NOACs for the Medically Ill and Risk of Extended Prophylaxis

Manesh Patel, MD: We talked about chronic vascular disease. We talked about atrial fibrillation [AFib]. Maybe I’ll end with what I’ll call medically ill and DVT [deep-vein thrombosis], the VTE [venous thromboembolism] prophylaxis. I think the agents have all been shown to help with at least treatment of those. In thromboprophylaxis maybe, Sean, you could tell us a little about how you think about some of the data from the agents there. Certainly I know there’s been a conversation from MARINER and others about how we think about these patients.

Christopher Granger, MD: It’s a really interesting area. The MARINER trial was a 12,000-patient trial that looked at patients who were acutely ill and randomized them to 10 mg of rivaroxaban versus placebo and treated those patients with rivaroxaban for 45 days, looking at events of clinically significant DVT PE [pulmonary embolism]. What the trial found was that there was no statistically significant difference in the rivaroxaban arm versus the placebo arm. I think people were somewhat surprised.

Bernard J. Gersh, MBChb, DPhil, MACC: Wait. Was it the placebo-arm or warfarin?

Sean D. Pokorney, MD: It was no therapy. This was extending the medically ill prophylaxis out past hospitalization. It’s an interesting population because when you look at DVT…

Bernard J. Gersh, MBChb, DPhil, MACC: It’s not a DVT population. It’s just prevention.

Sean D. Pokorney, MD: Prevention. It’s prevention. When you look at patients who go on to have DVTs after hospitalization, about three-quarters of people who have DVTs have them within 30 days of hospitalization. For those patients who leave the hospital, it’s a high-risk period. They usually have higher rates of inflammation. They are less mobile for a lot of reasons. Those patients tend to have higher risk, higher event rates. But in MARINER there was no statistically significant difference and clinically significant events. Again, that was somewhat surprising to people. That was really a follow-up trial of MAGELLAN. And in the MAGELLAN trial it was also a rivaroxaban study that included asymptomatic DVT. When you look at all the trials that were done, including MAGELLAN, they all showed that there was a...

Manesh Patel, MD: There was a population.

Sean D. Pokorney, MD: There was a decrease in the rates of DVT PE events, but it was mostly in the asymptomatic population. There were signals in MAGELLAN that showed that there might be a difference in clinically significant events. Again, that’s why MARINER was done. Unfortunately, they weren’t.

Manesh Patel, MD: It’s important to know that it’s 1 of these things we often do in trials. Like who’s the population that gets the most benefit. Putting the 2 trials together, there’s at least some indication that there’s a benefit and some therapeutic use potentially in those patients. One of the things I would say is the risk score and then the high D-dimers tend to identify patients who are medically ill who have a higher risk. For each individual now in practice, this is less like our AFib data in which we were very clear. Here you’re going to be careful about that population that’s medically ill that’s been in the extended...

Sean D. Pokorney, MD: We still need to identify the exact population, the exact risk scores. You’re right. I think there is a subpopulation that really truly is going to benefit for a longer-term prophylaxis after hospitalization, but that population is a little less clear.

Manesh Patel, MD: What a tremendous time, though. Rob, to your point, when we started this we were trying to replace warfarin for AFib. Now we have AFib, AFib plus PCI [percutaneous coronary intervention]. We didn’t talk about mechanical valves. We’ll come back to that; that’s a future date, probably. Then we talk about chronic vascular disease. Treating DVT and PE and now indicated in and able to potentially treat some medically ill patients who have thromboprophylaxis. It’s been a pretty amazing 10 years about evidence. Certainly some of these compounds have gotten several indications.

Chris, maybe I’ll end with saying we talked about the agents, we talked about how we got them through the noninferiority barrier into actual effect. How big a deal is, what are the risks of extended thromboprophylaxis? And are the reversal agents and those that are now on the market helping? Have you seen them used a lot? Tell me about that.

Christopher Granger, MD: Really not very much, Manesh. I do think the challenge is defining the population. It’s such a heterogeneous group. It includes patients who’ve got pneumonia, patients who are debilitated going to skilled nursing facilities.

Manesh Patel, MD: Cancer data now with patients...

Christopher Granger, MD: Cancer, heart failure. There are the high-risk patients—some of whom are getting treated who are essentially still bed-bound but with some chance of ultimate recovery—where the risk is so high that this is better. They used to be sent home on enoxaparin, and this is a lot easier and less expensive. There is a population where it’s being used, and the data are strongly supportive of it. But it’s still a pretty small population.

Manesh Patel, MD: That’s probably right. Then I think about just overall use of NOACs [novel oral anticoagulants]. You would say what a blockbuster it’s been for the care of our patients and the number of indications and things that were actually making their lives easier and hopefully having less bleeding and actually having less strokes or thrombus in their legs or coronary events. It’s been a pretty big effect.

Bernard J. Gersh, MBChb, DPhil, MACC: I think it has, and we’re on the threshold of even a bigger game changer, as we sort out over the next 3 to 5 years how to deal with asymptomatic silent or clinically silent atrial fibrillation. Which brings us back to 1 of the very first questions: the duration of AFib. How much is enough? How much is important? This is a huge population. We recently completed a trial called the REVEAL trial, in which we took patients in sinus rhythm—who had a CHA₂DS₂-VASc score of 2 plus 1 other risk factor—and put implantable loop monitors into them. They had no history of atrial fibrillation. Well, 29% at 18 months had documented atrial fibrillation. It wasn’t a treatment trial, exactly the same, I think almost exactly the same percentage in the Canadian ASSERT-II trial. This is another huge population out there that maybe will benefit with anti-coagulation. We don’t know. But that would change the landscape.

Transcript edited for clarity.