In this episode I’ll:
1. Discuss an article about the safety and efficacy of apixaban in patients at extremes of body weight.
2. Answer a drug information question about the diagnosis of adrenocortical insufficiency without using Cortosyn.
Lead author: Stefan H. Hohnloser
Published in Circulation March 2019
Guidelines from the International Society on Thrombosis and Haemostasis recommend against the use of apixaban in patients with extremely high (>120 kg) or low (≤60 kg) body weight. The reason given for this recommendation is a lack of clinical data in this population, as well as pharmacokinetic data from healthy volunteers that showed statistically different levels of drug exposure at extremes of body weight.
The authors of this study sought to increase the amount of clinical data available by performing a post-hoc analysis of the ARISTOTLE trial. This was a randomized study of 18,000 patients comparing apixaban with warfarin for the prevention of stroke in patients with atrial fibrillation. Patients were stratified by body weight (≤60, >60-120, >120 kg) using a Cox regression model. The primary efficacy and safety outcomes were stroke or systemic embolism and major bleeding.
Of the more than 18,000 patients in the ARISTOTLE trial, almost 2,000 weighed 60 kg or less and almost 1,000 weighed more than 120 kg. When analyzed, there was a consistent treatment effect across the 3 weight categories for apixaban versus warfarin for the efficacy outcomes of stroke/systemic embolism, all-cause death, or myocardial infarction. The safety profile of apixaban for major bleeding episodes was better than warfarin in all 3 weight categories. Although counter-intuitive, apixaban showed a greater relative risk reduction in patients in the lowest weight category with a hazard ratio of 0.55.
The authors concluded:
Our findings provide evidence that apixaban is efficacious and safe across the spectrum of weight, including in low (≤60 kg) and high weight patients (>120 kg). The superiority on efficacy and safety outcomes of apixaban compared with warfarin persists across weight groups, with even greater reductions in major bleeding in patients with AF with low-normal weight as compared with high weight. The superiority of apixaban over warfarin in regard to efficacy and safety for stroke prevention seems to be similar in patients with AF across the spectrum of weight, including in the low and very high weight patients. Thus, apixaban appears to be appropriate for patients with AF irrespective of body weight.
Because of the unmonitored, one-size-fits-all dosing of apixaban, it would be reasonable to think that apixaban has different safety and efficacy measures in patients at extremes of body weight, but this analysis helps to assuage those concerns. A post-hoc analysis is inherently risky and cannot be considered high-quality evidence. However, this analysis is in line with other retrospective reviews on the subject such as this one and this one.
Drug information question
Q: Given the Cortosyn shortage, is there an alternative agent for the diagnosis of adrenocortical insufficiency?
A: Although there is not another medication that can be used to support the diagnosis of adrenocortical insufficiency, According to the Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017 a random cortisol level less than 10 can be used in the diagnosis of adrenal insufficiency.
The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60 min of <9 µg/dl) after cosyntropin (250 µg) administration and a random plasma cortisol of <10 µg/dl may be used by clinicians. We suggest against using plasma free cortisol or salivary cortisol level over plasma total cortisol (conditional, very low quality of evidence).
For a copy of the guidelines I use for journal club with pharmacy students go to my free download area at pharmacyjoe.com/free. It’s download #5 on the list.
If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.