- Email: [email protected]
Mid-term follow up of thromboembolic complications in left ventricular endocardial cardiac resynchronization therapy
Mid-term follow up of thromboembolic complications in left ventricular endocardial cardiac resynchronization therapy Leonard M. Rademakers, MD, PhD,* Berry M. van Gelder, PhD,* Mike G. Scheffer, MD,† Frank A. Bracke, MD, PhD* From the *Department of Cardiology, Catharina Hospital Eindhoven, Eindhoven, The Netherlands, and † Department of Cardiology, Reinier de Graaf Hospital, Delft, The Netherlands. BACKGROUND Endocardial left ventricular (LV) pacing for cardiac resynchronization therapy (CRT) has been proposed as an alternative to traditional LV transvenous epicardial pacing with equal or superior cardiac performance. The risks of cerebral thromboembolism and possible interference with mitral valve function moderate its clinical application. OBJECTIVE The purpose of this study was to investigate cerebral thromboembolic complications after LV endocardial lead placement. Mitral regurgitation (MR) was the secondary outcome measure. METHODS CRT candidates with a failed coronary sinus approach or nonresponders to conventional CRT underwent endocardial LV lead implantation (45 atrial transseptal, 6 transapical). Coumarin was prescribed with a targeted international normalized ratio between 3.5 and 4.5. Patient records were checked and general practitioners were contacted regarding cerebral thromboembolic complications. MR was evaluated by echocardiography at baseline and after 6 months. RESULTS In 7 patients, 6 ischemic strokes and 2 transient ischemic attacks occurred, corresponding to 6.1 thromboembolic events per 100 patient-years (95% confidence interval 3.4–15.8).
Introduction Cardiac resynchronization therapy (CRT) improves pump function and clinical status. It reduces morbidity and mortality in patients with moderate-to-severe heart failure and left bundle branch block.1–4 Usually, the left ventricular (LV) lead is placed epicardially in a tributary of the coronary sinus. However, approximately 10% of coronary sinus lead implant attempts are unsuccessful.5 In addition, a substantial proportion of patients do not benefit from CRT.6 A surgical epicardial approach via lateral thoracotomy carries morbidity Dr. van Gelder is a clinical advisor to Medtronic Trading Netherlands BV, Heerlen, The Netherlands, and serves as a consultant to RADI Medical Systems, Reading, MA. Address reprint requests and correspondence: Dr. Leonard M. Rademakers, Department of Cardiology, Catharina Hospital, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
One patient refused hospital admission; all other patients had a subtherapeutic anticoagulation level at the time of the event. No major bleeding complications occurred. There was no change in the grade of MR (grade 2, P ¼ .727) after 6 months. CONCLUSION Endocardial LV lead placement in patients with advanced heart failure is associated with thromboembolic risk. However, all but 1 patient had a subtherapeutic level of anticoagulation. Endocardial LV lead placement is not associated with aggravation of MR. KEYWORDS Cardiac resynchronization therapy; Endocardial left ventricular lead placement; Thromboembolic risks; Cerebrovascular accident; Stroke ABBREVIATIONS CI ¼ confidence interval; CRT ¼ cardiac resynchronization therapy; INR ¼ international normalized ratio; IQR ¼ interquartile range; LA ¼ left atrium; LV ¼ left ventricle; MR ¼ mitral regurgitation; SR ¼ sinus rhythm; TIA ¼ transient ischemic attack (Heart Rhythm 2014;11:609–613) I 2014 Heart Rhythm Society. All rights reserved.
and risks in patients with advanced heart failure.7 Recent data provided evidence of increased cardiac performance with endocardial LV stimulation compared to conventional epicardial LV stimulation and therefore may be a good alternative.8–13 Most endovascular LV endocardial lead placement techniques use an atrial transseptal approach11,14–16; alternatively, a surgical LV transapical insertion technique has been reported.17 However, LV endocardial pacing lead placement exposes the lead to the systemic circulation, with the potential of systemic thromboembolism. In addition, a lead crossing the mitral valve has the potential to affect mitral valve function with subsequent (worsened) mitral regurgitation (MR). The purpose of this retrospective, two-center study was to determine the long-term incidence of thromboembolism and possible interference with the mitral valve apparatus resulting from LV endocardial lead placement. http://dx.doi.org/10.1016/j.hrthm.2014.01.031
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Methods From January 2006 to April 2013, 51 patients who fulfilled criteria for CRT were implanted with an LV endocardial pacing lead. Candidates for LV endocardial lead implantation had a previous failed coronary sinus approach (i.e., inability to cannulate the coronary sinus, LV lead dislodgment, unacceptable high pacing thresholds, or phrenic nerve stimulation; n ¼ 48) or were nonresponders to conventional epicardial CRT but had demonstrated acute hemodynamic improvement (LV dP/dtmax) during a preimplantation temporary LV endocardial pacing study (n ¼ 3). Exclusion criteria included a contraindication to oral anticoagulants, the presence of intracardiac thrombus as defined by preimplantation (transesophageal) echocardiography, and New York Heart Association functional class I or II. The procedures were carried out at 2 cardiovascular tertiary referral centers. An atrial transseptal implantation technique was used in 45 patients.11,15,16 Six patients underwent surgical transapical LV lead implantation (3 patients were unsuitable for atrial transseptal lead placement because of a mitral valve prosthesis; atrial transseptal approach was unsuccessful in 3 patients). The first 10 patients were implanted with a 4076 CapSureFix Novus pacing lead (Medtronic, Minneapolis, MN). In the last 41 procedures, a 110-cm 3830 SelectSecure active pacing lead (Medtronic) was used. Favorable R-wave sensing and pacing thresholds were obtained in all patients. Patients were fully Table 1
Baseline clinical and demographic characteristics
Parameter Age at enrollment (years) Sex Male Female Lead type Medtronic 3830 Medtronic 4076 Cardiomyopathy Dilated cardiomyopathy Ischemic cardiomyopathy New York Heart Association functional class I–II III IV Left ventricular ejection fraction (%) Intrinsic QRS duration (ms) QRS morphology Left bundle branch block Right bundle branch block Intraventricular conduction disturbance Right ventricular pacing Rhythm Sinus rhythm AV block Atrial fibrillation Mitral regurgitation grade I II III IV Data are given as mean ⫾ SD or no. (%).
68 ⫾ 9 35 (69%) 16 (31%) 42 (82%) 9 (18%) 20 (39%) 31 (61%) 1 (2%) 42 (82%) 8 (16%) 23 ⫾ 7 170 ⫾ 32 39 (76%) 0 (0%) 1 (2%) 11 (22%) 34 (67%) 5 (10%) 12 (23%) 16 (37%) 13 (30%) 12 (28%) 2 (5%)
heparinized during the implant procedure, and chronic oral anticoagulation with coumarin was initiated as soon as possible after LV endocardial lead placement. Bridging with heparin (at therapeutic dose) was applied until the targeted international normalized ratio (INR) was reached (between 3.5 and 4.5). After hospital discharge, oral anticoagulation was monitored by the Dutch Thrombosis Service. The primary study end-point was the occurrence of transient ischemic attack (TIA) or stroke. Patients with a suspected cerebrovascular accident were referred to a neurologist to confirm the diagnosis. The secondary outcome measure was increased mitral valve regurgitation. Patient records were examined and general practitioners were contacted to document the occurrence of thromboembolism. Follow-up echocardiography was performed after 6 months of implantation to document any aggravation of MR. Patients who underwent transapical LV lead implantation were excluded from MR analyses.
Statistical analysis Continuous data are presented as mean and standard deviation and discrete variables as count and percentage, unless otherwise stated. No missing data imputation was performed. Nonparametric tests were chosen for analyses. A 2-sided P of 0.05 was considered significant. Statistical analyses were performed using SPSS (version 17, SPSS Inc, Chicago, IL).
Results Table 1 summarizes clinical and demographic patient characteristics. A total of 50 patients were followed up for a median of 24 months (interquartile range [IQR] 9–40 months). One patient was lost to follow-up because of refusal to adhere to regular checkups. Medical records of all other patients were available and checked, and all general practitioners were contacted. A total of 20 patients died with a median survival of 9 months (IQR 6–20 months). Twelve patients died of progressive heart failure, 1 stroke, 1 septic shock secondary to right ventricular ICD lead endocarditis without evidence of LV lead involvement, and 6 noncardiac causes, including disseminated cancer, lung fibrosis, and pneumonia.
Thromboembolic complications During the hospital stay, no cerebrovascular ischemic or hemorrhagic accidents occurred. In addition, there were no hematomas requiring reexploration at the femoral puncture site or device pocket. Table 2 lists the characteristics of patients with thromboembolic complications. A total of 8 thromboembolic events in 7 patients were confirmed, corresponding to 6.1 thromboembolic events per 100 patientyears (95% confidence interval [CI] 3.4–15.8). Five patients suffered from an ischemic stroke (1 had both a stroke and a TIA), whereas 2 patients had a TIA only. One of those 7 patients presented to his general practitioner with clinical signs and (persistent) symptoms of a stroke but refused hospital admission. One of the patients died of complications
Normal AIS AIS AIS Unknown 10.4 17.7 1.3 14.1 18.3 3 4 5 6 7
M M M M M
SR SR SR SR SR
No No No No No
ATS ATS ATS TA ATS
TIA Stroke Stroke Stroke Stroke
2.5 1.4 1.5 2.0 Unknown
Normal 2.6 41.1 TIA ATS No SR F
AIS ¼ acute ischemic stroke; ATS ¼ atrial transseptal; CT ¼ computed tomography; SR ¼ sinus rhythm; TA ¼ transapical; TIA ¼ transient ischemic attack. * Had 2 events.
No stenoses No stenoses No stenoses No stenoses Not performed
No stenoses
No stenoses
No thrombus LV lead No thrombus LV lead Not performed Thrombus LV lead Thrombus LV lead Not performed Not performed 28.2 F 2*
No
ATS
Stroke
2.2
AIS
No stenoses Not performed AIS 1.0
Persistent atrial fibrillation SR M 1
No
ATS
Stroke
1.2
Echocardiography INR at event Time to event (months) Stroke/ TIA Implantation technique History of stroke/TIA Sex Rhythm Pt. no.
Cerebrovascular complications Table 2
Thromboembolic Complications After LV Endocardial Lead Placement
Cerebral CT scan
Carotid duplex ultrasound
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of the stroke soon after admission. The anticoagulation level at the time of the thromboembolic event was below the targeted level in all admitted patients (Table 2). All patients with stroke were implanted with a 3830 SelectSecure pacing lead, 6 patients underwent an atrial transseptal LV lead implantation technique, and 1 patient underwent a transapical procedure. Four of the patients with a stroke underwent transesophageal echocardiography. In 2 cases there was clear evidence of thrombus attached at the pacing lead with no evidence of lead thrombus in the left atrium (LA). Carotid duplex ultrasound was performed in all admitted patients with a cerebrovascular accident. No evidence of significant stenosis was found in any of these patients. Only 1 of the 7 patients suffering from thromboembolic complications had a history of atrial fibrillation. This patient had an electrical cardioversion 2 weeks before he had the stroke.
Lead interference with mitral valve leaflets At baseline, median grade of MR was 2 (range 14). At echocardiography 6 months after lead implantation, there was no change in the median grade of MR, irrespective of the pacing lead model used (P ¼ .727, McNemar test). There was no indication of pacing lead–induced damage of the mitral leaflets. None of the patients showed evidence of LV lead dislodgment or pacing lead infections.
Discussion
The main findings of this study were as follows: (1) advanced heart failure patients with endocardial LV leads have a substantial thromboembolic risk, and (2) there is no interference of the pacing lead with the mitral valve apparatus. Furthermore, bleeding complications or pacing lead endocarditis did not occur.
Cerebrovascular events Only a few reports have mentioned thromboembolic complications with LV endocardial pacing. With follow-up of 15 ⫾ 12 months and 85 ⫾ 2 months, respectively, Jais et al18 and Pasquie et al19 reported a TIA in 1 of 11 patients and 1 of 6 patients, respectively. In both cases, anticoagulation was interrupted at the time of the incident. Stroke or TIA occur more frequently in patients with versus those without heart failure. The reported incidence in patients without a history of atrial fibrillation varied between 1.5 and 3.5 events per 100 patient-years.20,21 Also, during anticoagulation with warfarin, patients with heart failure in sinus rhythm had an incidence of 0.72 thromboembolic events per 100 patient-years (P o.001, 95% CI 3.65–20.72 vs our study).22 The incidence in our study was 6.1 thromboembolic events per 100 patient-years (95% CI 3.4– 15.8). Several factors may have influenced this risk. A substantial proportion of the patients (16%) had New York Heart Association functional class IV (compared to 6% of patients enrolled in the CARE-HF trial3), indicating the severity of heart failure in this population. This is
612 corroborated by our finding of all-cause mortality twice as high as that reported in CRT trials.3 The severity of heart failure may substantially influence the risk of thromboembolism. In the SAVE trial, the risk of stroke doubled if LV ejection fraction was o28%.23 As in the studies of Jais et al18 and Pasquie et al,19 all of our patients had a subtherapeutic INR at the time of thromboembolism (Table 2). However, subtherapeutic anticoagulation levels with coumarin occur frequently in daily practice.24 Patients are within the targeted INR range approximately 60% to 65% of the time.25,26 Time in the therapeutic range is a strong predictor of the risk of stroke, with decreasing anticoagulation control generally associated with an increased risk of stroke.26 Therefore, subtherapeutic anticoagulation with coumarin may be considered unavoidable in spite of a well-organized Dutch Thrombosis Service. Although the efficacy of novel direct thrombin or oral factor Xa inhibitors may be more predictable, currently there is no experience with LV endocardial pacing. Because mechanical mitral valve replacement carries a greater risk of thrombosis than aortic valves, influenced by the low flow state of the LA, it may follow that transapical surgical or transventricular septal implants theoretically may lead to fewer thromboembolic complications.27 Although 1 of the patients with transapical implants in our study had a stroke, the numbers are too small to compare the thromboembolic risk between the both approaches. Lead build also may influence thromboembolic risk. Silicone insulation carries a greater risk than polyurethane leads, and these leads should be avoided in LV endocardial procedures.28 Although we expected that the smallerdiameter SelectSecure leads would be less prone to thrombosis, all events in our cohort occurred with this lead. Because both the CapSureFix Novus 4076 and 3830 SelectSecure have the same polyurethane outer insulation, it seems unlikely that the latter is a decisive factor. We could not establish any difference in anticoagulation adherence between the two patient groups. The presence of the anodal electrode is an unknown factor as a source of thrombus formation in LV pacing. Therefore, unipolar electrodes may be preferable to exclude anodal electrodes as a thromboembolic source.
Heart Rhythm, Vol 11, No 4, April 2014 coaptation. Second, because echocardiographic follow-up was performed several months after implantation, reverse remodeling may have masked a pacing lead–dependent increase in MR. Although patients who were nonresponders to CRT on echocardiography did not show an increase in MR, the small sample size hampers drawing conclusions from this observation.
Future considerations The lack of a control group in our study prevents establishing the real contribution of endocardially positioned leads in the left heart to thromboembolic complications. In addition, the selection of advanced heart failure patients may have biased the results toward more thromboembolic complications. Nevertheless, the potential risk of thromboembolism is an important factor in deciding to apply this technique. Although proven in animal experiments,31 no clinical study has yet shown an advantage of endocardial over epicardial pacing at opposite LV sites, although the possibility of delivering LV pacing at sites not accessible from the coronary sinus may be advantageous.10,32 However, in a population with advanced heart failure, the alternative of surgical epicardial LV lead delivery requiring general anesthesia may be hazardous as well. Learning from our experience and awaiting the results of the ongoing ALSYNC and EPI-ENDO trials with chronic endocardial pacing (www.clinicaltrials.gov), we confine the application to patients who are not suitable candidates for surgical LV lead placement. Future novel techniques may be promising in reducing thrombosis-related complications. The transinterventricular septal approach described by Gamble et al27 and leadless endocardial LV pacing33 both provide a route to pace the LV endocardium without passing the LA.
Conclusion Endocardial LV lead placement in advanced heart failure patients is associated with significant thromboembolic risk at mid-term follow up. The occurrence seems to be strongly correlated with a subtherapeutic level of anticoagulation. Until further results are available, application of this technique should be limited to patients with no suitable alternatives. In addition, endocardial LV lead placement is not associated with the occurrence or aggravation of MR.
Lead interference with mitral valve leaflets An LV lead implanted through the interatrial septum traverses the mitral valve, which may induce or aggravate MR and increase the risk of endocarditis. In a canine model of heart failure, Bordachar et al29 did not observe MR with the LV lead passing the mitral valve. Bordachar et al30 previously reported a higher mitral integral time velocity with endocardial pacing than during epicardial pacing, which could result from reduced MR. Similarly, our study demonstrated no aggravation of MR after LV endocardial lead placement. There may be several reasons. It is reasonable that the small diameter and floppy nature of the pacing lead do not induce valve damage or interfere with mitral leaflet
References 1. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 2. 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. 3. 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. 4. St. John Sutton MG, Plappert T, Abraham WT, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003;107:1985–1990. 5. Leon AR, Abraham WT, Curtis AB, et al. Safety of transvenous cardiac resynchronization system implantation in patients with chronic heart failure: combined results of over 2,000 patients from a multicenter study program. J Am Coll Cardiol 2005;46:2348–2356.
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6. Saxon LA, Ellenbogen KA. Resynchronization therapy for the treatment of heart failure. Circulation 2003;108:1044–1048. 7. Miller AL, Kramer DB, Lewis EF, et al. Event-free survival following CRT with surgically implanted LV leads versus standard transvenous approach. Pacing Clin Electrophysiol 2011;34:490–500. 8. van Deursen C, van Geldorp IE, Rademakers LM, et al. Left ventricular endocardial pacing improves resynchronization therapy in canine left bundlebranch hearts. Circ Arrhythm Electrophysiol 2009;2:580–587. 9. Rademakers LM, van Kerckhoven R, van Deursen CJ, et al. Myocardial infarction does not preclude electrical and hemodynamic benefits of cardiac resynchronization therapy in dyssynchronous canine hearts. Circ Arrhythm Electrophysiol 2010;3:361–368. 10. Derval N, Steendijk P, Gula LJ, et al. Optimizing hemodynamics in heart failure patients by systematic screening of left ventricular pacing sites: the lateral left ventricular wall and the coronary sinus are rarely the best sites. J Am Coll Cardiol 2010;55:566–575. 11. van Gelder BM, Scheffer MG, Meijer A, Bracke FA. Transseptal endocardial left ventricular pacing: an alternative technique for coronary sinus lead placement in cardiac resynchronization therapy. Heart Rhythm 2007;4:454–460. 12. Garrigue S, Jais P, Espil G, et al. Comparison of chronic biventricular pacing between epicardial and endocardial left ventricular stimulation using Doppler tissue imaging in patients with heart failure. Am J Cardiol 2001;88:858–862. 13. Bracke FA, Houthuizen P, Rahel BM, van Gelder BM. Left ventricular endocardial pacing improves the clinical efficacy in a non-responder to cardiac resynchronization therapy: role of acute haemodynamic testing. Europace 2010;12:1032–1034. 14. Morgan JM, Scott PA, Turner NG, Yue AM, Roberts PR. Targeted left ventricular endocardial pacing using a steerable introducing guide catheter and active fixation pacing lead. Europace 2009;11:502–506. 15. van Gelder BM, Houthuizen P, Bracke FA. Transseptal left ventricular endocardial pacing: preliminary experience from a femoral approach with subclavian pull-through. Europace 2011;13:1454–1458. 16. Bracke FA, van Gelder BM, Dekker LR, et al. Left ventricular endocardial pacing in cardiac resynchronisation therapy: moving from bench to bedside. Neth Heart J 2012;20:118–124. 17. Kassai I, Friedrich O, Ratnatunga C, et al. Feasibility of percutaneous implantation of transapical endocardial left ventricular pacing electrode for cardiac resynchronization therapy. Europace 2011;13:1653–1657. 18. Jais P, Takahashi A, Garrigue S, et al. Mid-term follow-up of endocardial biventricular pacing. Pacing Clin Electrophysiol 2000;23:1744–1747. 19. Pasquie JL, Massin F, Macia JC, et al. Long-term follow-up of biventricular pacing using a totally endocardial approach in patients with end-stage cardiac failure. Pacing Clin Electrophysiol 2007;30(Suppl 1):S31–S33.
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20. Sirajuddin RA, Miller AB, Geraci SA. Anticoagulation in patients with dilated cardiomyopathy and sinus rhythm: a critical literature review. J Card Fail 2002;8: 48–53. 21. Dries DL, Rosenberg YD, Waclawiw MA, Domanski MJ. Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials. J Am Coll Cardiol 1997;29:1074–1080. 22. Homma S, Thompson JL, Pullicino PM, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 2012;366:1859–1869. 23. Loh E, Sutton MS, Wun CC, et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med 1997;336:251–257. 24. Wilke T, Groth A, Mueller S, et al. Oral anticoagulation use by patients with atrial fibrillation in Germany. Adherence to guidelines, causes of anticoagulation under-use and its clinical outcomes, based on claims-data of 183,448 patients. Thromb Haemost 2012;107:1053–1065. 25. Bezemer ID, Roemer WH, Penning-van Beest FJ, van Eekelen E, Kramer MH. INR control calculation: comparison of Dutch and international methods. Neth J Med 2013;71:194–198. 26. Gallagher AM, Setakis E, Plumb JM, Clemens A, van Staa TP. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost 2011;106:968–977. 27. Gamble JH, Bashir Y, Rajappan K, Betts TR. Left ventricular endocardial pacing via the interventricular septum for cardiac resynchronization therapy: first report. Heart Rhythm 2013;10:1812–1814. 28. Palatianos GM, Dewanjee MK, Panoutsopoulos G, et al. Comparative thrombogenicity of pacemaker leads. Pacing Clin Electrophysiol 1994;17:141–145. 29. Bordachar P, Grenz N, Jais P, et al. Left ventricular endocardial or triventricular pacing to optimize cardiac resynchronization therapy in a chronic canine model of ischemic heart failure. Am J Physiol Heart Circ Physiol 2012;303:H207–H215. 30. Bordachar P, Derval N, Ploux S, et al. Left ventricular endocardial stimulation for severe heart failure. J Am Coll Cardiol 2010;56:747–753. 31. Rademakers LM, van Kerckhoven R, van Deursen CJ, et al. Myocardial infarction does not preclude electrical and hemodynamic benefits of cardiac resynchronization therapy in dyssynchronous canine hearts. Circ Arrhythm Electrophysiol 2010;3:361–368. 32. Spragg DD, Dong J, Fetics BJ, et al. Optimal left ventricular endocardial pacing sites for cardiac resynchronization therapy in patients with ischemic cardiomyopathy. J Am Coll Cardiol 2010;56:774–781. 33. Auricchio A, Delnoy PP, Regoli F, et al. First-in-man implantation of leadless ultrasound-based cardiac stimulation pacing system: novel endocardial left ventricular resynchronization therapy in heart failure patients. Europace 2013;15: 1191–1197.
Introduction Cardiac resynchronization therapy (CRT) improves pump function and clinical status. It reduces morbidity and mortality in patients with moderate-to-severe heart failure and left bundle branch block.1–4 Usually, the left ventricular (LV) lead is placed epicardially in a tributary of the coronary sinus. However, approximately 10% of coronary sinus lead implant attempts are unsuccessful.5 In addition, a substantial proportion of patients do not benefit from CRT.6 A surgical epicardial approach via lateral thoracotomy carries morbidity Dr. van Gelder is a clinical advisor to Medtronic Trading Netherlands BV, Heerlen, The Netherlands, and serves as a consultant to RADI Medical Systems, Reading, MA. Address reprint requests and correspondence: Dr. Leonard M. Rademakers, Department of Cardiology, Catharina Hospital, Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands. E-mail address: [email protected].
1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.
One patient refused hospital admission; all other patients had a subtherapeutic anticoagulation level at the time of the event. No major bleeding complications occurred. There was no change in the grade of MR (grade 2, P ¼ .727) after 6 months. CONCLUSION Endocardial LV lead placement in patients with advanced heart failure is associated with thromboembolic risk. However, all but 1 patient had a subtherapeutic level of anticoagulation. Endocardial LV lead placement is not associated with aggravation of MR. KEYWORDS Cardiac resynchronization therapy; Endocardial left ventricular lead placement; Thromboembolic risks; Cerebrovascular accident; Stroke ABBREVIATIONS CI ¼ confidence interval; CRT ¼ cardiac resynchronization therapy; INR ¼ international normalized ratio; IQR ¼ interquartile range; LA ¼ left atrium; LV ¼ left ventricle; MR ¼ mitral regurgitation; SR ¼ sinus rhythm; TIA ¼ transient ischemic attack (Heart Rhythm 2014;11:609–613) I 2014 Heart Rhythm Society. All rights reserved.
and risks in patients with advanced heart failure.7 Recent data provided evidence of increased cardiac performance with endocardial LV stimulation compared to conventional epicardial LV stimulation and therefore may be a good alternative.8–13 Most endovascular LV endocardial lead placement techniques use an atrial transseptal approach11,14–16; alternatively, a surgical LV transapical insertion technique has been reported.17 However, LV endocardial pacing lead placement exposes the lead to the systemic circulation, with the potential of systemic thromboembolism. In addition, a lead crossing the mitral valve has the potential to affect mitral valve function with subsequent (worsened) mitral regurgitation (MR). The purpose of this retrospective, two-center study was to determine the long-term incidence of thromboembolism and possible interference with the mitral valve apparatus resulting from LV endocardial lead placement. http://dx.doi.org/10.1016/j.hrthm.2014.01.031
610
Heart Rhythm, Vol 11, No 4, April 2014
Methods From January 2006 to April 2013, 51 patients who fulfilled criteria for CRT were implanted with an LV endocardial pacing lead. Candidates for LV endocardial lead implantation had a previous failed coronary sinus approach (i.e., inability to cannulate the coronary sinus, LV lead dislodgment, unacceptable high pacing thresholds, or phrenic nerve stimulation; n ¼ 48) or were nonresponders to conventional epicardial CRT but had demonstrated acute hemodynamic improvement (LV dP/dtmax) during a preimplantation temporary LV endocardial pacing study (n ¼ 3). Exclusion criteria included a contraindication to oral anticoagulants, the presence of intracardiac thrombus as defined by preimplantation (transesophageal) echocardiography, and New York Heart Association functional class I or II. The procedures were carried out at 2 cardiovascular tertiary referral centers. An atrial transseptal implantation technique was used in 45 patients.11,15,16 Six patients underwent surgical transapical LV lead implantation (3 patients were unsuitable for atrial transseptal lead placement because of a mitral valve prosthesis; atrial transseptal approach was unsuccessful in 3 patients). The first 10 patients were implanted with a 4076 CapSureFix Novus pacing lead (Medtronic, Minneapolis, MN). In the last 41 procedures, a 110-cm 3830 SelectSecure active pacing lead (Medtronic) was used. Favorable R-wave sensing and pacing thresholds were obtained in all patients. Patients were fully Table 1
Baseline clinical and demographic characteristics
Parameter Age at enrollment (years) Sex Male Female Lead type Medtronic 3830 Medtronic 4076 Cardiomyopathy Dilated cardiomyopathy Ischemic cardiomyopathy New York Heart Association functional class I–II III IV Left ventricular ejection fraction (%) Intrinsic QRS duration (ms) QRS morphology Left bundle branch block Right bundle branch block Intraventricular conduction disturbance Right ventricular pacing Rhythm Sinus rhythm AV block Atrial fibrillation Mitral regurgitation grade I II III IV Data are given as mean ⫾ SD or no. (%).
68 ⫾ 9 35 (69%) 16 (31%) 42 (82%) 9 (18%) 20 (39%) 31 (61%) 1 (2%) 42 (82%) 8 (16%) 23 ⫾ 7 170 ⫾ 32 39 (76%) 0 (0%) 1 (2%) 11 (22%) 34 (67%) 5 (10%) 12 (23%) 16 (37%) 13 (30%) 12 (28%) 2 (5%)
heparinized during the implant procedure, and chronic oral anticoagulation with coumarin was initiated as soon as possible after LV endocardial lead placement. Bridging with heparin (at therapeutic dose) was applied until the targeted international normalized ratio (INR) was reached (between 3.5 and 4.5). After hospital discharge, oral anticoagulation was monitored by the Dutch Thrombosis Service. The primary study end-point was the occurrence of transient ischemic attack (TIA) or stroke. Patients with a suspected cerebrovascular accident were referred to a neurologist to confirm the diagnosis. The secondary outcome measure was increased mitral valve regurgitation. Patient records were examined and general practitioners were contacted to document the occurrence of thromboembolism. Follow-up echocardiography was performed after 6 months of implantation to document any aggravation of MR. Patients who underwent transapical LV lead implantation were excluded from MR analyses.
Statistical analysis Continuous data are presented as mean and standard deviation and discrete variables as count and percentage, unless otherwise stated. No missing data imputation was performed. Nonparametric tests were chosen for analyses. A 2-sided P of 0.05 was considered significant. Statistical analyses were performed using SPSS (version 17, SPSS Inc, Chicago, IL).
Results Table 1 summarizes clinical and demographic patient characteristics. A total of 50 patients were followed up for a median of 24 months (interquartile range [IQR] 9–40 months). One patient was lost to follow-up because of refusal to adhere to regular checkups. Medical records of all other patients were available and checked, and all general practitioners were contacted. A total of 20 patients died with a median survival of 9 months (IQR 6–20 months). Twelve patients died of progressive heart failure, 1 stroke, 1 septic shock secondary to right ventricular ICD lead endocarditis without evidence of LV lead involvement, and 6 noncardiac causes, including disseminated cancer, lung fibrosis, and pneumonia.
Thromboembolic complications During the hospital stay, no cerebrovascular ischemic or hemorrhagic accidents occurred. In addition, there were no hematomas requiring reexploration at the femoral puncture site or device pocket. Table 2 lists the characteristics of patients with thromboembolic complications. A total of 8 thromboembolic events in 7 patients were confirmed, corresponding to 6.1 thromboembolic events per 100 patientyears (95% confidence interval [CI] 3.4–15.8). Five patients suffered from an ischemic stroke (1 had both a stroke and a TIA), whereas 2 patients had a TIA only. One of those 7 patients presented to his general practitioner with clinical signs and (persistent) symptoms of a stroke but refused hospital admission. One of the patients died of complications
Normal AIS AIS AIS Unknown 10.4 17.7 1.3 14.1 18.3 3 4 5 6 7
M M M M M
SR SR SR SR SR
No No No No No
ATS ATS ATS TA ATS
TIA Stroke Stroke Stroke Stroke
2.5 1.4 1.5 2.0 Unknown
Normal 2.6 41.1 TIA ATS No SR F
AIS ¼ acute ischemic stroke; ATS ¼ atrial transseptal; CT ¼ computed tomography; SR ¼ sinus rhythm; TA ¼ transapical; TIA ¼ transient ischemic attack. * Had 2 events.
No stenoses No stenoses No stenoses No stenoses Not performed
No stenoses
No stenoses
No thrombus LV lead No thrombus LV lead Not performed Thrombus LV lead Thrombus LV lead Not performed Not performed 28.2 F 2*
No
ATS
Stroke
2.2
AIS
No stenoses Not performed AIS 1.0
Persistent atrial fibrillation SR M 1
No
ATS
Stroke
1.2
Echocardiography INR at event Time to event (months) Stroke/ TIA Implantation technique History of stroke/TIA Sex Rhythm Pt. no.
Cerebrovascular complications Table 2
Thromboembolic Complications After LV Endocardial Lead Placement
Cerebral CT scan
Carotid duplex ultrasound
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of the stroke soon after admission. The anticoagulation level at the time of the thromboembolic event was below the targeted level in all admitted patients (Table 2). All patients with stroke were implanted with a 3830 SelectSecure pacing lead, 6 patients underwent an atrial transseptal LV lead implantation technique, and 1 patient underwent a transapical procedure. Four of the patients with a stroke underwent transesophageal echocardiography. In 2 cases there was clear evidence of thrombus attached at the pacing lead with no evidence of lead thrombus in the left atrium (LA). Carotid duplex ultrasound was performed in all admitted patients with a cerebrovascular accident. No evidence of significant stenosis was found in any of these patients. Only 1 of the 7 patients suffering from thromboembolic complications had a history of atrial fibrillation. This patient had an electrical cardioversion 2 weeks before he had the stroke.
Lead interference with mitral valve leaflets At baseline, median grade of MR was 2 (range 14). At echocardiography 6 months after lead implantation, there was no change in the median grade of MR, irrespective of the pacing lead model used (P ¼ .727, McNemar test). There was no indication of pacing lead–induced damage of the mitral leaflets. None of the patients showed evidence of LV lead dislodgment or pacing lead infections.
Discussion
The main findings of this study were as follows: (1) advanced heart failure patients with endocardial LV leads have a substantial thromboembolic risk, and (2) there is no interference of the pacing lead with the mitral valve apparatus. Furthermore, bleeding complications or pacing lead endocarditis did not occur.
Cerebrovascular events Only a few reports have mentioned thromboembolic complications with LV endocardial pacing. With follow-up of 15 ⫾ 12 months and 85 ⫾ 2 months, respectively, Jais et al18 and Pasquie et al19 reported a TIA in 1 of 11 patients and 1 of 6 patients, respectively. In both cases, anticoagulation was interrupted at the time of the incident. Stroke or TIA occur more frequently in patients with versus those without heart failure. The reported incidence in patients without a history of atrial fibrillation varied between 1.5 and 3.5 events per 100 patient-years.20,21 Also, during anticoagulation with warfarin, patients with heart failure in sinus rhythm had an incidence of 0.72 thromboembolic events per 100 patient-years (P o.001, 95% CI 3.65–20.72 vs our study).22 The incidence in our study was 6.1 thromboembolic events per 100 patient-years (95% CI 3.4– 15.8). Several factors may have influenced this risk. A substantial proportion of the patients (16%) had New York Heart Association functional class IV (compared to 6% of patients enrolled in the CARE-HF trial3), indicating the severity of heart failure in this population. This is
612 corroborated by our finding of all-cause mortality twice as high as that reported in CRT trials.3 The severity of heart failure may substantially influence the risk of thromboembolism. In the SAVE trial, the risk of stroke doubled if LV ejection fraction was o28%.23 As in the studies of Jais et al18 and Pasquie et al,19 all of our patients had a subtherapeutic INR at the time of thromboembolism (Table 2). However, subtherapeutic anticoagulation levels with coumarin occur frequently in daily practice.24 Patients are within the targeted INR range approximately 60% to 65% of the time.25,26 Time in the therapeutic range is a strong predictor of the risk of stroke, with decreasing anticoagulation control generally associated with an increased risk of stroke.26 Therefore, subtherapeutic anticoagulation with coumarin may be considered unavoidable in spite of a well-organized Dutch Thrombosis Service. Although the efficacy of novel direct thrombin or oral factor Xa inhibitors may be more predictable, currently there is no experience with LV endocardial pacing. Because mechanical mitral valve replacement carries a greater risk of thrombosis than aortic valves, influenced by the low flow state of the LA, it may follow that transapical surgical or transventricular septal implants theoretically may lead to fewer thromboembolic complications.27 Although 1 of the patients with transapical implants in our study had a stroke, the numbers are too small to compare the thromboembolic risk between the both approaches. Lead build also may influence thromboembolic risk. Silicone insulation carries a greater risk than polyurethane leads, and these leads should be avoided in LV endocardial procedures.28 Although we expected that the smallerdiameter SelectSecure leads would be less prone to thrombosis, all events in our cohort occurred with this lead. Because both the CapSureFix Novus 4076 and 3830 SelectSecure have the same polyurethane outer insulation, it seems unlikely that the latter is a decisive factor. We could not establish any difference in anticoagulation adherence between the two patient groups. The presence of the anodal electrode is an unknown factor as a source of thrombus formation in LV pacing. Therefore, unipolar electrodes may be preferable to exclude anodal electrodes as a thromboembolic source.
Heart Rhythm, Vol 11, No 4, April 2014 coaptation. Second, because echocardiographic follow-up was performed several months after implantation, reverse remodeling may have masked a pacing lead–dependent increase in MR. Although patients who were nonresponders to CRT on echocardiography did not show an increase in MR, the small sample size hampers drawing conclusions from this observation.
Future considerations The lack of a control group in our study prevents establishing the real contribution of endocardially positioned leads in the left heart to thromboembolic complications. In addition, the selection of advanced heart failure patients may have biased the results toward more thromboembolic complications. Nevertheless, the potential risk of thromboembolism is an important factor in deciding to apply this technique. Although proven in animal experiments,31 no clinical study has yet shown an advantage of endocardial over epicardial pacing at opposite LV sites, although the possibility of delivering LV pacing at sites not accessible from the coronary sinus may be advantageous.10,32 However, in a population with advanced heart failure, the alternative of surgical epicardial LV lead delivery requiring general anesthesia may be hazardous as well. Learning from our experience and awaiting the results of the ongoing ALSYNC and EPI-ENDO trials with chronic endocardial pacing (www.clinicaltrials.gov), we confine the application to patients who are not suitable candidates for surgical LV lead placement. Future novel techniques may be promising in reducing thrombosis-related complications. The transinterventricular septal approach described by Gamble et al27 and leadless endocardial LV pacing33 both provide a route to pace the LV endocardium without passing the LA.
Conclusion Endocardial LV lead placement in advanced heart failure patients is associated with significant thromboembolic risk at mid-term follow up. The occurrence seems to be strongly correlated with a subtherapeutic level of anticoagulation. Until further results are available, application of this technique should be limited to patients with no suitable alternatives. In addition, endocardial LV lead placement is not associated with the occurrence or aggravation of MR.
Lead interference with mitral valve leaflets An LV lead implanted through the interatrial septum traverses the mitral valve, which may induce or aggravate MR and increase the risk of endocarditis. In a canine model of heart failure, Bordachar et al29 did not observe MR with the LV lead passing the mitral valve. Bordachar et al30 previously reported a higher mitral integral time velocity with endocardial pacing than during epicardial pacing, which could result from reduced MR. Similarly, our study demonstrated no aggravation of MR after LV endocardial lead placement. There may be several reasons. It is reasonable that the small diameter and floppy nature of the pacing lead do not induce valve damage or interfere with mitral leaflet
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