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The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes
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ORIGINAL ARTICLE
Heart, Lung and Circulation (2017) xx, 1–8 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2017.01.002
The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes
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Burhan Mohamedali, MD a*, Geetha Bhat, MD, PhD b a
Division of Cardiology, Rush University Medical Center, Chicago, IL, USA Division of Cardiology, Advocate Christ Medical Center, Oak Lawn, IL, USA
b
Received 13 October 2016; received in revised form 19 December 2016; accepted 3 January 2017; online published-ahead-of-print xxx
Background
Chronic kidney disease (CKD) is a known predictor for adverse outcomes in patients with advanced heart failure requiring left ventricular assist devices (LVADs). The effect of pre-LVAD glomerular filtration rate (GFR) on post-LVAD outcomes in CKD patients is not completely understood. Additionally, a subset of patients improve their GFR after LVAD placement. In this study we sought to determine the effects of preLVAD GFR on post-LVAD outcomes.
Methods
Two hundred and seventy patients with LVADs were enrolled. Patients were stratified based on a GFR cutoff of 60 mL/min/1.73 m2. Patients with preoperative GFR <60 were further divided into two sub groups based post-LVAD discharge GFR of 60. Post-LVAD major adverse effects were analysed.
Results
Patients with pre-implant GFR <60 had higher All cause mortality than patients with pre-implant GFR 60 (45% vs. 27%, p = 0.006). These patients also had higher incidence of early right ventricular failure and congestive heart failure hospitalisations. Kaplan Meier survival analysis confirmed poor survival in this group. When the subgroup analysis of patients in the GFR <60 cohort was performed, the above findings were heavily weighted towards patients who did not improve their GFR to 60 post-LVAD.
Conclusion
Pre-implant GFR is an important prognostic marker in LVAD patients. Patients with pre-implant GFR <60 are at higher risk of cardiovascular morbidity and mortality. Our findings suggest that the patients who do not improve their GFR post-LVAD are at the highest risk.
Keywords
LVAD GFR CKD Right ventricular failure Survival
Introduction Continuous flow left ventricular assist devices (LVADs) continue to be a standard of care for treatment of end stage heart failure [1]. However, chronic kidney disease (CKD) is a major source of morbidity and mortality in such patients [2]. Although much of the CKD can be attributable to cardiorenal syndrome (CRS) from advanced heart failure (ADHF), a
significant portion of patients have intrinsic renal dysfunction which is discovered during work-up for LVAD implantation [3–5]. Such patients are conventionally thought to be at high risk of adverse outcomes post-LVAD implantation, especially for worsening postoperative renal function and potential requirement for haemodialysis (HD) [6]. Although the exact cut-off renal parameter used for such prognosis is subject to
*Corresponding author at: Rush University Medical Center, Division of Cardiology, 1653 W. Harrison St, Chicago, IL 60612., Email: [email protected] © 2017 Published by Elsevier B.V. on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
Please cite this article in press as: Mohamedali B, Bhat G. The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes. Heart, Lung and Circulation (2017), http://dx.doi. org/10.1016/j.hlc.2017.01.002
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immense debate, many have advocated for the use of glomerular filtration rate (GFR) [7,8], blood urea nitrogen (BUN) [9,10], or serum creatinine [11,12] to evaluate risk on a patient-to-patient basis. Many ADHF patients undergo an extensive workup prior to LVAD implantation to evaluate candidacy. This workup includes: haemodynamic optimisation with diuretics, afterload reduction and the use of inotropic support. Such endeavours often correct the reversible cause of renal dysfunction in these patients. Patients with poor renal function post-optimisation are often considered to be at a higher baseline risk of adverse outcomes compared to their peers, who normalise their renal function [8,13,14]. In this study, we sought to determine the relationship between pre-LVAD implant GFR and post-LVAD outcomes. Additionally, since a subset of patients has been described, who after receiving LVADs appear to improve their renal function with an increase in GFR [15–17], we further analysed LVAD recipients who had a pre-implant GFR <60, but subsequently had an improved renal profile with a hospital discharge GFR 60, and compared them to patients with pre- and post-LVAD implant GFR of <60, and patients with pre- and post-LVAD GFR of 60.
29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
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Method
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In this single centre, retrospective, study, consecutive bridge to transplant (BTT) and destination therapy (DT) patients with were followed. Patients were stratified on the basis of immediate pre-LVAD implant (after haemodynamic optimisation) GFR cut-off of 60 mL/min/1.73m2. Glomerular filtration rate was estimated using the abbreviated CockcroftGault formula [18]. Three additional subgroups were created for subgroup analysis. Group I comprised patients with a pre- and post-implant GFR of <60. Group II consisted of preimplant GFR of <60, but subsequent improvement to 60 post-LVAD, and Group III comprised patients with pre- or post-LVAD GFR of 60. Post-implant GFR was defined as GFR at discharge after LVAD placement. Demographic information and baseline medical information at the time of LVAD placement was tabulated. This data included cardiac risk factors, prior cardiac history, haemodynamic and echocardiographic data on admission. PreLVAD laboratory parameters, as well as hospital discharge laboratory values were collected. Patients with a previous medical history of CKD on admission were labelled as having CKD information on post-LVAD major adverse outcomes including mortality, early right ventricular failure, hospitalisations for heart failure, gastrointestinal bleeding, stroke/ transient ischaemic attack, intracranial haemorrhage, haemolysis, thrombosis, pump exchanges and infections. Right ventricular failure was defined as post-LVAD right ventricular assist device requirement or need for inotropic support for two weeks or more. The Study was approved by the institutional review board at Advocate Christ Medical Center.
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Statistical Analysis
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Continuous variables were summarised as mean standard deviation (SD), while categorical variables were displayed as percentages. Shapiro-Wilkins tests were used to assess distribution of the data arrays. Mann-Whitney analysis and chisquare testing were employed to analyse differences between the groups, as appropriate. A p-value 0.05 was considered significant. Kaplan-Meier survival analysis was used to compare survival between the groups. Multivariate Cox regression survival analysis was performed. Data were analysed using SPSS 20 statistical software package (IBM, Chicago IL).
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Results
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Baseline Pre-LVAD Data
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A total of 270 consecutive post-LVAD patients were enrolled in the study. Bridge to transplant patients who were subsequently transplanted (38/270) or patients who transferred their care to other centres (8/270) were excluded from the analysis. Eleven patients with pre-implant GFR 60 but posttransplant GFR <60 were excluded, as the focus of the study was patients with pre-implant GFR <60 (Figure 1). The remaining 213 patients were included in this study.
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Stratification Based on Pre-Implant GFR Only
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The study cohort comprised 167 (78%) men and 46 (22%) women, with 190 (89%) DT patients. The cohort with
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270 BTT and DT LVAD Recipients
38 patients transplanted
8 Patients transferred care to other centres
224 Patients Enrolled
11 Patients with Pre-implant GFR ≥ 60, but postimplant GFR < 60
213 Patients Followed
Figure 1 Patient Selection. BTT: Bridge to Transplant, DT; Destination Therapy, GFR: Glomerular filtration rate[1_TD$IF].
Please cite this article in press as: Mohamedali B, Bhat G. The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes. Heart, Lung and Circulation (2017), http://dx.doi. org/10.1016/j.hlc.2017.01.002
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Table 1 Baseline Demographic Data.
Age (years)
Groups based osn pre-LVAD GFR
Groups based on pre/post-Implant GFR
Pre-LVAD
Pre-LVAD
Group I
Group II
Group III
Overall
GFR <60
GFR 60
(79/213)
(56/213)
(78/213)
p-Value
(135/213)
(78/213) Pre-LVAD
Pre-LVAD
Pre-LVAD
GFR <60
GFR <60
GFR 60
Discharge
Discharge
Discharge
GFR <60
GFR 60
GFR 60
<0.001
65(10)
63(12)
56(14)
76 (33%)
41(18%)
64 (30%)
0.39
19(8%)
15(7%)
14(7%)
64(11)
56(14)
Male
103(48%)
64(30%)
Female
32(15%)
14(7%)
p-value
<0.001
Gender 0.43
Race Caucasian
77(36%)
35(16%)
59(26%)
29(13%)
35(15%)
African-American
46(22%)
36(17%)
30(13%)
20(9%)
36(16%)
Hispanic
9(4%)
7(3%)
4(2%)
5(2%)
7(3%)
Other
3(1%)
0(0%)
0.25
2(1%)
2(1%)
0(0%)
0.18
6(2.8%) 129(61%)
17(8%) 61(29%)
<0.001
1(0.5%) 78 (37%)
5(2%) 51(24%)
17(8%) 61(29%)
<0.001
Indication BTT DT Height (cm)
174(10)
177(9)
0.02
175(10)
172(10)
177(9)
0.01
Weight (Kg)
84(20)
89(25)
0.12
85(20)
81(20)
89(25)
0.19
Body Mass Index (kg/m2)
28(6)
28(7)
0.52
28(6)
27(6)
28(7)
0.64
Coronary Artery Disease
90(67%)
42(54%)
0.08
64(67%)
36(64%)
42(54%)
0.18
Hypertension
91(67%)
51(65%)
0.77
63(66%)
39(70%)
51(65%)
0.86
Diabetes Mellitus Atrial Fibrillation
69(51%) 63(47%)
28(36%) 24(30%)
0.03 0.03
54(57%) 45(47%)
22(39%) 22(39%)
28(36%) 24(31%)
0.01 0.09
Ventricular Tachycardia
33(24%)
24(31%)
0.34
21(22%)
14(25%)
24(31%)
0.43
COPD
25(19%)
9(12%)
0.24
16(17%)
12(21%)
9(12%)
0.3
Obstructive Sleep Apnoea
28(21%)
18(23%)
0.73
22(10%)
10(18%)
18(23%)
0.71
Peripheral Artery Disease
18(13%)
8(10%)
0.67
16(17%)
5(9%)
8(10%)
0.27
Chronic Kidney Disease
105(78%)
26(33%)
<0.001
79(83%)
39(70%)
26(33%)
<0.001
Stroke
26(19%)
13(17%)
0.72
16(16%)
12(21%)
13(17%)
0.73
BTT: Bridge to transplant, COPD: Chronic obstructive pulmonary disease, DT: Destination therapy, GFR: Glomerular filtration rate, LVAD: Left ventricular assist device.
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pre-implant GFR <60 comprised 63% of patients (135/213), while those with pre-implant GFR 60 made up 37% (78/213). Demographic data is summarised in Table 1. Other than a statistically significant difference in mean age, prevalence of DM and atrial fibrillation, between the groups there were no significant differences between the cohorts. There was a higher prevalence of CKD in low GFR groups.
laboratory and haemodynamic data were largely similar in both groups (Table 2).
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Post-LVAD laboratory variables Post-LVAD laboratory data demonstrated a persistent decrease in renal function in patients with pre-LVAD GFR <60, (GFR 57 vs. 89, p < 0.001, BUN 27 vs 18, p < 0.001, and creatinine 1.4 vs 0.96, p < 0.001) (Table 2).
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Pre-implant laboratory and haemodynamic variables Baseline laboratory parameters revealed no statistical difference between the two groups except for a higher BUN (31 vs. 19, p < 0.001), a higher creatinine (1.66 vs. 1.04, p < 0.001) and a lower GFR (44 vs 80, p < 0.001) in patients with preimplant GFR <60 (Table 2). Furthermore, pre-LVAD
Stratification Based on Pre- and Post-Implant GFR
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The cohort was also divided into three subgroups. Group I (79/213, 37%) comprised patients with pre- and post-implant GFR of <60. Group II (56/213, 26%) comprised patients with
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Please cite this article in press as: Mohamedali B, Bhat G. The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes. Heart, Lung and Circulation (2017), http://dx.doi. org/10.1016/j.hlc.2017.01.002
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Table 2 Groups based on pre-LVAD GFR
Groups based on pre/post-Implant GFR
Pre-LVAD
Pre-LVAD
Group I
Group II
Group III
Overall
GFR <60
GFR 60
(79/213)
(56/213)
(78/213)
p-value
(135/213)
(78/213) Pre-LVAD
Pre-LVAD
Pre-LVAD
GFR <60
GFR <60
GFR 60
Discharge
Discharge
Discharge
GFR <60
GFR 60
GFR 60
p-value
Sodium (mg/dL)
134(4)
135(3)
0.31
135(4)
134(4)
135(3)
0.31
BUN (mg/dL)
31(17)
19(9)
<0.001
32(16)
29(17)
19(9)
<0.001 <0.001
Creatinine (mg/dL)
1.66(0.41)
1.04(0.19)
<0.001
1.75(0.47)
1.51(0.34)
1.04(0.19)
GFR (mL/min/1.73m2)
44(10)
80(18)
<0.001
43(13)
48(8)
80(18)
<0.001
BNP (pg/dL) AST units/L
524(261-1030) 25(21-35)
463(218-796) 32(23-46)
0.25 0.02
505(208-997) 28(22-37)
587(331-1197) 25(21-30)
463(218-796) 32(23-46)
0.2 0.008
ALT units/L
35(27-43)
42(29-59)
0.006
36(29-48)
31(27-40)
42(29-59)
0.006
Albumin (gm/dL)
3.0(0.5)
3.0(0.4)
0.63
3.0(0.5)
3.0(0.5)
3.0(0.4)
0.75
T.Bili (mg/dL)
1.0(0.7)
1.1(0.8)
0.64
1.1(0.7)
1.1(0.7)
1.1(0.8)
0.94
INR
1.27(0.34)
1.19(0.22)
0.06
1.26(0.41)
1.28(0.27)
1.19(0.22)
0.08
Haemoglobin (gm/dL)
11.1(1.7)
11.6(1.9)
0.08
11.3(1.7)
11.5(1.6)
11.6(1.9)
0.29
CVP (mmHg)
12(5)
11(6)
0.82
12(6)
11(5)
11(6)
0.78
SPAP (mmHg) DPAP (mmHg)
53(13) 25(7)
49(15) 25(8)
0.11 0.83
50(14) 25(6)
54(13) 25(8)
49(15) 25(8)
0.14 0.67
MPAP (mmHg)
35(8)
34(10)
0.43
34(8)
36(9)
34(10)
0.45
PCWP (mmHg)
23(8)
23(8)
0.67
22(7)
24(9)
23(8)
0.47
Cardiac Output (L/min)
4.5(1.5)
4.7(1.5)
0.27
4.8(1.8)
3.9(1.1)
4.7(1.5)
0.002
Cardiac Index (L/min/m2)
2.3(0.7)
2.3(0.7)
0.74
2.4(0.9)
2.1(0.5)
2.3(0.7)
0.04
SVR (dynes sec/cm5)
1303(456)
1316(460)
0.85
1192(460)
1428(425)
1316(460)
0.005
PVR (WU)
2.9(1.5)
2.9(1.8)
0.76
2.8(1.5)
3.2(1.6)
2.9(1.8)
0.23
Systolic BP (mmHg) Diastolic BP (mmHg)
108(15) 63(12)
106(19) 69(13)
0.28 0.001
109(16) 61(13)
106(13) 63(12)
106(19) 69(13)
0.4 0.003
Mean BP (mmHg)
77(11)
82(12)
0.02
77(12)
77(11)
82(12)
0.07
Heart Rate (BPM)
82(15)
89(18)
0.01
83(16)
84(17)
89(18)
0.11
LVEDD (cm)
67 11
69 11
0.28
64 10
71 12
69 11
0.26
LVESD (cm)
60 12
63 10
0.11
57 12
64 14
63 10
0.15
LVEF (%)
20 8
18 7
0.04
21 8
18 7
18 7
0.35
ALT: Alanine aminotransferase, AST: aspartate aminotransferase, BNP: Beta natriuretic peptide, BP: Blood pressure, BUN: Blood urea nitrogen, CVP: central venous pressure, DPAP: Diastolic pulmonary artery pressure, GFR: Glomerular filtration rate, INR: International normalised ratio: LVAD: Left ventricular assist device, LVEDD: Left ventricular end diastolic dimension, LVEF: Left ventricular ejection fraction, LVESD: Left ventricular end systolic dimension, MPAP: mean pulmonary artery pressure, PCWP: pulmonary capillary wedge pressure, PVR: pulmonary vascular resistance, SPAP: Systolic pulmonary artery pressure, SVR: Systemic Vascular Resistance, T.Bili: Total bilirubin.
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pre-implant GFR of <60, but subsequent post-LVAD GFR of 60, while Group III (78/213, 37%) contained patients who maintained their GFR 60 both before and after LVAD implantation. Baseline demographic information is summarised in Table 1. Pre-implant laboratory and haemodynamic variables Pre-implant data, as seen in Table 2, further confirmed worse renal parameters (blood urea nitrogen (BUN), creatinine (Cr), and GFR) in groups I and II compared to Group III. The mean pre-LVAD GFR in Group I was 43 13, compared to a mean
GFR of 48 8 in Group II and a mean GFR of 80 18 in Group III. Baseline AST and ALT were also statistically significantly different between the three groups (Table 2). Baseline preLVAD haemodynamic information is summarised in Table 2.
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Post LVAD laboratory variables There were statistically significant differences in discharge renal parameters between the three groups.(BUN: 31 vs. 22 vs. 18, p < 0.001, Cr: 1.66 vs.1.04 vs.0.96, p < 0.001, GFR: 45 vs.74 vs.89, p < 0.0001, in Group I, II and III respectively) (Table 2).
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Please cite this article in press as: Mohamedali B, Bhat G. The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes. Heart, Lung and Circulation (2017), http://dx.doi. org/10.1016/j.hlc.2017.01.002
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Table 3 Groups based on pre-LVAD GFR
Groups based on pre/post-Implant GFR
Pre-LVAD
Pre-LVAD
Group I
Group II
Group III
Overall
GFR <60
GFR 60
(79/213)
(56/213)
(78/213)
p-value
(135/213)
(78/213) Pre-LVAD
Pre-LVAD
Pre-LVAD
GFR <60
GFR <60
GFR 60
Discharge
Discharge
Discharge
GFR <60
GFR 60
GFR 60
p-value
DC Sodium (mg/dL)
135(3)
135(14)
0.28
136(3)
136(3)
135(14)
DC BUN (mg/dL)
27(13)
18(8)
<0.001
31(14)
22(8)
18(8)
0.88 <0.001
DC Creatinine (mg/dL)
1.4(0.5)
0.96(0.21)
<0.001
1.66(0.45)
1.04(0.22)
0.96(0.21)
<0.001
DC GFR (mL/min/1.73m2)
57(19)
89(22)
<0.001
45(10)
74(15)
89(22)
<0.001
DC BNP (pg/dL) DC AST units/L
403(243-654) 41(25-45)
347(216-524) 33(26-45)
0.04 0.54
408(269-666) 34(26-45)
380(213-552) 32(25-47)
347(216-524) 33(26-45)
0.06 0.82
DC ALT units/L
46(31-48)
41(31-56)
0.81
39(32-49)
36(29-46)
41(31-56)
0.34
DC Albumin (gm/dL)
2.8(0.4)
3.0(0.5)
0.62
2.9(0.3)
2.7(0.4)
3.0(0.5)
0.11
DC T.Bili (mg/dL)
0.91(0.46)
0.85(0.47)
0.35
0.99(0.5)
0.8(0.3)
0.85(0.47)
0.06
DC Haemoglobin (gm/dL)
9.9(1.1)
9.6(1.3)
0.05
10(1.2)
9.9(1.1)
9.6(1.3)
0.05
ALT: Alanine aminotransferase, AST: aspartate aminotransferase, BNP: Beta natriuretic peptide, BUN: Blood urea nitrogen, GFR: Glomerular filtration rate, INR: International normalised ratio: LVAD: Left ventricular assist device, T.Bili: Total bilirubin.
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Post-LVAD Outcomes
Discussion
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Post-LVAD outcomes based on pre-implant GFR only The incidences of early right ventricular failure were higher in patients in the low GFR group, (47 (34%) vs 15 (19%), p = 0.02) (Table 3). The incidence of stroke or transient ischaemic events and heart failure hospitalisations was significantly higher in patients with GFR <60, 25 (18%) vs. 5(6%), p = 0.01, and 33(24%) vs 5(6%), p = 0.001, respectively (Table 3). All cause mortality was higher in the low GFR group compared to the control cohort (45% vs 27%, p = 0.006). Kaplan-Meier survival analysis further confirmed our findings, indicating a statistically significantly higher survival in patients with higher GFR (mean survival 1460 vs.1846 days log rank p = 0.01) (Figure 2).
Renal impairment is often considered a risk factor for adverse outcomes in heart failure patients requiring advanced therapies [8,19]. However, the degree of impairment that may lead to adverse outcomes in congestive heart failure patients is often a subject of debate. Imamura et al. identified pre-LVAD serum creatinine as a better predictor of adverse outcomes than BUN or GFR [20]. In non-LVAD heart failure studies,
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Post-LVAD outcomes based on pre- and post-implant GFR Major outcomes are summarised in Table 3. There was a statistically significantly higher rate of early right ventricular failure in Group I, 28(35%) vs. Group II 19(34%) vs. Group III 15(19%), p = 0.05. Similarly, heart failure hospitalisations were higher in the low GFR group as well (Group I: 23 (29%) vs. Group II:10(18%) vs. Group III: 5(6%), p = 0.001). Overall incidence of strokes was statistically significantly higher in Groups I and II (Table 3). All cause mortality was statistically significantly higher in Group I compared to the other two groups, (51% vs.38% vs. 27%, p = 0.009) (Table 3). Kaplan Meier analysis further confirmed this observation, with a mean survival of 1331 days in Group 1, vs.1690 days in Group II, and 1846 days in Group III, log rank p-value = 0.035 (Figure 3).
Figure 2 Kaplan Meier-Survival Plot of the Entire Cohort stratified by GFR 60 and GFR <60. GFR: Glomerular filtration rate[1_TD$IF].
Please cite this article in press as: Mohamedali B, Bhat G. The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes. Heart, Lung and Circulation (2017), http://dx.doi. org/10.1016/j.hlc.2017.01.002
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Figure 3 Kaplan Meier Survival between the three groups. GFR: Glomerular filtration rate[1_TD$IF][2.
190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225
BUN has often emerged as a strong predictor of morbidity and mortality [10,19,21]. Alternatively, other studies have demonstrated GFR, due to its ability to account for patients age, sex and race, is strongly associated with adverse outcomes [22–24]. For every 10 ml/min reduction in GFR, it is thought to increase one year mortality by 15% [25]. Many LVAD centres utilise an extensive work-up to determine LVAD eligibility prior to implantation. However, the exact cut-off value for GFR below which an LVAD should not be implanted is poorly understood. Although end stage renal disease and severely reduced renal function often leads to disqualification for LVAD candidacy [26], patients with moderately and severely reduced renal function based on GFR often fall into a grey zone where objective evaluation is not well established. Low GFR as a marker for adverse outcomes in decompensated heart failure is well known. Similarly, Kirklin et al. demonstrated worse outcomes in patients post-LVAD based on CKD staging stratified by GFR [8]. Other studies have demonstrated similar mortality findings with post-LVAD renal failure [7,27]. The National Kidney foundation (NKF) distinguishes mild from moderate renal impairment on the basis of GFR cut-off point of 60 mL/min/1.73 m2 [18]. In this study, we divided our cohort into two groups based on this definition to produce a cohort of patients with normal/mildly impaired renal function vs. patients with moderate/severely reduced renal function. We also sub-divided our cohort into three subgroups based on post-LVAD GFR recovery in accordance with the National Kidney Foundation’s definition. Our subgroups were mainly driven by an interest to analyse the subset of LVAD population who do not completely reverse their renal dysfunction during pre-LVAD evaluation and optimisation, but subsequently improve their renal function to GFR 60 after LVAD implantation. The physiological relationship between low GFR and worse outcomes is not well understood. The increased
incidence of early RVF in patients with low GFR was surprising, especially since haemodynamic profiles did not demonstrate any major differences between the two groups (Table 2) that could have suggested an increased risk of early right ventricular failure (RVF) in the low GFR cohort. Right ventricular failure is a well-known risk factor for postoperative mortality, morbidity, and increased length of stay [28– 30]. Whether renal failure precipitates RVF or vice versa is not well understood; however, our data suggests that renal failure may predispose patients to early RVF. The observation has also been previously reported [31]. The incidence of congestive heart failure hospitalisations was statistically higher in the study group, and may be due to late RVF in an LVAD supported left ventricle (Table 4). A gradual volume overload state from impaired renal function and increased flow to the right ventricle from the LVAD supported left ventricle may cause gradual development right ventricular dysfunction. However, the putative mechanism that may predispose this cohort to late RVF remains unknown. There were higher incidences of strokes or transient ischaemic attacks in the low GFR group. Chronic kidney disease is a well-known risk factor for stroke and it is mainly thought to be a result of increased comorbidities that may predispose patients to a higher risk of events [32]. Although this may be true in our population, whether low GFR predisposes patients at a higher risk of strokes is poorly understood. However, in a small study by Morgan et al., analysing the predictors of postoperative strokes in patients with LVAD, renal insufficiency was not a factor for incidences of strokes [33]. Similarly, Boyle et al. investigated over 900 LVAD patients and did not demonstrate serum Cr or BUN to be predictors of strokes [34]. A multivariate analysis of our data indicated that, even after controlling for diabetes and atrial fibrillation, pre-implant GFR <60 was an independent predictor of strokes (OR 3.84 (95% CI: 1.38–10.71, p = 0.01). Our findings reveal that further analysis on this matter is warranted. Our study is unique in the sense that it not only stratified patients by pre-implant GFR, but further divided the cohort based on discharge GFR. To the best of our knowledge, this is the first study to analyse this population. Our subgroup analysis examined the special sub-set of patients who had a pre-implant GFR <60 but subsequently improved their GFR to 60 (Group II). Mortality was higher in Group I compared to Group II and III (51% vs. 38% vs. 27%, p = 0.009).
226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 Q4
261 262 263 264 265 266 267 268 269 270 271 272
Limitations
273
This was a single centre, retrospective study utilising chart review and hence was subject to limitations inherent to the study design. The sample size was relatively small. Only DT patients and BTT patients who did not undergo transplantation were enrolled in this study and there was a predominance of male patients. Patients who transferred their care to
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Please cite this article in press as: Mohamedali B, Bhat G. The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes. Heart, Lung and Circulation (2017), http://dx.doi. org/10.1016/j.hlc.2017.01.002
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LVADs and GFR
Table 4 Morbidity and mortality in the three groups. Groups based on pre-LVAD GFR Pre-LVAD
Pre-LVAD
GFR <60
GFR 60
(135/213)
(78/213)
Groups based on pre/post-Implant GFR P-value
Group I
Group II
Group III
overall
(79/213)
(56/213)
(78/213)
p-Value
Pre-LVAD
Pre-LVAD
Pre-LVAD
GFR <60
GFR <60
GFR 60
Discharge
Discharge
Discharge
GFR <60
GFR 60
GFR 60
LVAD Infections
45(33%)
25(32%)
0.88
27 (34%)
18(32%)
25(32%)
0.95
Non LVAD infections
34(25%)
13(17%)
0.17
19(24%)
15(27%)
13(17%)
0.33
Gl Bleed
32(24%)
25(32%)
0.2
24(30%)
8(14%)
25(32%)
0.06
Non GI bleeding
13(10%)
4(4%)
0.3
9(11%)
4(7%)
4(5%)
0.34
LVAD Thrombosis Haemolysis
8(6%) 8(6%)
4(5%) 6(8%)
0.99 0.78
4(5%) 5(6%)
4(7%) 3(5%)
4(5%) 6(8%)
0.85 0.86
Stroke/TIA
25(18%)
5(6%)
0.01
14(18%)
11(20%)
5(6%)
0.05
ICH
8(6%)
5(6%)
1
5(6%)
3(5%)
5(6%)
0.96
CHF Hospitalisations
33(24%)
5(6%)
0.001
23(29%)
10(18%)
5(6%)
0.001
VT
16(12%)
11(14%)
0.67
7(9%)
9(16%)
11(14%)
0.41
Atrial Arrhythmia
4(3%)
2(3%)
1
1(1%)
3(5%)
2(3%)
0.36
Early RV Failure
47(34%)
15(19%)
0.02
28(35%)
19(34%)
15(19%)
0.05
All Cause Mortality
61(45%)
21(27%)
0.006
40(51%)
21(38%)
21(27%)
0.009
CHF: Congestive heart failure, GI: gastrointestinal, GFR: Glomerular filtration rate, ICH: Intracranial haemorrhage LVAD: Left ventricular assist device, RV: Right ventricular, TIA: transient ischaemic attack, VT: Ventricular tachycardia.
280 281 282 283 284 285 286 287 288
other centres were excluded from the analysis. Eleven patients with preoperative GFR 60, but postoperative <60 were excluded from the study to preserve the integrity of our secondary analysis. However, when those 11 patients were included in the statistical analysis, no changes in the overall outcomes reported above were noted. Despite these limitations, we believe this study offers important new information and furthers clinical awareness of pre-LVAD GFR as a prognostic tool for adverse outcomes post-LVAD placement.
289
Clinical Perspective
290
299
Our findings suggest that patients undergoing a work-up for LVAD implantation, after optimisation of haemodynamic and loading conditions, can be risk stratified based on a preimplant GFR of <60. Furthermore, even if patients with preLVAD GFR <60 improve their GFR to greater than 60 postLVAD, these patients continue to have similar morbidity and mortality compared to patients who do not improve their postLVAD GFR to greater than 60. These findings suggest that preimplant GFR, and not post-implant GFR, is a better predictor of adverse outcomes after LVAD placement.
300
Conclusion
301
Patients with GFR <60, are at increased risk of adverse outcomes post-LVAD placement, particularly early RVF, CHF
291 292 293 294 295 296 297 298
302
hospitalisations and incidence of stroke or TIA compared to patients with pre-LVAD GFR 60. Survival in this group was lower than the control group. When the patients with preimplant GFR <60 were further divided into the subgroup of patients who either improved their GFR to 60 post-LVAD placement or had a persistent low GFR of <60 post-LVAD implantation and were compared to their peers with preimplant GFR >60, it appeared that most of the adverse outcomes were driven by patients who had persistently low GFR post-LVAD. Glomerular filtration rate can be employed as a quick and easy tool for rapid risk stratification for patients with increased risk of morbidity and mortality after LVAD implantation.
303
References
316
304 305 306 307 308 309 310 311 312 313 314 315
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HLC 2290 1–8
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ORIGINAL ARTICLE
Heart, Lung and Circulation (2017) xx, 1–8 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2017.01.002
The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes
1 2 3 4 5
6 7 8 9 10
11 12 13 14 15 16 17 18 19
Q1
Burhan Mohamedali, MD a*, Geetha Bhat, MD, PhD b a
Division of Cardiology, Rush University Medical Center, Chicago, IL, USA Division of Cardiology, Advocate Christ Medical Center, Oak Lawn, IL, USA
b
Received 13 October 2016; received in revised form 19 December 2016; accepted 3 January 2017; online published-ahead-of-print xxx
Background
Chronic kidney disease (CKD) is a known predictor for adverse outcomes in patients with advanced heart failure requiring left ventricular assist devices (LVADs). The effect of pre-LVAD glomerular filtration rate (GFR) on post-LVAD outcomes in CKD patients is not completely understood. Additionally, a subset of patients improve their GFR after LVAD placement. In this study we sought to determine the effects of preLVAD GFR on post-LVAD outcomes.
Methods
Two hundred and seventy patients with LVADs were enrolled. Patients were stratified based on a GFR cutoff of 60 mL/min/1.73 m2. Patients with preoperative GFR <60 were further divided into two sub groups based post-LVAD discharge GFR of 60. Post-LVAD major adverse effects were analysed.
Results
Patients with pre-implant GFR <60 had higher All cause mortality than patients with pre-implant GFR 60 (45% vs. 27%, p = 0.006). These patients also had higher incidence of early right ventricular failure and congestive heart failure hospitalisations. Kaplan Meier survival analysis confirmed poor survival in this group. When the subgroup analysis of patients in the GFR <60 cohort was performed, the above findings were heavily weighted towards patients who did not improve their GFR to 60 post-LVAD.
Conclusion
Pre-implant GFR is an important prognostic marker in LVAD patients. Patients with pre-implant GFR <60 are at higher risk of cardiovascular morbidity and mortality. Our findings suggest that the patients who do not improve their GFR post-LVAD are at the highest risk.
Keywords
LVAD GFR CKD Right ventricular failure Survival
Introduction Continuous flow left ventricular assist devices (LVADs) continue to be a standard of care for treatment of end stage heart failure [1]. However, chronic kidney disease (CKD) is a major source of morbidity and mortality in such patients [2]. Although much of the CKD can be attributable to cardiorenal syndrome (CRS) from advanced heart failure (ADHF), a
significant portion of patients have intrinsic renal dysfunction which is discovered during work-up for LVAD implantation [3–5]. Such patients are conventionally thought to be at high risk of adverse outcomes post-LVAD implantation, especially for worsening postoperative renal function and potential requirement for haemodialysis (HD) [6]. Although the exact cut-off renal parameter used for such prognosis is subject to
*Corresponding author at: Rush University Medical Center, Division of Cardiology, 1653 W. Harrison St, Chicago, IL 60612., Email: [email protected] © 2017 Published by Elsevier B.V. on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
Please cite this article in press as: Mohamedali B, Bhat G. The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes. Heart, Lung and Circulation (2017), http://dx.doi. org/10.1016/j.hlc.2017.01.002
20 21 Q2 22
23 24 25 26 27
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2
28
B. Mohamedali, G. Bhat
immense debate, many have advocated for the use of glomerular filtration rate (GFR) [7,8], blood urea nitrogen (BUN) [9,10], or serum creatinine [11,12] to evaluate risk on a patient-to-patient basis. Many ADHF patients undergo an extensive workup prior to LVAD implantation to evaluate candidacy. This workup includes: haemodynamic optimisation with diuretics, afterload reduction and the use of inotropic support. Such endeavours often correct the reversible cause of renal dysfunction in these patients. Patients with poor renal function post-optimisation are often considered to be at a higher baseline risk of adverse outcomes compared to their peers, who normalise their renal function [8,13,14]. In this study, we sought to determine the relationship between pre-LVAD implant GFR and post-LVAD outcomes. Additionally, since a subset of patients has been described, who after receiving LVADs appear to improve their renal function with an increase in GFR [15–17], we further analysed LVAD recipients who had a pre-implant GFR <60, but subsequently had an improved renal profile with a hospital discharge GFR 60, and compared them to patients with pre- and post-LVAD implant GFR of <60, and patients with pre- and post-LVAD GFR of 60.
29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
51
Method
52
In this single centre, retrospective, study, consecutive bridge to transplant (BTT) and destination therapy (DT) patients with were followed. Patients were stratified on the basis of immediate pre-LVAD implant (after haemodynamic optimisation) GFR cut-off of 60 mL/min/1.73m2. Glomerular filtration rate was estimated using the abbreviated CockcroftGault formula [18]. Three additional subgroups were created for subgroup analysis. Group I comprised patients with a pre- and post-implant GFR of <60. Group II consisted of preimplant GFR of <60, but subsequent improvement to 60 post-LVAD, and Group III comprised patients with pre- or post-LVAD GFR of 60. Post-implant GFR was defined as GFR at discharge after LVAD placement. Demographic information and baseline medical information at the time of LVAD placement was tabulated. This data included cardiac risk factors, prior cardiac history, haemodynamic and echocardiographic data on admission. PreLVAD laboratory parameters, as well as hospital discharge laboratory values were collected. Patients with a previous medical history of CKD on admission were labelled as having CKD information on post-LVAD major adverse outcomes including mortality, early right ventricular failure, hospitalisations for heart failure, gastrointestinal bleeding, stroke/ transient ischaemic attack, intracranial haemorrhage, haemolysis, thrombosis, pump exchanges and infections. Right ventricular failure was defined as post-LVAD right ventricular assist device requirement or need for inotropic support for two weeks or more. The Study was approved by the institutional review board at Advocate Christ Medical Center.
53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81
Q3
Statistical Analysis
82
Continuous variables were summarised as mean standard deviation (SD), while categorical variables were displayed as percentages. Shapiro-Wilkins tests were used to assess distribution of the data arrays. Mann-Whitney analysis and chisquare testing were employed to analyse differences between the groups, as appropriate. A p-value 0.05 was considered significant. Kaplan-Meier survival analysis was used to compare survival between the groups. Multivariate Cox regression survival analysis was performed. Data were analysed using SPSS 20 statistical software package (IBM, Chicago IL).
83
Results
93
Baseline Pre-LVAD Data
94
A total of 270 consecutive post-LVAD patients were enrolled in the study. Bridge to transplant patients who were subsequently transplanted (38/270) or patients who transferred their care to other centres (8/270) were excluded from the analysis. Eleven patients with pre-implant GFR 60 but posttransplant GFR <60 were excluded, as the focus of the study was patients with pre-implant GFR <60 (Figure 1). The remaining 213 patients were included in this study.
95
Stratification Based on Pre-Implant GFR Only
103
The study cohort comprised 167 (78%) men and 46 (22%) women, with 190 (89%) DT patients. The cohort with
105
270 BTT and DT LVAD Recipients
38 patients transplanted
8 Patients transferred care to other centres
224 Patients Enrolled
11 Patients with Pre-implant GFR ≥ 60, but postimplant GFR < 60
213 Patients Followed
Figure 1 Patient Selection. BTT: Bridge to Transplant, DT; Destination Therapy, GFR: Glomerular filtration rate[1_TD$IF].
Please cite this article in press as: Mohamedali B, Bhat G. The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes. Heart, Lung and Circulation (2017), http://dx.doi. org/10.1016/j.hlc.2017.01.002
84 85 86 87 88 89 90 91 92
96 97 98 99 100 101 102
104 106
HLC 2290 1–8
3
LVADs and GFR
Table 1 Baseline Demographic Data.
Age (years)
Groups based osn pre-LVAD GFR
Groups based on pre/post-Implant GFR
Pre-LVAD
Pre-LVAD
Group I
Group II
Group III
Overall
GFR <60
GFR 60
(79/213)
(56/213)
(78/213)
p-Value
(135/213)
(78/213) Pre-LVAD
Pre-LVAD
Pre-LVAD
GFR <60
GFR <60
GFR 60
Discharge
Discharge
Discharge
GFR <60
GFR 60
GFR 60
<0.001
65(10)
63(12)
56(14)
76 (33%)
41(18%)
64 (30%)
0.39
19(8%)
15(7%)
14(7%)
64(11)
56(14)
Male
103(48%)
64(30%)
Female
32(15%)
14(7%)
p-value
<0.001
Gender 0.43
Race Caucasian
77(36%)
35(16%)
59(26%)
29(13%)
35(15%)
African-American
46(22%)
36(17%)
30(13%)
20(9%)
36(16%)
Hispanic
9(4%)
7(3%)
4(2%)
5(2%)
7(3%)
Other
3(1%)
0(0%)
0.25
2(1%)
2(1%)
0(0%)
0.18
6(2.8%) 129(61%)
17(8%) 61(29%)
<0.001
1(0.5%) 78 (37%)
5(2%) 51(24%)
17(8%) 61(29%)
<0.001
Indication BTT DT Height (cm)
174(10)
177(9)
0.02
175(10)
172(10)
177(9)
0.01
Weight (Kg)
84(20)
89(25)
0.12
85(20)
81(20)
89(25)
0.19
Body Mass Index (kg/m2)
28(6)
28(7)
0.52
28(6)
27(6)
28(7)
0.64
Coronary Artery Disease
90(67%)
42(54%)
0.08
64(67%)
36(64%)
42(54%)
0.18
Hypertension
91(67%)
51(65%)
0.77
63(66%)
39(70%)
51(65%)
0.86
Diabetes Mellitus Atrial Fibrillation
69(51%) 63(47%)
28(36%) 24(30%)
0.03 0.03
54(57%) 45(47%)
22(39%) 22(39%)
28(36%) 24(31%)
0.01 0.09
Ventricular Tachycardia
33(24%)
24(31%)
0.34
21(22%)
14(25%)
24(31%)
0.43
COPD
25(19%)
9(12%)
0.24
16(17%)
12(21%)
9(12%)
0.3
Obstructive Sleep Apnoea
28(21%)
18(23%)
0.73
22(10%)
10(18%)
18(23%)
0.71
Peripheral Artery Disease
18(13%)
8(10%)
0.67
16(17%)
5(9%)
8(10%)
0.27
Chronic Kidney Disease
105(78%)
26(33%)
<0.001
79(83%)
39(70%)
26(33%)
<0.001
Stroke
26(19%)
13(17%)
0.72
16(16%)
12(21%)
13(17%)
0.73
BTT: Bridge to transplant, COPD: Chronic obstructive pulmonary disease, DT: Destination therapy, GFR: Glomerular filtration rate, LVAD: Left ventricular assist device.
107 108 109 110 111 112 113 114 115 116 117 118 119
pre-implant GFR <60 comprised 63% of patients (135/213), while those with pre-implant GFR 60 made up 37% (78/213). Demographic data is summarised in Table 1. Other than a statistically significant difference in mean age, prevalence of DM and atrial fibrillation, between the groups there were no significant differences between the cohorts. There was a higher prevalence of CKD in low GFR groups.
laboratory and haemodynamic data were largely similar in both groups (Table 2).
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Post-LVAD laboratory variables Post-LVAD laboratory data demonstrated a persistent decrease in renal function in patients with pre-LVAD GFR <60, (GFR 57 vs. 89, p < 0.001, BUN 27 vs 18, p < 0.001, and creatinine 1.4 vs 0.96, p < 0.001) (Table 2).
122 123
Pre-implant laboratory and haemodynamic variables Baseline laboratory parameters revealed no statistical difference between the two groups except for a higher BUN (31 vs. 19, p < 0.001), a higher creatinine (1.66 vs. 1.04, p < 0.001) and a lower GFR (44 vs 80, p < 0.001) in patients with preimplant GFR <60 (Table 2). Furthermore, pre-LVAD
Stratification Based on Pre- and Post-Implant GFR
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The cohort was also divided into three subgroups. Group I (79/213, 37%) comprised patients with pre- and post-implant GFR of <60. Group II (56/213, 26%) comprised patients with
129 130
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Table 2 Groups based on pre-LVAD GFR
Groups based on pre/post-Implant GFR
Pre-LVAD
Pre-LVAD
Group I
Group II
Group III
Overall
GFR <60
GFR 60
(79/213)
(56/213)
(78/213)
p-value
(135/213)
(78/213) Pre-LVAD
Pre-LVAD
Pre-LVAD
GFR <60
GFR <60
GFR 60
Discharge
Discharge
Discharge
GFR <60
GFR 60
GFR 60
p-value
Sodium (mg/dL)
134(4)
135(3)
0.31
135(4)
134(4)
135(3)
0.31
BUN (mg/dL)
31(17)
19(9)
<0.001
32(16)
29(17)
19(9)
<0.001 <0.001
Creatinine (mg/dL)
1.66(0.41)
1.04(0.19)
<0.001
1.75(0.47)
1.51(0.34)
1.04(0.19)
GFR (mL/min/1.73m2)
44(10)
80(18)
<0.001
43(13)
48(8)
80(18)
<0.001
BNP (pg/dL) AST units/L
524(261-1030) 25(21-35)
463(218-796) 32(23-46)
0.25 0.02
505(208-997) 28(22-37)
587(331-1197) 25(21-30)
463(218-796) 32(23-46)
0.2 0.008
ALT units/L
35(27-43)
42(29-59)
0.006
36(29-48)
31(27-40)
42(29-59)
0.006
Albumin (gm/dL)
3.0(0.5)
3.0(0.4)
0.63
3.0(0.5)
3.0(0.5)
3.0(0.4)
0.75
T.Bili (mg/dL)
1.0(0.7)
1.1(0.8)
0.64
1.1(0.7)
1.1(0.7)
1.1(0.8)
0.94
INR
1.27(0.34)
1.19(0.22)
0.06
1.26(0.41)
1.28(0.27)
1.19(0.22)
0.08
Haemoglobin (gm/dL)
11.1(1.7)
11.6(1.9)
0.08
11.3(1.7)
11.5(1.6)
11.6(1.9)
0.29
CVP (mmHg)
12(5)
11(6)
0.82
12(6)
11(5)
11(6)
0.78
SPAP (mmHg) DPAP (mmHg)
53(13) 25(7)
49(15) 25(8)
0.11 0.83
50(14) 25(6)
54(13) 25(8)
49(15) 25(8)
0.14 0.67
MPAP (mmHg)
35(8)
34(10)
0.43
34(8)
36(9)
34(10)
0.45
PCWP (mmHg)
23(8)
23(8)
0.67
22(7)
24(9)
23(8)
0.47
Cardiac Output (L/min)
4.5(1.5)
4.7(1.5)
0.27
4.8(1.8)
3.9(1.1)
4.7(1.5)
0.002
Cardiac Index (L/min/m2)
2.3(0.7)
2.3(0.7)
0.74
2.4(0.9)
2.1(0.5)
2.3(0.7)
0.04
SVR (dynes sec/cm5)
1303(456)
1316(460)
0.85
1192(460)
1428(425)
1316(460)
0.005
PVR (WU)
2.9(1.5)
2.9(1.8)
0.76
2.8(1.5)
3.2(1.6)
2.9(1.8)
0.23
Systolic BP (mmHg) Diastolic BP (mmHg)
108(15) 63(12)
106(19) 69(13)
0.28 0.001
109(16) 61(13)
106(13) 63(12)
106(19) 69(13)
0.4 0.003
Mean BP (mmHg)
77(11)
82(12)
0.02
77(12)
77(11)
82(12)
0.07
Heart Rate (BPM)
82(15)
89(18)
0.01
83(16)
84(17)
89(18)
0.11
LVEDD (cm)
67 11
69 11
0.28
64 10
71 12
69 11
0.26
LVESD (cm)
60 12
63 10
0.11
57 12
64 14
63 10
0.15
LVEF (%)
20 8
18 7
0.04
21 8
18 7
18 7
0.35
ALT: Alanine aminotransferase, AST: aspartate aminotransferase, BNP: Beta natriuretic peptide, BP: Blood pressure, BUN: Blood urea nitrogen, CVP: central venous pressure, DPAP: Diastolic pulmonary artery pressure, GFR: Glomerular filtration rate, INR: International normalised ratio: LVAD: Left ventricular assist device, LVEDD: Left ventricular end diastolic dimension, LVEF: Left ventricular ejection fraction, LVESD: Left ventricular end systolic dimension, MPAP: mean pulmonary artery pressure, PCWP: pulmonary capillary wedge pressure, PVR: pulmonary vascular resistance, SPAP: Systolic pulmonary artery pressure, SVR: Systemic Vascular Resistance, T.Bili: Total bilirubin.
132 133 134 135 136 137 138 139 140 141
pre-implant GFR of <60, but subsequent post-LVAD GFR of 60, while Group III (78/213, 37%) contained patients who maintained their GFR 60 both before and after LVAD implantation. Baseline demographic information is summarised in Table 1. Pre-implant laboratory and haemodynamic variables Pre-implant data, as seen in Table 2, further confirmed worse renal parameters (blood urea nitrogen (BUN), creatinine (Cr), and GFR) in groups I and II compared to Group III. The mean pre-LVAD GFR in Group I was 43 13, compared to a mean
GFR of 48 8 in Group II and a mean GFR of 80 18 in Group III. Baseline AST and ALT were also statistically significantly different between the three groups (Table 2). Baseline preLVAD haemodynamic information is summarised in Table 2.
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Post LVAD laboratory variables There were statistically significant differences in discharge renal parameters between the three groups.(BUN: 31 vs. 22 vs. 18, p < 0.001, Cr: 1.66 vs.1.04 vs.0.96, p < 0.001, GFR: 45 vs.74 vs.89, p < 0.0001, in Group I, II and III respectively) (Table 2).
146 147
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Table 3 Groups based on pre-LVAD GFR
Groups based on pre/post-Implant GFR
Pre-LVAD
Pre-LVAD
Group I
Group II
Group III
Overall
GFR <60
GFR 60
(79/213)
(56/213)
(78/213)
p-value
(135/213)
(78/213) Pre-LVAD
Pre-LVAD
Pre-LVAD
GFR <60
GFR <60
GFR 60
Discharge
Discharge
Discharge
GFR <60
GFR 60
GFR 60
p-value
DC Sodium (mg/dL)
135(3)
135(14)
0.28
136(3)
136(3)
135(14)
DC BUN (mg/dL)
27(13)
18(8)
<0.001
31(14)
22(8)
18(8)
0.88 <0.001
DC Creatinine (mg/dL)
1.4(0.5)
0.96(0.21)
<0.001
1.66(0.45)
1.04(0.22)
0.96(0.21)
<0.001
DC GFR (mL/min/1.73m2)
57(19)
89(22)
<0.001
45(10)
74(15)
89(22)
<0.001
DC BNP (pg/dL) DC AST units/L
403(243-654) 41(25-45)
347(216-524) 33(26-45)
0.04 0.54
408(269-666) 34(26-45)
380(213-552) 32(25-47)
347(216-524) 33(26-45)
0.06 0.82
DC ALT units/L
46(31-48)
41(31-56)
0.81
39(32-49)
36(29-46)
41(31-56)
0.34
DC Albumin (gm/dL)
2.8(0.4)
3.0(0.5)
0.62
2.9(0.3)
2.7(0.4)
3.0(0.5)
0.11
DC T.Bili (mg/dL)
0.91(0.46)
0.85(0.47)
0.35
0.99(0.5)
0.8(0.3)
0.85(0.47)
0.06
DC Haemoglobin (gm/dL)
9.9(1.1)
9.6(1.3)
0.05
10(1.2)
9.9(1.1)
9.6(1.3)
0.05
ALT: Alanine aminotransferase, AST: aspartate aminotransferase, BNP: Beta natriuretic peptide, BUN: Blood urea nitrogen, GFR: Glomerular filtration rate, INR: International normalised ratio: LVAD: Left ventricular assist device, T.Bili: Total bilirubin.
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Post-LVAD Outcomes
Discussion
182
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Post-LVAD outcomes based on pre-implant GFR only The incidences of early right ventricular failure were higher in patients in the low GFR group, (47 (34%) vs 15 (19%), p = 0.02) (Table 3). The incidence of stroke or transient ischaemic events and heart failure hospitalisations was significantly higher in patients with GFR <60, 25 (18%) vs. 5(6%), p = 0.01, and 33(24%) vs 5(6%), p = 0.001, respectively (Table 3). All cause mortality was higher in the low GFR group compared to the control cohort (45% vs 27%, p = 0.006). Kaplan-Meier survival analysis further confirmed our findings, indicating a statistically significantly higher survival in patients with higher GFR (mean survival 1460 vs.1846 days log rank p = 0.01) (Figure 2).
Renal impairment is often considered a risk factor for adverse outcomes in heart failure patients requiring advanced therapies [8,19]. However, the degree of impairment that may lead to adverse outcomes in congestive heart failure patients is often a subject of debate. Imamura et al. identified pre-LVAD serum creatinine as a better predictor of adverse outcomes than BUN or GFR [20]. In non-LVAD heart failure studies,
183
155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181
Post-LVAD outcomes based on pre- and post-implant GFR Major outcomes are summarised in Table 3. There was a statistically significantly higher rate of early right ventricular failure in Group I, 28(35%) vs. Group II 19(34%) vs. Group III 15(19%), p = 0.05. Similarly, heart failure hospitalisations were higher in the low GFR group as well (Group I: 23 (29%) vs. Group II:10(18%) vs. Group III: 5(6%), p = 0.001). Overall incidence of strokes was statistically significantly higher in Groups I and II (Table 3). All cause mortality was statistically significantly higher in Group I compared to the other two groups, (51% vs.38% vs. 27%, p = 0.009) (Table 3). Kaplan Meier analysis further confirmed this observation, with a mean survival of 1331 days in Group 1, vs.1690 days in Group II, and 1846 days in Group III, log rank p-value = 0.035 (Figure 3).
Figure 2 Kaplan Meier-Survival Plot of the Entire Cohort stratified by GFR 60 and GFR <60. GFR: Glomerular filtration rate[1_TD$IF].
Please cite this article in press as: Mohamedali B, Bhat G. The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes. Heart, Lung and Circulation (2017), http://dx.doi. org/10.1016/j.hlc.2017.01.002
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Figure 3 Kaplan Meier Survival between the three groups. GFR: Glomerular filtration rate[1_TD$IF][2.
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BUN has often emerged as a strong predictor of morbidity and mortality [10,19,21]. Alternatively, other studies have demonstrated GFR, due to its ability to account for patients age, sex and race, is strongly associated with adverse outcomes [22–24]. For every 10 ml/min reduction in GFR, it is thought to increase one year mortality by 15% [25]. Many LVAD centres utilise an extensive work-up to determine LVAD eligibility prior to implantation. However, the exact cut-off value for GFR below which an LVAD should not be implanted is poorly understood. Although end stage renal disease and severely reduced renal function often leads to disqualification for LVAD candidacy [26], patients with moderately and severely reduced renal function based on GFR often fall into a grey zone where objective evaluation is not well established. Low GFR as a marker for adverse outcomes in decompensated heart failure is well known. Similarly, Kirklin et al. demonstrated worse outcomes in patients post-LVAD based on CKD staging stratified by GFR [8]. Other studies have demonstrated similar mortality findings with post-LVAD renal failure [7,27]. The National Kidney foundation (NKF) distinguishes mild from moderate renal impairment on the basis of GFR cut-off point of 60 mL/min/1.73 m2 [18]. In this study, we divided our cohort into two groups based on this definition to produce a cohort of patients with normal/mildly impaired renal function vs. patients with moderate/severely reduced renal function. We also sub-divided our cohort into three subgroups based on post-LVAD GFR recovery in accordance with the National Kidney Foundation’s definition. Our subgroups were mainly driven by an interest to analyse the subset of LVAD population who do not completely reverse their renal dysfunction during pre-LVAD evaluation and optimisation, but subsequently improve their renal function to GFR 60 after LVAD implantation. The physiological relationship between low GFR and worse outcomes is not well understood. The increased
incidence of early RVF in patients with low GFR was surprising, especially since haemodynamic profiles did not demonstrate any major differences between the two groups (Table 2) that could have suggested an increased risk of early right ventricular failure (RVF) in the low GFR cohort. Right ventricular failure is a well-known risk factor for postoperative mortality, morbidity, and increased length of stay [28– 30]. Whether renal failure precipitates RVF or vice versa is not well understood; however, our data suggests that renal failure may predispose patients to early RVF. The observation has also been previously reported [31]. The incidence of congestive heart failure hospitalisations was statistically higher in the study group, and may be due to late RVF in an LVAD supported left ventricle (Table 4). A gradual volume overload state from impaired renal function and increased flow to the right ventricle from the LVAD supported left ventricle may cause gradual development right ventricular dysfunction. However, the putative mechanism that may predispose this cohort to late RVF remains unknown. There were higher incidences of strokes or transient ischaemic attacks in the low GFR group. Chronic kidney disease is a well-known risk factor for stroke and it is mainly thought to be a result of increased comorbidities that may predispose patients to a higher risk of events [32]. Although this may be true in our population, whether low GFR predisposes patients at a higher risk of strokes is poorly understood. However, in a small study by Morgan et al., analysing the predictors of postoperative strokes in patients with LVAD, renal insufficiency was not a factor for incidences of strokes [33]. Similarly, Boyle et al. investigated over 900 LVAD patients and did not demonstrate serum Cr or BUN to be predictors of strokes [34]. A multivariate analysis of our data indicated that, even after controlling for diabetes and atrial fibrillation, pre-implant GFR <60 was an independent predictor of strokes (OR 3.84 (95% CI: 1.38–10.71, p = 0.01). Our findings reveal that further analysis on this matter is warranted. Our study is unique in the sense that it not only stratified patients by pre-implant GFR, but further divided the cohort based on discharge GFR. To the best of our knowledge, this is the first study to analyse this population. Our subgroup analysis examined the special sub-set of patients who had a pre-implant GFR <60 but subsequently improved their GFR to 60 (Group II). Mortality was higher in Group I compared to Group II and III (51% vs. 38% vs. 27%, p = 0.009).
226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 Q4
261 262 263 264 265 266 267 268 269 270 271 272
Limitations
273
This was a single centre, retrospective study utilising chart review and hence was subject to limitations inherent to the study design. The sample size was relatively small. Only DT patients and BTT patients who did not undergo transplantation were enrolled in this study and there was a predominance of male patients. Patients who transferred their care to
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Table 4 Morbidity and mortality in the three groups. Groups based on pre-LVAD GFR Pre-LVAD
Pre-LVAD
GFR <60
GFR 60
(135/213)
(78/213)
Groups based on pre/post-Implant GFR P-value
Group I
Group II
Group III
overall
(79/213)
(56/213)
(78/213)
p-Value
Pre-LVAD
Pre-LVAD
Pre-LVAD
GFR <60
GFR <60
GFR 60
Discharge
Discharge
Discharge
GFR <60
GFR 60
GFR 60
LVAD Infections
45(33%)
25(32%)
0.88
27 (34%)
18(32%)
25(32%)
0.95
Non LVAD infections
34(25%)
13(17%)
0.17
19(24%)
15(27%)
13(17%)
0.33
Gl Bleed
32(24%)
25(32%)
0.2
24(30%)
8(14%)
25(32%)
0.06
Non GI bleeding
13(10%)
4(4%)
0.3
9(11%)
4(7%)
4(5%)
0.34
LVAD Thrombosis Haemolysis
8(6%) 8(6%)
4(5%) 6(8%)
0.99 0.78
4(5%) 5(6%)
4(7%) 3(5%)
4(5%) 6(8%)
0.85 0.86
Stroke/TIA
25(18%)
5(6%)
0.01
14(18%)
11(20%)
5(6%)
0.05
ICH
8(6%)
5(6%)
1
5(6%)
3(5%)
5(6%)
0.96
CHF Hospitalisations
33(24%)
5(6%)
0.001
23(29%)
10(18%)
5(6%)
0.001
VT
16(12%)
11(14%)
0.67
7(9%)
9(16%)
11(14%)
0.41
Atrial Arrhythmia
4(3%)
2(3%)
1
1(1%)
3(5%)
2(3%)
0.36
Early RV Failure
47(34%)
15(19%)
0.02
28(35%)
19(34%)
15(19%)
0.05
All Cause Mortality
61(45%)
21(27%)
0.006
40(51%)
21(38%)
21(27%)
0.009
CHF: Congestive heart failure, GI: gastrointestinal, GFR: Glomerular filtration rate, ICH: Intracranial haemorrhage LVAD: Left ventricular assist device, RV: Right ventricular, TIA: transient ischaemic attack, VT: Ventricular tachycardia.
280 281 282 283 284 285 286 287 288
other centres were excluded from the analysis. Eleven patients with preoperative GFR 60, but postoperative <60 were excluded from the study to preserve the integrity of our secondary analysis. However, when those 11 patients were included in the statistical analysis, no changes in the overall outcomes reported above were noted. Despite these limitations, we believe this study offers important new information and furthers clinical awareness of pre-LVAD GFR as a prognostic tool for adverse outcomes post-LVAD placement.
289
Clinical Perspective
290
299
Our findings suggest that patients undergoing a work-up for LVAD implantation, after optimisation of haemodynamic and loading conditions, can be risk stratified based on a preimplant GFR of <60. Furthermore, even if patients with preLVAD GFR <60 improve their GFR to greater than 60 postLVAD, these patients continue to have similar morbidity and mortality compared to patients who do not improve their postLVAD GFR to greater than 60. These findings suggest that preimplant GFR, and not post-implant GFR, is a better predictor of adverse outcomes after LVAD placement.
300
Conclusion
301
Patients with GFR <60, are at increased risk of adverse outcomes post-LVAD placement, particularly early RVF, CHF
291 292 293 294 295 296 297 298
302
hospitalisations and incidence of stroke or TIA compared to patients with pre-LVAD GFR 60. Survival in this group was lower than the control group. When the patients with preimplant GFR <60 were further divided into the subgroup of patients who either improved their GFR to 60 post-LVAD placement or had a persistent low GFR of <60 post-LVAD implantation and were compared to their peers with preimplant GFR >60, it appeared that most of the adverse outcomes were driven by patients who had persistently low GFR post-LVAD. Glomerular filtration rate can be employed as a quick and easy tool for rapid risk stratification for patients with increased risk of morbidity and mortality after LVAD implantation.
303
References
316
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[1] Kirklin JK, Naftel DC, Pagani FD, et al. Sixth INTERMACS annual report: Q5 317 a 10,000-patient database. The Journal of Heart and Lung Transplanta318 tion: the official publication of the International Society for Heart Trans319 plantation 2014;33(Jun (6)):555–64. 320 [2] Zannad F, Mebazaa A, Juilliere Y, et al. Clinical profile, contemporary 321 management and one-year mortality in patients with severe acute heart 322 failure syndromes: The EFICA study. European Journal of Heart Failure 323 2006;8(Nov (7)):697–705. 324 [3] Ruggenenti P, Remuzzi G. Worsening kidney function in decompensated 325 heart failure: treat the heart, don’t mind the kidney. European Heart 326 Journal 2011;32(Oct (20)):2476–8. 327 [4] Mullens W, Abrahams Z, Francis GS, et al. Importance of venous con328 gestion for worsening of renal function in advanced decompensated 329 heart failure. Journal of the American College of Cardiology 2009; 330 53(Feb (7)):589–96. 331
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Please cite this article in press as: Mohamedali B, Bhat G. The Influence of Pre-Left Ventricular Assist Device (LVAD) Implantation Glomerular Filtration Rate on Long-Term LVAD Outcomes. Heart, Lung and Circulation (2017), http://dx.doi. org/10.1016/j.hlc.2017.01.002
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