Abstract:
Background:
There is a paucity of data regarding durable LVAD outcomes in patients with chronic kidney disease (CKD) stage 3-5 and CKD stage 5 on dialysis (ESRD: end-stage renal disease).
NEW HERBAL FORMULATION FOR CHRONIC KIDNEY DISEASE (CKD)
Methods:
We conducted a retrospective study of Medicare beneficiaries with ESRD and a 5% sample of CKD with LVAD (2006 to 2018) to determine one-year outcomes utilizing the United States Renal Data System (USRDS) database. The LVAD implantation, comorbidities, and outcomes were identified using appropriate ICD-9 and ICD-10 codes.
Results:
We identified 496 CKD and 95 ESRD patients who underwent LVAD implantation. The ESRD patients were younger (59 vs 66 years; p <0.001), and had more Blacks (40% vs 24.6%; p=0.009), compared to the CKD group. One-year mortality (49.5% vs 30.9%; p <0.001) and index mortality (27.4% vs 16.7%; p=0.014) were higher in ESRD. Subgroup analysis showed significantly higher mortality in ESRD vs CKD 3 (49.5% vs 30.2%, adjusted p=0.009), but no significant difference in mortality between stage 3 vs 4/5 (30.2% vs 30.8%; adjusted p=0.941). There was no significant difference in secondary outcomes (bleeding, stroke, and sepsis/infection) during follow-up between the two groups.
Conclusions:
Patients with ESRD undergoing LVAD implantation had a significantly higher index and 1-year mortality compared to CKD patients.
Key Words: Left Ventricular Assist Device (LVAD), chronic kidney disease (CKD), End Stage renal/Kidney Disease (ESRD), Dialysis, Mortality
Abbreviations:
CKD: Chronic kidney disease
CMS: Centers for Medicare & Medicaid Services
CAPD: continuous ambulatory peritoneal dialysis
CCPD: continuous cyclic peritoneal dialysis
ESRD: End-stage renal disease
FGF-23: Fibroblast growth factor 23
KM curve: Kaplan Meier curve
KRT: kidney replacement therapy
LVAD: left ventricular assist device
MCS: Mechanical circulatory support device
NIDDK: National Institute of Diabetes and Digestive and Kidney Disease
OHT: Orthotopic heart transplant
TIA: Transient ischemic attack
USRDS: United States Renal Data System
Manuscript
Introduction:
In advanced heart failure patients, studies have shown improved survival and quality of life in the patients who undergo left ventricular assist device (LVAD) implantation compared to conventional medical therapy alone. [1-3] There are limited data and societal guidelines regarding LVAD utilization in patients with advanced CKD and ESRD. As such, the decision regarding durable LVAD implantation in these patients varies by program.[4] Retrospective and observational studies have shown that patients with pre-existing CKD and ESRD who underwent temporary and durable LVAD implantation, have worse outcomes when compared to normal kidney function. [5-7] There has been significant improvement in LVAD technology over the years, with the vast majority of contemporary LVAD implants involving continuous centrifugal flow (including magnetically levitating) impellers.[8] Consequently, patient outcomes involving these
more contemporary LVAD devices have improved compared to earlier LVAD devices involving predominately pulsatile or axial flow.[9] To address the above-mentioned knowledge gaps, we conducted this study to determine outcomes in advanced CKD and ESRD patients who underwent durable LVAD implantation utilizing the national United States Renal Data System (USRDS) database. Our main objectives were to determine 1) baseline characteristics of patients
with preexisting CKD and ESRD who underwent LVAD implantation; and 2) relative outcomes including mortality in CKD and ESRD patients during index LVAD implant admission and at one-year follow-up.
Methods:
Data Source:
The study cohort was derived from United States Renal Data System (USRDS) analytical files from 2006-2018, which was the most recent data available at the time of the inception of this study. The 31st of December 2017 was utilized as the last date for LVAD implant to include 1-year follow-up. USRDS collects, analyzes, and distributes information about CKD and ESRD in the United States in collaboration with the Centers for Medicare & Medicaid Services (CMS).[10] The USRDS is
funded directly by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK). The study was reviewed and approved by the institutional review board of the University of Kansas Medical Center and NIDDK. The interpretation and reporting of this data should not be seen as an official policy or interpretation of the US government.
Study Population:
For the ESRD group:
The ESRD in the USRDS database is defined as chronic renal failure requiring renal replacement treatment- dialysis or transplant to sustain life. Nephrologists complete a medical evidence form for all ESRD patients and certify the disease after which the patients are included in the CMS
ESRD database.
Our study only included those Medicare beneficiaries with ESRD who were dialysis dependent,≥ 18 years old, and underwent durable LVAD implantation between 2006 to 2017. We excluded patients who underwent kidney transplants before LVAD implants. The International Classification of Diseases, Ninth (ICD-9) and Tenth (ICD-10) procedure codes: 37.66 and 02HA0QZ were used to identify LVAD patients. This yielded an initial sample of 321 patients. Patients who are living outside the United States of America (USA) and don't have continuous Medicare AB coverage during 1-year follow-up (n=164), who received LVAD before the onset of ESRD (n=27), who received kidney transplant before or during LVAD implantation (n=20) and those who were not on continued dialysis (continued dialysis means that they were on dialysis for at least 60 days before LVAD implant; n=15) were excluded. This yielded a final sample size of 95 ESRD patients who were dependent on hemodialysis for at least 60 days or more before admission (Figure 1A).
For CKD group:
To incorporate CKD patients in the analysis, the data from CMS Medicare's 5% sample linked to the USRDS registry was used. The CMS utilizes one inpatient claim, or two outpatient claims with specified diagnosis codes to determine the presence of CKD in the USRDS database. If the patient has more than one claim with stage codes, the stage on the last claim was used. If the last claim has more than one stage, the highest stage was used. We included CKD patients who underwent durable LVAD implantation from 2006 to 2017. This yielded an initial sample size of 605 patients. Patients who are living outside the USA, don't have continuous Medicare AB coverage during 1 year follow-up, and who already developed ESRD before LVAD implantation (n=109) were excluded. This yielded a final sample size of 496 patients (Figure 1B). The baseline CKD staging information was collected from the index hospitalization. The baseline CKD staging data was available for 193 (39%) patients and out of these 91% of patients had advanced CKD (Stage 3 or higher).
Figure 1: Study Population. A) ESRD patients who underwent LVAD implantation and B) CKD patients who underwent LVAD implantation between 2006 and 2017.
Baseline characteristics and Comorbidities:
The demographics included were age, gender, and self-reported race (White, Black, Asian, or Others). The comorbidities included were non-ischemic cardiomyopathy, hypertension, diabetes mellitus, atherosclerotic heart disease, peripheral vascular disease, stroke/transient ischemic attack, and atrial fibrillation. The Center for Medicare and Medicaid Services (CMS) Form 2728, ICD-9-CM, and ICD-10-CM codes used to determine these comorbidities are provided in
the supplement file (supplement Table 1). The information regarding concomitant valvular surgeries during LVAD implant, length of stay, the primary cause of renal failure, dialysis type, and time on hemodialysis before the implant was also reported.
Follow-Up and Outcomes:
The patients were followed for 1 year post LVAD implantation. The primary outcome was all-cause mortality during one-year follow-up and the index admission. The one-year follow-up for the primary outcome was started from the admission date of the ndex hospitalization. We also did a sub-analysis to investigate all-cause mortality during the follow-up period post-hospital discharge excluding patients who underwent orthotopic heart transplant (OHT). As an exploratory analysis, we investigated 1-year mortality in OHT patients and also evaluated those 20 patients who had renal transplants before LVAD implant to determine how many of them got subsequent OHT during follow-up. We also performed a subanalysis to investigate index mortality outcomes in LVAD patients who underwent concomitant valve surgeries.
Other secondary outcomes included significant bleeding (bleeding requiring admission due to GI bleeding, choroidal hemorrhage, Orbit hemorrhage, Vitreous hemorrhage, hemorrhage in the optic sheath, hemarthrosis, hemoperitoneum,, and hemorrhage due to prosthetic device), pump thrombosis, hemorrhagic and ischemic stroke, sepsis, infection of LVAD within one-year followup. The one-year follow-up in secondary outcomes was started from the discharge date of the index
hospitalization. The ICD-9-CM and ICD-10-CM used to define these outcome variables are provided in the supplement file (Supplement Table 1). The subgroup analysis of patients with available CKD staging (n=193 patients) was done to determine the impact of CKD staging on the primary outcome.
Statistical Analysis:
Baseline characteristics and outcomes were compared between CKD and ESRD patients. Continuous variables were expressed as median with interquartile range [IQR] values and compared using a two-sample t-test or Wilcoxon rank sum test. Categoric variables were expressed as counts with percent of the total population and compared using Pearson's chi-squared test. The incidence of death was represented with cumulative incidence function (CIF) curves, treating heart transplants as a competing outcome. Gray's test was used to compare the incidence of death between ESRD with LVAD and CKD with LVAD and also compared the incidence of death between LVAD patients in CKD III, CKD IV/V, and ESRD. We used the Cox proportional hazards model to calculate hazard ratios for mortality comparing patients with CKD stage 4/5 and ESRD versus those with CKD 3. The model included adjustment for age, race, non-ischemic cardiomyopathy, hypertension, diabetes mellitus, atherosclerotic heart disease, peripheral vascular disease, and years of LVAD Implantation. Pearson's chi-squared test was used to compare the secondary outcomes. We further adjusted for multiple comparisons with a False Discovery Rate. We used the Cochran-Armitage Trend Test in these two groups to determine the trend of change in LVAD implantation over the years. We further conducted a Spearman correlation to see if these two groups share the same trend or not. All p-values were 2-sided, and a value of less than 0.05 was considered significant. Statistical Analysis was conducted using the SAS 9.4 (SAS Institute Inc, Cary, NC) software.
Results:
Baseline Characteristics:
Between 2006 to 2017, 95 Medicare beneficiaries with ESRD and 496 beneficiaries with CKD in the Medicare 5% sample underwent a durable LVAD. The details of baseline characteristics including comorbidities are shown in Table 1. The patients with ESRD were almost 7 years younger (59 vs 66 years; p=<0.0001) compared to the CKD group. African Americans were more common in the ESRD group (40.0% vs 24.6%; p=<0.01). The ESRD group had more patients with hypertension (90.5% vs 38.3%; p=<0.0001), peripheral vascular disease (13.7% vs 7.3%; p=0.04), atherosclerotic heart disease (62.1% vs 50.6%; p=0.04) and diabetes mellitus (48.4% vs 20.2%; p=<0.001). There were more patients with non-ischemic cardiomyopathy in the CKD group (50.0% vs 32.6%; p=<0.002). The most common valve repair or replacement was aortic valve in both ESRD (13.7%) and CKD (9.1%) patients. In ESRD, more patients underwent any surgical valve repair/replacement (28.4% vs 14.3%, p=<0.001) when compared to the CKD group during index LVAD admission. In ESRD, the major form of maintenance dialysis was hemodialysis
(84.2%) and very few on peritoneal dialysis. The median time on hemodialysis for our patients was 3.3 (IQR: 0.8-6.0) years. Hence, the majority of patients in our study were on long-standing hemodialysis before LVAD implantation. The percentage of LVAD implanted in the CKD group over the study years was: 74 (14.9%) in 2006-2009, 187 (37.7%) in 2010-2013, and 235 (47.4%) in 2014-2017 (p=0.06). Whereas in ESRD, LVAD implanted over study years were: 23 (24%) in 2006-2009, 36 (37.9%) in 2010-2013, and 36 (37.9%) in 2014-2017 (p=0.06). There was no significant change in the trend of LVAD implantation in patients with ESRD (11.3 per 1,000,000 patients in 2006 and 13.5 per 1,000,000 patients in 2017; Ptrend =0.910). The LVAD implantation in patients with CKD increased from 90.3 per 1,000,000 patients to 236 per 1,000,000 patients from 2006 to 2017 (Ptrend<0.001). The Spearman correlation showed that there is a mild positive correlation between ESRD and CKD with Spearman correlation coefficients: of 0.523 (p-value: 0.081). (supplement figure 1)
Table 1. Baseline Characteristics of LVAD patients with CKD and ESRD, 2006-2018
During index admission of LVAD implantation, 26 (27.4%) of patients died in the ESRD group and 83 (16.7%) of patients died in the CKD group. (Table 2a) Out of 496 total CKD patients, 33 patients required kidney replacement therapy (KRT) during index admission (any KRT type like continuous renal replacement therapy; continuous venovenous hemofiltration; continuous venovenous hemodialysis; continuous venovenous hemodiafiltration; intermittent hemodialysis were included). Out of those 33 CKD patients who required KRT during index admission, 21 (63.6%) died. Out of 463 CKD patients who did not require KRT during index admission, only 62 (13.4%) died. The mortality was significantly higher in CKD patients who required KRT (63.6% vs 13.4%; p<0.001) when compared to patients who did not require KRT.
We further analyzed those LVAD patients who underwent concomitant surgical valve repair or replacement during LVAD index admission. The ESRD patients who underwent any concomitant surgical valve (aortic, mitral, or tricuspid) repair or replacement had higher index mortality (44.4% vs 20.6%, p=0.02) compared to those who did not undergo valve surgery (details in supplement table 2). Similarly, in the CKD group, those patients who underwent any concomitant valve repair or replacement during index LVAD admission had higher mortality(33.8% vs 13.9%, p=<0.0001) as compared to those who did not (details in supplement table 3)
Table 2b. All-cause one-year mortality stratified according to CKD staging, 2006-2018
When stratified by CKD stage, there was no significant difference in mortality between CKD stages 3 vs 4/5 (30.2 % vs 30.8 %; adjusted p= 0.941) and ESRD patients compared to CKD stage 4/5 (49.5% vs 30.8%; adjusted p=0.071). There was significantly higher mortality in ESRD patients compared to CKD stage 3 (49.5% vs 30.2%; adjusted p=0.009) (Table 2b). The CIF curve showing the incidence of death and treating heart transplant as a competing outcome comparing
ESRD to CKD III to CKD IV/V LVAD recipients is shown in Figure 2B. The complement of the Kaplan–Meier (KM) survival estimate is provided in supplement figure 2b. The incidence of death using cumulative incidence function (CIF) curves for 2006 to 2018 (12-years outcome) comparing ESRD to CKD III to CKD IV/V group is shown in supplement figure 3b.
Figure 3. Forest plot of multivariable Cox proportional hazard model* *The model included adjustment for age, race, non-ischemic cardiomyopathy, hypertension,
diabetes mellitus, atherosclerotic heart disease, peripheral vascular disease, and years of LVAD Implantation
Secondary Outcomes:
In ESRD group, 12 (12.6%) and 49 (9.9%) patients in CKD group underwent OHT within 1 year of LVAD implantation (Table 3). In the ESRD group, all the patients who received OHT survived for 1 year post transplant. For the patients who received OHT in CKD group, less than 11 patients (14.3%) died during follow-up (per USRDS agreement for release of information, we were unable to report absolute values) [supplement Table 4]. We also investigated the 20 ESRD
patients who underwent renal transplant prior to or during LVAD implant admission (they were excluded from primary or secondary analysis as our focus in this study was ESRD patients on HD) and found that 25% out of these 20 patients underwent OHT within 1 year (supplement table 5).
There was no significant difference in secondary LVAD outcomes including significant bleeding (20.0% vs 16.1%, p=0.355), ischemic stroke (9.5% vs 9.3%; p=0.951), hemorrhagic stroke (3.2% vs 3.4%, p=0.894) pump thrombosis (4.2% vs 6.7%, p=0.368) and sepsis/infection (25.3% vs 18.8%, p=0.144) between ESRD vs CKD group during 1-year follow up (Table 3).
Table 3. Secondary outcomes in CKD and ESRD patients who underwent LVAD implantation, 2006- 2018
Discussion:
There are several noteworthy findings in this nationwide study of Medicare beneficiaries with CKD and ESRD. First, there was high 1-year mortality among CKD and ESRD patients who underwent LVAD implantation. Second, patients with ESRD who underwent LVAD implantation had significantly higher index and 1-year mortality when compared to patients with CKD. Third, the mortality among CKD patients who required KRT during index LVAD admission was higher compared to CKD patients who did not. Fourth, the CKD and ESRD patients who underwent concomitant surgical valve replacement or repair during index LVAD
admission had higher index mortality. Fifth, after utilizing multivariable cox proportional model,ESRD was an independent predictor of mortality.
The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) is a national database of FDA approved mechanical circulatory support devices. In their Eighth annual report which included patients from June 2006 to December 2016 and had predominant continuous flow axial devices, showed overall mortality of approximately 20% at 1 year. [11] It also showed, abnormal kidney function, especially pre-implant dialysis is a significant risk factor
for mortality (Hazard ratio of 3.29). In our study which only had CKD and ESRD patients, 1-year all-cause mortality was higher (49.5% in ESRD and 30.9% in CKD group) compared to overall all-cause 1-year mortality in Eighth annual INTERMACS report. In general, it is known that worsening kidney function (CKD and ESRD on maintenance dialysis) is associated with higher mortality as compared to patients with normal kidney function.[12] Hence, the one possible explanation for the higher mortality in our study can be underlying CKD and ESRD status of patients at time of LVAD implantation.
A prior study from the USRDS database included LVAD patients from 2003-2013 with median follow up of 762 days showed higher mortality in ESRD group (81.2%) compared to patients without ESRD (36.4%).[7] Unlike our study, this study included both temporary mechanical circulatory support devices (MCS) (ICD-9-CM 37.62 and 37.65) and durable LVAD. The temporary MCS devices are mostly utilized in dire circumstances like cardiogenic shock,refractory arrhythmias.[13] This may explain higher index mortality noted in their study (51.6%) compared to our study (27.4%) in ESRD group. Another study from USRDS database including ESRD patients from 2006-2014 who underwent LVAD implantation showed one-year mortality of 61.5%.[14] In this study, outcomes were not compared to CKD or non-ESRD patients. We only included durable LVAD patients, and our study includes most patients with newer generation centrifugal LVADs. Our study updates prior reports and confirms similar higher one year mortality among ESRD patients who underwent LVAD implantation. Our study also shows that in recent years 2014-17, the mortality in CKD patients has decreased as compared to prior years, this is most likely due to better patient selection, improvement in surgical techniques and better peri-operative management.
The mechanisms behind kidney dysfunction and worse outcomes in LVAD patients is poorly understood. In patients with kidney dysfunction there is decreased clearance of urea, uremic toxins, proteins like FGF-23 (Fibroblast growth factor 23) and Klotho, which all had been associated with increased cardiovascular events and mortality.[15-18] Studies have shown kidney dysfunction prior to LVAD implantation can lead to increased incidence of early right ventricular (RV) failure and increased heart failure hospitalizations.[19] Several studies have identified post implant RV failure as a risk factor for worse outcomes in LVAD patients.[20, 21] Ventricular-arterial coupling which is assessed as ratio between arterial elastance (E(a)) and endsystolic ventricular elastance (E(es)).[22] Ventricular-vascular coupling can be altered in patients with ESRD and is associated with increased mortality.[23, 24] ESRD carries a high risk of death
compared to CKD.[25] Above mentioned reasons may explain worse outcomes noted in LVAD recipients in ESRD population compared to CKD.
We found a high mortality during index LVAD admission in both CKD (17%) and ESRD on maintenance dialysis (27%) patients. On further sub-analysis, we found that CKD patients who required KRT during index admission had higher mortality compared to CKD patients who did not (63.6% vs 13.4%; p<0.001). We also found ESRD (on maintenance dialysis) status was independent predictor of mortality in patients undergoing LVAD implantation. In prior studies,not including LVAD patients, it is well known in nephrology literature that mortality among dialysis patients is higher than CKD patients. [27, 28] Our study also suggests that LVAD patients who require dialysis have higher mortality compared to CKD patients with LVAD. We found those LVAD patients (in both CKD and ESRD) who undergo concomitant valve surgeries have higher index mortality. Few prior studies had also shown higher in hospital mortality in LVAD patients who undergo concomitant valve surgeries, irrespective of their renal function.[29]
There were no major differences in adverse events (bleeding, infection, and stroke) between two groups during one-year follow up suggesting ESRD remains a major contributor to mortality independent of LVAD complications. Infection and bleeding were the most common adverse effects. The INTERMACS registry also showed that after bleeding, infection is the most common adverse in first 3 months and then most common adverse event thereafter.[11]
Per the Scientific statement for MCS devices, 2017, the durable MCS should be avoided in patients with irreversible kidney damage.[30] Each program has their own approach in selecting patients with underlying kidney disease for LVAD implantation. Based on our findings, we would like to stress the importance of careful selection of advanced CKD and ESRD patients for LVAD consideration. The Heart Failure Society of America Guidelines committee for stage D
heart failure patients recommends incorporating palliative team care approach for patients considered for MCS.[31] We also echo the incorporation of palliative team care and integrated team discussion prior to implantation of LVAD in this unique cohort. Our study results will not only aid physicians in decision making regarding utilization of LVAD therapies in CKD and ESRD group, but also aid in the end-of-life discussions with the family.
Limitations:
Even though our study represents most recent data available from USRDS national Medicare database regarding outcomes in durable LVAD devices, it has some important limitations. First, as it is based on administrative data, we are unable to determine details or types of implantable devices. Second, we were missing several key clinical parameters of preoperative patient illness that may have impacted mortality, including Intermacs profile, preoperative use of temporary
mechanical support, markers of frailty or cachexia. Additionally, we lacked information on preoperative and postoperative right heart function. Third, we were unable to find information on LVAD intent or indication like bridge to transplant, bridge to recovery or destination therapy which may impact mortality post LVAD implant. Fourth, we relied on diagnostic and procedure codes to determine the comorbities and outcomes. However, given inability to perform manual
review in administrative data, this approach had been utilized in prior studies. Fifth, median age of our population is >55 years hence generalizability of our results to younger population may be limited. Sixth, we were unable to find information on acute renal failure patients requiring hemodialysis awaiting to undergo LVAD implant.
Conclusion:
During 1-year follow-up, the ESRD patients on maintenance dialysis with LVAD had increased mortality when compared to CKD patients during index admission and during one-year followup. The CKD patients who required kidney replacement therapy during index admission had higher mortality compared to those who did not. LVADs in patients with advanced CKD and ESRD should only be considered after shared decision making between physicians, and their patients and may be best utilized in ESRD patients getting stabilized for expedited dual organ transplant.
Lay Summary:
Very few patients with end-stage renal disease (ESRD) on maintenance dialysis undergo LVAD implantation
Mortality among ESRD patients on maintenance dialysis who undergo LVAD implantation was significantly higher during 1-year follow-up when compared to chronic kidney disease
LVADs in patients with advanced CKD and ESRD on maintenance dialysis should only be considered after shared decision making between physicians, and their patients. We believe the incorporation of palliative team care and integrated team discussion prior to implantation of LVAD is crucial in this unique cohort of patients.
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