MitraClip Therapy Research Articles

TCT-541 Multi-center experience of MitraClip therapy in patients with Ischaemic and Non-ischaemic Functional Mitral Regurgitation: 2-year outcomes

MitraClip implantation has evolved as a new tool for treatment of inoperable or high-risk patients with severe functional mitral regurgitation (FMR) due to dilated cardiomyopathy (DCM). Limited data are available regarding MitraClip outcomes comparing patients with ischemic and non-ischemic DCM.

Functional status and quality of life after transcatheter mitral valve repair: a prospective cohort study and systematic review.

Estimating the quantitative effect of transcatheter mitral valve repair on functional parameters and quality of life is important for individual treatment decision-making. We combined data from a prospective monocentric cohort study (N=215) with data from a systematic literature review (PubMed search term "mitraclip", till 30.04.2016) on patients undergoing MitraClip with at least mortality after discharge reported as an outcome. Effects on functional parameters were reported as range of mean change. 36 observational studies and 1 randomized controlled trial were identified. Due to substantial heterogeneity of effect estimates (I 2-heterogeneity >75%) and inadequate quality of studies with a lack of comparison group in 97.4% and lack of an independent assessment of outcomes in 86.8%, no pooled estimates were calculated. All studies reported improvements of mean New York Heart Association (NYHA) class (0.5-1.9 classes), Short-Form (SF)-12/36 scores (4.4-9.2 for physical component score, 2.6-8.9 for mental component score), 6-min walk distance [(6MWD) 2-336m] and Minnesota Living with Heart failure questionnaire (MLWHFQ) score (-7 to -18 points), with improvements regarded as clinically relevant in 20 of 29 studies for NYHA class, in all of 7 studies for SF12/36, in 9 of 15 studies for 6MWD and in all of 8 studies for MLWHFQ. MitraClip therapy provides improvements in physical capacity, physical and mental functioning and disease-specific quality of life in the majority of patients. However, more comparative and high-quality studies are required for understanding the heterogeneity of results, which is crucial for optimal patient selection.

P1363Spherical ventricle, large left atrium size and anemia predict 1-year failure of MitraClip therapy in patients with functional mitral regurgitation

P1363Spherical ventricle, large left atrium size and anemia predict 1-year failure of MitraClip therapy in patients with functional mitral regurgitation

P153Risk assessment in patients undergoing MitraClip therapy: the usefulness of NT-proBNP

P153Risk assessment in patients undergoing MitraClip therapy: the usefulness of NT-proBNP

Implication of pulmonary hypertension in patients undergoing MitraClip therapy: results from the German transcatheter mitral valve interventions (TRAMI) registry.

We sought to evaluate the impact of pulmonary hypertension on outcomes following MitraClip therapy. The 643 patients in the TRAnscatheter Mitral valve Interventions (TRAMI) registry were divided into three groups according to echocardiographically graded systolic pulmonary artery pressure (sPAP) (Group 1: patients with sPAP of ≤36 mmHg; Group 2: patients with sPAP of 37-50 mmHg; Group 3: patients with sPAP of >50 mmHg) and followed for 1 year. Recent cardiac decompensation, aortic valve disease and tricuspid valve insufficiency were observed more frequently in patients with higher sPAP. Furthermore, logEuroSCORE, Society of Thoracic Surgeons score and age were higher with rising sPAP values. No differences were observed in mitral regurgitation (MR) severity, co-morbidities or clinical findings (New York Heart Association class, 6-min walking distance). Reduction to MR of grade 1 or lower was achieved more often in patients with lower sPAP levels (P = 0.01). In Groups 2 and 3, sPAP was reduced significantly. Major adverse cardiac or cardiovascular events (MACCEs) occurring in hospital (death, myocardial infarction, stroke; <4% in each group), as well as 30-day rates of MACCEs (6.1% in Group 1, 11.9% in Group 2, 12.4% in Group 3) and rehospitalization (18.9% in Group 1, 24.8% in Group 2, 24.8% in Group 3) did not differ significantly. At 1 year, differences in rates of mortality and MACCEs (20.3% in Group 1, 33.1% in Group 2, 34.7% in Group 3; P < 0.01) were significant. Both Groups 2 [hazard ratio (HR) 1.81, P = 0.0122] and 3 (HR 1.85, P = 0.0092) were independently predictive of death. Rehospitalization rates did not differ during follow-up. Despite higher mortality in patients with elevated sPAP, these data suggest the safety, feasibility and benefit of MitraClip therapy even in advanced stages of disease. An early approach might prevent the progress of pulmonary hypertension and improve outcomes.

Acute Hemodynamic Changes after Mitraclip Implantation Comparing Patients with Degenerative and Functional Mitral Regurgitation

ABSTRACTBackground:MitraClip (MC) therapy is a percutaneous treatment option for surgical high-risk patients with both degenerative (DMR) and functional mitral regurgitation (FMR). We compared the acute hemodynamic outcomes of MC therapy in DMR and FMR patients.Methods:A total of 339 successfully treated patients (77 ± 9 years; 215 men [63%]; 129 DMR [38%], 210 FMR [62%]; LV ejection fraction 40 ± 17%) were hemodynamically assessed pre- and post-MC.Results:FMR patients had significantly higher pre- and post-MC filling pressures, as well as higher pulmonary capillary wedge and mean pulmonary artery pressures, than DMR patients, but the increase or decrease in these variables did not differ significantly between etiologies. Cardiac output increased significantly in both groups (DMR: 4.1–4.9 l/min; FMR: 4.1–5.1 l/min; both p < 0.0001); the increase was statistically not different between etiologies (DMR: 0.8 ± 1.1 l/min; FMR: 1.0 ± 1.1 l/min; p = 0.06). With heart rate constant pre- and post-MC, significant increases were also observed in forward stroke volume (DMR: 70–84 ml; FMR: 70–86 ml; both p < 0.0001). The mean left atrial v-wave was statistically not different between etiologies at baseline and decreased significantly after MC (DMR: 26–17 mmHg; FMR: 27–21 mmHg; both p < 0.0001).Conclusion:Successful MC therapy results acutely in marked increases in cardiac output and forward stroke volume, and a significant decrease in the left atrial v-wave, in both DMR and FMR patients. Our results attest to the beneficial effect of percutaneous mitral valve repair, particularly in the latter patients with generally poorer baseline health.

Combined mitro-aortic pathology: impact of previous aortic valve replacement upon outcomes of MitraClip therapy (from the German transcatheter mitral valve interventions registry).

The aim of this study was to identify the impact of previous aortic valve replacement (AVR) in MitraClip (MC) patients. Data from the German transcatheter mitral valve interventions (TRAMI) registry were analysed in the light of previous AVR by means of either standard AVR (SAVR) or transcatheter AVR (TAVR). Out of 791 MC patients, 68 (8.6%) had been submitted to AVR (68.4% SAVR and 31.6% TAVR). The AVR group was significantly older (77.2±8.0 years vs. 75.1±8.6 years; p<0.05) and had a trend towards a higher risk profile (median STS score 10 [8.0-12.0] vs. 6.0 [3.0-11.0]; p=0.1). No procedural mortality was observed. Severe residual MV regurgitation was reported in 6.2% of AVR vs. 3.7% of the no-AVR patients (p=0.1). Thirty-day mortality was 10.6% in the previous AVR group vs. 3.9% in the no-AVR group (p<0.05). One-year estimated survival was lower in the AVR group (AVR 63% vs. no-AVR 81%; p<0.0001; HR 2.25, 95% CI: 1.42-3.55). Estimated survival in TAVR compared to SAVR was lower (TAVR 44.4% vs. SAVR 70%; p=0.039; HR 2.32, 95% CI: 0.99-5.37). AVR was a determinant of follow-up mortality (HR 2.18, 95% CI: 1.4-3.4; p<0.001). Previous AVR in patients undergoing MC therapy carries a heavy and independent burden of mortality/morbidity.

Preliminary Short-term Results of a Population of Patients Treated with MitraClip Therapy: One Center Experience

&lt;p&gt;&lt;span&gt;Objectives: This retrospective analysis sought to evaluate 1-month outcomes and therapy effectiveness of a population of patients treated with MitraClip therapy. We describe in this article the preliminary results of primary effictiveness endpoint.&lt;/span&gt;&lt;/p&gt;&lt;p&gt;&lt;span&gt;Background: Percutaneous Mitral Repair is being developed to treat severe mitral regurgitation (MR),with increasing real-world cases of functional MR(FMR). In the EVEREST(Endovascular Valve Edge-to-Edge Repair Study)II trial,percutaneous device showed superior safety but less reduction in MR at 1year. 4-year outcomes from EVEREST II trial showed no difference in the prevalence of moderate-severe and severe MR or mortality at 4years between surgical mitral repair and percutaneous approach.&lt;/span&gt;&lt;/p&gt;&lt;p&gt;&lt;span&gt;Methods: We analysed retrospectively collected data from one center experience in Italy enrolled from January2011 to December2016. The study included 62patients[mean age74±11years, 43 men(69%)] with MR of at least grade3+. Most of patients had functional MR, were in New York Heart Association(NYHA) functional class III or IV,with a large portion(78%) of mild-to-moderate Tricuspid Regurgitation(TR). One or more clips were implanted in 67procedures(62 patients).&lt;span&gt; &lt;/span&gt;&lt;/span&gt;&lt;/p&gt;&lt;span&gt;Results and Conclusions: Severity of MR was reduced in all successfully treated patients,54(90%) were discharged with MR≤2+(primary effictiveness endpoint). Clinical 1-month follow-up data showed an improvement in NYHA functional class (42patients (70%) in NYHA class I-II). 60 of 62 (97 %) successfully treated patients were free from death and mitral valve surgery at 1-month follow-up. MitraClip therapy reduces functional MR with acute MR reduction to &amp;lt;2+ in the great majority of patients,with a large freedom from death, surgery or recurrent MR in a great portion of patients.&lt;/span&gt;

Effect of Percutaneous Edge-to-Edge Repair on Mitral Valve Area and Its Association With Pulmonary Hypertension and Outcomes

Percutaneous edge-to-edge repair using the MitraClip system causes reduction in mitral valve area (MVA). However, its clinical impact is not fully elucidated. This study assessed the impact of postprocedural MVA reduction on pulmonary hypertension and outcomes. A total of 92 patients with grades 3 to 4+ mitral regurgitation (MR) who underwent MitraClip therapy were retrospectively reviewed. Using intraprocedural, 3-dimensional transesophageal echocardiography, postprocedural MVA was obtained by 2 optimized planes through the medial and lateral orifices of the repaired valve. MVA was reduced by 60.1% immediately after MitraClip procedure (p <0.001). Postprocedural MVA correlated moderately with mean transmitral pressure gradient (TMPG) in the majority of patients (r=-0.56, p <0.001), but discordance of MVA and TMPG was observed in 40% of patients. In multivariable linear regression analysis, postprocedural MVA ≤1.94cm2 was independently associated with a blunted decrease in systolic pulmonary artery pressure at 1-month follow-up (β-estimate-4.63, 95% confidence interval-9.71 to-0.15, p=0.042). Postprocedural MVA ≤1.94cm2 was an independent predictor of all-cause mortality and heart failure hospitalization after MitraClip (hazard ratio 4.28, 95% confidence interval 1.56 to 11.7, p= 0.005) even after adjustment for age, gender, atrial fibrillation, cause of MR, left ventricular systolic function, pre-existing pulmonary hypertension, and residual MR. After further adjustment for TMPG ≥5mm Hg, postprocedural MVA ≤1.94cm2 remained predictive for adverse outcomes (p= 0.048). In conclusion, the intraprocedural assessment of MVA by 3-dimensional transesophageal echocardiography can predict hemodynamic response and postprocedural prognosis after MitraClip therapy.

Poland: coronary and structural heart interventions from 2010 to 2015.

For the last five years, invasive cardiology in Poland has developed extensively. Currently, 98% of the 161 Polish cathlabs operate in 24/7 mode, 37 of them supported by cardiac surgery departments on-site. A certification curriculum for interventional cardiology operators is supported by dedicated workshops and scientific meetings during national conferences. The rise in the number of coronary angiographies and PCIs was paralleled by an increased use of drug-eluting stents, bioresorbable vascular scaffolds and physiologic assessment of coronary arteries. Radial artery access has become the default option for PCI. A rapid adoption of the EAPCI Stent for Life Initiative resulted in a significant increase in primary PCIs. Unlike coronary interventions, structural heart interventions have evolved unevenly, despite the solid network of Heart Teams set up in the 21 most experienced centres. Left atrial appendage closure is offered in an increasing number of cathlabs. MitraClip therapy remains largely underused (1 procedure/million population/year). Despite the slow growth of TAVI since 2008, the current annual number of 17.1 TAVI procedures per million population is incomparable with countries in Western Europe. A recently introduced EAPCI Valve for Life campaign was followed by a 42.6% annual increase in TAVI procedures and an improvement in patients' access to therapy in life-saving indications.

(287) - MitraClip Therapy for Patients with End-Stage Heart Failure: A Durable Option?

The aim of this study was to assess feasibility and clinical outcome of MitraClip® therapy for mitral regurgitation (MR) in patients with end-stage heart failure and severely reduced left ventricular ejection fraction (LVEF) ≤ 25%.

Corrigendum to 'Optimal results immediately after MitraClip therapy or surgical edge-to-edge repair for functional mitral regurgitation: are they really stable at 4 years?' [Eur J Cardiothorac Surg 2016;50:488-494

Corrigendum to 'Optimal results immediately after MitraClip therapy or surgical edge-to-edge repair for functional mitral regurgitation: are they really stable at 4 years?' [Eur J Cardiothorac Surg 2016;50:488-494

Clinical outcomes of conventional surgery versus MitraClip\xae therapy for moderate to severe symptomatic mitral valve regurgitation in the elderly population: an institutional experience

BackgroundThe aim of this study was to compare treatment of moderate to severe symptomatic mitral regurgitation (MR) with either conventional surgery or the mitral valve edge-to-edge device (MitraClip®) in very elderly patients. The newly introduced MitraClip device has demonstrated promising acute results in treating this patient cohort. Also noteworthy is the fact that patients who otherwise would have been denied surgery are increasingly referred for treatment with the MitraClip device. We sought to review our institutional experience, comparing outcomes in both surgical and MitraClip arms of treatment in the elderly population with symptomatic MR.MethodsFrom October 2008 through October 2014, 136 consecutive patients aged ≥ 80 with moderate to severe symptomatic MR were scheduled for either conventional surgery or MitraClip intervention. 56 patients ≥ 80 were operated for symptomatic MR and 80 patients ≥ 80 were treated with the mitraClip device. Patients suitable for this study were identified from our hospital database. Patients ≥80 with moderate/severe symptomatic MR treated with either conventional surgery or the MitraClip device were eligible for our analysis. We compared the surgical patient cohort with the mitraClip patient cohort after eliminating patients that did not meet our inclusion criteria. Forty-two patients were identified from the conventional cohort who were then compared with 42 patients from the mitraClip cohort. Forty-two patients (50%) underwent mitral valve repair or replacement (40.5% functional MR, 59.5% organic/mixed MR) and 42 patients (50%) underwent MitraClip intervention (50% functional MR, 50% organic/mixed MR). Associated procedures in the conventional surgical group were myocardial revascularization 38%, pulmonary vein ablation 23.8%, left atrial appendage resection 52.4% and PFO occlusion 11.9%.ResultsPatients who underwent MitraClip treatment were though slightly older but the differences did not attain statistical significance (mean, 82.2 ± 1.65 vs 81.7 ± 1.35 years, p = 0,100), had lower LVEF (mean, 47.6 ± 14.2 vs 53.4 ± 14.3, p = 0.072), lower logistic EuroScore II (mean, 11.3 ± 5.63 vs 12.1 ± 10.6, p = 0.655) but higher STS risk score (mean, 11.8 ± 6.7 vs 8.1 ± 5.6, p = 0.008) respectively compared to surgical patients. Procedural success was 100% vs 96% in surgery and MitraClip groups respectively. Thirty -day mortality was 7.1% vs 4.8% (p = 1.000) in surgery and MitraClip group respectively. Residual postoperative MR ≥2 at discharge was present in none of the patients treated surgically, whereas this was the case in 10 (23.8%) patients treated with the MitraClip device. At 1 year a cumulative number of four (9.52%) patients died in the surgical group vs 9 (21.4%) patients who died in the MitraClip group.ConclusionsElderly patients presenting with moderate to severe symptomatic MR may either be treated by conventional surgery or with the MitraClip device with acceptable acute outcomes. The decision for treatment with the MitraClip device should not depend on age alone rather on cumulative risk of conventional surgery. Concomitant cardiac pathologies, often times treated simultaneously during surgery for symptomatic MR may be omitted, if patients are scheduled outright to MitraClip treatment. The effect of concomitant cardiac pathologies left untreated at the time of interventional mitral valve repair on outcome after MitraClip therapy remain widely unknown.

Prognostic implication of post-MitraClip vena contracta area in heart failure patients with functional mitral regurgitation.

Significant functional mitral regurgitation (FMR) in elderly heart failure patients is increasingly being treated by MitraClip implantation. We sought to assess the prognostic implications of the intraprocedural assessment of vena contracta area (VCA) after MitraClip therapy in such patients. MitraClip therapy with intraprocedural assessment of VCA was performed in 97 heart failure patients (74±10 years; 66 men; left ventricular ejection fraction [LVEF] 31±12%; 93 patients in New York Heart Association [NYHA] functional Class III [n=59] or IV [n=34]; 86 patients with FMR severity 3+ [n=65] or 4+ [n=21]). Ninety-one patients (94%) were discharged with FMR severity ≤2+. During a median follow-up of 13.4 (interquartile range 4.6-21.1) months, 32 patients died. Multivariable Cox regression identified increasing age (HR [95% confidence interval]=1.05 [1.00-1.09], p=0.0395), a glomerular filtration rate <50 ml/min/1.73 m² (HR=2.7 [1.3-5.7], p=0.0115), and post-MitraClip VCA >25 mm² (HR=4.5 [2.1-9.5], p=0.0001) as independent predictors of mortality. In heart failure patients with FMR undergoing MitraClip therapy, increasing age, impaired baseline renal function and post-MitraClip VCA >25 mm² are strongly associated with mortality. Post-MitraClip VCA may be used as intraprocedural guidance with respect to patients' long-term outcome.

Percutaneous edge-to-edge mitral valve repair for the treatment of acute mitral regurgitation complicating myocardial infarction: A single centre experience

BackgroundLimited evidence is available about MitraClip therapy in patients with acute mitral regurgitation (MR) complicating myocardial infarction (MI). Methods and resultsAmong 80 consecutive patients undergoing MitraClip treatment, 5 (6.3%) had been admitted for acute MI complicated by severe MR. Mean age was 73±6years and 3 were males. At the time of admission they were in cardiogenic shock (80%) or pulmonary oedema (20%), with severe MR, left ventricular dysfunction and pulmonary hypertension. The indication to MitraClip treatment was based on severe hemodynamic instability with dependence on intravenous therapy and mechanical supports despite percutaneous coronary revascularization and on high surgical risk of 27.1±13% and 10.2±6% using Euroscore II and STS score respectively. MitraClip procedure was performed at 53±33days from admission. One or two clips were employed in 2 and 3 patients respectively. Procedural success (MR≤2+) was achieved in all patients without complications and with successful weaning from mechanical supports and intravenous drugs in all but one patient who underwent left ventricular assist device implantation at 60days from MitraClip procedure. MR recurrence occurred at 30-day follow-up in one patient who had concomitant aortic regurgitation. One patient died during follow-up for non-cardiovascular cause. However, recovery of hemodynamic balance with significant and persistent pulmonary pressure reduction and functional status improvement up to 2-year follow-up was observed in most of the patients. ConclusionsCritical patients with acute ischemic MR post-MI with persistence of hemodynamic instability after coronary revascularization may benefit from MitraClip therapy acutely with favourable long-term follow-up results.

Conventional Surgery for Early and Late Symptomatic Mitral Valve Stenosis After MitraClip® Intervention: An Institutional Experience With Four Consecutive Patients

Surgical mitral valve repair is the gold standard for treatment of mitral regurgitation. Recently, the transcatheter treatment of mitral regurgitation with the MitraClip® device (Abbot Vascular Structural Heart, Menlo Park, CA) has demonstrated promising results in treating patients not amenable for surgical correction of mitral valve regurgitation. Most patients reported in the literature requiring surgical bailout after MitraClip treatment presented with residual or recurrent mitral valve regurgitation. Mitral valve stenosis after MitraClip treatment has been rarely reported. From February 2010 to December 2014, four patients out of 165 patients who underwent MitraClip therapy developed symptomatic mitral valve stenosis (2.4%) and needed surgical correction. Data of the four patients were reviewed retrospectively. Follow-up data were obtained from each patient's general practitioner/cardiologist by phone calls and facsimile and were complete in all patients. All four patients were treated with ≥ 2 MitraClip (MC) devices during their initial presentation. All four patients underwent MV replacement with a tissue valve. The postoperative course was uneventful and there was no 30-day mortality. At 6-month follow-up, all patients were alive and in NYHA class I-III. Placement of multiple clip devices may lead to slightly elevated transmitral gradients. This may not necessarily interpret into symptomatic mitral stenosis. However, in some cases this is possible. Caution should be exercised at this phase of the learning curve of the percutaneous MC treatment, especially in use of multiple MC devices.

MitraClip Therapy in “Ideal” Patients with a Post-Interventional Mitral Regurgitation ≤1

MitraClip Therapy in “Ideal” Patients with a Post-Interventional Mitral Regurgitation ≤1

MitraClip Therapy for Patients with End-Stage Heart Failure: A Durable Option?

MitraClip Therapy for Patients with End-Stage Heart Failure: A Durable Option?

Mitral annular motion in patients after transcatheter MitraClip and mitral valve surgery.

Longitudinal motion of the mitral annulus is an index that reflects left ventricular (LV) function. The aim of this study was to evaluate and compare the effects of transcatheter mitral valve (MV) repair and open heart surgery for mitral regurgitation (MR) on mitral annular motion (MAM). We retrospectively analyzed in total 115 patients who underwent isolated transcatheter MV repair using MitraClip (n=50) or surgical MV interventions (n=65, 50 repairs and 15 replacements) for MR. MAM was assessed by two-dimensional B-mode echocardiography in the four- and two-chamber views. MAM was measured before and within 1month after the mitral procedure. Compared with patients undergoing MV surgery, patients undergoing the MitraClip procedure were older and had more comorbidities. MR grade improved significantly in both groups after MV intervention. MAM decreased significantly in the surgery group (12.0±3.1 to 8.1±2.2mm, P<.01), whereas MAM did not change in the MitraClip group (8.8±2.6 to 8.6±2.5mm, P=.59). In multivariate analysis, mitral surgery was associated with a decrease in MAM when compared to the MitraClip procedure. Furthermore, LV ejection fraction (EF) decreased to a greater degree in patients undergoing surgery than those undergoing MitraClip placement (MV surgery; -10.1±7.6% vs MitraClip; -3.0±10.5%, P<.01). MitraClip therapy does not adversely influence MAM and is associated with less postprocedural EF reduction compared to surgical intervention. Our results suggest that patients with reduced LV systolic function may benefit from the MitraClip procedure compared to mitral surgery.

Early and Mid-Term Safety and Efficacy Outcomes After Mitra Clip Implantation in a Real- World Patient Cohort with High Surgical Risk – Insights from the Dresdner Mitra Clip Registry

Background: MitraClip therapy has recently gained clinical attention after EU and US approval. The Dresdner MitraClip registry reflects real world clinical demographic findings and midterm outcomes in an older patient cohort at high or prohibitive surgical risk with mixed mitral regurgitation (MR) etiology. Methods and results: A retrospective data analysis was conducted for consecutive patients with severe MR treated with the MitraClip system in a single institution between 08/2012 and 08/2015. 160 patients (46% ischemic cardiomyopathy (ICM), 22% dilative cardiomyopathy (DCM) and 32% degenerative mitral regurgitation (DMR) participated in this study. Patients in the ICM group had a significantly higher EURO-II-Score (22 (ICM) vs. 15 (DCM) vs 13 (DMR), p<0,05), representing a more complex comorbidity profile. MitraClip implantation was successful in 97 % of patients among all groups with low peri-procedural complication rates (0,9% for stroke, myocardial infarction). No case of total clip embolization, death or conversion to open heart surgery occurred. There was a significant improvement of MR-severity in all groups when compared to baseline. About 59% of patients achieved NYHA class 2 or less. During 6-month follow up, cumulative mortality for all patients was 13,1%, with a significant higher mortality rate for patients with ICM (18,9 vs. 11,4% DCM; 5,9% DMR, p<0,05). In conclusion, in this real-world cohort of elderly patients at high surgical risk, the MitraClip procedure appears to be safe, feasible and quite effective with low major adverse event rates and positive mid-term results. Patients with reduced LVEF (<30%) and ICM are at the highest risk.