Annual Bleeding Rates: Pitfalls of Clinical Trial Outcomes in Hemophilia Patients.

Emerging treatment options for hemophilia, including gene therapy, modified factor products, antibody-based products, and other nonreplacement therapies, are in development or on their way to marketing authorization. For proof of efficacy, annual bleeding rates (ABRs) have become an increasingly important endpoint in hemophilia trials. We hypothesized that ABR analyses differ substantially between and within medicinal product classes and that the ABR observation period constitutes a major bias. For ABR characterization, an internal factor VIII (FVIII) treatment database has been built based on confidential clinical trial data submitted to the Paul-Ehrlich-Institut (PEI). Furthermore, anonymized data from 46 trial protocols submitted for review to the PEI were analyzed (FVIII replacement, n = 27; antibody-based, n = 12; and gene therapy, n = 7) for methodology. Definitions of bleeding episodes and ABR observational periods differed substantially in clinical trials. In the initial observation phase, individual ABRs of patients, treated prophylactically for 1 year, vary by about 40% (P < 0.001), which finally led to a significant reduction of the ABR group mean by 20% (P < 0.05). Furthermore, the high variance in ABRs constitutes a major challenge in statistical analyses. In conclusion, considerable heterogeneity and bias in the ABR estimation in clinical trials was identified, which makes it substantially more difficult to compare the efficacy of different treatment regimens and products. Thus, awareness of the important pitfalls when using ABR as a clinical outcome is needed in the evaluation of hemophilia therapies for patients, physicians, regulators, and health technology assessment agencies.

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.

Bleeding risk assessment in hemophilia A carriers from Dakar, Senegal.

: Hemophilia A carriers have an abnormal X chromosome with a molecular abnormality of FVIII gene. These carriers, long considered to be free of bleeding risk, could have the same symptoms as mild hemophiliacs. This study aim to assess bleeding risk of hemophilia A carriers monitored at the Clinical Hematology Department of Dakar. This is a prospective study of a period of 6 months including 22 hemophilia A carriers aged between 8 and 48 years. Hemophilia carriers were recruited using the genealogical tree of hemophiliacs followed in the service. Their diagnosis was carried out by long range PCR and Sanger sequencing method searching the molecular abnormality responsible for hemophilia in their family. Bleeding risk was determined using a questionnaire consisting of different bleeding symptoms quoted from -1 to 4 according to the severity. Total of different values allow to determine the bleeding score which was pathological if it was greater than or equal to 1. Medium age was 22.5 years (8-48) (SD = 9.28). Four hemophilia A carriers (18.1%) presented bleeding symptoms and had a bleeding score at least 1 (P = 0.02). Menorrhagia was predominant (13.6%) followed by epistaxis (9%), gingivorrhagia (9%), and prolonged bleeding after tooth extraction (9%). Factor VIII level was lower in hemophilia carriers who presented bleeding (42 ±â€Š8.61 UI/l) versus hemophilia carriers without bleeding (100 ±â€Š50.95 UI/l) (P = 0.001). There was no significant correlation between bleeding occurrence and age (P = 0.81), activated patial thromboplastin time value (P = 0.97) and FVIII/Von Willebrand Factor ratio (P = 0.12). One in five hemophilia carriers presented bleeding and the questionnaire was effective to identify hemophilia carriers who had a risk of bleeding.

Venous thromboembolism risk in patients with cancer receiving chemotherapy: a real-world analysis.

UNLABELLED: The occurrence of malignant disease increases the risk for venous thromboembolism (VTE). Here we evaluate the risk for VTE in a large unselected cohort of patients with cancer receiving chemotherapy. METHODS: The United States IMPACT health care claims database was retrospectively analyzed to identify patients with a range of solid tumors who started chemotherapy from January 2005 through December 2008. International Classification of Diseases, 9th revision, Clinical Modification Codes were used to identify cancer location, presence of VTE 3.5 months and 12 months after starting chemotherapy, and incidence of major bleeding complications. Health care costs were assessed one year before initiation of chemotherapy and one year after initiation of chemotherapy. RESULTS: The overall incidence of VTE 3.5 months after starting chemotherapy was 7.3% (range 4.6%-11.6% across cancer locations) rising to 13.5% at 12 months (range 9.8%-21.3%). The highest VTE risk was identified in patients with pancreatic, stomach, and lung cancer. Patients in whom VTE developed had a higher risk for major bleeding at 3.5 months and at 12 months (11.0% and 19.8% vs. 3.8% and 9.6%, respectively). Health care costs were significantly higher in patients in whom VTE developed. CONCLUSION: Those undergoing chemotherapy as outpatients are at increased risk for VTE and for major bleeding complications. Thromboprophylaxis may be considered for such patients after carefully assessing the risks and benefits of treatment.

Clinical applications of pharmacogenomics guided warfarin dosing.

AIM OF THE REVIEW: To assess the state of the literature concerning pharmacogenomic testing in patients requiring vitamin K antagonists, specifically warfarin. METHOD: We conducted a literature search of MEDLINE and International Pharmaceutical Abstracts using the following words: warfarin, pharmacogenetic, and pharmacogenomic. The search results were reviewed by the authors and papers concerning pharmacogenomic testing in warfarin dosing were procured and reviewed. Additionally bibliographies of papers procured were also examined for other studies. The authors focused on clinical trials concerning the use of pharmacogenomic testing in warfarin dosing. RESULTS: Although numerous studies have demonstrated that a significant portion of warfarin dosing variability can be explained by genetic polymorphisms, few prospective studies have been conducted that examine the integration of this information in practical dosing situations. Those that have, have shown that using pharmacogenomic information improves initial dosing estimates and decreases the need for frequent clinic visits and laboratory testing. Data showing a reduction in serious bleeding events is sparse. Cost-effectiveness analyses have generally shown a small but positive effect with pharmacogenomic testing in patients receiving warfarin. CONCLUSION: Several studies have shown that pharmacogenomic testing for warfarin dosing is more accurate that other dosing schemes. Pharmacogenomic testing improves time to a therapeutic international normalized ratio while requiring fewer dosing adjustments. Patients who require higher or lower than usual doses seem to benefit the most. The cost-effectiveness of pharmacogenomic testing as well as preventing of outcomes such as bleeding or thrombosis are not yet elucidated. Pharmacists, especially those in a community setting can play a role in this new technology by educating prescribers and patients concerning pharmacogenomic testing, and by developing and using dosing protocols that incorporate its use.

Should we be applying warfarin pharmacogenetics to clinical practice? No, not now.

The U.S. Food and Drug Administration modified warfarin labeling in 2007 to suggest, but not mandate, pharmacogenetic testing. Genetic analysis is now commercially available. However, results predict only one third of all dosing variation, the value of testing in reducing bleeding and thrombosis rates remains unproved, and cost-effectiveness is not established. Careful consideration of clinical factors that influence dosing, conscientious prothrombin time monitoring, and sage dosage adjustment remain paramount in warfarin management. Further study is required before routine warfarin pharmacogenetic testing can be recommended.

Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor.

Investigation of 3 families with bleeding symptoms demonstrated a defect in the collagen-binding activity of von Willebrand factor (VWF) in association with a normal VWF multimeric pattern. Genetic analysis showed affected persons to be heterozygous for mutations in the A3 domain of VWF: S1731T, W1745C, and S1783A. One person showed compound heterozygosity for W1745C and R760H. W1745C and S1783A have not been reported previously. The mutations were reproduced by site-directed mutagenesis and mutant VWF expressed in HEK293T cells. Collagen-binding activity measured by immunosorbent assay varied according to collagen type: W1745C and S1783A were associated with a pronounced binding defect to both type I and type III collagen, whereas the principal abnormality in S1731T patients was a reduction in binding to type I collagen only. The multimer pattern and distribution of mutant proteins were indistinguishable from wild-type recombinant VWF, confirming that the defect in collagen binding resulted from the loss of affinity at the binding site and not impairment of high-molecular-weight multimer formation. Our findings demonstrate that mutations causing an abnormality in the binding of VWF to collagen may contribute to clinically significant bleeding symptoms. We propose that isolated collagen-binding defects are classified as a distinct subtype of von Willebrand disease.

Should we test for CYP2C9 before initiating anticoagulant therapy in patients with atrial fibrillation?

BACKGROUND: Genetic variants of the warfarin sensitivity gene CYP2C9 have been associated with increased bleeding risk during warfarin initiation. Studies also suggest that such patients remain at risk throughout treatment. OBJECTIVE: Would testing patients with non-valvular atrial fibrillation (AF) for CYP2C9 before initiating warfarin improve outcomes? DESIGN: Markov state transition decision model. SETTING: Ambulatory or inpatient settings necessitating new initiation of anticoagulation. PATIENTS: The base case was a 69-year-old man with newly diagnosed non-valvular AF. Interventions included: (1) warfarin, (2) aspirin, or (3) no antithrombotic therapy without genetic testing; and genetic testing followed by (4) aspirin or (5) no antithrombotic therapy in those with culprit CYP2C9 alleles. MEASURES: Quality-adjusted life years (QALYs). RESULTS: In the base case, testing and treating patients with CYP2C9*2 and/or CYP2C9*3 with aspirin rather than warfarin was best (8.97 QALYs). However, warfarin without genetic testing was a close second (8.96 QALYs), a difference of roughly 5 days. Sensitivity analyses demonstrated that genetic testing followed by aspirin was best for patients at lower risk of embolic events. Warfarin without testing was preferred if the rate of embolic events was greater than 5% per year, or the risk of major bleeding while receiving warfarin was lower. CONCLUSION: For patients at average risk for ischemic stroke due to AF and at average risk for major hemorrhage, treatment based on genetic testing offers no benefit compared to warfarin initiation without testing. The gain from testing may be larger in patients at lower risk of embolic events or at greater risk of bleeding.

Pharmacogenomics of 4-hydroxycoumarin anticoagulants.

Oral anticoagulants of the 4-hydroxycoumarin class, typified by warfarin, are used worldwide to treat thromboembolic disease. These drugs show the beneficial attributes of high efficacy and low cost, but patient management can be complicated by their narrow therapeutic index and wide inter-individual variability in dosing. Our understanding of the latter complication has improved significantly in recent years due to intense investigation of genetic factors influencing drug pharmacokinetics (CYP2C9) and pharmacodynamic response (VKORC1). In particular, the discovery of polymorphisms in the VKORC1 gene that strongly impact oral anticoagulant dose has heightened expectations that genetic testing for a relatively small cadre of warfarin-response genes might substantially enhance patient care in this area, especially during the initiation phase of therapy. However, enthusiasm for genotype-based dosing of oral anticoagulants must be balanced against the ready availability of both a simple phenotypic test (prothrombin time) and an antidote to over-anticoagulation (vitamin K). Wide-spread acceptance of genetically based tests for establishing therapy with warfarin and its congeners will likely require additional evidence that such an approach offers protection against a variety of negative anticoagulation outcomes, especially severe bleeding, as well as offering utility across many racial populations. This article will review recent events in these and other related areas.

Is survival time after hemorrhage a heritable, quantitative trait?: an initial assessment.

Enhancing survival to hemorrhage of both civilian and military patients is a major emphasis for trauma research. Previous observations in humans and outbred rats show differential survival to similar levels of hemorrhage. In an initial attempt to determine potential genetic components of such differential outcomes, survival time after a controlled hemorrhage was measured in 15 inbred strains of rats. Anesthetized rats were catheterized, and approximately 24 h later, 55% of the calculated blood volume was removed during a 26-min period from conscious unrestrained animals. Rats were observed for a maximum of 6 h. Survival time was 7.7-fold longer in the longest-lived strain (Brown Norway/Medical College of Wisconsin; 306 +/- 36 min; mean +/- SEM) than in the shortest-lived strain (DA; 40 +/- 5 min; P < or = 0.01). Mean survival times for the remaining inbred strains ranged from 273 +/- 44 to 49 +/- 4 min (Dahl-Salt Sensitive > Brown Norway > Munich Wistar Fromter> Dahl-Salt Resistant > Copenhagen > Noble > Spontaneous-hypertensive > Lewis > BDIX > Fawn Hooded Hypertensive > FISCHER 344 > Black agouti > PVG). The variance in the hazard of death attributable to different strains was estimated to be 1.22 log-hazard units, corresponding to a heritability of approximately 48%. Graded and divergent survival times to hemorrhage in inbred rat strains are remarkable and suggest multiple genetic components for this characteristic. However, this interpretation of differential responses to hemorrhage may be confounded by potential strain-associated differences related to the surgical preparation. Identification of inbred strains divergent in survival time to hemorrhage provides the opportunity for future use of these strains to identify genes associated with this complex response.

Polymorphism induced sensitivity to warfarin: a review of the literature.

Warfarin is a widely prescribed anticoagulant used for prophylaxis and treatment of venous and arterial thrombosis. Although warfarin is considered very efficacious, it has substantial risks associated with its use, specifically the risk of hemorrhage. Genetic variants associated with the metabolism of (S)-warfarin by cytochrome P450 2C9 may have specific implications on untoward effects. Twelve CYP2C9 allelic variants have been identified, of which CYP2C9*3 and CYP2C9*2 are the most clinically important. Studies have demonstrated that initial dosing of warfarin with CYP2C9*3 with a five-milligram dose caused an increase in the international normalized ratio and significant risk of bleeding. Studies conducted with CYP2C9*2, on the other hand are conflicting. Some data suggest that the CYP2C9*2 variant is associated with an increased propensity for bleeding whereas other studies do not demonstrate a substantial risk of adverse events. Researchers suggest that detection of genetic variants in susceptible individuals will not only decrease the risks associated with warfarin therapy but also decrease costs of adverse events.