R. E. G. Schutgens

How I treat age-related morbidities in elderly persons with hemophilia

In persons with hemophilia, life expectancy is now approaching that of the general male population, at least in countries that can afford regular replacement therapy with coagulation factor concentrates. The new challenges for comprehensive treatment centers are thus to provide optimal health care for this aging population of patients, who often present not only with the comorbidities typically associated with hemophilia (arthropathy, chronic pain, blood-borne infections), but also with common age-related illnesses such as cardiovascular disease and cancer. There are no evidence-based guidelines for the management of these conditions, which often require drugs that interfere with hemostasis, enhance the bleeding tendency, and warrant more intensive replacement therapy. At the moment, elderly patients with hemophilia affected by other diseases should be managed like their age-group peers without hemophilia, provided replacement therapy is tailored to the heightened risk of bleeding associated with the need for invasive procedures and drugs that further compromise the deranged hemostasis. More detailed advice is provided on the schedules of replacement therapy needed to tackle cardiovascular diseases, such as acute coronary syndromes and nonvalvular atrial fibrillation, because these conditions will become more and more frequent challenges for the comprehensive treatment centers.

Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level

Summary.  Background: Low NT‐proBNP levels are associated with an uncomplicated course in patients with pulmonary embolism (PE). The aim of this multicenter management study was to investigate the safety of home treatment of patients with PE with low (< 500 pg mL−1) NT‐proBNP. Methods and results: Hemodynamically stable outpatients with acute PE and NT‐proBNP level < 500 pg mL−1 were included. Patients were discharged immediately from the emergency room or within a maximum of 24 h after admission. The primary study objective was the absence of mortality during the first 10 days of treatment. Secondary objectives were the incidence of re‐admission due to PE or its treatment and the patient’s satisfaction during the first 10 days of treatment as well as the incidence of serious adverse events during the 3‐month follow‐up period. Of 351 patients, 152 (43%) fulfilled the inclusion criteria and were treated as outpatients. No deaths, major bleedings or recurrent venous thromboembolism occurred in the first 10 days of treatment or in the follow‐up period of 3 months in these patients. Seven patients required readmission in the first 10 days: three because of complaints that could be related to PE and four due to an illness unrelated to PE. The HADS‐A anxiety score did not change significantly between day 0 and day 10. The PSQ‐18 showed a high score for satisfaction with home treatment. Conclusion: Out of hospital treatment is safe in hemodynamically stable patients with PE with low (< 500 pg mL−1) NT‐proBNP levels. Approximately 45% of patients with PE can be treated in an outpatient setting. Patients do not consider out of hospital treatment as inconvenient and have no increase in anxiety scores. Clinical Trial Registration Information: http://clinicaltrials.gov/ct2/show/NCT00455819.

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

Summary.  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 0–3 years, whereas patients with moderate haemophilia reached these milestones around toddler age, 2–7 years, and patients with mild haemophilia reached them when they were in elementary school, around the ages of 5–14 years. 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.

Cardiovascular disease in patients with hemophilia

Summary.  Mortality due to ischemic heart disease in hemophilia patients is lower as compared to the general male population. Differences in the prevalence of cardiovascular risk factors cannot explain this finding. The hypocoagulable state of hemophilia patients might have a protective effect on thrombus formation, which precipitates infarction. It remains unclear whether the deficiency of coagulation factor VIII or IX exerts a protective effect on the development of atherosclerosis. Despite the relative protection against cardiovascular events, the incidence of ischemic cardiovascular disease in hemophilia patients is increasing, because life expectancy of these patients now approaches that of the general population. This review focuses on what is currently known about cardiovascular risk factors, atherosclerosis, arterial thrombosis and ischemic cardiovascular disease in hemophilia patients.

Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis

Objective To assess the accuracy of the Wells rule for excluding deep vein thrombosis and whether this accuracy applies to different subgroups of patients. Design Meta-analysis of individual patient data. Data sources Authors of 13 studies (n=10 002) provided their datasets, and these individual patient data were merged into one dataset. Eligibility criteria Studies were eligible if they enrolled consecutive outpatients with suspected deep vein thrombosis, scored all variables of the Wells rule, and performed an appropriate reference standard. Main outcome measures Multilevel logistic regression models, including an interaction term for each subgroup, were used to estimate differences in predicted probabilities of deep vein thrombosis by the Wells rule. In addition, D-dimer testing was added to assess differences in the ability to exclude deep vein thrombosis using an unlikely score on the Wells rule combined with a negative D-dimer test result. Results Overall, increasing scores on the Wells rule were associated with an increasing probability of having deep vein thrombosis. Estimated probabilities were almost twofold higher in patients with cancer, in patients with suspected recurrent events, and (to a lesser extent) in males. An unlikely score on the Wells rule (≤1) combined with a negative D-dimer test result was associated with an extremely low probability of deep vein thrombosis (1.2%, 95% confidence interval 0.7% to 1.8%). This combination occurred in 29% (95% confidence interval 20% to 40%) of patients. These findings were consistent in subgroups defined by type of D-dimer assay (quantitative or qualitative), sex, and care setting (primary or hospital care). For patients with cancer, the combination of an unlikely score on the Wells rule and a negative D-dimer test result occurred in only 9% of patients and was associated with a 2.2% probability of deep vein thrombosis being present. In patients with suspected recurrent events, only the modified Wells rule (adding one point for the previous event) is safe. Conclusion Combined with a negative D-dimer test result (both quantitative and qualitative), deep vein thrombosis can be excluded in patients with an unlikely score on the Wells rule. This finding is true for both sexes, as well as for patients presenting in primary and hospital care. In patients with cancer, the combination is neither safe nor efficient. For patients with suspected recurrent disease, one extra point should be added to the rule to enable a safe exclusion.

Co-morbidity in the ageing haemophilia patient: the down side of increased life expectancy

Summary.  Because of an increased life expectancy, (age‐related) co‐morbidity is becoming a common occurrence in haemophilia patients. In this review, haemophilia‐related and non‐haemophilia‐related medical problems, treatment recommendations and psychosocial consequences in ageing haemophilia patients are discussed. Haemophilic arthropathy is an important cause of pain and disability, and a frequent indication for surgery in haemophilia patients. In addition, many adult patients are infected with hepatitis C or HIV, the consequences and treatment of which can add to physical and mental discomfort. Moreover, inhibitors against factor VIII can also develop in adulthood, especially in patients with mild haemophilia. Hypertension is reported to occur more often in haemophilia patients than in the general population. Other internal problems, like renal abnormalities, overweight, diabetes mellitus and hypercholesterolemia are discussed. Haemophilia seems to protect against cardiovascular disease, although the incidence is increasing. Recommendations are given on dealing with tooth extractions, surgical interventions and sexuality problems in patients with haemophilia. In addition to haemophilia in itself, co‐morbidity has a major psychological impact, and an important effect on quality of life. It can also result in complex treatment regimens, in which coordination between health care workers is essential.

Effect of Repetitive Intra-Arterial Infusion of Bone Marrow Mononuclear Cells in Patients With No-Option Limb Ischemia The Randomized, Double-Blind, Placebo-Controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) Trial

Background —Patients with severe limb ischemia may not be eligible for conventional therapeutic interventions. Pioneering clinical trials suggest that bone marrow (BM)-derived cell therapy enhances neovascularization, improves tissue perfusion, and prevents amputation. The objective of this trial was to determine whether repetitive intra-arterial infusion of BM mononuclear cells (BMMNC) in patients with severe, non-revascularizable limb ischemia can prevent major amputation. Methods and Results —The Juventas-trial is a randomized, double-blind, placebo-controlled clinical trial in 160 patients with severe, non-revascularizable limb ischemia. Patients were randomized to repetitive (3x; 3-weeks interval) intra-arterial infusion of BMMNC or placebo. No significant differences were observed for the primary outcome, i.e. major amputation at 6 months, with major amputation rates of 19% in the BMMNC vs. 13% in the placebo group (Relative risk [RR] 1.46; 95% confidence interval [CI] 0.62 to 3.42). The safety outcome (all-cause mortality, occurrence of malignancy or hospitalization due to infection) was not significantly different between the groups (RR 1.46; 95%CI 0.63 to 3.38), neither was all-cause mortality at six months with 5% vs. 6% (RR 0.78; 95%CI 0.22 to 2.80). Secondary outcomes quality of life, rest pain, ankle-brachial index, and transcutaneous oxygen pressure improved during follow-up, but there were no significant differences between the groups. Conclusions —Repetitive intra-arterial infusion of autologous BMMNC into the common femoral artery did not reduce major amputation rate in patients with severe, non-revascularizable limb ischemia compared to placebo. The general improvement in secondary outcomes during follow-up in both the BMMNC as well as the placebo group underlines the essential role for placebo-controlled design of future trials. Clinical Trial Registration Information —ClinicalTrials.gov. Identifier: [NCT00371371][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00371371&atom=%2Fcirculationaha%2Fearly%2F2015%2F01%2F07%2FCIRCULATIONAHA.114.012913.atomBackground— Patients with severe limb ischemia may not be eligible for conventional therapeutic interventions. Pioneering clinical trials suggest that bone marrow–derived cell therapy enhances neovascularization, improves tissue perfusion, and prevents amputation. The objective of this trial was to determine whether repetitive intra-arterial infusion of bone marrow mononuclear cells (BMMNCs) in patients with severe, nonrevascularizable limb ischemia can prevent major amputation. Methods and Results— The Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial is a randomized, double-blind, placebo-controlled clinical trial in 160 patients with severe, nonrevascularizable limb ischemia. Patients were randomly assigned to repetitive (3 times; 3-week interval) intra-arterial infusion of BMMNC or placebo. No significant differences were observed for the primary outcome, ie, major amputation at 6 months, with major amputation rates of 19% in the BMMNC versus 13% in the placebo group (relative risk, 1.46; 95% confidence interval, 0.62–3.42). The safety outcome (all-cause mortality, occurrence of malignancy, or hospitalization due to infection) was not significantly different between the groups (relative risk, 1.46; 95% confidence interval, 0.63–3.38), neither was all-cause mortality at 6 months with 5% versus 6% (relative risk, 0.78; 95% confidence interval, 0.22–2.80). Secondary outcomes quality of life, rest pain, ankle-brachial index, and transcutaneous oxygen pressure improved during follow-up, but there were no significant differences between the groups. Conclusions— Repetitive intra-arterial infusion of autologous BMMNCs into the common femoral artery did not reduce major amputation rates in patients with severe, nonrevascularizable limb ischemia in comparison with placebo. The general improvement in secondary outcomes during follow-up in both the BMMNC and the placebo group, as well, underlines the essential role for placebo-controlled design of future trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00371371.

Using an age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded.

Background D-dimer testing to rule out deep vein thrombosis is less useful in older patients because of a lower specificity. An age-adjusted D-dimer cut-off value increased the proportion of older patients (>50 years) in whom pulmonary embolism could be excluded. We retrospectively validated the efficacy of this cut-off combined with clinical probability for the exclusion of deep vein thrombosis. Design and Methods Five management study cohorts of 2818 consecutive outpatients with suspected deep vein thrombosis were used. Patients with non-high or unlikely probability of deep vein thrombosis were included in the analysis; four different D-dimer tests were used. The proportion of patients with a normal D-dimer test and the failure rates were calculated using the conventional (500 μg/L) and the age-adjusted D-dimer cut-off (patients age x 10 μg/L in patients >50 years). Results In 1672 patients with non-high probability, deep vein thrombosis could be excluded in 850 (51%) patients with the age-adjusted cut-off value versus 707 (42%) patients with the conventional cut-off value. The failure rates were 7 (0.8; 95% confidence interval 0.3-1.7%) for the age-adjusted cut-off value and 5 (0.7%, 0.2-1.6%) for the conventional cut-off value. The absolute increase in patients in whom deep vein thrombosis could be ruled out using the age-adjusted cut-off value was largest in patients >70 years: 19% among patients with non-high probability. Conclusions The age-adjusted cut-off of the D-dimer combined with clinical probability greatly increases the proportion of older patients in whom deep vein thrombosis can be safely excluded.

Effect of Repetitive Intra-Arterial Infusion of Bone Marrow Mononuclear Cells in Patients With No-Option Limb Ischemia: The Randomized, Double-Blind, Placebo-Controlled JUVENTAS Trial

Background —Patients with severe limb ischemia may not be eligible for conventional therapeutic interventions. Pioneering clinical trials suggest that bone marrow (BM)-derived cell therapy enhances neovascularization, improves tissue perfusion, and prevents amputation. The objective of this trial was to determine whether repetitive intra-arterial infusion of BM mononuclear cells (BMMNC) in patients with severe, non-revascularizable limb ischemia can prevent major amputation. Methods and Results —The Juventas-trial is a randomized, double-blind, placebo-controlled clinical trial in 160 patients with severe, non-revascularizable limb ischemia. Patients were randomized to repetitive (3x; 3-weeks interval) intra-arterial infusion of BMMNC or placebo. No significant differences were observed for the primary outcome, i.e. major amputation at 6 months, with major amputation rates of 19% in the BMMNC vs. 13% in the placebo group (Relative risk [RR] 1.46; 95% confidence interval [CI] 0.62 to 3.42). The safety outcome (all-cause mortality, occurrence of malignancy or hospitalization due to infection) was not significantly different between the groups (RR 1.46; 95%CI 0.63 to 3.38), neither was all-cause mortality at six months with 5% vs. 6% (RR 0.78; 95%CI 0.22 to 2.80). Secondary outcomes quality of life, rest pain, ankle-brachial index, and transcutaneous oxygen pressure improved during follow-up, but there were no significant differences between the groups. Conclusions —Repetitive intra-arterial infusion of autologous BMMNC into the common femoral artery did not reduce major amputation rate in patients with severe, non-revascularizable limb ischemia compared to placebo. The general improvement in secondary outcomes during follow-up in both the BMMNC as well as the placebo group underlines the essential role for placebo-controlled design of future trials. Clinical Trial Registration Information —ClinicalTrials.gov. Identifier: [NCT00371371][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00371371&atom=%2Fcirculationaha%2Fearly%2F2015%2F01%2F07%2FCIRCULATIONAHA.114.012913.atomBackground— Patients with severe limb ischemia may not be eligible for conventional therapeutic interventions. Pioneering clinical trials suggest that bone marrow–derived cell therapy enhances neovascularization, improves tissue perfusion, and prevents amputation. The objective of this trial was to determine whether repetitive intra-arterial infusion of bone marrow mononuclear cells (BMMNCs) in patients with severe, nonrevascularizable limb ischemia can prevent major amputation. Methods and Results— The Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial is a randomized, double-blind, placebo-controlled clinical trial in 160 patients with severe, nonrevascularizable limb ischemia. Patients were randomly assigned to repetitive (3 times; 3-week interval) intra-arterial infusion of BMMNC or placebo. No significant differences were observed for the primary outcome, ie, major amputation at 6 months, with major amputation rates of 19% in the BMMNC versus 13% in the placebo group (relative risk, 1.46; 95% confidence interval, 0.62–3.42). The safety outcome (all-cause mortality, occurrence of malignancy, or hospitalization due to infection) was not significantly different between the groups (relative risk, 1.46; 95% confidence interval, 0.63–3.38), neither was all-cause mortality at 6 months with 5% versus 6% (relative risk, 0.78; 95% confidence interval, 0.22–2.80). Secondary outcomes quality of life, rest pain, ankle-brachial index, and transcutaneous oxygen pressure improved during follow-up, but there were no significant differences between the groups. Conclusions— Repetitive intra-arterial infusion of autologous BMMNCs into the common femoral artery did not reduce major amputation rates in patients with severe, nonrevascularizable limb ischemia in comparison with placebo. The general improvement in secondary outcomes during follow-up in both the BMMNC and the placebo group, as well, underlines the essential role for placebo-controlled design of future trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00371371.

Haemophilic arthropathy: the importance of the earliest haemarthroses and consequences for treatment

Summary.  In a case of massive bleeding, the possibility of puncturing the joint can be considered to reduce the total load of intra‐articular blood, and thus the total load of iron which, in time, can be found in the synovium with devastating long‐term effects. Subsequent initiation of prophylaxis, still very early in life, might be more beneficial for the preservation of joints. Thus, it might be argued that the initiation of primary prophylaxis should be based on joint haemorrhage history rather than age and, according to some authors, preferably after the bleed in a single joint. The high cost of recombinant factor VIII may make widespread acceptance of prophylaxis impractical. Thus, beneficial results should be balanced with cost considerations. In this balance of treatment cost and efficacy, it must be taken into account that improperly treated haemophilia patients make great demands on healthcare systems (in terms of costs) because of their need for additional treatments such as expensive joint replacement surgery. However, where resources are limited, it can be argued that prophylaxis may be stopped in adulthood, in a certain proportion of all adult patients, with acceptable consequences for orthopaedic outcome in the long term. By doing so, limited amounts of clotting factor can be used for young patients with optimal cost effectiveness.