A Cross-Sectional Analysis of Cardiovascular Disease in the Hemophilia Population

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.