Comment on Five-Year Follow-up after Transcatheter Repair of Secondary Mitral Regurgitation (COAPT trial)

5-year Follow-Up After Transcatheter Treatment of Secondary Mitral Regurgitation
The COAPT Trial

Background:

Treatment of secondary mitral regurgitation in heart failure patients gained popularity in the last few years. The initial results of the transcatheter edge-to-edge repair showed promising results in the COAPT population, and mTEER was included in international guidelines as the therapy of choice in suitable patients1,2. Long-term randomized data on interventional treatment of severe secondary MR were still lacking until March this year when Stone et al. reported 5-year outcome data in the NEJM3.

Study question:

5-year clinical outcomes of patients enrolled in the COAPT trial
Analyze the impact of MitraClip treatment in patients assigned to GMD alone.

Study design:

The COAPT Trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) is an industry-sponsored (Abbott, manufacturer of the Mitraclip device) study looking at the effectiveness of transcatheter edge-to-edge repair in heart failure patients with mitral regurgitation3. Designed as a parallel-controlled, open-label, multicenter trial, 614 patients with heart failure and moderate (3+) or severe (4+) secondary MR who remained symptomatic despite maximally tolerated GDMT ±CRT were included at 78 sites in the US and Canada and 1:1 randomized to receive MitraClip + GDMT or GDMT alone. Patients were stratified by etiology of cardiomyopathy and site. Hemodynamic instability, significant coronary artery disease requiring revascularization, aortic/tricuspid valve disease requiring therapy, and severe pulmonary hypertension represented exclusion criteria. 
Subjects randomized to GDMT alone were allowed to cross over to MitraClip treatment after 24 months.
The primary effectiveness endpoint was all hospitalizations for heart failure through 2 years of follow-up. The annualized rate of all hospitalizations for heart failure, all-cause mortality, the risk for death or hospitalization for heart failure, and safety, among other outcomes, were assessed over five years.

Major results:

Of the 614 patients enrolled, 302 were assigned to the device treatment group and 312 to the control group. 87% completed a 5-year follow-up. The etiology of secondary mitral regurgitation was well balanced between groups (60% ischemic, 40% non-ischemic). The mean EROA was about 0.4 cm2, indicating severe MR in both groups. 
The primary effectiveness endpoint of all heart failure hospitalizations at five-year follow-up favored the device treatment group (33.1% per year vs. 57.2% per year; HR 0.53 [0.41-0.68]). No difference in the primary endpoint was seen between years 3-5. At 24 months of follow-up, half of the patients in the control group have died. Of the remaining population, 44.9% crossed treatment arms. All-cause mortality through five years was 57.3% in the device group vs. 67.2% in the control group HR 0.72 [0.58-0.89]. Death or hospitalization for heart failure occurred in 73.6% of device patients vs. 91.5% of the control group HR 0.53 [0.44-0.64]. MR≤2+ at five years 94.7% vs. 91.3% (device vs. control group; 103 patients analyzed by a core lab). Device-specific events occurred in 4 of 293 treated patients, all within 30 days of the procedure. Device treatment was associated with a 28% relative risk reduction for all-cause mortality.

Interpretation:

5-year data of the COAPT trial demonstrated favorable results for the treatment group. However, we see a reduced treatment effect after 2-3 years due to many crossovers from the control group to the device group. Half of the patients in the control group died within the first two years after enrollment. 44.9% of the remaining control group who survived beyond two years received mTEER after that.
At five years follow-ups, 57.3% vs. 67.2% of patients have died. Most of the deaths occurred in patients with relevant or worsening MR. These findings correspond to end-stage heart failure patients and non-responders. This study's high mortality rate raises the question of whether death was a competing risk factor. 
Reduction in MR was stable over time with a difference of 3.4% [-7.1, 15.6] of patients showing MR ≤2+ between groups, 94.7% vs. 91.3% (device vs. control group) presented with MR≤2+ at five years. These results are hard to interpret because of the large number of crossovers and high mortality rate. Furthermore, the effect of missing annuloplasty, as Alfieri and his group demonstrated in surgical edge-to-edge repair, is still unclear in mTEER4.

The study design specified a composite outcome parameter, "mitral valve stenosis leading to surgery", which was not reached by any patient during the study period. Detailed data on mitral stenosis quantification are available in the supplements of the publication3. MVA at five years was 3.06±0.9cm2 vs. 4.47±1.6cm2 (device vs. control group).

Despite improvement in HF symptoms over time (at five years: 24.1% vs. 15.7% NYHA class I or II; device vs. control group), nearly 75% of device-treated patients have died or been hospitalized for heart failure. Patients who crossed over to the device group after 24 months showed almost similar death or heart failure hospitalization rates as the device group.
GDMT adherence in the study was not given in the later years of the trial. SGLT2 inhibitors and sacubitril/valsartan were not well established, indicating the necessity of multimodal treatment in heart failure patients. So, this raises the question to whom we compare this study cohort to, with the knowledge of a 44.9% crossover of survivors from the control group to the device group and a withdrawal/loss to follow-up rate of 15% of the control group and 10% of the device group.

Conclusion:

In patients with heart failure and severe secondary mitral regurgitation, GDMT ±CRT should be the first-line therapy to reduce adverse events. In patients who remain symptomatic despite optimal medical treatment, and present with significant MR, early mTEER is beneficial with durable reduction of MR at five years follow-up. Given the high rates of mortality and heart failure hospitalization during follow-up in the COAPT trial, the four-pillar medical therapy should be the fundament of heart failure therapy - before planning interventional treatment, and further treatment options for underlying left ventricular dysfunction are needed.