COMMENTARY

COMMANDER HF: What Now for Anticoagulation in Heart Failure?

Ileana L. Piña, MD, MPH; Mandeep R. Mehra, MBBS

Disclosures

September 18, 2018

Ileana L. Piña, MD, MPH: Hello. I'm Ileana Piña from Albert Einstein College of Medicine and Montefiore Medical Center in the Bronx. I'm here at the European Society of Cardiology (ESC) Congress in Munich, where there are 32,000 attendees, making it one of the largest congresses in the world on cardiology.

With me today is a dear friend of many years, Dr Mandeep Mehra, who is the director of the heart and vascular center at Brigham and Women's Hospital and professor of medicine at Harvard. He's joining us today to speak about COMMANDER HF. Welcome, Mandeep.

Mandeep R. Mehra, MBBS: Thank you for having me.

Anticoagulation in HFrEF With CAD

Piña: My pleasure. First, give us an overview of COMMANDER HF.

Mehra: COMMANDER HF was a unique trial in the space of heart failure with reduced ejection fraction.[1] It's based on the hypothesis that hypercoagulable states and hypercoagulable pathway activation may play an important physiologic role in the natural history of heart failure. Why is that? Well, we've become accustomed to the neurohormonal hypothesis and remodeling.

We're now learning that when patients are hospitalized with heart failure, a third of them can leak troponin, for instance, and there's inflammation. One of the sentinel components that may be influencing coagulation pathway activation, inflammation, and endothelial dysfunction is thrombin generation—that is, bursts of thrombin that occur as a result of hypercoagulable state and pathway activation.

Piña: Do you think the inflammation is another trigger of the hypercoagulable state?

Mehra: I think so. It's just like Virchow's triad. You get circulatory impairment, inflammation, and you have endothelial dysfunction. The rationale for COMMANDER HF rests on the notion that the field of testing warfarin in heart failure with reduced ejection fraction has been an abysmal failure. We haven't been able to enroll patients to completion, the trials have shown inconclusive signals, or they've been just plain negative.

Piña: WARCEF[2] was plainly negative, right?

Mehra: Right. These trials did have some interesting findings about signals in ischemic stroke reduction, but they were overwhelmed by the bleeding complications. Anticoagulants in heart failure patients with reduced ejection fraction and sinus rhythm have been a failure.

But what about using non-vitamin K oral anticoagulants (NOACs) that directly inhibit the thrombin pathway? The concept of COMMANDER HF was really based after ATLAS ACS 2-TIMI 51.[3] ATLAS 2 was a trial in acute coronary syndromes, and one of the interesting findings was that patients with acute coronary syndrome who also had heart failure showed a significant benefit on the endpoint of cardiovascular death, myocardial infarction (MI), and stroke.

Piña: It's exciting to see that signal.

Mehra: It was. That signal was based on low-dose use of NOACs—in this case, 2.5 mg twice a day of rivaroxaban—and it was quite interesting to then postulate that maybe you don't need anticoagulant doses where the bleeding risk is overwhelmed. Perhaps we can just inhibit thrombin bursts in heart failure and that may be just like neurohormonal therapy. We use mineralocorticoid antagonists to antagonize the neurohormonal pathway and not as a diuretic. So we try to use angiotensin-converting enzyme (ACE) inhibitors, not as a hypertensive but as a neurohormonal.

Piña: Yes, we've been doing this for a long time.

Mehra: So that was the rationale; it's an exciting postulation. We developed COMMANDER HF as a trial to look at this population of patients with heart failure and reduced ejection fraction in sinus rhythm who had just had recent clinical worsening.

Piña: Did they have to have a hospitalization or just a visit?

Mehra: Both. Most of the patients were enrolled post-hospitalization, but if you had a clinical worsening where you were in an emergency department and required diuretics, you [were enrolled]. Patients in the trial were enrolled within a week after the events were stabilized.

Piña: That's very early, where you would think that the thromboembolic risk is the highest, right?

Mehra: Correct. We've learned from the medical illness trials in venous thromboembolism that these patients not only have a risk for thromboembolism during the hospitalization, but the post-hospitalization phase is equally, if not more, vulnerable because the risk for events actually starts to accumulate.

We designed [COMMANDER HF] as a definitive trial. This is a trial of 5000 patients randomized post-worsening of heart failure who were in sinus rhythm with reduced ejection fraction. The trial was placebo controlled and managed for a chronic phase. The median follow-up in COMMANDER HF was about 21 months.

The other unique thing about COMMANDER is that it was an event-driven trial. We had postulated that for the trial to be definitive, we would need to accrue at least 1200 events to give it sufficient power, and we did. So the trial was conducted in a timely manner. It enrolled the patients that we envisioned we would enroll. It also was followed to the accrual of sufficient endpoints.

Mostly Outside US Sites

Piña: How many sites did you have?

Mehra: We had somewhere around 40-50 sites. (Editor’s Note: Dr Mehra misspoke there were 628 sites across 32 countries in COMMANDER-HF)

Piña: Where were they?

Mehra: The sites were all over the world. In fact, nearly two thirds of our patients came from Eastern Europe. This has become a trend now with most heart failure trials. It was quite difficult to enroll patients from within the United States.

Piña: Really? Were there competing trials?

Mehra: I don't think there were competing trials. We don't really understand this, but about 64% of our patients came from Eastern Europe. Of course, we were quite cautious with that because right when COMMANDER HF was ongoing, we began to receive reports from trials like TOPCAT,[4] demonstrating that there is significant regional heterogeneity in event rates, and that really did give us some pause.

It was very concerning to us. We actually did something quite interesting in the trial. We had an early trial amendment where we forced the inclusion of a B-type natriuretic peptide (BNP) entry criterion.

Piña: What was your criterion for entry?

Mehra: If you look at the population as a whole, the bioactive BNP median levels were about 700 pg/mL and the NT-proBNP levels were about 2500 pg/mL. It's a really well-constructed population of heart failure patients. In fact, the event rates that accrued suggest that that was indeed the case.

Piña: So, in 21 months you saw the event rates you were looking for?

Mehra: Oh, absolutely. In a median 21 months of follow-up, we accrued 1200 events in the trial. Of course, the trial results are quite interesting. Our null hypothesis was proven and we were unable to show any significant benefit on the primary composite endpoint, which was death, MI, or stroke.

Unlike other trials, which were cardiovascular death, MI, or stroke, this was all-cause death, MI, or stroke as a primary endpoint.

Piña: You didn't have a Clinical Events Committee?

Mehra: We did not have a Clinical Events Committee because we did expect that deaths would be the predominant outcome variable. Strokes are fairly easy to adjudicate at the local point of care. One could argue about MI.

Piña: What about hospitalizations? Did you collect them?

Mehra: Our secondary endpoint was to look at rehospitalizations for heart failure, to look at all hospitalizations, and to look at cardiovascular death and heart failure rehospitalization. We found no difference in hospitalizations. We found no difference in the primary endpoint or in rehospitalization rates.

What was interesting, though, is that vascular events like stroke and MI did trend in the right direction. Of course, when the primary endpoint is negative, that's all we can say. However, the hazard ratio for stroke was 0.66, indicating that there was a 34% reduction in strokes; and the hazard ratio for MI was 0.81, indicating that there was about a 19% reduction in MI.

Neutral Trial

Piña: I'm sure you're going to delve more and more into the data to try to compare the patients of different regions.

We must respect the heterogeneity of heart failure populations.

Mehra: We are, and what is pretty clear to us is that this trial was neutral because it was overwhelmed by deaths and pump failure. There is, in our minds, a very clear signal on the atherothrombosis pathway, where the drug does appear to do what has been observed from ATLAS 2 or from COMPASS.[5]

Piña: Are those the ischemic cardiomyopathy patients who benefited or have you been able to [determine which patients]?

Mehra: [In COMMANDER HF], we only included patients who had at least one coronary vessel with a 50% or more stenosis. Over two thirds of the patients in the trial had had a prior MI.

Piña: So you had a pretty high-risk population?

Mehra: Yes. This would be a patient population with heart failure and reduced ejection fraction with coronary artery disease. That's the nuance. And yet, we did not see that the outcomes and the natural history of this population changed.

Piña: Do you think it's time for us in the heart failure world to abandon the concept that we are at risk for thromboembolic events post-discharge? We don't anticoagulate patients anymore.

Mehra: I think that we must respect the heterogeneity of heart failure populations. I think if there's anything we've learned from neutral or negative trials in our space, it is that you cannot look at heart failure as a seafood stew. The idea that this trial definitively closes the argument of thromboprophylaxis in other populations is perhaps erroneous. What it does tell you is that in this particular population, there is no clear rationale for using it.

Piña: Sounds like a sick population with a previous hospitalization, a proBNP that's pretty high, but you still could not find a difference.

Mehra: If in 21 months you have 5000 patients and you accrue 1200 events, the majority of which are all-cause deaths, that's a pretty sick population. We've shown that in this post-hospitalization or post-worsening population with coronary heart disease, there is no population-wide benefit that we can get.

Piña: So they may have to individualize for somebody who's had a stroke previously.

Mehra: I would love to see a deep dive into strokes, for instance, in this trial to try to understand the risk markers for strokes.

Piña: Your MI patients are probably on dual antiplatelet therapy (DAPT).

Mehra: That's a great point. A large number of these patients were on DAPT, and there's another analysis that needs to be done. We've shown that overall the results are neutral.

Piña: I think you're going to learn something from this study as you start to really dissect [the data].

Mehra: The learning is just beginning. I think what we need to start doing now is reconciling the information we have from COMMANDER HF in the context of what was observed post-hoc in COMPASS or in ATLAS 2-TIMI 51.

We have to start comparing populations. This is not the first time that a beneficial drug has not worked in heart failure. Statins are a classic example.

Piña: Several aspirin trials here, too, have also been negative. I want to thank you for your time. Congratulations [on your work on this trial].

I want to thank the audience for joining us today. Stay tuned for more reports from ESC. Have a great day.

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