COMMENTARY

Don't Ignore the Many Lessons of the MitraClip Failure

John M. Mandrola, MD

Disclosures

August 30, 2018

Medical students learn many basics when they start cardiology rotations.

One fact is that the heart compensates for left ventricular (LV) failure by dilating. Another is that LV dilation causes mitral annular dilation, papillary muscle dysfunction, and "secondary" mitral regurgitation (MR).

The third lesson transcends cardiac physiology and extends to all of medical practice: It's best to treat the underlying cause of a problem than its effects.

MR due to LV failure is more common than MR due to disease of the valve apparatus (primary MR). Secondary MR is an important problem because it strongly associates with worse outcomes in patients with heart failure.

MitraClip (Abbott Structural Heart) is a percutaneously placed device that emulates an edge-to-edge surgical repair of the mitral valve.[1] Approval of MitraClip in the United States is limited to repair of primary MR, but in Europe the device is "approved for general use" and has been used extensively in patients at high risk or contraindicated for MV surgery, most often for secondary MR.[1]

These were exactly the patients studied in MITRA-FR,[2] a randomized controlled trial (RCT) presented here at the European Society of Cardiology (ESC) Congress 2018.

The MITRA-FR Trial

French investigators randomized slightly more than 300 patients who had severe secondary MR, an LV ejection fraction between 15% and 40%, and symptomatic heart failure to mitral valve repair with MitraClip or medical therapy. The primary outcome was a composite of all-cause death or unplanned hospitalization for heart failure.

Our news story has the details, but the results are easy to report: At 1 year, there were no significant differences in the primary outcome or the two components of the primary outcome. Further evidence that the device lacked efficacy was that the per protocol analysis, which excluded patients in the active treatment group who did not receive the device, also revealed no difference in any of the outcomes.

Procedural complications occurred in 14.6% of patients, including tamponade (n = 2), cardiac embolism (n = 2), cardiogenic shock (n = 4), and serious hemorrhage (n = 5). By the end of the study period, 7 patients in the intervention group had ischemic or hemorrhagic stroke compared with only 1 in the medical group.

Comments

It would be wrong to say that use of this device for this indication provided no benefit to patients. The more accurate conclusion is that the MitraClip caused net harm. That's because in addition to no benefit in the efficacy endpoints, patients in the device group endured a procedural complication rate of more than 10%, including a sevenfold higher rate of stroke. 

Once again, we can learn both specific lessons about the treatment of people with heart failure and more general lessons on the acceptance of untested therapeutics.

On the matter of secondary MR complicating LV failure, I led with the basics of cardiology because a medical student could have predicted the outcome of this trial—and likely the COAPT trial, which will be reported soon. In secondary MR, the mitral valve is normal; the problem is with the ventricle. Even if you had a perfect fix for functional MR, and MitraClip is far from perfect, if you don't fix the failing ventricle, heart failure continues.

The more important lesson here is the excess optimism for this unproven device. Hindsight is sharp, but support for using MitraClip in patients for secondary MR rested on two dubious lines of evidence. 

The first of these faulty ideas was that since the device "worked" for primary MR, it might also work for secondary MR. That assertion stretches the meaning of the verb worked.

Let's review the pivotal MitraClip study. EVEREST II[3] was an RCT testing MitraClip vs surgical therapy in nearly 300 patients with severe primary MR. MitraClip proved inferior to surgery because significantly fewer patients in the device group reached the primary efficacy endpoint of freedom from death, surgery for mitral valve dysfunction, or grade 3+-4+ MR at 12 months (55% vs 73%; P = .007). Five-year follow-up confirmed these results.[4] Inferiority of the device was driven by increased rates of  3+-4+ MR (12.3% vs 1.8%; P = .02) and surgery (27.9% vs 8.9%; P = .003) in patients treated percutaneously.

The other dubious line of reasoning for using MitraClip in patients with secondary MR was that data from 14 registries of nearly 4000 patients provided reassurance the device works (see Table 4 in this reference).[1] Registry studies without control groups—no matter how many are published—give scant few clues on efficacy.

The lesson of MITRA-FR extends to many other areas of medicine: Just because there is an unmet need for new ways to treat people with advanced disease doesn't mean we should embrace unproven devices, especially those that come with serious harms and significant costs.

If the other two trials of MitraClip show similar results, which is likely, thousands of patients will have been harmed by embrace of this technology.

One simple way to avoid this degree of iatrogenesis is to require RCT data before widespread adoption. Imagine if  even a fraction of the thousands of patients with secondary MR implanted with this device were enrolled in clinical trials. We'd have had this answer a lot sooner.

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