Over the last 20 years, there have been numerous advances in pharmacologic options for the treatment of venous thromboembolism (VTE), including low-molecular-weight heparins (LMWHs), pentasaccharides, and, most recently, targeted oral anticoagulants. Within certain patient populations, though, the optimal management of VTE – the third most common cardiovascular illness – is unclear. At the 56th ASH Annual Meeting, Anita Rajasekhar, MD, from the University of Florida, and Leslie Raffini, MD, from The Children’s Hospital of Philadelphia, discussed the problems associated with treating VTE in vulnerable patients, including obese patients, those with renal impairment, and pediatric patients.
“Treatment guidelines and dosing schedules have generally targeted the ‘normal’ patient,” said Dr. Rajasekhar. “Dose-finding trials in the obese, renally impaired, and elderly have not been conducted, and the ideal drug regimen is unknown.” The lack of data in these populations is concerning – these characteristics are widely prevalent in patients with acute VTE.
VTE and Obesity
For obese patients with VTE, Dr. Rajasekhar explained, the challenge of treating VTE lies in determining appropriate dosing. “On the one hand there is an increased volume of drug distribution, leading to decreased plasma concentration of drugs that in turn can lead to potential under-dosing,” she said. “On the other hand, reduced vascularity of adipose tissue may result in overdosing if dosed based on total body weight.”
While the ideal drug and dose for obese patients remains unknown, Dr. Rajasekhar recommended a few approaches as treatment options:
- LMWH dosing should be based on actual body weight rather than ideal body weight
- Once-daily dosing should be avoided with enoxaparin, but seems to be safe with dalteparin and tinzaparin
- Fondaparinux 10mg/day is as effective and safe as LMWH in obese patients
Whether hospitals are properly identifying obesity as a risk factor for VTE is also a question. Dr. Rajasekhar was the lead author of a study evaluating how well physicians recognized hospitalized obese patients as being at-risk for VTE and, subsequently, prescribed appropriate thromboprophylaxis.¹ Researchers found that the majority of hospitalized obese patients were appropriately stratified as “moderate risk” for VTE, but a significant portion of obese patients were incorrectly categorized as “low risk” and not prescribed thromboprophylaxis. The impact of this underuse of thromboprophylaxis agents on patient outcomes needs to be further investigated, they concluded.
VTE and Renal Impairment
Up to 25 percent of patients hospitalized for VTE present with moderate to severe renal impairment. “The single pharmacokinetic liability of LMWH is its reliance on the kidney as a primary route for elimination,” said Dr. Rajasekhar. “Renal impairment leads to prolonged elimination, and severe renal impairment may increase the risk of bleeding, particularly with multiple doses.”
For patients with renal insufficiency, clinicians should consider reducing LMWH dosing or monitoring anti-factor Xa levels, she noted. “We all do this, but there are not enough data showing that it makes a difference in clinical outcomes,” Dr. Rajasekhar said. “Evidence-based guidelines are generally lacking in this area, and the bottom line is that we need further research to determine best practices.”
VTE and Pediatric Patients
Pediatric patients with VTE can be categorized into two groups: premature newborns and young children (<1 year) with congenital anomalies, and adolescents with an array of associated conditions. Each group of pediatric patients have their own set of clinical challenges – some related to the difficulties of treating children with drugs that are dosed for adults, and others related to the risks for child development that anticoagulants carry.
“Children are not little adults,” said Dr. Raffini. “There are many unique issues in pediatric patients with VTE.” These include a rapidly evolving coagulation system; limited vascular access that reduces the ability to effectively deliver anticoagulants; and differences in diet – particularly vitamin K concentrations in young children. “Despite these known differences, there is very little high-quality evidence regarding the use of anticoagulants in children,” she said, as well as a lack of pediatric-specific drug formulations. For instance, there is no liquid formula for warfarin, and pre-filled LMWH syringes are based on adult weights. Multiple sets of dosing recommendations for neonates and children further complicate matters.
In another study presented at the ASH annual meeting, researchers identified multiple factors that increased the risk of VTE and bleeding for children receiving hematopoietic stem cell transplant (HCT), including: older age, prolonged hospitalization, and hematologic malignancy. More than 8,000 children underwent HCT; 5.26 percent of them developed VTE after discharge, but the incidence of VTE among this population has remained stable over the last 10 years.²
Another major concern in children who require chronic anticoagulation therapy is the risk for anticoagulant-induced osteopenia in patients with developing bones. “This is a theoretical concern for all the drugs being used, and unfortunately it hasn’t been investigated,” said Dr. Raffini, adding that many children who are on anticoagulants have additional risk factors for osteopenia.
While the management of VTE in children is challenging, whenever possible “the management should be guided by pediatric hematologists with experience with thrombosis,” Dr. Raffini concluded. “Age-related issues need to be considered when developing a treatment plan, and we also need dosing recommendations for old and new anticoagulants.”
- Rajasekhar A, Piccicacco N, Pittman J, et al. Practice patterns of venous thromboembolism prophylaxis and adherence to standardized VTE order sets in hospitalized obese patients. Abstract #3523. Presented at the 2014 ASH Annual Meeting, December 7, 2014.
- Batra S, Salud L, Duda P, et al. Trends of venous thromboembolism (VTE) and risk factors for developing VTE in pediatric patients undergoing hematopoietic stem cell transplant (HSCT) in children’s hospitals – a PHIS Database study. Abstract #3688. Presented at the 2014 ASH Annual Meeting, December 6, 2014.