Meeting NewsPerspective

COAPT: Transcatheter mitral valve replacement brings health status improvements

Federico M. Asch
Federico M. Asch

NEW ORLEANS —Two substudies from the COAPT trial presented at the American College of Cardiology Scientific Session found that patients with moderate-to-severe or severe mitral regurgitation who had transcatheter mitral valve repair and guideline-directed medical therapy had improvements in health status as soon as 1 month.

Moreover, an echocardiographic substudy determined that all subgroups analyzed based on their echocardiographic characteristics at baseline obtained a benefit from the MitraClip (MitraClip, Abbott) implantation.

As Cardiology Today’s Intervention previously reported, in the main results of COAPT, patients with HF with moderate-to-severe or severe functional mitral regurgitation who underwent transcatheter mitral valve repair and received optimal medical therapy had reduced risk for HF hospitalization and mortality compared with patients treated with optimal medical therapy alone.

Echocardiographic substudy

In the echocardiographic substudy, those assigned guideline-directed medical therapy alone had four independent baseline echocardiographic predictors of poor outcomes (LV ejection fraction, mitral and tricuspid regurgitation severity and right ventricular systolic pressure), while only right ventricular systolic pressure predicted a poor outcome in those who had device therapy. But even among those with higher right ventricular systolic pressures, patients that received the device did better than those in optimal medical treatment alone.

“To duplicate the COAPT results in our daily clinical practice, specific COAPT screening echo criteria and expert echo analysis should be applied to identify proper candidates for the MitraClip,” Federico M. Asch, MD, director of the Echocardiography Core Lab at MedStar Health Research Institute in Washington, D.C., and associate professor of medicine at Georgetown University, said during the presentation.

In this substudy of 614 patients, all underwent transthoracic echocardiograms at baseline, 1 month, 6 months, 12 months, 18 months and 24 months, which would continue to 5 years. At baseline, both groups of patients that were assigned treatment in the COAPT trial had similar echocardiographic characteristics, although the only difference was seen in pulmonary vein flow, as 56.7% of the device group and 44% of the control group had a severe case of it.

Two substudies from the COAPT trial presented at the American College of Cardiology Scientific Session found that patients with moderate-to-severe or severe aortic regurgitation who had transcatheter mitral valve repair and guideline-directed medical therapy had improvements in health status as soon as 1 month.
Source: Adobe Stock

Both groups of patients had increases in left ventricular end diastolic volume up to 24 months (P < .05), although there was less of an increase in the device group. This was also seen for changes in LV end systolic volume up to 24 months (P < .05).

LV ejection fraction decreased over time in the device and control groups up to 24 months of follow-up (P < .05).

Mitral regurgitation improved more in the MitraClip at all times of follow-up. Compared with the control group, more patients in the device group had a mitral regurgitation severity of 2+ or less at 30 days (92.7% vs. 34.2%), 6 months (93.8% vs. 38.1%), 12 months (94.8% vs. 46.9%), 18 months (95% vs. 40.4%) and 24 months (99.1% vs. 43.4%; P for all < .001).

From baseline to 12 months, 84.1% of patients assigned the device had improved their mitral regurgitation severity by at least two grades compared with 15.9% in those assigned medical therapy alone (P < .0001). Both groups had similar rates of changed to 12 months in tricuspid regurgitation severity (P = .34) and RV systolic pressure (P = .13).

When the top half and bottom half of each echocardiographic subgroup was compared with each other, those assigned to the device therapy always had better outcomes, Asch said.

Predictors of mortality or first HF hospitalization at 24 months for patients in the control group included a tricuspid regurgitation grade equal or greater than 2+, those with lower LVEF and those with higher right ventricular systolic pressure and mitral regurgitant effective regurgitant orifice area. The only predictor of poor outcomes in the device group was a higher RV systolic pressure.

“It is important to understand that the high pulmonary pressures in this population are not necessarily because of the mitral regurgitation by itself, but also because of the cardiomyopathy,” Asch said during the discussion portion of the presentation. “These patients have a dual disease, and we are taking care [of them] with the MitraClip for the mitral regurgitation aspect of that. Is there any other threshold we should be using for this? I really don’t know. I don’t think we can get the answers at least from the data that we have so far, but it is a very interesting observation.”

Quality-of-life substudy

Suzanne V. Arnold
Suzanne V. Arnold

Suzanne V. Arnold, MD, cardiologist at St. Luke’s Mid America Heart Institute in Kansas City, associate professor of medicine at University of Missouri-Kansas City and a Cardiology Today Next Gen Innovator, and colleagues analyzed health status as reported by patients in the COAPT trial who were assigned the device (n = 302) or standard care (n = 309). Three patients from the COAPT trial were excluded for not completing health status assessments at baseline.

Health status was assessed at baseline, 1 month, 6 months, 12 months and 24 months using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and SF-36 Physical and Mental Summary Scores.

The primary outcome was the KCCQ summary score over a 24-month period.

At baseline, the overall KCCQ summary score was 53.2 in the treatment group and 51.6 in the control group, with the quality of life domain being most impacted.

“This roughly correlates to NYHA class III,” Arnold said during the presentation.

The SF-36 physical summary score was 33 in the treatment group and 32.6 in the control group, which was nearly 2 standard deviations below the mean of the general population.

At 1 month, the mean between-group difference in KCCQ score was 15.9 points (95% CI, 12.3-19.5) in favor of the device-therapy group, which was maintained with minimal attenuation at 24 months (12.8 points; 95% CI, 7.5-18.2).

“This represents a moderately large clinical change over three times the minimal clinically important difference for the KCCQ,” Arnold said.

Similar patterns were seen in individual KCCQ domains including quality of life, physical limitations, social limitations and total symptoms.

At 24 months, the mean difference in Short Form-36 scores was 3.6 for both the physical and mental summary scores, with a greater improvement in patients assigned the device.

In subgroup analyses, researchers found consistent benefit in the treatment group across several demographic and clinical factors, including frailty measures. In addition, patients in the treatment group who had ischemic cardiomyopathy had a greater health status benefit (mean difference = 18.3; 95% CI, 13.6-22.9) compared with those with non-ischemic cardiomyopathy (mean difference = 8.4; 95% CI, 2.7-14.1; P for interaction = .02). There were substantial and significant benefits of the treatment compared with standard care in both of these groups with cardiomyopathy, according to the researchers.

“Furthermore, this result should be considered exploratory given the number of secondary outcomes that were tested,” Arnold said during the presentation.

Although there were observed improvements in health status as per this analysis, there are challenges in performing these kinds of studies, especially in studies with a high mortality rate.

“Health status can only be assessed amongst survivors, and yet we know that patients with worse health status are more likely to die,” Arnold said during the presentation. “When we look at the COAPT population, we see that not only is the mortality rate high, but it also differs between groups. When we ignore these deaths, it biases our results, as the sickest patients are systematically removed from the analysis due to death. This makes health status appear to be better than it otherwise would had these patients survived.”

Given this, researchers in this analysis employed several strategies to address this challenge, including categorical analyses and to jointly model health status and mortality.

“Considering the previously reported benefits of [transcatheter mitral valve repair] on survival and heart failure hospitalization, these health status results further support the use of MitraClip for patients with heart failure and 3+ or 4+ secondary MR who remain symptomatic despite maximally tolerated guideline-derived medical therapy,” Arnold said during the presentation.

The findings of the quality-of-life study were also simultaneously published in JACC: Cardiovascular Interventions. – by Darlene Dobkowski with additional reporting by Katie Kalvaitis

References:

Arnold SV, et al.

Asch FM, et al. Joint American College of Cardiology/New England Journal of Medicine Late-Breaking Clinical Trials. Both presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.

Arnold SV, et al. JACC: Cardiovasc Interv. 2019;doi:10.1016/j.jcin.2018.11.008.

Disclosures: The COAPT trial was funded by Abbott. Arnold and Asch report no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

Editor’s Note: This article was updated on March 22, 2019 to clarify the conclusions of the COAPT echocardiographic study.

 

Federico M. Asch
Federico M. Asch

NEW ORLEANS —Two substudies from the COAPT trial presented at the American College of Cardiology Scientific Session found that patients with moderate-to-severe or severe mitral regurgitation who had transcatheter mitral valve repair and guideline-directed medical therapy had improvements in health status as soon as 1 month.

Moreover, an echocardiographic substudy determined that all subgroups analyzed based on their echocardiographic characteristics at baseline obtained a benefit from the MitraClip (MitraClip, Abbott) implantation.

As Cardiology Today’s Intervention previously reported, in the main results of COAPT, patients with HF with moderate-to-severe or severe functional mitral regurgitation who underwent transcatheter mitral valve repair and received optimal medical therapy had reduced risk for HF hospitalization and mortality compared with patients treated with optimal medical therapy alone.

Echocardiographic substudy

In the echocardiographic substudy, those assigned guideline-directed medical therapy alone had four independent baseline echocardiographic predictors of poor outcomes (LV ejection fraction, mitral and tricuspid regurgitation severity and right ventricular systolic pressure), while only right ventricular systolic pressure predicted a poor outcome in those who had device therapy. But even among those with higher right ventricular systolic pressures, patients that received the device did better than those in optimal medical treatment alone.

“To duplicate the COAPT results in our daily clinical practice, specific COAPT screening echo criteria and expert echo analysis should be applied to identify proper candidates for the MitraClip,” Federico M. Asch, MD, director of the Echocardiography Core Lab at MedStar Health Research Institute in Washington, D.C., and associate professor of medicine at Georgetown University, said during the presentation.

In this substudy of 614 patients, all underwent transthoracic echocardiograms at baseline, 1 month, 6 months, 12 months, 18 months and 24 months, which would continue to 5 years. At baseline, both groups of patients that were assigned treatment in the COAPT trial had similar echocardiographic characteristics, although the only difference was seen in pulmonary vein flow, as 56.7% of the device group and 44% of the control group had a severe case of it.

Two substudies from the COAPT trial presented at the American College of Cardiology Scientific Session found that patients with moderate-to-severe or severe aortic regurgitation who had transcatheter mitral valve repair and guideline-directed medical therapy had improvements in health status as soon as 1 month.
Source: Adobe Stock

Both groups of patients had increases in left ventricular end diastolic volume up to 24 months (P < .05), although there was less of an increase in the device group. This was also seen for changes in LV end systolic volume up to 24 months (P < .05).

LV ejection fraction decreased over time in the device and control groups up to 24 months of follow-up (P < .05).

Mitral regurgitation improved more in the MitraClip at all times of follow-up. Compared with the control group, more patients in the device group had a mitral regurgitation severity of 2+ or less at 30 days (92.7% vs. 34.2%), 6 months (93.8% vs. 38.1%), 12 months (94.8% vs. 46.9%), 18 months (95% vs. 40.4%) and 24 months (99.1% vs. 43.4%; P for all < .001).

PAGE BREAK

From baseline to 12 months, 84.1% of patients assigned the device had improved their mitral regurgitation severity by at least two grades compared with 15.9% in those assigned medical therapy alone (P < .0001). Both groups had similar rates of changed to 12 months in tricuspid regurgitation severity (P = .34) and RV systolic pressure (P = .13).

When the top half and bottom half of each echocardiographic subgroup was compared with each other, those assigned to the device therapy always had better outcomes, Asch said.

Predictors of mortality or first HF hospitalization at 24 months for patients in the control group included a tricuspid regurgitation grade equal or greater than 2+, those with lower LVEF and those with higher right ventricular systolic pressure and mitral regurgitant effective regurgitant orifice area. The only predictor of poor outcomes in the device group was a higher RV systolic pressure.

“It is important to understand that the high pulmonary pressures in this population are not necessarily because of the mitral regurgitation by itself, but also because of the cardiomyopathy,” Asch said during the discussion portion of the presentation. “These patients have a dual disease, and we are taking care [of them] with the MitraClip for the mitral regurgitation aspect of that. Is there any other threshold we should be using for this? I really don’t know. I don’t think we can get the answers at least from the data that we have so far, but it is a very interesting observation.”

Quality-of-life substudy

Suzanne V. Arnold
Suzanne V. Arnold

Suzanne V. Arnold, MD, cardiologist at St. Luke’s Mid America Heart Institute in Kansas City, associate professor of medicine at University of Missouri-Kansas City and a Cardiology Today Next Gen Innovator, and colleagues analyzed health status as reported by patients in the COAPT trial who were assigned the device (n = 302) or standard care (n = 309). Three patients from the COAPT trial were excluded for not completing health status assessments at baseline.

Health status was assessed at baseline, 1 month, 6 months, 12 months and 24 months using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and SF-36 Physical and Mental Summary Scores.

The primary outcome was the KCCQ summary score over a 24-month period.

At baseline, the overall KCCQ summary score was 53.2 in the treatment group and 51.6 in the control group, with the quality of life domain being most impacted.

“This roughly correlates to NYHA class III,” Arnold said during the presentation.

PAGE BREAK

The SF-36 physical summary score was 33 in the treatment group and 32.6 in the control group, which was nearly 2 standard deviations below the mean of the general population.

At 1 month, the mean between-group difference in KCCQ score was 15.9 points (95% CI, 12.3-19.5) in favor of the device-therapy group, which was maintained with minimal attenuation at 24 months (12.8 points; 95% CI, 7.5-18.2).

“This represents a moderately large clinical change over three times the minimal clinically important difference for the KCCQ,” Arnold said.

Similar patterns were seen in individual KCCQ domains including quality of life, physical limitations, social limitations and total symptoms.

At 24 months, the mean difference in Short Form-36 scores was 3.6 for both the physical and mental summary scores, with a greater improvement in patients assigned the device.

In subgroup analyses, researchers found consistent benefit in the treatment group across several demographic and clinical factors, including frailty measures. In addition, patients in the treatment group who had ischemic cardiomyopathy had a greater health status benefit (mean difference = 18.3; 95% CI, 13.6-22.9) compared with those with non-ischemic cardiomyopathy (mean difference = 8.4; 95% CI, 2.7-14.1; P for interaction = .02). There were substantial and significant benefits of the treatment compared with standard care in both of these groups with cardiomyopathy, according to the researchers.

“Furthermore, this result should be considered exploratory given the number of secondary outcomes that were tested,” Arnold said during the presentation.

Although there were observed improvements in health status as per this analysis, there are challenges in performing these kinds of studies, especially in studies with a high mortality rate.

“Health status can only be assessed amongst survivors, and yet we know that patients with worse health status are more likely to die,” Arnold said during the presentation. “When we look at the COAPT population, we see that not only is the mortality rate high, but it also differs between groups. When we ignore these deaths, it biases our results, as the sickest patients are systematically removed from the analysis due to death. This makes health status appear to be better than it otherwise would had these patients survived.”

Given this, researchers in this analysis employed several strategies to address this challenge, including categorical analyses and to jointly model health status and mortality.

“Considering the previously reported benefits of [transcatheter mitral valve repair] on survival and heart failure hospitalization, these health status results further support the use of MitraClip for patients with heart failure and 3+ or 4+ secondary MR who remain symptomatic despite maximally tolerated guideline-derived medical therapy,” Arnold said during the presentation.

The findings of the quality-of-life study were also simultaneously published in JACC: Cardiovascular Interventions. – by Darlene Dobkowski with additional reporting by Katie Kalvaitis

References:

Arnold SV, et al.

Asch FM, et al. Joint American College of Cardiology/New England Journal of Medicine Late-Breaking Clinical Trials. Both presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.

Arnold SV, et al. JACC: Cardiovasc Interv. 2019;doi:10.1016/j.jcin.2018.11.008.

Disclosures: The COAPT trial was funded by Abbott. Arnold and Asch report no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

Editor’s Note: This article was updated on March 22, 2019 to clarify the conclusions of the COAPT echocardiographic study.

 

    Perspective
    Chandan Devireddy

    Chandan Devireddy

    COAPT was a very dramatic result, and these two reports further demonstrate that mitral clipping has benefits in these carefully selected patients.

    While patients were chosen based on these strict echocardiographic parameters and clinical features, they had a fairly dramatic regression in LV enlargement, which is a big problem for these patients.

    There was some nuance that was raised and discretion about the fact that patients with pulmonary artery hypertension were excluded, but then as the trial went forward, the RV pressure did seem to be some marker of identification of patients at higher risk. That is going to need to be teased out a little bit about what that means in patient selection and in monitoring these patients overall. It is a fairly dramatic, sustained reduction in mitral regurgitation in these carefully selected patients.

    With the recent FDA approval, all eyes are on the payers to really provide some guidance of how they are going to navigate the pathway of patient selection.

    • Chandan Devireddy, MD, FACC, FSCAI
    • Cardiology Today Next Gen Innovator
      Associate Professor of Medicine
      Associate Fellowship Director, Interventional Cardiology
      Emory University School of Medicine
      Emory University Hospital Midtown

    Disclosures: Devireddy reports he is on the data safety monitoring board for Medtronic and works at a participating center for the PARTNER 3 study with the Edwards Lifesciences TAVR device.

    Perspective
    Howard C. Herrmann

    Howard C. Herrmann

    It is important that we analyze this data set carefully to understand not only who the best candidates are for MitraClip in the functional mitral regurgitation space, but also to understand who did not benefit. We still have a high rate of mortality and HF hospitalization even in the treated group, close to half of patients at 2 years. It is hard to feel good about that despite the demonstrated improvement from the control group. We still have a lot to learn and analyze.

    The echocardiographic substudy suggested that it may be difficult to select the best responders and those that won’t respond based on echocardiographic parameters alone. This analysis was more comprehensive than the initial subset analysis that was presented at TCT by Gregg Stone, MD, where a subset of people who had less mitral regurgitation and larger ventricles seemed to not get benefit, similar to the findings in MITRA-FR.

    That analysis was done with a dichotomous cut point on LV end-diastolic volume and the primary endpoint. This analysis was done using LV and end-diastolic volume as a continuous variable and a slightly different endpoint. The present study used mortality and first HF hospitalization rather than mortality and all HF hospitalizations. I am not sure whether this explains the difference.

    This study suggests that we still do not know exactly how to pick the patients who are going to get the most benefit from MitraClip beyond the COAPT trial general inclusions and exclusions. I would like to understand better why the patients who did not get benefit did not get it, so that we can avoid unnecessary therapy and potentially offer other therapies to these patients.

    The quality-of-life analysis was impressive. The researchers demonstrated real and sustained benefits and answered a lot of potential statistical criticisms with careful analyses.

    Additional analyses that I would like to see include those based on residual mitral regurgitation and stratified by ejection fraction to try to understand how much of the observed benefit is due to mitral regurgitation reduction. We presume it is, but does it matter how much mitral regurgitation reduction? Is there a role for transcatheter mitral valve placement because one gets better mitral regurgitation reduction, even though it is a more complex procedure with its own issues of safety and efficacy?

    With the FDA approval for secondary mitral regurgitation, these questions have become even more important and relevant. We need to carefully understand not only who benefits, but also who does not benefit so that we can apply these technologies rationally and to our patient’s best benefit.

    • Howard C. Herrmann, MD
    • Cardiology Today’s Intervention Editorial Board Member
      Hospital of the University of Pennsylvania

    Disclosures: Herrmann reports he was an investigator in the COAPT trial, consults for companies including Edwards Lifesciences and Medtronic and received institutional research funding for several mitral valve therapy trials.

    Perspective
    Michael J. Rinaldi

    Michael J. Rinaldi

    In these two substudies, one looked at quality of life metrics and the other looked at echocardiographic parameters and predictors.

    During the COAPT trial, we looked at quality-of-life metrics first. Like all good clinical trials, you need to not simply analyze measures such as survival and HF hospitalizations, which matter in a very important way, but also patient-centered metrics. Patients do not always necessarily just want to live longer; they want to live better. We need to have a formal way of measuring quality of life so that we can discover whether we really are making them feel better.

    Patients who received clip therapy compared with patients who did not receive it saw their metrics in quality of life improve substantially. Those improvements were fairly immediate as soon as they received the treatment and they were durable over the 2 years of follow-up. These improvements are important, building on the concept that you are not just making people live longer or keeping them out of the hospital, which impacts the cost of health care, but you are actually improving the patient’s quality of life. Those markers were apparent even within the first month of treatment. The curves were fairly parallel, as the benefit did not drop off over time. It improved quality of life and that improvement was durable.

    The improvement in quality of life was across the board and not just in some small subgroup patients, which is also important to note.

    Previous studies and the COAPT trial showed that when you treat patients with the MitraClip, it mechanically improves the way their heart functions. Their ventricular volumes were remodeled in a positive way and everything improves from an echocardiographic standpoint. The heart pumps better, and that correlates completely with patients’ quality of life.

    The question about placebo effect correlates with physiologic parameters, measuring how healthy the ventricle is with these ventricular volumes and ventricular measurements. It all fits tightly in a nice and positive way.

    In the echocardiographic substudy, if patients have severe mitral regurgitation, known as 3-4+, the measurement of that is controversial and is difficult, but there are standardized ways of quantifying the severity. We know that patients with true mitral insufficiency benefit from MitraClip therapy, and this echocardiographic substudy tells us that it is not all grouped together, that half the patients had 3+ mitral insufficiency and the other half had 4+ mitral insufficiency. Whether they had 3+ or 4+ mitral insufficiency, they similarly improved.

    When researchers looked at all the subgroups, no matter what your LVEF, you benefitted. It did not matter how big the ventricle was, as all those markers of the health of the ventricle did not matter. Treating mitral insufficiency, if it was severe, helped patients.

    It also showed that whether it was 3+ or 4+ mitral insufficiency, patients benefitted essentially equally.

    There are other markers that suggest something sick about the heart that may make care futile. For instance, severe tricuspid insufficiency is associated with a poor prognosis. If you had no tricuspid insufficiency or 2+ to 3+ tricuspid insufficiency, you benefited equally from clip therapy as well. Even in patients with pulmonary hypertension, the clip group benefited regardless of severity.

    These substudies reinforce the principles of the COAPT trial and showed a marked and clinically relevant benefit.

    • Michael J. Rinaldi, MD
    • Interventional Cardiologist
      Director, Clinical Research
      Sanger Heart and Vascular Institute
      Atrium Health, Charlotte, North Carolina

    Disclosures: Rinaldi reports he was a primary investigator for the COAPT trial; teaches courses for Abbott and Edwards Lifesciences; is a speaker for Abbott, Boston Scientific and Edwards Lifesciences, and is on the advisory board for Abbott and Boston Scientific.

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