One-year Outcomes and Predictors of Mortality After MitraClip Therapy in Contemporary Clinical Practice: Results From the German Transcatheter Mitral Valve Interventions Registry

Miriam Puls; Edith Lubos; Peter Boekstegers; Ralph Stephan von Bardeleben; Taoufik Ouarrak; Christian Butter; Christine S. Zuern; Raffi Bekeredjian; Horst Sievert; Georg Nickenig; Holger Eggebrecht; Jochen Senges; Wolfgang Schillinger

Disclosures

Eur Heart J. 2016;37(8):703-712. 

In This Article

Discussion

To date, the industry-independent TRAMI registry comprises the largest real-world cohort of patients treated by percutaneous edge-to-edge mitral valve repair with MitraClip. In the following, we will contrast the early and 1-year data of 749 TRAMI patients with the initial EVEREST II-cohort[7] on the one hand, and with the 2 largest series of MitraClip patients published so far on the other hand: The ACCESS-EU study, a prospective European multicenter non-randomized post-approval study, enrolled 567 patients in 14 centres in Germany, Italy and Denmark. Early and 1-year results were published in 2013.[10] Subsequently, the independent Transcatheter Valve Treatment Sentinel Pilot Registry (TCVT registry) reported immediate and 1-year results of 628 patients treated with MitraClip in 25 centres in 8 European countries in 2014.[11]

Baseline Characteristics

The baseline demographics of the entire prospective TRAMI cohort are very similar to those that have already been published as preliminary results.[9] In concordance with other registries,[10,11] the TRAMI data also underline that patients treated with MitraClip implantation in contemporary 'real life' are very different from the initial EVEREST cohort (for comparison of baseline characteristics, see Table 1). In current European practice, MitraClip patients are older (in TRAMI ~10 years older than in EVEREST II), in more advanced stages of heart failure (NYHA class III/IV: 89% in TRAMI, 86% in TCVT, 85% in ACCESS-EU, and 51% in EVEREST II), have the opposite distribution of MR aetiology (secondary MR in 71% of cases in TRAMI, 72% in TCVT, and 77% in ACCESS-EU, vs. in 27% of cases in EVEREST II), and exhibit a higher burden of comorbidities (see Table 1).[7,10,11] Comparing the three registries, a tendency towards the treatment of increasingly older and sicker patients seems to be present, with patients at highest age, highest stages of heart failure and highest prevalence of specific comorbidities like coronary artery disease and renal failure enrolled in the TRAMI registry. Importantly, subgroup analyses in EVEREST II[7] had identified patients with an age of at least 70 years and patients with functional MR as subgroups in which surgery was not superior to percutaneous treatment with regard to efficacy—cohorts, which are indeed treated with MitraClip implantation today according to TRAMI data. Thus, the low-risk percutaneous MitraClip implantation is in fact (and as intended according to current guidelines)[18] reserved for patients who are no surgical candidates (due to high age, high estimated surgical risk, multiple comorbidities, and predominantly secondary aetiology of MR) in contemporary clinical practice in Germany, whereas operable patients with primary MR are still treated by conventional surgery according to current guidelines.[18]

In-hospital Outcome

Despite patients' high-risk status, the incidence of specific procedural complications in TRAMI was comparable with previous reports (see Table 2), with stroke rates <1% and no peri-procedural myocardial infarctions. As in other publications, the most common adverse event was severe bleeding (7.0% in TRAMI); the incidence varied between 3.9% in ACCESS-EU[10] and 13% in EVEREST II,[7] most likely driven by strictness of definitions. In-hospital and 30 days mortality in TRAMI were 2.4 and 4.5% (30 days mortality according to Kaplan–Meier analysis: 4.3% [95%CI: 3.1–5.9%]), which was well in line with other registries (ACCESS-EU: 2.0%/3.4%; TCVT: 2.9%/not reported).

Median length of hospital stay after MitraClip implantation was longer in TRAMI than in previous reports (9 days in TRAMI, 6 days in ACCESS-EU,[10] and 5 days in TCVT),[11] probably reflecting national treatment practices and the high burden of comorbidity in the TRAMI cohort. However, the vast majority of patients could directly be discharged home suggesting a quick recovery from the procedure.

In TRAMI, the rate of procedural success was particularly high (97%). If compared with earlier reports (in which procedural success was commonly defined as MR reduction to ≤2+), an improvement of success rate in chronological order of publication (between 2009 and 2014) is noticeable: 74% in EVEREST I,[19] 77% in EVEREST II,[7] 80% in the EVEREST II High Risk Cohort,[22] 80% in the PERMIT-CARE study,[23] 85% in the Swiss registry,[24] 91% in ACCESS-EU,[10] and 95% in TCVT),[11] reflecting the growing experience with this complex technique over time. Accordingly, the need for additional mitral valve procedures during the index hospitalization occurred less frequently in TRAMI (1.3%) than in other reports (15.2% in EVEREST II,[7] 2.8% in ACCESS-EU,[10] not reported for TCVT).

The echocardiographic results of the procedure cannot be directly compared due to different assessment of MR severity (Grades 0+, 1+, 2+, 3+, 4+ in EVEREST II and ACCESS-EU; grades none, mild, moderate, severe in TRAMI and TCVT). Furthermore, echo data were core-lab-adjudicated only in EVEREST II and ACCESS-EU, but not in TRAMI and TCVT. In ACCESS-EU, MR grade 0–1+ was present in 51% of patients, whereas 73% of TCVT patients and 76% of TRAMI patients had none or mild MR at time of discharge (site-reported).

1-year Outcomes: Safety, Efficacy, Heart Failure, and Quality of Life

One-year mortality in TRAMI (20.3%; according to Kaplan–Meier analysis 19.8% [95% CI: 17.2–22.8%]; see also Figure 1 and Table 3) was slightly higher than in ACCESS-EU (17.3%)[10] and in TCVT (15.3%),[11] but not unexpected high in a cohort at advanced age, with a high burden of comorbidity, and with nearly 60% of patients reporting heart failure hospitalizations during the 6 months before enrolment in TRAMI. For comparison: Jhund et al.[25] examined long-term trends in survival after a first hospitalization for heart failure (1986–2003) and found a slightly improved but still poor prognosis even in 2003, with a 1-year mortality of 27.6% (95% CI: 24.5–31.1) in men and of 25.6% (95% CI: 22.6–28.8) in women. However, in the absence of a meaningful comparator group, a possible survival benefit cannot be estimated. This burning issue is addressed by ongoing clinical trials with randomization of MitraClip implantation against optimal medical therapy in patients with secondary MR.

The prevention of repeated hospital admissions in heart failure patients is a second valid target of medical interventions. Heart failure-related re-hospitalizations during the first year after MitraClip implantation occurred less frequently in TRAMI-patients (14.1%) than in the TCVT cohort (22.8%)[11] (ACCESS-EU does not report the incidence of re-hospitalizations).

Moreover, the interventional success can be measured by the incidence of repeat mitral valve procedures. In TRAMI, an additional intervention became necessary in 8.5% of patients, whereas 9.7% in ACCESS-EU[10] and 3.8% in TCVT[11] underwent repeat procedures (in contrast to 21% in EVEREST II).[7] Whereas the second interventions had been predominantly surgical in the earlier studies (21% in EVEREST II,[7] 6.3% in ACCESS-EU),[10] mainly repeat MitraClip procedures were carried out in the younger registries (5.3% in TRAMI, 2.9% in TCVT).[11] The decreasing indication for re-interventions in the more recent publications and the trend towards the performance of repeat clip implantations both mirror growing knowledge and technical experience in MitraClip interventions in European clinical practice.

In the absence of randomized trials in contemporary real-world cohorts, the consideration of functional outcomes is the most appropriate possibility to assess the efficacy of MitraClip therapy. At 1 year, 63.3% of TRAMI patients pertained to NYHA functional classes I or II (compared with 11.0% at baseline), and self-rated health status (on EQ VAS) also improved significantly by 10 points. Importantly, a significant proportion of patients regained the complete independence in self-care after MitraClip implantation (independence in 74.0 vs. 58.6% at baseline, P = 0.005), an issue of utmost importance in the context of health care economy. Given that most patients included in TRAMI had no surgical option, the expectation of clinical benefit from the procedure has been met in the majority of cases: The procedural success translated into improvements in heart failure class and quality-of-life-measures. Likewise, a significant NYHA functional class improvement, a significantly increased 6-min walking test distance, and a significantly improved result in the Minnesota Living with heart failure Quality of Life-Questionnaire could be documented in ACCESS-EU[10] 12 months after MitraClip therapy. The TCVT registry[11] did not contain quality-of-life-measures, but in this registry the highest proportion of patients pertained to NYHA classes I and II after 1 year of follow-up (74.2%).

Furthermore, we aimed at identifying predictors of 1-year mortality in the TRAMI cohort. According to multivariable analysis, the procedural failure had the highest hazard ratio concerning the prediction of 1-year mortality (HR 4.36) (see also Table 4). Similarly, the failure of procedural success has also been identified as important predictor of mortality in a German single-centre cohort[26] and in the Swiss registry.[24] Conversely, a successful clip deployment was independently associated with the composite endpoint (death or heart failure-related readmission) at 1 year in TCVT patients (OR 0.12).[11] Thus, the successful procedure with meaningful MR reduction seems to be the best guarantee of a favourable course. In patients at prohibitive surgical risk enrolled in the EVEREST II-trial,[27] the degree of residual MR also was significantly associated with worse outcome. Patients who were discharged with MR severity of ≤1+ or of 2+ had comparable survival rates at 12 months (83.3 vs. 80.0%, P = 0.61). In contrast, 1-year survival was significantly reduced in patients with MR 3+/4+ at discharge—commonly referred to as procedural failures (52.4%, P = 0.001 in comparison with MR ≤1+ and P = 0.02 in comparison with MR 2+, respectively).

Other predictors of 1-year mortality in TRAMI were NYHA class IV (HR 1.62), anaemia (HR 2.44), previous aortic valve intervention (HR 2.12), renal failure with serum creatinine ≥1.5 mg/dL (HR 1.77), peripheral artery disease (HR 2.12), left ventricular ejection fraction <30% (HR 1.59), and severe tricuspid regurgitation (HR 1.84) (Table 4; the surgical risk scores were excluded from multivariable analysis due to redundancies). Regarding previous publications, EuroSCORE (OR 1.44) and LVEF <30% (OR 2.69) were identified as additional independent risk factors in the TCVT cohort.[11]

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