There has been increasing use of continuous-flow left ventricular assist devices (CF-LVAD) as data have shown improved survival compared with earlier devices.1 Many patients undergoing implantation of a CF-LVAD have a cardiac implantable electrical device (CIED: pacemaker, implantable cardioverter defibrillator [ICD] or cardiac resynchronization therapy device with or without defibrillation [CRT-D or CRT-P, respectively]) before implant, often performed as primary or secondary prophylaxis for life-threatening arrhythmia as a result of pivotal studies.2–4 However, once implantation of an LVAD proceeds, the incidence of ventricular arrhythmias (VAs) is typically higher than baseline rates or remains elevated.5–8 Evidence of increased incidence of arrhythmias has prompted consideration of prophylactic implantation of an ICD in this population,9,10 although other studies suggest that ICDs may not impart a survival advantage.11
Despite the high prevalence of this dual device therapy, concerns about negative interactions between the two devices persist. Electrical interference was considered a theoretical risk;12 however, utilization of a CIED in LVAD patients has not revealed a significant effect.13 There are changes in lead parameters, such as changes in lead sensing and capture,14 lead impedance, and amplitude12 after LVAD implantation that may affect performance of the CIED device.14
The long-term incidence of clinically significant arrhythmias has not been fully investigated. Studies have rarely used CIED data to comprehensively analyze arrhythmia events. Furthermore, the trends in these arrhythmias over time have not been investigated with device-level data in conjunction with long-term changes in electrical parameters and medication usage, which could serve to increase the cumulative understanding of electrical changes in the myocardium, prompting changes in medical management and questions of prophylactic ICD placement. Our purpose was to thoroughly investigate the changes in electrical parameters and arrhythmias over time after implantation of a LVAD in patients with CIED, specifically ICD or CRT-D, using device-level data. We also sought to compare early arrhythmias to a control set of cardiac surgery patients to determine unique LVAD implantation-related factors, such as ventriculotomy, may be related to arrhythmic events.
We conducted a retrospective review of 178 consecutive patients who had a previous CIED (Boston Scientific/Guidant [Boston Scientific Corporation, Marlborough, MA]; Medtronic [Medtronic plc, Dublin, Ireland]; or St. Jude [St. Jude Medical, Inc., St. Paul, MN]) in place and were implanted with a continuous-flow LVAD (Heartmate II [Thoratec Corp, Pleasanton, CA]; Ventrassist [Ventracor Ltd., Sydney, Australia]; or HeartWare [HeartWare International, Inc., Framingham, MA]) from November 2005 to April of 2010 at a single institution. All CIEDs in this study were ICD or CRT-D. A list of all mechanical circulatory support patients is kept for administrative purposes and all patients in the database have consented to utilization of their medical data for research purposes. The Institutional Review Board at the University of Minnesota approved the current study.
Data were gathered from the electronic and paper medical records and primary CIED interrogation records. Baseline characteristics were obtained, including device type, etiology of heart failure and pertinent electrophysiological, clinical data, such as history of atrial fibrillation, ablations, and ventricular ablations. Preoperative medication data were obtained, including standard heart failure medications, inotropes, and antiarrhythmic medications.
CIED device data included indication for implant; history of ICD shocks; brand and model of CIED (all CRT devices were CRT-D); lead impedance, amplitude, pulse width and sensitivity; mode; and episodes or events. Atrial events were derived from device-level data, including supraventricular tachycardia episodes and time in atrial fibrillation. Two types of VAs were identified: monitored VA episodes, defined as slow ventricular tachycardia and nonsustained ventricular tachycardia within the “monitor” zone (without programmed therapies based on device-level programming), and treated VA episodes, defined as ventricular fibrillation or ventricular tachycardia within the “treat” zone, which received therapies. Therapies for treated episodes included multiple options for ATP or shocks, with some devices including an option for ATP during initial capacitor charge. All decisions regarding programming thresholds were left to the discretion of individual clinicians. Baseline rates of arrhythmias were derived from interrogations within 1 year before LVAD implant. Preimplant and postimplant 12 lead EKG interval data were obtained.
Postimplant medications at discharge, CIED lead data, including impedance, programmed amplitude and pulse width, and sensitivity were obtained. Postimplant medications were medications given at the time of discharge from the implantation hospitalization. All LVADs were functioning properly at the time of discharge as well. Monitored and treated episodes in the first 30 days postimplant were extracted from CIED-level data and episodes over the subsequent 150 days were compared (days 30–180 postimplant).
A cohort of 38 patients with a CIED in place who underwent any cardiac surgery via sternotomy were obtained for comparison to the LVAD cohort. These patients were gathered to control for surgical factors related to cardiac surgery as they relate to arrhythmias in the postoperative setting. Surgeries included any combination of valve replacement (mitral: 34%, aortic: 34%), coronary artery bypass grafting (34%), MAZE (8%), and pericardiectomy/pericardial window (5%), and none of the control surgeries included ventriculotomy. All the baseline data and postsurgical data were obtained in a similar fashion to the LVAD patients.
Characteristics between groups were compared using the t test or Fisher’s exact test as appropriate. Matched data were compared with a matched pair t test for continuous data or McNemar’s test for binomial data as appropriate. Postsurgical quantitative variables, e.g., monthly-adjusted arrhythmias, were compared between the surgical groups using analysis of covariance (ANCOVA) including the baseline value as a covariate. For treated ventricular episode and event data, values used in the analysis were capped at 10, i.e., values greater than 10 were replaced by 10, to reduce the influence of outliers. Odds ratios (ORs) were used to assess risk factors for VAs. Survival analysis was conducted using log-rank tests between Kaplan–Meier curves. For survival analysis involving postsurgery assessments, landmark analysis was conducted to avoid immortality bias.15 Distribution of survival times were assessed and landmark time was determined to be 28 days or 6 months, depending on the predictor. All data were analyzed using JMP 10 Pro (SAS Institute Inc., Cary, NC).
Baseline characteristics are described in Table 1. Baseline characteristics for LVAD patients (n = 178) include a mean (± SD) age of 57 ± 14 years, 81% male, 58% with an ischemic etiology of heart failure. Thirty-seven percent of LVAD patients had a history of atrial fibrillation. Six percent of the LVAD patients had a history of ventricular tachycardia ablation. The distribution of CIED devices was 44% ICD and 56% CRT. Left ventricular assist device patients were followed for a median of 14.4 months (IQR: 6.5, 26.8). 8.5% of patients were lost to follow-up during the study period. There were no major LVAD malfunctions during the follow-up period (pump thrombosis or need for exchange).
Medications before and after LVAD implant are also presented in Table 1. Beta-blocker usage decreased from 76% preimplant to 27% at discharge on LVAD therapy (p < 0.01). ACE inhibitor or angiotensin receptor blocker (ACEi/ARB) usage decreased as well from 69% preimplant to 26% at discharge on LVAD therapy (p < 0.01). Aldosterone antagonist usage decreased from 33% to 6% (p < 0.01). Oral potassium supplementation increased after LVAD placement with 63% discharged with oral potassium replacement compared with 34% preimplant (p < 0.01). Amiodarone use increased significantly after implant from 30% to 47% (p < 0.01), while decreasing in the control group (p < 0.01). Milrinone and dobutamine were typically stopped. Sotalol use decreased from 4% to 2% (p = 0.25), whereas dofetilide was rarely used and mexiletine use did not change (4% to 5%, p = 0.71).
Electrocardiographic and CIED Data
Trends in electrocardiographic data are shown in Table 2. At a median follow-up time of 30 days postimplant (IQR: 14, 110), QRS duration decreased significantly (149 to 128 ms, p < 0.01). QT interval decreased significantly (449 to 412 ms, p < 0.01) and heart rate increased from 83 to 98 bpm (p < 0.01) such that QTc did not change significantly (520 to 522, p = 0.85). QTc changes were independent of amiodarone use (p = 0.15). Cardiac implantable electrical device parameters were notable for decreases in most mean lead impedances: RA (491 to 463 Ω, p = 0.01), RV (460 to 451 Ω, p = 0.27), LV (551 to 505 Ω, p < 0.01), and HV (42 to 38 Ω, p < 0.01). In comparison, no significant changes in lead impedances were observed in the control patients: RA (459 to 432 Ω, p = 0.88), RV (493 to 453 Ω, p = 0.24), LV (391 to 423 Ω, p = 0.86), and HV (41 to 38 Ω, p = 0.45).
Arrhythmias in the LVAD Population
The occurrence of arrhythmias in the pre- and post-implant setting was compared. Frequency of arrhythmias over time was analyzed (Table 3 and Figure 1). Monthly mean rates of arrhythmias were assessed preimplant, within 30 days after LVAD implant, and days 30–180 after LVAD implant. There were no differences in time in atrial fibrillation (10% to 12%, p =0.33), nor percent time ventricularly paced (63% to 59%, p = 0.28) before and after implant. Treated VAs increased from baseline to the first 30 days postimplant (0.46 to 1.6 events/mo, p < 0.01), but did not decrease significantly for the next 5 months (1.6 to 1.1 events/month, p = 0.22). Monitored-zone VAs also increased (2.3 to 4.3 events/month, p < 0.01) but did not decrease significantly toward baseline (4.3 to 3.4 events/month, p = 0.11). Among treated VA, ATP-terminated episodes increased from baseline (0.22 to 0.79 events/month, p < 0.01) but did not decrease significantly after the first month (0.79 to 0.62 events/month, p = 0.46). However, shock-terminated VA episodes increased from baseline (0.37 to 0.89 events/month, p = 0.03) and decreased after 1 month (0.89 to 0.18 events/month, p < 0.01). A similar effect was observed for total shocks (0.36 to 0.88 to 0.23 events/month, p = 0.01 and p < 0.01). Presence of a preimplant VA was associated with postoperative VA (OR 4.31; CI: 1.5–12.3, p < 0.01).
Medication usage in the postimplant period did not generally affect incidence of arrhythmias. Amiodarone use was not associated with a reduction in the incidence of VAs (p = 0.90). The use of beta-blockade in the postimplant setting was associated with a greater incidence of VA (p = 0.02)—an effect which persisted even after adjustment for baseline VAs (p = 0.02). Furthermore, in patients who were treated with beta-blockade preimplant, beta-blocker nonusage at discharge was not associated with increased VAs (p = 0.07).
Cardiac Surgery Control Subjects
The cohort of non-VAD cardiac surgery patients (n = 38) was similar in age and sex distribution to LVAD patients (p = 0.18 and p = 0.08). They had a similar history of AF, AF ablation, and VT ablation (p = 0.10, p = 0.11, and p = 0.57). Similarly, their baseline medication usage only differed in terms of the proportion receiving amiodarone, milrinone, and dobutamine at baseline. Trends in medication usage are shown in Table 1. ANCOVA analysis was performed to adjust for baseline differences between LVAD patients and cardiac surgery control subjects. Differences between groups adjusting for baseline arrhythmias are shown in Table 4. In brief perioperative differences between frequencies of arrhythmias were noted with monitored VAs (p < 0.01), shock-terminated episodes (p = 0.04), and total shocks (p = 0.04). The difference persisted over the next 5 months for monitored VAs and total shocks (p < 0.01 and p = 0.04).
In patients whose QTc increased by 4 weeks, there was an increased mortality (p = 0.02), thereafter, which was not driven by early VAs as rate of arrhythmias did not differ between patients whose QTc increased and those that did not (p = 0.60). However, in patients who experienced increasing QT interval or QRS duration by 4 weeks, we did not see an increase in mortality (p = 0.23 and p = 0.30). Number of ICD shocks before LVAD implant did not predict survival (p = 0.07). Postimplant VF episodes or shocks by 4 weeks postimplant did not predict long-term mortality (p = 0.46 and 0.51), nor did presence VAs during the first 6 months after implantation (p = 0.08), nor early VA (p = 0.55), nor late VA (p = 0.54).
This is the first study to demonstrate interval time effects of clinically significant arrhythmias after LVAD implantation using device-level data in a relatively large CF-LVAD cohort. We describe several notable findings. The first is the demonstration of a rise and subsequent fall in VAs with return to near-baseline rates after 1 month postimplantation. Second, using cardiac surgery control subjects, we demonstrated that early postimplant arrhythmias were often significantly associated with LVAD implant, a procedure that notably includes ventriculotomy, rather than cardiac surgery, per se. Third, we support previous observations of electrocardiographic data,16,17 with decreases in electrocardiographic intervals and provide evidence that lack of improvement is associated with poor outcomes. This reflects the previously described “reverse electric remodeling,” one aspect of the beneficial effects of ventricular unloading by LVAD support.18 We confirm prior CIED-parameter data14 showing lead impedance decreases, likely not clinically significant, with a contemporary (CF-LVAD) cohort. Finally, we extend observations that 1) preimplant VAs predict VAs on LVAD therapy and 2) neither preimplant nor postimplant VAs have a significant effect on mortality.
Ventricular Arrhythmias After LVAD Implantation
Incidence of VAs in the early postoperative period after LVAD implantation have been shown to be high (22–52%).6–8,19–23 It has been argued that underlying electrical changes in the myocardium are responsible for the increases in arrhythmias after LVAD implantation,9 yet some studies have shown history of VAs to be either the most important predictor of significant postimplant arrhythmia8,21 or a significant predictor,11,22,24 suggesting the underlying substrate is the most important factor. Our study supports the substrate theory as preimplant VAs predicted postimplant arrhythmias. However, our data also suggest that ventriculotomy carries a unique risk for increased arrhythmias; we saw increases in each of monitored episodes, shocks, and shock-terminated episodes, with a trend toward an overall increase in treated VAs.
Another pertinent factor is the substantially decreased use of beta-blockade at dismissal (27% from 76% preimplant), which likely resulted in increased heart rates postimplant in the LVAD patients (Table 2). Although heart rates were higher, we did not find a significant correlation between episodes of arrhythmias and beta-blocker withdrawal (p = 0.07), which differs somewhat from prior data where nonusage of beta-blockade was associated with increased arrhythmias.25,26 Although somewhat counterintuitive, our data may reflect withdrawal of beta-blockade in many patients and increased utilization of beta blockade in patients with VAs, representing a shift in indication of beta-blockade from heart failure to secondary prevention of VAs but a sample wide decrease in usage resulting in increased heart rates. Notably, recommendations from general cardiac surgery data suggest beta-blockade postoperatively.27 However, dosing of beta-blockade is limited by the threat of precipitating right-sided heart failure, so more evidence is required before aggressive beta-blocker use is used on patients on LVAD therapy. Increased VA also likely resulted in the increased use of amiodarone seen in our cohort. As previously described, amiodarone was not associated with a decrement in the incidence of VAs.
Prophylactic ICD Therapy
There has been considerable debate about the use of prophylactic ICDs in patients undergoing LVAD implantation. Some have argued that the presence of postimplant VAs supports the need for prophylactic ICD alone,6,10 and others cite evidence that VAs are a risk factor for postimplantation mortality,7,21,28 similar to data in the general heart failure population.29 One large retrospective cohort study, which examined the association of ICD placement before LVAD therapy with long-term survival after LVAD implantation, found a protective effect with ICD therapy.24
However, studies have disagreed regarding the prognostic value of postoperative arrhythmias, challenging the assertion that postimplant arrhythmias are associated with increased mortality.22,30 Furthermore, evidence suggests that LVAD patients with an ICD implantation for primary prevention carry a lower risk of major arrhythmia than secondary prevention8 Given the often strong association between pre- and post-implant VAs, some have suggested that simply the presence of preimplantation VAs could be used to guide management toward implantation of an ICD after LVAD placement.30 Despite the fact that our patients had ICDs in place, our data indicate that neither early nor late VAs predict increased mortality in patients. Furthermore, the morbidity associated with VAs is unclear in the LVAD population.11,31
CIED Device-Level Changes
Consistent with prior data on lead changes after LVAD implantation showing a decrease in lead impedance,12,14 our data in CF-LVAD patients showed that impedances decreased for nearly all leads (RA, LV, and HV). This trend did not hold for patients undergoing other cardiac surgeries as shown in Table 2. Nevertheless, it is not clear whether this is related to maturation of the leads themselves as there is a natural decrease in lead impedance over time.32,33
We acknowledge several limitations to the current study. As it was a retrospective cohort study, it was subject to potential confounders in selection of patients for VAD. These are mitigated by utilizing the sample of all patients with an LVAD and a CIED device. However, the current study was also single center and thus is subject to site-specific practices regarding CIED programming and specific device utilization, which can jeopardize generalizability. Overall CIED device interrogation data were not complete, which limits sample size and can result in sampling bias. Arrhythmia episodes were taken from device interrogation without adjudication of individual event; however, data were analyzed using each patient as their own control. Moreover, the occurrence of shocks, per se, is clinically relevant regardless of etiology. Left ventricular assist device flow values were not obtained and thus the bearing of various arrhythmias on hemodynamics in LVAD patients was not adjudicated, although the relationship between various wide-complex rhythms and their hemodynamic effects was not a goal of the current study. Furthermore, we were not able to positively identify suction events with the LVAD patients to the extent that they could be responsible for some of the electrical episodes in our data.
In addition, the number of patients lost to follow-up (8.5%) was high, and this was caused by loss of patients to follow-up at other institutions, either for their CIED device or LVAD management. There was some degree of variability in our postimplantation EKG time because of some of the previously mentioned constraints, which subjects the data to a broader range of confounders. In addition, we were also limited in our ability to analyze cardiac surgery control subjects as our dataset of patients was confined by requiring a contemporary dataset of patients with a pre-existing CIED in place at the time of surgery. Furthermore, these patients tended to have fewer arrhythmias overall compared with the LVAD cohort, which could affect some of our analyses.
Our experience demonstrates time-dependent effects on clinically significant arrhythmias after LVAD implantation, revealing an early increase and late return toward baseline of VAs as well as data suggesting that early LVAD-related arrhythmias are at least in part caused by the unique arrhythmogenic effects of ventriculotomy. We also extend prior observations of electrocardiographic changes, CIED-level data trends, and prior data regarding the risk factors for arrhythmias in their relation to long-term mortality in the LVAD setting. Future studies should prospectively analyze ICD implantation on a randomized sample.
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