Cardiovascular risk assessment in haemophilia patients

274

© Schattauer 2011

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Cardiovascular risk assessment in haemophilia patients Sara Biere-Rafi1; Manuel A. Baarslag1; Marjolein Peters2; Marieke J. H. A Kruip3; Roderik A. Kraaijenhagen4; Martin Den Heijer5; Harry R. Büller1; Pieter W. Kamphuisen1 1Department

of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands; 2Department of Pediatric Hematology, Emma Children’s Hospital AMC, Amsterdam, The Netherlands; 3Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands; 4NDDO Institute for Prevention and Early Diagnostics, Amsterdam, The Netherlands; 5Department of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands

Summary Haemophilia patients have a reduced cardiovascular mortality, which may be the result of a lifelong deficiency of factor VIII or IX. On the other hand, the prevalence of risk factors may differ in these chronically ill patients compared to the general population. The prevalence of risk factors and expected risk of cardiovascular disease was compared in haemophilia patients and healthy controls. In adult haemophilia A and B patients, body mass index, blood pressure, cholesterol levels and fasting glucose levels were measured and compared to healthy agematched males. The expected risk of mortality due to cardiovascular disease was calculated using a European risk prediction algorithm (SCORE). A total of 100 haemophilia A and B patients and 200 healthy controls were analysed. The mean age of the patients was 47 years (range 18–83). The number of haemophiliacs with hyperglycaemia (24%) and hypertension (51%) was higher than in the controls (p-valu-

Correspondence to: Sara Biere-Rafi, MD Department of Vascular Medicine, F4–140 Academic Medical Center Meibergdreef 9 1105 AZ Amsterdam, The Netherlands Tel.: +31 20 5667050, Fax: +31 20 5669343 E-mail: [email protected]

es 0.001 and 0.03, respectively). The mean low-density lipoprotein (LDL) cholesterol level in cases was lower than the controls (3.02 mM (0.69–6.57) and 3.60 mM (1.68–5.95), respectively, p < 0.001). Fewer cases had increased LDL levels (p=0.045). No difference was found in the 10-year cardiovascular mortality risk >10% between cases and controls (12% and 7%, respectively, p = 0.18). The prevalence of risk factors and expected risk of cardiovascular disease in haemophilia patients is comparable to the general population. This strengthens the hypothesis that hypocoagulability may reduce cardiovascular mortality in haemophilia patients.

Keywords Cardiovascular disease, diabetes mellitus, haemophilia, hypertension, risk factors

Received: July 19, 2010 Accepted after major revision: October 22, 2010 Prepublished online: December 6, 2010 doi:10.1160/TH10-07-0460 Thromb Haemost 2011; 105: 274–278

Introduction The concept of risk factors for cardiovascular disease has been well established. Besides classical risk factors such as hypertension (1, 2), hypercholesterolaemia (3), smoking (4), diabetes mellitus (5) and obesity, (6) a prothrombotic state may also play a role in the development of fatal and non-fatal cardiovascular events. Increased levels of fibrinogen (7), von Willebrand factor (VWF) (8) and factor VIII levels (9, 10) have all been associated with an increased risk of cardiovascular disease. As there is increasing evidence that a hypercoagulable state is associated with arterial disease, the opposite may also hold true. Individuals with an inherited coagulation deficiency, as is the case in haemophilia patients, have a decreased mortality due to cardiovascular disease (11–13). In a survey among all haemophilia patients in The Netherlands, the Standardised Mortality Ratio (SMR) for cardiovascular mortality was 0.2 (95% confidence interval [CI] 0.0–1.1) between 1973 and 1986 (11). Following this same cohort, the SMR was 0.5 (0.2–1.1) between 1992 and 2001 (14). In 2007, a large UK survey also found a reduced cardiovascular mortality

(SMR 0.62; 95% CI 0.51–0.76) between 1977 and 1999 in haemophilia patients not infected with human immunodeficiency virus (HIV) (12). This reduced mortality from cardiovascular disease has been explained by a protective effect of having lifelong low coagulation factor levels and a more favourable cardiovascular risk profile (15). The life expectancy of haemophilia patients has increased considerably, which means the risk of mortality due to cardiovascular disease has increased. Yet, the question whether haemophilia patients have a better cardiovascular risk profile is still unclear. We hypothesised that the prevalence of cardiovascular risk factors in haemophilia patients is similar to healthy controls and that the reduced mortality due to cardiovascular disease can be explained by the lifelong hypocoagulability. In the present study, we compared the prevalence of major cardiovascular risk factors between haemophilia patients and matched controls, who did not have a previous cardiovascular event. In addition, we assessed the number of patients and controls with a high cardiovascular mortality risk.

Thrombosis and Haemostasis 105.2/2011

Downloaded from www.thrombosis-online.com on 2013-05-20 | ID: 1000471566 | IP: 134.68.189.135 For personal or educational use only. No other uses without permission. All rights reserved.

Biere-Rafi et al. Cardiovascular risk assessment in haemophilia patients

rol/ HDL ratio (15). It estimates the total mortality due to ischemic heart disease and stroke. A score of higher than 10% confers a high risk, necessitating intervention.

Methods Study design Haemophilia patients were recruited from two haemophilia treatment centres (the Academic Medical Center, Amsterdam, and the Erasmus Medical Center, Rotterdam) in the Netherlands. The study had been approved by the local medical ethical committee. All haemophilia A and B patients, 18 years and older, without a history of cardiovascular disease, were asked to participate. Haemophilia patients were selected irrespective of the severity of their disease. Patients were invited to visit their treatment centre or were included during their regular outpatient clinic visit. Control subjects were a representation of the general Dutch population, consisting of healthy individuals who were screened for risk factors by their general practitioner and employees of Dutch companies, who underwent a screening for cardiovascular risk factors. The controls were also not allowed to have a history of cardiovascular disease. These subjects were sex- and age-matched, at a ratio of 2:1 to the patients.

Cardiovascular risk assessment History on cardiovascular risk factors was obtained from the cases during the study visit. A physical examination was performed to measure blood pressure, waist circumference, weight and height. In all subjects, a fasting blood sample was taken, and included glucose, total cholesterol, low-density lipoprotein (LDL)-cholesterol and high-density lipoprotein (HDL)-cholesterol and triglyceride levels. All measurements were performed on one single occasion. Total cholesterol (TC) levels, LDL cholesterol and triglyceride levels were considered to be increased when they exceeded the 95th percentile of the reference values of the concerning age categories. HDL levels were considered to be low when they were below the fifth percentile of the reference values of the concerning age categories. Hyperglycaemia was defined as fasting glucose levels of more than 6.1 mM on one occasion. Hypertension was defined a systolic blood pressure higher than 140 mmHg or a diastolic blood pressure of 90 mmHg or more on three consecutive measurements or if cases reported use of anti-hypertensives. The laboratory measurements were performed separately in certified laboratories of the two participating centres. Obesity was defined as a body mass index (BMI) ≥30 kg/m2. The controls had previously undergone similar procedures for the collection of data. Furthermore, since the risk of cardiovascular disease often results from a combination of risk factors, first the prevalence of one and multiple risk factors was assessed in both groups. To further specify the expected risk associated with these risk factors, the 10-year mortality risk due to cardiovascular disease was calculated with The European risk prediction system, Systemic Coronary Risk Evaluation (SCORE) (16). This risk score results in a percentage as a risk estimate for cardiovascular death and is based on age, sex, smoking habits, systolic blood pressure and either total cholesterol or choleste© Schattauer 2011

Statistical analysis Data was analysed using SPSS Statistical Software version 16.0. Baseline characteristics were summarised in case of normally distributed data by means and standard deviations (SD) and by using medians and ranges in case of skewed distributed data. Student’s t-test was applied for continuous variables and by Chi2-test for discrete variables, after log-transformation when appropriate. The prevalence of risk factors was reported in numbers and percentages.

Results A total of 100 haemophilia patients and 200 healthy age-matched males were included in the study with a mean age of 47 years (range 18–83) (씰Table 1). As expected the majority of the patients (89%) were haemophilia A patients, only 11 patients (11%) suffered from haemophilia B. Twenty-four patients were known with severe haemophilia (factor VIII or IX < 0.01 IE/ml), 12 patients had moderate haemophilia (factor VIII or IX 0.01–0.05 IE/ml) and 64 had mild haemophilia (factor VIII or IX 0.06–0.4 IE/ml). Of the haemophilia patients 86% received on-demand treatment with factor VIII or IX concentrate, whereas 14% were treated with prophylaxis. The prevalence of inhibitors was 3%.The majority of the haemophilia patients (90%) and healthy matched controls (98%) were of Caucasian origin (p=0.08). Of the cases, three patients were Hispanic, four patients were of Mediterranean origin, two patients were of African origin and one was of Asian origin. Among the control subjects, six subjects had a mixed ethnicity.

Prevalence of cardiovascular risk factors The prevalence of hypertension (51% and 37.5%, respectively, p30 kg/m2) 19%

13%

0.20

Median BMI (kg/m2)

26 (16–50)

26 (18–41) 0.26

Low HDL-cholesterol

0%

0%

>0.05

High LDL-cholesterol

1%

6%

0.045

High triglycerides

2%

6%

0.612

High total cholesterol

3%

8.5%

0.72

High glucose levels

24%

7.5%

0.001

-

HIV positive

3%

-

CVD history

None

None

Medication –Diabetes –Antihypertensives –Lipid lowering drugs

6% 25% 8%

1.5% 11.5% 7.5%

0.08 0.006 0.88

When assessing the influence of the severity of haemophilia on the prevalence of risk factors, smoking, hypertension, obesity and hyperglycaemia in combination with use antidiabetic drugs, were equally prevalent in severe and non-severe haemophiliacs (씰Table 3).

Laboratory results Mean and median values TC, HDL cholesterol, LDL cholesterol, triglyceride levels and glucose are shown in 씰Table 3. Overall, mean total cholesterol (4.87 mM and 5.50 mM, respectively, p 30 kg/m )

8.3%

58.3%

20.3%

0.13

High glucose levels or use of diabetes medication

21%

58.3%

26.6%

0.68

SCORE >10%

8.3%

16.7%

12.5%

0.53

*P-value

severe haemophilia vs. non-severe haemophilia.

Table 4: Laboratory

Haemophilia Severe Moderate Mild Controls patients haemophilia haemophilia haemophilia (n=200) (n=100)

P-value*

3.02

2.90

2.64

3.13

3.60

0.001

Mean HDL-cholesterol (mM) 1.28

1.33

1.20

1.28

1.28

0.99

Mean total cholesterol (mM) 4.87

4.72

4.57

4.98

5.50

0.001

Mean triglycerides (mM)

1.29

1.13

1.37

1.34

1.43

0.45

Median glucose (mM)

5.30 (3.50–15.4) 5.73

5.80

5.70

5.06 (3.45–12.5) 0.05

results. Mean LDL-cholesterol (mM)

*P-value total group of haemophilia patients versus controls.

About 20 years ago Rosendaal et al. assessed the prevalence of cardiovascular risk factors in 95 haemophilia patients (15). They also found an increased prevalence of hypertension and lower mean total cholesterol levels among the patients with haemophilia compared to the general population. Foley et al. previously found that both the prevalence of risk factors, as well as the degree of coronary luminal stenosis at autopsy was comparable between haemophiliacs and controls (17). In contrast to Rosendaal et al., severity of haemophilia had no influence on total cholesterol levels in our study. Although in general 43–50% of the haemophilia population is expected to have a severe genotype, in the present study this number was considerably lower (18). This unexpected distribution occurred in spite of a random inclusion of the patients. The observed higher prevalence of hypertension and use of anti-hypertensive medication between haemophilia patients and the controls is most likely the result of the regular visits of the haemophiliacs to the outpatient clinics, where hypertension will be more readily diagnosed and treated than in controls. Far less likely but possible, may be the occurrence of intra-parenchymal haemorrhages in the kidneys of haemophilia patients leading to hypertension (19). Likewise, also diabetes mellitus may have been detected at a lower threshold in the haemophilia patients. Cardiovascular risk factors associated with a Western lifestyle have increased, not only for the general population but also for the haemophilia patients. The fact that over 50% of our haemophilia patients had hypertension and 25% had hyperglycaemia is alarming, the more so since the average age of the patients was only 47 years. These patients will need preventive measures, such as either diet and weight loss or medication. Since cardiovascular disease is © Schattauer 2011

multifactorial, people who develop atherosclerotic cardiovascular disease have several risk factors, which interact to produce their total risk. A single cardiovascular risk factor will have a poor predictive value. Current recommendations on the prevention of coronary heart disease in clinical practice are based on an assessment of the individual's total burden of risk rather than on the level of any particular risk factor. Overall no differences were seen when assessing the cardiovascular risk using the prevalence of multiple concurrent risk factors. We analysed the overall cardiovascular mortality risk with the SCORE algorithm, since it was derived, unlike the Framingham score, from the European population. The SCORE estimation for high-risk region was applied for the Netherlands.

Figure 1: Prevalence of risk factors cardiovascular disease. Thrombosis and Haemostasis 105.2/2011


277

278

Biere-Rafi et al. Cardiovascular risk assessment in haemophilia patients

What is known about this topic? ●

●

Haemophilia patients have a reduced mortality due to cardiovascular disease. This reduced mortality due to cardiovascular disease has been explained by a protective effect of having life-long low coagulation factors.

What does this paper add? ●

The difference in cardiovascular mortality can not be attributed to a difference in cardiovascular risk profile.

The present study has several limitations. Although this risk algorithm has not been validated in the haemophilia population, it will give an estimation of the expected cardiovascular mortality in this group. Ideally, the present population should be followed in time to assess if the risk stratification according to SCORE is reliable in haemophilia patients. Unfortunately, we could not correct for the use of cardiopreventive medication in the SCORE analysis. However, when excluding individuals using this medication from the analysis, the number of haemophilia patients and controls with a high risk remained comparable between the two groups. Furthermore, since the study population was heterogeneous (wide age range, consisting of both haemophilia A and B patients), the results on the risk of cardiovascular disease of the present study don’t necessarily apply to the entire haemophilia population. A more representative study population would perhaps include more elderly patients with both severity and type of haemophilia evenly distributed, allowing subgroup analyses. However, only recently the life-expectancy of haemophilia patients has considerably increased. Nevertheless, our results showed no differences between both study groups and therefore underline that the observed difference in mortality due to cardiovascular disease does not result from a more favourable risk profile. Irrespective of the potential benefit of haemophilia patients for cardiovascular mortality, our results stress the need for an active screening for cardiovascular risk factors. Treatment of acute cardiovascular events is challenging in haemophilia patients (20). Besides, hypertension and hyperglycaemia not only increase the risk for cardiovascular events, but also increase the risk for microvascular disease and cerebral haemorrhage for which haemophilia has no (known) preventive effect. In conclusion, adult haemophilia patients do not have a lower prevalence of cardiovascular risk factors compared to the general population. This strengthens the hypothesis that the beneficial ef-

fect of haemophilia on cardiovascular mortality may be due to hypocoagulability. On the other hand, considering the high prevalence of patients with cardiovascular risk factors, active screening for these risk factors is recommended.

References 1. Lewington S, Clarke R, Qizilbash N, et al. Prospective Studies Collaboration. Agespecific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903–1913. 2. Miura K, Daviglus ML, Dyer AR, et al. Relationship of blood pressure to 25-year mortality due to coronary heart disease, cardiovascular diseases and all causes in young adult men. Arch Intern Med 2001; 161: 1501–1508. 3. Steinberg D, Glass CK, Witztum JL. Evidence mandating earlier and more aggressive treatment of hypercholesterolemia. Circulation 2008; 118: 672–677. 4. Ockene IS, Miller NH; For the American Heart Association Task Force on Risk Reduction. Cigarette Smoking, Cardiovascular Disease, and Stroke. Circulation 1997; 96: 3243–3247. 5. Kannel WB, McGee Dl. Diabetes and cardiovascular risk factors: the Framingham study. Circulation 1979; 59: 8–13. 6. Krauss RM, Winston M, Fletcher BJ, et al. Obesity: impact on cardiovascular disease. Circulation 1998; 98: 1472–1476. 7. Stec JJ, Silbershatz H, Tofler GH, et al. Association of fibrinogen with cardiovascular risk factors and cardiovascular disease in the Framingham Offspring population. Circulation 2000; 102: 1634–1638. 8. Frankel DS, Meigs JB, Massaro JM, et al. Von Willebrand factor, type 2 diabetes mellitus, and risk of cardiovascular disease: the Framingham offspring study. Circulation 2008; 118: 2533–2539. 9. Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001; 21: 731–738. 10. Bank I, Libourel EJ, Middeldorp S, et al. Elevated levels of FVIII:C within families are associated with an increased risk for venous and arterial thrombosis. J Thromb Haemost 2005; 3: 79–84. 11. Rosendaal FR, Varekamp I, Smit C, et al. Mortality and causes of death in Dutch haemophiliacs, 1973–86. Br J Haematol 1989; 71: 71–76. 12. Darby SC, Kan SW, Spooner RJ, et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007; 110: 815–825. 13. Tagliaferri A, Rivolta GF, Iorio A, et al. Mortality and causes of death in Italian persons with haemophilia, 1990–2007. Haemophilia 2010; 16: 437–446. 14. Plug I, van der Bom JG, Peters M, et al. Mortality and causes of death in patients with haemophilia, 1992–2001: a prospective cohort study. J Thromb Haemost 2006; 4: 510–516. 15. Rosendaal FR, Briet E, Stibbe J, et al. Haemophilia protects against ischaemic heart disease: a study of risk factors. Br J Haematol 1990; 75: 525–530. 16. Conroy RM, Pyörälä K, Fitzgerald AP, et al; SCORE project group. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003; 24: 987–1003. 17. Foley CJ, Nichols L, Jeong K, et al. Coronary atherosclerosis and cardiovascular mortality in Hemophilia J Thromb Haemost 2010; 8: 208–2011. 18. Franchini M, Favaloro EJ, Lippi G. Mild hemophilia A. J Thromb Haemost 2010; 8: 421–432. 19. Funston R, Levine E, Stables DP. Spontaneous renal hemorrhage. Urology 1976; 8: 610–617. 20. Coppola A, De Simone C, Di Capua M, et al. Acute coronary syndrome and severe haemophilia: An unusual association with challenging treatment. Thromb Haemost 2010; 103: 1270–1272.

Thrombosis and Haemostasis 105.2/2011


© Schattauer 2011