The ISTH Bleeding Assessment Tool and the risk of future bleeding.

Essentials ISTH Bleeding Assessment Tool (ISTH-BAT) is used to assist the diagnosis of bleeding disorders. We examined whether the ISTH-BAT is capable of predicting the risk of future bleeding. 136 subjects were administered the ISTH-BAT and followed for up to four years. The ISTH-BAT score failed to predict the risk of future bleeding. SUMMARY: Background The ISTH Bleeding Assessment Tool (ISTH-BAT) is a diagnostic tool used in subjects with suspected inherited bleeding disorders. Aim To evaluate whether the ISTH-BAT, applied at first work-up in a tertiary-care center, predicts the risk of subsequent bleeding events. Methods This was an observational cohort study including all consecutive subjects, of either sex and any age, referred between 2011 and 2015 because of a suspected bleeding disorder. The analysis was restricted to those with an ISTH-BAT score of ≥ 3. Incidence rates (IRs) of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) events were calculated as the number of events over accrued person-years. The main analysis was performed with Cox regression analysis, assessing an ISTH-BAT score of ≤ 5 versus a score of > 5, as well as the score as a continuous variable, and various covariates (sex, age, and presence/absence of a final diagnosis). Results One hundred and thirty-six subjects had a median ISTH-BAT score of 4 (range 3-18). Eleven subjects (8.1%) had a bleeding event during follow-up (one MB event; 10 CRNMB events). The overall IR of bleeding events per 100 person-years was 3.7 (95% confidence interval [CI] 1.8-6.6). No difference was observed between subjects with an ISTH-BAT score of ≤ 5 and those with a score of > 5 (hazard ratio [HR] 1.2, 95% CI 0.3-4.6). The results were similar when the ISTH-BAT score was considered as a continuous variable (HR 1.1, 95% CI 0.9-1.4). The IR of bleeding was increased in individuals with a diagnosis of a hemostatic defect (IR of 7.5 per 100 person-years; HR 3.0, 95% CI 0.8-11.8). Conclusions The ISTH-BAT does not identify patients at increased risk of future bleeding events.

Sex difference in the risk of recurrent venous thrombosis: a detailed analysis in four European cohorts.

BACKGROUND: Previous analyses reported a higher risk of recurrent venous thrombosis in men than women. OBJECTIVES: We aimed to assess the risk of recurrence in men compared with women whilst taking female reproductive risk factors (oral contraception, postmenopausal hormone therapy and pregnancy) into account. In addition, we hypothesized that the sex difference in venous thrombosis was related to F9 Malmö, an X-linked prothrombotic factor. METHODS: In four pooled European cohorts (CARROT study, Glasgow, UK; CVTE study, Cambridge, UK; AUREC study, Vienna, Austria; and LETS follow-up study, Leiden, the Netherlands), the risk of recurrent venous thrombosis was calculated in men, women with reproductive risk factors and women without reproductive risk factors at the time of their first venous thrombosis. F9 Malmö was genotyped and carriers and non-carriers contrasted. RESULTS: In total, 2185 patients with a first venous thrombosis, 1043 men and 1142 women, were included. Overall, men had a 2.8-fold (95% confidence interval [CI], 2.2-3.4) higher risk of recurrent venous thrombosis than women. This risk was 5.2-fold (95% CI, 3.5-7.7) higher in men than in women with reproductive risk factors, and 2.3-fold (95% CI, 1.7-3.2) higher in men than in women without reproductive risk factors. No difference in risk of recurrence was found for carriers vs. non-carriers of F9 Malmö. CONCLUSION: Men experienced a recurrent venous thrombosis twice as often as women without reproductive risk factors. These findings indicate that men have a higher intrinsic risk of venous thrombosis than women, which is partly masked by female reproductive risk factors. The sex difference cannot be explained by F9 Malmö.

Clinical outcome of moderate haemophilia compared with severe and mild haemophilia.

UNLABELLED: Information on outcome and treatment of patients with moderate haemophilia is scarce. In this study, we compared self-reported burden of disease in moderate haemophilia to severe and mild haemophilia. A nationwide questionnaire on bleeding pattern, treatment, impairment and quality of life was sent to 1567 Dutch patients with haemophilia. Out of 1066 respondents (response rate: 68%), 16% had moderate, 44% severe and 39% mild haemophilia. Median age was 36 years. Although overall outcome in moderate haemophilia was in between severe and mild haemophilia, moderate haemophilia patients did report a substantial burden of disease. The majority of patients with moderate haemophilia (73%) reported bleeds in the previous year; and a considerable proportion of moderate patients reported joint impairment (43%), chronic pain (15%), needed orthopaedic aids (24%) or were unemployed because of disability (27%). Within the group of moderate haemophilia patients, a large variation in bleeding pattern and outcome was observed. A quarter of patients with moderate haemophilia reported a more severe phenotype and intermittent use of prophylaxis. These patients reported frequent bleeding, with a median of eight bleeds per year, including two joint bleeds, and 68% reported joint impairment. IN CONCLUSION: Although outcome in moderate haemophilia is generally in between severe and mild haemophilia, moderate haemophilia patients reported a substantial burden of disease, and for more than 25% of patients with moderate haemophilia long term prophylaxis was implemented because of frequent bleeds.

[Handling small relative risks in science and management: the third-generation pill]. / Omgaan met kleine relatieve risico's in wetenschap en beleid: de 3e-generatiepil.

Small relative risks (a twofold or lesser increase in disease frequency) become scientifically acceptable with (a) repeated consistent findings from studies that (b) address the most important forms of bias and confounding, and (c) when there is a plausible biologic mechanism. The third-generation oral contraceptive controversy is an example of such a relevant but small relative risk and demonstrates the problem of interpretation and implementation into medical practice guidelines.

Ultrasound assessment of atherosclerotic vessel wall changes: reproducibility of intima-media thickness measurements in carotid and femoral arteries.

RATIONALE AND OBJECTIVES: Ultrasonography is widely used in cardiovascular research to quantify early atherosclerotic vessel wall changes. In this article, we examined the short- and long-term reproducibility of this technique in the common carotid artery, carotid bifurcation, common femoral artery, and superficial femoral artery. Furthermore, we assessed the effect of progressed atherosclerosis on reproducibility. METHODS: Repeated ultrasound examinations were performed by one observer on 15 healthy individuals and 18 patients suffering from coronary heart disease. Intima-media thickness was determined by B-mode ultrasonography. The examinations were repeated by the same observer after a short time interval (short-term) and after a few weeks (long-term) and expressed as the mean difference between the measurements and the coefficient of variation (CV). RESULTS: The reproducibility of the intima-media thickness determination turned out to be best in the common carotid artery and the superficial femoral artery when performed in healthy controls (CV 5.6% and 5.5%, respectively). Reproducibility was less in patients with clinical atherosclerosis; this especially affected the reliability of the superficial femoral artery measurement (CV in healthy controls was 5.5%; in coronary heart disease patients, 17.5 %). The reliability of the intima-media thickness measurements in the common carotid artery (CV in healthy controls was 5.6%; in coronary heart disease patients, 9.5%) proved to be least affected by progressed atherosclerosis. A longer time interval between measurements did not affect the reproducibility of intima-media thickness measurements in healthy controls, whereas in the patients it led to some decrease of reproducibility and to a major decrease in reproducibility of the superficial femoral artery measurements (CV changed from 12.7% to 17.5%). CONCLUSIONS: Ultrasonography is a reliable and accurate technique to determine intima-media thickness in superficial arteries. In studies in which the intima-media thickness determination is used as a marker for generalized and coronary atherosclerosis, the common carotid artery should always be included, whereas the benefit of inclusion of other arteries depends on age and the expected extent of atherosclerosis in the individuals studied.

Assessment and control for confounding by indication in observational studies.

In the evaluation of pharmacologic therapies, the controlled clinical trial is the preferred design. When clinical trial results are not available, the alternative designs are observational epidemiologic studies. A traditional concern about the validity of findings from epidemiologic studies is the possibility of bias from uncontrolled confounding. In studies of pharmacologic therapies, confounding by indication may arise when a drug treatment serves as a marker for a clinical characteristic or medical condition that triggers the use of the treatment and that, at the same time, increases the risk of the outcome under study. Confounding by indication is not conceptually different from confounding by other factors, and the approaches to detect and control for confounding--matching, stratification, restriction, and multivariate adjustment--are the same. Even after adjustment for known risk factors, residual confounding may occur because of measurement error or unmeasured or unknown risk factors. Although residual confounding is difficult to exclude in observational studies, there are limits to what this "unknown" confounding can explain. The degree of confounding depends on the prevalence of the putative confounding factor, the level of its association with the disease, and the level of its association with the exposure. For example, a confounding factor with a prevalence of 20% would have to increase the relative odds of both outcome and exposure by factors of 4 to 5 before the relative risk of 1.57 would be reduced to 1.00. Observational studies have provided important scientific evidence about the risks associated with several risk factors, including drug therapies, and they are often the only option for assessing safety. Understanding the methods to detect and control for confounding makes it possible to assess the plausibility of claims that confounding is an alternative explanation for the findings of particular studies.

Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants.

In two cohorts of patients on oral anticoagulant therapy, routinely treated by the Leiden Thrombosis Service, the frequency of major bleeding complications was assessed during two years (1988 and 1991). With Poisson regression analysis the influence of the risk factors age, sex, target zone, achieved INR and type of coumarin derivative used were determined. Subsequently, a bleeding risk index was calculated, combining the results of the two cohorts. For various types of patients the relative risk of major bleeding complications was assessed. Age and achieved INR were the most important and consistent risk factors: rate ratio (RR) for age in 1988 1.46 per 10 years increase (95% confidence interval [CI] 1.20-1.78) and in 1991 1.57 per 10 years increase (95% CI 1.23-2.00); RR per unit increase in achieved INR in 1988 1.42 (95% CI 1.21-1.68) and in 1991 1.44 per unit increase in achieved INR (95% CI 1.18-1.74). Two methods were used to combine the results of 1988 and 1991. In the first method the mean bleeding risk index was calculated: In (incidence) [natural logarithm of the incidence rate of major bleeding] = -5.64+ 0.42 * age +0.26 * sex -0.29 * target range +0.36 * achieved INR -0.36 * coumarin type. In the second method only the consistent risk factors age and achieved INR were used: In (incidence) = -5.64 -0.42 * age +0.36 * achieved INR. These bleeding risk indexes can be used to assess the risk of major bleeding complications of individual patients and allow more individualized care by individual tailoring the desired anticoagulation.

Assessment of therapeutic quality control in a long-term anticoagulant trial in post-myocardial infarction patients.

Various methods have been described to evaluate efficacy of anticoagulant therapy using the international normalized ratio (INR). We compared the following approaches: (1) total INR's or the most recent measurement; (2) percent time within therapeutic range, with INR changing directly or halfway between visits; and (3) total observation time assuming INR changing linearly. The study population comprised 1700 post myocardial infarction patients. Treatment comprised 3725 patient-years. There were 61,471 INR assessments with target therapeutic level of 2.8-4.8. Acenocoumarol as well as phenprocoumon were employed. Therapeutic achievement in the first months of treatment was low: less than 60% of INR's were in range. Treatment stabilized after 6 months. Patients on acenocoumarol were within range 70% of the time compared to 80% for phenprocoumon. Method 3 is preferred because it incorporates time and is capable of calculating incidence rates at different INR levels. Our findings call for an urgent improvement of standard of anticoagulant control in the first months following commencement of treatment.

A randomized and blinded comparison of three bleeding time techniques: the Ivy method, and the Simplate II method in two directions.

We compared the Ivy bleeding time method and two alternatives of the Simplate II method (incisions in horizontal and vertical direction) with each other, with regard to the sensitivity, the specificity, the costs and the burden for the patient. In the aspirin study an aspirin-induced bleeding defect was used. Seventy-two healthy volunteers were randomized to receive either 500 mg acetylsalicylic acid (ASA) or a placebo. Double blinding was maintained throughout the study. In the anticoagulation study 62 patients participated, who received oral anticoagulants (OAC) for various reasons. All participants received two bleeding time methods. The burden for the participants of each method was screened by a small standard questionnaire. The differences in sensitivity and specificity between the three methods proved minimal. The Ivy method was more often preferred by the participants than the Simplate methods. Since a choice on the basis of sensitivity and specificity appears not possible, we prefer the Ivy method because of lower costs and less burden.

Physical condition, longevity, and social performance of Dutch haemophiliacs, 1972-85.

A study was carried out among haemophiliacs in The Netherlands to evaluate the effect of modern substitution treatment (replacing the missing clotting factors) on medical and social performance. Three questionnaires were sent between 1972 and 1985. The use of prophylactic treatment in the group of patients with severe and moderately severe haemophilia increased from 21% (n = 242) in 1972 to 36% (n = 559) in 1985. Home treatment programmes increased from 4% to 53%. Overall mortality was 2.1 times higher than in the general male population, which leads to a calculated life expectancy of 66 years compared with 74 years in the general male population. Severe joint impairment was prominent in the older age groups, reflecting insufficient treatment in the past. A sharp decrease in the use of inpatient and outpatient hospital facilities was observed as well as much less absence from school and work. It is concluded that the high costs of modern substitution treatment are fully justified.