Effect of Continued Cardiac Resynchronization Therapy on Ventricular Arrhythmias After Left Ventricular Assist Device Implantation

Effect of Continued Cardiac Resynchronization Therapy on Ventricular Arrhythmias After Left Ventricular Assist Device Implantation John William Schleifer, MDa,b, Farouk Mookadam, MBBCha, Evan P. Kransdorf, MD, PhDa, Udai Nanda, DOc, Jonathon C. Adams, MDd, Stephen Cha, MSce, Octavio E. Pajaro, MD, PhDf, David Eric Steidley, MDa, Robert L. Scott, MD, PhDa, Tomas Carvajal, MDg, Rayya A. Saadiq, DOb, and Komandoor Srivathsan, MDa,* Cardiac resynchronization therapy (CRT) reduces ventricular arrhythmia (VA) burden in some patients with heart failure, but its effect after left ventricular assist device (LVAD) implantation is unknown. We compared VA burden in patients with CRT devices in situ who underwent LVAD implantation and continued CRT (n [ 39) to those who had CRT turned off before discharge (n [ 26). Implantable cardioverter-defibrillator (ICD) shocks were significantly reduced in patients with continued CRT (1.5 – 2.7 shocks per patient vs 5.5 – 9.3 with CRT off, p [ 0.014). There was a nonsignificant reduction in cumulative VA episodes per patient with CRT continued at discharge (42 – 105 VA per patient vs 82 – 198 with CRT off, p [ 0.29). On-treatment analysis by whether CRT was on or off identified a significantly lower burden of VA (17 – 1 per patient-year CRT on vs 37 – 1 per patient-year CRT off, p <0.0001) and ICD shocks (1.2 – 0.3 per patient-year CRT on vs 1.7 – 0.3 per patient-year CRT off, p [ 0.018). In conclusion, continued CRT is associated with significantly reduced ICD shocks and VA burden after LVAD implantation. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;118:556e559)

Several clinical trials have demonstrated that cardiac resynchronization therapy (CRT) with biventricular pacing improves symptoms, cardiac function, and mortality in patients with heart failure with a reduced ejection fraction and a wide QRS complex.1e6 CRT appears to reduce the burden of ventricular arrhythmias (VAs) in some subgroups in these studies.7e12 A small number of patients with chronic heart failure progress to medically refractory disease, requiring durable mechanical cardiovascular support with a continuous flow left ventricular assist device (LVAD). The number of patients implanted with LVADs is increasing,13 but patients with LVADs were not included in prospective trials of CRT devices. Many patients with LVADs have previously implanted CRT devices, but the effect of continuing CRT in these patients is unknown. We hypothesized that continued CRT would significantly reduce VA burden or

Departments of aCardiovascular Diseases, fCardiac and Thoracic Surgery, and gAnesthesiology, Mayo Clinic Arizona, Phoenix, Arizona; bDepartment of Cardiology and Vascular Medicine, Mayo Clinic, Rochester, Minnesota; cDepartment of Internal Medicine, Maricopa Medical Center, Phoenix, Arizona; dDepartment of Cardiology, North Central Heart, Avera Heart Hospital of South Dakota, Sioux Falls, South Dakota; eDepartment of Research Biostatistics, Mayo Clinic Arizona, Scottsdale, Arizona. Manuscript received March 1, 2016; revised manuscript received and accepted May 23, 2016. This study was conducted at Mayo Clinic Hospital, Phoenix, Arizona. See page 559 for disclosure information. *Corresponding author: Tel: (þ1) 480-342-1695; fax: (þ1) 480-3421606. E-mail address: [email protected] (K. Srivathsan). 0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.05.050

appropriate implantable cardioverter-defibrillator (ICD) shocks after LVAD implantation. Methods All patients with existing CRT devices implanted with a continuous flow LVAD from January 1, 2007, to December 31, 2012, at a single institution who provided informed consent were included in this study. All data were prospectively collected by regular clinical follow-up at our institution and remote or in-clinic ICD interrogations every 3 months. Patients in whom CRT was continued after discharge after LVAD implantation were included in group 1, and patients in whom CRT was turned off were included in group 2. The decision to turn off CRT was made at the discretion of the treating clinicians. Reasons for turning CRT off included lead malfunction, new onset diaphragm stimulation, battery preservation concerns, and lead extraction because of device infection. Patient demographics, cardiovascular history, laboratory data, ICD interrogations, medication changes, hospitalizations, and device-related surgical interventions were reviewed. VA events were defined as distinct arrhythmia episodes recorded by the ICD within the programmed monitor and therapy zones, excluding nonsustained ventricular tachycardia but including episodes recorded in monitor-only zones and episodes treated by antitachycardia pacing (ATP) or ICD shock. All episodes were confirmed by visual inspection of intracardiac electrograms. Cumulative VA events were defined as the sum of VA events recorded by the ICD between LVAD implantation and termination of data collection at death, heart transplantation, LVAD explantation, or www.ajconline.org

Heart Failure/Ventricular Arrhythmias, LVAD With CRT

557

Table 1 Baseline characteristics of patients with a cardiac resynchronization therapy (CRT) device in situ undergoing left ventricular assist device (LVAD) implantation Variable

CRT On (n ¼ 39)

CRT Off (n ¼ 26)

P Value

Men Age at LVAD implantation (years) Body mass index (kg/m2) Ischemic cardiomyopathy Hypertension Atrial fibrillation Diabetes mellitus Serum creatinine (mg/dL) Serum sodium (mmol/L) Brain natriuretic peptide (pg/mL) Native QRS duration (ms) Paced QRS duration (ms) LV ejection fraction LV end-diastolic dimension (mm) ICD implanted for primary prevention Ventricular arrhythmias prior to LVAD ICD shocks prior to LVAD implantation Days between ICD and LVAD implantations Implanted with HeartMate II LVAD implanted as bridge to transplantation Antiarrhythmic at discharge Beta-blocker at discharge

31 (79%) 62  13

24 (92%) 62  14

0.16 0.92

27  6 15 (38%) 11 (28%) 23 (59%) 15 (38%) 1.2  0.4 134  5 1233  1056 141  27 168  23 17%  6% 72  9 33 (85%)

28  6 16 (62%) 8 (31%) 19 (73%) 10 (38%) 1.3  0.4 134  5 799  560 138  43 164  24 18%  6% 71  12 17 (65%)

0.49 0.07 0.82 0.24 1.00 0.46 0.98 0.11 0.87 0.44 0.73 0.87 0.07

20 (51%)

15 (58%)

0.61

Table 2 Ventricular arrhythmias and subsequent clinical events after left ventricular assist device implantation, analyzed according to whether cardiac resynchronization therapy was continued at discharge or turned off

16 (41%)

13 (50%)

0.48

Variable

718  505

654  617

0.65

34 (87%) 18 (46%)

23 (88%) 8 (31%)

0.88 0.21

16 (41%) 15 (38%)

13 (50%) 13 (50%)

0.48 0.36

VA per patient Total ICD shocks per patient Inappropriate ICD shocks per patient VA treated with antitachycardia pacing per patient Hospitalizations after LVAD implantation per patient Patients requiring LVAD pump exchanges ICD pulse generator changes

Data expressed as number (%) or mean  SD. ICD ¼ implantable cardioverter-defibrillator; LV ¼ left ventricle; LVAD ¼ left ventricular assist device.

completion of the study. VA burden was defined as the mean VA events per patient per year. All ICD programming was at the discretion of the treating clinicians, with the general principals of long VA detection times, high-rate thresholds for device therapies, and several attempts at ATP before ICD shock, strategies that have been associated with improved outcomes.14,15 This study was performed under an approved institutional review board protocol. Informed consent was obtained from all individual participants included in the study. Descriptive statistics (including mean and SD for continuous variables and frequency and percentage for categorical variables) were used for demographic data. Twosample t test, one-way analysis of variance, Fisher’s exact test, and Pearson chi-square test were used to compare 2 groups when appropriate. Regression analyses with a stepwise elimination approach were used to find predictors for VA after LVAD implantation. Survival curves were constructed by the KaplaneMeier method and compared by the log-rank test. Any p value <0.05 was considered as statistically significant. Statistical analyses were performed with SAS, version 9.4 software (SAS Institute Inc., Cary, North Carolina).

Figure 1. A KaplaneMeier survival curve comparing survival free of death or heart transplantation in patients whether CRT was continued after discharge, with no significant difference between groups (p ¼ 0.7).

CRT On (n ¼ 39) 42 1.5 0.7 19

   

105 2.7 2.2 64

CRT Off (n ¼ 26)

P Value

   

0.29 0.014 0.81 0.27

82 5.5 0.6 52

198 9.3 2.2 168

4.5  4.2

7.6  8.5

0.06

8 (21%)

8 (31%)

0.51

10 (26%)

11 (42%)

0.29

Data expressed as number (%) or mean  SD. ICD ¼ implantable cardioverter-defibrillator; LVAD ¼ left ventricular assist device; VA ¼ ventricular arrhythmia.

Results HeartMate II (Thoratec, Pleasanton, California) or HeartWare (HeartWare International, Inc., Framingham, Massachusetts) continuous flow LVADs were implanted in 93 patients from January 1, 2007, to December 31, 2012, at our institution. Sixty-five patients (70% of all patients implanted) had functioning CRT defibrillators, and these patients were included in this study. The patients’ mean age was 62 years (range 26 to 79 years); 55 (85%) were men, and 31 (48%) had ischemic cardiomyopathy. The indication for ICD implantation was primary prevention in 50 patients (77%); 35 patients (54%) had VA events documented between ICD and LVAD implantation, and 29 (45%) received appropriate ICD shocks before LVAD implantation. The mean time between CRT device implantation to LVAD implantation was 693  549 days (median 576, range 14 to 1,947 days). The indication for LVAD implantation was bridge to transplantation in 26 patients (40%) and destination therapy in 39 patients (60%). After discharge after LVAD implantation, 39 patients (60%) continued CRT and

558

The American Journal of Cardiology (www.ajconline.org)

support, 5 of whom were awaiting transplant. Orthotopic heart transplantation was performed for 15 patients (23%). There was no significant difference in survival between groups, as shown in Figure 1. VA episodes and ICD therapies are compared between groups in Table 2. Patients with continued CRT had fewer cumulative VA episodes, including those requiring treatment with ATP or ICD shocks. Figure 2 compares cumulative VA events between groups, including VA requiring treatment with ICD shocks or ATP. The number of ICD pulse generator changes was not significantly different between groups. Only 1 patient required >1 pulse generator change because of continued CRT with an elevated left ventricular lead threshold. CRT was turned off in all patients in group 2 during the hospitalization for LVAD implantation and at a later time in 12 patients (31%) in group 1. The VA burden based on CRT being on or off was calculated based on 837 VA over 50.8 patient-years with CRT on and 2,955 VA over 82.5 patientyears with CRT off. Therefore, the overall burden of VA was 16.5  1.1 VA per patient-year with CRT on and 35.8  1.3 VA per patient-year with CRT off (p <0.0001). There were 61 ICD shocks with CRT on and 142 ICD shocks with CRT off, giving an overall burden of ICD shocks of 1.2  0.3 per patient-year with CRT on and 1.7  0.3 per patientyear with CRT off (p ¼ 0.018). Three patients had CRT turned off due to a heavy VA burden; 2 of these patients had a reduction in VA burden with CRT off. Multivariate regression analysis of baseline clinical variables was performed for the entire cohort of 93 patients undergoing LVAD implantation to determine predictors of VA. Variables analyzed included age, origin of cardiomyopathy (ischemic vs nonischemic), severity of heart failure (ejection fraction and brain natriuretic peptide levels), and electrophysiologic parameters (history of atrial fibrillation, VA before LVAD implantation, QRS width >150 ms, and dependence on ventricular pacing). VA after LVAD implantation was best predicted by a history of previous VA (p ¼ 0.049). Discussion

Figure 2. Distribution of cumulative VA events (A), defibrillator shocks (B), and ATP therapies (C), comparing patients with CRT on to those with CRT off.

were analyzed as group 1; the 26 remaining patients with CRT turned off were analyzed in group 2. There were no significant baseline differences between groups, as indicated in Table 1. Mean duration of follow-up was 2.1 years (median 1.6 years, range 1 day to 6.3 years). During the follow-up period, 29 patients (45%) died while on LVAD

Our data show a significant reduction in cumulative appropriate ICD shocks and a trend toward reduction in cumulative VA events in patients with continued CRT at discharge after LVAD implantation. The burden of VA events and ICD shocks per patient-year were significantly reduced with CRT on. However, the strongest predictor of VA after LVAD implantation is VA before LVAD implantation, as shown by multivariate analysis. Our finding that VA before LVAD implantation predicted VA after LVAD implantation is consistent with previous studies,16,17 but these studies did not assess cumulative VA events and ICD shock burdens. The implications of our study are significant considering many patients undergoing LVAD implantation will have CRT devices previously implanted, as was the case in 70% of our patients undergoing LVAD implantation. Currently, there is no consensus regarding CRT device management in LVAD patients. We studied a homogenous population who already had CRT devices in situ with no significant baseline

Heart Failure/Ventricular Arrhythmias, LVAD With CRT

differences among multiple clinical variables. The reduction in ICD shock burden and VA rates seen in our study is a benefit of continued CRT that should be validated in a randomized prospective trial of LVAD patients. An objection to continued CRT in LVAD patients is accelerated depletion of the ICD battery; however, there was no significant difference in pulse generator changes between groups. Only 1 (2.6%) of the 39 patients with continued CRT had an elevated left ventricular pacing threshold resulting in accelerated battery depletion and required 3 pulse generator replacements in the study period. Reduced VA burden provides a compelling reason to continue CRT despite the small possibility of accelerated battery depletion. Strengths of this study are in the number of patients analyzed and the completeness of the data available, with mean follow-up >2 years per patient and no gaps in ICD interrogation information. No patients were lost to followup. In addition, our study includes the largest reported population of patients with CRT devices in situ at the time of LVAD implantation. Analyses of our data both by the device setting at time of discharge and at time of VA event confirm the internal consistency of our data. In addition, analyzing VA burden based on whether CRT was continued on discharge after LVAD implantation represents a relevant, real-world decision facing all clinicians who care for patients with CRT devices undergoing LVAD implantation. Study limitations are related to the nonrandom determination of whether CRT would be continued. Intergroup differences, although not reaching statistical significance, may have affected our results. Device settings were programmed at the treating clinician’s discretion and not standardized across the study. This limits our study by affecting the recording of VA events by ICDs, which by its very nature is dependent on the programmed monitor and therapy zones of the device. Therefore, slow VA events below the lower limit of the monitor zone will be missed, and the application of ATP or shock therapies will vary based on these programmed settings. In addition, follow-up duration is limited by cardiac transplantation. The longest surviving patients with LVAD support are typically patients with significant co-morbid medical conditions that make them candidates for destination therapy only. The palliative nature of destination therapy in LVAD patients may lead to less aggressive ICD programming than in patients awaiting cardiac transplantation.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

Disclosures The authors have no conflicts of interest to disclose. 15. 1. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J; MIRACLE Study Group. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845e1853. 2. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, DiCarlo L, DeMets D, White BG, DeVries DW, Feldman AM; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140e2150. 3. Cleland JGF, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L; Cardiac Resynchronization—Heart Failure

16.

17.

559

(CARE— HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539e1549. Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, Hohnloser SH, Nichol G, Birnie DH, Sapp JL, Yee R, Healey JS, Rouleau JL; Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators. Cardiac-resynchronization therapy for mildto-moderate heart failure. N Engl J Med 2010;363:2385e2395. Gold MR, Daubert JC, Abraham WT, Hassager C, Dinerman JL, Hudnall JH, Cerkvenik J, Linde C. Implantable defibrillators improve survival in patients with mildly symptomatic heart failure receiving cardiac resynchronization therapy: analysis of the long-term follow-up of remodeling in systolic left ventricular dysfunction (REVERSE). Circ Arrhythm Electrophysiol 2013;6:1163e1168. Goldenberg I, Kutyifa V, Klein HU, Cannom DS, Brown MW, Dan A, Daubert JP, Estes NAM 3rd, Foster E, Greenberg H, Kautzner J, Klempfner R, Kuniss M, Merkely B, Pfeffer MA, Quesada A, Viskin S, McNitt S, Polonsky B, Ghanem A, Solomon SD, Wilber D, Zareba W, Moss AJ. Survival with cardiac-resynchronization therapy in mild heart failure. N Engl J Med 2014;370:1694e1701. Ouellet G, Huang DT, Moss AJ, Hall WJ, Barsheshet A, McNitt S, Klein H, Zareba W, Goldenberg I. Effect of cardiac resynchronization therapy on the risk of first and recurrent ventricular tachyarrhythmic events in MADIT-CRT. J Am Coll Cardiol 2012;60:1809e1816. Ermis C, Seutter R, Zhu AX, Benditt LC, VanHeel L, Sakaguchi S, Lurie KG, Lu F, Benditt DG. Impact of upgrade to cardiac resynchronization therapy on ventricular arrhythmia frequency in patients with implantable cardioverter-defibrillators. J Am Coll Cardiol 2005;46: 2258e2263. Thijssen J, Borleffs CJW, Delgado V, van Rees JB, Mooyaart EAQ, van Bommel RJ, van Erven L, Boersma E, Bax JJ, Schalij MJ. Implantable cardioverter-defibrillator patients who are upgraded and respond to cardiac resynchronization therapy have less ventricular arrhythmias compared with nonresponders. J Am Coll Cardiol 2011;58: 2282e2289. Eickholt C, Siekiera M, Kirmanoglou K, Rodenbeck A, Heussen N, Schauerte P, Lichtenberg A, Balzer J, Rassaf T, Perings S, Kelm M, Shin DI, Meyer C. Improvement of left ventricular function under cardiac resynchronization therapy goes along with a reduced incidence of ventricular arrhythmias. PLoS One 2012;7:e48926. Kutyifa V, Pouleur AC, Knappe D, Al-Ahmad A, Gibinski M, Wang PJ, McNitt S, Merkely B, Goldenberg I, Solomon SD, Moss AJ, Zareba W. Dyssynchrony and the risk of ventricular arrhythmias. JACC Cardiovasc Imaging 2013;6:432e444. Gold MR, Linde C, Abraham WT, Gardiwal A, Daubert JC. The impact of cardiac resynchronization therapy on the incidence of ventricular arrhythmias in mild heart failure. Heart Rhythm 2011;8: 679e684. Kirklin JK, Naftel DC, Pagani FD, Kormos RL, Stevenson LW, Blume ED, Myers SL, Miller MA, Baldwin JT, Young JB. Seventh INTERMACS annual report: 15,000 patients and counting. J Heart Lung Transpl 2015;34:1495e1504. Ruwald AC, Schuger C, Moss AJ, Kutyifa V, Olshansky B, Greenberg H, Cannom DS, Estes NAM 3rd, Ruwald MH, Huang DT, Klein H, McNitt S, Beck CA, Goldstein R, Brown MW, Kautzner J, Shoda M, Wilber D, Zareba W, Daubert JP. Mortality reduction in relation to implantable cardioverter defibrillator programming in the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT). Circ Arrhythm Electrophysiol 2014;7:785e792. Mastenbroek MH, Pedersen SS, van der Tweel I, Doevendans PA, Meine M. Defibrillator programming to reduce therapies and improve quality of life (from the ENHANCED-ICD study). Am J Cardiol 2016;117:596e604. Garan AR, Yuzefpolskaya Y, Colombo PC, Morrow JP, Te-Frey R, Dano D, Takayama H, Naka Y, Garan H, Jorde UP, Uriel N. Ventricular arrhythmias and implantable cardioverter-defibrillator therapy in patients with continuous-flow left ventricular assist devices: need for primary prevention? J Am Coll Cardiol 2013;61:2542e2550. Gopinathannair R, Birks EJ, Trivedi JR, McCants KC, Sutton BS, Deam AG, Slaughter MS, Hottigoudar RU. Impact of cardiac resynchronization therapy on clinical outcomes in patients with continuous-flow left ventricular assist devices. J Card Fail 2015;21: 226e232.