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Presence of Implantable Cardioverter-Defibrillators and Wait-List Mortality of Patients Supported with Left Ventricular Assist Devices as Bridge to Heart Transplantation
IJCA-24326; No of Pages 5 International Journal of Cardiology xxx (2016) xxx–xxx
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Presence of Implantable Cardioverter-Defibrillators and Wait-List Mortality of Patients Supported with Left Ventricular Assist Devices as Bridge to Heart Transplantation Ahmad Younes 1, Sadeer G. Al-Kindi 1, Wissam Alajaji, Judith A. Mackall, Guilherme H. Oliveira ⁎ Advanced Heart Failure & Transplant Center and the Arrhythmia Center, Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
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Article history: Received 29 September 2016 Accepted 21 December 2016 Available online xxxx Keywords: ICD LVAD Wait-list mortality
a b s t r a c t Background: The role of implantable cardioverter defibrillator (ICD) in reducing mortality in patients with left ventricular assisted devices (LVADs) listed for heart transplant remains unclear. We therefore, sought to interrogate whether ICDs are associated with reduced mortality in patients with LVADs listed for heart transplantation. Methods: We searched the United Network for Organ Sharing (UNOS) Registry for LVAD patients (age ≥ 18 years) with dilated cardiomyopathies listed for heart transplantation (2008-2015). The group was matched by propensity scores with respect to presence of ICD at listing. The primary end-point was waitlist mortality, while secondary endpoints were waitlist mortality, delisting, or cardiovascular cause-specific mortality in patients with and without ICD. Results: A total of 1444 LVAD patients were included in this analysis (722 with ICD, 722 without ICD). No statistically-significant differences were present between the two groups in demographics, device type, listing status, or hemodynamics. The presence of an ICD was not associated with decreased wait-list mortality (Hazard Ratio 1.19 [0.75-1.88], p = 0.46), waitlist mortality/delisting (Hazard Ratio 1.20 [0.86-1.67], p = 0.28), or cardiovascular wait-list mortality (HR 1.24 [0.45-3.43], p = 0.67) over a median of 5.6 months. Only 7 deaths occurred due to arrhythmia/cardiac arrest (2 in the ICD group and 5 in the non-ICD group). Conclusion: Presence of ICDs at listing in heart failure patients bridged to transplantation with durable LVADs is not associated with lower waitlist mortality, cardiovascular wait-list mortality or wait-list mortality or delisting; however, there were numerically fewer arrhythmic deaths in the ICD group. Additional prospective studies should be undertaken to confirm these findings. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Left ventricular assist devices (LVADs) are approved as bridge to transplantation or as destination therapy for patients with advanced heart failure [1,2], and their use continues to grow [3]. Ventricular tachyarrhythmias (VTA) are common after implantation of LVADs [4–6], and are thought to result from progressive heart failure, preexisting electrical instability, as well as myocardial irritation caused by the inflow cannula [7]. Postoperative VTAs have been documented in Abbreviations: LVAD, Left ventricular assist device; ICD, implantable cardioverterdefibrillator; VTA, ventricular tachyarrhythmia; ECMO, extracorporeal membrane oxygenation; IABP, intraaortic balloon pump; UNOS, united network for organ sharing. ⁎ Corresponding author at: Advanced Heart Failure and Transplantation Center, Harrington Heart & Vascular Institute and Seidman Cancer Center, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, 11100 Euclid Avenue LKS 3012, Cleveland, Ohio 44106. E-mail address: [email protected] (G.H. Oliveira). 1 AY and SGA are co-first authors.
up to 35% of patients within 30 days [4], and are associated with increased mortality in patients with LVADs [8]; however, multiple reports have suggested that VTAs are hemodynamically well tolerated in LVAD patients [9,10]. Implantable cardioverter defibrillators (ICDs) reduce the incidence of sudden cardiac death in adults with heart failure [11,12]; however, their role in reducing mortality in LVAD patients remains unclear [13,14]. We therefore sought to evaluate the impact of ICDs on waitlist mortality in LVAD patients awaiting heart transplantation, as well as to determine risk factors for sudden cardiac death in this population. 2. Methods Dataset: We used the United Network for Organ Sharing (UNOS) Registry contracted with the Health Resources and Services Administration (HRSA). UNOS records and publicly reports all listings and transplantations for solid organs through a compulsory program. Individual variables are collected at listing, at transplantation, and regularly thereafter. Data are entered by the transplantation centers in the United States through an electronic
http://dx.doi.org/10.1016/j.ijcard.2016.12.148 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: A. Younes, et al., Presence of Implantable Cardioverter-Defibrillators and Wait-List Mortality of Patients Supported with Left Ventricular Assist Dev..., Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.148
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data collection gateway, UNet. Data collected through UNOS undergo quality control by UNOS/OPTN. As UNOS contains only de-identified data, this study was not considered human research and did not require institutional review board approval. Cohort selection and end-points: For this analysis, we included adults (age ≥ 18 years) with dilated cardiomyopathy listed for heart transplantation (2008-2015) with durable LVAD (Heartmate II or Heartware), status 1A, 1B, or 7 with or without ICDs at listing. We excluded patients with biventricular assist devices or those with total artificial hearts. Primary end-point was adjusted waitlist mortality and secondary endpoints were adjusted wait-list death or delisting, cardiovascular cause-specific mortality in patients with or without ICDs. Fig. 1 shows the flow of the study cohort. Statistical analysis: Categorical variables are presented as numbers and percentages and compared with χ2 test. Continuous variables are presented as means and standard deviations, and compared with one-way analysis of variance. All tests are two sided. Propensity score matching was performed using the MatchIt package in R, with respect to ICD presence. Covariates for propensity score calculation were: age, gender, ethnicity, listing UNOS status, LVAD type, diabetes, cigarette use, body mass index (BMI), serum creatinine, pulmonary artery systolic, diastolic, and mean pressures, pulmonary capillary wedge pressure, cardiac output, blood group, extracorporeal membrane oxygenation (ECMO), intraaortic balloon pump (IABP), inotropes, and mechanical ventilation. Time-dependent analyses (waitlist mortality, cardiovascular cause-specific mortality) were all analyzed with Kaplan Meier method with censoring for other outcomes, and compared with Log Rank (Mantel-Cox) test. Multivariable models were adjusted for covariates listed in Table 1 and were analyzed using Cox proportional-hazard models. Analyses were done in Statistical Package for Social Sciences v19 and R v. 3.3.1.
3. Results We identified 2890 patients with ICDs and 736 patients without ICDs at listing. Prior to matching, patients with ICDs were older (ICD vs no ICD; 54.0 vs 49.9 years, p b 0.001), more likely to be male (81.5% vs 75.8%, p = 0.001), black (27.2% vs 23.6%, p = 0.02), listed as 1A (32% vs 27.3%, p = 0.049), higher creatinine (1.3 vs 1.2 mg/dL, p = 0.038), BMI (29 vs 27.7 kg/m2, p b 0.001), lower use of IABP (1.3% vs 2.4%, p = 0.045), ECMP (0.2% vs 0.8%, p = 0.021), and higher PASP (41.3 vs 40.0 mmHg, p = 0.029), Table 1. A total of 722 ICDs were propensity-score matched to 722 patients without ICD. Distribution of propensity scores are shown in Fig. 2. All baseline characteristics were balanced after propensity score matching. Over a median of 5.6 months on the waitlist, there were 74 deaths (15 cardiovascular deaths; including 7 arrhythmic deaths) and 68 delistings for deterioration. The presence of an ICD was not associated with decreased waitlist mortality (Hazard Ratio 1.19 [0.75-1.88], p = 0.46), waitlist mortality/delisting (Hazard Ratio 1.20 [0.86-1.67], p = 0.28), or cardiovascular wait-list mortality (HR 1.24 [0.45-3.43], p = 0.67) over a median of 5.6 months, Fig. 3. There were numerically fewer
arrhythmic deaths in ICD vs non-ICD groups (2 in the ICD group and 5 in the non-ICD group). In subgroup analyses, ICDs were not associated with decreased waitlist mortality among patients with age groups (b50 vs N50 years), Heartmate II, Heartware, ischemic cardiomyopathy, non-ischemic cardiomyopathy, status 1A or status 1B. There were significant interactions of outcomes with sex and ethnicity, with statistically increased poor outcomes in women and blacks, Fig. 4. 4. Discussion In the largest propensity-score matched study of ICDs in BTT CF-LVAD, we show that the presence of ICDs at listing was not associated with decreased waitlist or cardiovascular mortality among continuous-flow LVAD patients bridged to heart transplantation, despite numerically fewer arrhythmic deaths. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) in adults has convincingly demonstrated the favorable effects of ICD in primary prevention of SCD in patients with ischemic and non–ischemic dilated cardiomyopathies with New York Heart Association class II or III heart failure and a left ventricular ejection fraction of 35% or below [11,15]. However, the benefit of ICDs in patients with LVADs implanted as bridge to transplantation has not been established and there is a large amount of conflicting literature on this issue. Previous retrospective studies have suggested that ICD implantation in LVAD patients is associated with extended survival [16,17]. However, the majority of these studies were smaller, single centered, also included patient with LVADs as destination therapy, with both continuous and pulsatile flow LVADs. One study evaluated ICD therapy among 144 patients awaiting transplantation with pulsatile LVADs found that ICDs were associated with increased survival (OR 2.72; 95% CI, 1.03– 7.16; P = 0.04) [17]. However, another retrospective report included 106 patients with heartmate II, concluded that VTAs post LVAD were not associated with worse prognosis, and ICD implantation in this population may not reduce mortality (HR, 1.12 [0.37–3.35]) (12). In addition, a more recent study of 94 patients with continuous flow LVADs found no difference in survival between patients with or without ICD. The authors recommended no ICD generator change for patients without VTAs prior to LVAD implantation despite the fact that only 18% of study patients had no ICD (13). VTAs have been observed to occur with greater frequency after LVAD implantation, although reported incidence varies widely in observational
Fig. 1. Study Cohort Flow Chart.
Please cite this article as: A. Younes, et al., Presence of Implantable Cardioverter-Defibrillators and Wait-List Mortality of Patients Supported with Left Ventricular Assist Dev..., Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.148
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Table 1 Patient characteristics with or without ICD. Before Propensity Score Matching
Age at listing (years) Male Ethnicity White Black Other Initial status 1A 1B 7 Blood type A B AB O Creatinine BMI (kg/m2) Cigarette use Diabetes Type of Device Heartmate 2 Heartware Ischemic disease Therapies Ventilator IABP ECMO Inotropes Hemodynamics PA mean pressure (mmHg) PASP (mmHg) PADP (mmHg) Cardiac output (L/min) PCWP (mmHg) PVR (Wood Units)
ICD (n = 2890)
p-value
No ICD (n = 722)
ICD (n = 722)
p-value
49.9 ± 13.6 558 (75.8%)
54.0 ± 11.2 2354 (81.5%)
b0.001 0.001 0.02
50.4 ± 13.2 553 (76.6%)
51.4 ± 12.4 556 (77.0%)
0.126 0.901 0.593
478 (64.9%) 174 (23.6%) 84 (11.4%)
1856 (64.2%) 785 (27.2%) 249 (8.6%)
467 (64.7%) 172 (23.8%) 83 (11.5%)
457 (63.3%) 188 (26.0%) 77 (10.7%)
201 (27.3%) 499 (67.8%) 36 (4.9%)
925 (32.0%) 1832 (63.4%) 133 (4.6%)
195 (27%) 491 (68%) 36 (5%)
224 (31%) 466 (64.5%) 32 (4.4%)
285 (38.7%) 82 (11.1%) 28 (3.8%) 341 (46.3%) 1.2 ± 0.8 27.7 ± 4.6 351 (47.7%) 227 (30.8%)
990 (34.3%) 389 (13.5%) 97 (3.4%) 1414 (48.9%) 1.3 ± 0.6 29.0 ± 5.0 1647 (57.0%) 996 (34.5%)
282 (39.1%) 82 (11.4%) 25 (3.5%) 333 (46.1%) 1.2 ± 0.8 27.8 ± 4.5 350 (48.5%) 224 (31%)
269 (37.3%) 83 (11.5%) 28 (3.9%) 342 (47.4%) 1.2 ± 0.6 27.8 ± 5.1 357 (49.4%) 237 (32.8%)
628 (85.3%) 108 (14.7%) 428 (58.2%)
2529 (87.5%) 361 (12.5%) 1722 (59.6%)
0.501
616 (85.3%) 106 (14.7%) 306 (42.4%)
625 (86.6%) 97 (13.4%) 320 (44.3%)
0.490
19 (2.6%) 18 (2.4%) 6 (0.8%) 60 (8.2%)
63 (2.2%) 39 (1.3%) 6 (0.2%) 221 (7.6%)
0.489 0.045 0.021 0.643
17 (2.4%) 18 (2.5%) 4 (0.6%) 55 (7.6%)
13 (1.8%) 16 (2.2%) 3 (0.4%) 63 (8.7%)
0.581 0.863 1.000 0.501
27.6 ± 10.9 40.0 ± 13.8 19.7 ± 9.7 4.6 ± 1.5 18.4 ± 9.6 2.3 ± 1.7
27.9 ± 10.9 41.3 ± 14.8 19.7 ± 9.4 4.7 ± 1.4 17.8 ± 9.7 2.4 ± 1.6
0.529 0.029 0.879 0.072 0.158 0.160
27.7 ± 10.9 40.2 ± 13.8 19.7 ± 9.7 4.6 ± 1.5 18.4 ± 9.6 2.3 ± 1.7
27.6 ± 11.5 40.2 ± 15.4 19.6 ± 9.9 4.6 ± 1.5 18.2 ± 10.2 2.3 ± 1.7
0.847 0.999 0.828 0.930 0.731 0.871
0.049
Unmatched Treatment Units
Matched Treatment Units
Matched Control Units
Unmatched Control Units
0.4
0.235
0.075
studies [2,4,5,18]. A recent meta-analysis postulated that VTAs before LVAD predicted VTAs after LVAD and were associated with increased mortality; however, up to 30% of patients had LVADs as destination therapy [8]. In addition, ICDs are associated with significant morbidity and impact quality of life. Inappropriate ICD shocks were reported in up to
0.2
After Propensity Score Matching
No ICD (n = 736)
0.6
0.8
1.0
Propensity Score Fig. 2. Distribution of Propensity scores in matched and unmatched patients.
0.038 b0.001 b0.001 0.067 0.124
0.896
0.932 0.914 0.752 0.498 0.545
18% of patients with LVADs [13,16,18] leading patients to request ICD deactivation. Psychosocial distress, particularly anxiety and post-traumatic stress disorder, occur in 13% to 38% of patients with an ICD [19], and ICD discharges have been shown to decrease quality of life substantially [20,21]. Adding to that, the presence of multiple devices markedly increases the risk of infection, which can be detrimental for patients with LVADs listed for transplant [22]. There also appear to be technical implications of ICD placement in LVAD patients. Continuous-flow LVADs have been associated with changes in the performance of preexisting ICDs. Adverse events including over- and under-sensing, electromagnetic interference, and changes in defibrillation threshold, have been reported. Addressing these interactions to maintain appropriate ICD function and prevent inappropriate shock requires both invasive and noninvasive ICD system modification [23–25]. Many have postulated that because LVADs can offer up to ten liters of cardiac output independent of left ventricular function, VTAs have less hemodynamic impact on LVAD patients. As a result, VTAs are often asymptomatic and detected on routine ICD interrogation in the ambulatory setting [26]. To further illustrate the controversy, the 2012 ACCF/AHA/HRS Guidelines for device-based therapy, do not recommend ICD implantation for primary prevention of sudden cardiac death in NYHA Class IV patients [27] and the 2013 ACCF/HRS/AHA/ ASE/HFSA/SCAI/SCCT/SCMR appropriate use criteria assigned a score of 8 (“appropriate”) for patients who are NYHA class IV and listed for heart transplant, but still assigned a score of 6 (“may be appropriate”) if they had an LVAD [15]. In this largest study to-date, the presence of ICD was not associated with reduced mortality in LVAD patients listed for transplant, independent of sex, LVAD type, listing status and even etiology of cardiomyopathy. These results suggest that routine ICD implantation to reduce
Please cite this article as: A. Younes, et al., Presence of Implantable Cardioverter-Defibrillators and Wait-List Mortality of Patients Supported with Left Ventricular Assist Dev..., Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.148
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Fig. 3. Wait-list mortality or delisting in matched patients with or without ICD.
waitlist mortality in patients supported with durable LVADs awaiting heart transplantation may be unnecessary. This study has many important limitations that need to be considered. First, this is a retrospective analysis of a large database that only collected ICD information at listing, and not throughout the waiting period. This raises the possibility that some patients without an ICD at time of listing, may have had one implanted during the waiting period and were in fact protected from sudden death. Second, there may be considerable selection bias from the treating cardiologists, indicating that the patients selected not to have ICDs really did not need them or were expected to be transplanted very quickly, as opposed to those who did receive ICDs. Additionally, in this end-stage population, the risk of dying from progressive pump failure is proportionately much higher than the risk of dying from ventricular arrhythmias [28]. Given the short period of time on the wait-list (5.8 months) ICD benefit may not be apparent. Care should be taken to not extrapolate these findings to patients receiving LVAD for destination therapy, because these patients are supported by LVADs much longer and may benefit from ICDs. Lastly, we did not have details on type of defibrillator, presence of cardiac resynchronization therapy, and sensing/defibrillation settings. We also did not have the indications and timing of ICD implantation, history of preoperative VTA, postimplantation shocks, or quality of life information. Nevertheless, the
findings of this large study suggest that ICD in LVAD patients listed for heart transplant is not associated with increased waitlist survival. 5. Conclusions Presence of ICDs at listing in patients bridged to transplantation with durable continuous flow LVADs appears not to be associated with lower waitlist mortality or cardiovascular mortality, despite numerically fewer arrhythmic deaths. Additional prospective studies should be undertaken to confirm these findings. Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. Clinical perspectives There is paucity of data regarding the efficacy of ICD in patients with LVADs. Analysis of a large registry presented here shows no difference in wait-list mortality between patients with or without ICDs. While
Fig. 4. Subgroup Analyses of ICD o wait-list mortality or WLM/delisting.
Please cite this article as: A. Younes, et al., Presence of Implantable Cardioverter-Defibrillators and Wait-List Mortality of Patients Supported with Left Ventricular Assist Dev..., Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.148
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this is hypothesis generating, data presented here do not support routine ICD implantation during LVAD placement. Carefully selected patients with LVAD could be bridged to transplantation without ICDs. Translational outlook Data presented here suggest that carefully selected patients with LVAD may be safely bridged to heart transplantation without ICD. Randomized clinical trials are needed to elucidate the efficacy of implantable defibrillators in patients with left ventricular assist devices. Disclosures None of the authors have any disclosures relevant to this manuscript. References [1] E.A. Rose, A.C. Gelijns, A.J. Moskowitz, et al., Long-term use of a left ventricular assist device for end-stage heart failure, N. Engl. J. Med. 345 (Nov 15 2001) 1435–1443. [2] M.S. Slaughter, J.G. Rogers, C.A. Milano, et al., Advanced heart failure treated with continuous-flow left ventricular assist device, N. Engl. J. Med. 361 (Dec 3 2009) 2241–2251. [3] E.J. Birks, A changing trend toward destination therapy: are we treating the same patients differently? Tex. Heart Inst. J. 38 (2011) 552–554. [4] O. Ziv, J. Dizon, A. Thosani, Y. Naka, A.R. Magnano, H. Garan, Effects of left ventricular assist device therapy on ventricular arrhythmias, J. Am. Coll. Cardiol. 45 (May 3 2005) 1428–1434. [5] M. Andersen, R. Videbaek, S. Boesgaard, K. Sander, P.B. Hansen, F. Gustafsson, Incidence of ventricular arrhythmias in patients on long-term support with a continuous-flow assist device (HeartMate II), J. Heart Lung Transplant 28 (Jul 2009) 733–735. [6] M.S. Slaughter, J.G. Rogers, C.A. Milano, et al., Advanced Heart Failure Treated with Continuous-Flow Left Ventricular Assist Device, N. Engl. J. Med. 361 (2009) 2241–2251. [7] J.D. Harding, V. Piacentino 3rd, S. Rothman, S. Chambers, M. Jessup, K.B. Margulies, Prolonged repolarization after ventricular assist device support is associated with arrhythmias in humans with congestive heart failure, J. Card. Fail. 11 (Apr 2005) 227–232. [8] N. Makki, O. Mesubi, C. Steyers, B. Olshansky, W.T. Abraham, Meta-Analysis of the Relation of Ventricular Arrhythmias to All-Cause Mortality After Implantation of a Left Ventricular Assist Device, Am. J. Cardiol. 116 (Nov 1 2015) 1385–1390. [9] M.C. Busch, M. Haap, A. Kristen, C.S. Haas, Asymptomatic sustained ventricular fibrillation in a patient with left ventricular assist device, Ann. Emerg. Med. 57 (Jan 2011) 25–28. [10] M.C. Oz, E.A. Rose, J. Slater, J.J. Kuiper, K.A. Catanese, H.R. Levin, Malignant ventricular arrhythmias are well tolerated in patients receiving long-term left ventricular assist devices, J. Am. Coll. Cardiol. 24 (Dec 1994) 1688–1691. [11] G.H. Bardy, K.L. Lee, D.B. Mark, et al., Amiodarone or an implantable cardioverterdefibrillator for congestive heart failure, N. Engl. J. Med. 352 (Jan 20 2005) 225–237. [12] A.J. Moss, W. Zareba, W.J. Hall, H. Klein, D.J. Wilber, D.S. Cannom, J.P. Daubert, S.L. Higgins, M.W. Brown, M.L. Andrews, Multicenter Automatic Defibrillator Implantation Trial III. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction, N. Engl. J. Med. 346 (Mar 21 2002) 877–883. [13] A.D. Enriquez, B. Calenda, M.A. Miller, A.C. Anyanwu, S.P. Pinney, The role of implantable cardioverter-defibrillators in patients with continuous flow left ventricular assist devices, Circ. Arrhythm. Electrophysiol. 6 (Aug 2013) 668–674.
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Presence of Implantable Cardioverter-Defibrillators and Wait-List Mortality of Patients Supported with Left Ventricular Assist Devices as Bridge to Heart Transplantation Ahmad Younes 1, Sadeer G. Al-Kindi 1, Wissam Alajaji, Judith A. Mackall, Guilherme H. Oliveira ⁎ Advanced Heart Failure & Transplant Center and the Arrhythmia Center, Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
a r t i c l e
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Article history: Received 29 September 2016 Accepted 21 December 2016 Available online xxxx Keywords: ICD LVAD Wait-list mortality
a b s t r a c t Background: The role of implantable cardioverter defibrillator (ICD) in reducing mortality in patients with left ventricular assisted devices (LVADs) listed for heart transplant remains unclear. We therefore, sought to interrogate whether ICDs are associated with reduced mortality in patients with LVADs listed for heart transplantation. Methods: We searched the United Network for Organ Sharing (UNOS) Registry for LVAD patients (age ≥ 18 years) with dilated cardiomyopathies listed for heart transplantation (2008-2015). The group was matched by propensity scores with respect to presence of ICD at listing. The primary end-point was waitlist mortality, while secondary endpoints were waitlist mortality, delisting, or cardiovascular cause-specific mortality in patients with and without ICD. Results: A total of 1444 LVAD patients were included in this analysis (722 with ICD, 722 without ICD). No statistically-significant differences were present between the two groups in demographics, device type, listing status, or hemodynamics. The presence of an ICD was not associated with decreased wait-list mortality (Hazard Ratio 1.19 [0.75-1.88], p = 0.46), waitlist mortality/delisting (Hazard Ratio 1.20 [0.86-1.67], p = 0.28), or cardiovascular wait-list mortality (HR 1.24 [0.45-3.43], p = 0.67) over a median of 5.6 months. Only 7 deaths occurred due to arrhythmia/cardiac arrest (2 in the ICD group and 5 in the non-ICD group). Conclusion: Presence of ICDs at listing in heart failure patients bridged to transplantation with durable LVADs is not associated with lower waitlist mortality, cardiovascular wait-list mortality or wait-list mortality or delisting; however, there were numerically fewer arrhythmic deaths in the ICD group. Additional prospective studies should be undertaken to confirm these findings. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Left ventricular assist devices (LVADs) are approved as bridge to transplantation or as destination therapy for patients with advanced heart failure [1,2], and their use continues to grow [3]. Ventricular tachyarrhythmias (VTA) are common after implantation of LVADs [4–6], and are thought to result from progressive heart failure, preexisting electrical instability, as well as myocardial irritation caused by the inflow cannula [7]. Postoperative VTAs have been documented in Abbreviations: LVAD, Left ventricular assist device; ICD, implantable cardioverterdefibrillator; VTA, ventricular tachyarrhythmia; ECMO, extracorporeal membrane oxygenation; IABP, intraaortic balloon pump; UNOS, united network for organ sharing. ⁎ Corresponding author at: Advanced Heart Failure and Transplantation Center, Harrington Heart & Vascular Institute and Seidman Cancer Center, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, 11100 Euclid Avenue LKS 3012, Cleveland, Ohio 44106. E-mail address: [email protected] (G.H. Oliveira). 1 AY and SGA are co-first authors.
up to 35% of patients within 30 days [4], and are associated with increased mortality in patients with LVADs [8]; however, multiple reports have suggested that VTAs are hemodynamically well tolerated in LVAD patients [9,10]. Implantable cardioverter defibrillators (ICDs) reduce the incidence of sudden cardiac death in adults with heart failure [11,12]; however, their role in reducing mortality in LVAD patients remains unclear [13,14]. We therefore sought to evaluate the impact of ICDs on waitlist mortality in LVAD patients awaiting heart transplantation, as well as to determine risk factors for sudden cardiac death in this population. 2. Methods Dataset: We used the United Network for Organ Sharing (UNOS) Registry contracted with the Health Resources and Services Administration (HRSA). UNOS records and publicly reports all listings and transplantations for solid organs through a compulsory program. Individual variables are collected at listing, at transplantation, and regularly thereafter. Data are entered by the transplantation centers in the United States through an electronic
http://dx.doi.org/10.1016/j.ijcard.2016.12.148 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: A. Younes, et al., Presence of Implantable Cardioverter-Defibrillators and Wait-List Mortality of Patients Supported with Left Ventricular Assist Dev..., Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.148
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data collection gateway, UNet. Data collected through UNOS undergo quality control by UNOS/OPTN. As UNOS contains only de-identified data, this study was not considered human research and did not require institutional review board approval. Cohort selection and end-points: For this analysis, we included adults (age ≥ 18 years) with dilated cardiomyopathy listed for heart transplantation (2008-2015) with durable LVAD (Heartmate II or Heartware), status 1A, 1B, or 7 with or without ICDs at listing. We excluded patients with biventricular assist devices or those with total artificial hearts. Primary end-point was adjusted waitlist mortality and secondary endpoints were adjusted wait-list death or delisting, cardiovascular cause-specific mortality in patients with or without ICDs. Fig. 1 shows the flow of the study cohort. Statistical analysis: Categorical variables are presented as numbers and percentages and compared with χ2 test. Continuous variables are presented as means and standard deviations, and compared with one-way analysis of variance. All tests are two sided. Propensity score matching was performed using the MatchIt package in R, with respect to ICD presence. Covariates for propensity score calculation were: age, gender, ethnicity, listing UNOS status, LVAD type, diabetes, cigarette use, body mass index (BMI), serum creatinine, pulmonary artery systolic, diastolic, and mean pressures, pulmonary capillary wedge pressure, cardiac output, blood group, extracorporeal membrane oxygenation (ECMO), intraaortic balloon pump (IABP), inotropes, and mechanical ventilation. Time-dependent analyses (waitlist mortality, cardiovascular cause-specific mortality) were all analyzed with Kaplan Meier method with censoring for other outcomes, and compared with Log Rank (Mantel-Cox) test. Multivariable models were adjusted for covariates listed in Table 1 and were analyzed using Cox proportional-hazard models. Analyses were done in Statistical Package for Social Sciences v19 and R v. 3.3.1.
3. Results We identified 2890 patients with ICDs and 736 patients without ICDs at listing. Prior to matching, patients with ICDs were older (ICD vs no ICD; 54.0 vs 49.9 years, p b 0.001), more likely to be male (81.5% vs 75.8%, p = 0.001), black (27.2% vs 23.6%, p = 0.02), listed as 1A (32% vs 27.3%, p = 0.049), higher creatinine (1.3 vs 1.2 mg/dL, p = 0.038), BMI (29 vs 27.7 kg/m2, p b 0.001), lower use of IABP (1.3% vs 2.4%, p = 0.045), ECMP (0.2% vs 0.8%, p = 0.021), and higher PASP (41.3 vs 40.0 mmHg, p = 0.029), Table 1. A total of 722 ICDs were propensity-score matched to 722 patients without ICD. Distribution of propensity scores are shown in Fig. 2. All baseline characteristics were balanced after propensity score matching. Over a median of 5.6 months on the waitlist, there were 74 deaths (15 cardiovascular deaths; including 7 arrhythmic deaths) and 68 delistings for deterioration. The presence of an ICD was not associated with decreased waitlist mortality (Hazard Ratio 1.19 [0.75-1.88], p = 0.46), waitlist mortality/delisting (Hazard Ratio 1.20 [0.86-1.67], p = 0.28), or cardiovascular wait-list mortality (HR 1.24 [0.45-3.43], p = 0.67) over a median of 5.6 months, Fig. 3. There were numerically fewer
arrhythmic deaths in ICD vs non-ICD groups (2 in the ICD group and 5 in the non-ICD group). In subgroup analyses, ICDs were not associated with decreased waitlist mortality among patients with age groups (b50 vs N50 years), Heartmate II, Heartware, ischemic cardiomyopathy, non-ischemic cardiomyopathy, status 1A or status 1B. There were significant interactions of outcomes with sex and ethnicity, with statistically increased poor outcomes in women and blacks, Fig. 4. 4. Discussion In the largest propensity-score matched study of ICDs in BTT CF-LVAD, we show that the presence of ICDs at listing was not associated with decreased waitlist or cardiovascular mortality among continuous-flow LVAD patients bridged to heart transplantation, despite numerically fewer arrhythmic deaths. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) in adults has convincingly demonstrated the favorable effects of ICD in primary prevention of SCD in patients with ischemic and non–ischemic dilated cardiomyopathies with New York Heart Association class II or III heart failure and a left ventricular ejection fraction of 35% or below [11,15]. However, the benefit of ICDs in patients with LVADs implanted as bridge to transplantation has not been established and there is a large amount of conflicting literature on this issue. Previous retrospective studies have suggested that ICD implantation in LVAD patients is associated with extended survival [16,17]. However, the majority of these studies were smaller, single centered, also included patient with LVADs as destination therapy, with both continuous and pulsatile flow LVADs. One study evaluated ICD therapy among 144 patients awaiting transplantation with pulsatile LVADs found that ICDs were associated with increased survival (OR 2.72; 95% CI, 1.03– 7.16; P = 0.04) [17]. However, another retrospective report included 106 patients with heartmate II, concluded that VTAs post LVAD were not associated with worse prognosis, and ICD implantation in this population may not reduce mortality (HR, 1.12 [0.37–3.35]) (12). In addition, a more recent study of 94 patients with continuous flow LVADs found no difference in survival between patients with or without ICD. The authors recommended no ICD generator change for patients without VTAs prior to LVAD implantation despite the fact that only 18% of study patients had no ICD (13). VTAs have been observed to occur with greater frequency after LVAD implantation, although reported incidence varies widely in observational
Fig. 1. Study Cohort Flow Chart.
Please cite this article as: A. Younes, et al., Presence of Implantable Cardioverter-Defibrillators and Wait-List Mortality of Patients Supported with Left Ventricular Assist Dev..., Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.148
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Table 1 Patient characteristics with or without ICD. Before Propensity Score Matching
Age at listing (years) Male Ethnicity White Black Other Initial status 1A 1B 7 Blood type A B AB O Creatinine BMI (kg/m2) Cigarette use Diabetes Type of Device Heartmate 2 Heartware Ischemic disease Therapies Ventilator IABP ECMO Inotropes Hemodynamics PA mean pressure (mmHg) PASP (mmHg) PADP (mmHg) Cardiac output (L/min) PCWP (mmHg) PVR (Wood Units)
ICD (n = 2890)
p-value
No ICD (n = 722)
ICD (n = 722)
p-value
49.9 ± 13.6 558 (75.8%)
54.0 ± 11.2 2354 (81.5%)
b0.001 0.001 0.02
50.4 ± 13.2 553 (76.6%)
51.4 ± 12.4 556 (77.0%)
0.126 0.901 0.593
478 (64.9%) 174 (23.6%) 84 (11.4%)
1856 (64.2%) 785 (27.2%) 249 (8.6%)
467 (64.7%) 172 (23.8%) 83 (11.5%)
457 (63.3%) 188 (26.0%) 77 (10.7%)
201 (27.3%) 499 (67.8%) 36 (4.9%)
925 (32.0%) 1832 (63.4%) 133 (4.6%)
195 (27%) 491 (68%) 36 (5%)
224 (31%) 466 (64.5%) 32 (4.4%)
285 (38.7%) 82 (11.1%) 28 (3.8%) 341 (46.3%) 1.2 ± 0.8 27.7 ± 4.6 351 (47.7%) 227 (30.8%)
990 (34.3%) 389 (13.5%) 97 (3.4%) 1414 (48.9%) 1.3 ± 0.6 29.0 ± 5.0 1647 (57.0%) 996 (34.5%)
282 (39.1%) 82 (11.4%) 25 (3.5%) 333 (46.1%) 1.2 ± 0.8 27.8 ± 4.5 350 (48.5%) 224 (31%)
269 (37.3%) 83 (11.5%) 28 (3.9%) 342 (47.4%) 1.2 ± 0.6 27.8 ± 5.1 357 (49.4%) 237 (32.8%)
628 (85.3%) 108 (14.7%) 428 (58.2%)
2529 (87.5%) 361 (12.5%) 1722 (59.6%)
0.501
616 (85.3%) 106 (14.7%) 306 (42.4%)
625 (86.6%) 97 (13.4%) 320 (44.3%)
0.490
19 (2.6%) 18 (2.4%) 6 (0.8%) 60 (8.2%)
63 (2.2%) 39 (1.3%) 6 (0.2%) 221 (7.6%)
0.489 0.045 0.021 0.643
17 (2.4%) 18 (2.5%) 4 (0.6%) 55 (7.6%)
13 (1.8%) 16 (2.2%) 3 (0.4%) 63 (8.7%)
0.581 0.863 1.000 0.501
27.6 ± 10.9 40.0 ± 13.8 19.7 ± 9.7 4.6 ± 1.5 18.4 ± 9.6 2.3 ± 1.7
27.9 ± 10.9 41.3 ± 14.8 19.7 ± 9.4 4.7 ± 1.4 17.8 ± 9.7 2.4 ± 1.6
0.529 0.029 0.879 0.072 0.158 0.160
27.7 ± 10.9 40.2 ± 13.8 19.7 ± 9.7 4.6 ± 1.5 18.4 ± 9.6 2.3 ± 1.7
27.6 ± 11.5 40.2 ± 15.4 19.6 ± 9.9 4.6 ± 1.5 18.2 ± 10.2 2.3 ± 1.7
0.847 0.999 0.828 0.930 0.731 0.871
0.049
Unmatched Treatment Units
Matched Treatment Units
Matched Control Units
Unmatched Control Units
0.4
0.235
0.075
studies [2,4,5,18]. A recent meta-analysis postulated that VTAs before LVAD predicted VTAs after LVAD and were associated with increased mortality; however, up to 30% of patients had LVADs as destination therapy [8]. In addition, ICDs are associated with significant morbidity and impact quality of life. Inappropriate ICD shocks were reported in up to
0.2
After Propensity Score Matching
No ICD (n = 736)
0.6
0.8
1.0
Propensity Score Fig. 2. Distribution of Propensity scores in matched and unmatched patients.
0.038 b0.001 b0.001 0.067 0.124
0.896
0.932 0.914 0.752 0.498 0.545
18% of patients with LVADs [13,16,18] leading patients to request ICD deactivation. Psychosocial distress, particularly anxiety and post-traumatic stress disorder, occur in 13% to 38% of patients with an ICD [19], and ICD discharges have been shown to decrease quality of life substantially [20,21]. Adding to that, the presence of multiple devices markedly increases the risk of infection, which can be detrimental for patients with LVADs listed for transplant [22]. There also appear to be technical implications of ICD placement in LVAD patients. Continuous-flow LVADs have been associated with changes in the performance of preexisting ICDs. Adverse events including over- and under-sensing, electromagnetic interference, and changes in defibrillation threshold, have been reported. Addressing these interactions to maintain appropriate ICD function and prevent inappropriate shock requires both invasive and noninvasive ICD system modification [23–25]. Many have postulated that because LVADs can offer up to ten liters of cardiac output independent of left ventricular function, VTAs have less hemodynamic impact on LVAD patients. As a result, VTAs are often asymptomatic and detected on routine ICD interrogation in the ambulatory setting [26]. To further illustrate the controversy, the 2012 ACCF/AHA/HRS Guidelines for device-based therapy, do not recommend ICD implantation for primary prevention of sudden cardiac death in NYHA Class IV patients [27] and the 2013 ACCF/HRS/AHA/ ASE/HFSA/SCAI/SCCT/SCMR appropriate use criteria assigned a score of 8 (“appropriate”) for patients who are NYHA class IV and listed for heart transplant, but still assigned a score of 6 (“may be appropriate”) if they had an LVAD [15]. In this largest study to-date, the presence of ICD was not associated with reduced mortality in LVAD patients listed for transplant, independent of sex, LVAD type, listing status and even etiology of cardiomyopathy. These results suggest that routine ICD implantation to reduce
Please cite this article as: A. Younes, et al., Presence of Implantable Cardioverter-Defibrillators and Wait-List Mortality of Patients Supported with Left Ventricular Assist Dev..., Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.148
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Fig. 3. Wait-list mortality or delisting in matched patients with or without ICD.
waitlist mortality in patients supported with durable LVADs awaiting heart transplantation may be unnecessary. This study has many important limitations that need to be considered. First, this is a retrospective analysis of a large database that only collected ICD information at listing, and not throughout the waiting period. This raises the possibility that some patients without an ICD at time of listing, may have had one implanted during the waiting period and were in fact protected from sudden death. Second, there may be considerable selection bias from the treating cardiologists, indicating that the patients selected not to have ICDs really did not need them or were expected to be transplanted very quickly, as opposed to those who did receive ICDs. Additionally, in this end-stage population, the risk of dying from progressive pump failure is proportionately much higher than the risk of dying from ventricular arrhythmias [28]. Given the short period of time on the wait-list (5.8 months) ICD benefit may not be apparent. Care should be taken to not extrapolate these findings to patients receiving LVAD for destination therapy, because these patients are supported by LVADs much longer and may benefit from ICDs. Lastly, we did not have details on type of defibrillator, presence of cardiac resynchronization therapy, and sensing/defibrillation settings. We also did not have the indications and timing of ICD implantation, history of preoperative VTA, postimplantation shocks, or quality of life information. Nevertheless, the
findings of this large study suggest that ICD in LVAD patients listed for heart transplant is not associated with increased waitlist survival. 5. Conclusions Presence of ICDs at listing in patients bridged to transplantation with durable continuous flow LVADs appears not to be associated with lower waitlist mortality or cardiovascular mortality, despite numerically fewer arrhythmic deaths. Additional prospective studies should be undertaken to confirm these findings. Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. Clinical perspectives There is paucity of data regarding the efficacy of ICD in patients with LVADs. Analysis of a large registry presented here shows no difference in wait-list mortality between patients with or without ICDs. While
Fig. 4. Subgroup Analyses of ICD o wait-list mortality or WLM/delisting.
Please cite this article as: A. Younes, et al., Presence of Implantable Cardioverter-Defibrillators and Wait-List Mortality of Patients Supported with Left Ventricular Assist Dev..., Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.148
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this is hypothesis generating, data presented here do not support routine ICD implantation during LVAD placement. Carefully selected patients with LVAD could be bridged to transplantation without ICDs. Translational outlook Data presented here suggest that carefully selected patients with LVAD may be safely bridged to heart transplantation without ICD. Randomized clinical trials are needed to elucidate the efficacy of implantable defibrillators in patients with left ventricular assist devices. Disclosures None of the authors have any disclosures relevant to this manuscript. References [1] E.A. Rose, A.C. Gelijns, A.J. Moskowitz, et al., Long-term use of a left ventricular assist device for end-stage heart failure, N. Engl. J. Med. 345 (Nov 15 2001) 1435–1443. [2] M.S. Slaughter, J.G. Rogers, C.A. Milano, et al., Advanced heart failure treated with continuous-flow left ventricular assist device, N. Engl. J. Med. 361 (Dec 3 2009) 2241–2251. [3] E.J. Birks, A changing trend toward destination therapy: are we treating the same patients differently? Tex. Heart Inst. J. 38 (2011) 552–554. [4] O. Ziv, J. Dizon, A. Thosani, Y. Naka, A.R. Magnano, H. Garan, Effects of left ventricular assist device therapy on ventricular arrhythmias, J. Am. Coll. Cardiol. 45 (May 3 2005) 1428–1434. [5] M. Andersen, R. Videbaek, S. Boesgaard, K. Sander, P.B. Hansen, F. Gustafsson, Incidence of ventricular arrhythmias in patients on long-term support with a continuous-flow assist device (HeartMate II), J. Heart Lung Transplant 28 (Jul 2009) 733–735. [6] M.S. Slaughter, J.G. Rogers, C.A. Milano, et al., Advanced Heart Failure Treated with Continuous-Flow Left Ventricular Assist Device, N. Engl. J. Med. 361 (2009) 2241–2251. [7] J.D. Harding, V. Piacentino 3rd, S. Rothman, S. Chambers, M. Jessup, K.B. Margulies, Prolonged repolarization after ventricular assist device support is associated with arrhythmias in humans with congestive heart failure, J. Card. Fail. 11 (Apr 2005) 227–232. [8] N. Makki, O. Mesubi, C. Steyers, B. Olshansky, W.T. Abraham, Meta-Analysis of the Relation of Ventricular Arrhythmias to All-Cause Mortality After Implantation of a Left Ventricular Assist Device, Am. J. Cardiol. 116 (Nov 1 2015) 1385–1390. [9] M.C. Busch, M. Haap, A. Kristen, C.S. Haas, Asymptomatic sustained ventricular fibrillation in a patient with left ventricular assist device, Ann. Emerg. Med. 57 (Jan 2011) 25–28. [10] M.C. Oz, E.A. Rose, J. Slater, J.J. Kuiper, K.A. Catanese, H.R. Levin, Malignant ventricular arrhythmias are well tolerated in patients receiving long-term left ventricular assist devices, J. Am. Coll. Cardiol. 24 (Dec 1994) 1688–1691. [11] G.H. Bardy, K.L. Lee, D.B. Mark, et al., Amiodarone or an implantable cardioverterdefibrillator for congestive heart failure, N. Engl. J. Med. 352 (Jan 20 2005) 225–237. [12] A.J. Moss, W. Zareba, W.J. Hall, H. Klein, D.J. Wilber, D.S. Cannom, J.P. Daubert, S.L. Higgins, M.W. Brown, M.L. Andrews, Multicenter Automatic Defibrillator Implantation Trial III. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction, N. Engl. J. Med. 346 (Mar 21 2002) 877–883. [13] A.D. Enriquez, B. Calenda, M.A. Miller, A.C. Anyanwu, S.P. Pinney, The role of implantable cardioverter-defibrillators in patients with continuous flow left ventricular assist devices, Circ. Arrhythm. Electrophysiol. 6 (Aug 2013) 668–674.
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Please cite this article as: A. Younes, et al., Presence of Implantable Cardioverter-Defibrillators and Wait-List Mortality of Patients Supported with Left Ventricular Assist Dev..., Int J Cardiol (2016), http://dx.doi.org/10.1016/j.ijcard.2016.12.148