Balancing Risk Versus Benefit: Lessons from the REPLACE Registry

Jeanne E. Poole, MD, Marye J. Gleva, MD†, Crystal Miller, MS‡, Kevin Mitchell, RN, BS‡, Richard G. Holcomb, PhD* University of Washington, Seattle, WA; †Washington University School of Medicine, St. Louis, MO; ‡Biotronik Inc., Lake Oswego, OR; *Private practice, Minneapolis, MN
Jeanne E. Poole, MD, Marye J. Gleva, MD†, Crystal Miller, MS‡, Kevin Mitchell, RN, BS‡, Richard G. Holcomb, PhD* University of Washington, Seattle, WA; †Washington University School of Medicine, St. Louis, MO; ‡Biotronik Inc., Lake Oswego, OR; *Private practice, Minneapolis, MN

The relatively high complication rates identified in the REPLACE Registry highlight the need to carefully consider the risk associated with more complex devices. In this article, the authors present the data relevant to this and include data from recent studies for comparative discussion.

The results of the REPLACE Registry have been previously published.1 This article summarizes the trial design, the results and provides practical insights from this study. The REPLACE Registry was a prospective, multicenter study that collected complication data on patients for six months following replacement of a pacemaker, implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) generator.1 The study pre-specified two cohorts of patients undergoing generator replacement: patients without (cohort 1) and those with (cohort 2) the intent to add or revise a transvenous lead(s). We found a 4.0% major complication rate for patients whose planned procedure was generator replacement only and a 15.3% major complication rate for patients with a plan to add or revise a lead at the time of generator replacement.

Patients whose procedure was to add or revise a transvenous left ventricular (LV) lead had the highest overall six-month major complication rate: 18.7%. The results of REPLACE: 1) emphasized the need to consider not only acute surgical complications, but the longer term effects of cardiac implantable electronic device (CIED) replacement procedures; and 2) identified a particularly high risk associated with CRT upgrade procedures.

REPLACE Registry Design and Enrollment

A comprehensive group of pre-defined major and minor complications were collected. Major complications were defined as any surgical or medical adverse event directly related to the enrollment procedure that placed the patient at significant risk requiring an intervention, procedure, or hospitalization for management. Minor complications were unanticipated patient symptoms, events, or a decline in status that were either managed as an outpatient or did not require an intervention, procedure, or hospitalization. Complications were adjudicated by a Clinical Events Committee blinded to institution and site physician. Procedural infectious definitions were adapted from the Center for Disease Control definitions of deep and superficial surgical site infections exclusive of stitch abscesses.2 Physicians could implant any commercially available generator or lead, and the decision to perform a replacement or to upgrade an existing device was determined by each patient’s physician. Patient enrollment began in July of 2007 with the final patient reaching six-month follow-up in June of 2009. Seventy-two U.S. sites participated, which were distributed equally between private practice and academic sites. Complication data were analyzed from a total of 1,031 cohort 1 patients and 713 cohort 2 patients.

Baseline Clinical and Procedural Factors

Compared with the cohort 1 patients (replacement only), a cohort 2 patient (planned lead addition or revision) was more likely to be male, to have had prior cardiac surgery and/or remote myocardial infarction, to have a lower ejection fraction (EF), and to have advanced heart failure (HF) symptoms or have been admitted to the hospital for HF exacerbation in the 12 months prior to the replacement procedure. (Table 1)

Figure 1 shows the existing PM or ICD generator types that the patients had at the time of enrollment and prior to the replacement procedure. Approximately one-half of patients entered into the registry had a pacemaker. The physician-specified indications for generator replacement are shown in Figures 2 and 3 for cohort 1 and cohort 2, respectively. The dominant reason for generator replacement in cohort 1 patients was normal battery depletion (96.7%) with only 1.2% of patients undergoing replacement for an advisory indication. In the majority of cohort 2 patients (57.1%), the indication for the procedure was to upgrade to a CRT from a previously placed pacemaker or ICD.

Complications

A summary of the major, minor, and infectious complications is shown in Table 2. Patients could have experienced more than one major and/or minor complication. A complete listing of complication types for cohort 1 has been previously published.

All complications were considered in two time categories, within 24 hours of the procedure (peri-procedural), and subsequent out to six months. The major complications for cohort 2 are shown in Figures 4 and 5. The peri-procedural major complication rate was 2.4%, including five patients who had a cardiac perforation and six patients with either a pneumothorax or hemothorax. The subsequent major complication rate was 14.0%, including a lead dislodgement or malfunction rate requiring reoperation in 56 patients (7.9%), prolonged hospitalization for worsened HF or renal failure in 18 patients (2.5%, all were CRT upgrades), and eight patient deaths within 30 days of the procedure (1.1%). Further analysis of the eight patient deaths revealed that four patients had a failed attempt to place a transvenous LV lead, were referred for an epicardial LV lead placement and died from subsequent complications. Of the remaining four patient deaths, two patients had a successful placement of a transvenous LV lead, one patient had a successful new RV pace/sense lead and one patient had a successful new RV high voltage (ICD) lead. All four of these patients died following hospital discharge with no alternate explanation for their death.

Analysis of major complications by type of upgrade procedure is shown in Figure 6. The six-month major complication rate for patients who underwent generator replacement with a plan to revise or add a new right atrial or right ventricular lead was 11.1%. The major complication rate for patients who underwent a generator replacement with a plan to revise or add a transvenous LV lead for CRT was 18.7%. In the remaining 45 patients, the physician’s stated plan was to upgrade or revise a lead. However, at the time of the procedure, the physician chose to replace a generator only. This could have occurred, for instance, if a suspected failed lead ultimately tested normal for use. For these patients, the major complication rate was only 4.4%, similar to the complication rate of 4.0% observed in the cohort 1 patients.

Discussion

The number of patients in North America and Europe who have received a new pacemaker, ICD, or CRT has risen over the past years due to expanding therapeutic indications and increased patient longevity.3–11 The results of the REPLACE Registry demonstrated a modest 4.0% complication rate for patients who undergo a generator replacement without a new lead added. These data are similar to prior retrospective multicenter reports, but greater than that reported from retrospective single-center experiences.12-16 The prospective design of the REPLACE Registry with pre-defined and broad capture of complications likely accounts for the differences in reported complications among these studies.

For patients who develop HF symptoms after initial PM or ICD placement, CRT is often considered. Minimal data has been available to understand the consequences of upgrade procedures in these individuals. Several small retrospective studies have reported complication rates between 8.3% and 45.5% in a combined total of 179 patients.17–20

The prospective REPLACE Registry was the first multicenter study to demonstrate both the acute surgical and longer term risks of upgrade procedures. The reason for this high complication rate may relate to the challenges faced with adding more leads to venous structures with existing leads or the advanced cardiovascular and medical diseases in these individuals. Consider a typical situation for a patient who receives an ICD for primary prevention at a time of relatively modest HF symptoms, i.e., New York Heart Association Class (NYHA) Class 2. The patient later develops worsening HF, is admitted to the hospital one or more times for volume overload, exhibits widening of their QRS complex, and thus becomes a candidate for CRT. By this point, the patient may have had multiple device generator exchanges with lead additions, worsened general health, including, for example, the development of diabetes and renal dysfunction. While not representative of all patient candidates for CRT upgrade, this scenario is certainly familiar to physicians who perform these procedures. While the acute procedural complication rate is not unreasonable (2.4%), the longer term complication rates are significant. Dislodgement of the newly implanted LV lead, major hematomas requiring evacuation, worsened HF and renal dysfunction, re-hospitalizations for acute worsening of HF, and death are all findings from this study that should prompt physicians to carefully weigh the potential for harm vs. benefit in certain high-risk individuals. Physicians should counsel patients regarding both the peri-procedural complication risks and the potential for longer-term adverse events.

The complication rates associated with CRT upgrade procedures in REPLACE raises the question whether adverse events would be lower if patients received a CRT device earlier in the course of their disease. The results of recent studies that have evaluated the benefit of CRT in predominantly NYHA Class II HF provides some insight.8,9 Both the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) and the Resynchronization/Defibrillation for Ambulatory Heart Failure Trial (RAFT) studies demonstrated superiority of CRT combined with a defibrillator (CRT-D) over defibrillator therapy alone on the primary endpoints of death free of HF or death free of HF hospitalization, respectively. In these trials, adverse events occurring within 30 days of implant (Table 3) were more common in patients who received a CRT-D vs. an ICD. LV lead dislodgement occurred in 4.0% of CRT-D patients in MADIT-CRT and in 6.9% of patients in the RAFT study. A total 30-day complication rate was reported by the RAFT investigators as 13.3% in the CRT-D patients compared with 6.8% in the ICD patients. In a third study, the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study, 610 patients with NYHA Class I or II HF symptoms received a CRT device. Peri-procedural significant complications were reported in 4%, and the subsequent to one-year significant complication rate was 16%.21

A direct comparison of the complications reported from these studies of “early” CRT implantation to the results of the REPLACE Registry is limited due to differences in patient demographics, reporting and adjudication of complications, and variable follow-up periods. Nonetheless, the complication rates associated with de novo CRT implantation in patients with mild-moderate HF are not trivial. While complications might be greater with upgrades, direct comparative data is not available. Therefore, complication rates need to be considered for any patient for whom either de novo or upgrade CRT therapy is considered, with careful consideration given to the weight of evidence supporting benefit vs. the potential harm to an individual patient.

Conclusions

Pacemaker, ICD and CRT therapy are important in the management of cardiovascular disease, and particularly HF. While the complication rates associated with de novo implants have generally been considered low, the REPLACE Registry highlights the spectrum of adverse events possible when generator replacements and upgrade procedures are performed. These data can assist implanting physicians considering the lifetime risks for patients receiving CIED therapy. Regarding upgrade procedures, REPLACE suggests that some patients, though not all, may simply have a risk that is greater than the possible benefit. In situations of borderline indications, these risks should be factored into the decision making process. Using the simplest device possible that will address the foreseeable needs of the patient is reasonable. Predicting the progression of heart failure symptoms with and without conduction abnormalities in an individual patient is difficult. More complex devices with advanced therapy, such as CRT, should be implanted according to the clinical trial evidence and with a consideration of both the immediate procedural and longer term risk vs. the anticipated benefit for each individual patient.

References

  1. Poole JE, Gleva MJ, Mela T, et al. Complication rates associated with pacemaker or implantable cardioverter-defibrillator generator replacements and upgrade procedures: Results from the REPLACE registry. Circulation 2010;122:1553–1561.
  2. Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of surgical site infection, 1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol 1999;20:250–278.
  3. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–883.
  4. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–237.
  5. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151–2158.
  6. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140–2150.
  7. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–1549. 
  8. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1–10. 
  9. Tang AS, Wells GA, Talajic M, et al. Cardiac resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010;363:2385–2395.
  10. Uslan DZ, Tleyjeh IM, Baddour LM, et al. Temporal trends in permanent pacemaker implantation: A population-based study. Am Heart J 2008;155:896–903.
  11. Bernstein AD, Parsonnet V. Survey of cardiac pacing and implanted defibrillator practice patterns in the United States in 1997. Pacing Clin Electrophysiol 2001;24:842–855.
  12. Gould PA, Gula LJ, Champagne J, et al. Outcome of advisory implantable cardioverter-defibrillator replacement: One-year follow-up. Heart Rhythm 2008;5:1675–1681.
  13. Gould PA, Krahn AD; Canadian Heart Rhythm Society Working Group on Device Advisories. Complications associated with implantable cardioverter-defibrillator replacement in response to device advisories. JAMA 2006;295:1907–1911.
  14. Kapa S, Hyberger L, Rea RF, Hayes DL. Complication risk with pulse generator change: Implications when reacting to a device advisory or recall. Pacing Clin Electrophysiol 2007;30:730–733.
  15. Costea A, Rardon DP, Padanilam BJ, et al. Complications associated with generator replacement in response to device advisories. J Cardiovasc Electrophysiol 2008;19:266–269.
  16. Moore JW III, Barrington W, Bazzaz R, et al. Complications of replacing implantable devices in response to advisories: A single center experience. Int J Cardiol 2009;134:42–46.
  17. Hildick-Smith DJR, Lowe MD, Newell SA, et al. Ventricular pacemaker upgrade: Experience, complications and recommendations. Heart 1998;79:383–387.
  18. Duray GZ, Israel CW, Pajitnev D, Hohnloser SH. Upgrading to biventricular pacing/defibrillation systems in right ventricular paced congestive heart failure patients: Prospective assessment of procedural parameters and response rate. Europace 2008;10:48–52.
  19. Baker CM, Christopher TJ, Smith PF, et al. Addition of a left ventricular lead to conventional pacing systems in patients with congestive heart failure: Feasibility, safety, and early results in 60 consecutive patients. Pacing Clin Electrophysiol 2002;25:1166–1171.
  20. Sweeney MO, Shea JB, Ellison KE. Upgrade of permanent pacemakers and single chamber implantable cardioverter defibrillators to pectoral dual chamber implantable cardioverter defibrillators: indications, surgical approach, and long-term clinical results. Pacing Clin Electrophysiol 2002;25:1715–1723.
  21. Linde C, Abraham WT, Gold MR, et al. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol 2008;52:1834–1843.

Disclosures: Dr. Poole reports receiving research grant support from BIOTRONIK and the National Heart, Lung, and Blood Institute; speaking honoraria from Medtronic and Boston Scientific; travel reimbursement from BIOTRONIK, Medtronic, and Boston Scientific; and honoraria from BIOTRONIK, Cardiac Science, and sanofi aventis. Dr. Poole has been an expert witness. Dr. Poole also reports fellowship training grants to her institution from Medtronic, Boston Scientific, and St. Jude Medical. Dr. Gleva has received research support from BIOTRONIK, honoraria from Medtronic and BIOTRONIK, and travel reimbursement from BIOTRONIK; Dr. Gleva’s spouse previously had ownership stock in Medtronic. Crystal Miller is a paid employee of BIOTRONIK and receives a fixed salary with no bonus payments tied to research results. Kevin Mitchell is a paid employee of BIOTRONIK and receives a fixed salary with no bonus payments tied to research results. Dr. Holcomb has received consulting fees from BIOTRONIK to perform the statistical analysis for the study.