One-year survival in recipients older than 50 bridged to heart transplant with Impella 5.5 via axillary approach

Smit Paghdar, Smruti Desai, Ji-Min Jang, Jose Ruiz, Sharan Malkani, Parag Patel, Daniel S Yip, Juan C Leoni, Jose Nativi, Basar Sareyyupoglu, Kevin Landolfo, Si Pham, Rohan M Goswami,

1.Division of Heart Failure and Transplant, Mayo Clinic in Florida, USA; 2.Department of Cardiothoracic Surgery,Mayo Clinic in Florida, USA

ABSTRACT BACKGROUND Optimizing patients with advanced heart failure before orthotopic heart transplantation (OHT), especially in patients greater than 50 years old, is imperative to achieving successful post-transplant outcomes.Complications are well-described for patients bridged to transplant (BTT) with durable left ventricular assist device (LVAD) support.Given the lack of data available in older recipients after the recent increase in mechanical support use, we felt it crucial to report our center’s one-year outcomes in older recipients after heart transplantation with percutaneously placed Impella 5.5 as a BTT.METHODS Forty-nine OHT patients were supported with the Impella 5.5 intended as a bridge between December 2019 and October 2022 at Mayo Clinic in Florida.Data were extracted from the electronic health record at baseline and during their transplant episode of care after Institutional Review Boards approval as exempt for retrospective data collection.RESULTS Thirty-eight patients aged 50 or older were supported with Impella 5.5 as BTT.Ten patients underwent heart and kidney transplantation within this cohort.The median age at OHT was 63 (58-68) years, with 32 male (84%) and six female patients (16%).Etiology was divided into ischemic (63%) and non-ischemic cardiomyopathy (37%).The baseline median ejection fraction was 19% (15-24).Most patients were in blood group O (60%), and 50% were diabetic.The average duration of support was 27 days (range 6-94).The median duration of follow-up is 488 days (185-693).For patients that have reached the 1-year follow-up timeframe (22 of 38, 58%), the 1-year post-transplant survival is 95%.CONCLUSION Our single-center data provides awareness for using the Impella 5.5 percutaneously placed axillary support device in older heart failure patients in cardiogenic shock as a bridge to transplantation.One-year survival outcomes after heart transplantation are excellent despite the older recipient’s age and prolonged pre-transplant support.

Older patients generally have more comorbidities besides heart failure (HF),such as diabetes, vascular disease, hypertension, chronic kidney disease, decreased mobility, and increased frailty.Recent trends in chronic heart failure survival in older Americans have continued to increase as patients age, despite the availability of more effective guideline-directed medical therapy (GDMT).[1]Optimizing a patient with advanced heart failure before potential orthotopic heart transplantation (OHT), especially in older patients,is imperative to achieving successful post-transplant outcomes (e.g., survival, infection, organ function,and mobility).Older patients refractory to GDMT will traditionally be worked up for advanced therapies.Some of these patients in the setting of stage C or D heart failure may need support either as a bridge to transplant (BTT) or durable left ventricular assist devices (LVAD) and have conventionally been supported with continuous intravenous vasoactive support while awaiting candidacy for either, respectively (Figure 1).

Figure 1 Visualized decision tree in end-stage heart failure patients.AHA: American Heart Association; BTT: bridge to transplant;BTVAD: bridge to ventricular assist device; INTERMACS: interagency registry for mechanically assisted circulatory support; LVAD:left ventricular assist device; NYHA: New York Heart Association.

The risk of complications is well-described for patients bridged to OHT with durable LVAD support.As Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles progress, worsening outcomes for patients receiving LVAD therapy also can increase (Figure 2).[2]Thiscan include stroke, infection, allosensitization, renal failure, gastrointestinal bleeding, and right ventricular failure.[3,4]These complications are of even more concern in older patients at the time of transplant.The nature of LVAD explantation, united network for organ sharing (UNOS) allocation change in 2018, deprioritization of LVAD support, and associated complications at OHT can lead to increased mortality.[5]Furthermore, peri-transplant survival based on bridge strategy has been extensively evaluated after the UNOS allocation change for heart transplant recipients in 2018.[6]Dr.Lala and colleagues mined the UNOS and INTERMACS registries, comparing 1 and 5-year survival in patients with the use of LVAD as BTT or destination therapy (DT).[7]They concluded that BTT survival was superior to DT LVAD survival.This trend for 1-year survival persisted in older patients with BTT compared to those with LVAD DT.[7]

Figure 2 AHA stage, NYHA functional class, and INTERMACS profile correlation in advanced heart failure.AHA: American Heart Association; INTERMACS: Interagency registry for mechanically assisted circulatory support; NYHA: New York Heart Association.

As a result of the high rates of complications and the high-risk nature of transplanting older patients in general, many centers have a relative age cut-off,after which patients may not be considered transplant candidates.The only currently described remaining options in such cases are destination LVAD(if candidates) or destination inotrope therapy with a plan for hospice care.However, successful survival results in older patients from several transplant centers have increased the consideration of this population for heart transplant candidacy.[8]

Given the lack of data available in older recipients after 2018 and the increase in temporary mechanical circulatory support (tMCS) use, we felt it crucial to report our center’s one-year outcomes in older recipients after heart transplantation who were bridged with percutaneously placed LVAD, Impella 5.5 with Smart Assist (pVAD) support.

METHODS

Our center, to date, has performed 49 orthotropic heart transplants in patients supported with the Impella 5.5 intended as a BTT between December 2019 and October 2022 at Mayo Clinic in Florida.Of these,38 patients were above 50 and were included in the analysis.Data were extracted from the electronic health record at baseline and during their transplant episode of care after IRB approval as exempt for retrospective data collection with the approval number 22-004000.Statistical analysis was performed using SPSS v27 utilizing the Wilcoxon-Mann-Whitney testto determine the significance between the two groups with aP-value of ＜ 0.05.We chose to use the Mann-WhitneyU-test (also known as the Wilcoxon Rank Sum Test) due to our population, given that we looked to identify how two independent samples of observations drawn from the same or identical distributions compared.An advantage with this test is that the two samples under consideration do not necessarily need to have the same number of observations or instances.

Inclusion and Exclusion Criteria

Patients included were adult males or females greater than age 50, hospitalized as inpatients, and found to have either a recent history of acute on chronic decompensated heart failure or acute cardiogenic shock with New York Heart Association (NYHA)functional class 3 or greater and were candidates for advanced therapies (elaborated on below).Patients who did not meet any of these criteria were excluded from consideration for advanced therapies.Institution-specific processes are further outlined below.

Patient Selection

Careful patient selection criteria must be used to apply appropriate support to patients.Individuals with NYHA class 3 or greater, AHA Stage D in need of or on inotrope therapy with progression to dual inotropes or refractory to optimizing guideline-directed medical therapy, and those with clinical testing (e.g., CPET, RHC, 6-min walk, etc.) consistent with the need for transplant or LVAD evaluation fit the spectrum of patients that have been selected for the utilization of surgically placed Impella support as a BTT.The potential for optimizing patients and their end organ function with tMCS before declaring them unsuitable for OHT should be considered.

Institutional Standard of Care

Our institutional practice includes patients' medical, physical, and nutritional optimization as best tolerated as outpatients, with or without continuous home inotrope therapy.Subsequently, those patients with clinical or laboratory evidence of decline (e.g., increasing serum creatinine, progressive deterioration in functional status, inability to maintain a healthy weight, or intolerant of cardiopulmonary rehabilitation) are considered for admission and optimization.The standard of care for optimization at our institution for advanced heart failure patients includes the placement of a peripherally inserted central catheter (PICC) to monitor central venous pressures and record mixed venous saturation, thereby allowing us to calculate Fick cardiac output and index.We then devise a care plan based on the patient’s Stevenson profile.Finally, appropriate care, as determined by the treating physician, is undertaken.For those individuals that remain refractory to therapy, considerations for advanced treatments follow suit.

Multi-disciplinary Impella Management

Monitoring after Impella support at our institution is standardized.Consists of weekly transthoracic echocardiogram and daily chest radiograph with daily securement device assessment for patient comfort, as well as serum lactate dehydrogenase, renal profile, and complete blood counts.Additionally, patients have baseline pulmonary artery(PA) catheterization during their assessment for requiring advanced mechanical support if not already present before inotrope initiation.Most patients are monitored with an indwelling PA catheter for up to 96 hours after Impella placement.Lastly, daily multi-disciplinary rounds comprising cardiovascular intensive care, transplant cardiology, cardiothoracic surgery, physical therapy, and critical care nursing teams review patient maintenance of support and potential needs for escalating care.

RESULTS

Thirty-eight patients aged 50 or greater were supported with Impella 5.5, intended as a BTT during our review period (Table 1).The median age at transplantation was 63 (58- 68) years, with 32 (84%) male and six female patients (16%).The patients’ race was split as 53% Caucasian, 45% African American,and 2% declining identification.The etiology was divided into ischemic (63%) and non-ischemic cardiomyopathy (37%) based on available standardized testing at the time of their evaluation (e.g., cardiac catheterization or nuclear stress test), with a baseline median ejection fraction of 18% (14%-23%).At device placement, the median BMI was 29 (26-32) kg/m2.Most patients were in blood group O(60%), and 50% were diabetic.The baseline median blood pressure was 104 (97-115)/73 (66-79), with a median mean arterial pressure of 83 (77-91).All patients were on a combination of maximally tolerated guideline-directed medical therapy including betablocker, either ace inhibitor or angiotensin-neprilysin inhibitor, mineralocorticoid receptor antagonist,and weight-based diuretic.Guideline-directed medical therapy was managed at the discretion of the outpatient primary cardiologist.

Table 1 Baseline characteristics.

Before support, all patients were managed for acute heart failure cardiogenic shock with single or dual inotrope support and escalated to Impella 5.5 due to progressive failure, as outlined in our methods.The average duration of Impella 5.5 support was 27 (6-94) days.The UNOS status at transplant was 2 in most patients based on standardized criteria, with two escalated to UNOS Status 1 due to bi-ventricular mechanical support needs.[6]28 patients underwent heart only and ten patients underwent heart and kidney transplantation within our cohort.All 38 patients (100%) survived bridge-totransplantation.

The median duration of follow-up is 448 (185-693) days.For patients that have reached the 1-year follow-up timeframe (22 of 38), their 1-year posttransplant survival rate is 95%, with one death due to acute graft failure and severe vasculopathy at 296 days after transplant.Of the remaining 16 patients awaiting their one-year follow-up, one has died due to occult primary sclerosing cholangitis 88 days after transplantation.Fifteen are still alive but have not yet reached the 1-year follow-up timeframe.

Hemodynamic data

Pre- and post-impella implantation pulmonary artery catheter-based hemodynamics are summarized in Table 2.Perioperative management of Impella patients demonstrated baseline hemodynam-ics of right atrial pressure (RA) 10 (5-16) mmHg,PA systolic 53 (45-63) mmHg, PA diastolic 27(24-32) mmHg, mean PA 36 (32-43) mmHg, pulmonary capillary wedge pressure (PCWP) 26 (19-32) mmHg, mixed venous saturation (SVO2%) 58%(50%-65%), Fick cardiac output (CO) 3.7 (3.2-4.7)L/min, Fick cardiac index (CI) 1.8 (1.6-2.3) L/min per m2, peripheral vascular resistance (PVR) 2.5 (1.6-2.3) woods unit, pulmonary artery pulsatility index(PAPi) 3.1 (1.7-5.3), and central venous pressure/wedge pressure ratio 0.3 (0.2-0.5).

Table 2 Description of baseline and post-Impella hemodynamic.

Post-impella placement hemodynamics demonstrated significant improvements in RA pressure to 6.5 (4-11) mmHg,P= 0.04; PA systolic to 49 (42-52)mmHg,P= 0.02; PA diastolic to 22 (17-26) mmHg,P= 0.006; mean PA to 31 (27-35) mmHg,P= 0.006;PCWP to 21 (17-24) mmHg,P= 0.006; mixed SVO2to 65% (57-69),P= 0.006; Fick CO to 5 L/min(4.7-7.0),P≤ 0.001; and Fick CI to 2.7 (2-3) L/min per m2,P≤ 0.001.

Device Related Complications

As outlined here, all patients demonstrated markedly improved hemodynamic profiles, as expected with the placement of pVAD support.Only one of our patients supported with Impella 5.5 experienced device-specific complications requiring pump replacement - due to excess physical therapy resulting in the device flipping into the ascending aorta,Figure 3.[9]

Figure 3 Transposition of the Impella 5.5 into the aorta.- ＊:Implantable cardioverter defibrillator, ^: peripherally inserted central catheter line, arrow: Impella 5.5 inverted into the ascending aorta.

Two patients had a progressive decline in RV function after Impella placement (despite inotrope support) and required escalation with RV-specific mechanical support with Protek Duo placement.No concern for hemolysis was identified based on daily lactate dehydrogenase (LDH) and Impella 5.5 SmartAssist console purge flow and pressure measurements(measurements recorded after Impella placement and before heart transplantation), Figure 4.All patients survived bridge-to-heart or heart-kidney transplantation.

Figure 4 Peak and trough LDH values per patient.LDH: lactate dehydrogenase.

Perioperative Laboratory Data-Impella 5.5

Pre- and post-Impella implantation laboratorydata are summarized in Table 3.Laboratory data is reported from the day before Impella placement to the day before organ transplantation to provide a larger observation timeframe and a better understanding of the systemic effects of Impella support.The median serum creatinine before Impella placement was 1.7 (1-2) mg/dL and GFR of 43 (28-55)mmol/L.We observed improvement in post-Impella serum creatinine of 1.6 (1.2-2.0) mg/dL,P= 0.38 and continued improvement to 1.5 (1-2) mg/dL,P=0.14 at discharge.Post-Impella placement GFR improved to 48 (34-62) mmol/L,P= 0.07 and continued to maintain improvement at 44 (33 - 71) mmol/L,P=0.04 at discharge.There was a decline in hematocrit from pre-Impella 31% (29%-36%) to post-Impella 28% (26%-32%),P≤ 0.001 and at discharge 29% (27-32),P= 0.13.Pre- and post-Impella INR were unchanged 1.3 (1.2-1.5),P= 0.17 with at discharge INR of 1.2 (1-1.3),P= 0.22.The pre-Impella median serum aspartate transaminase (AST) was 24 (17-36)mg/dL with post-Impella AST of 25 (19-38) mg/dL,P= 0.09 and at discharge AST of 53 (23-104)mg/dL,P= 0.02.The pre-Impella median serum alanine transaminase (ALT) was 20 (12-33) mg/dL with post-Impella ALT of 21 (12-32) mg/dL,P=0.04 and at discharge ALT of 23 (20-33) mg/dL,P=0.06.There was no significant difference between pre-Impella serum bilirubin of 0.65 (0.5-1.5) mg/dL and post-Impella bilirubin of 0.6 (0.4-1.0) mg/dL,P=0.1 with a discharge value of 0.9 (0.6-1.5) mg/dL,P=0.3.Median LDH after Impella placement through transplant was 284 (234-385) units/L, post-transplant LDH was not followed serially due to the removal of Impella at transplantation.Our LDH range suggests minimal hemolysis.We did not utilize plasma free hemoglobin despite declining hemoglobin due to the delay in results, as we require sendout samples with a turnaround time of 1 week.There was also no clear evidence of hemolysis or active bleeding in this population, limiting the concern for significant bleeding in this population.The median baseline NT-Pro BNP level was 8375 (2931-13483)pg/mL in our patient population.Serial NT-Pro BNP was not assessed, as there has been much literature highlighting the lack of serial measurements in decompensated heart failure to help guide therapy.

Table 3 Perioperative laboratory data.

Perioperative Data-Solid Organ Transplantation

Perioperative data are summarized in Table 4.The median duration of cardiopulmonary bypass was 181 (155-195) min, with a median cold ischemic time of 226 (200-251) min.Median intraoperative blood products were as follows: packed red blood cells four units (4-6), fresh frozen plasma 505 (400-1000) mL, cryoprecipitate 100 (0-200) mL, platelets 413 (506-769) mL, and autologous red blood cell(cell saver) 900 (506-1125) mL.The post-operative median vasoactive inotrope score within 24 h of intensive care unit (ICU) arrival was 5 (3-10).The total hospital duration of stay from device to transplant was 23 (13-38) days with a listing time of 40 (26-78)days.The post-transplant median duration of ICU stay was five days (4-10), and the median total hospital stay during the transplant episode of care was 53 (39-77) days.

Table 4 Perioperative data.

Perioperative (impella) Echocardiography Data

Pre- and post-Impella implantation echocardiography data are summarized in Table 5.Post-Impella echo was performed 14 days after the Impella placement.The median pre-Impella LVEF of 18%(14%-23%) and post-Impella LVEF of 21% (17%-28%) showed a statistically significant improvement in LVEF withP= 0.009.Left ventricular diameters at baseline were LVEDD 65 (61-70) mm, LVESD 59 (53-63) mm and after Impella placement diameters were LVEDD 65 (60-72) mm,P= 0.4; LVESD 58 (52-63) mm,P= 0.29.Left ventricular volumes were not found to be significant at baseline: LVEDV 258(195-304) mL, LVESV 193 (131-249) mL or after Impella placement: LVEDV 244 (204-334) mL,P= 0.31;LVESV 205 (130-242) mL,P= 0.43, likely highlighting the impact of chronic volume overload that is not mitigated immediately after Impella 5.5 placement.

Table 5 Perioperative echocardiography data.

DISCUSSION

HF is among the most common chronic diseases in the United States.[10]The risk of HF increases as the population ages.[11]Advancement in medical therapy has improved clinical outcomes, but heart transplantation remains the best treatment for endstage HF patients who have failed medical management and continue to decline.[12]Below we discuss patient and device-specific observations that may be relevant to the reader.

Understanding Recipient Age

Recipient age limit cut-off has been controversial in heart transplantation due to the disparity between chronological and physiological age, organ availability, and center variability in practice patterns.Older recipient age has traditionally been considered a risk factor for heart transplantation due to the association of more comorbidities and an increased likelihood of post-transplant complications compared to younger recipients.[13]Prior published data looking at recipient age on outcomes has defined older age at transplant or listing between 50 and 55.[14]Furthermore, temporal trends in heart transplantation centers in the United States published between 1990 and 2019 have shown fewer patients older than 65 being listed, thereby constraining the‘older age’ definition to a window of only ten years,compared to the window between 18 and 55, respectively.As such, we felt that utilizing a broader definition may enhance the understanding of outcomes in the advanced heart failure population.[15,16]Based on this data, we defined a recipient age of 50 as our cutoff for inclusion.To our surprise, based on annualized data, there has been a 110% increase in heart transplantation in patients aged 50-64 (from 2018 to 2020).[17,18]Based on our experience with the Impella 5.5 in this population, our age cutoff of 50 years can potentially expand consideration for heart or heart-kidney transplantation options in patients with more comorbidities.To support this hypothesis, we describe further organ system improvements observed in our population below.

It is well known that post-transplant clinical outcomes in older patients greatly depend on the pretransplant selection and optimization of end-organ status.Baseline characteristics, including race, BMI,history of hypertension, prior LVAD or cardiac surgery, chronic kidney disease, and need for renal replacement therapies, play a significant role in posttransplant outcomes.[8,19,20]

Our center’s data highlights critical knowledge gaps that exist in the current field of solid organ transplantation for older recipients: (1) successful optimization of older recipients with tMCS support,over long durations (＞ 14 days), with Impella 5.5 and minimal hemolysis or device-related complication, (2) pre-transplant improvement in multi-organ function, and (3) Improving functional capacity while awaiting transplantation.

Pulmonary Hypertension

Our data also sheds light on the ability to safely transplant patients with moderate or greater pretransplant pulmonary hypertension (defined as a mean PA pressure of ＞ 35 mmHg) that may not be primary transplant candidates at other centers.This is an important finding given our group’s excellent 1-year post-transplant survival.The suggestion for considering a longer duration of Impella support to unmask previous non-responders or those not challenged with hemodynamic right heart catheterization could increase treatment options for this patient population (supplemental Table 1).This may underline the limitations in utilizing pulmonary vascular resistance as a relative or absolute contraindication for heart-only transplantation.

Chronic Renal Failure (Type-2 Cardiorenal Syndrome)

Renal function stabilization, recovery, or support for those with renal-replacement therapy before dual organ transplant was unique in our group.Within a small percentage of patients previously described by our group and presented internationally, we have seen evidence of renal recovery with Impella support in as few as 14 days.[21]The potential implications of obviating the need for dual organ transplantation are far-reaching and should be further evaluated.Postulated methods are increased cardiac outflow, improving type-2 cardiorenal pathophysiology.Other mechanisms to be considered include the improved renal venous decongestion and offloading of the splanchnic circulation—by way of right ventricular remodeling and pulmonary hyperten-sion reversal—that allows for improved creatinine clearance and filtration.We demonstrate the delicate balance between preload dependency and afterload sensitivity in Figure 5.

Figure 5 RV and LV modifiable factors.LV: left ventricle; RV: right ventricle.

Hemolysis

Prior experience with non-5.5-based Impella devices has clearly demonstrated an increased tendency for hemolysis.However, with Impella 5.5, we did not observe this in our institution.As outlined in Table 3, our LDH remains stable without significant spikes and correlates with relatively stable renal function.We did find a difference in hematocrit post-Impella placement that was significant (P＜ 0.001)however, the significance of this in patients with chronic renal disease is unclear.Systemic anticoagulant therapy and purge solution interactions may create an imbalance in the role of assessing hematocrit and platelet counts without other identifiable sources of bleeding.Our centers recently presented data highlights this potential, with further research needed to solidify this potential interaction.[22]

After the UNOS allocation change for heart transplant recipients in 2018, a more significant percentage of tMCS utilized comprises intra-aortic balloon pump (IABP) compared to Impella placement.[23,24]The limited increase in Impella use likely stems from prior experience, individual center practice patterns,or surgical comfort.As outlined in our introduction and based on nationally published data, the de-escalation of UNOS status for LVAD therapy has limited their use as BTT.Given the trend, and difficulty in comparison of this group to temporary support devices (due to length of support, selection bias, and institutional practices), we did not include them as part of our review in this study, focusing solely on patients with Impella 5.5 with Smart Assist utilized as BTT.Additionally, in patients with LVAD, the time at risk for a complication can be significantly higher than in the Impella population, rendering a one-toone comparison difficult and fraught with innate bias.

Our data suggest that using Impella 5.5 with Smart Assist as a bridge to transplant in older patients has acceptable survival, both to transplantation and at one year, and is associated with fewer device-related complications despite a similar axillary surgical approach.[25-28]

LIMITATIONS

As a single-center retrospective study, these outcomes are hypothesis-generating and may not reflect the results of other centers - but should be taken with merit given the large population of patients compared to other centers currently available with long-term outcome data.Due to the novelty of this device and practice adaptation, some patients’ postimplantation hemodynamic data are unavailable.Standardization of pre-and post-Impella implantation PA catheter use may improve over time, allowing for better data abstraction.

CONCLUSION

Our single-center data provides awareness for using the Impella 5.5 percutaneously placed axillary support device in older heart failure patients in cardiogenic shock as a bridge to transplantation.We also identify key areas of optimization that could have potential implications for renal recovery and pulmonary hypertension reversal.One-year survival outcomes after heart transplantation are excellent despite the older recipient’s age and prolonged pretransplant support.

DISCLOSURE

Rohan Goswami is a consultant for Abiomed butdoes not receive financial support for research.No other authors have financial disclosures.All listed authors performed a comprehensive data review,manuscript preparation, and final review before submission.Dr.Smit Paghdar and Dr.Smruti Desai contributed equally to the manuscript and should both be considered first author for this publication.