Use of Abbott’s MitraClip to repair patients’ mitral valve confers a significant – and enormous – mortality benefit, according to the results of the Coapt study presented at the TCT meeting at the weekend. Great news for Abbott – except for the fact that the finding could not be more different to that of the previous trial of the device, Mitra-FR.
The question now occupying cardiologists and medtech industry watchers is why Coapt succeeded when the previous trial failed. The populations enrolled and the trials’ endpoints were slightly different, but the hit in Coapt is so dazzling it is almost hard to understand how this can have happened – and what conclusions can fairly be drawn about MitraClip’s utility.
Another party that will soon be drawing conclusions is the FDA: Abbott intends to submit the Coapt data in support of an expanded indication for the device. MitraClip is currently only approved for primary mitral regurgitation (MR), in which a congenital malformation of the valve allows blood to leak back into the left atrium.
Coapt and Mitra-FR tested the device in secondary MR, where regurgitation instead results from malfunction of the left ventricle. Secondary MR is much more common than the primary form, and MitraClip is widely used off-label here. The Mitra-FR data endangered this revenue stream and the Illinois group will be keen to legitimise use for secondary MR by getting it on the label (Abbott’s MitraClip takes a knock, August 27, 2018).
Death or glory
Coapt tested MitraClip in 614 patients with heart failure and severe secondary MR, and demonstrated a statistically significant reduction in heart failure hospitalisation at two years compared with medical therapy alone. The annualised rate of hospitalisation was 35.8% with the device versus 67.9% in the control group.
Even more notably, it showed a significant cut in the death rate: 29.1% of the patients in the device group died, compared with 46.1% of those on drugs alone.
Mitra-FR analysed similar endpoints, albeit at one year, as a combined primary endpoint; no significant difference was seen between MitraClip and control. Taking death and hospitalisation separately also failed to show a difference (Upcoming events – Galapagos needs Falcon to fly, but Abbott risks having its wings clipped, September 14, 2018).
|Yea or nay? Contradictory MitraClip data|
|Mitra-FR (NCT01920698)||Coapt (NCT01626079)|
|MitraClip||Control||P value||MitraClip||Control||P value|
|Death or rehospitalisation
for heart failure
|Note: endpoints measured at 1 year in Mitra-FR and 2 years in Coapt.
Source: NEJM; TCT slides
A comparison of data from two different trials is never ideal, and some discrepancies are to be expected. But the magnitude of the difference – one trial misses, the other is an undreamed-of smash hit – has to raise questions.
Possible explanations mooted for the inter-trial discrepancy include the fact that Mitra-FR, being a French trial, used the European definition of severe MR when recruiting its patients; Coapt used the US criteria. Patients in Mitra-FR had milder regurgitation, so Coapt might have succeeded since it would have been easier to show a difference in sicker patients.
However, there is a suggestion that the more stringent selection criteria used in Coapt means the Mitra-FR population better represents the patients getting the MitraClip in real-world practice. This hypothesis will not help Abbott’s case.
Coapt lead investigator Gregg Stone also suggested that the doctors implanting MitraClip were more experienced than those in Mitra-FR, and that medication use differed between the two trials.
It seems unlikely, however, that slightly different enrolment criteria or drug levels, or varying levels of cardiologist expertise – or, for that matter, the fact that Coapt was sponsored by Abbott where Mitra-FR was academic – can explain the chasm between the trials.
Whatever the explanation, cardiologists must now choose which set of data to believe. Opinions might be swayed when yet another trial of the device in secondary MR, the investigator-sponsored, 420-patient Reshape-HF2, reads out at the end of next year.
Regulators, however, might well favour the Coapt data. The study was conducted under an investigational device exemption, meaning the FDA has buy-in on the trial’s design; the palpable hit means the FDA will be well disposed to Abbott’s application for the new indication.