo: Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Bio Products Laboratory: Consultancy; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kessler:Biomarin: Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees; DSMB: Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; Novo Nordisk: Honoraria, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Key:UniQure BV: Research Funding. Quon:Bioverativ, a Sanofi Company: Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Bayer: Consultancy; Shire: Speakers Bureau; Genetech: Consultancy, Speakers Bureau; Octapharma: Consultancy. Manco-Johnson:Novo Nordisk: Honoraria; CSL Behring: Honoraria; Bayer AG: Honoraria, Research Funding; Biogentek: Honoraria; Baxalta, now part of Shire: Honoraria. Cuker:Kedrion: Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy; Spark Therapeutics: Research Funding; Synergy: Consultancy. Ragni:Novo Nordisk: Research Funding; Shire: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo: Research Funding; SPARK: Consultancy, Research Funding; CSL Behring: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Consultancy, Research Funding; SPARK: Consultancy, Research Funding. von Drygalski:UniQure BV, Bayer, Bioverativ/Sanofi, Pfizer, Novo Nordisk, Biomarin, Shire, CSL Behring: Consultancy. Kouides:UniQure: Other: DSMB; Octapharma: Research Funding. Escobar:Bayer, CSL Behring, Genentech, Hemabiologics, Kedrion, Novo Nordisk, Octapharma, Pfizer and Shire: Consultancy; Pfizer: Research Funding. Wang:Daiichi Sankyo: Consultancy, Other: Travel. Konkle:Shire: Research Funding; Genentech: Consultancy; Bioverativ: Research Funding; BioMarin: Consultancy; Pfizer: Research Funding; Gilead: Consultancy; Spark: Consultancy, Research Funding; CSL Behring: Consultancy; Sangamo: Research Funding.
Introduction: Over a 3 year period, U.S. men with hemophilia were found to be 50 times more likely to die from renal disease than the general population (SMR 50; 95% CI 26.8-92.8) (Soucie et al., ...Blood 2000). Despite this finding, data regarding chronic kidney disease (CKD) and its risk factors in patients with hemophilia remain limited. The objective of this study is to determine the prevalence of CKD and CKD risk factors among older men with moderate and severe hemophilia.
Methods: A U.S. national study (ATHN-1) began enrollment in 10/2012. Inclusion criteria are men with moderate or severe congenital hemophilia A or B (FVIII or IX level ≤ 5%), age 54-73. Men with an additional bleeding disorder (besides liver dysfunction) were excluded. In this extension study, CKD risk factors, historical creatinine levels, and history of renal events were obtained from patient interview and chart review after obtaining informed consent. Glomerular filtration rate (GFR) values were calculated using the CKD-EPI equation and compared to values in the general population using the NHANES dataset (Coresh et al., JAMA 2007). CKD is defined as the presence of either kidney damage or decreased kidney function with GFR < 60 ml/min/1.73 m2 for ≥ 3 months, irrespective of cause.
Results: As of 6/30/2017, data from 98/200 subjects from 18 U.S. Hemophilia Treatment Centers have been collected, and interim analysis is presented here. The majority were white (88; 89.8%) or African American (9; 9.2%). Mean current age was 64 years (SD: 5; range: 57-77). 37.8% (37/98) were on prophylaxis, defined as ≥2 doses of FVIII or ≥ 1 dose FIX/week. Two (2.0%) had a current inhibitor. Viral infection was common: 35.7% currently had hepatitis C (HCV), and 17.4% HIV. Hypertension (HTN) was reported in 52.0% of subjects, 13.3% diabetes (DM), and average BMI was 28.1 kg/m2 (35.7% obese). 6.1% (6/98) were found to have CVD (defined as angina, MI, TIA, or ischemic or embolic stroke).
Fasting blood work showed an abnormally elevated creatinine in 30.9% subjects (mean 1.1 mg/dl, SD 0.4). Mean historical maximum creatinine was 1.0 (range 0.6-4.8), with mean GFR 68 (range 12-126). 11.3% (8/71) met the definition of CKD. Stages of CKD by GFR in the hemophilia cohort were similar to the NHANES general population (p=0.60).
A history of hematuria was reported in 45.1% (41/91) of subjects, mostly at age under 20. 26.4% (24/91) of subjects had a history of nephrolithiasis, 57.1% (52/91) past use of NSAIDs, and 45.1% (41/91) antifibrinolytic agents. 15.4% (14/91) of subjects reported obstructive symptoms with urination; 14.3% (13/91) had benign prostate disease. 7.7% (7/91) of subjects had a history of intrinsic kidney disease. Of these, 28.6% (2/7) had a renal biopsy, 71.4% (5/7) had seen a nephrologist, and 14.3% (1/7) were on dialysis. The renal disease in these 7 subjects was related to: DM (3), HCV (2), HTN (1), and glomerulonephritis (1).
In our cohort, hemophilia subjects with CKD non-significantly trended to have increased DM (20% vs 8.2%), age ≥65 years (15.6% vs 7.7%), and HTN (14.6% vs 6.7%) compared to subjects without CKD. No other significant trends were identified, including no association with CVD, HCV, HIV, BMI or hematuria.
Conclusions: In this interim analysis of an ongoing national prospective cohort study, older men with moderate to severe hemophilia commonly report risk factors for CKD, including HTN (52.0%), DM (13.3%), viral infection (35.7% HCV, 17.4% HIV), and potential renal damaging medication use (57.1% past use of NSAIDs, 45.1% antifibrinolytic agents). Only 6.1% had CVD. Urological symptoms were also common, including hematuria (45.1%, with 26.4% reporting a history of nephrolithiasis); 15.4% of subjects reported obstructive symptoms with urination, and 14.3% had benign prostate disease.
In our cohort, 11.3% (8/71) subjects met the definition of CKD, defined as the presence of either kidney damage or GFR < 60 ml/min/1.73 m2 for ≥ 3 months. The distribution of GFR values appeared similar to the general population. As in the general population, hemophilia subjects with CKD non-significantly trended to have more DM, older age, and HTN compared to subjects without CKD. We plan to formally compare the prevalence of CKD and CKD risk factors with similarly aged men in the ARIC database once enrollment is complete, as understanding the risk factors that contribute to CKD is essential to halt its progression.
Sood:Bayer: Research Funding. Kempton:Genentech: Membership on an entity's Board of Directors or advisory committees. Cuker:T2 Biosystems: Research Funding; Spark Therapeutics: Research Funding. Ragni:Alnylam, CSL Behring, BAYER, Biomarin, Biomarin, Bioverativ, Genetech/Roche, Pfizer, Shire, SPARK: Research Funding; A Anylam, Biomarin, Bioverativ, Shire: Honoraria. Gill:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Von Drygalski:Baxalta/Shire: Honoraria; Bayer: Honoraria; Biogen: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Pfizer: Honoraria; Hematherix LLC: Membership on an entity's Board of Directors or advisory committees. Escobar:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wheeler:NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.
Hepcidin regulation is linked to both iron and inflammatory signals and may influence iron loading in nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the relationships among ...HFE genotype, serum hepcidin level, hepatic iron deposition, and histology in nonalcoholic fatty liver disease (NAFLD). Single‐nucleotide polymorphism genotyping for C282Y (rs1800562) and H63D (rs1799945) HFE mutations was performed in 786 adult subjects in the NASH Clinical Research Network (CRN). Clinical, histologic, and laboratory data were compared using nonparametric statistics and multivariate logistic regression. NAFLD patients with C282Y, but not H63D mutations, had lower median serum hepcidin levels (57 versus 65 ng/mL; P = 0.01) and higher mean hepatocellular (HC) iron grades (0.59 versus 0.28; P < 0.001), compared to wild‐type (WT) subjects. Subjects with hepatic iron deposition had higher serum hepcidin levels than subjects without iron for all HFE genotypes (P < 0.0001). Hepcidin levels were highest among patients with mixed HC/reticuloendothelial system cell (RES) iron deposition. H63D mutations were associated with higher steatosis grades and NAFLD activity scores (odds ratio OR, ≥1.4; 95% confidence interval CI: >1.0, ≤2.5; P ≤ 0.041), compared to WT, but not with either HC or RES iron. NAFLD patients with C282Y mutations had less ballooning or NASH (OR, ≤0.62; 95% CI: >0.39, <0.94; P ≤ 0.024), compared to WT subjects. Conclusions: The presence of C282Y mutations in patients with NAFLD is associated with greater HC iron deposition and decreased serum hepcidin levels, and there is a positive relationship between hepatic iron stores and serum hepcidin level across all HFE genotypes. These data suggest that body iron stores are the major determinant of hepcidin regulation in NAFLD, regardless of HFE genotype. A potential role for H63D mutations in NAFLD pathogenesis is possible through iron‐independent mechanisms. (HEPATOLOGY 2012;56:1730–1740)
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Introduction: Cardiovascular disease (CVD) is a disease of aging. While men with hemophilia were initially thought to be protected from CVD, it is now clear that atherothrombotic events do occur. ...The objective of this study is to determine the prevalence of CVD and CV risk factors in older men with moderate and severe hemophilia.
Methods: A U.S. national cross-sectional study began enrollment in 10/2012. Included are men with moderate or severe congenital hemophilia A or B (FVIII or IX level ≤ 5%), age 54-73. Men with an additional bleeding disorder (besides liver dysfunction) were excluded. After informed consent, CV risk factors, medications, and thrombotic event history were obtained from patient interview and chart review. A fasting blood sample was assayed centrally.
Results: As of 7/24/2015, 194 of 200 planned subjects were recruited with enrollment to be completed by 9/2015 and analysis by 12/2015. Planned interim analysis on 165 subjects from 19 U.S. Hemophilia Treatment Centers is presented here. The majority were white (148; 89.7%) or African American (14; 8.5%). Mean age was 61 years (SD: 5; range: 54-73). Most used factor on demand, with only 30.3% (50/165) on prophylaxis, defined as ≥2 doses of FVIII or ≥ 1 dose FIX/week. Eight (4.9%) had a current inhibitor. Viral infection was common; 61.2% had hepatitis C, and 28.5% HIV.
Hypertension (HTN) was reported in 61.2% of subjects, dyslipidemia in 35.1%, and diabetes (DM) in 21.8%; 49.1% had ever smoked, 55.2% denied engaging in at least moderate physical activity and 43.0% had a family history of CVD. Average BMI was 28 kg/m2 (30.3% obese) and waist circumference 96 cm (32.1% enlarged). Fasting blood work showed an abnormally elevated: creatinine in 26.7% subjects (mean, SD) (1.1 mg/dl, 0.5), CRP in 9.7% (5.2 mg/L, 13.7), total cholesterol in 23.0% (174.1 mg/dl, 38.8), triglycerides in 27.9% (129.1 mg/dl, 68.3), LDL in 21.8% (105.1 mg/dl, 34.7); and low HDL in 42.4% (43.2 mg/dl, 11.8).
A minority, 14 subjects (8.5%) reported prior angina or atrial fibrillation/flutter; 5 (3.0%) leg deep venous thrombosis; 4 (2.4%) myocardial infarction (MI) or pulmonary embolism; 3 (1.8%) coronary artery stent placement; 2 (1.2%) transient ischemic event (TIA); and 1 (0.6%) coronary artery angioplasty, CABG, or peripheral arterial disease history.
The prevalence rate of CVD (defined as angina, MI, TIA, or ischemic or embolic stroke) was 9.7% (16 subjects), significantly lower than the 23% prevalence of CVD in similar aged men without hemophilia in the longitudinal Atherosclerosis Risk in Communities (ARIC) cohort (p-value <0.001). None of the men with CVD were on antiplatelet or anticoagulant medications.
Compared to never smokers, ever smokers had a significant odds ratio (OR) of 3.5 (95% CI 1.1-11.3) of CVD. For HTN, dyslipidemia, and DM, the OR (95% CI) of CVD were 2.0 (0.6-6.6), 2.0 (0.7-5.6), and 1.2 (0.4-4.0), respectively. Positive family history (OR 1.4 (0.5-3.8)) and low-level physical activity (1.1 (0.4-3.3)) also suggested some association with increased CVD risk. Higher triglycerides (1.2 (0.4-3.7)) and lower HDL (1.4 (0.5-3.9)) tended to increase CVD risk, but obesity was not a risk factor.
Men using prophylaxis appeared less likely to have CVD (3/50, 6.0%) than men not on prophylaxis (13/115, 11.3%), OR 0.5 (0.1-1.8), although the difference was not statistically significant. HIV+ men (2/47, 4.3%) were also less likely to have CVD compared to non-HIV+ men (14/115, 12.2%), OR 0.3 (0.07-1.5), but not significantly so. Current use of anti-HTN medications (42.4% of all subjects), cholesterol lowering agents (17.6%), and DM medications (13.3%) did not decrease CVD risk. Analysis of cause and effect is limited by the cross-sectional design.
Conclusions: In this interim analysis of an ongoing national cross-sectional study, older men with moderate to severe hemophilia commonly report risk factors for CVD, including HTN (61.2%), dyslipidemia (35.2%) and renal insufficiency (26.7%). Despite this, the prevalence of reported CVD is low at 9.7%, suggesting that men with hemophilia may be protected from forming pathogenic thrombi. Smoking significantly increased the OR of CVD events among men with hemophilia. More data are needed to determine if the approach to prophylaxis or other therapies should be altered in this population. We plan to formally compare the prevalence of CVD and CV risk factors with similarly aged men in the ARIC database once enrollment is complete.
Sood:Bayer: Research Funding. Ragni:Vascular Medicine Institute: Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Research Funding; Biogen: Research Funding; Alnylam: Research Funding; Bristol Myers Squibb: Research Funding; Bayer: Research Funding; Genentech Roche: Research Funding; SPARK: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Dimension: Research Funding. Quon:Baxter: Other: Advisory Board, Speakers Bureau; Bayer: Other: Advisory Board; Biogen: Other: Advisory Board, Speakers Bureau; Novo Nordisk: Other: Advisory Board, Speakers Bureau; Grifols: Speakers Bureau. Shapiro:Baxalta, Novo Nordisk, Biogen, ProMetic Life Sciences, and Kedrion Biopharma: Consultancy; Baxalta, Novo Nordisk, Biogen,: Membership on an entity's Board of Directors or advisory committees; Biogen: Speakers Bureau; Bayer Healthcare, Baxalta, Biogen, CSL Behring, Daiichi Sankyo, Kedrion Biopharma, Octapharma, OPKO, ProMetic Life Sciences, PTC Therapeutics, and Selexys: Research Funding. Cuker:Bracco: Consultancy; Genzyme: Consultancy; T2 Biosystems: Research Funding; CSL Behring: Consultancy. von Drygalski:CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gill:Baxalta, Bayer, and CSL-Behring: Membership on an entity's Board of Directors or advisory committees. Leissinger:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding. Konkle:Pfizer: Consultancy; CSL Behring: Consultancy; Octapharma: Research Funding; Baxalta: Consultancy, Research Funding; Biogen: Consultancy, Research Funding; Novo Nordisk: Consultancy.
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Introduction: Cardiovascular disease (CVD) is a disease of aging. While men with hemophilia were initially thought to be protected from CVD, it is now clear that atherothrombotic events do occur. ...The objective of this study is to determine the prevalence of CVD and CV risk factors among older men with moderate and severe hemophilia.
Methods: A U.S. national cross-sectional study began enrollment in 10/2012. Inclusion criteria are men with moderate or severe congenital hemophilia A or B (FVIII or IX level ≤ 5%), age 54-73. Men with an additional bleeding disorder (besides liver dysfunction) were excluded. After obtaining informed consent, CV risk factors, medications, and history of thrombotic events were obtained from patient interview and chart review. A fasting blood sample was assayed centrally.
Results: As of 8/1/2014, 160/200 planned subjects were recruited and interim analysis on 126 subjects from 18 U.S. Hemophilia Treatment Centers is presented here. The majority were white (109; 86.9%) or African American (15; 11.5%). Mean age was 62 years (SD: 5; range: 54-74). Most used factor on demand, with only 34.1% (43/126) on prophylaxis, defined as ≥2 doses of FVIII or ≥ 1 dose FIX/week. Five (4.0%) had a current inhibitor. Viral infection was common; 68.3% currently had hepatitis C, and 25% HIV.
Hypertension (HTN) was reported in 65.6% of subjects, 37.3% dyslipidemia and 24.6% diabetes (DM); 44.5% had ever smoked, 56.3% denied engaging in at least moderate physical activity and 43.7% had a family history of CVD. Average BMI was 28 kg/m2 (29.4% obese) and waist circumference 97 cm. Fasting blood work showed an abnormally elevated: creatinine in 27.6% subjects (mean 1.09 mg/dl, SD 0.5), CRP in 6.3% (4.15 mg/L, 10.6), total cholesterol in 18.1% (169.49 mg/dl, 35.8), triglycerides in 25.2% (122.10 mg/dl, 58.2), LDL in 19.7% (102.27 mg/dl, 32.3); and low HDL in 45.7% (42.80 mg/dl, 12.2).
Ten subjects (7.9%) reported prior angina; 7 (5.6%) atrial fibrillation/flutter; 3 (2.4%) leg deep venous thrombosis; 2 (1.6%) myocardial infarction (MI), transient ischemic event (TIA), or pulmonary emboli; and 1 (0.8%) coronary artery angioplasty, stent placement, CABG, or peripheral arterial angioplasty.
In total, 11 subjects had CVD (defined as angina, MI, TIA, or ischemic or embolic stroke), a prevalence rate of 8.7%. This is significantly lower than the reported prevalence of 23% CVD in similar aged men without hemophilia in the longitudinal ARIC cohort (p-value <0.001). The qualifying diagnoses in our cohort included angina, MI and TIA. None of the men with CVD were on antiplatelet or anticoagulant medications.
Due to the small number of events, individual CV risk factors thus far did not achieve statistical significance in predicting CVD. Compared to never smokers, ever smokers had an odds ratio (OR) of 3.7 (95% CI: 0.9-14.8) of CVD. For HTN, dyslipidemia, and DM, the OR (95% CI) of CVD were 2.5 (0.5-12.1), 2.2 (0.6-7.5), and 1.9 (0.5-6.8), respectively. Positive family history (OR 2.4 (0.7-8.8)) and low-level of physical activity (1.4 (0.4-5.0)) also suggested some association with increased CVD risk. Obese BMI and large waist circumference were not significant.
Men using prophylaxis appeared less likely to have CVD (1/43, 2.3%) than men not on prophylaxis (10/83, 12.1%), OR 0.2 (0.02-1.4), although the difference was not statistically significant. HIV+ men (1/32, 3.1%) were also less likely to have CVD compared to non-HIV+ men (10/92, 10.9%), OR 0.3 (0.2-10.9), but not significantly so.
Lastly we investigated the role of anti-HTN (used in 36.5% of all subjects), cholesterol lowering (16.7%), and DM medications (10.3%) in reducing CVD. Not taking anti-HTN, cholesterol or DM medications non-significantly increased CVD risk with an OR in all subjects of 1.5, 3.3, or 3.9 respectively.
Conclusions: In this interim analysis of an ongoing national cross-sectional study, older men with moderate to severe hemophilia commonly report risk factors for CVD, including HTN (65.6%), dyslipidemia (37.3%) and renal insufficiency (27.6%). Despite this, the prevalence of reported CVD is low at 8.7%, suggesting that men with hemophilia may be protected from forming pathogenic thrombi. More data is needed to determine if the approach to prophylaxis or other therapies should be altered in this population. We plan to formally compare the prevalence of CVD and CV risk factors with similarly aged men in the ARIC database once enrollment is complete.
Sood:Bayer: Research Funding. Shapiro:Baxter: Consultancy, Global Steering Committee Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Global Steering Committee, Global Steering Committee Other, Research Funding; CSL Behring: Research Funding; Biogen Idec: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Kedrion: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kempton:Baxter Healthcare, Inc: Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Membership on an entity’s Board of Directors or advisory committees; Kedrion Biopharma: Membership on an entity’s Board of Directors or advisory committees; NovoNordisk, Inc: Research Funding. Fogarty:Amgen Inc: Consultancy; Bayer HealthCare Pharmaceuticals: Consultancy; Baxter: Consultancy; Biogen Idec Inc.: Consultancy; Chugai Pharma USA: Consultancy; Pfizer Inc: Consultancy; Baxter: Research Funding; Biogen Idec Inc.: Research Funding; CSL Behring: Research Funding; Pfizer Inc: Research Funding; Medscape LLC: Honoraria; VindicoMed: Honoraria. Ragni:Biogen Idec: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Tacere Benitec: Consultancy, Drug Safety Monitoring Board, Drug Safety Monitoring Board Other; Baxter: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Merck: Research Funding; Novartis: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Vascular Medicine Institute, PIttsburgh, PA: Research Funding. Neff:Baxter: Membership on an entity’s Board of Directors or advisory committees. Konkle:CDC: Research Funding, This work was supported by CDC grant 1U01DD000761-01 Other.
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