Review of APEX and MARINER Trials

Deepak Bhatt, MD, MPH: Let’s get into the trials a little bit. Maybe start with APEX.

C. Michael Gibson, MS, MD: I think we’ve heard a lot in the opening discussion. I have to put a little finer point though on the problem with the injectables, which is the injection. A lot of patients don’t want to be injected. About 15% to 20% of patients will say, “Please don’t come at me with that needle again.”

Deepak Bhatt, MD, MPH: And there’s probably another 15%, 20% who don’t say it but then don’t do it.

C. Michael Gibson, MS, MD: Don’t do it. That’s in the inpatient setting, imagine in the outpatient setting. I had a family member who got injected not subcutaneously, but intramuscularly with enoxaparin and had a rectus sheath hematoma and a basketball sized hematoma.

Deepak Bhatt, MD, MPH: I don’t think it’s as uncommon as one might otherwise imagine it.

C. Michael Gibson, MS, MD: I’ve seen the safety side. I had 2 parents both with pulmonary emboli. I’ve seen both sides of this.

Deepak Bhatt, MD, MPH: A rectus sheath hematoma, those are extremely painful, by the way, if anyone in the audience hasn’t seen one.

C. Michael Gibson, MS, MD: We need better solutions. In the APEX study, we really wanted to see could we strike the right balance? Could we reduce these events without causing bleeding? That’s really the issue. We randomized patients to either the standard treatment, enoxaparin in the hospital, or to an oral drug called betrixaban, which has a longer half-life, a factor Xa inhibitor, for an extended duration out to 35, 42 days, double-blind. You got both active drug and a placebo, matching placebo, so no one knew what was going on. The primary endpoint was both symptomatic VTE [venous thromboembolism], as defined earlier, as well as a positive ultrasound. And we saw an event reduction from 8.5% down to 6.9%. In terms of absolute risk reduction and number needed to treat, very good. That came with no penalty in terms of major bleeding. I think it was 0.6 % and 0.7% rates of major bleeds.

I think some of this is because the drug did have a half-life that didn’t get big peaks and valleys, a longer half-life. The renal clearance is such that you could give it across a range of patients with different renal clearances. We overcame some of the problems that have been seen before with too much bleeding. We could prevent some events with extended duration prophylaxis, but the penalty was too high. I think it gave us hope that we might be able to accomplish this without excess bleeding.

Deepak Bhatt, MD, MPH: Yes, I know a really great trial and great results, great acronym as well. I like APEX.

C. Michael Gibson, MS, MD: Yes.

Deepak Bhatt, MD, MPH: Maybe we can talk a bit about MARINER and MAGELLAN. Any takers for those trials?

Gary Raskob, PhD: Sure. I’ll start with MARINER, and then maybe Alex wants to build on that with MAGELLAN because it’s a progression.

Deepak Bhatt, MD, MPH: Yes, it is.

Gary Raskob, PhD: The MARINER study really sought to address a simple question, which is in high-risk medical patients admitted to hospital like we’ve talked about, they get prophylaxis in hospital, they don’t have venous thromboembolism, they’re ready to be discharged. Should I now prescribe extended prophylaxis for up to 45 days? The patients were randomized to 10 mg of rivaroxaban or 7.5 mg of rivaroxaban in a stratified way, or placebo. The study focused on symptomatic events and VTE-related deaths out to that time. The study was large, 12,000 patients, was not able to show a statistical reduction in fatal events, but did show a reduction symptomatic venous thromboembolic events independently adjudicated by an independent committee. Similarly to APEX, and Mike’s point is very important, the risk of major bleeding was very low, at about 0.3%, 0.4%.

We have 2 studies now, and I think this is a crucial thing. We have 2 studies now with oral anticoagulant options that we can give safely for prevention. That means we should get away from any lingering psychology about anticoagulant bleeding in these prevention situations, which is really driven from our history with warfarin and how people have thought about that. The final thing is, just to build on Mike’s what was impressive, is that if you look at these studies, now we talk about these rates of events and major bleeding, it’s pretty clear that the number of deaths due to pulmonary embolism in these big studies, the APEX—7500 patients and MARINER–12,000 patients, the number of deaths due to pulmonary embolism was about 20 times the number of deaths that we cause by a bleed.

Deepak Bhatt, MD, MPH: That’s a really important ratio.

Gary Raskob, PhD: VTE causes much more death and morbidity over 4 to 6 weeks after hospital than we cause harm by trying to prevent it. It’s important because doctors first do no harm, and they’re really worried about causing bleeding in these patients. Our regimens now are much improved if you select the patients properly.

Deepak Bhatt, MD, MPH: Sort of like AFib [atrial fibrillation] where physicians under anticoagulate, not because they don’t know the data or they don’t want to help their patients, it’s just that fear of bleeding. As you know, that often is exacerbated in that higher-risk, older patient who’s at the highest risk for a thromboembolic complication from AFib where they don’t get anticoagulated. Sort of the same thing here, it’s that fear of bleeding.

C. Michael Gibson, MS, MD: We saw NOACs’ [new oral anticoagulants’] risk of fatal bleeds with betrixaban, and then we looked at net clinical benefit, being what was the risk of fatal or irreversible harm events. On the fatal irreversible side and on the ischemic side, we looked at pulmonary embolism. We actually added in stroke and heart attack. On the bleeding side, we had ICH [intracerebral hemorrhage] and fatal bleeds. And there, treatment really was more in favor on the net benefit side. When you lump in all the things you worry most about, there’s a tremendous advantage for treatment.

Transcript edited for clarity.