The Pacemaker

AUTHORS

Andy-kach_thumbnail
Andy Kach
Principal
Bhargav_Mantha_thumbnail Brian_Chapman_thumbnail
Brian Chapman
Principal
Maria_thumbnail Matt-Scheitlin-London_thumbnail Tobi_Laczkowski_thumbnail Will_Randall_thumbnail

Latest Posts

How COAPT’s ‘All or Nothing’ Trial Design Is Making Sense of a Messy Disease

Posted by Kate Templeton on October 12, 2018



targeted clinical trialsLandmark. Groundbreaking. Blockbuster. All of these words, and then some, have been used to describe Abbott’s recent trial (COAPT) to support MitraClip’s indication expansion to include functional mitral regurgitation.

The trial decisively demonstrated that transcatheter mitral valve repair using MitraClip reduced hospitalizations for heart failure by 47% and all-cause two-year mortality by 38% when compared to medical therapy alone in patients with heart failure and severe functional mitral regurgitation (FMR). When the principal investigator, Dr. Greg Stone, announced the results to a standing-room-only crowd at TCT 2018 last month, the data was met with spontaneous applause.

In a field where non-inferiority trials are often the norm, it’s easy to see why the dramatic improvement caught many off-guard, especially as it comes not even a month after the results of another study using the device (MITRA-FR). In stark contrast, MITRA-FR found no improvement in rehospitalizations or all-cause mortality.

Following the announcement of the COAPT results, a frequent discussion topic was how to make sense of two such different results using the same device to treat FMR. A number of theories have been suggested:

  • Overall trial size: COAPT ultimately enrolled 614 patients, while MITRA-FR had a smaller patient sample at 304.

  • Patient selection: COAPT patients had more severe disease and, for the most part, had smaller, less dilated left ventricles. This is particularly noteworthy given the ongoing debate about whether the valve disease causes the ventricular disease or vice versa, or if it’s a self-reinforcing downward spiral. Interestingly, though the analysis hasn’t been formally shared yet, there was discussion that some COAPT patients who didn’t benefit as significantly from MitraClip had similar ventricle characteristics to the patients enrolled in MITRA-FR.

  • Trial design: MITRA-FR was designed to be a pragmatic trial, and its principal investigator argued that the patient selection mirrors what he would expect to see in a “real-life” setting. In contrast, COAPT had stringent patient selection processes in place to ensure that only a certain patient profile would be enrolled. An independent echocardiographic core lab verified each candidate’s FMR disease severity, and a multidisciplinary heart team at each site reviewed the candidate before forwarding him or her onto a central patient eligibility committee for a final decision. The rigorous process and careful adherence to the study protocol stretched trial enrollment out to six years.

  • Medical therapy: In MITRA-FR, patients’ medications could be changed throughout the trial, and some have suggested that patients randomized to the control arm were given more aggressive medical therapy than they’d received prior to trial enrollment. Conversely, to be enrolled in COAPT, a patient had to be symptomatic while taking the maximum tolerated guideline-directed medical therapy. This requirement is largely why enrollment took so long to complete, though the extra time seemingly paid off as many attributed the dramatic result to the rigor of the trial.

RELATED CONTENT 

BLOG POST: Three Takeaways From AdvaMed’s 2018 MedTech Conference

BLOG POST: How the Johnson & Johnson Medical Devices Companies Are Responding to the Changing Healthcare Landscape


 

While TCT 2018 may be over, the debate on how to interpret COAPT and MITRA-FR is not. By the end of the conference, the general consensus seemed to be that the trials told a compelling story together that neither could alone—specifically, that patient selection will play a vital role for FMR treatment moving forward. The optimal FMR patient for MitraClip seems to be someone who has failed to improve on maximum guideline-directed medical therapy, has moderate to severe mitral disease, but critically does not have an enlarged ventricle.

As we look onward to the likely expansion of MitraClip’s label, a key success factor will be how Abbott addresses the messaging and educational challenges of having multiple randomized trials for the same device. If, following three days of constant debate, the interventional cardiology community couldn’t come to a clear consensus on how COAPT and MITRA-FR will impact the way that they practice, it seems difficult to believe that more removed general cardiologists, heart failure specialists and primary care physicians will get to the bottom of it.

For those who decide to do a research on their own, they’ll find two seemingly conflicting articles published in the New England Journal of Medicine within a month, a mixed New York Times piece, and plenty of TCTmd articles showcasing a wide variety of opinions. Unfortunately, in an age of 140-character takeaways, it’s increasingly unrealistic to expect someone to dig to the level of detail that they’d need to in order to piece together the bigger story told by these two trials. COAPT represents a tremendous step forward, but for that potential to be realized, this bigger story must be convincingly told. Without that clarity, patients who otherwise could have been successfully treated with a MitraClip will simply continue on their meds as they’ve done in the past.

Abbott and the principal investigators behind COAPT took a significant roll of the dice when they designed the study, not only in powering it for superiority but also in the specificity of the patient profile they selected. With a narrow patient population, they were able to remove many potential confounding variables, and, in doing so, set themselves up to have either a blockbuster study if they had chosen the patient profile correctly, or a flop if they hadn’t.

In an era in which we’ve learned to successfully treat many of the obvious causes of death that haunted our parents’ and grandparents’ generations, we’re now pushing the boundaries of science into increasingly messy disease modalities like FMR, where trial design is both more complex and more critical to get right than it has been previously. As we look forward to future trials in this space and others like it, perhaps the critical lesson we’ve learned from COAPT is the importance of putting a stake in the ground, rigidly adhering to the protocols, and hoping that it pays off in the end. Thanks to the hard work of Dr. Greg Stone and his fellow investigators, we now know a lot more about this disease type than we ever have before, and clinicians (hopefully) will soon be armed with a new tool to treat a group of patients who historically have had few options.

Topics: abbott, clinical trials, clinical trial results, targeted therapy, clinical trial recruitment, medtech innovation, cardiology, trial size, COAPT, patient selection

Click here to subscribe to The Pacemaker

Leave a comment

AUTHORS
Brian_Chapman_thumbnail
Brian Chapman
Principal,
ZS Associates
Tobi_Laczkowski_thumbnail
Tobi Laczkowski
Principal,
ZS Associates
Will_Randall_thumbnail
Will Randall
Manager,
ZS Associates
Matt-Scheitlin-London_thumbnail
Matt Scheitlin
Associate Principal,
ZS Associates
Andy-kach_thumbnail
Andy Kach
Associate Principal,
ZS Associates
Bhargav_Mantha_thumbnail
Bhargav Mantha
Associate Principal,
ZS Associates
SUBSCRIBE

Get 'THE PACEMAKER' Updates

Subscribe to receive email notifications whenever new blog posts are published.

×

Subscribe by Email

Search by Topic

see all