Safety Profile of Warfarin Summarized From Various Trials

Manesh Patel, MD: Let’s summarize the trial data we found and then talk about where we went from that. I would just say by a quick summary that the 4 trials pretty quickly over a year and a half came out and met the mark broadly against warfarin and showed that all were noninferior. Some met the superior standard. Some showed and all of them showed that there was a reduction in fatal bleeding when it was ICH [intracerebral hemorrhage]. A lot of people would have said with those findings, a therapy that’s able to be taken without monitoring, a therapy that doesn’t lead to fatal bleeding or ICH at the same level—which we were worried about when we started the studies, and is at least as good if not better than warfarin—should be taken up...

Robert M. Califf, MD, MACC: It’s a real lesson in how little we actually know. I didn’t hear anybody saying that these drugs were going to reduce a risk of ICH when the trials started. That was really not ours and, in fact, the worry was in the opposite direction.

Bernard J. Gersh, MBChb, DPhil, MACC: Why do you think that reduced the risk?

Robert M. Califf, MD, MACC: There are some reasonable theories about differential effects and different parts of the human biology, but I don’t think anybody really knows.

Bernard J. Gersh, MBChb, DPhil, MACC: There was one interesting substudy from the ARISTOTLE trial. And Chris was co-PI [principal investigator] of that trial.

One of the papers showed that apixaban is a slightly less harmful anticoagulant than warfarin. This may be why it is safer. Apixaban is probably less effective, at least based on biomarkers of coagulation. It may be less effective, and this also may be why 1 of the NOACs [new oral anticoagulants] was tested in mechanical valve, prosthetic valves...

Robert M. Califf, MD, MACC: Bernard, your theories are nice. But as long as we’re talking about heaven, I still love the phrase, “In God we trust. All others must bring data.” There are all kinds of theories, but the only thing that really matters is what the data show from the clinical trials. Otherwise, you’re just guessing.

Bernard J. Gersh, MBChb, DPhil, MACC: Well, what we did do is we looked at coagulation factors and the effect of warfarin versus apixaban on coagulation factors, and it’s less.

Robert M. Califf, MD, MACC: But if we based our therapy on coagulation factors, think about what bad shape we’d be in right now.

Manesh Patel, MD: No, and I think the point you’re making, Rob, is what’s unique. I think what Dr Gersh said is that some of that might be the effect. The second might be, what is the warfarin hazard? Because then there’s another opportunity in these patients. We didn’t think, when starting, that it was so effective that there would be a warfarin hazard. But 1 of the hazards clearly that warfarin has, at least in all 4 studies across different mechanisms, is a reduction in ICH [intracerebral hemorrhage]. From the perspective of someone who started, we didn’t know much. We didn’t think we were going to win on that front. We didn’t think patients would have opportunity. But let me take the last few minutes of this session and say, yeah, so we did all that, but 2020 is the first time that patients around the world, more than 50%, have had 1 of the new drugs. It took us 10 years from talking about them and presenting the evidence to get to here, where we still have the majority of people in the world getting warfarin until last year or into this year.

Bernard J. Gersh, MBChb, DPhil, MACC: And the guidelines changed.

Manesh Patel, MD: What do we do, Chris, about this? I call it the lag, the 10-year lag that took us from getting from where we stood on podiums and presented data that said these drugs are effective and different and better than warfarin. And now we’re here, at least 10 years later, where we’re starting to see them used in the majority of patients.

Christopher Granger, MD: Yeah, and I think it’s better than it used to be. I mean, we used to say it would take 15 or 20 years. And this is better. There are several themes. There’s therapeutic inertia. People are just familiar with something and they don’t like to change. Even if it’s not very good, they know it. Cost is a big barrier, especially in lower-income health systems, and insurance companies of course want to limit the use of new, expensive medications. Then there are concerns about some things that we didn’t anticipate, like the fact that there was no reversal agent. There’s not really a very good reversal agent for warfarin. It was irrational to say because there’s not a good reversal agent for a drug that has a half-life of 12 hours. You wouldn’t use it. Nonetheless, I think people look for reasons not to do new things sometimes.

Robert M. Califf, MD, MACC: I actually think this has been pretty quick on a relative scale. I mean, when did the trials actually present their results? What was the year?

Manesh Patel, MD: 2010, 2011.

Robert M. Califf, MD, MACC: It takes time. For every truthful statement out there about a new therapy, there are dozens of untruthful statements. People are rightfully cautious. If there was anything that we didn’t do as well as we could have, it was having harmony about what all the data showed together, that it is more important to at least get on 1 of the new agents. I look at it and say, “What if every disease was approached this way?” We saw a problem, we wanted to maintain the benefit of warfarin. We empirically demonstrated that the big difference was a reduction in ICH. It was unexpected. We went on to develop the reversals, which I know we’ll talk about, but the goal is to optimize the benefit while reducing the risk side of the equation. I think we’ve made a lot of progress.

Trancript edited for clarity.