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Pal et al. Vessel Plus 2019;3:39 I http://dx.doi.org/10.20517/2574-1209.2019.24 Page 3 of 6

study subjects were required to have at least one of three criteria: at least one hospitalization for HF within
2
12 months, BNP > 300 pg/mL or NT-proBNP > 1500 pg/mL, or MR severity with EROA > 30 mm or RV
[10]
> 45 mL. The primary outcome was HF hospitalizations within 24 months of follow-up . As a result,
in MITRA-FR trial versus COAPT trial the average NT-proBNP, 12 months prior annual hospitalizations
2
2
and LVEDV were approximately 3349 ng/L vs. 5558 pg/mL; 100% vs. 57%; and 135 mL/m vs. 101 mL/m
[11]
respectively. Nishimura et al. in their accompanying editorial point out several features that could
explain the differences: first, the strategy of medical management before and after enrollment differed.
In COAPT trial, maximal HF treatment took place solely prior to randomization, therefore identifying
patients truly refractory to medical therapy. After enrollment, further adjustments to medical therapy
were not allowed. In MITRA-FR trial, medical therapy modifications were permitted before and after
randomization. Second, the baseline valvular and ventricular characteristics were different. In COAPT, the
2
2
MR was more severe compared to MITRA-FR (average EROA, 41 mm vs. 31 mm ) but with a smaller LV
2
2
size [left ventricular end diastolic volume index (LVEDVI) 101 mL/m vs. 135 mL/m & left ventricular end
diastolic diameter, 62 mm vs. 69 mm]. Third, procedural skill may have contributed, as COAPT had more
patients with multiple clips than MITRA-FR and possibly more experienced proceduralists since the study
took place at a later date. Primary endpoint in COAPT trial which was HF hospitalization within 24 months
of procedure was 35.8% in intervention vs. 67.9% in control arm (P < 0.001). Primary endpoint in MITRA-
FR, which was death or HF hospitalization at 12 months was 54.6% in intervention group vs. 51.3% in
control (P = 0.53).

After the studies and editorial were published, readers from all over the world submitted queries. Regarding
COAPT trial, Crestanello et al. were curious about the echocardiographic methodology in calculation of
[12]
EROA as for them (Simpson’s method of discs) it would generate impractical numbers for both regurgitant
volume and stroke volume. The authors explain this discrepancy due to difference in echocardiographic
[13]
measurement techniques (Simpson’s vs. Doppler) . To us, this emphasizes the inherent limitations of
echocardiography, and questions validity of conclusion based on semiquantitative echocardiographic
[14]
estimates. Drake et al. speculate that detailed knowledge of the preoperative transesophageal
echocardiography could have introduced a bias to the interventionists’ in COAPT trial leading to better
outcomes. The authors agree with this observation emphasizing the value of preoperative advanced
imaging and thus its use is representative of current medical practice and therefore should be included
[7]
[15]
[8]
in the study protocol. Garbi et al. recognize that the “disproportionate” or “tertiary” MR along
with reduced left atrial pressure observed in COAPT patients, both may have contributed to improved
symptoms post-procedurally which the authors agree with as a possibility. Despite that the COAPT trial
was company sponsored (Kalavrouziotis et al. ), the authors posit an independence of medical decision
[16]
making.
[17]
Godino et al. expressed concerns about the very frequent (> 20%) occurrence of mortality in both
intervention and control groups in MITRA-FR trial. In response, the authors compared mortality at one-
[18]
year in both the MITRA-FR and COAPT trials and found relatively similar mortality at one year . The
study investigators also explain that the other major heart failure trials with lesser one year mortality
were not comparable due to differences in study designs. For example, the PARADIGM-HF trial explicitly
[19]
excluded “all hemodynamically significant mitral disease”. Goliasch et al. point out that the differing
2
2
definition of severe MR between the COAPT (EROA 0.3 cm ) and the MITRA-FR (EROA 0.2 cm ) trials,
reflecting American vs. European guidelines, could have contributed to the difference in results as well.
[20]
Nevertheless, a sub-analysis controlling for EROA did not change the results. Silverio et al. posit that
the lack of benefit observed in the MITRA FR trial could be due to relatively nonrestrictive study center-
eligibility criteria, and inexperience on part of the proceduralist. The MITRA-FR authors point out that,
despite the fact that they had only a five procedure per center minimal requirement, the COAPT had three
subjects per center for active enrollment. Therefore, although COAPT trial ended up with more patients