10 Top Tips for Safe DOAC prescribing

Thanks to all of you for reading and commenting on my blog last week on the current push for edoxaban as the preferred choice of DOAC. It generated a few sharp responses, which is not surprising as the recommendations are not without controversy! However, one of the issues I did not have enough space to cover, and which has been highlighted by a number of you, was DOAC safety. So as a follow-up, I thought it would useful to do a review of what we can do in primary care to mitigate risks with DOACs.

It’s amazing how quickly things can change with ‘novel’ drugs. I’m sure many of you remember, like me, when DOACs first came in and being really nervous about the bleeding risk (what no blood monitoring?! Not sure about that…) yet now we are dishing them out left, right and centre. There is a risk when we get to this stage of our prescribing of ‘less novel’ drugs that some of the messages about safety and appropriate prescribing can get lost or forgotten. So here are my 10 Top Tips and useful snippets for safe DOAC prescribing that we’ve collated over the past few years, and considerations if we are being asked to switch to edoxaban:

1. Here’s the ‘science bit’ - A useful therapeutics review in the Lancet in 2020 highlighted the background, evidence and unresolved issues with DOACs at the time. DOACs bind to the active sites of either thrombin (factor IIb) or factor Xa. They are all at least partially renal cleared (hence the crucial need for dose adjustment with declining renal function - see below) and can all interact to a greater or lesser degree with drugs that induce or inhibit P-glycoprotein or cytochrome P450 (importance discussed below).
2. Review the other ‘bleeders’ - sounds obvious but easy to overlook other regular medications that can increase bleeding risk e.g. NSAIDS including aspirin (ask about OTC use), SSRIs etc - can they be reduced or stopped? 
3. Review BP - correcting hypertension can obviously reduce bleeding risk (particularly intracranial haemorrhage) and in the case of AF can also reduce overall CVD risk.
4. Be aware of P-glycoprotein (P-gp) and cytochrome P450 (cyt-P450) inhibiting drugs. These enzymes are involved in DOAC clearance so if they are inhibited plasma DOAC levels can rise and bleeding risk increases. Important ones to be aware of are the macrolides (highlighted in Drug Safety Update Dec 2020) and with specific regard to edoxaban if cyclosporin, dronedarone, erythromycin or ketoconazole are concurrently used the dose should be reduced to the lower 30mg OD dose (assuming normal renal function).
5. Don’t chuck out the rat poison just yet - as discussed in my blog Aug 2021 there are some crucial times when we should NOT switch from warfarin to a DOAC - a) mechanical heart valves (as discussed in National Patient Safety alert July 2021) b) moderate/severe mitral stenosis and c) people with anti phospholipid syndrome (Drug Safety Update June 2019)
6. Be aware of extremes of weight - those over, or under weight are significantly under-represented in the trials so safe dosing in those <60kg and >120kg is uncertain. Some of the DOACs need dose adjusting if weight <60kg, including edoxaban (see CKS below). The latest ISTH statement July 2021 recommends that dabigatran and edoxaban should not be used for treatment of VTE if either BMI >40 or weight >120kg due to lack of data.
7. Should I use a PPI to reduce GI bleeding risk? Well, possibly. A lager observational study (Heart 2021) suggests that using PPIs in older adults >75 or those with high bleeding risk may reduce the risk of severe UGI bleeds. It is only observational data so we need to be careful to be too certain on this finding, but it seems a relative safe option to add a PPI for those you identify at higher bleeding risk. 
8. Use the updated CKS June 2022! All the relevant advice on doac dosing, interactions etc. including some useful other bits like advice on dental procedures are all there. CKS June 2022 link here.
9. Reversal agents - this was an important point highlighted by a colleague after my blog last week. It is important to note that edoxaban is the only DOAC that does not have a licensed reversal agent for use in the case of severe or life threatening bleeding. Andexanet alfa (Ondexxya®) is available for apixaban and rivaroxaban, and Idarucizumab (Praxbind®) is available for dabigatran. 
10. Monitor and adjust dose based on renal function - if there is one crucial take home point it is this one. As discussed above, as DOACs are all at least partially renal cleared, we need to be absolutely ‘on it’ to monitor and adjust the dose depending on renal function. Declining renal function and therefore overdosing is one significant bleeding risk we can effectively mitigate. Do NOT be tempted to use eGFR for dosing, as it is not accurate enough - use estimated creatinine clearance (easily worked out via most GP clinical systems or if not use the MDCalc online calculator), and make sure you are monitoring renal function at relevant time frames (good ‘rule of thumb’ recommended by the European Heart Rhythm Association is that once estimated creatinine clearance has fallen below 60, divide the CrCl by 10, to give the frequency of monitoring in months (e.g. CrCl = 50; divide 50/10 = 5, so do renal function every ~5 months). A good QI project for you and your team!