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Microaxial Left Ventricular Assist Device in Cardiogenic Shock: A Systematic Review and Meta-Analysis

Microaxial left ventricular assist devices (LVAD) are increasingly used to support patients with cardiogenic shock; however, outcome results are limited to single-center studies, registry data and select reviews. We conducted a systematic review and meta-analysis, searching three databases for relevant studies reporting on microaxial LVAD use in adults with cardiogenic shock. We conducted a random-effects meta-analysis (DerSimonian and Laird) based on short-term mortality (primary outcome), long-term mortality and device complications (secondary outcomes). We assessed the risk of bias and certainty of evidence using the Joanna Briggs Institute and the GRADE approaches, respectively. A total of 63 observational studies (3896 patients), 6 propensity-score matched (PSM) studies and 2 randomized controlled trials (RCTs) were included (384 patients). The pooled short-term mortality from observational studies was 46.5% (95%-CI: 42.7–50.3%); this was 48.9% (95%-CI: 43.8–54.1%) amongst PSM studies and RCTs. The pooled mortality at 90 days, 6 months and 1 year was 41.8%, 51.1% and 54.3%, respectively. Hemolysis and access-site bleeding were the most common complications, each with a pooled incidence of around 20%. The reported mortality rate of microaxial LVADs was not significantly lower than extracorporeal membrane oxygenation (ECMO) or intra-aortic balloon pumps (IABP). Current evidence does not suggest any mortality benefit when compared to ECMO or IABP.


Introduction
The incidence of cardiogenic shock (CS) has increased in recent years, yet long-term mortality has not substantially improved in the last 20 years [1]. It is associated with significant multi-organ failure and in-hospital mortality reaching in excess of 60% [2,3]. Amongst survivors, up to 20% are re-admitted within 30 days [1]. Acute myocardial infarction is the most common cause of CS and accounts for 10% of patients with CS [1,4]. A spectrum of disease exists in cardiogenic shock-the Society of Cardiovascular Angiography and Interventions (SCAI) classifies CS from Stages A (at-risk) to E (in extremis). Within Stage C (classic) CS, patients typically present with hypoperfusion requiring either inotropes or temporary circulatory support devices [5]. Various temporary circulatory support devices are available for these patients-this ranges from counterpulsation devices such as the intra-aortic balloon pump (IABP), percutaneously inserted left ventricular assist devices (pLVADs, including microaxial and centrifugal), paracorporeal VADs and extracorporeal membrane oxygenation [6,7].
In addition to the multiple device options, existing studies and reviews investigating its use report favorable survival outcomes and safety outcomes in patients with CS [9,24]. However, the outcomes of microaxial LVADs based on the various types and different etiologies of CS have not been elucidated in detail [24]. In addition, potential predictors of mortality have yet to be explored. We conducted this systematic review and metaanalysis to investigate the short-and long-term mortality outcomes and device-related complications of microaxial LVADs in all etiologies of CS, and to explore the potential risk factors associated with mortality.

Search Strategy and Selection Criteria
This review was registered on PROSPERO (CRD42020202807) and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement (Table S1) [25]. We searched MEDLINE, Embase and Scopus databases from 1 January 2003 to 13 July 2022 using the keywords 'Impella' and 'cardiogenic shock' (Table S2). We included studies published in English, reporting on ≥10 non-overlapping adult patients (>18 years) receiving microaxial LVADs for CS. In cases of overlapping patient data, we included the larger study. We excluded studies reporting on animals and where device was inserted prophylactically or electively during percutaneous coronary intervention. We also excluded those studies where outcomes were not stratified by device option in CS, and national or international registry databases that could contribute to duplication of patient data.

Data Extraction
Data collection included study design (author and study name, year of publication, country, setting, number of patients), patient demographics (age, gender, comorbidities), pre-LVAD clinical characteristics (body mass index, left ventricular ejection fraction [LVEF], comorbidities), etiology of CS (acute myocardial infarction cardiogenic shock [AMICS] or non-myocardial infarction cardiogenic shock [NMICS]), device characteristics (mode of insertion, cannulation access, concomitant extracorporeal membrane oxygenation [ECMO] use, duration of support) and outcomes of interest (in-hospital mortality, 30 days, 90 days, 6 months, 1 year and device-related complications).

Risk of Bias and Certainty Assessment
Risk of bias in individual studies was assessed using the appropriate Joanna Briggs Institute (JBI) checklists. Egger's test was used to assess the possibility of publication bias. As inter-study heterogeneity can be misleadingly large when assessed using I2 statistics for observational studies [26], we used the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach to rate the certainty of evidence [27,28]. The screening of articles, data collection and risk of bias assessment were conducted independently by two reviewers (TSR and NWL), and any conflicts were resolved by a third reviewer (KR).

Outcomes
The primary outcome was short-term mortality, defined as 30-day mortality or inhospital mortality, whichever was longer. Secondary outcomes include long-term mortality at 90 days, 6 months and 1 year, and device-related complications (device malfunction, access-site bleeding, hemolysis, limb ischemia and stroke). Tables S3 and S4 summarize the definitions of CS, device-related complications and severity of LVEF [29].

Statistical Analysis
For continuous variables, we pooled the means and standard deviations (SDs) in accordance with Wan et al. [30]. Categorical data are reported as pooled proportions with 95% confidence intervals (CIs), whereas continuous outcomes are reported as pooled means with 95% CIs. All analyses were conducted in R4.0.1. Random effects meta-analyses (DerSimonian and Laird) were conducted using the Freeman-Tukey double arcsine transformation, and 95% CIs were computed using the Clopper-Pearson method [31][32][33]. We pooled the results of the propensity-score matched (PSM) studies and RCTs together as previous studies have shown that the estimates obtained from PSM studies are similar and as robust as RCTs [34][35][36]. Sensitivity analysis was conducted by excluding studies with higher risks of bias (defined as <7). Planned subgroup analyses were conducted with continuity correction of 0.5 to allow for inclusion of studies with zero events, and included the geographical region (Europe, North America or Asia), etiology of CS (AMICS or NMICS), the mode of insertion (percutaneous (which comprises Impella 2.5 and CP) or surgical (which comprises Impella 5.0 and Impella 5.5)), cannulation access for insertion (axillary or femoral), duration of support (more or less than 4 days), concomitant use of ECMO, IABP prior to microaxial LVAD use and pre-LVAD LVEF (above or below 20%). Summary-level meta-regression was conducted if there was a minimum of 6 data points in order to explore sources of heterogeneity and to identify potential prognostically relevant study-level covariates [37].

Role of the Funding Source
This study had no funding source.

Results
From 4173 articles, we reviewed 206 full-text articles. In total, we included 71 studies (63 observational, 8 PSM/RCTs) detailing 4280 adult patients that reported on the use of microaxial LVADs in CS ( Figure 1) [16,. The findings of the one-armed observational studies and the findings of the PSM/RCTs are reported separately. Of the observational studies, 34 were reported by centers from Europe, 25 from North America, 3 from Asia and 1 from South America, whereas all of the RCTs and PSMs were reported by centers from Europe. Percutaneously inserted devices were more commonly used than surgically inserted devices.

Figure 1.
Flow diagram of selection of articles based on PRISMA statement. Abbreviations: PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses; pVAD = percutaneous ventricular assist device; RCT = randomized controlled trial.
No significant differences were found in short-term mortality when considering the geographical location (North America, South America, Europe or Asia), patient demographic factors (pre-LVAD LVEF (≤20% or >20%)) or device factors (duration of microaxial LVAD support (≤4 days or >4 days) and cannulation site (axillary or femoral)). Table S5 summarizes the results of the subgroup analysis.

Risk of Bias and Certainty of Evidence Assessment
Using appropriate JBI checklists, all studies were of high quality (score of ≥7, Table  S7). We assessed the certainty of evidence for all primary and secondary outcome measures using the GRADE approach (Table S8). For both observational studies and RCTs, the certainty of evidence was high according to the GRADE evaluation for our primary outcome of short-term mortality and that of long-term mortality, whereas the complications were deemed to be of moderate-to-high certainty. Egger's test found that Pegger was 0.96, indicating that publication bias is unlikely.

Discussion
This review comprising 71 studies and 4280 patients demonstrated that microaxial LVAD in CS was associated with mortality rates approaching 50%. Patients were predominantly middle-aged males. The 90-day, 6-month and 1-year mortality (observational studies) was 41.8%, 51.1% and 54.3%, respectively. Short-term mortality was relatively higher in patients with surgical insertion compared to percutaneous insertion. Comorbitidies including previous cerebrovascular accidents and hyperlipidemia were associated with mortality, whereas longer durations of device support were associated with survival.

Risk of Bias and Certainty of Evidence Assessment
Using appropriate JBI checklists, all studies were of high quality (score of ≥7, Table S7). We assessed the certainty of evidence for all primary and secondary outcome measures using the GRADE approach (Table S8). For both observational studies and RCTs, the certainty of evidence was high according to the GRADE evaluation for our primary outcome of short-term mortality and that of long-term mortality, whereas the complications were deemed to be of moderate-to-high certainty. Egger's test found that P egger was 0.96, indicating that publication bias is unlikely.

Discussion
This review comprising 71 studies and 4280 patients demonstrated that microaxial LVAD in CS was associated with mortality rates approaching 50%. Patients were predominantly middle-aged males. The 90-day, 6-month and 1-year mortality (observational studies) was 41.8%, 51.1% and 54.3%, respectively. Short-term mortality was relatively higher in patients with surgical insertion compared to percutaneous insertion. Comorbitidies including previous cerebrovascular accidents and hyperlipidemia were associated with mortality, whereas longer durations of device support were associated with survival.
Our study provides further insights into the characteristics of microaxial LVAD devices that may affect mortality. We found that patients receiving surgically inserted devices had a relatively higher mortality rate than percutaneously inserted devices. This is likely to be because multifactorial-percutaneously inserted devices generate a maximum of 2.5 to 4.0 L/min of blood flow, [107] whereas surgically inserted devices generate up to 5.0 and 6.0 L/min [107,108]. Patients with more severe cardiogenic shock may have higher support requirements and intrinsically higher mortality rates due to their clinical presentation. In addition, the surgical insertion of devices might increase the rates of surgical site infection and bleeding. Finally, higher flows generated by surgically inserted devices may lead to higher rates of hemolysis. We also found that the duration of the device support was not associated with a higher mortality. This is contrary to previous studies that have shown that the use of microaxial LVADs for >4 days led to an increased mortality and duration of hospital and coronary care unit stay [109]. Nonetheless, this could be attributed to immortal time bias, which has been described in observational studies [110] and in patients on life-saving devices [111,112], where patients in the treated group have to survive and be event-free until the treatment definition is fulfilled [113].
Mortality rates for CS remain high despite timely goal-directed medical management [7,114,115]. The variable survival rates of CS between the use of mechanical cardiac support devices is evident from the IABP-SHOCK I and II trials that showed that IABP did not significantly improve 30-day survival [10,116], whereas the international Extracorporeal Life Support Organization registry found that 42% of patients receiving venoarterial ECMO survived to discharge [117]. This contrasts with the 51% survival rate of patients receiving microaxial LVADs in the United States [18]. Similarly, in our observational cohort of patients with microaxial LVAD support, we observed short-term survival rates of 53%. However, survival rates of 70% have been reported in advanced cardiac centers with robust protocols comprising the stringent selection criteria team-based management of CS [118,119]. The concomitant use of microaxial LVADs and ECMO is an area of increasing interest to improve outcomes. Microaxial LVADs unload the left ventricle (LV) and may help offset the LV distension secondary to retrograde aortic blood flow in patients on peripheral venoarterial ECMO [120]. Our study found that patients receiving concomitant ECMO had a significantly higher mortality rate than those receiving microaxial LVADs alone (51.5% vs. 44.6%, p = 0.04). However, this can be confounded by the severity of cardiogenic shock, and VA-ECMO may only be initiated in the context of cardiogenic shock refractory to other therapies. As such, it is unclear whether VA-ECMO causes an increase in mortality, or if it is simply initiated in patients with more severe cardiogenic shock.
The long-term mortality reported in our review was higher compared to those reported in major trials on microaxial LVADs [17,121]. The reasons may be multifactorial: both RCTs had fewer patients with a smaller range of etiologies of CS, and robust patient selection criteria and management protocols. On the other hand, patients recruited in the observational studies were heterogenous in selection and management. The higher incidence of complication rates could also have impacted the long-term outcomes. The most frequently reported device-related complication was hemolysis, which was higher than those reported in previous registry reviews [24,122,123]. There was also a discrepancy between RCTs and PSM studies, and observational studies in the incidence of hemolysis (40.8% vs. 23.8%) and access site bleeding (6.4% vs. 25.8%). Possible reasons include a longer pooled duration of device support in observational studies compared to RCTs, varying definitions of hemolysis and the predominant use of percutaneous devices with a smaller pump design. Access-site bleeding was reported in 15 studies with a pooled prevalence of 19.4%, similar to the USpella cohort [122] but lower than the EUROSHOCK cohort [108,123,124]. Notably, our study found that the pooled incidence of limb ischemia was comparable between the observational studies and RCTs (6.3% vs. 8.2%), and was lower compared to ECMO and IABP, whereas the incidence of access-site bleeding was higher compared to ECMO and IABP [37,125,126]. Nonetheless, the incidence of limb ischemia and bleeding may have been affected by multiple factors, such as the use of anticoagulants or presence of peripheral vascular disease, for which, adequate data were not clearly available [7].
The strengths of this review include a comprehensive search strategy and robust inclusion criteria that encompassed all etiologies of CS and types of devices used. It also included a detailed analysis of various patient and intervention factors and their impact on mortality outcomes. Nonetheless, we recognize several limitations. First, there is significant heterogeneity in patient demographics, definitions, variations in patient selection, practices and reporting patterns and the observational nature of the included studies, which we tried to account for by using subgroup and meta-regression analyses. Meta-regression analyses are also inherently constrained by a lack of power, resulting in an increased risk of type II errors. Almost all of the analyses have also been limited to North America and Europe, whereas studies from Asia remain scarce. Hence, the results might not be generalizable to other parts of the world where healthcare systems and workflows are different. Nonetheless, our subgroup analysis on geographical location did not find any significant difference in short-term mortality. Moreover, the GRADE assessment suggested a high certainty in the evidence for the primary outcome and long-term mortality, whereas complications were of moderate to high certainty. With scores of 7 or higher, JBI critical appraisal also deemed all 71 articles as high quality and suitable for inclusion.

Conclusions
This review summarizes the mortality outcomes and complications of microaxial LVADs in patients with CS. Short-term mortality was 46.5% whereas 6-month and 1-year mortalities were 51% and 54%, respectively. Complications such as hemolysis and access site bleeding were high as reported in the observational studies. Nonetheless, the use of temporary circulatory support in cardiogenic shock remains inherently challenging as patients are usually critically ill with multi-organ pathologies, and patient care is heterogenous. In addition, the current evidence base is limited in concluding whether or not microaxial LVADs confer a survival benefit in patients with CS. Further RCTs are warranted to better assess the effectiveness and role of microaxial LVADs in CS.

Data Availability Statement:
No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest:
Kollengode Ramanathan serves as a co-chair of the Scientific Oversight Committee of the Extracorporeal Life support Organization (ELSO), and reports honoraria for educational lectures from Baxter Ltd., and Fresenius Ltd. All other authors declare no competing interest.