Publications

An individual patient data meta‐analysis was conducted from 3 prospective studies that enrolled 209 heart failure patients with reduced ejection fraction patients and functional mitral regurgitation (FMR). Patients implanted with the Carillon Mitral Contour System or control were assessed for 12-month outcomes relating to mitral regurgitation severity, left ventricular (LV) remodeling, functional status, and heart failure‐related hospitalization.

  • Patients implanted with the device showed significantly improved hemodynamics, MR severity (regurgitant volume and MR grade), left ventricular volume (LVEDV) and left atrial volume (LAV), as compared to those patients who did not receive a device at 12 months.
  • Improvement of symptoms as assessed by change in NYHA class also significantly favored device implantation vs control (p<0.00001) with 69.9% (51/73) of implanted patients with baseline class III or IV improving by at least one class at 12 months.
  • Similarly, the rate of hospitalizations due to heart failure (HFH) was significantly reduced in implanted patients (45.3% vs 64%, p=0.04).
  • Sensitivity analysis performed on subjects with more severe MR (MR grade 3+/4+) at baseline supported the overall cohort in terms of hemodynamic improvement and maintained a significant improvement in HFH (43.9% vs 82.9%, p=0.04).

In conclusion, this comprehensive meta‐analysis of individual patient data has shown that the CARILLON device provides statistically significant and clinically meaningful benefits in LV volumes, NYHA functional class and indexes of mitral valve performance, along with a reduction in the rate of subsequent HFH.

Embracing secondary mitral regurgitation with Carillon: past, present, and future15
ESC Heart Failure
Mitja Lainscak and Michael Böhm
December 2020

In this editorial Dr. Lainscak and Professor Böhm discuss the optimal management strategy for patients with Functional Mitral Regurgitation. There is a need in the therapeutic spectrum for additional therapies that are safe and can be deployed as an early intervention to reduce the need for repeated hospitalizations. The data presented by Gialluria et al. supports the use of the Carillon Mitral Contour System to achieve this goal. Owing to less invasive approaches, favourable effects on left ventricular volumes, and possibility of step‐wise upgrade with other interventions, Carillon could be considered early in the patient trajectory for a timely and effective management of heart failure patients with reduced ejection fraction and functional mitral regurgitation.

Echographic outcomes of patients with atrial derived FMR (aFMR) and heart failure with preserved ejection fraction (HFpEF) were compared to patients with ventricular derived FMR (vFMR) and heart failure with reduced ejection fraction (HFrEF) after percutaneous mitral valve repair with the Carillon Mitral Contour System.

  • Patients with aFMR showed similar reductions in mitral annulus diameter and concomitant reduction in regurgitant volume through 3 months compared to those with vFMR.
  • Significant reduction in MR as assessed by vena contracta, effective regurgitant volume as well as MR was seen as soon as 3 months after procedure in both groups.
  • Similarly, after 3 months the proportion of patients with NYHA class III or IV was reduced from 92.8% to 42.8% which was maintained throughout 12 month follow-up.

The Carillon device is feasible in HFpEF patients with aFMR and is associated with significant reductions in MR.

  • Patients implanted with the Carillon Mitral Contour System were evaluated for long‐term follow‐up post‐procedure up to 7.5 years.
  • Patients experienced a clinically significant reduction in heart failure hospitalizations and symptom improvement post procedure which was sustained through the 6+ year follow-up period.
  • Long-term mortality was 40% at 6 years, which compares favorably to several prior studies that have evaluated medically managed patients with FMR.

Patients treated with the Carillon device continue to show sustained improvements in mitral regurgitation, left ventricular volume, ejection fraction, and clinical status 6+ years post procedure. All patients at 6 year follow-up had MR 2+ or less with over half having MR 1+ or trace, and LVEDV was reduced from 154.0 ± 65.7 mL at baseline to 104.5 ± 59.2 mL (p=0.03).

Comparison of effectiveness and survival after the MitraClip or Carillon procedure for severe functional mitral regurgitation: a single-center retrospective analysis3
Department of Cardiology, Frankfurt University Hospital, Frankfurt, Germany
doi: 10.5114/amsad.2020.97160
June 2020
  • First study to directly compare patients treated with either Carillon (n=37) or MitraClip (n=137).
  • MR grade was significantly reduced (p<0.001) in both groups after procedure.
    • MR grade remained reduced in Carillon patients at 2 years (n=9).
  • Survival was assessed up to 5 years.
    • Median survival in the Carillon group was 3.92 years vs 1.66 years in the MitraClip group (p = 0.01).
    • Numerous baseline factors may contribute to the difference in survival benefit observed.
  • Pulmonary artery pressure was reduced in both groups after intervention (p<0.05), however, continued decrease at later follow up was observed only in the Carillon group.

  • 30 patients with symptomatic moderate or severe SMR [FMR] were assessed for the acute effects of Carillon therapy by advanced echocardiography 1 day prior to procedure and at discharge.
  • Treatment of SMR [FMR] with the Carillon device leads to acute reduction of MR severity in 83% of patients after the procedure.
    • Both PISA based measurements of regurgitant volume as well as measurements derived from regurgitant fraction were significantly improved (p<0.05) after the procedure.
  • Effective [forward] stroke volume was significantly improved (p<0.001) and ejection fraction was non-significantly improved (p = 0.06) immediately after the intervention.

  • 37 patients implanted with the Carillon device were included in this retrospective, single-center study.
  • First study to show significant reduction in annular diameter in both anterior-posterior and anterolateral-posteromedial aspects (p<0.001) after any transcatheter mitral valve repair therapy.
  • Left atrial volume significantly reduced (p<0.02) at 30 days follow up and maintained through 1 year.

This analysis brings new insights into the long-term role of the Carillon Mitral Contour system for the treatment of symptomatic congestive heart failure with functional mitral regurgitation.

A total of 74 patients from the TITAN, TITAN II and REDUCE FMR clinical studies who had symptomatic congestive heart failure despite guideline-directed medical therapy, grade 2+ to 4+ FMR, left ventricular enlargement, and reduced ejection fraction were assessed as part of the analysis. For all patients, echocardiographic parameters were available through the 12-month visit and vital status was available through 5 years.

  • Over 1 year of follow-up, the New York Heart Association (NYHA) class decreased in 64% of patients, distance on the 6-minute walk test increased, and echocardiographic measures indicated significant decreases in MR grade and favorable left ventricular remodeling.
  • The Kaplan-Meier survival rate was 83.6% at 1 year, 73.1% at 2 years, 67.9% at 3 years and 56.2% at 4 and 5 years of follow-up.
  • Primary determinants of long-term survival were a decrease in NYHA class, an increase in 6-minute walk test distance, and a decrease in regurgitant volume during the first year of follow-up.
  • Three-year mortality rate compared to published outcomes of COAPT and guideline directed medical therapy (GDMT), using matched patient populations, was 33.7% for Carillon, 42.8% for MitraClip in COAPT and 55.5% for GDMT.

REDUCE FMR
JACC: Heart Failure
doi: 10.1016/j.jchf.2019.06.011
November 2019

The REDUCE FMR study was the first double-blinded trial of a percutaneous heart valve therapy, achieved its primary endpoint, and demonstrated favorable reverse LV remodeling. A median 22% reduction in regurgitant volume was demonstrated, as assessed by a blinded, independent echo core lab. The results of The REDUCE FMR study are consistent with the prior Carillon device studies.

1Data on file. Percent calculated by averaging individual patient percent changes.
ITT = Intent to Treat

REDUCE FMR was the first ever double-blinded, randomized, parallel, sham-controlled RCT of a percutaneous heart valve therapy. The objective was to assess the safety and effectiveness of the Carillon Mitral Contour System for treatment of secondary (functional) mitral regurgitation (FMR) associated with heart failure. Key eligibility criteria were similar to the prior trials of the Carillon system including NYHA class II-IV, MR grade 2+ to 4+, LVEDD >55mm and an ejection fraction <50%, despite the use of stable guideline-directed medical therapy. The primary endpoint was change in regurgitant volume (RV) at 1 year by intention-to-treat analysis. Being double-blind, the study was of the highest scientific rigor – patients and assessors were blinded throughout follow-up and the independent echo core lab not only was blinded to treatment and the timing of the images but also read the images in random order.

In total, 120 patients were randomly allocated to treatment (87) or the sham-control (33) arm at 31 sites in Europe, Australia and New Zealand.

Echocardiographic evaluation was performed at the site prior to enrollment, and 35 patients (29.2%) were later judged by the echo core laboratory to have had MR 1+ at baseline. In 14 (16%) of those allocated to treatment, no device was implanted, due most commonly to coronary impingement (n=8) which resolved following device removal in all cases. The average device implant time was 64.2±34.8 minutes and total procedure time averaged 102.7±54.9 minutes. Freedom from device-related major adverse events (MAE) was 98.9%, with no device embolizations, device fractures, cardiac perforations or intra-procedural ischemic events. There were two deaths within 30 days, both in implanted patients attributed to progressive cardio-renal deterioration. The incidence of MAE at 1 year was not statistically different between the treatment and control groups (16.1% in treatment group vs. 18.2% in control group).

The primary endpoint was met with a statistically significant reduction in mitral RV in the treatment group as compared to the control group (decrease of 7.1 mL/beat vs. an increase of 3.3 mL/beat, p=0.049). A secondary analysis of patients with more severe FMR (MR grade ≥3+) demonstrated a similar pattern of changes. Patients in the treatment group (n=15) experienced a reduction in mitral RV of 12.8 mL/beat whereas patients in the control group (n=8) experienced an increase of 0.6 mL/beat (p=0.14). In addition to improvements in RV, favorable reverse LV remodeling was demonstrated, with a significant reduction in LV volumes in patients receiving the device vs. the control group.

Patients in the treatment group also experienced a significant improvement in 6-minute walk distance at 12 months compared with their baseline (p=0.002), whereas patients allocated to the control group did not (p=0.29). Likewise, the treatment group had a significant improvement in NYHA class at 12 months compared with baseline (p=0.002) whereas patients allocated to the control group did not (p=0.75).

With REDUCE FMR, the Carillon system became the first TMVr therapy to demonstrate significant favorable reverse LV remodeling at 1 year and significant reduction in RV in a blinded, randomized, sham-controlled trial.

This analysis showed that Carillon addresses FMR and, in as little as one-month, successful implantation results in left ventricular reverse remodelling and increased systolic performance. Mitral tenting area is an important baseline parameter in predicting treatment efficacy with Carillon.

  • 35 patients were enrolled and 22 were successfully implanted with the Carillon device. Some patients were not implanted due to coronary sinus size (n=3), impaired access (n=2), compromised coronary flow (n=4), or insufficient mitral regurgitation reduction (n=4).
  • At one-month follow-up, statistically significant reductions in the following parameters were observed: anteroposterior (AP) diameter, regurgitant volume (RV), vena contracta (VC), effective regurgitant orifice area (EROA), proximal isovelocity surface area (PISA), mitral tenting area, mitral tethering, and mean diastolic interpapillary distance.
  • Patients with increased left atrial diameters saw greater improvement in ejection fraction, following implantation.

TITAN II
Open Heart
doi: 10.1136/openhrt-2016-000411
June 2016

The TITAN II study achieved its endpoint and showed significant improvements in echo parameters and patient function.

TITAN II was a single-arm study designed to assess the safety and efficacy of an updated version of the Carillon system. Inclusion and exclusion criteria were similar to those in TITAN. Patients had symptomatic congestive heart failure (NYHA class ≥2), MR grade 2+ to 4+, a dilated LV (LVEDD >55 mm) and an ejection fraction <40%. Quantitative assessments of MR were performed by an independent core echo laboratory, and MAE were reviewed by an independent data and safety monitoring board. In total, 36 patients were enrolled; 30 received a permanent implant.

This study showed that potential coronary artery compromise can be managed safely and effectively in all patients with 95% successfully implanted.

  • 17 patients were implanted with the Carillon device in a prospective, single-center, non-randomized study.
  • Patients experienced a mean one grade reduction of MR acutely (2.8 to 1.9, p<0.005) with an additional improvement at 3 months (1.5, p<0.005).
  • In 41.2% of patients an acute reduction of coronary artery flow was detected intraoperatively and in all except one patient this could be easily managed such that the patients successfully received the implant.

This study showed that percutaneous mitral valve repair may be cost-effective in patients with FMR due to heart failure.

  • Cost-utility analysis of Carillon Mitral Contour System was performed based on the TITAN trial results using a combination of a decision tree and Markov process. The analysis was performed from the German statutory health insurance perspective over 10-year time horizon.
  • Carillon provided additional benefits to patients with an 1.15 incremental quality-adjusted life years (QALY) and an 1.41 incremental life years. The procedure was cost-effective in comparison to optimal medical therapy (OMT) with an incremental cost-effectiveness ratio of €15,533/QALY. With a willing- ness-to-pay threshold of €35,000/QALY, PMVR had a 84% probability of being cost-effective.

Restoration of normal left ventricular geometry after percutaneous mitral annuloplasty: case report and review of literature10
Catheterization and Cardiovascular Interventions
doi: 10.1002/ccd.25689
September 2014

In patients with severe heart failure and mitral regurgitation, Carillon can be successfully used as a first line medical device intervention.

  • Case report of a NYHA class IV patient who presented with severe dyspnea progressing to orthopnea and paroxysmal nocturnal dyspnea. He was found to have severe functional mitral regurgitation Grade 4 and severe left ventricle systolic dysfunction. Surgical mitral intervention was not considered suitable and percutaneous mitral annuloplasty was performed with Carillon Mitral Contour System.
  • From baseline to 6-months following implantation of Carillon the patient experienced a 70% reduction in vena contracta (0.25cm vs. 0.84cm), 90% reduction in regurgitant volume (29ml vs. 291ml). MR Grade was reduced from a grade 4 to grade 2 and NYHA class improved from IV to I.
  • Remodelling of the left ventricle was observed and resulted in an absolute improvement in ejection fraction of 30% (from 20% to 50%).
  • The patient’s symptoms improved so significantly that he was no longer considered an immediate candidate for CRT.

Carillon can be implanted prior to CRT and may provide additional benefit to HF patients with FMR, low ejection fraction and wide QRS.

  • Case study of a 45-year-old male with ischemic heart failure who underwent successful implantation of a Carillon device.
  • The procedure resulted in clinical improvements and a decrease in FMR.
  • Fifteen months post implant, the patient was a candidate for CRT and underwent successful implantation, which resulted in further improvement of clinical and echocardiographic parameters.

TITAN
European Journal of Heart Failure
doi:10.1093/eurjhf/hfs076
May 2012

The TITAN study met its endpoint and showed the Carillon device can significantly and safely reduce FMR severity in heart failure patients, resulting in significant favorable reverse LV remodeling over 12 months and improved measures of clinical outcomes over 24 months.

The TITAN study was a prospective, non-randomized multi-center European study. The objective of the study was to determine if the Carillon device could safely and effectively reduce FMR and yield a durable long-term clinical benefit. Follow-up included typical clinical and echo assessments through 1 year and implanted patients had an additional clinical follow-up assessment at 2 years. The study was rigorously conducted with oversight by independent parties including an echo core lab, clinical events committee, and a data and safety monitoring board. Key inclusion criteria included MR grade 2+ to 4+, NYHA Class II-IV and LVEF <40%.

Of the 53 patients enrolled in the study, 36 underwent permanent implant of the device. In 17 patients, the device was recaptured (due to transient coronary impingement (n=8) or <1 grade FMR reduction (n=9). These non-implant patients were followed as a comparator group.

Carillon increased functional capacity and improved echocardiographic parameters in FMR patients.

  • This study enrolled 14 consecutive patients who underwent Carillon implantation.
  • Echocardiographic parameters, 6MWD, Naughton treadmill exercise test, NYHA class and QOL were assessed at baseline and after one month.
  • All measurements demonstrated statistically significant improvement at one month from baseline.
  • Echocardiographic MR parameters were observed immediately after the procedure and during the one month follow up; these parameters included vena contracta (0.36cm after procedure and 0.31cm at one month vs. 0.65cm at baseline, both p<0.001) and effective regurgitant orifice area (0.18cm2 after procedure and 0.20cm2 at one month vs. 0.28cm2 at baseline, p<0.05 and p<0.005, respectively).
  • One month after the procedure the 6MWT (25%, p<0.001), Naughton treadmill exercise test (45.0%, p<0.005) and NYHA classifications (34.1%, p<0.005) were significantly improved.

Carillon improved echocardiographic parameters in functional mitral regurgitation patients.

  • In this study, nine patients were enrolled and successfully implanted with the Carillon device.
  • One-month post-implant, vena contracta, the ratio of the jet area to the left atrial area, and other echocardiographic parameters were assessed relative to baseline.
  • Vena contracta and jet area to left atrial area improved (p<0.05 and p<0.005, respectively).

It is possible to implant the Carillon device prior to a CRT device in HF patients with low ejection fraction, wide QRS and FMR.

  • Three patients meeting current guidelines for cardiac resynchronization therapy (CRT) included in the AMADEUS trial underwent CRT implantation 7-8 months after implantation of a mitral valve annuloplasty device.
  • Access to the coronary sinus and placement of the left ventricular lead into a posterolateral cardiac vein was not at all compromised by the mitral valve annuloplasty device in any patient.

AMADEUS
Circulation
doi: 10.1161/CIRCULATIONAHA.109.849885
July 2009

The first-in-human AMADEUS study met its endpoint and demonstrated successful deployment of the Carillon device and a significant reduction in FMR.

AMADEUS was a single-arm, first-in-human study designed to evaluate the safety and feasibility of the Carillon system. The study utilized several independent bodies to minimize bias and increase rigor, including a blinded echo core lab, clinical events committee, and data and safety monitoring board. Key inclusion criteria included moderate to severe FMR, NYHA class II-IV, LVEDD >55mm, and ejection fraction <40% receiving sustained stable and optimal HF medication regimen. The study enrolled 48 patients with the device successfully implanted in 30 patients. At six months, the degree of FMR reduction among five different quantitative echo measures ranged from 22-32%.

  • Patients implanted with the Carillon Mitral Contour System were evaluated for long‐term follow‐up post‐procedure up to 7.5 years.
  • Patients experienced a clinically significant reduction in heart failure hospitalizations and symptom improvement post procedure which was sustained through the 6+ year follow-up period.
  • Long-term mortality was 40% at 6 years, which compares favorably to several prior studies that have evaluated medically managed patients with FMR.

Patients treated with the Carillon device continue to show sustained improvements in mitral regurgitation, left ventricular volume, ejection fraction, and clinical status 6+ years post procedure. All patients at 6 year follow-up had MR 2+ or less with over half having MR 1+ or trace, and LVEDV was reduced from 154.0 ± 65.7 mL at baseline to 104.5 ± 59.2 mL (p=0.03).

Comparison of effectiveness and survival after the MitraClip or Carillon procedure for severe functional mitral regurgitation: a single-center retrospective analysis3
Department of Cardiology, Frankfurt University Hospital, Frankfurt, Germany
doi: 10.5114/amsad.2020.97160
June 2020
  • First study to directly compare patients treated with either Carillon (n=37) or MitraClip (n=137).
  • MR grade was significantly reduced (p<0.001) in both groups after procedure.
    • MR grade remained reduced in Carillon patients at 2 years (n=9).
  • Survival was assessed up to 5 years.
    • Median survival in the Carillon group was 3.92 years vs 1.66 years in the MitraClip group (p = 0.01).
    • Numerous baseline factors may contribute to the difference in survival benefit observed.
  • Pulmonary artery pressure was reduced in both groups after intervention (p<0.05), however, continued decrease at later follow up was observed only in the Carillon group.

This analysis brings new insights into the long-term role of the Carillon Mitral Contour system for the treatment of symptomatic congestive heart failure with functional mitral regurgitation.

A total of 74 patients from the TITAN, TITAN II and REDUCE FMR clinical studies who had symptomatic congestive heart failure despite guideline-directed medical therapy, grade 2+ to 4+ FMR, left ventricular enlargement, and reduced ejection fraction were assessed as part of the analysis. For all patients, echocardiographic parameters were available through the 12-month visit and vital status was available through 5 years.

  • Over 1 year of follow-up, the New York Heart Association (NYHA) class decreased in 64% of patients, distance on the 6-minute walk test increased, and echocardiographic measures indicated significant decreases in MR grade and favorable left ventricular remodeling.
  • The Kaplan-Meier survival rate was 83.6% at 1 year, 73.1% at 2 years, 67.9% at 3 years and 56.2% at 4 and 5 years of follow-up.
  • Primary determinants of long-term survival were a decrease in NYHA class, an increase in 6-minute walk test distance, and a decrease in regurgitant volume during the first year of follow-up.
  • Three-year mortality rate compared to published outcomes of COAPT and guideline directed medical therapy (GDMT), using matched patient populations, was 33.7% for Carillon, 42.8% for MitraClip in COAPT and 55.5% for GDMT.

An individual patient data meta‐analysis was conducted from 3 prospective studies that enrolled 209 heart failure patients with reduced ejection fraction patients and functional mitral regurgitation (FMR). Patients implanted with the Carillon Mitral Contour System or control were assessed for 12-month outcomes relating to mitral regurgitation severity, left ventricular (LV) remodeling, functional status, and heart failure‐related hospitalization.

  • Patients implanted with the device showed significantly improved hemodynamics, MR severity (regurgitant volume and MR grade), left ventricular volume (LVEDV) and left atrial volume (LAV), as compared to those patients who did not receive a device at 12 months.
  • Improvement of symptoms as assessed by change in NYHA class also significantly favored device implantation vs control (p<0.00001) with 69.9% (51/73) of implanted patients with baseline class III or IV improving by at least one class at 12 months.
  • Similarly, the rate of hospitalizations due to heart failure (HFH) was significantly reduced in implanted patients (45.3% vs 64%, p=0.04).
  • Sensitivity analysis performed on subjects with more severe MR (MR grade 3+/4+) at baseline supported the overall cohort in terms of hemodynamic improvement and maintained a significant improvement in HFH (43.9% vs 82.9%, p=0.04).

In conclusion, this comprehensive meta‐analysis of individual patient data has shown that the CARILLON device provides statistically significant and clinically meaningful benefits in LV volumes, NYHA functional class and indexes of mitral valve performance, along with a reduction in the rate of subsequent HFH.

Embracing secondary mitral regurgitation with Carillon: past, present, and future15
ESC Heart Failure
Mitja Lainscak and Michael Böhm
December 2020

In this editorial Dr. Lainscak and Professor Böhm discuss the optimal management strategy for patients with Functional Mitral Regurgitation. There is a need in the therapeutic spectrum for additional therapies that are safe and can be deployed as an early intervention to reduce the need for repeated hospitalizations. The data presented by Gialluria et al. supports the use of the Carillon Mitral Contour System to achieve this goal. Owing to less invasive approaches, favourable effects on left ventricular volumes, and possibility of step‐wise upgrade with other interventions, Carillon could be considered early in the patient trajectory for a timely and effective management of heart failure patients with reduced ejection fraction and functional mitral regurgitation.

Echographic outcomes of patients with atrial derived FMR (aFMR) and heart failure with preserved ejection fraction (HFpEF) were compared to patients with ventricular derived FMR (vFMR) and heart failure with reduced ejection fraction (HFrEF) after percutaneous mitral valve repair with the Carillon Mitral Contour System.

  • Patients with aFMR showed similar reductions in mitral annulus diameter and concomitant reduction in regurgitant volume through 3 months compared to those with vFMR.
  • Significant reduction in MR as assessed by vena contracta, effective regurgitant volume as well as MR was seen as soon as 3 months after procedure in both groups.
  • Similarly, after 3 months the proportion of patients with NYHA class III or IV was reduced from 92.8% to 42.8% which was maintained throughout 12 month follow-up.

The Carillon device is feasible in HFpEF patients with aFMR and is associated with significant reductions in MR.

  • 30 patients with symptomatic moderate or severe SMR [FMR] were assessed for the acute effects of Carillon therapy by advanced echocardiography 1 day prior to procedure and at discharge.
  • Treatment of SMR [FMR] with the Carillon device leads to acute reduction of MR severity in 83% of patients after the procedure.
    • Both PISA based measurements of regurgitant volume as well as measurements derived from regurgitant fraction were significantly improved (p<0.05) after the procedure.
  • Effective [forward] stroke volume was significantly improved (p<0.001) and ejection fraction was non-significantly improved (p = 0.06) immediately after the intervention.

  • 37 patients implanted with the Carillon device were included in this retrospective, single-center study.
  • First study to show significant reduction in annular diameter in both anterior-posterior and anterolateral-posteromedial aspects (p<0.001) after any transcatheter mitral valve repair therapy.
  • Left atrial volume significantly reduced (p<0.02) at 30 days follow up and maintained through 1 year.

REDUCE FMR
JACC: Heart Failure
doi: 10.1016/j.jchf.2019.06.011
November 2019

The REDUCE FMR study was the first double-blinded trial of a percutaneous heart valve therapy, achieved its primary endpoint, and demonstrated favorable reverse LV remodeling. A median 22% reduction in regurgitant volume was demonstrated, as assessed by a blinded, independent echo core lab. The results of The REDUCE FMR study are consistent with the prior Carillon device studies.

1Data on file. Percent calculated by averaging individual patient percent changes.
ITT = Intent to Treat

REDUCE FMR was the first ever double-blinded, randomized, parallel, sham-controlled RCT of a percutaneous heart valve therapy. The objective was to assess the safety and effectiveness of the Carillon Mitral Contour System for treatment of secondary (functional) mitral regurgitation (FMR) associated with heart failure. Key eligibility criteria were similar to the prior trials of the Carillon system including NYHA class II-IV, MR grade 2+ to 4+, LVEDD >55mm and an ejection fraction <50%, despite the use of stable guideline-directed medical therapy. The primary endpoint was change in regurgitant volume (RV) at 1 year by intention-to-treat analysis. Being double-blind, the study was of the highest scientific rigor – patients and assessors were blinded throughout follow-up and the independent echo core lab not only was blinded to treatment and the timing of the images but also read the images in random order.

In total, 120 patients were randomly allocated to treatment (87) or the sham-control (33) arm at 31 sites in Europe, Australia and New Zealand.

Echocardiographic evaluation was performed at the site prior to enrollment, and 35 patients (29.2%) were later judged by the echo core laboratory to have had MR 1+ at baseline. In 14 (16%) of those allocated to treatment, no device was implanted, due most commonly to coronary impingement (n=8) which resolved following device removal in all cases. The average device implant time was 64.2±34.8 minutes and total procedure time averaged 102.7±54.9 minutes. Freedom from device-related major adverse events (MAE) was 98.9%, with no device embolizations, device fractures, cardiac perforations or intra-procedural ischemic events. There were two deaths within 30 days, both in implanted patients attributed to progressive cardio-renal deterioration. The incidence of MAE at 1 year was not statistically different between the treatment and control groups (16.1% in treatment group vs. 18.2% in control group).

The primary endpoint was met with a statistically significant reduction in mitral RV in the treatment group as compared to the control group (decrease of 7.1 mL/beat vs. an increase of 3.3 mL/beat, p=0.049). A secondary analysis of patients with more severe FMR (MR grade ≥3+) demonstrated a similar pattern of changes. Patients in the treatment group (n=15) experienced a reduction in mitral RV of 12.8 mL/beat whereas patients in the control group (n=8) experienced an increase of 0.6 mL/beat (p=0.14). In addition to improvements in RV, favorable reverse LV remodeling was demonstrated, with a significant reduction in LV volumes in patients receiving the device vs. the control group.

Patients in the treatment group also experienced a significant improvement in 6-minute walk distance at 12 months compared with their baseline (p=0.002), whereas patients allocated to the control group did not (p=0.29). Likewise, the treatment group had a significant improvement in NYHA class at 12 months compared with baseline (p=0.002) whereas patients allocated to the control group did not (p=0.75).

With REDUCE FMR, the Carillon system became the first TMVr therapy to demonstrate significant favorable reverse LV remodeling at 1 year and significant reduction in RV in a blinded, randomized, sham-controlled trial.

This analysis showed that Carillon addresses FMR and, in as little as one-month, successful implantation results in left ventricular reverse remodelling and increased systolic performance. Mitral tenting area is an important baseline parameter in predicting treatment efficacy with Carillon.

  • 35 patients were enrolled and 22 were successfully implanted with the Carillon device. Some patients were not implanted due to coronary sinus size (n=3), impaired access (n=2), compromised coronary flow (n=4), or insufficient mitral regurgitation reduction (n=4).
  • At one-month follow-up, statistically significant reductions in the following parameters were observed: anteroposterior (AP) diameter, regurgitant volume (RV), vena contracta (VC), effective regurgitant orifice area (EROA), proximal isovelocity surface area (PISA), mitral tenting area, mitral tethering, and mean diastolic interpapillary distance.
  • Patients with increased left atrial diameters saw greater improvement in ejection fraction, following implantation.

TITAN II
Open Heart
doi: 10.1136/openhrt-2016-000411
June 2016

The TITAN II study achieved its endpoint and showed significant improvements in echo parameters and patient function.

TITAN II was a single-arm study designed to assess the safety and efficacy of an updated version of the Carillon system. Inclusion and exclusion criteria were similar to those in TITAN. Patients had symptomatic congestive heart failure (NYHA class ≥2), MR grade 2+ to 4+, a dilated LV (LVEDD >55 mm) and an ejection fraction <40%. Quantitative assessments of MR were performed by an independent core echo laboratory, and MAE were reviewed by an independent data and safety monitoring board. In total, 36 patients were enrolled; 30 received a permanent implant.

This study showed that potential coronary artery compromise can be managed safely and effectively in all patients with 95% successfully implanted.

  • 17 patients were implanted with the Carillon device in a prospective, single-center, non-randomized study.
  • Patients experienced a mean one grade reduction of MR acutely (2.8 to 1.9, p<0.005) with an additional improvement at 3 months (1.5, p<0.005).
  • In 41.2% of patients an acute reduction of coronary artery flow was detected intraoperatively and in all except one patient this could be easily managed such that the patients successfully received the implant.

Restoration of normal left ventricular geometry after percutaneous mitral annuloplasty: case report and review of literature10
Catheterization and Cardiovascular Interventions
doi: 10.1002/ccd.25689
September 2014

In patients with severe heart failure and mitral regurgitation, Carillon can be successfully used as a first line medical device intervention.

  • Case report of a NYHA class IV patient who presented with severe dyspnea progressing to orthopnea and paroxysmal nocturnal dyspnea. He was found to have severe functional mitral regurgitation Grade 4 and severe left ventricle systolic dysfunction. Surgical mitral intervention was not considered suitable and percutaneous mitral annuloplasty was performed with Carillon Mitral Contour System.
  • From baseline to 6-months following implantation of Carillon the patient experienced a 70% reduction in vena contracta (0.25cm vs. 0.84cm), 90% reduction in regurgitant volume (29ml vs. 291ml). MR Grade was reduced from a grade 4 to grade 2 and NYHA class improved from IV to I.
  • Remodelling of the left ventricle was observed and resulted in an absolute improvement in ejection fraction of 30% (from 20% to 50%).
  • The patient’s symptoms improved so significantly that he was no longer considered an immediate candidate for CRT.

TITAN
European Journal of Heart Failure
doi:10.1093/eurjhf/hfs076
May 2012

The TITAN study met its endpoint and showed the Carillon device can significantly and safely reduce FMR severity in heart failure patients, resulting in significant favorable reverse LV remodeling over 12 months and improved measures of clinical outcomes over 24 months.

The TITAN study was a prospective, non-randomized multi-center European study. The objective of the study was to determine if the Carillon device could safely and effectively reduce FMR and yield a durable long-term clinical benefit. Follow-up included typical clinical and echo assessments through 1 year and implanted patients had an additional clinical follow-up assessment at 2 years. The study was rigorously conducted with oversight by independent parties including an echo core lab, clinical events committee, and a data and safety monitoring board. Key inclusion criteria included MR grade 2+ to 4+, NYHA Class II-IV and LVEF <40%.

Of the 53 patients enrolled in the study, 36 underwent permanent implant of the device. In 17 patients, the device was recaptured (due to transient coronary impingement (n=8) or <1 grade FMR reduction (n=9). These non-implant patients were followed as a comparator group.

Carillon increased functional capacity and improved echocardiographic parameters in FMR patients.

  • This study enrolled 14 consecutive patients who underwent Carillon implantation.
  • Echocardiographic parameters, 6MWD, Naughton treadmill exercise test, NYHA class and QOL were assessed at baseline and after one month.
  • All measurements demonstrated statistically significant improvement at one month from baseline.
  • Echocardiographic MR parameters were observed immediately after the procedure and during the one month follow up; these parameters included vena contracta (0.36cm after procedure and 0.31cm at one month vs. 0.65cm at baseline, both p<0.001) and effective regurgitant orifice area (0.18cm2 after procedure and 0.20cm2 at one month vs. 0.28cm2 at baseline, p<0.05 and p<0.005, respectively).
  • One month after the procedure the 6MWT (25%, p<0.001), Naughton treadmill exercise test (45.0%, p<0.005) and NYHA classifications (34.1%, p<0.005) were significantly improved.

Carillon improved echocardiographic parameters in functional mitral regurgitation patients.

  • In this study, nine patients were enrolled and successfully implanted with the Carillon device.
  • One-month post-implant, vena contracta, the ratio of the jet area to the left atrial area, and other echocardiographic parameters were assessed relative to baseline.
  • Vena contracta and jet area to left atrial area improved (p<0.05 and p<0.005, respectively).

AMADEUS
Circulation
doi: 10.1161/CIRCULATIONAHA.109.849885
July 2009

The first-in-human AMADEUS study met its endpoint and demonstrated successful deployment of the Carillon device and a significant reduction in FMR.

AMADEUS was a single-arm, first-in-human study designed to evaluate the safety and feasibility of the Carillon system. The study utilized several independent bodies to minimize bias and increase rigor, including a blinded echo core lab, clinical events committee, and data and safety monitoring board. Key inclusion criteria included moderate to severe FMR, NYHA class II-IV, LVEDD >55mm, and ejection fraction <40% receiving sustained stable and optimal HF medication regimen. The study enrolled 48 patients with the device successfully implanted in 30 patients. At six months, the degree of FMR reduction among five different quantitative echo measures ranged from 22-32%.

This study showed that percutaneous mitral valve repair may be cost-effective in patients with FMR due to heart failure.

  • Cost-utility analysis of Carillon Mitral Contour System was performed based on the TITAN trial results using a combination of a decision tree and Markov process. The analysis was performed from the German statutory health insurance perspective over 10-year time horizon.
  • Carillon provided additional benefits to patients with an 1.15 incremental quality-adjusted life years (QALY) and an 1.41 incremental life years. The procedure was cost-effective in comparison to optimal medical therapy (OMT) with an incremental cost-effectiveness ratio of €15,533/QALY. With a willing- ness-to-pay threshold of €35,000/QALY, PMVR had a 84% probability of being cost-effective.

Carillon can be implanted prior to CRT and may provide additional benefit to HF patients with FMR, low ejection fraction and wide QRS.

  • Case study of a 45-year-old male with ischemic heart failure who underwent successful implantation of a Carillon device.
  • The procedure resulted in clinical improvements and a decrease in FMR.
  • Fifteen months post implant, the patient was a candidate for CRT and underwent successful implantation, which resulted in further improvement of clinical and echocardiographic parameters.

It is possible to implant the Carillon device prior to a CRT device in HF patients with low ejection fraction, wide QRS and FMR.

  • Three patients meeting current guidelines for cardiac resynchronization therapy (CRT) included in the AMADEUS trial underwent CRT implantation 7-8 months after implantation of a mitral valve annuloplasty device.
  • Access to the coronary sinus and placement of the left ventricular lead into a posterolateral cardiac vein was not at all compromised by the mitral valve annuloplasty device in any patient.

  1. Dennis Rottländer, MD; Miriel Gödde, MD; Hubertus Degen, MD; Alev Ögütcü, MD; Michael Haude, MD, PhD. Percutaneous Coronary Sinus-Based Mitral Valve Annuloplasty in Atrial Functional Mitral Regurgitation. JACC: Cardiovascular Interventions. December 28, 2020
  2. Lipiecki, J, Fahrat, H, Séverine, M, et al. Long-term prognosis of patients treated by coronary sinus-based annuloplasty: single centre experience. ESC Heart Failure. October, 2020.
  3. Stephan Heyl, Aria Nikkhoo, Markus Wieszner, Stephan Fichtlscherer, Florian Seeger, Birgit Assmus, Brigitte Luu, Katrin Hemmann, Claudia Walther, Joerg Honold. Comparison of effectiveness and survival after the MitraClip or Carillon procedure for severe functional mitral regurgitation: a single-center retrospective analysis. Arch Med Sci Atheroscler Dis. June, 2020.
  4. Stephan Stöbe, Kristin Kreyer, Daniel Jurisch, Dietrich Pfeiffer, Daniel Lavall, Gerardo Farese, Ulrich Laufs, Andreas Hagendorff. Echocardiographic analysis of acute effects of percutaneous mitral annuloplasty on severity of secondary mitral regurgitation. ESC Heart Failure. May, 2020.
  5. Tobias Friedrich Ruf, Felix Kreidel, Alexander Robert Tamm, Martin Geyer, Omar Hahad, Julia Claudia Zirbs, Ben Luca Schwidtal, Andres Beiras-Fernandez, Klaus K. Witte, Thomas Münzel, Ralph Stephan von Bardeleben. Transcatheter indirect mitral annuloplasty induces annular and left atrial remodelling in secondary mitral regurgitation. ESC Heart Failure. April, 2020.
  6. Lipiecki, J, Kaye DM, Witte KK, et al. Long-Term Survival Following Transcatheter Mitral Valve Repair: Pooled Analysis of Prospective Trials with the Carillon Device. Cardiovascular Revascularization Medicine. February, 2020.
  7. Kałmucki P., Jerzykowska O., Dankowski R., Baszko A., Kramer L., Szyszka A., Siminiak T. Percutaneous Trans-Coronary Venous Mitral Annuloplasty in Patients With Functional Mitral Regurgitation: Analysis of Poznan Carillon Registry Data. J Interv Cardiol. 2016.
  8. Klein, N. et al. Mitral Annuloplasty Device Implantation for Non-Surgical Treatment of Mitral Regurgitation: Clinical Experience after the Approval Studies. Journal of Invasive Cardiology. February, 2016.
  9. Borisenko, O., Haude, M., Hoppe, UC., Siminiak, T., Lipiecki, J., Goldberg, S., Mehta, N., Bouknight, O., Bjessmo S., Reuter DG. Cost-utility analysis of percutaneous mitral valve repair in inoperable patients with functional mitral regurgitation in German settings. BMC Cardiovascular Disorders. 2015;15:43.
  10. Soofi, M.A., Alsamadi F. Restoration of Normal Left Ventricular Geometry after Percutaneous Mitral Annuloplasty: Case Report and Review of Literature. Catheterization and Cardiovascular Interventions. 2014.
  11. Siminiak T, Jerzykowska O, Kałmucki P, Link R, Baszko A. Cardiac resynchronization therapy after percutaneous trans-coronary-venous mitral annuloplasty. Kardiol Pol. 2013;71(12):1293-4.
  12. Woloszyn M, Jerzykowska O, Kałmucki P, Lunk R, Firek L, Kuzemczak M, Siminiak T. Functional assessment of patients after percutaneous mitral valvuloplasty with Carillon device: a preliminary report. Kardiol Pol. 2011;69(3):228-33.
  13. Jerzykowska O, Kalmucki P, Woloszyn M, Smuszkiewicz P, Firek L, Siminiak T. Echocardiographic evaluation of percutaneous vavle repair in patients with mitral regurgitation using the Carillon system. Kardiol Pol. 2010;68(1):57-63.
  14. Hoppe UC, Brandt MC, Degen H, Dodos F, Schneider T, Stoepel C, Kroener A, Haude M. Percutaneous mitral annuloplasty device leaves free access to cardiac veins for resynchronization therapy. Catheter Cardiovasc Interv. 2009;74(3):506-11.
  15. Lainscak M, Bohm, M. Embracing secondary mitral regurgitation with Carillon: past, present, and future. ESC Heart Failure 2020; 7: 3268-3270.
  16. Giallauria F, Di Lorenzo A, Parlato A, et. al. Individual patient data meta-analysis of the effects of the CARILLON® mitral contour system. ESC Heart Failure 2020; 7: 3383-3391.