Europace Advance Access originally published online on May 31, 2007
Europace 2007 9(7):516-522; doi:10.1093/europace/eum080
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BIVENTRICULAR PACING
Implantation of cardiac resynchronization therapy systems in the CARE-HF trial: procedural success rate and safety
1 Nouvelles Cliniques Nantaises, Nantes, France; 2 Departement of Cardiology and Angiology, University Hospital, Münster, Germany; 3 Ospedale Niguarda Ca' Granda, Dipartimento di Cardiologia ‘De Gasperis’, Elettrofisiologia, Milano, Italy; 4 Cardiovascular Research Institute, Maastricht, The Netherlands; 5 University of Birmingham, Edgbaston, UK; 6 Département de Cardiologie et maladies vasculaires, Centre cardio-pneumologique, Hôpital Pontchaillou, Centre hospitalier universitaire, 2, rue Henri le Guilloux, 35033 Rennes Cedex 9, France; 7 Division of Cardiology, Centre Hospitalier, Universitaire Vaudois, Lausanne, Switzerland; 8 Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico San Matteo, Pavia, Italy; 9 Department of Internal Medicine III, University of Cologne, Cologne, Germany; 10 Department of Cardiology, Castle Hill Hospital, Kingston-upon-Hull, UK
Manuscript submitted 13 December 2006. Accepted after revision 30 March 2007.
* Corresponding author. Tel: +33 299 282 525; fax: +33 299 282 510. E-mail address: jean-claude.daubert{at}chu-rennes.fr
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Abstract |
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Top
Abstract
IntroductionAims To assess procedural characteristics and adjudicated procedure-related (
30 days) major adverse events among patients who underwent cardiac resynchronization therapy (CRT) implantation in the CARE-HF study. The CARE-HF study shows that CRT improves symptoms and reduces morbidity and mortality in New York Heart Association (NYHA) class III/IV chronic heart failure (CHF) patients. However, safe and proper implantation of pacing systems remains key to effective CRT delivery.
Methods and results Generalized linear modeling was used to examine the relationships between first implant success/failure and: NYHA class; beta-adrenergic blocker use; underlying ischemic vs. non-ischemic heart disease; history of coronary artery bypass graft or valve surgery; left ventricular (LV) end-diastolic volumevs. >300 cm3; and, influence of the participating study-centres. Implantation was attempted in 404/409 patients assigned to CRT, and in 65/404 patients assigned to medical therapy. Among these 469 patients, 450 (95.9%) received a successfully implanted and activated device. Complications occurred within 24 h in 47 patients (10.0%), mainly lead dislodgments (n = 10, 2.1%) and coronary sinus dissection/perforation (n = 10, 2.1%), and between 24 h and 30 days in 26 patients (5.5%), mainly lead dislodgment (n = 13, 2.8%). Mean LV lead stimulation threshold was significantly higher than at the right atrium or right ventricle, though remained stable, delivering effective, and reliable CRT. Implanting experience was the only predictor of procedural outcome.
Conclusion Transvenous CRT system implantation, using a CS lead designed for long-term LV pacing, was safe and reliable. As implanting centres become more experienced, this success rate is expected to increase further.
Key Words: Cardiac resynchronization therapy, Heart failure, Procedural complications, Operative complications, Left ventricular stimulation
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Introduction |
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Despite advances in pharmacological therapy, the morbidity and mortality of patients presenting with chronic heart failure (CHF) due to left ventricular (LV) systolic dysfunction remain high. In guidelines issued by international professional societies, cardiac resynchronization therapy (CRT) has been accepted as an effective treatment for patients presenting with moderate to severe manifestations of CHF refractory to drug therapy, LV systolic dysfunction, and cardiac dyssynchrony.1
,2 The concordant results of several randomized clinical trials have confirmed that CRT can prolong survival and improve quality of life.3–11 However, the potential clinical benefits of CRT hinge (or depend) on the proper implantation of an atrio-biventricular pacing system, to deliver effective and uninterrupted resynchronization. This procedure includes several technical challenges, in particular, the accurate placement of an LV lead inside a tributary of the coronary sinus (CS) to pace the left ventricle reliably and incessantly. Safety issues related to the procedure are still debated.
We report procedural and safety-related observations made at the time of CRT system implantation in patients who were enrolled in the CARE-HF trial.3–5 The relationship between key clinical variables and implant success vs. failure was examined, with a view to identifying predictors of successful CRT implantation.
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Patient population and methods |
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The design, enrollment criteria, patient characteristics, and results of the multicentre CARE-HF trial have been previously reported.3
,4 Briefly, consenting patients recruited from 82 medical centres in 12 European countries who presented: (1) in New York Heart Association (NYHA) CHF functional class III or IV despite optimal medical treatment, including loop diuretics; (2) with advanced LV systolic dysfunction; and, (3) with a QRS duration >120 ms, were randomly assigned to receive a CRT system with optimal therapy, vs. continued optimal therapy only. Efforts were made to optimize medical therapy using angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, and aldosterone antagonists in both treatment groups. Patients presenting in permanent atrial fibrillation, or who had conventional indications for permanent pacing or implantable cardioversion-defibrillation were excluded from the trial. Patients assigned to CRT were scheduled to undergo the implant procedure within 5 days of randomization. The first implantation procedure was performed in January 2001, and enrollment completed in March 2003. |
Implantation of the cardiac resynchronization system |
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Patients assigned to CRT, underwent implantation of InSync® models 8040 or 8042 atrio-biventricular pulse generators (Medtronic Inc.) connected via separate ports to transvenous leads placed in the right atrium (RA), the right ventricle (RV), and in a tributary of the CS to stimulate the left ventricle. Standard leads were used to stimulate the RA and RV, and an AttainTM (Medtronic) cardiac vein lead, specifically designed for stimulation inside a CS tributary, was used to stimulate the LV epicardial surface, using the method described originally by Daubert et al.12
No precise recommendation was made with regard to positioning of RA or RV leads. The latter could be placed at the RV apex, septal wall, or outflow tract. Conversely, investigators were advised to target a lateral or a postero-lateral cardiac vein with the LV lead, since these sites are most likely to achieve resynchronization.8,13 A CS angiography was recommended to identify cardiac veins most appropriate for LV stimulation. Final lead positioning was documented by post-operative antero-posterior and lateral chest radiograph, and electrocardiogram templates were recorded during single-site RV and LV stimulation. All patients were monitored overnight after implantation of the CRT system. |
Operative adverse events |
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Major adverse events (MAE) were classified as early, when occurring within 24 h after the index implantation procedure (defined as the first attempt to implant the CRT system), or delayed, when observed between 24 h and 30 days post-procedure. Following adjudication by the Events Committee, MAEs were then classified as device or procedure-related vs. non-procedure-related by an independent Device-Related Adverse-Event Assessor (D Böcker, MD). Events that prompted an intervention, such as a re-operation, or pericardial or pleural drainage, were identified. Unsuccessful, uncomplicated implantation attempts were not classified as MAEs in this analysis.
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Statistical analysis |
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Descriptive statistics were applied, as appropriate, according to the distribution of variables. Categorical data are reported as incidence (percent), and non-categorical data as mean ± standard deviation (SD) or 95% confidence interval (CI). Once allocated as either successful or unsuccessful primary implantation, the data were assessed according to: (1
) NYHA functional class III or IV; (2) presence or absence of treatment with a beta-adrenergic blocker; (3) ischemic or non-ischemic origin of LV dysfunction; (4) presence or absence of history of coronary artery bypass graft (CABG) or valve surgery; and, (5) LV end-diastolic volumeor >300 cm3. Low and high centre experience were defined as 10 and >10 CRT implant attempts/procedures, respectively. P-values are nominal. All analyses were performed using SAS software v9.1 (SAS Institute Inc., Cary, NC). |
Results |
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Between January 2001 and March 2003, 813 patients were enrolled in the CARE-HF trial, of whom 409 were assigned to CRT and 404 to the control group. Patient characteristics, echo parameters, glomerular filtration rate, and medical management of CHF at baseline were similar in both groups.3
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Implantation success rate |
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Among the 409 patients assigned to CRT, implantation of the system was attempted in 404 and successfully completed in 390 patients (96.5%). Implant was successful at the first attempt in 349 (89.5%), second attempt in 36 (9.2%), and third attempt in 5 (1.3%) patients (Table 1). Eight patients assigned to active treatment had CRT devices with additional defibrillator functions implanted and activated. The implant was not attempted in one patient who died before the procedure, and in four patients because of the investigators' decision not to proceed.
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Among the 404 patients assigned to the control group, implantation of a CRT system was attempted during follow-up in 65 patients (16.1%), including 23 devices with and 43 without internal cardioverter defibrillator (ICD) functions (1 patient underwent implant attempts with both types of device). A CRT or CRT-ICD system was successfully implanted in 60 patients and fully activated in 50, while in 10 patients the device was programmed to provide pacing or ICD functions only, to avoid crossover.
Ultimately, the overall success rate of CRT system implantation was 95.6% (450 of 469 patients). Causes of initial implant failures are summarized in Table 2. The CS was inaccessible in 21 patients, no suitable cardiac vein was accessible in 6 patients, the LV lead was unstable in 16 patients, 4 patients had unacceptable LV stimulation characteristics, 2 patients experienced intolerable phrenic nerve stimulation, and 4 patients did not tolerate the procedure.
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Stimulation characteristics at implant and during follow-up |
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The stimulation thresholds remained stable during follow-up (Table 3), confirming a consistent delivery of CRT, though were higher at the LV than at the RA and RV leads on average (Figure 1). Lead impedance remained stable with all leads (Figure 2). Mean LV epicardial electrogram amplitude, which was lower than that of the RV endocardial electrogram, remained remarkably stable overtime. Likewise, atrial endocardial electrogram amplitude remained stable, ensuring reliable atrial sensing during CRT.
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), right ventricular (
), and left ventricular (
) leads are shown at implant, and at 6 months, 1 year, 18 months, and 2 years of follow-up.
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) at the RA (
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Position of the LV lead tip |
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The final position of the LV lead tip was postero-lateral or lateral in 76%, antero-lateral in 12%, and anterior (in the great cardiac vein) in 12% of cases, respectively. Consequently, 88% of patients had an LV lead placed in a lateral region. The final position of the RV lead tip was apical in 56%, septal in 34%, and at the free wall in 6% of cases.
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Predictors of successful CRT implantation |
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The following variables did not predict the outcome of the index procedure: NYHA functional class (III vs. IV), administration of a beta-adrenergic blocker, underlying ischemic vs. non-ischemic heart disease, history of CABG or valve replacement, and an LV end-diastolic volume
300 cm3 vs. >300 cm3 (Table 4). However, the implanting experience of the medical centres participating in the trial, arbitrarily set atvs. >10 CRT implants attempts/procedures per year, did predict the outcome of the index procedures (Table 5). The difference in absolute terms is quite large, with a 90% success rate at first attempt, in more experienced centres compared with 82% in less experienced (P<0.0001).
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Major adverse events (MAEs) at 30 days |
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There were two procedure-related deaths. One patient in the CRT group died of CHF precipitated by dislodgment of the LV lead. One patient in the medical therapy group, who crossed over to CRT, died of septicemia after implantation of the device. All MAEs are listed in Table 6. In brief, 73 patients (15.6%) had
1 MAE within 30 days post-index procedure. Most events (n = 45; 63.4%) occurred during the procedure or within 24 h thereafter. The rate of MAEs was higher among patients originally assigned to the control group who crossed over to CRT (n = 36/65; 55.4%) than in the CRT group (n = 37/404; 7.9%). The most common MAEs were 23 lead dislodgments (4.9%) necessitating re-operation in 22 patients, 10 CS dissections or perforations (2.1%), with pericardial effusion or tamponade in 3, 8 cases of phrenic nerve stimulation not eliminated by reprogramming and requiring LV lead revisions (1.7%), and pneumothorax requiring chest drainage in 6 patients (1.3%).
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Discussion |
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The main observation made in this analysis of the outcomes and safety of CRT system implantations in CARE-HF was a 95.6% transvenous procedural success rate and a relatively low complication rate. Effective CRT requires an accurate implantation of the atrio-biventricular pacing system, which involves several technical challenges. An improper lead placement is a source of therapeutic failure since, despite consistent stimulation of the 3 chambers, the heart is not resynchronized. Proper positioning of the LV lead is critical, and a complete angiographic visualization of the CS and its tributaries, usually by intra-operative occlusive retrograde venography, can greatly increase the procedural success rate. New, non-invasive imaging techniques, such as 3-D multislice computed tomography,14
have recently been proposed as a pre-operative guide. However, the quality of the images is currently not high enough to allow forgoing direct venography.
The final choice of LV lead placement depends on several factors, including the highly variable anatomy of the coronary venous system,15,16 lead performance and stability in its final position, and absence of phrenic nerve stimulation. Considering all these factors, the LV lead might not, ultimately, be placed in the initially targeted zone, resulting in less than optimal cardiac resynchronization. In this trial, attempts to implant the CRT system via the CS were successful in 95.6% of the patients, a considerably higher rate than observed in previous controlled studies, where it ranged between 89 and 91%.6–10 This superior result is probably attributable to the study design, which allowed up to three transvenous implant attempts with, when requested, the assistance of a highly experienced consultant operator. This increased the overall success rate by 10%, after the second or third attempt, when necessary. Appropriate lead placement to deliver effective resynchronization is clear and has a profound impact on morbidity and mortality.3
Following the development of the over-the-wire LV lead technology, now used in nearly 100% of patients, the cannulation of the CS ostium has become the ‘strategic’ step of the procedure.13,16 Difficulties may be encountered in case of prominent Eustachian or Thebesian valves, which can prolapse in front of the ostium, or obstruct the proximal or the mid CS, respectively. Advanced cardiomyopathy with major LV dilatation, usually accompanied by enlargement or the RA, might severely hamper the access to the CS ostium due to changes in anatomical landmarks. However, neither the underlying heart disease, the presence of severe functional disability, or the administration of beta-adrenergic blockers at baseline predicted the procedural outcome. The only variable predictive of implant success was that related to the experience of the participating medical centres, an observation concordant with previous reports of a positive effect conferred by operator experience implantation outcome of ventricular single-chamber (VVI) and dual-chamber (DDD) pacemakers. This suggests that the likelihood of a successful implantation after a first unsuccessful attempt might be significantly greater if repeated with the assistance of another trained and more experienced operator. This might also encourage the development of centres of excellence that have surmounted the learning curve, in order to optimize the implant success for each individual patient.
Besides repeated attempts at implanting the LV lead via the CS, other techniques can be applied after a failed transvenous attempt, including the endocardial approach,17,18 or the implantation of an epicardial lead by a minimally invasive procedure.19–21 These alternatives, however, have not been scrutinized under controlled study conditions.
Considering the technical complexity of CRT systems implantation, and the relative fragility of patients suffering from advanced CHF, safety issues deserve special attention. Controlled studies of conventional antibradycardia pacing have shown that the rates of operative complications were directly dependent upon device complexity, in particular the number of leads that are implanted.22–24 In CTOPP22 and in UK-PACE,24 MAE rates were two-fold higher in recipients of dual- vs. single-chamber pacemakers. This excess risk associated with dual-chamber pacing was principally attributable to lead-related complications, particularly atrial lead dislodgment often requiring lead revisions.
Although the 15.6% mean rate of MAEs observed in the present study may appear relatively high, it reflects the sum of: (1) common complications associated with any pacemaker implantation (pneumothorax, infection, and pocket complications); (2) the additional risk incurred with the implantation of an atrial lead (as observed when comparing dual-chamber with single-chamber ventricular pacing); and, (3) the specific risks associated with implanting an LV lead, including dislodgment, CS dissection, perforation or both, and persistent phrenic nerve stimulation despite device reprogramming. While these specific LV lead-related MAEs prompted re-operations in nearly 7% of patients, this risk was largely compensated by the magnitude of the clinical benefit conferred by CRT, in a population of patients with moderate-to-severe CHF.3
One noteworthy observation made in the present study was the low rate of MAEs in the group assigned to CRT (7.9%), similar to that observed with standard dual-chamber pacing in the randomized trials on pacing mode selection,22–24 compared with the high rate observed among the crossovers (55.4%). The small number of patients treated with CRT who had been initially assigned to medical therapy precludes the drawing of definitive conclusions based on statistical comparisons. On the other hand, less care might have been given, and less attention paid by the operators to the patients who crossed over, compared with those who had been randomly assigned to CRT.
Finally, the electrical characteristics of the three leads remained remarkably stable overtime, explaining the sustained benefits observed in the group of patients assigned to CRT. However, the mean stimulation threshold at the LV lead was distinctly higher than that typically measured with standard RA or RV leads.
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Conclusions |
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Transvenous CRT using standard RA and RV leads, along with a CS lead designed for long-term LV stimulation was reliable and relatively safe. A broad individual centre experience was the only factor that predicted a higher procedural success rate. Appropriate indications for CRT are associated with a sustained clinical improvement and a positive impact on morbidity and mortality. Further increases in the success of CRT implantation procedures should occur with a better understanding of the CS venous anatomy, the early recognition of the overall potential procedural risks, and with continued refinements in LV lead design and placement techniques.
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Acknowledgements |
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We are very grateful to Monique Marijianowski, Rodolphe Ruffy, and Yves Verboven for reviewing the manuscript, together with Sandra Jacobs and the CARE-HF Study team for their work on the CARE-HF trial.
Conflict of interest: H.J.J.W. is a consultant for Medtronic. M.C. reports having undertaken research sponsored by Medtronic. L.T. is a member of the Speakers' Bureau of Medtronic. J.-C.D. is a consultant for Medtronic and St Jude Medical.
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