Abstract: Objective. Balloon aortic valvuloplasty (BAV) as a bridge to transcatheter aortic valve implantation (TAVI) is a well-established treatment option in patients who are in a critical state or who suffer from underlying comorbidities that disguise the severity of aortic stenosis (AS). If convalescence is achieved, TAVI can be performed with good results in high-gradient aortic stenosis (HG-AS) patients. Whether this approach is safe and effective in low-flow low-gradient aortic stenosis (LFLG-AS) has not been analyzed; therefore, we investigated whether BAV followed by TAVI as a staged procedure is an effective treatment option in patients with LFLG-AS. Methods. Patients with severe AS who received BAV followed by staged TAVI were identified. Baseline data, periprocedural and postprocedural information, echocardiographic data, and follow-up data were collected. The patient population was divided into LFLG-AS and HG-AS groups. Results. From July 2009 until September 2017, we identified 38 eligible patients (16 LFLG-AS and 22 HG-AS). Log EuroScore I (51.8 ± 20.9% LFLG-AS vs 33.7 ± 19.1% HG-AS; P<.01) differed significantly between groups, as did baseline echocardiographic data that were used to categorize groups. BAV and staged TAVI were carried out 100% successfully with comparable results. Instant symptom relief and pressure gradient reduction were accomplished after both procedures. Thirty-day mortality rates (0% LFLG-AS vs 9% HG-AS; P=.21) and 1-year mortality rates (18.8% LFLG-AS vs 27.2% HG-AS; P=.54) did not differ between groups. Conclusion. BAV followed by staged TAVI is a safe and effective treatment option in sick or questionable candidates, irrespective whether LFLG-AS or HG-AS is present.
J INVASIVE CARDIOL 2018;30(12):437-442.
Key words: TAVI, balloon valvuloplasty, low-flow low-gradient aortic stenosis
In an aging society, the incidence of severe aortic stenosis (AS) has been increasing worldwide, presenting a substantial burden to our health-care system.1-3 In recent years, the disease entity presents more heterogeneously, with important subsets of patient populations. This subdivision is reflected in current guidelines for the management of structural heart diseases,4,5 and multiple approaches exist to grade and classify appropriate AS subtypes.4,6
Balloon aortic valvuloplasty (BAV) alone is an ineffective treatment option for severe AS, with high in-hospital, 30-day, and 1-year mortality rates. In the TAVI era, BAV offers a relevant bridging therapy option in patients who are in a critical state, who suffer from underlying comorbidities that disguise the severity of AS, or who are not immediately suitable for transcatheter aortic valve implantation (TAVI).7-10 Multiple trials already established that TAVI is a safe and effective treatment option for patients with severe high-gradient AS (HG-AS) who cannot undergo surgery or even those who have an intermediate surgical risk profile.11-13 To date, it has not been established whether BAV followed by TAVI is safe and effective in patients with low-flow low-gradient AS (LFLG-AS), even though this cohort presents an important but small proportion (up to 10%) of all patients with severe AS.14 Therefore, we investigated whether BAV followed by TAVI as a staged procedure was an effective treatment option in patients with LFLG-AS.
We reviewed our prospectively aligned single-center database and initially identified 150 patients with severe AS who underwent BAV, regardless of their flow state, from July, 2009 until September, 2017. A total of 106 patients were excluded due to different therapy strategies (BAV as a single procedure or BAV followed by surgical aortic valve replacement). Patients with missing echocardiographic data or presenting with paradoxical LFLG-AS (determined by multimodal imaging like transthoracic, transesophageal, or dobutamine stress echocardiography and cardiac computed tomography scans) were excluded from our analysis. BAV followed by TAVI as a staged procedure was conducted in 38 consecutive patients, and the cohort was split into those with or without LFLG-AS who had BAV as bridge to TAVI. The patient selection process is illustrated in a consort diagram (Figure 1). Flow states were defined using current American Heart Association/American College of Cardiology (AHA/ACC) guidelines on the management of patients with valvular heart disease;5 all patients presented with symptomatic severe AS (stage D) and were categorized as either D1 (HG-AS: aortic valve area [AVA] <1 cm2, mean gradient >40 mm Hg, maximum peak velocity >4 m/s) or D2 (LFLG-AS: AVA <1 cm2, maximum peak velocity 3-4 m/s, ejection fraction <50%).
We collected baseline data, periprocedural and postprocedural information, and echocardiographic data. Collected data and outcomes were compared between the LFLG-AS and HG-AS groups. Clinical endpoints were reported according to the Valve Academic Research Consortium (VARC)-2 consensus statement.15 Echocardiographic and clinical follow-up was routinely carried out at our institution. Patients regularly received a telephone interview to assess functional capacity and mortality. All patients provided written informed consent for TAVI and for the use of clinical, procedural, and follow-up data for research. The study procedures were in accordance with the Declaration of Helsinki, and the institutional Ethics Committee of the Heinrich-Heine University approved the study protocol (4080). The study is registered at www.clinicaltrials.gov (NCT01805739).
Statistical analysis. The dataset was assessed for normal distribution by the Kolmogorov-Smirnov test. Continuous variables are expressed as mean ± standard deviation if normally distributed or as median and interquartile range (Q1-Q3) if not normally distributed. Categorical data are expressed as numbers and percentages of total. Differences between groups were determined by Chi-square or Fisher’s exact test for discrete variables. Continuous variables were evaluated with the Student’s t-test or Wilcoxon-Mann-Whitney U-test. Longitudinally measured parameters were compared with paired Student’s t-test and reported as mean with standard deviation or 95% confidence interval (CI) if appropriate. All tests were two sided, and P<.05 was considered significant. Statistical analysis was performed using SPSS software (IBM).
We identified 38 eligible patients who underwent BAV followed by TAVI as a staged procedure. The patient population was divided into the LFLG-AS group (n = 16; 42.1%) and the HG-AS cohort (n = 22; 57.9%). The most common underlying condition for a staged approach was critical preoperative state/cardiogenic shock, with a higher percentage in the LFLG-AS group (56.2% vs 31.9% in the HG-AS group; P=.13), followed by an undetermined prognosis of non-cardiopulmonary comorbidities, ie, frailty and multimorbidity with questionable convalescence (25.0% in the LFLG-AS group vs 27.3% in the HG-AS group; P=.88). Reasons for BAV followed by TAVI as a staged procedure are detailed in Table 1.
Baseline criteria. The mean age of the study population was 82.2 ± 7.6 years, and more than one-half of the patients (55.3%) were female, with a significantly higher number of females in the HG-AS group (31.3% in the LFLG-AS group vs 72.7% in the HG-AS group; P=.02). Other baseline characteristics did not differ significantly, except for previous bypass surgery (31.3% in the LFLG-AS group vs 0.0% in the HG-AS group; P<.01) and log EuroScore I (51.8 ± 20.9% in the LFLG-AS group vs 33.7 ± 19.7% in the HG-AS group; P=.01).
Mean AVA was 0.6 ± 0.2 cm2. According to the aforementioned hemodynamic subentities, mean aortic valve gradient (26.5 ± 8.7 mm Hg in the LFLG-AS group vs 58.5 ± 14.7 mm Hg in the HG-AS group; P<.01) and ejection fraction (37.9 ± 12.3% in the LFLG-AS group vs 55.9 ± 11.4% in the HG-AS group; P<.01) differed significantly between groups. Median level of brain natriuretic peptide was 4757.0 pg/mL (IQR, 2612.0-23334.5 pg/mL) and over 80% of patients presented with New York Heart Association (NYHA) class ≥3 at baseline. Further baseline characteristics are presented in Table 2.
Hemodynamic changes after BAV. Hemodynamic changes were assessed by transthoracic echocardiography 2-4 days after the procedure. BAV significantly decreased the mean gradient by 14.3 mm Hg (95% CI, 6.2-22.3; P=.04) in the HG-AS group (58.5 ± 14.7 mm Hg before vs 42.8 ± 15.9 mm Hg after) and the peak gradient by 4.0 mm Hg (95% CI, 2.6-10.0; P<.01) in the LFLG-AS group (47.6 ± 14.8 mm Hg before vs 43.1 ± 18.4 mm Hg after). The ejection fraction substantially increased by 6.4% in LFLG-AS patients (37.9 ± 12.3% before vs 45.0 ± 16.0% after; 95% CI, 0.6-12.2; P<.01).
Of note, pressure gradient reduction after BAV was small due to a cautiously selected balloon to aortic annulus ratio (0.8 ± 0.1 in the LFLG-AS group vs 0.8 ± 0.1 in the HG-AS group; P=.43) to avoid annulus rupture or significant aortic regurgitation, to name the most relevant adverse events. A second balloon inflation was necessary in 22.8% of the LFLG-AS group and in 31.8% of the HG-AS group (P=.97). Additional data regarding balloon brand, size, and hemodynamic changes can be obtained in Table 3. We applied 83.0 ± 56.4 mL contrast agent during BAV sessions because in almost all cases, a concomitant coronary diagnostic and (if indicated) immediate percutaneous coronary intervention were performed.
Hemodynamic changes after TAVI. BAV and staged TAVI were carried out successfully in all cases. Time of bridge to TAVI was 51.0 days (IQR, 24.0-51.0 days) in the LFLG-AS group and 80 days (IQR, 43.5-80.0 days) in the HG-AS group (P=.45). Further procedure-related data are presented in Table 3.
TAVI led to decreases in mean pressure gradient (7.1 ± 4.3 mm Hg in the LFLG-AS group vs 9.0 ± 6.5 mm Hg in the HG-AS group; P=.67) and peak pressure gradient (11.6 ± 5.4 mm Hg in the LFLG-AS group vs 16.5 ± 5.7 mm Hg in the HG-AS group; P=.43) in both groups, whereas no further changes in the ejection fraction could be observed. Instant pressure gradient reduction and symptom relief (presented by lower NYHA scores) were documented after both procedures (Figure 2).
Periprocedural and postprocedural complications. Periprocedural and postprocedural complications (as defined by VARC-2 classification) did not differ significantly between groups after BAV and staged TAVI. The transfemoral access route for TAVI was chosen in 30 patients (78.9%) and transapical access in 8 patients (21.1%). Major access-site complications were relatively frequent during BAV (8.6% in the LFLG-AS group vs 22.7% in the HG-AS group; P=.76), as was acute kidney injury (25.0% in the LFLG-AS group vs 4.5% in the HG-AS group; P=.06), which is possibly due to the sick patient clientele and the small number of patients in this study cohort. The observed 30-day mortality rate was 5.3%, and the 1-year mortality rate was 23.7%, with no significant differences between groups. Further information is presented in Table 3.
BAV as bridge to TAVI is an established treatment strategy in patients who are in a critical state or who suffer from underlying comorbidities that disguise the severity of AS. However, it is not known whether this approach is also effective in patients with LFLG-AS, who have poor outcomes with medical therapy and worse outcomes post TAVR as compared to normal-flow patients.14 Our analysis revealed the following: (1) BAV as a bridge to staged TAVI is an option in complex, high-risk patients; (2) patients with LFLG-AS benefit in the same way as HG-AS patients; and (3) the positive results show consistency over a follow-up period of 1 year.
An accurate assessment of hemodynamic subtypes of AS is crucial to the choice of treatment strategy. Diagnostic and therapeutic strategies in LFLG-AS patients continue to constitute a special challenge that is reflected in rather complex guideline recommendations.
LFLG-AS and its characteristic comorbidities, including reduced ejection fraction and other underlying valvular or ischemic heart diseases, increase mortality and impair functional outcome after intervention.16 Confounders are mostly covered in risk-stratification models that are reflected in a significantly higher log EuroScore I in our LFLG-AS group. Notably, we did not detect significant differences in our baseline assessment of other comorbidities. The sole exception was the number of previous bypass surgeries in the LFLG-AS group (31.3% vs 0.0% in the HG-AS group; P<.01), whereas the incidence of coronary artery disease did not differ between groups. However, more LFLG-AS patients presented in a critical preoperative state or cardiogenic shock when undergoing initial BAV treatment.
Divergent data in the literature exist regarding the graduated benefit of interventional treatment in patients with LFLG-AS. Eleid et al showed that reduced left ventricular function and stroke volume index, as well as low mean aortic valve gradient, are all associated with increased overall mortality after aortic valve replacement.17 However, O’Sullivan et al concluded that every subset of LGAS benefits from interventional treatment, with overall comparable mortality rates and similar extent of symptomatic improvement.18 Those findings were observed in our staged procedure strategy as well: overall 30-day mortality was 5.3% (0.0% in the LFLG-AS group vs 9.0% in the HG-AS group; P=.21), and results were consistent over a follow-up period of 1 year (18.8% in the LFLG-AS group vs 27.2% in the HG-AS group; P=.54).
After BAV and staged TAVI, instant improvement in functional parameters was achieved (Figure 2). Clinical safety endpoints, defined according to VARC-2 criteria, did not show a significant difference between groups and were comparable with large registry findings.
Our analysis could not predict a difference in periprocedural and postprocedural outcomes or a survival disadvantage for patients presenting with LFLG-AS as compared to HG-AS. Hence, BAV proved to be the optimal bridging therapy to ensure cardiac recovery in patients with LFLG-AS. After improvement of the initial hemodynamic situation, TAVI was performed with comparable outcomes to a best prognosis group (HG-AS) in a cohort with supposed limited prognosis (LFLG-AS). In the future, the Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis (TOPAS) trial, which also includes LFLG-AS patients, could add more evidence to this vigorously discussed field.
Study limitations. Our study describes only a single-center experience; nevertheless, it comprises a high number of patients, considering their special clinical situation. Therefore, there was limited freedom of choice with respect to bridging therapy. Re-evaluation in larger prospective trials with differentiation of all subtypes of severe AS should be considered.
BAV followed by TAVI as a staged procedure with a median bridging length of 69.5 days (IQR, 27.7-121.5 days) is a safe and effective treatment option for patients presenting with severe LFLG-AS.
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From the Division of Cardiology, Pulmonology, and Vascular Medicine, 1Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; 2CardioVascularCenter (CVC) Frankfurt, Frankfurt, Germany; 3Swedish Heart and Vascular, Seattle, Washington; and 4Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Jung reports grant support, personal fees, and non-financial support from Actelion and Novartis; grant funds and personal fees from Bayer Healthcare, Vifor Pharma, Zoll Medical; personal fees from Pfizer, Bristol Meyer Squibb, and Boston Scientific; personal fees and non-financial support from Abbott Vascular and Orion Pharma; personal fees from Boehringer Ingelheim and Sanofi Aventis; grant support from Medicure. Dr Sievert reports study honoraria, travel expenses, and consultant fees from 4tech Cardio, Abbott, Ablative Solutions, Ancora Heart, Bavaria Medizin Technologie GmbH, Bioventrix, Boston Scientific, Carag, Cardiac Dimensions, Celonova, Comed B.V., Contego, CVRx, Edwards Lifesciences, Endologix, Hemoteq, Lifetech, Maquet Getinge Group, Medtronic, Nuomao Medtech, Occlutech, pfm Medical, Recor, Renal Guard, Rox Medical, Terumo, Vascular Dynamics, Vectorious Medtech, and Vivasure Medical. Dr Veulemans reports grant support and non-financial support from Edwards Lifesciences; personal fees and non-financial support from Medtronic. Dr Zeus reports personal fees from Medtronic and Edwards Lifesciences. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript submitted May 21, 2018, provisional acceptance given July 3, 2018, final version accepted August 27, 2018.
Address for correspondence: Kerstin Piayda, MD, Heinrich-Heine-University Düsseldorf, Medical Faculty, Division of Cardiology, Pulmonology and Vascular Medicine, Moorenstrasse 5, Düsseldorf 40225, Germany. Email: firstname.lastname@example.org