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Original article
Evolution and prognostic impact of low flow after transcatheter aortic valve replacement
  1. Florent Le Ven,
  2. Christophe Thébault,
  3. Abdellaziz Dahou,
  4. Henrique B Ribeiro,
  5. Romain Capoulade,
  6. Haïfa Mahjoub,
  7. Marina Urena,
  8. Luis Nombela-Franco,
  9. Ricardo Allende Carrera,
  10. Marie-Annick Clavel,
  11. Éric Dumont,
  12. Jean Dumesnil,
  13. Robert De Larochellière,
  14. Josep Rodés-Cabau,
  15. Philippe Pibarot
  1. Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart and Lung Institute, Laval University, Québec, Canada
  1. Correspondence to Dr Philippe Pibarot, Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Sainte-Foy, Québec, QC, Canada G1V-4G5; philippe.pibarot{at}med.ulaval.ca

Abstract

Objective Low flow (LF), defined as stroke volume index (SVi) <35 mL/m2, prior to the procedure has been recently identified as a powerful independent predictor of early and late mortality in patients undergoing transcatheter aortic valve replacement (TAVR). The objectives of this study were to determine the evolution of SVi following TAVR and to assess the determinants and impact on mortality of early postprocedural SVi (EP-SVi).

Methods We retrospectively analysed the clinical, Doppler echocardiographic and outcome data prospectively collected in 255 patients who underwent TAVR. Echocardiograms were performed before (baseline), within 5 days after procedure (early post procedure) and 6 months to 1 year following TAVR (late post procedure).

Results Patients with EP-SVi <35 mL/m2 (n=138; 54%) had increased mortality (HR 1.97, p=0.003) compared with those with EP-SVi ≥35 mL/m2 (n=117; 46%). Furthermore, patients with baseline SVi (B-SVi) <35 mL/m2 and EP-SVI ≥35 mL/m2, that is, normalised flow, had better survival (HR 0.46, p=0.03) than those with both B-SVi and EP-SVi <35 mL/m2, that is, persistent LF, and similar survival compared with those with both B-SVi and EP-SVi ≥35 mL/m2, that is, maintained normal flow. In a multivariable model analysis, EP-SVi was independently associated with increased risk of mortality (HR 1.41 per 10 mL/m2 decrease, p=0.03). The preprocedural/intraprocedural factors associated with lower EP-SVi were lower B-SVi (standardised β [β] 0.36, p<0.001) atrial fibrillation (β −0.13, p=0.02) and transapical approach (β −0.22, p<0.001).

Conclusions The measurement of EP-SVi is useful to assess the immediate haemodynamic benefit of TAVR and to predict the risk of late mortality.

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Introduction

Several studies reported that low LV outflow is associated with reduced survival in patients with aortic stenosis (AS).1–3 This low flow (LF) condition may occur in the context of either a reduced (ie, classical LF) or preserved (ie, paradoxical LF) LVEF, and is often associated with a low gradient.4 In a substudy of the Placement of Aortic Transcatheter Valve-I trial5 and a study from the Quebec-Vancouver Experience of transcatheter aortic valve replacement (TAVR),6 the presence of LF defined as a stroke volume index (SVi) <35 mL/m2 was the most powerful echocardiographic predictor of mortality and this impact was independent of the LVEF or the gradient. Although patients with LF have worse prognosis compared with patients with normal flow (NF), their survival and functional status are generally improved with surgical or TAVR.5 ,7–9 The evolution of LV flow and its clinical impact following aortic valve replacement are however unknown. The objectives of this study were (i) to assess the changes in flow (ie, SVi) following TAVR and (ii) to establish the determinants and impact on mortality of early postprocedural SVi (EP-SVi).

Methods

We retrospectively analysed the clinical and Doppler echocardiographic data prospectively collected in 324 consecutive patients who underwent TAVR with a balloon-expandable valve for symptomatic severe AS between May 2007 and October 2012 at the Quebec Heart and Lung Institute (QHLI). We excluded patients who had (i) ‘valve-in-valve’ procedure, (ii) TAVR for other indication than severe AS and (iii) incomplete preprocedural Doppler echocardiographic data. Finally, 288 patients (89%) were included.

Doppler echocardiography

All echocardiograms were analysed at the echo core laboratory of the QHLI. Core laboratory readers were blinded to clinical and outcome data. Parameters of LV and aortic valve function were measured by Doppler echocardiography as previously described.6 ,10 Follow-up echocardiograms were performed within 5 days (3.3±0.9 days) following intervention, then at 6 months, 1 year and yearly thereafter. Preprocedural echocardiograms are referred to as ‘baseline’ echocardiograms, those performed within 5 days after intervention as ‘early postprocedural’ (EP) and those between 6 months and 1 year as ‘late postprocedural’ (LP), prioritising the latest exam if more than one was available. LVEF was measured using the biplane Simpson method, except when poor image quality precluded reliable delineation of endocardial borders. In this situation, a visual estimation of LVEF was performed. Stroke volume was measured by pulsed wave Doppler in the LV outflow tract (LVOT) and was indexed for body surface area (SVi). Before TAVR, the LVOT diameter and velocity used to calculate stroke volume were measured just below the insertion of aortic valve cusps, whereas after TAVR they were measured just underneath the apical border of the stent.11 ,12 LF is defined as SVi <35 mL/m2 and NF as SVi ≥35 mL/m2.13 The patients were separated into four groups according to their baseline SVi (B-SVi) and EP-SVi: maintained NF group (B-SVi ≥35 mL/m2 and EP-SVi ≥35 mL/m2); new onset LF group (B-SVi ≥35 mL/m2 and EP-SVi <35 mL/m2); Normalised Flow group (B-SVi <35 mL/m2 and EP-SVi ≥35 mL/m2); and persistent LF group (B-SVi <35 mL/m2 and EP-SVI <35 mL/m2). LV relative wall thickness (RWT) is calculated as the sum of the septal and posterior wall thickness divided by the LV end-diastolic diameter obtained from the parasternal long-axis view.

Statistical analysis

The primary end point of this study was all-cause mortality. Continuous variables were expressed as mean±SD or median and IQR, as appropriate. Since the European System for Cardiac Operative Risk Evaluation (EuroSCORE) and Society of Thoracic Surgeons (STS) score were not normally distributed, a natural log transformation was used for these variables. Differences between groups were assessed using one-way analysis of variance (ANOVA) for continuous variables followed by Tukey's post hoc test and the χ2 test or Fisher's exact test for categorical variables as appropriate. Longitudinal analysis of echocardiographic parameters of the same patients at different timings was performed with one-way or two-way ANOVA for repeated measures followed by Tukey's post hoc test and paired Student's t test. Survival curves were presented as Kaplan–Meier curves, and the log-rank test was used for comparison between groups. The effect of the clinical and Doppler echocardiographic variables on survival was assessed with Cox proportional hazard regression models. The proportional hazards assumption was checked with the use of Schoenfeld residuals. Association of clinical and echocardiographic variables with EP-SVi was assessed with linear regressions, and results are expressed as standardised β coefficients (β): each variable was standardised by subtracting its mean from each of its value and then dividing these new values by the SD of the variable. Clinically relevant variables with a p value ≤0.05 on individual analysis were included in the multivariable models. A p value ≤0.05 was considered statistically significant. Statistical analyses were performed with Stata V.11.0 (StataCorp, College Station, Texas, USA).

Results

From the initial 288 patients, complete postprocedure echocardiograms were available in 255 patients (88.5%). Causes of unavailability were unstable condition or death (n=12) and poor image quality (n=21). In total, 76 patients (29.8%) had maintained NF; 49 (19.2%) had new onset LF; 41 (16.1%) had normalised flow and 89 (34.9%) had persistent LF. Table 1 shows the comparison of the patients’ baseline characteristics according to the four study groups.

Table 1

Baseline and postprocedural clinical and Doppler echocardiographic data

Impact of early postprocedural SVi on late mortality

Eighty-five deaths occurred during a median follow-up of 12 (IQR 6 to 25) months. Patients with EP-SVi <35 mL/m2 (n=138, 54.1%) had increased late mortality compared with those with EP-SVi ≥35 mL/m2 (1-year mortality: 18.6±3.5% vs 12.7±3.2%; HR (95% CI) (HR (95% CI)) 1.97 (1.26 to 3.10), p=0.003) (figure 1). Furthermore, patients with normalised flow (B-SVi <35 and EP-SVi ≥35 mL/m2) had better survival (HR (95% CI) 0.46 (0.22 to 0.94), p=0.03) than those with persistent LF (B-SVi <35 and EP-SVi <35 mL/m2) and similar survival (HR (95% CI) 1.06 (0.73 to 1.53), p=0.77) compared with those with maintained NF (B-SVi ≥35 and EP-SVi ≥35 mL/m2 (figure 2). Patients with EP-SVi <35 mL/m2, regardless of their B-SVi status, had increased mortality in comparison with patients with maintained NF (new onset LF vs maintained NF, HR (95% CI) 1.97 (1.05 to 3.71), p=0.03; persistent LF vs maintained NF, HR (95% CI) 1.28 (1.06 to 1.56), p=0.01).

Figure 1

Kaplan–Meier curves for overall mortality according to early postprocedural stroke volume index. EP-SVi, early postprocedural stroke volume indexed to body surface area.

Figure 2

Kaplan–Meier curves for overall mortality according to baseline and early postprocedural stroke volume index. SVi, stroke volume indexed to body surface area; B-SVi, baseline SVi; EP-SVi, early postprocedural SVi.

Univariable and multivariable analyses are described in table 2. In univariable analysis, lower EP-SVi was associated with increased risk of late mortality. In multivariable analysis, independent predictor of all-cause mortality were male gender, permanent atrial fibrillation/flutter, transapical (TA) approach, EP-SVi, moderate or severe postprocedural aortic regurgitation (AR) and moderate or severe postprocedural mitral regurgitation (multivariable model #1, table 2). We did not find any interaction between EP-SVi and EP-moderate/severe mitral regurgitation or EP-moderate/severe AR. EP-SVi remained significantly associated with mortality after further adjustment for B-SVi (multivariable model #2, table 2).

Table 2

Univariable and multivariable analyses of predictors of late mortality

Preprocedural and periprocedural predictors of early postprocedural SVi

Baseline and periprocedural variables associated with EP-SVi are presented in table 3. In multivariable analysis, lower B-SVi, permanent atrial fibrillation/flutter and TA approach were independent predictors of lower EP-SVi. Early postprocedural moderate or severe AR was independently associated with higher EP-SVi after adjustment for baseline clinical and echocardiographic factors.

Table 3

Baseline predictors of early postprocedural stroke volume index

Postprocedural changes in SVi

Complete baseline, EP and LP Doppler echocardiograms were available in 182 patients (71.4%). SVi increased significantly from baseline (35±8 mL/m2) to late follow-up (38±8 mL/m2, p<0.001) (figure 3). No significant difference was observed between B-SVi and EP-SVi. However, in patients with B-SVi <35 mL/m2 (n=91, 50%), SVi increased at early follow-up and even further at late follow-up (B-SVi: 28±4 mL/m2, EP-SVi: 32±6 mL/m2 and LP-SVi: 35±7 mL/m2, all p<0.001) (figure 3).

Figure 3

Evolution of stroke volume index according to its baseline value. B-SVi, baseline stroke volume indexed to body surface area. *p<0.05 vs baseline; §p<0.05 vs postprocedural; #p<0.05 vs B-SVi <35 mL/m2. Whiskers represent maximum and minimum values.

Figure 4 illustrates the evolution of SVi according to the type of approach used for TAVR, that is, transfemoral (TF, n=71, 39%) vs TA (n=111, 61%). At baseline and late postprocedure, SVi was similar between both groups (B-SVi: 35.3±7.8 mL/m2 for TF vs 34.3±7.7 mL/m2 for TA, p=0.38; LP-SVi: 38.8±7.0 mL/m2 for TF vs 37.4±8.3 mL/m2 for TA, p=0.24). However, SVi increased between baseline and early postprocedure exclusively in the TF group (35.3±7.8 mL/m2 to 37.7±7.4 mL/m2, p=0.02). As depicted in figure 5, the evolution of SVi was similar in patients with classical LF (ie, LVEF <50% and SVi <35 mL/m2) and in patients with paradoxical LF (ie, LVEF ≥50% and SVi <35 mL/m2).

Figure 4

Evolution of stroke volume index according to the approach: transapical versus transfemoral. *p<0.05 vs baseline; §p<0.05 vs postprocedural; #p<0.05 vs transapical. Whiskers represent maximum and minimum values.

Figure 5

Evolution of stroke volume index according to the low flow pattern: Classical low flow (LF) (LVEF <50% and SVi <35 mL/m2) vs paradoxical LF (LVEF ≥50% and SVi <35 mL/m2). *p<0.05 vs baseline; §p<0.05 vs early postprocedure; #p<0.05 vs transapical. Whiskers represent maximum and minimum values.

Evolution of LVEF, indexed LV end-diastolic diameter and LV RWT is illustrated in the online supplementary figure S1. LVEF was higher in the NF group at baseline and late postprocedure compared with the LF group (61±12 vs 52±14%, p<0.001; 60±12 vs 56±14%, p=0.049, respectively). Overall LVEF increased slightly during follow-up (56±14 to 58±13%, p=0.046). Nevertheless, after dichotomisation according to B-SVi (<35 mL/m2 or ≥35 mL/m2, ie, baseline LF or NF), improvement was only significant in the LF group (52±14 to 56±14%, p=0.002). Indexed LV end-diastolic diameter was higher at baseline in the NF group compared with the LF group (28.1±4.2 mm/m2 vs 26.7±3.8 mm/m2, p=0.02), and increased only in the LF group (26.7±3.8 mm/m2 to 27.4±3.8 mm/m2, p=0.02). LV RWT decreased over time (50.6±11.0% to 48.5±10.5%, p=0.01). However, after dichotomisation for B-SVi, this change was present only in the LF group (51.6±11.1% to 48.5±11.3%, p=0.01).

Discussion

The main findings of this study are (i) in patients with severe AS undergoing TAVR, the presence of LF at early postprocedure is associated with a significant increase in late mortality; (ii) patients with NF after procedure have better survival than those with persistent or new onset LF, and similar survival compared with those with maintained NF; (iii) the predictors of early postprocedural LF are lower B-SVi, the presence of atrial fibrillation and the use of the TA approach; and (iv) SVi increased following TAVR in the subset of patients with LF at baseline.

Preprocedural SVi has recently been identified as a predictor of early and late mortality in patients with symptomatic severe AS undergoing TAVR or surgical aortic valve replacement.5 ,6 In the present study, B-SVi was strongly associated with mortality in univariable analysis (table 2), but this association was no longer significant after adjusting for early postprocedural SVi. This may be explained by the fact that early postprocedural SVi correlates with B-SVi and thus expresses, at least in part, the contribution of baseline flow to increased risk of mortality. Furthermore, and importantly, several patients with low B-SVi died in the periprocedural period before having a postprocedural echo, and therefore, as opposed to previous studies,5 ,6 these patients were not included in the present study. This survivorship bias may have contributed to substantially underestimate the impact of preprocedural LF on postprocedural risk of mortality. Although several studies have identified an association between low LVEF and low mean gradient and higher mortality after AVR, this association often does not persist after adjustment for flow. SVi is a direct measure of the efficiency of the cardiac pump function,4 whereas LVEF may underestimate the extent of myocardial systolic dysfunction in the presence of concentric remodelling, such as generally observed in patients with severe AS. On the other hand, the association between baseline low gradient and postprocedural mortality following TAVR is probably, in large part, explained by the presence of LF. The increase in SVi appears to be mediated by improvement in LVEF and/or regression of LV concentric remodelling with ensuing improvement in LV diastolic filling.

In the present study, patients with persistent or new onset LF had increased risk of mortality following TAVR compared with patients with NF. Persistent LF may reflect the presence of more advanced myocardial fibrosis and dysfunction, which may not regress despite successful procedure.14 In contrast, normalisation of flow following TAVR likely occurs in patients with less extensive myocardial fibrosis and with significant contractile reserve. The correction of pressure overload by TAVR in such patients is generally beneficial and translates into improved survival. Arterial compliance and systemic vascular resistance are often abnormal in the elderly patients with severe AS.1 ,15 These abnormalities generally persist following TAVR and may have a negative impact on the normalisation of LV pump function and flow after procedure.16 Further studies are needed to examine the impact of arterial haemodynamics and residual arterial load on the evolution of LV outflow and clinical outcomes following TAVR.

In patients with NF, we observed a high early mortality and then no death between 3 and 12 months, bringing the mortality curve closer to that of the maintained NF group at 1 year. Even if they progressively normalise their LV pump function and flow following TAVR, the patients with pre-existing LF may be more vulnerable than those with NF, particularly during the periprocedural and early postprocedural periods, which may explain the increased risk of early mortality. Furthermore, as shown in table 2, there is a continuous increase in the risk of mortality with decreasing postprocedural flow. And although the flow is within normal range in both groups at the early postprocedural echo, it remains significantly lower in the NF group than in the maintained NF group (table 1). In the patients who survived this early phase and have normalised their LV outflow, the subsequent prognosis is good and similar to that of patients with maintained NF.

The new onset of LF after TAVR may be explained by the occurrence of periprocedural complications (eg, atrial fibrillation, myocardial infarction) or by the myocardial injury related to type of approach (TA vs TF). Several studies including the FRANCE-217 and UK registries,18 and a recent meta-analysis19 have reported that the TA approach is associated with a 1.5-fold to twofold higher risk of mortality compared with the TF approach. The higher risk profile of the patients treated with the TA approach and the impossibility to adjust for all of the potential confounders may, at least in part, explain such differences in mortality. In addition, there is also growing evidence that the TA approach may have a negative impact on LV function.20 The high proportion of TA TAVR (60%) in our series reflects the early experience in our centre where the majority of the procedures were performed by the TA approach given that, in the early years, only large introducer sheaths were available. This does not reflect the proportion of TA procedures in the contemporary TAVR series, but, on the other hand, this dataset provides an opportunity to compare TA versus TF approaches with regard to changes in LV outflow following TAVR. The use of TA approach was associated with lower EP-SVi even after adjustment for B-SVi. Furthermore, SVi increased significantly from baseline to early postprocedural exam in the patients undergoing TF TAVR, whereas it remained unchanged in those who had TA TAVR. Nevertheless, among patients who survived at least six months, the SVi increased from early to late follow-up exam in the TA subset to reach similar values as in the TF subset.

Several previous studies reported that moderate–severe AR following TAVR is associated with increased risk of mortality21 and this was corroborated by the results of the present study. Of note, there was a positive correlation between the presence of moderate–severe postprocedural AR and EP-SVi. This finding may reflect the fact that total LV forward flow is increased in the presence of significant AR and preserved LV function. However, the association between low EP-SVi and late mortality persisted after adjustment for postprocedural moderate–severe AR. Among patients with moderate–severe AR, the presence of LF is likely associated with worse prognosis because it reflects the inability of the LV to tolerate the AR and maintain normal cardiac output.

Clinical implications and future perspectives

The findings of this study suggest that the measurement of early postprocedural SVi is useful to assess the immediate haemodynamic benefit of TAVR and to predict the risk of late mortality. The patients with persistent LF as well as those with new onset LF should receive a particular attention with close follow-up and optimisation of medical therapy. Non-invasive imaging techniques such as assessment of global longitudinal strain by speckle tracking, assessment of myocardial reserve by dobutamine stress echocardiography and the quantification of myocardial fibrosis by MRI may be useful to identify, prior to TAVR, the patients who may be at higher risk of persistent LF after the procedure. More aggressive treatment of atrial fibrillation before and after TAVR as well as the use of newer generations of smaller delivery systems to enable TF rather than TA implantation may help to avoid the occurrence of LF early after the procedure. On the other hand, the design of the present study does not allow us to determine whether low EP-SVi is the causal factor of adverse events following TAVR or simply a marker for other underlying factors such as more advanced and potentially irreversible impairment of myocardial function. Hence, further studies are needed to determine whether baseline and/or early postprocedural SVi should become a target of therapy in patients undergoing TAVR.

Strengths and limitations

Data were prospectively collected in a large consecutive series of patients, and there were no exclusion criteria with regard to low LVEF or low gradient. However, the data were retrospectively queried. Doppler echocardiographic estimation of SVi may be subject to measurement errors, particularly in the presence of poor image quality, elliptic shape of the LVOT, bulky calcification of the aortic annulus extending into the LVOT, sigmoid septum and atrial fibrillation.22 Moreover, the presence of the stent after the procedure may cause reverberations and acoustic shadowing and thus reduce the accuracy of the measure of LVOT diameter. Underestimation or overestimation of SVi may yield to misclassification of the patients in the LF or NF groups, which is one of the reasons why patients with ‘paradoxical’ LF, low-gradient severe AS represent a heterogeneous group with variable outcomes depending on the studies. Concomitant presence of hypertension, inter-individual differences in body size and presence or absence of LV flow reserve and extensive myocardial fibrosis might also explain this heterogeneity.23

The analysis of the impact of EP-SVi could only be performed in patients who survived until first echocardiography. This survival bias may have resulted in an underestimation of the negative impact of persistent or new onset LF immediately after the procedure. Survivorship effect may also have influenced the results of the analysis of late procedural changes in SVi.

Conclusion

The presence of LF early after procedure is independently associated with increased risk of late mortality in high-risk patients with severe AS undergoing TAVR. The presence of LF and atrial fibrillation before the procedure as well as the use of the TA approach are the main factors associated with LF state after the procedure. Further studies are needed to clarify which are the independent risk factors for new onset or persistent LF following TAVR, which strategies may help to prevent this sequelae and whether such strategies would translate into improved clinical outcomes.

Key messages

What is already known on this subject?

  • Low LV outflow, which may occur in the context of either a reduced or preserved EF, is associated with reduced survival in patients with aortic stenosis. However, the evolution of LV flow and its clinical impact following aortic valve replacement (transcatheter aortic valve replacement (TAVR)) is unknown.

What might this study add?

  • The presence of low flow (LF) defined as stroke volume index <35 mL/m2 early after TAVR is associated with increased risk of late mortality. The predictors of early postprocedural LF are lower preprocedural stroke volume index, the presence of preprocedural atrial fibrillation and the use of the transapical approach.

How might this impact on clinical practice?

  • The patients with persistent LF as well as those with new onset LF after TAVR procedure should receive a particular attention with close follow-up and optimisation of medical therapy. The use of newer generations of valve delivery systems to enable transfemoral rather than transapical implantation as well as the optimisation of periprocedural management of atrial fibrillation may help to avoid the occurrence of LF early after TAVR.

References

Footnotes

  • Correction notice This article has been corrected since it was published Online First. The spelling of author name ‘Abdelaziz Dahou’ was corrected to ‘Abdellaziz Dahou’.

  • Contributors All authors have read and approved submission of the manuscript. All authors have contributed to this work as follows: substantial contributions to the conception and design, acquisition of data or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published.

  • Funding This study was funded by a research grant (MOP-126072) from the Canadian Institutes of Health Research (CIHR). FLV and CT are supported by a clinical and research fellowship from the ‘Fédération Française de Cardiologie’. HBR is supported by a research PhD grant from ‘CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico—Brasil’. LN-F received funding via a research grant from the ‘Fundación Mutua Madrileña’ (Spain). M-AC is supported by a postdoctoral fellowship from CIHR. PP holds the Canada Research Chair in Valvular Heart Disease supported by CIHR.

  • Competing interests ED is a consultant for Edwards Lifesciences. RDL is a consultant for St. Jude Medical. JR-C is consultant for Edwards Lifesciences and St. Jude Medical. PP has received a research grant from Edwards Lifesciences.

  • Patient consent Obtained.

  • Ethics approval The procedures were performed under a compassionate Clinical Program approved by Health Canada.

  • Provenance and peer review Not commissioned; externally peer reviewed.