D.E. Grobbee

Prophylactic versus on‐demand treatment strategies for severe haemophilia: a comparison of costs and long‐term outcome

Summary.u2002 A multicentre study was performed to compare clotting factor use and outcome between on‐demand and prophylactic treatment strategies for patients with severe haemophilia. Data on treatment and outcome of 49 Dutch patients with severe haemophilia, born 1970–80, primarily treated with prophylaxis, were compared with those of 106 French patients, who were primarily treated on demand. Dutch patients received intermediate dose prophylaxis, for a median duration of 12.7u2003years. Patients primarily treated with prophylaxis had fewer joint bleeds per year (median 2.8 vs. 11.5), a higher proportion of patients without joint bleeds (29% vs. 9%), lower clinical scores (median 2.0 vs. 8.0), and less arthropathy as measured by the Pettersson score (median 7 points vs. 16 points). Mean annual clotting factor use was equal at 1488u2003±u2003783u2003IUu2003kg−1u2003year−1 (meanu2003±u2003standard deviation) for patients primarily treated with prophylaxis and 1612u2003±u20031442u2003IUu2003kg−1u2003year−1 for patients primarily treated on demand. These findings suggest that, compared with a primarily on‐demand treatment strategy, a primarily prophylactic treatment strategy leads to better outcome at equal treatment costs in young adults with severe haemophilia.

Prophylactic treatment for severe haemophilia: comparison of an intermediate‐dose to a high‐dose regimen

Summary.u2002 A multicentre study was performed in Sweden and the Netherlands, comparing effects of two prophylactic regimens in 128 patients with severe haemophilia, born 1970–90. 42 Swedish patients (high‐dose prophylaxis), were compared with 86 Dutch patients (intermediate‐dose prophylaxis). Patients were evaluated at the date of their last radiological score according to Pettersson. Annual clotting factor consumption and bleeding frequency were registered for a period of three years before evaluation. Patients in the high‐dose group were younger at evaluation (median 15.2 vs. 17.9u2003years), started prophylaxis earlier (median 2 vs. 5u2003years), and used 2.19 times more clotting factoru2003kg−1u2003year−1. Patients treated with high‐dose prophylaxis had fewer joint bleeds (median 0.3u2003year−1 vs. 3.3u2003year−1) and the proportion of patients without arthropathy as measured by the Pettersson score was higher (69% vs. 32%), however, the age‐adjusted difference in scores (median 0 points vs. 4 points) was small and at present not statistically significant. Clinical scores and quality of life were similar. These findings suggest that, compared with intermediate‐dose prophylaxis, high‐dose prophylaxis significantly increases treatment costs and reduces joint bleeds over a period of 3u2003years, but only slightly reduces arthropathy after 17u2003years of follow‐up.

Reduced response to activated protein C is associated with increased risk for cerebrovascular disease

Resistance to activated protein C (APC) is a recently described coagulation abnormality [1] that is associated with increased risk for venous thromboembolism [2, 3]. The balance of procoagulant and anticoagulant factors undoubtedly plays a critical role in determining the risk for coronary [4, 5] and cerebral thromboembolism [6, 7]. Therefore, some studies [8, 9] have suggested that resistance to APC may also be associated with increased risk for arterial disease. Other studies [10-13], however, have not found evidence to support this conclusion. An extremely low response to APC is often caused by the single-base, Arg 506 to Gln mutation of the factor V gene [14, 15]. This mutation affects the site of cleavage of activated factor V by APC, rendering it relatively resistant to inactivation; the resistance, in turn, leads to increased thrombotic tendency. Accordingly, a functional test for response to APC is used to screen for the factor V mutation. Patients with values below an arbitrarily chosen point are considered potential carriers of the mutation. However, a low response to APC can be caused by other factors; not all patients with low values are carriers of the factor V mutation [16]. We studied whether response to APC is associated with arterial disease by comparing levels of response to APC and prevalence of the factor V Leiden mutation in patients with and without a history of stroke, transient ischemic attack, or myocardial infarction. We also examined other determinants of the level of response to APC. Methods Population We did a casecontrol study of participants in the Rotterdam Study, which is a prospective study of 7983 men and women 55 years of age and older. The rationale and design of the Rotterdam Study have been described elsewhere [17]. Between March 1990 and July 1993, all men and women 55 years of age and older living in Ommoord, a district of Rotterdam, the Netherlands, were invited to participate (n = 10 275). The overall response rate was 78%. The study was approved by the ethics committee of Erasmus University, and written informed consent was obtained from all participants. Selection Patients with a history of myocardial infarction (n = 115) were selected if they had an infarction shown by electrocardiography. Selection was made using the diagnostic classification system of the Modular Electrocardiogram Analysis System (MEANS) [18, 19], independent of a history of chest pain. Patients with a definite or probable history of transient ischemic attack (n = 55) were selected if they had a positive medical history of transient ischemic attack. Four screening questions were asked about temporary visual, locomotor, sensory, or speech disturbances; when responses were affirmative, a detailed history of symptoms was obtained. Symptoms were classified by a neurologist as indicating that the patient had definitely, had probably, or had not had a transient ischemic attack, using methods described elsewhere [20]. Patients with a history of stroke (n = 62) were selected by the question, Did you ever suffer from stroke, diagnosed by a physician? Five patients had a history of both transient ischemic attack and stroke. Therefore, 112 patients were classified as having cerebrovascular disease, which was defined as a stroke, a transient ischemic attack, or both. Controls (n = 222) were selected from among those persons with a normal electrocardiogram, an ankle-to-arm systolic pressure ratio greater than 0.9 (the ankle-to-arm systolic pressure ratio is the ratio of the systolic blood pressure at the posterior tibial artery to the systolic blood pressure at the arm), and no arterial disease (that is, no history of myocardial infarction, stroke, or transient ischemic attack) [21]. Controls were matched in 5-year age strata to persons who had had myocardial infarction. Patients using anticoagulant drugs were excluded. Measurements Information on current health status, medical history, drug use, and smoking was obtained by using a questionnaire. We measured height and weight and calculated body mass index. We measured blood pressure at the right upper arm while patients were seated by using a random-zero sphygmomanometer, and we used the average of two measurements obtained on one occasion. The electrocardiogram was coded using the MEANS computerized coding system [18, 19]. The methods we used for blood sampling and storage have been described elsewhere [22]. Blood was collected in tubes containing 0.129 mol/L sodium citrate. Platelet-poor plasma was obtained by two-stage centrifugation: Samples were centrifuged at 1600 g and 4 C for 10 minutes; after the plasma midlayer was carefully transferred, a second centrifugation was done at 10 000 g and 4 C for 10 minutes. Plasma was immediately frozen in liquid nitrogen and stored at 80C for a mean of 2 years. Plasma from 30 healthy volunteers was centrifuged for 30 minutes at 2000 g and 4 C and was pooled to serve as reference plasma for the test of response to APC. The response to APC for the reference plasma was 3.27. The response of the plasma-activated partial thromboplastin time to APC was determined using the Coatest APC resistance test of Chromogenix (kit 0548-51, Molndal, Sweden) and is expressed as the ratio of the activated partial thromboplastin time with the addition of APC to the activated partial thromboplastin time without the addition of APC. Serum total and high-density lipoprotein (HDL) cholesterol levels were measured with an automated enzymatic procedure. Whole blood that was collected and stored at baseline was thawed for DNA extraction. Genotype assay using polymerase chain reaction was done by laboratory personnel who were blinded to case or control status. The Arg 506 to Gln mutation was detected by amplification of a 220-base pair fragment of exon 10-intron 10 of the factor V gene, followed by digestion with the restriction enzyme Mnl I. The primers and conditions that we used have been described elsewhere [14, 23]. Statistical Analysis We calculated means and proportions for potential determinants for five categories of response to APC and adjusted for a history of myocardial infarction or cerebrovascular disease (two dummy variables in the regression model) using linear regression analysis. Logistic regression was used to assess the association of response to APC and the factor V Leiden mutation with cerebrovascular disease and myocardial infarction. Odds ratios with corresponding 95% CIs estimated from the logistic model were used as the measure of association. With myocardial infarction or cerebrovascular disease as the outcome variable, we compared levels of response to APC and genotypes of the factor V mutation adjusted for age and sex. By adding current smoking, total cholesterol level, and activated partial thromboplastin time as covariates in the logistic regression model, we evaluated whether these potentially confounding factors affected the estimates of the odds ratios. In addition, logistic regression was used to explore the association of disease status with response to APC as a continuous variable. Information on factor V mutation was missing for five participants for whom no blood cells were available. In the regression models with factor V as a confounder, the indicator method for missing data was used [24]. The results were similar to analyses done without these participants. Results Response to Activated Protein C The response to APC ranged from 1.5 to 9.5. Mean responses (SD) were 4.3 1.1 among controls, 3.9 1.0 among patients with a history of cerebrovascular disease, and 4.3 1.1 among patients with a history of myocardial infarction. Mean response to APC was 2.5 0.6 in participants with the factor V mutation and 4.3 1.0 in those without the mutation. The response to APC was higher in men (n = 202; response, 4.5 [CI, 4.4 to 4.7]) than in women (n = 247; response, 3.9 [CI, 3.8 to 4.1]). Several cardiovascular risk factors were compared across five levels of response for men and women (Table 1). In men, response to APC decreased with increasing age by 0.18 (CI, 0.01 to 0.35) per decade. In women, a trend of 0.08 (CI, 0.06 to 0.23) per decade was seen toward an increase in response to APC with advancing age. Men who smoked had a mean response that was 0.47 (CI, 0.16 to 0.78) higher than that of men who did not smoke. Response to APC of women who smoked did not differ from that of women who did not. Increased cholesterol levels were associated with a decreased response to APC in men but not in women. In men, an increase in cholesterol level of 1 mmol/L was associated with a decrease in response to APC of 0.14 (CI, 0.01 to 0.27). Table 1. Cardiovascular Risk Factors in Response to Activated Protein C* The odds ratio of cerebrovascular disease (stroke and transient ischemic attack) increased gradually with decreasing response to APC (odds ratio per 1-unit decrease, 1.43 [CI, 1.12 to 1.81]) after adjustment for age and sex. Separate analyses for stroke (odds ratio, 1.32 [CI, 0.99 to 1.77]) and transient ischemic attack (odds ratio, 1.56 [CI, 1.14 to 2.14]) showed no material difference in their relation to decreasing response to APC. The odds ratios for cerebrovascular disease according to varying levels of response to APC are presented in Table 2. Adjustment for presence of the factor V mutant allele did not substantially change the results; the adjusted odds ratio of cerebrovascular disease for each 1-unit decrease in response to APC was 1.43 (CI, 1.12 to 1.81). Table 2. Prevalence of Cerebrovascular Disease and Myocardial Infarction by Levels of Response to Activated Protein C* Response to APC was not associated with myocardial infarction; the odds ratio for response to APC as a continuous variable was 1.10 (CI, 0.89 to 1.37) (Table 2). Factor V Mutation Heterozygosity for the factor V mutation was present in 5% of controls (11 of 222), 6% of patients with cerebrovascular disease (6 of 107), and 4% of patients with myocar

Tissue plasminogen activator and risk of myocardial infarction : The Rotterdam study

BACKGROUNDnImpaired fibrinolytic capacity, as assessed by euglobulin clot lysis time or plasma concentration of fibrinolytic parameters, has been associated with an increased risk of myocardial infarction (MI). We studied the association of a polymorphism in the gene for TPA and of plasma concentrations of TPA (antigen and activity) with the prevalence of MI.nnnMETHODS AND RESULTSnA case-control study was performed. Subjects with a history of MI (n = 121) and controls (n = 250) were drawn from the Rotterdam Study, a population-based cohort study of 7983 subjects > or = 55 years old. We determined TPA antigen and activity in plasma and genotyped all subjects for the Alu repeat insertion/deletion polymorphism in intron h in the TPA gene. Homozygosity for the insertion was associated with twice as many cases of MI as was homozygosity for the deletion (odds ratio, 2.24; 95% CI, 1.11-4.50). TPA antigen was positively associated with the risk of MI; compared with that in the lowest quartile, the relative risks (odds ratio) in the second, third, and upper quartiles were 1.7 (CI, 0.9-3.3), 2.3 (1.2-4.4), and 2.0 (1.0-3.8), respectively. When adjusted for body mass index, HDL and total cholesterol, systolic and diastolic blood pressures, and current smoking, the risk associated with TPA antigen concentration was attenuated. Increased concentrations of TPA activity tended to be associated with an increased risk of MI.nnnCONCLUSIONSnThis study provides evidence for an independent association of the insertion allele of the insertion/deletion polymorphism in the TPA gene with nonfatal MI. Increased TPA antigen is associated with an increased risk of MI; however, this association was not independent of cardiovascular disease risk factors.

Changes in treatment strategies for severe haemophilia over the last 3 decades: effects on clotting factor consumption and arthropathy

A cohort study was performed among 214 patients with severe haemophilia, born 1944–1994, to describe changes in treatment over the last 3u2003decades and its effects on clotting factor consumption and haemophilic arthropathy. Data on treatment strategy, clotting factor consumption, and outcome were collected for 3567 patient years (from 1972 to 1998), and 493 Pettersson scores were analysed. Median follow up was 17u2003years (range 6–27u2003years), and median age in 1998 was 27.6u2003years. Since 1965, replacement therapy, prophylaxis, and home treatment have been used and treatment intensified. Over the last 3u2003decades, annual clotting factor consumption increased by 260%, for both prophylactic and on‐demand treatment. Annual clotting factor consumptionu2003kg–1 increased during childhood and appeared to stabilize in early adulthood for patients born 1965–79, who were treated with early replacement therapy or early prophylaxis. In contrast, clotting factor consumption increased continuously for patients born before 1965, who had had no access to replacement therapy during the early years of their life. The annual number of joint bleeds decreased over the years. Arthropathy as measured by the Pettersson score generally became apparent around the age of 15u2003years and was lowest in patients treated with primary prophylaxis. In conclusion, clotting factor consumption has increased and haemophilic arthropathy has decreased due to the intensification of treatment for severe haemophilia over the last 3u2003decades. Annual clotting factor consumption stabilizes in adulthood for patients who receive early intensive treatment.

Variability in clinical phenotype of severe haemophilia: the role of the first joint bleed

Summary.u2002 To quantify variation in clinical phenotype of severe haemophilia we performed a single centre cohort study among 171 severe haemophilia patients. Age at first joint bleed, treatment requirement (i.e. annual clotting factor use), annual bleeding frequency and arthropathy were documented. Because treatment strategies intensified during follow‐up, patients were stratified in two age groups: patients born 1968–1985 (nu2003=u200391), or 1985–2002 (nu2003=u200380). A total of 2166 patient‐years of follow‐up were available (median 12.0u2003years per patient). Age at first joint bleed ranged from 0.2 to 5.8u2003years. Patients who had their first joint bleed later needed less treatment and developed less arthropathy. In patients born 1968–1985 during both on‐demand and prophylactic treatment, the 75th percentile of annual joint bleed frequency was consistently four times as high as the 25th percentile. In both age groups variation in annual clotting factor use between 25th and 75th percentiles was 1.4–1.5 times for prophylaxis and 3.8 times for on‐demand treatment. To conclude, the onset of joint bleeding is inversely related with treatment requirement and arthropathy and may serve as an indicator of clinical phenotype. Thus, providing a starting point for aetiological research and individualization of treatment.

Clinical severity of haemophilia A: does the classification of the 1950s still stand?

Summary.u2002 The classification of haemophilia originates from 1950s and has been adopted unchallengedly by the ISTH in 2001. The aim of this study was: does the current classification compare onset of bleeding and age at first treatment, as well as annual joint bleeding frequency according to baseline FVIII activity? Data on age and reason of diagnosis, onset of treatment, onset of bleeding and bleeding frequency from 411 patients with haemophilia A born after 1970 were collected. Data were analysed according to base‐line FVIII activity levels. Age at diagnosis, onset of bleeding and start of treatment according to FVIII activity were compared with the current classification. Overall, the distinction between severe and non‐severe haemophilia was clear. The distinction between mild and moderate haemophilia was more difficult, mostly due to the wide variability in the group of patients with moderate haemophilia. Patients with severe haemophilia experienced their milestones like diagnosis, first treatment and joint bleed earliest, mostly as infants aged 0–3u2003years, whereas patients with moderate haemophilia reached these milestones around toddler age, 2–7u2003years, and patients with mild haemophilia reached them when they were in elementary school, around the ages of 5–14u2003years. This study confirms the clinical distinction between severe and non‐severe haemophilia A. However, the group of moderate haemophilia patients showed a wide variability, warranting close follow‐up and individualized treatment.

Discontinuation of prophylactic therapy in severe haemophilia: incidence and effects on outcome.

A cohort study was performed to assess adherence to early prophylactic therapy and its effects on outcome in 49 patients with severe haemophilia born 1970–1980. Median age at start of prophylaxis was 5.5u2003years. The majority (69%) of patients interrupted prophylactic treatment one or more times of their own accord (median total interruption 2.2u2003years). Patients who discontinued prophylaxis at any point tended to have more arthropathy as measured by the Pettersson scale (median 8 points versus 4 points). One‐third of these patients interrupted prophylaxis for longer periods and had permanently stopped taking prophylaxis at a mean age of 20.1u2003years (meanu2003±u2003SD duration 4.1u2003±u20034u2003years) and consequently experienced 5.4u2003±u20033.4) joint bleeds per year. This subgroup could be identified by a predictive score based on age at start of prophylaxis, weekly dose of prophylaxis, and joint bleed frequency on prophylaxis. In conclusion, while on prophylaxis, more than two‐thirds of patients with severe haemophilia try to discontinue treatment, resulting in slightly more arthropathy. One‐third of these patients permanently discontinue prophylaxis in adulthood, while maintaining a low number of joint bleeds.

Elevated Plasma Fibrinogen Cause or Consequence of Cardiovascular Disease

An association between increased plasma fibrinogen and an increased risk for myocardial infarction (MI) is well established, but the nature of this association is subject to debate. Our aim was to shed light on the potentially causal nature of this association. We examined whether increased plasma fibrinogen, due to a condition that is independent of cardiovascular events, also increases the risk for MI. A case-control study was performed in 139 subjects with a history of MI and 287 control subjects selected from the Rotterdam Study, a population-based cohort of 7983 subjects aged 55 years and older. The genotype of the -455G/A polymorphism in the fibrinogen beta-gene was determined by polymerase chain reaction. Functional plasma fibrinogen levels were determined according to von Clauss. The plasma level of fibrinogen was significantly higher in subjects with one or two A alleles compared with subjects with the GG genotype: 3.8 (95% confidence interval [CI], 3.6 to 3.9) g/L and 3.6 (3.5 to 3.7) g/L, respectively. With increasing plasma fibrinogen level, the risk for MI increased gradually; a rise in fibrinogen of 1 g/L was associated with a 45% increased risk (odds ratio adjusted for age, sex, and smoking, 1.45; 95% CI, 1.12 to 1.88). There was no association between the genotype of the -455G/A polymorphism and the risk for MI. The -455G/A polymorphism is therefore associated with increased plasma fibrinogen levels but not with an increased risk for MI. These findings indicate that an increased plasma fibrinogen level due to this genetic factor does not increase the risk for MI.

Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels.

Summary.u2002 Many studies in the field of haemophilia and other coagulation deficiencies require analyses of bleeding frequencies. In haemophilia, the association of bleeding frequency with factor VIII (FVIII) activity levels is known from experience, but significant results are lacking. Bleeding frequencies in haemophilia are highly skewed count data, with large proportions of zeros. Both the skewness and the high amount of zeros pose a problem for standard (linear) modelling techniques. This study investigated the optimal analysing strategy for bleeding data by using the association of residual clotting factor level and number of joint bleeds in moderate and mild patients treated on demand as example. In total, 433 patients with moderate (27%) and mild (73%) haemophilia A treated on demand were included in this study. One year of self‐reported data on joint bleed frequency and baseline clotting factor activity were analysed using Poisson, negative binomial, zero‐inflated Poisson, and zero‐inflated negative binomial distributions. Multivariate regression analysis using negative binomial distribution provided the optimum data analytical strategy. This model showed 18% reduction [Rate ratio (RR) 0.82; 95%confidence interval (CI) 0.77–0.86] of bleeding frequency with every IU dL‐1 increase in residual FVIII activity. The actual association is expected to be higher because of exclusion (30 out of 463 patients) of patients on prophylaxis (baseline FVIII levels 0.01–0.06u2003IU mL−1). The best way to analyse low frequency bleeding data is using a negative binomial distribution.