Original Contribution

Systematic Review and Meta-Analysis of Interventional Emergency Treatment of Decompensated Severe Aortic Stenosis

Bernhard Wernly, MD1;  Peter Jirak, MD1;  Michael Lichtenauer, MD, PhD1;  Verena Veulemans, MD2;  Tobias Zeus, MD2;  Kerstin Piayda, MD2;  Uta C. Hoppe, MD1;  Alexander Lauten, MD3;  Christian Frerker, MD4;  Christian Jung, MD, PhD2

Bernhard Wernly, MD1;  Peter Jirak, MD1;  Michael Lichtenauer, MD, PhD1;  Verena Veulemans, MD2;  Tobias Zeus, MD2;  Kerstin Piayda, MD2;  Uta C. Hoppe, MD1;  Alexander Lauten, MD3;  Christian Frerker, MD4;  Christian Jung, MD, PhD2

Abstract: Aims. Patients in cardiogenic shock (CS) due to decompensated aortic stenosis (AS) evidence poor prognosis. Both emergency transcatheter aortic valve replacement (eTAVR) and emergency balloon aortic valvuloplasty (eBAV) have been reported in CS patients. We aimed to summarize and compare available studies on eBAV and eTAVR in patients suffering from CS due to decompensated AS with regard to safety and efficacy. Methods and Results. Study-level data were analyzed. Heterogeneity was assessed using the I2 statistic. Pooled proportions, ie, event rates, were calculated and obtained using a random-effects model (DerSimonian and Laird). Eight studies were found suitable for the final analysis, including 311 patients. Primary endpoint was mortality at 30 days. For eBAV (n = 238), 30-day mortality rate was 46.2% (95% confidence interval [CI], 30.3%-62.5%; I2=74%), major bleeding rate was 10% (95% CI, 5.4%-15.7%; I2=13%), and stroke rate was 0.7% (95% CI, 0.0%-2.7%; I2=0%). Aortic regurgitation (AR) ≥II was present in 8.6% (95% CI, 0.4%-23.5%; I2=86%). For eTAVR (n = 73), 30-day mortality rate was 22.6% (95% CI, 12.0%-35.2%; I2=26%), major bleeding rate was 5.8% (95% CI, 0.5%-14.7%; I2=0%), and stroke rate was 5.8% (95% CI, 0.5%-14.7%; I2=0%). AR ≥II was present in 4% (95% CI, 0.0%-12.1%; I2=0%). Conclusion. Mortality in CS patients due to decompensated severe AS is high, regardless of interventional treatment strategy. Both eBAV and eTAVR seem feasible. As eTAVR is associated with better initial improvements in hemodynamics and simultaneously avoids sequential interventions, it might be favorable to eBAV in select patients. If eTAVR is not available, eBAV might serve as a “bridge” to elective TAVR.

J INVASIVE CARDIOL 2019 October 15 (Epub Ahead of Print).

Key words: balloon valvuloplasty, cardiogenic shock, emergency treatment, severe AS, transcatheter aortic valve replacement


Aortic stenosis (AS) is one of the most common valvular pathologies in the western world.1 Surgical aortic valve replacement (SAVR) is well established and associated with relatively low perioperative mortality and morbidity in selected patients.2 Since AS is mainly a degenerative disease developing over decades, it predominantly becomes symptomatic in the elderly; these patients often suffer from relevant comorbidities, putting them at a very high risk for SAVR.3 

In 1986, Cribier et al described percutaneous balloon aortic valvuloplasty (BAV) as a treatment option for severe, symptomatic AS in patients unfit for SAVR.4 BAV is nowadays not considered a definitive treatment option for severe AS because high rates of restenosis, aortic regurgitation, and vascular complications are reported, and BAV is currently considered as a “bridge” to definitive treatment or for severely sick patients in a palliative setting.5,6 

During the last few years, transcatheter aortic valve replacement (TAVR) evolved as a treatment option for patients with severe AS who are deemed inoperable and even in patients with an intermediate perioperative risk.7,8 

Patients in cardiogenic shock (CS) due to decompensated AS have a poor prognosis and their perioperative risk when undergoing SAVR (operative mortality up to one-quarter) is considered very high.9,10 Both emergency TAVR (eTAVR) and emergency BAV (eBAV) have been reported in CS patients.11,12 Current guidelines are vague on this topic, as TAVR is relatively contraindicated in hemodynamically unstable patients.13,14 We aimed to pool and analyze available studies on eBAV and eTAVR and tried to add more evidence to this broadly discussed field. 

Methods

This study was performed according to established methods and in adherence with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement for reporting systematic reviews and meta-analyses in healthcare interventions.15,16

Literature search. The PRISMA flow chart illustrating publication screening and reasons for exclusion is shown in Supplemental Figure S1 (available at www.invasivecardiology.com). We performed our search in PubMed Central in English language. Keywords used were combinations of “transcatheter aortic valve implantation,” “transcatheter aortic valve replacement,” “aortic valve balloon valvuloplasty,” and “shock,” “emergency,” “heart failure,” and “acute.” Databases were screened until August 1st, 2018.  The most updated and inclusive data for each study were used for abstraction. References of original and review articles were cross-checked.

Selection criteria and internal validity. Citations were screened on title/abstract level and retrieved as full reports if they fulfilled the inclusion criteria: (1) human studies; (2) studies reporting postinterventional mortality and outcomes for eTAVR or eBAV in patients suffering from CS due to AS of >10 patients; (3) English language; and (4) publication after 2004 (ie, in the TAVR era). Two independent reviewers (BW and PJ) selected the studies and extracted study/patient characteristics of interest and relevant outcomes; divergences were resolved by consensus after discussion with a third reviewer (CJ). 

Study endpoints. The primary endpoint was 30-day mortality. Secondary endpoints were stroke, major bleeding, and > trace postinterventional aortic valve regurgitation. Study definitions for CS and success were applied. 

Data synthesis and analysis. Study-level data were analyzed. Heterogeneity was assessed using the I2 statistic. Pooled proportions, ie, event rates, were calculated using a random-effects model (DerSimonian and Laird) incorporating Freeman-Tukey double-arcsine transformation of proportions.17 Pooled event rates were obtained for each subset of studies and combined in a random-effects meta-analysis. Open Meta-Analyst was used for statistical computations and graphical work-up based on the metafor package for R.18,19 Results

Interventional treatment options. After exclusion of duplicates, a total of 1348 studies were screened on title and abstract level. Five studies on eBAV and 3 studies on eTAVR were included in the final analysis; of note, the manuscript from Bongiovanni et al reports data on both eBAV and eTAVR, bringing the total number of studies to 7.11,12,20-24 Patients in the studies by Eugene et al20 and Bongiovanni et al12 did not necessarily fulfill definitions of hypotensive CS, but patients suffered from severe decompensated AS and were considered to need emergency treatment. Therefore, for the sake of this analysis, these patients were considered to suffer from non-hypotensive CS. The included studies are summarized in Table 1.

Emergency balloon aortic valvuloplasty. Recently, Debry et al11 investigated eBAV in a cohort of 44 patients with CS. Mortality rate was 47% at 1 month, and was as high as 70% after 1 year. Even though 23 survivors after the initial successful eBAV underwent concomitant TAVR or SAVR as definitive treatment, the 1-year mortality rate was quite high. In this study,11 the delay of eBAV >48 hours after starting inotrope agents was associated with adverse outcomes (86% vs 53%; P=.02).

In another study of 118 CS patients, the 1-month mortality rate was 33% after eBAV.12 Interestingly, in this study, none of the eBAV patients suffered from peri-interventional stroke, but roughly one-quarter (27%) suffered from significant (≥II) aortic regurgitation (AR). Again, a total of 32 survivors underwent elective TAVR after eBAV as definitive treatment. Excluding these eBAV patients undergoing elective TAVR, there was no statistically significant difference in a 2-year follow-up between eTAVR and eBAV after correction for age, EuroScore, and other relevant confounders in this cohort.

Eugene et al20 investigated a cohort of 40 patients with either refractory pulmonary edema (n = 23) or CS (n = 17). Early mortality rate (median time to death, 5 days) was 48% in patients suffering from CS and 30% in the overall cohort. Of 28 survivors, a total of 16 underwent concomitant TAVR (n = 9) or SAVR (n = 7). 

Two older studies from 2013 reported outcomes on 13 patients (Theiss et al)21 and 23 patients (Saia et al)22 with CS due to decompensated AS. In Saia et al, early in-hospital mortality rate was 57%; after 2 years, mortality rate reached 80%. More than 50% of these patients suffered from at least moderate AR after eBAV. Theiss et al21 reported early in-hospital mortality in 5 of 13 patients (38%). 

Baseline characteristics of available studies on eBAV are summarized in Table 1. Echocardiographic data are summarized in Table 2. Mean aortic valve area after eBAV was 0.86 cm2 (range, 0.80-0.92 cm2; I2=0%).

In a meta-analysis of all available studies of eBAV in CS, 30-day mortality rate was 46.2% (95% CI, 30.3%-62.5%; I2=74%) (Figure 1). AR ≥II was present in 8.6% (95% CI, 0.4%-23.5%; I2=86%). Major bleeding rate was 10.0% (95% CI, 5.4%-15.7%; I2=13%) and stroke rate was 0.7% (95% CI, 0.0%-2.7%; I2=0%) (Figure 2). 

Emergency transcatheter aortic valve replacement. Three studies reported data on eTAVR; baseline characteristics are summarized in Table 1 and echocardiographic data are reported in Table 2. In a study by Bongiovanni et al,12 CS patients underwent eTAVR and showed a periprocedural mortality rate of 8.7%. AR ≥II was present in 1 patient (4.3%). After 1 month, mortality rate was 24%.

In a study by Frerker et al24 reporting on 27 patients suffering from CS, the early mortality rate was 11% and almost 33% at 1 month.24 In a landmark analysis at 1 month, CS patients undergoing eTAVR showed no difference in 1-year mortality rate compared with high-risk patients undergoing TAVR in an elective setting. 

In 2014, Unbehaun et al23 reported on 23 CS patients who underwent transapical eTAVR; 1-month mortality rate was 13% in this cohort. 

In a meta-analysis of available studies on eTAVR in CS, 30-day mortality rate was 22.6% (95% CI, 12.0%-35.2%; I2=26%) (Figure 3). Major bleeding rate was 5.8% (95% CI, 0.5%-14.7%; I2=0%) and stroke rate was 5.8% (95% CI, 0.5%-14.7%; I2=0%). AR II was present in 4% (95% CI, 0.0%-12.1%; I2=0%) (Figure 2). Aortic valve area after eTAVR was reported in only 1 study by Ferker et al (2.0 ± 0.4 cm2).24

Discussion

Both eTAVR and eBAV show high mortality rates, with a trend toward a lower mortality rate in eTAVR patients. The postinterventional aortic valve area was not >1 cm2 in any of the eBAV studies, indicating a high rate of persisting, severe AS. Furthermore, relevant AR tends to be higher after eBAV when compared with eTAVR. The trend toward a lower overall mortality rate in eTAVR studies is driven by a relatively old study reporting data on transapical eTAVR. Importantly, selection bias might contribute to this finding as well; in our experience, patients referred to eTAVR versus eBAV tend to be clinically less sick. On the other hand, patients undergoing eTAVR in reported studies evidenced high logistic EuroScore and STS scores. In select patients, eTAVR might be favorable over eBAV.

Certainly, there will always be patients too sick, too old, and too frail to undergo further treatment. In these patients, the best supportive care is certainly the most humane, reasonable, and cost effective. Aside from available risk scores, structured assessment of frailty — and most importantly, the patient’s wishes — should guide clinicians in these situations.25 

Still, in a landmark analysis of CS patients suffering from decompensated AS undergoing eTAVR, survivors after 1 month did show an increased mortality rate when compared with other high-risk TAVR patients in an elective setting.24 In a small historic cohort of decompensated severe AS patients, even SAVR was performed successfully, demonstrating that not all hope is lost in these patients.26 

If we decide to perform interventional treatment in a patient with CS due to decompensated AS, the question arises whether eBAV or eTAVR should be favored. From current literature, we know that BAV is accompanied by high rates of persistent AS.6 In our analysis of 5 available eBAV studies, even initial postinterventional mean aortic valve area remained <1 cm2, indicating remaining severe AS in most patients. Considering inherent periprocedural complications and risks, the key question remains: why not directly perform eTAVR?

In our analysis, eTAVR was associated with a trend toward lower 1-month mortality. Mean aortic valve area after TAVR was well above 1 cm2, indicating clear superiority of eTAVR compared with eBAV from a strict hemodynamic standpoint. Furthermore, the need for a sequential intervention after eBAV can be reduced. 

Another important advantage of TAVR is a lower risk for postprocedural AR. Data from BAV in elective patients indicate that AR is present in at least 16%, whereas AR rates are as low as 1.6% in TAVR using second-generation valves.6,7 This is important, as > moderate AR after TAVR is accompanied by a 2-fold increase in 1-year mortality.27

Newer second- and third-generation valves further invalidate another historic prejudice against TAVR that favors BAV in instable patients: modern TAVR devices can be implanted via 14-16 Fr access. Therefore, the sheath size difference seems clinically irrelevant. One cohort from Germany reported eTAVR with a transapical approach.28 Interestingly, mortality rates in this cohort of CS patients with low left ventricular ejection fraction were particularly low, considering modern TAVR delivery systems and reports of superiority of transfemoral TAVR in an elective setting.29 From our clinical experience, eTAVR nowadays is primarily done transfemorally, and therefore these results should be interpreted and extrapolated with utmost caution. 

Furthermore, eTAVR is accompanied by several issues. First, device sizing might be challenging, as the aortic annulus can only be validly measured by three-dimensional echocardiography30 and not by multislice computed tomography, which is the current standard in elective situations. Second, TAVR or sufficient expertise with eTAVR might not be available at all hospital sites, and CS patients cannot be transferred to qualified centers due to a hemodynamically instable situation. Clearly, in this situation, eBAV — if available — might be superior, although eBAV should preferably be conducted in centers offering TAVR as well.

Another point favoring eBAV might be cost-effectiveness. According to guidelines on both sides of the argument, patients considered for TAVR should have a life expectancy of 1 year post TAVR — a fact that is difficult to ascertain in acute CS patients.13,14 Furthermore, most non-survivors might die periprocedurally regardless of eBAV or eTAVR due to the disease dynamics of CS, per se, or because of other limiting concomitant medical conditions. Emergency BAV, which is cheaper and less resource-consuming with regard to time of the cath-lab team, might identify those patients who profit from initial improvement in hemodynamics and might overcome CS. Another point in favor of eBAV is the low peri-interventional stroke rate (0.7% vs 5.8% with eTAVR).After eBAV, the survivors can be referred to elective TAVR (or even SAVR), a strategy that theoretically improves outcomes and save costs. Still, we think that this view under-estimates both the long-term benefits of an eTAVR strategy (ie, better initial improvements in hemodynamics and less AR) and the inherent risk of multiple sequential interventions. With second- and third-generation devices, TAVR with self-expanding prostheses might spare BAV during the intervention, which is associated with favorable outcomes and less complications.31 In our analysis, both self-expanding and balloon-expandable (as well as first- and second-generation) TAVR devices were used. 

We think that initial patient selection needs to be improved for emergency interventions in CS due to AS (Figure 4). Assessment of frailty by means of clinical frailty scale (CFS), level of self care, and geriatric assessment together with the patients’ relatives might contribute to a complete picture.32 Heart teams should counsel geriatric experts in such situations to obtain realistic expectations for treatment goals. Compared with the elective TAVR clientele, pooled patients in this analysis were younger, but still classified as elderly. Surgical risk scores (STS, log EuroScore I, EuroScore II) might be unsuitable for risk prediction in an elderly, severely sick, intensive-care patient group, as they were not developed for this setting.33 Scores and biomarkers assessing multiorgan function, such as APACHE (Acute Physiology And Chronic Health Evaluation) II, SOFA (Sequential Organ Failure Assessment), and lactate might help, as scores assessing systemic inflammatory response syndrome are superior in predicting mortality in CS compared with biomarkers of heart failure.34-39 Another particularly helpful prognostic tool in CS due to decompensated AS might be the CardShock classification, which is based on age, mental status at presentation, lab values, and medical history.40 Reporting and evaluating these scores in future studies on eTAVR and eBAV might help to reach comparability between different centers. In 1 study, CS patients undergoing eTAVR suffering from impaired renal function, cardiac output <3.0 L/min, and mechanical ventilation evidenced particularly unfavorable outcomes.24 From a cost-effectiveness standpoint, in patients with high suspected mortality regardless of interventional treatment, the cheaper eBAV might have a role even in the presence of eTAVR capabilities (Figure 4).

A fast decision process might be necessary, as in 1 study, delayed eBAV was associated with adverse outcomes after 1 year — pointing to a time frame of 48 hours for adequate decision making on the optimal treatment strategy. Randomized controlled trials comparing eBAV versus eTAVR are needed.

Study limitations. Although this study analyzes the biggest pooled cohort of CS patients undergoing either eTAVR or eBAV, total patient numbers remain low. eBAV and eTAVR were not directly compared in any study. Selection bias toward eBAV in clinically sicker patients might contribute to unfavorable results in eBAV. As discussed above, the lower mortality rate in eTAVR patients was mainly driven by a single older study reporting outcomes on transapical eTAVR, and these results should be extrapolated to transfemoral eTAVR with caution.

Conclusion

Mortality rate in CS patients due to decompensated severe AS is high, regardless of interventional treatment. Both eBAV and eTAVR seem generally feasible. As eTAVR is associated with better initial improvements in hemodynamics and could reduce multiple sequential interventions, it might be favorable over eBAV in select patients. A randomized controlled trial addressing this question is necessary. If eTAVR is not available, eBAV might serve as a “bridge” to elective TAVR.

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From the 1Clinic of Internal Medicine II, Department of Cardiology, Paracelsus Medical University of Salzburg, Salzburg, Austria; 2Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf, Germany; 3Department of Cardiology, Charité – Universitaetsmedizin Berlin, Berlin, Germany; and 4Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Frerker reports lecture honoraria and travel support from Edwards Lifesciences, Medtronic, and Abbott Vascular. Dr Jung reports grant support, personal fees, and non-financial support from Actellon and Novartis; grant support and personal fees from Bayer Healthcare, Vifor Pharma, Zoll Medical; personal fees from Pfizer, Bristol Meyer Squibb, Boston Scientific, Boehringer Ingelheim, and Sanofi Aventis; grant support from Medicure; personal fees and non-financial support from Abbott Vascular and Orion Pharma. Dr Veulemans reports grant support, personal fees, and non-financial support from Edwards Lifesciences and Medtronic. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted January 3, 2019, provisional acceptance given February 21, 2019, final version accepted June 10, 2019.

Address for correspondence: Christian Jung, MD, PhD, University Hospital Düsseldorf, Department of Medicine, Division of Cardiology, Pulmonary Diseases and Vascular Medicine, 40225 Düsseldorf, Germany. Email: Christian.Jung@med.uni-duesseldorf.de 

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