The impact of moderate Aortic Valve Disease in patients undergoing MitraClip for severe MR

Abstract

BACKGROUND:

High surgical risk patients presenting with severe mitral valve regurgitation (MR) and concomitant aortic valve disease are frequently a challenge for the interdisciplinary heart team meeting. If open-heart surgery for severe MR is performed, aortic stenosis (AS) or regurgitation (AR) is corrected during the same procedure if at least moderate severity of AS or AR has been confirmed. In patients with prohibitive surgical risk, optimal management strategies in the light of available transcatheter interventions still needs to be established.

METHODS AND RESULTS:

In this retrospective single center study, we aimed to investigate the impact of coincident moderate aortic valve disease on the outcome of patients undergoing MitraClip for severe MR. In 286 MitraClip procedures performed in our institution, 21 patients (7,3%) were identified to suffer from concomitant moderate AS and 28 patients had moderate AR (9,8%). Patients with AS were found to have a higher incidence of >moderate MR following the procedure when compared to patients without aortic valve disease (14,3% vs. 8,9%, p = 0.001). No differences between the groups were found regarding a combined endpoint of all cause deaths and heart failure hospitalizations after 1 year follow up (no aortic-valve disease vs. moderate AS: 19% vs 18%; p = 0,881 and no aortic valve disease vs moderate AR: 19% vs. 25%; p = 0.477). However, mortality was significantly higher in patients with coincidental moderate AR (3.8% patients without aortic valve disease, 5% in patients with AS, 17,9% in patients with AR; p = 0.006).

CONCLUSION:

According to our analysis coincidental Aortic valve stenosis may be associated with worse technical results regarding residual MR after MitraClip. Although our results regarding a combined endpoint of all-cause mortality and heart failure hospitalizations within one year of follow up were comparable between the groups, patients with moderate AR had significantly higher mortality rates. Due to the limited number of patients, our study is only hypothesis generating. Larger trials are necessary to confirm our result.

Keywords

Mitral valve regurgitation interventional mitral valve repair MitraClip aortic valve stenosis aortic valve regurgitation TAVI

1 Introduction

Mitral valve regurgitation (MR) comprises 35% of all native valvular heart diseases with a prevalence of about 2% in the general population. The incidence of MR increases with age, raising up to 10% in patients older than 75 years [1, 2]. Furthermore, concomitant aortic valve disease – aortic valve stenosis (AS) or regurgitation (AR) – is reported in a substantial number of these patients and often affects the recommended management [3 –5]. According to current guidelines of the American Heart Association/American College of Cardiology (AHA/ACC) and the European Society of Cardiology (ESC) low surgical risk patients undergoing open heart surgery for severe MR, concomitant aortic valve stenosis (AS) or aortic valve regurgitation (AR) is corrected during the same procedure if at least moderate severity of AS or AR has been confirmed [6, 7].

Beside trans-catheter treatment of severe aortic valve stenosis (TAVI), interventional Mitral-valve repair with the MitraClip-device (Abbott Vascular, Menlo Park, CA) has emerged as a potential treatment option in patients with severe MR and high or prohibitive surgical risk [8 –10]. As previously reported, Mitral regurgitation improves in a high proportion of patients after treatment of severe AS with TAVI, which is why TAVI is recommended as first-line treatment in high surgical risk patients with severe AS and concomitant severe or moderate MR [11, 12].

If necessary, Mitral regurgitation may be addressed later, as a staged approach.[7] On the other hand, the management of inoperable patients with severe MR and moderate aortic valve disease is less established. Since the latest randomized studies (MitraFR and COAPT) have reported controversial results for the treatment of MR with the MitraClip, identification of subgroups who are likely to benefit from this procedure is of great interest [10, 13].

2 Methods

The aim of this retrospective single center analysis was to study the outcome of patients with concomitant moderate aortic valve disease after MitraClip for severe MR.

2.1 Study population

This retrospective study included 286 patients undergoing a MitraClip procedure at Charité Universitätsmedizin Berlin, Campus Benjamin Franklin. All patients were discussed in an interdisciplinary heart team and judged at high surgical risk or inoperable. The surgical risk was estimated using the Society of Thoracic Surgeons’ Risk Score (STS score). All patients suffered from persistent heart failure symptoms of at least NYHA class II, most likely attributable to significant MR, despite optimized heart failure medications. Transthoracic and transoesophageal echocardiography were used to determine severity of MR, AS and AR. In general, patients with multivalve disease were preferentially referred to surgery if replacement/repair of additional valve pathologies were considered necessary. Only high surgical risk patients were considered for transcatheter treatment of MR. This retrospective Study was approved by our local ethics committee (reference number: EA4/079/17, date of acceptance: 06.06.2017).

2.2 Echocardiographic assessment

All patients underwent TTE and TOE by experienced echocardiographers at baseline to assess valvular dysfunctions and to evaluate for technical feasibility regarding the MitraClip-procedure according to current recommendations [14, 15]. The severity of MR, AR and AS was defined according to the American Society of Echocardiography and the European Association of Echocardiography [16 –18]. Evaluation of the mitral valve was performed by 2D and 3D image acquisition (Philips iE33 and EPIQ 7, Philips Healthcare, Andover, MA, USA; GE Vivid 7, GE Healthcare, Milwaukee, WI, USA). All patients underwent transthoracic echocardiograms at the time of discharge to determine residual MR and concomitant valve dysfunctions. Follow up TTE were performed after 12 months.

2.3 Follow-up and endpoint-definitions

According to most recent MVARC criteria, the outcome of patients after MitraClip was evaluated by residual MR at discharge. Furthermore, a compound endpoint of heart failure hospitalization and all-cause mortality was investigated [19, 20]. Procedural outcome was defined by the parameters indicated in Table 2. In brief, technical success was defined as successful clip delivery without consideration of MR relief. Bleeding complications were defined as major or minor hemorrhage depending on the necessity of any intervention or application of blood transfusions.

2.4 Statistical analysis

All categorial variables are stated as absolute numbers of individuals (n) and percentage. All continuous variables are depicted as mean (±SD). Baseline and post-procedure outcome of all Groups were compared using Kruskal-Wallis-Test, Mann-Whitney-U test, ANOVA, t-test and chi-squared test wherever appropriate. Regarding the combined endpoint of all-cause mortality and heart failure hospitalization a Kaplan-Meier analysis was performed and comparisons between the groups were made with the Log-rank test. A cox regression analyses was performed including all parameters where significant differences between the groups at baseline were observed. P-values <0.05 were deemed significant. All statistical analyses were executed using SPSS version 25 for windows (IBM SPSS Statistics, IBM corporation, USA).

3 Results

3.1 Demographic data at baseline

Baseline characteristics of the investigated groups are represented in Table 1. In brief, 286 high surgical risk patients were included in this analysis. Moderate aortic valve disease was observed in 49 (17,1%) individuals of this cohort (21 with AS and 28 with AR). STS scores were significantly higher in the moderate AS group (5.39±4.57 vs. 3.59±4.55, p = 0.013) and our AR cohort was significantly older (82±6 vs. 78±11, p = 0.017), when compared to patients without aortic valve disease.

Table 1
Baseline characteristics AS, AR versus no aortic disease

Parameter Moderate AS Moderate AR No aortic valve disease p

(n = 21) (n = 28) (n = 236)

Age 79 (±6) 82 (±6)^† 78 (±11) 0.043

Gender (female) 7 (33.3%) 11(39.3%) 125 (53%) 0.108

STS 5.39(±4.57)^† 5.14(±7,74) 3.59(±4.55) 0.013

Creatinin 1.46(±0.86) 1,32(±0.54) 1.22(±0.71) 0.225

Diabetes 6 (28.6%) 7(25%) 64 (27.1%) 0.959

COPD 4 (19.1%) 5(17.9%) 42 (17.8%) 0.990

CAD 16(76.2%) 20(71.4%) 143 (60.6%) 0.224

3-vessel-disease 8(38.1%) 12(42.9%) 71(30.1%) 0.502

Pacemaker (SM) 1(4,8%) 6(21.4%) 35(14,8%) 0.264

CRT 2(9.5%) 2(7.1%) 24(10,2%) 0.878

ICD 5(23.8%) 2(7.1%) 42(17,8%) 0.260

pAVK 3(14.2%) 1(3.6%) 27(11.4%) 0.392

Prev. CABG 6(28.6%) 6(21.4%) 46(19.5%) 0.606

Echocardiographic parameters baseline

LVEF 45(±23) 50(±20) 47(±28) 0.248

LVEDd 58(±12) 54(±10) 54(±13) 0.443

PAPs 48(±13) 54(±15) 46(±17) 0.124

MR etiology (functional) 10(76.9%) 14(60.9%) 149(80.1%) 0.110

Vmax 2.62(±0.61)

Pmean 23(±8)

AVA 1.4(±0.40)

Pressure half time 317 (±82)

VC in% of LVOT 52 (±11)

Parameter	Moderate AS	Moderate AR	No aortic valve disease	p
Age	79 (±6)	82 (±6)^†	78 (±11)	0.043
Gender (female)	7 (33.3%)	11(39.3%)	125 (53%)	0.108
STS	5.39(±4.57)^†	5.14(±7,74)	3.59(±4.55)	0.013
Creatinin	1.46(±0.86)	1,32(±0.54)	1.22(±0.71)	0.225
Diabetes	6 (28.6%)	7(25%)	64 (27.1%)	0.959
COPD	4 (19.1%)	5(17.9%)	42 (17.8%)	0.990
CAD	16(76.2%)	20(71.4%)	143 (60.6%)	0.224
3-vessel-disease	8(38.1%)	12(42.9%)	71(30.1%)	0.502
Pacemaker (SM)	1(4,8%)	6(21.4%)	35(14,8%)	0.264
CRT	2(9.5%)	2(7.1%)	24(10,2%)	0.878
ICD	5(23.8%)	2(7.1%)	42(17,8%)	0.260
pAVK	3(14.2%)	1(3.6%)	27(11.4%)	0.392
Prev. CABG	6(28.6%)	6(21.4%)	46(19.5%)	0.606
Echocardiographic parameters baseline
LVEF	45(±23)	50(±20)	47(±28)	0.248
LVEDd	58(±12)	54(±10)	54(±13)	0.443
PAPs	48(±13)	54(±15)	46(±17)	0.124
MR etiology (functional)	10(76.9%)	14(60.9%)	149(80.1%)	0.110
Vmax	2.62(±0.61)
Pmean	23(±8)
AVA	1.4(±0.40)
Pressure half time		317 (±82)
VC in% of LVOT		52 (±11)

^†Significantly different compared to no aortic valve disease.

Baseline creatinine levels, MR etiology, the presence of diabetes mellitus, chronic obstructive pulmonary disease and coronary artery disease did not differ between the groups.

Echocardiographic parameters such as LVEF, LVEDd and TAPSE were also comparable between the analyzed groups. A detailed description of baseline echocardiographic characteristics is given in Table 1.

3.2 Procedure characteristics and outcome

The follow-up time was 1 year. The incidence of vascular and other procedure related complications did not significantly divagate between the investigated groups (Table 2). At the time of discharge after the procedure patients with moderate aortic valve stenosis had significantly worse results in terms of residual MR. A Kaplan Meier analysis of the combined endpoint did not reveal any significant differences between the investigated groups (Figs. 1 –3). In multivariate analysis, including patient age and STS score together, the above-mentioned results remained unchanged (Tables 3 and 4).

Table 2
Procedural outcome AS, AR versus no aortic disease

AS A No aortic valve disease p

(n = 21) (n = 28) (n = 236)

No of clips implanted

≥2 12(57.1%) 15(53.6%) 102(47.5%) 0.305

3 4(19%) 3(10.7%) 15(6.4%) 0.093

Transvalvular mitral gradient 4(±1.75) 3.8(±1.4) 3.5 (±2.45) 0.539

Device success 19(90.5%) 28 (100%) 231 (98%) 0.055

Minor Access bleeding 4(19%) 3(10.7%) 36(15.3%) 0.712

Major Access bleeding 1(4.8%) 0(0%) 14(5.9%) 0.411

Pericardial tamponade 1(4.8%) 1(3.6%) 17(7.2%) 0.713

Residual MR > 2 discharge 3 (14.3%)^*, † 2 (7.1%) 21(8.9%) 0,002

	AS	A	No aortic valve disease	p
No of clips implanted
≥2	12(57.1%)	15(53.6%)	102(47.5%)	0.305
3	4(19%)	3(10.7%)	15(6.4%)	0.093
Transvalvular mitral gradient	4(±1.75)	3.8(±1.4)	3.5 (±2.45)	0.539
Device success	19(90.5%)	28 (100%)	231 (98%)	0.055
Minor Access bleeding	4(19%)	3(10.7%)	36(15.3%)	0.712
Major Access bleeding	1(4.8%)	0(0%)	14(5.9%)	0.411
Pericardial tamponade	1(4.8%)	1(3.6%)	17(7.2%)	0.713
Residual MR > 2 discharge	3 (14.3%)^*, †	2 (7.1%)	21(8.9%)	0,002

^*Significantly different compared to moderate AR. ^†significantly different compared to no aortic valve disease.

Table 3

Uni- and multivariate analysis regarding prognostic relevance of AS

	Univariate analysis		Multivariate analysis
Combined endpoint
Parameter	CI (95%)	p	CI (95%)	p
Moderate AS	0.91 (0.33–2.52)	0.859	0.96 (0.34–2.73)	0.935
STS	0.98 (0.93–1.03)	0,487	0.98 (0,93–1.04)	0.487
Mortality
Moderate AS	1.50 (0.19–11.92)	0.700	0.59 (0.07–5.23)	0.634
STS	1.02 (0.92–1.12)	0.773	1.01 (0.91–1.12)	0.872
HF Hospitalizations
Moderate AS	0.79 (0.24–2.53)	0.685	1.08 (0.33–3.59)	0.895
STS	0.97 (0.91–1.03)	0.301	0.97 (0.91–1.03)	0.325

Table 4

Uni- and multivariate analysis regarding prognostic relevance of AR

	Univariate analysis		Multivariate analysis
Combined endpoint
Parameter	CI (95%)	p	CI (95%)	p
Moderate AR	0.81 (0.38–1.69)	0.569	0.79 (0.38–1.68)	0.548
Age	0.98 (0.96–1.02)	0.345	0.98 (0.96–1.02)	0.334
Mortality
Moderate AR	5.06 (1.69–15.12)	0.004	0.20 (0.07–0.61)	0.004
Age	1.02 (0.95–1.09)	0.641	1.01 (0.94–1.08)	0.873
HF hospitalizations
Moderate AR	0.71 (0.254–1.96)	0.504	1.41 (0.51–3.91)	0.514
Age	0.98 (0.95–1.01)	0.261	0.98 (0.95–1.02)	0.268

Fig. 1

Kaplan Meier Analysis comparing the combined endpoint in patients with coincidental AS and patients without aortic valve disease.

Fig. 2

Kaplan Meier Analysis comparing the combined endpoint in patients with coincidental AR and patients without aortic valve disease.

Fig. 3

Kaplan Meier Analysis comparing the combined endpoint in patients with coincidental AS, AR and patients without aortic valve disease.

Mortality rates at 1 year on the other hand were significantly higher in our AR group (no aortic valve disease: 3.8% vs. AS: 5% vs. AR 17,9%; p = 0.006) whereas the number of HF hospitalizations within one year of follow up were comparable between the groups (no aortic valve disease: 19,7% vs. AS: 15% vs. AR 14,3%; p = 0.740) (Figs. 3 and 4). In our AR group, 3 of the observed 5 events of death were considered cardiovascular whereas septic shock was the cause of death in 1 patient. In another patient the cause of death remained unclear.

Fig. 4

Kaplan Meier Analysis comparing all-cause mortality in patients with coincidental AS, AR and patients without aortic valve disease.

Fig. 5

Kaplan Meier Analysis comparing heart failure hospitalizations in patients with coincidental AS, AR and patients without aortic valve disease.

4 Discussion

This retrospective single center study investigated the outcome of patients with concomitant moderate aortic valve disease undergoing a MitraClip-procedure for severe MR. Improvement of MR after MitraClip was less pronounced in patients with concomitant AS. In contrast, AR did not impact the technical results of the procedure but was associated with increased all-cause mortality after 1 year. Despite this finding, the incidence of a combined endpoint of heart failure admissions and mortality was comparable in the investigated groups.

Our study represents a typical MitraClip cohort with individuals at an advanced age and increased surgical risk, impaired left ventricular functions and the presence of functional MR in most of the patients [9 , 13].

Especially patients with coincidental moderate AS had significantly higher operative risks as indicated by higher STS scores when compared to individuals with severe MR only. Similarly, patients with moderate AR were significantly older. Both findings most likely need to be considered as a consequence of selection-bias as according to our clinical practice patients with multivalve diseases were more likely to undergo surgery [7].

Our finding of increased 1-year mortality in patients with moderate AR may also be interpreted in this context. In contrast to Aortic valve stenosis where transcatheter aortic valve implantation is already an established option even in moderate risk patients, percutaneous treatment strategies are barely available in pure AR [24, 25]. As a consequence, these patients are more likely to undergo surgery, leaving the oldest and sickest patients for transcatheter treatment strategies. Furthermore, patients with severe MR and AR may be more likely to undergo a MitraClip procedure as a last option to improve their symptoms even if AR is considered significant. The observed vena contracta/LVOT ratio which was at the upper limit of moderate in our study is also reflecting this hypothesis.

However, on the other hand the 1 year outcome regarding a combined endpoint of all-cause mortality and heart failure hospitalizations was comparable in all investigated groups. Even after correcting for the observed confounders, the results remained unchanged.

Importantly, moderate AS was associated with significantly worse results in terms of residual MR after MitraClip. Calcification processes causing aortic valve stenosis may also involve the mitral apparatus with impaired suitability for the MitraClip-procedure. As previously published, calcification of the mitral annulus or the mitral leaflets may limit the ability to improve coaptation of the leaflets with the MitraClip device or may result in an increased incidence of leaflet detachment [26]. The observed non-significant trend towards limited technical success rates (defined as successful clip delivery) in the AS group may also be interpreted in this context. Unfortunately, our database does not contain information about the calcific burden of the mitral valve, which would have been necessary to confirm this hypothesis. However, we did not find an increased incidence of degenerative Mitral valve disease or an increased incidence of Clip detachment in this group of patients.

This is a retrospective study with a limited number of patients. Especially our findings regarding mortality and the combined endpoint in patients with aortic valve disease need to be interpreted with caution. Patients with multi-valve disease may be more likely to undergo surgery, which may have biased our results regarding residual MR following MitraClip in patients with moderate AS. Furthermore, previous studies showed prognostic relevance of microvascular dysfunction and other parameters, which were not investigated in our study [21 –23].

On the other hand, our data constitute a real life experience in patients undergoing percutaneous mitral valve repair with the MitraClip device in an experienced tertiary care center.

In conclusion, the presence of moderate aortic valve regurgitation in patients undergoing MitraClip for severe MR should not be underestimated in terms of prognostic implications. With the availability of dedicated devices for pure AR, treatment of the aortic valve should be considered as first choice when hemodynamic relevance of AR is assumed. As already confirmed in patients with severe AS, TAVI may also result in an improvement of MR in these patients. The presence of a calcific aortic valve stenosis may however be associated with worse technical result regarding relief of MR after MitraClip. Notably, this did not translate into worse clinical outcome of the patients. Studies with larger numbers of patients are needed to confirm our results.

Footnotes

Acknowledgments

This work was supported by the Helmholtz Association and Charité Berlin through program-oriented funding.

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	AS	A	No aortic valve disease	p
	(n = 21)	(n = 28)	(n = 236)
No of clips implanted
≥2	12(57.1%)	15(53.6%)	102(47.5%)	0.305
3	4(19%)	3(10.7%)	15(6.4%)	0.093
Transvalvular mitral gradient	4(±1.75)	3.8(±1.4)	3.5 (±2.45)	0.539
Device success	19(90.5%)	28 (100%)	231 (98%)	0.055
Minor Access bleeding	4(19%)	3(10.7%)	36(15.3%)	0.712
Major Access bleeding	1(4.8%)	0(0%)	14(5.9%)	0.411
Pericardial tamponade	1(4.8%)	1(3.6%)	17(7.2%)	0.713
Residual MR > 2 discharge	3 (14.3%)^*, †	2 (7.1%)	21(8.9%)	0,002