Incidence, risk factors, and management of bleeding in patients receiving anticoagulants for the treatment of cancer-associated thrombosis.

Updated clinical practice guidelines recommend the long-term use of low-molecular-weight heparins or direct oral anticoagulants as the preferred option for the treatment of cancer-associated thrombosis (CAT), using a personalized approach matching the right drug to the right patient. In most cases, the benefit of anticoagulant therapy outweighs the risk. However, the long-term use of anticoagulants is associated with a non-negligible risk of bleeding, which constitutes a rare but serious adverse effect. Bleeding complications have been reported to be overall 2 to 3 times more frequent in cancer patients with CAT receiving anticoagulation than in non-cancer patients, with a reported incidence of major bleeding ranging from 2.4 to 16.0% in randomized controlled trials (RCT). In the absence of validated risk assessment model to predict the risk of bleeding in these patients, a careful evaluation of each individual profile, with adequate selection of the most appropriate anticoagulant for each individual patient, is warranted for overcoming management challenges, taking in account the numerous factors which may potentiate the overall bleeding risk in these complex patients, such as advanced or metastatic disease, older age, anemia, thrombocytopenia, renal impairment, liver dysfunction, and concomitant anticancer therapies. The purpose of this review is to call for awareness on bleeding complications as a major safety issue of CAT treatment and to summarize data from recent RCT and real-world studies on the incidence and risk factors for bleeding in this unique and challenging population to further help clinicians in decision-making.

Results from the LIDO anemia survey: adherence to EORTC guidelines in cancer patients in France.

PURPOSE: The aim of the LIDOanemia surveys was to assess how anemia in cancer patients is managed by oncologists and hematologists according to the key messages of the EORTC guidelines. METHODS: LIDO 1 and LIDO 2 (Leaning upon International Directives for Optimization: Anemia) were declarative web-based surveys conducted in France. LIDO 1 specifically focused on clinical features triggering the decision to treat anemia, biological indicators of anemia, the hemoglobin (Hb) threshold for initiating treatment and blood transfusion, and the Hb treatment target. In LIDO 2, participants were presented the main messages of the EORTC guidelines and were asked four questions to assess the impact of the guideline's broadcast on their practice. RESULTS: A total of 133 and 319 physicians took part in the LIDO 1 and 2 surveys, respectively. The majority were oncologists (65 and 61 %, respectively). Responses from LIDO 1 showed practice habits that differed from those recommended in the EORTC guidelines. However, LIDO 2 showed that an average of 18 % of the participating physicians were willing to amend their clinical practice after receiving a summary of the EORTC recommendations for anemia management. CONCLUSION: These findings raise the questions of how often and how to most effectively disseminate key guideline messages. With the best interests of patients in mind, the ultimate objective is to improve the understanding of consensus recommendations and to close the gap between them and actual clinical practice.

Prevalence of renal abnormalities in chronic HBV infection: the HARPE study.

BACKGROUND & AIMS: Few data are available on the prevalence of renal abnormalities in chronic hepatitis B virus (HBV)-infected patients. The multicentric cross-sectional HARPE study evaluated the prevalence of kidney disease indicators, in chronic HBV surface antigen carriers patients (HBsAg+) with active or inactive infection. PATIENTS AND METHODS: Two hundred and sixty-eight HBsAg+ adult patients, naïve of any oral antihepatitis B virus treatment were prospectively included over 2 years. Data for renal assessment were collected once from patient files. Univariate tests and multiple linear regressions were performed with the SAS software, version 8.02 (SAS, Inc., Cary, NC, USA). RESULTS: Among the 260 patients analysed, 58% were men, the mean age was 42 ± 14 years, 59.6% were inactive carriers whereas 47 patients, mostly active, were about to start an antiviral therapy. Prevalence of proteinuria, haematuria, glycosuria, uninfectious leukocyturia was 38.1%, 20.6%, 3.9% and 9% respectively. According to the international definition, a total of 64.6% of patients were found to have kidney disease. Diabetes, hypertension and dyslipidaemia were observed, respectively, in 4.6%, 9.2% and 38.8% patients. There were no significant differences in these results within the three subgroups. CONCLUSION: Renal abnormalities are highly prevalent in our population and pre-exist before the initiation of any antihepatitis B virus treatment. This emphasizes the need for: (i) a baseline renal evaluation in all HBs antigen-positive patients; (ii) a regular renal monitoring before and during antihepatitis B virus treatment to diagnose and manage renal impairment and adjust antihepatitis B virus treatment doses to renal function when necessary.

Anticancer Drugs in End-Stage Kidney Disease Patients.

The increased incidence of malignancies in patients with chronic kidney patients and especially in end-stage kidney disease (ESKD) patients has been discussed since the mid-1970s. Consequently, oncologists, nephrologists, and pharmacists are increasingly facing challenging situations of cytotoxic drug handling in dialysis patients because of pharmacokinetic modifications. In these patients, two main issues must be considered. First, the absence of renal function in hemodialysis (HD) patients may necessitate drug dosage reduction. Therefore, drug prescription must be cautiously checked before administration with appropriate dosage adjustment whenever necessary to ensure efficacy while avoiding overdosage and related side effects. Second, drug clearance by dialysis session must be taken into account for appropriate chemotherapy timing administration to avoid drug removal, which may result in a loss of efficacy. These two main considerations must not be considered as a contra-indication to chemotherapy in ESKD patients, but more as a need for an individualized prescription according to available recommendations.

Acute renal failure associated with the new BRAF inhibitor vemurafenib: a case series of 8 patients.

BACKGROUND: Vemurafenib is a BRAF inhibitor that has become the cornerstone of metastatic or inoperable melanoma therapy since its approval in 2011 in the United States and 2012 in Europe. This targeted therapy has shown impressive results in terms of increased progression-free and overall survival as compared to dacarbazine. The safety profile did not include any renal manifestations at that time. METHODS: This report is the first case series of 8 patients who experienced significant to severe renal insufficiency under vemurafenib treatment. RESULTS: This case series shows that vemurafenib may induce potentially severe acute renal failure, including renal sequelae and persistent kidney disease in some cases. CONCLUSIONS: Further studies are needed to investigate the effects of vemurafenib on the kidneys. Meanwhile, renal function should be closely monitored in treated patients for early detection of any renal dysfunction occurrence. Cancer 2014;120:2158-2163. © 2014 American Cancer Society.

Renal insufficiency, mortality, and drug management in heart transplant. Results of the CARIN study.

Renal insufficiency (RI) is a frequent complication in heart transplant (HT) patients. The main objectives of the Cardiac trAnsplantation and Renal INsufficiency (CARIN) study were to follow the evolution of renal function after heart transplantation (HTx), to identify the factors associated with the decline of renal function, to describe the impact of RI on mortality during 3 years after the HT, and to observe the renal profile of the prescriptions. CARIN was a French retrospective, multicentric, study. Data were collected for patients who received a HT between 2000 and 2005. Data collection was performed at five time points: before HTx (T0), 1(T1), 6(T6), 12 (T12), and 36 (T36) months after HTx. Glomerular filtration rate (GFR) was estimated with aMDRD formula. RI was defined as GFR < 60 ml/min/1.73 m². Four hundred and forty-one patients from five HT centers were included. The prevalences of RI were 28.8% (T0), 54.0% (T1), 50.4% (T6), 51.6% (T12), and 59.6% (T36). Age and cyclosporine were independently linked to the decline of renal function. Hypertension and GFR < 60 at T0 were independent risk factors of mortality. 48.7-64.7% of the nonimmunosuppressive prescriptions were drugs that required dosage adjustment in RI patients or for which no data were available concerning administration in RI patients. RI is highly frequent after HTx. Because RI is a risk factor of mortality, any sparing renal strategies have to be undertaken.

How to manage the dose of drugs in cancer patients with acute kidney injury, practical recommendations.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are common in cancer patients. AKI is a brutal and reversible condition which makes it hard to manage from a pharmacological perspective when patients are receiving anticancer regimens and other supportive care drugs, such as anticoagulants, analgesics and other drugs. In contrast to CKD, which is a slow progressive disease, there is no clear guidance on how to manage and/or modify the dosage of drugs during AKI. Indeed, the slow progression of CKD allows physicians to monitor the renal function by using the glomerular filtration rate. Consequently, publications have explored the management of drugs in cancer patients with CKD, which is currently not the same for AKI. There are no recommendations or suggestions on how to manage drug doses in case of AKI in cancer patients. This commentary explores the different options to manage drugs (anticancer drugs, anticoagulants, and other supportive care drugs) during AKI in cancer patients.

Administration of intravenous iron complexes on implantable central venous access port in cancer patients in France: the FERPAC survey.

PURPOSE: Implantable central venous access port (portacath) is used to provide long-term venous access and to deliver chemotherapy in cancer patients. Intravenous iron complexes are frequently prescribed in this setting, and some physicians use a portacath for their administration. The aim of this survey was to assess the frequency of this practice and the reasons supporting it. METHODS: This declarative survey was conducted in France; 497 oncologists/hematologists were contacted to answer a survey on their practices regarding the administration of intravenous iron via a portacath. RESULTS: A total of 141 recipients (29.5 %) completed the questionnaire. The intravenous iron complexes most frequently used were iron sucrose and ferric carboxymaltose, and 55.2 % of the responders reported using a portacath to administer intravenous iron complexes. The main reasons mentioned for this practice were ease of administration (27.9 %) and preservation of venous capital (27.6 %). The main reasons reported for not using a portacath to administer intravenous iron were a history of thrombosis (45.1 %) or potential drug interactions (17.7 %). Efficacy and safety were expected to be similar to those observed with peripheral administration. A 47.6 % of physicians declared that they usually did not observe adverse reactions after use of a portacath for iron administration. Intravenous iron administration was always planned after chemotherapy for 46.6 % of the responders and before chemotherapy for 38.2 %, whereas 15.3 % did not have any preference for either option. CONCLUSIONS: Intravenous iron complexes (mainly iron sucrose and ferric carboxymaltose) are commonly administered through a portacath in cancer patients in France. The choice for this route of administration is supported by clinical considerations, but further studies are needed to confirm the efficacy and safety of this practice.

[How to adjust the dose of drugs in chronic kidney disease?]. / Comment adapter la dose des médicaments dans la maladie rénale chronique?

Renal insufficiency is a common disease, in the general population as well as in some specific diseases such as HIV infection or cancer. The vast majority of medicines require a dosage adjustment in case of renal dysfunction, it is thus of a crucial importance to know how to evaluate appropriately renal function, on one hand, but also to have access to reliable information sources on how to handle the drugs in such cases. Most often, the Summary of Drug Characteristics (SmPC) only provides partial information, which may even be false in some cases as compared to the most recent data from the literature. However, some information sources exist, reliable, updated, and easily accessible.

Inappropriate drug use and mortality in community-dwelling elderly with impaired kidney function--the Three-City population-based study.

BACKGROUND: Glomerular filtration rate (GFR) decline with age increases the risk of inappropriate dosing of drugs. We investigated the determinants and the mortality associated with the use of drugs that are contraindicated or require dose adjustment according to kidney function among the community-dwelling elderly. METHODS: The Three-City population-based study included 8701 participants ≥65 years from 1999 to 2001. Exposure to the risk of inappropriate drug dosage was defined as reported use of either a contraindicated drug or one requiring dose adjustment according to the individual baseline glomerular filtration rate estimated (eGFR) with the Modification of Diet in Renal disease study equation. Six-year mortality was analysed using Cox models adjusted for several sociodemographic, biologic and clinical risk factors. RESULTS: The overall percentage of exposure to the risk of inappropriate drug use was 13.3% (contraindication, 0.8%): it was 52.5% (4.5%) in those with an eGFR of 30-59 and 96% (48%) in those <30 mL/min/1.73 m(2). Antihypertensive agents, fibrates and psycholeptics accounted for most of the drugs with dosing recommendations and antidiabetic agents and antihistamines for those contraindicated. Individuals at risk were more likely to be men, older, and under treatment for hypertension or hypercholesterolemia. Exposure to either risk was independently related to higher all-cause mortality (hazard ratio 1.4, 95% confidence interval 1.0-1.9) in participants with eGFR <60 mL/min/1.73 m(2). CONCLUSIONS: Contraindicated drug prescription was uncommon but >10% of the population took drugs requiring renal dosing adjustments. Regular monitoring of eGFR may prevent excess mortality associated with inappropriate drug prescription in the elderly.

[Renal toxicity of anticancer drugs]. / Toxicité rénale des anticancéreux.

The renal toxicity of anticancer drugs is a clinical challenge because of the intrinsic toxicity of some anticancer drugs and because the cancer itself. Indeed, cancer patients are exposed to all types of renal disorders (obstructive, functional, organic because of radiotherapy, paraneoplastic glomerulopathy, thrombotic microangiopathy…). The therapeutic index of anticancer drugs is often narrow and the doses used for optimal efficacy are high. Improving safety requires a better dose adjustment, which depends on the correct evaluation of the renal function. Prevention remains important as the mortality associated with acute renal failure is very high.

Prevalence of renal insufficiency in breast cancer patients and related pharmacological issues.

The Renal Insufficiency and Anticancer Medications (IRMA) study is a French national, observational study which demonstrated the high prevalence of abnormal renal function in a population of 4,684 solid tumour patients. Among them, 50-60% had decreased renal function defined as CrCl below 90 and 80% were treated with anticancer drugs that either necessitated dosage adjustment in case of RI or were potentially nephrotoxic drugs. Since patients and drugs used differ depending on the type of tumour, the IRMA Study Group started analyses in different subgroups of patients. In the 1898 IRMA patients with breast cancer, the prevalence of RI was still very high in spite of a normal serum creatinine in almost all cases. Some anticancer drugs, as in particular some bisphosphonates, capecitabine and platinum salts, may be nephrotoxic and/or need dosage adjustment. However other important drugs in breast cancer do not require dose reduction, and do not present with potential nephrotoxicity (anthracyclines, taxanes, trastuzumab). Both issues seem to be slightly but significantly more important in patients with bone metastases as compared to patients with a non-metastatic disease.

Are Patients with Active Cancer and Those with History of Cancer Carrying the Same Risks of Recurrent VTE and Bleeding While on Anticoagulants?

Direct oral anticoagulants (DOAC) are now recommended for the treatment of cancer-associated thrombosis (CAT) based on the results of dedicated trials demonstrating that DOAC are non-inferior to low molecular weight heparins in preventing recurrent venous thromboembolism (VTE) in this population. The definition of "cancer patient" differs substantially among studies. Whether patients with active cancer and those with a history of cancer (HOC) carry the same risks of recurrent VTE and bleeding remains unclear. Few studies reported data on the efficacy and safety of anticoagulants according to active cancer or HOC categories. While in subgroup analyses of EINSTEIN and HOKUSAI the rates of recurrent VTE and bleeding did not differ between these categories, results from a subgroup analysis of AMPLIFY, from HOKUSAI-Cancer, and from the COMMAND cohort suggest that HOC patients might have a lower bleeding risk than active cancer patients. Whether the inclusion of HOC patients in CAT studies might introduce some bias by decreasing the rates of both recurrent VTE and bleeding remains an unanswered issue since no dedicated prospective study addressed this question. A strict definition of active cancer should be used in further trials.

Renal safety of gadolinium-based contrast media in patients with chronic renal insufficiency.

Contrast medium (CM)-induced nephropathy (CIN), defined as acute renal failure after administration of CM when alternative causes of renal damage have been excluded, is the third leading cause of acute renal injury necessitating hospitalization. However, the pathophysiology of CIN is complex and not fully understood. Gadolinium chelates, originally introduced as intravenous CM for magnetic resonance imaging and regarded as nonnephrotoxic, have been recommended to replace iodinated contrast agents in patients at risk for acute renal failure. Since then, some gadolinium-based CM have been reported to be associated with CIN, especially in patients with advanced renal disease. However, the biochemical and physicochemical properties of the gadolinium-chelates that are responsible for such nephrotoxicity have not been clearly defined, and the issue of gadolinium-induced nephrotoxicity remains controversial. This review surveys the literature with the purpose of clarifying the renal effects of gadolinium-based CM in patients with renal insufficiency.

Long-term renal function in liver transplant recipients and impact of immunosuppressive regimens (calcineurin inhibitors alone or in combination with mycophenolate mofetil): the TRY study.

The prevalence of renal insufficiency before and at 1, 12, and 60 months after liver transplantation (LTx; primary endpoint) and the changes in the glomerular filtration rate (GFR) at same time points according to the immunosuppressive regimen (coprimary endpoint) were investigated. The primary outcome was determined for the entire cohort, whereas the coprimary endpoint was determined only for 2 groups of patients: those who started and remained on a calcineurin inhibitor (CNI) alone, that is, the CNI-alone group (n = 624), and those who started and remained on a CNI in combination with mycophenolate mofetil (MMF), that is, the MMF group (n = 117). GFR was <60 mL/minute/1.73 kg/m(2) in 11%, 48%, 51% and 58% of the patients at baseline and at 1, 12, and 60 months, respectively. The decrease in GFR was significantly lower in the MMF group compared to the CNI-alone group at 12 and 60 months (-16% versus -30% and -15% versus -33%, respectively), whereas the GFR decrease at 1 month was not different between the 2 groups. There were no significant differences between the 2 groups in CNI doses or blood levels at 12 and 60 months. In conclusion, there was a worsening of renal failure in 83% of patients post-LTx; 58% and 5% had GFRs of <60 and <30 mL/minute/1.73 kg/m(2), respectively, at 5 years after LTx. The reduction of the GFR was significantly less marked in the MMF group compared to the CNI-alone group, and this could be related to less important CNI exposure early after LTx. It seems likely that early intervention for CNI reduction is best for reducing the use of CNIs in the long term.

[Non-iodinated contrast media nephrotoxicity]. / Toxicité rénale des produits de contraste non iodés.

The development of interventional radiology techniques regularly exposes patients to the potential renal toxocity of iodinated contrast media. Faced with this risk of nephrotoxicity, gadolinium-based contrast agents have long been considered as a safe alternative to iodinated contrast media, especially in sensitive or at risk patients. However, these gadolinium-based contrast agents are not devoid of nephrotoxicity and present another risk, a complication related to renal failure, the nephrogenic systemic fibrosis. European and US recommendations from health agencies have recently come closer, defining groups of patients at risk of nephrogenic systemic fibrosis according to their level of renal function and the type of gadolinium-based contrast agent used. What are the real renal risks for these products? How to evaluate the benefit-risk balance of the patient to choose a radiological examination in an informative, effective and safe way? This article focuses on the description of the risks of gadolinium-based contrast agents, reviews existing recommendations and best practices to guide the choice of clinicians.

Pharmacokinetic/pharmacodynamic considerations for cancer patients undergoing hemodialysis.

INTRODUCTION: The increased incidence of cancer in hemodialysis patients has been discussed since the mid-70s. Today, physicians regularly encounter situations where they must manage the prescription of anticancer drugs in hemodialysis patients. Areas covered: Hemodialysis patients are at risk of dose-related toxicities due to pharmacokinetic modifications. Hemodialysis patients are at risk of therapeutic drug removal during their hemodialysis session, which may result in a loss of efficacy. In the advent of novel immunotherapies, particularly tumor vaccines, there is an increased theoretical risk of pharmacodynamic modification. Indeed, pharmacodynamic modifications have already been reported for viral vaccines. Expert opinion: It is important to consider all of the potential pharmacokinetic/pharmacodynamic modifications before prescribing anticancer drugs in hemodialysis patients. However, pharmacokinetic/pharmacodynamic modification should not be considered a contraindication for anticancer drug use in hemodialysis patients, rather, clinicians should be aware of the need individualize treatment according to available recommendations.

Course of chronic kidney disease in French patients.

BACKGROUND: In 1998, a French survey showed that the referral of patients with chronic kidney disease to a nephrologist was delayed, resulting in many emergency initiations of dialysis. In 2009, the ORACLE study aimed to describe the renal course of dialysis patients from their first nephrology visit to their first dialysis session. METHODS: The ORACLE study was a multicentre retrospective study of all patients who started chronic dialysis. Data were collected at the first nephrology visit and at the first dialysis session. RESULTS: In total, 720 patients were included (69 centres). At the first nephrology visit, the mean Cockcroft-Gault (CG) indicator was 31.8 mL/min (22.7 in 1998) and 52.4% of patients (73% in 1998) had a CG <30. The mean time between the first nephrology visit and the first dialysis session was 48 months (35 months in 1998). CONCLUSION: In 2009, most patients were referred a long time before dialysis initiation, which likely allowed them to benefit from the impact of nephrology care on early outcomes when on dialysis. However, 34.2% of the dialysis sessions were still initiated under emergency conditions.

[Renovascular effects of antiangiogenic drugs]. / Effets rénovasculaires des antiangiogéniques.

During the last decade, inhibitors of the vascular endothelial growth factor (VEGF) were developed for the treatment of cancer. Many anti-VEGF are available but the issue is still the same: to inhibit the effect of the VEGF on their receptors. There are two main classes, depending on the mechanism of action by blocking the binding of the ligand on the receptor (VEGF trap or monoclonal antibody) or by affecting directly the receptor (tyrosine kinase inhibitor [TKI], monoclonal antibody directed against the VEGF receptor). These selective agents are safe. Nevertheless, side effects were described, in particular renal and vascular effects. In this article, we analyze the frequency of these renovascular complications, their clinical aspects and the interest of these indexes as a marker of treatment efficacy.

Renal insufficiency and cancer treatments.

Renal insufficiency has been shown to be highly prevalent in patients with cancer. This renal insufficiency has been reported to be associated with reduced overall survival and increased cancer-related mortality. Therefore, it is important to screen patients with cancer for renal insufficiency, using an adequate and reliable method of estimation of the renal function. Renal insufficiency may influence 1 or several of the 4 pharmacokinetic phases (absorption, distribution, metabolism, elimination/excretion), potentially resulting in marked modifications of the pharmacokinetic profile of a drug in patients with renal insufficiency. Consequently, it is potentially necessary to adjust the dosage of anticancer drugs in case of renal insufficiency in order to avoid drug accumulation and in order to reduce overdosage-related side effects. This dosage adjustment of anticancer drugs should be performed according to the level of renal function and with an appropriate and validated method. It is not always easy to find clear information on anticancer drug handling in these patients. However, several guidelines, publications and handbooks are available on how to adjust anticancer drug dosages in patients with renal insufficiency and will help practitioners to manage anticancer drugs in such patients.