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Multicenter prospective observational long-term follow-up study of endocardial cardiac resynchronization therapy using the Jurdham procedure

      Background

      Endocardial cardiac resynchronization therapy (eCRT) avoids the limitations and failures of coronary sinus (CS) resynchronization. However, data regarding long-term outcomes are lacking.

      Objective

      The purpose of this study was to report the long-term outcome of eCRT performed using the Jurdham procedure in a real-world setting.

      Methods

      eCRT was performed in patients who failed a CS implant or failed to respond to cardiac resynchronization therapy (CRT), or in selected patients requiring lifelong oral anticoagulation (OAC). Left ventricular ejection fraction (LVEF), New York Heart Association functional class (NYHA FC), and left ventricular stimulation parameters were assessed during long-term follow-up (FU).

      Results

      From August 2009 to March 2018, the Jurdham procedure was performed in 88 patients at 15 centers in 8 countries, with FU of 32.88 ± 61.52 months (range 0–88 months; 196 patient-years). NYHA FC improved from 2.9 preimplant to 1.3 during FU. LVEF increased <10 percentage points from baseline in 7% of patients, between 10 and 20 percentage points in 11% of patients, and >20 percentage points in 82% of patients. All-cause mortality at 60 months was 30.5%. Three transient ischemic attacks (1.53 per 100 patient-years) and 6 strokes (3.06 per 100 patient-years) occurred. Of the 6 patients with stroke, 4 (66%) had almost complete recovery.

      Conclusion

      eCRT using the Jurdham procedure is an effective and safe technique in anticoagulated patients. This approach may be an attractive option for patients with failed CS implants or nonresponders to CS CRT. In addition, it might be a reasonable approach as a first option for treatment of patients requiring lifelong OAC.

      Keywords

      Introduction

      Cardiac resynchronization therapy (CRT) is a well-established treatment of heart failure in patients with left ventricular (LV) dysfunction and asynchronous biventricular contraction. However, 5% to 10% of coronary sinus (CS) implants fail, and 20% to 30% of patients are deemed nonresponders.
      • Sohaib S.M.
      • Chen Z.
      • Whinnett Z.I.
      • et al.
      Meta-analysis of symptomatic response attributable to the pacing component of cardiac resynchronization therapy.
      • Birnie D.H.
      • Tang A.S.
      The problem of non-response to cardiac therapy.
      Endocardial cardiac resynchronization therapy (eCRT) overcomes those limitations with superior cardiac performance and clinical response, but with potential concerns regarding thromboembolism and stroke risk.
      • Morgan J.M.
      • Biffi M.
      • Gellér L.
      • et al.
      on behalf of the ALSYNC Investigators
      ALternate Site Cardiac ResYNChronization (ALSYNC): a prospective and multicentre study of left ventricular endocardial pacing for cardiac resynchronization therapy.
      Few data regarding the long-term outcome of eCRT are available. Here we present our experience with 88 patients in a real-world, long-term, prospective, multicenter observational study of eCRT using the Jurdham procedure. This procedure uses femoral venous access for transseptal (TS) endocardial LV lead placement, followed by percutaneous snaring of the proximal lead tip to translocate it to a subclavian device pocket for connection to a standard CRT device.

      Methods

       Study oversight

      The study was initiated, designed, and proctored by the investigators, who also collected and analyzed the data and prepared the manuscript, with no industry support. Meetings attached to regional conferences were used for study management.

       eCRT indications

       Inclusion criteria

      Patients eligible for the Jurdham procedure met standard criteria for CRT implantation. They also either had a failed attempt at CS lead placement (ie, inability to cannulate the CS, LV lead dislodgment, unacceptably high acute or chronic LV pacing thresholds, phrenic nerve stimulation [PNS]) or were considered nonresponders to conventional CRT, who were able and willing to be compliant with lifelong oral anticoagulation (OAC) (assessed as commitment to therapy, medical coverage, availability of control centers). If these conditions were not met, eCRT was deemed contraindicated. Some patients already receiving OAC for atrial fibrillation (AF) or who had a mechanical valve were offered eCRT as first-line therapy.
      • Negrete A.
      • Molina L.
      • Torres R.
      • et al.
      The Jurdham procedure for endocardial cardiac resynchronization therapy: surgical results and short term follow-up in 50 patients (abstract). International Dead Sea Symposium, Tel Aviv, Israel.

       Exclusion criteria

      Patients were excluded if they had a contraindication to OAC, had an intracardiac thrombus, were in New York Heart Association functional class (NYHA FC) I, had a mechanical mitral valve prosthesis, or had a surgically repaired interatrial septum preventing TS puncture. Patients with previous stroke or presenting with chronic AF were not excluded.
      All patients provided written informed consent. Each participating institution received local ethics committee approval. Diagnostic and follow-up (FU) studies were performed at each center, following a shared, agreed upon data collection form. One investigator (LD) coordinated procedures and data collection from all centers (for a list of the study centers and investigators involved in the Jurdham Group, see the Supplemental Material and Supplemental Appendix A).

       Follow-up

      Left ventricular ejection fraction (LVEF) was evaluated every 6 months for the first 2 years and every 12 months thereafter. NYHA FC and LV lead threshold were evaluated at additional intervals. Responders were defined as patients who at 6-month FU had improved by at least 1 NYHA FC or those in whom LVEF improved by at least 10 percentage points.

       Implant procedure

      The Jurdham procedure is a combined femoral and subclavian vein technique. A detailed description of the procedure has been previously reported.
      • Elencwajg B.
      • López Cabanillas N.
      • Cardinali E.L.
      The Jurdham procedure: endocardial left ventricular lead insertion via a femoral transseptal sheath for cardiac resynchronization therapy pectoral device implantation.
      In brief, an atrial TS puncture is performed via femoral venous access using standard and slightly modified tools. A standard pacing lead is advanced via the femoral TS sheath and fixed to the LV endocardium. The TS sheath is peeled, and the lead is advanced until it is entirely intravascular. Using tools created by modifying standard electrophysiology sheaths and supplies, the proximal end of the lead is snared via the left or right subclavian vein and mobilized so that it exits into the pulse generator pocket. This approach combines the mechanical advantage of femoral access to obtain left atrial and LV access with the benefit of a traditional infraclavicular pocket and use of standard pacing leads and pulse generators. A video of the procedure is available in the Supplemental Material. In the ALSYNC (Alternate Site Cardiac Resynchronization) trial, in which an LV endocardial approach was also used, TS puncture was performed via subclavian access using a specially designed TS needle, radiofrequency energy, and transesophageal echocardiographic guidance.
      • Morgan J.M.
      • Biffi M.
      • Gellér L.
      • et al.
      on behalf of the ALSYNC Investigators
      ALternate Site Cardiac ResYNChronization (ALSYNC): a prospective and multicentre study of left ventricular endocardial pacing for cardiac resynchronization therapy.
      The procedure and specific tools were investigator developed and tested. The procedure is performed using readily available device implant tools (some of which are manually modified) and standard techniques.

       Chronic OAC

      OAC with vitamin K antagonist (VKA) agents targeted an international normalized ratio of 3 (recommended range 2–4). Because there are no recommended dosages of direct oral anticoagulants (DOACs) for eCRT, the dose recommended for AF was used. Four patients in the study cohort of 88 patients had mechanical aortic valves and received VKA.
      • Vahanian A.
      • Alfieri O.
      • Andreotti F.
      • et al.
      Guidelines on the management of valvular heart disease (version 2012).
      Among the 18 patients at 1 center, 14 were taking DOACs, to which aspirin 100 mg was added. No thromboembolic events (TEs) were recorded during FU of 15.13 ± 7.3 months.

      Results

       Study population

      Between August 2009 and March 2018, the Jurdham procedure was performed in 88 patients (FU 32.88 ± 61.52 months; range 0–88 months; 196 per 100 patient-years; median 22 months). Supplemental Table S1 summarizes baseline clinical and demographic patient characteristics, indications for the endocardial approach, OAC administered, and lead models used in the LV.
      Implant procedures were successful in all cases. The same technique was used for both initial and upgrade procedures and for left- and right-sided implants, using the corresponding subclavian vein. Seven right-sided implants were performed, all in upgrade cases (see Supplemental Video for procedure training details).

       Periprocedural complications

      One case of aortic puncture with the BRK needle occurred. Transesophageal echocardiography showed no bleeding, so the TS puncture was repeated and the procedure successfully completed. No cases of pneumothorax, hemothorax, cardiac perforation, pericardial effusion, significant arrhythmias, transient ischemic attack (TIA), stroke, pocket hematoma requiring additional management, or death occurred. No groin complications were recorded. Two thoracic hematomas occurred at FU of 7 days and 3 months as a result of local trauma, not related to the implant procedure.
      The target site for the LV position was the mid lateral wall of the LV (Figure 1). Although the Jurdham procedure facilitates eCRT at any location, the optimal site during the early experience was not known, so the lateral wall was selected based on its utility in traditional CRT. Because our early results were positive, we continued to favor that site for eCRT. This site was reached in 73 patients (82.95%). In 15 patients (17.04%), the lead was placed in the latero-apical segment of the LV wall due to better fixation of the lead.
      Figure thumbnail gr1
      Figure 1Radiological views. Arrows indicate the distal end of the left ventricular (LV) endocardial lead. Note the mid lateral LV wall position. AP = anteroposterior; LAO = left anterior oblique; RAO = right anterior oblique.

       eCRT implant indication

      In 64 patients (72.7%), the indication for eCRT was CS approach failure (15 implant failure, 26 nonresponse, 12 chronic high threshold, 5 PNS, 6 CS lead dislodgment). Of the 6 dislodgments, 4 occurred more than 2 weeks after successful implant; the other 2 occurred at 24 and 48 hours. For difficult implants during which a satisfactory stable position could not be obtained and the dislodgment risk was anticipated to be high, no attempt was made to reposition the lead. A total of 49 patients had a preexisting CRT device. The time from first device implant to upgrade was available for 40 of these patients. Median time from first device to upgrade for the whole group was 7 months.
      Because there is no universally accepted definition of “nonresponder,” patients who had no improvement in NYHA FC or in echocardiographic EF after 8 months of FU with careful medical management were categorized as nonresponders. In 24 patients (27.2%), eCRT was the primary implant, in 17 (19.3%) due to a preexisting indication for lifelong OAC and in 7 (7.9%) because of patient preference. In 6 cases, eCRT was the third procedure after both percutaneous CS and surgical epicardial lead failures (Figure 2).
      Figure thumbnail gr2
      Figure 2Jurdham procedure performed after coronary sinus (CS) and epicardial (Epi) procedures failures. Left: The CS lead became dislodged, and an Epi lead was surgically implanted. Right: The Epi lead threshold increase led to loss of capture. An endocardial (Endo) lead was ultimately implanted.
      There were no confirmed cases of LV lead infection or endocarditis. LV leads were removed due to pocket infection or right-sided endocarditis in 2 cases. Both occurred in upgrade procedures, 1 after the initial upgrade procedure and the other after the third procedure, which was performed after 2 previous attempts at another center via a CS approach.
      All instances of fibrosis and lead adherence noted during LV lead extraction were located in the veins of the upper thorax, the superior vena cava, and the right atrium. The LV lead segments in the left-sided circulation were easily removed percutaneously with manual traction.

       Mitral regurgitation

      No clinically significant increase in mitral regurgitation (MR) was documented (for full details see Results: Mitral Regurgitation in the Supplemental Material).

       PNS

      No PNS was observed during implantation or FU.

       Electrical performance and programming

      LV capture thresholds had an average value of 0.71 ± 0.44 V (range 1.3–0.4V) at pulse width of 0.40 ms at implant and mean of 0.6 V ± 0.21 V at pulse width of 0.40 ms during FU (Figure 3). Details on Electrical Performance and Programming are given in the Supplemental Material.
      Figure thumbnail gr3
      Figure 3Left ventricular lead thresholds at implant and follow-up.
      During FU, biventricular pacing was achieved 96.57% ± 2.81% of the time. In cases of frequent ventricular arrhythmia, antiarrhythmic treatment was administered (mostly amiodarone). In 3 cases of AF, AV nodal ablation was performed because pharmacologic rate control was difficult.

       OAC: VKA and DOACs

      The decision to use VKA or DOACs was at the operator’s discretion. Details on the Anticoagulation Protocols are detailed in the Supplemental Material.

       Clinical response

      Clinical response by NYHA FC and LVEF is shown in Figures 4 and 5. NYHA FC improved from a baseline mean value of 2.9 ± 2.4 to 1.3 ± 0.8, and this remained stable during FU. LVEF was used to categorize patients as nonresponders, responders, or super-responders based on absolute improvement in EF percentage points <10%, 10%–20%, and >20% from baseline values, respectively, at 6-month FU. Of the population, 6.4% were nonresponders, 11.4% were responders, and 82.2% were super-responders. No patients had deterioration in EF in relation to basal values.
      Figure thumbnail gr4
      Figure 4New York Heart Association functional class (NYHA FC) at implant and follow-up. There was an early improvement of this parameter, which remained stable during follow-up.
      Figure thumbnail gr5
      Figure 5Evolution of left ventricular ejection fraction (LVEF). Percentage of patients with improvement in LVEF in relation to preimplant value. Most patients showed a sustained increase of >20 percentage points.
      Due to costs constraints, echocardiograms were not routinely performed before the 6-month FU visit. For the same reason, some patients missed scheduled echocardiograms, especially those with longer FU. Loss of FU was approximately 10%–20% for each time window (Figure 5). Most patients achieved super-response by 6 months, and all had achieved super-response by 12 months. Once a super-response developed, it typically persisted for the duration of available FU.

       Mortality

      A total of 26 patients (13.2 per 100 patient-years) died during FU (mean survival 10.86 ± 9.97 months; range 0–58 months; 30.55% all-cause mortality at 60 months). Mortality was higher during the first 18 months of FU, with subsequent flattening of the curve. Ten patients died of progressive heart failure, 1 hemorrhagic stroke, 2 septic shock secondary to right ventricular lead endocarditis (without evidence of LV lead involvement), 1 sudden death (sudden unwitnessed death, device interrogation not available), 3 refractory ventricular tachycardia/ventricular fibrillation in the coronary care unit, and 9 noncardiac causes (1 malignancy, 1 pneumonia, 7 noncardiac nonspecified reasons). The CRT system was removed in 3 patients, in 1 due to preexisting severe MR and placement of a MitraClip, 1 due to heart transplantation, and 1 due to infective endocarditis (IE) not related to the LV lead. Figure 6 shows the global mortality curve.
      Figure thumbnail gr6
      Figure 6Survival curve. Mortality was higher in the first 18 months, with subsequent flattening of the curve. At risk refers to the number of patients being followed at a given point in time.

       TEs

      During FU, a total of 9 TEs (10.2%; 4.59 per 100 patient-years) occurred: 3 TIAs (3.4%; 1.53 per 100 patient-years) and 6 strokes (6.8%; 3.06 per 100 patient-years). Of the 6 patients with stroke, 4 (66%) had mild, nondisabling strokes (mean Rankin score
      • Rankin J.
      Cerebral vascular accidents in patients over the age of 60.
      = 2) with almost complete functional recovery. One patient (1.35%) developed a hemorrhagic stroke at 11-month FU and died (incidence 1.02 per 100 patient-years). This patient had felt so well that he had discontinued taking all medications, including DOAC, with subsequent occurrence of severe ischemic stroke. He was then placed on warfarin but suffered a fatal hemorrhagic stroke. The other patients were taking their “original” drug when TE occurred.

      Discussion

      Although CRT has been available for several decades, the nonresponder rate remains 30%–35% and is associated with poor prognosis and quality of life, and high level of disability. eCRT overcomes these limitations. Our main finding was near-universal acute and long-term sustained response to eCRT. This dramatic response likely reflects the fact that the His–Purkinje network is endocardial and that eCRT likely rapidly activates it at a site distal to any block present (Figures 7 and 8). We also found the following: (1) eCRT using the Jurdham technique is safe and highly successful, and can be readily adopted for use by experienced electrophysiologists, with minimal specific training required as most of the maneuvers are routinely used in electrophysiology laboratories using mostly readily available tools; (2) endocardial LV leads can be placed at target locations and remain mechanically and electrically stable, with minimal clinical impact on mitral valve function; and (3) TEs occurred at a rate of 10%, with 9 of 10 events being TIAs or strokes with minimal functional impairment (mean Rankin score 2.0: 1 patient with score 4, 3 with score 2, and 2 with score 1). To our knowledge, this study provides the longest FU of an eCRT cohort and is a real-world, long-term, prospective, multicenter observational study of eCRT. It is also the first study to demonstrate the long-term stability of LV endocardial leads placed using the Jurdham procedure. By using modified, readily available components, this investigator-developed technique can be readily adopted by practicing electrophysiologists, even in resource-constrained environments.
      Figure thumbnail gr7
      Figure 7Coronary sinus (CS) and endocardial left ventricular (LV) leads. The CS lead (top arrow) is in a radiographically adequate position, but the patient was a nonresponder. The endocardial LV lead (bottom arrow) resulted in a good clinical response. See for a probable explanation of the cause.
      Figure thumbnail gr8
      Figure 8Electrocardiograms of the patient shown in . Left, Basal: Spontaneous QRS (QRS 220 ms). Middle, CS lead: Biventricular stimulation with the coronary sinus (CS) lead at a left ventricle–right ventricle (LV-RV) interval of 10 ms (QRS 190 ms). Right, eLV lead: Biventricular stimulation with the endocardial LV lead at an LV-RV interval of 10 ms (QRS 160 ms). Note in the middle panel the initial delay between the stimulus and ventricular activation, particularly in the left-sided leads. This probably reflects epicardial activation stimulating diseased, slowly conducting myocardium, leading to desynchronized LV contraction. In the right panel, no stimulus–QRS delay reflects faster intraventricular conduction due to endocardial stimulation, in juxtaposition to the His–Purkinje network bypassing the fibrotic tissue, leading to a synchronized contraction. See text for

       Response rate

      In our cohort, all patients had improvement of NYHA FC by ≥1 class. This effect occurred early (≤ 3 months) and was significant and sustained during FU. Of the patients, 82.2% were super-responders (absolute improvement in LVEF >20%), 11.4 % were responders (improvement 10%–20%), and only 6.4% were nonresponders (improvement <10%). No patient had worsening of LVEF.
      Several mechanisms may account for this widespread response, compared to the 65%–70% response with “traditional” CRT. First, with traditional CRT, epicardial activation may stimulate diseased, slowly conducting myocardium, leading to minimal LV pre-excitation. Endocardial stimulation, which is delivered in juxtaposition to the His–Purkinje network, may overcome this limitation. In addition, by capturing the distal His–Purkinje network, proximal sites of conduction block are bypassed, thus overcoming a potential disadvantage of His-bundle pacing. Finally, endocardial initial activation is more physiologic and may be more efficient and less arrhythmogenic than epicardial pacing.
      • Özcan E.E.
      • Szilagyi S.
      • Sallo Z.
      • et al.
      Comparison of the effects of epicardial and endocardial cardiac resynchronization therapy on transmural dispersion of repolarization.

       Jurdham procedure

      The Jurdham procedure leverages human anatomy to facilitate TS puncture, as it overcomes the challenge of attempting TS puncture from above, allowing successful LV lead placement with a minimum of custom equipment but long-term stable function. This approach may account for the high success rate we encountered. In the ALSYNC trial, which used a specially designed TS needle, radiofrequency energy, and transesophageal echocardiographic guidance, LV endocardial lead implantation was successful in 118 of 132 patients (89%), with 2 patients requiring a second implant attempt.
      • Morgan J.M.
      • Biffi M.
      • Gellér L.
      • et al.
      on behalf of the ALSYNC Investigators
      ALternate Site Cardiac ResYNChronization (ALSYNC): a prospective and multicentre study of left ventricular endocardial pacing for cardiac resynchronization therapy.
      In 11 of these 14 cases (78%), implant failures were related to failed TS puncture.
      • Morgan J.M.
      • Biffi M.
      • Gellér L.
      • et al.
      on behalf of the ALSYNC Investigators
      ALternate Site Cardiac ResYNChronization (ALSYNC): a prospective and multicentre study of left ventricular endocardial pacing for cardiac resynchronization therapy.
      The higher success rate (100%) found in the present study likely reflects the anatomic mechanical advantage afforded by an inferior as opposed to a superior approach.

       Complications and major risks

      MR, LV lead–related IE, and TEs have been the main concerns regarding eCRT. Our data add to the growing body of evidence demonstrating the safety and efficacy of eCRT. This is particularly true when considering the risk-to-benefit ratio for nonresponders given their poor outcomes.

       MR

      Moderate and severe MR before eCRT was present in 60% of the 69 patients for whom these data were available. Clinically significant MR due to the LV lead was found in only 1 case. As with other studies,
      • Morgan J.M.
      • Biffi M.
      • Gellér L.
      • et al.
      on behalf of the ALSYNC Investigators
      ALternate Site Cardiac ResYNChronization (ALSYNC): a prospective and multicentre study of left ventricular endocardial pacing for cardiac resynchronization therapy.
      • Gamble J.H.P.
      • Herring N.
      • Ginks M.
      • Rajappan K.
      • Bashir Y.
      • Betts T.R.
      Endocardial left ventricular pacing for cardiac resynchronization: systematic review and meta-analysis.
      • Rademakers L.M.
      • vanGelder B.M.
      • Scheffer M.G.
      • Bracke F.A.
      Mid-term follow up of thromboembolic complications in left ventricular endocardial cardiac resynchronization therapy.
      reduction in MR after LV lead implantation due to reverse remodeling and improvement in LV performance was found.

       IE

      There were no confirmed cases of IE related to the LV lead. In the few patients with pocket infection or right-sided endocarditis, the “left-sided portion” of the LV lead was easily removed with manual traction alone without complications. In 2 patients with pocket infection or right-sided endocarditis, infection occurred after an upgrade procedure, one after an initial upgrade procedure and the other after the third procedure, after 2 previous attempts at standard CS placement at other centers.

       TE

      TEs related to the LV endocardial lead remain a major concern with eCRT given their potential to be severe and highly disabling, and we believe that TEs remain the most common factor limiting widespread eCRT use. However, TEs comprise a wide variety of entities of varying severity and clinical significance.
      • Easton J.D.
      • Saver J.L.
      • Albers G.W.
      • et al.
      Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease.
      In the ALSYNC trial,
      • Morgan J.M.
      • Biffi M.
      • Gellér L.
      • et al.
      on behalf of the ALSYNC Investigators
      ALternate Site Cardiac ResYNChronization (ALSYNC): a prospective and multicentre study of left ventricular endocardial pacing for cardiac resynchronization therapy.
      in which the modified Rankin scale was used to characterize the severity of TE events,
      • Rankin J.
      Cerebral vascular accidents in patients over the age of 60.
      • Bonita R.
      • Beaglehole R.
      Modification of Rankin scale: recovery of motor function after stroke.
      all 5 strokes reported (2.6 events per 100 patient-years; 95% confidence interval 1.1–6.3) were mild (score values between 0 and 2). Jaïs et al
      • Jaïs P.
      • Takahashi A.
      • Garrigue S.
      • et al.
      Mid-term follow-up of endocardial biventricular pacing.
      and Pasquié et al
      • Pasquié J.L.
      • Massin F.
      • Macia J.C.
      • et al.
      Long-term follow-up of biventricular pacing using a totally endocardial approach in patients with end-stage cardiac failure.
      reported TIAs in 1 of 11 patients and 1 of 6 patients receiving eCRT, respectively, in both instances during periods of inadequate OAC. In our study, the incidence of TIA was lower (3/88 patients), probably due to better use of anticoagulation. In another study, Rademakers et al
      • Rademakers L.M.
      • vanGelder B.M.
      • Scheffer M.G.
      • Bracke F.A.
      Mid-term follow up of thromboembolic complications in left ventricular endocardial cardiac resynchronization therapy.
      reported TE in 7 patients (6 ischemic strokes and 2 TIAs, corresponding to 6.1 TEs per 100 patient-years; 95% confidence interval 3.4–15.8). Mean total TE rate (TIA + stroke) in our study was 4.59 per 100 patient-years, which compares favorably with the 6.2 per 100 patient-years reported by Gamble et al
      • Gamble J.H.P.
      • Herring N.
      • Ginks M.
      • Rajappan K.
      • Bashir Y.
      • Betts T.R.
      Endocardial left ventricular pacing for cardiac resynchronization: systematic review and meta-analysis.
      in a meta-analysis that included 7 long-term pivotal studies.
      Although any TE event is of concern, in patients who are routinely anticoagulated the thrombin filaments that form on leads may be diminutive, leading to limited clinical impact
      • Bruce C.J.
      • Friedman P.A.
      • Narayan O.
      • et al.
      Early heparinization decreases the incidence of left atrial thrombi detected by intracardiac echocardiography during radiofrequency ablation for atrial fibrillation.
      • Sugrue A.
      • DeSimone C.V.
      • Lenz C.J.
      • Packer D.L.
      • Asirvatham S.J.
      Mobile thrombus on cardiac implantable electronic device leads of patients undergoing cardiac ablation: incidence, management and outcomes.
      In patients with an indication for chronic anticoagulation who fail to respond to standard CRT (which itself has a poor prognosis),
      • Rickard J.
      • Cheng A.
      • Spragg D.
      • et al.
      Durability of the survival effect of cardiac resynchronization therapy by level of left ventricular functional improvement: fate of “non-responders”.
      eCRT—with its high response rate—may be an attractive option, particularly when fully weighing the risk-to-benefit ratio.
      Factors other than the presence of an endocardial LV lead likely contribute to thromboembolism in this population. There is a strong relationship between the severity of LV dysfunction, heart failure, and the incidence of TE. In the SAVE (Survival and Ventricular Enlargement) trial, Loh et al
      • Loh E.
      • St. John Sutton M.
      • Wun C.C.
      • et al.
      Ventricular dysfunction and the risk of stroke after myocardial infarction.
      demonstrated that patients with LVEF <28% after myocardial infarction had a relative risk of stroke of 1.86 compared to patients with EF >35% (P = .01). Even more compelling, for every 5% decrease in EF, there was an 18% increase in the risk of stroke and a cumulative risk of 8.5% at 5 years. Of note, the SAVE trial included only patients with LV dysfunction but without symptomatic heart failure.
      • Pfeffer M.A.
      • Braunwald E.
      • Moyé L.A.
      • et al.
      Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction—results of the Survival and Ventricular Enlargement Trial.
      Patients included in our study were sicker than most CRT populations: 90% were in NYHA FC III /IV refractory to optimal medical therapy, 29.5% had AF, 75% had intrinsic left bundle branch block, mean EF was 25%, and 8.1% were nonresponders (after successful implant); in most cases, eCRT was a second or third procedure. It seems reasonable that the expected stroke rate should be elevated in this population. In a meta-analysis of endocardial CRT that included patients who matched our cohort with regard to severity of LV dysfunction and comorbidities, Gamble et al
      • Gamble J.H.P.
      • Herring N.
      • Ginks M.
      • Rajappan K.
      • Bashir Y.
      • Betts T.R.
      Endocardial left ventricular pacing for cardiac resynchronization: systematic review and meta-analysis.
      concluded that the added risk of stroke due to the endocardial LV lead was no more than 1 additional stroke per 100 patient-years on top of a “baseline risk” of 3 strokes per 100 patient-years.

       Mortality

      The total mortality rate in our cohort was higher than in other studies (13.7 vs 6.5 per 100 patient-years)
      • Gamble J.H.P.
      • Herring N.
      • Ginks M.
      • Rajappan K.
      • Bashir Y.
      • Betts T.R.
      Endocardial left ventricular pacing for cardiac resynchronization: systematic review and meta-analysis.
      ; however, mortality is clearly influenced by patient selection, length of FU, and study size. Our study has the longest FU of eCRT studies published to date and has the second largest population, only surpassed by the ALSYNC study.
      • Morgan J.M.
      • Biffi M.
      • Gellér L.
      • et al.
      on behalf of the ALSYNC Investigators
      ALternate Site Cardiac ResYNChronization (ALSYNC): a prospective and multicentre study of left ventricular endocardial pacing for cardiac resynchronization therapy.
      However, by 18-month FU, the number of patients at risk was almost the same between studies; furthermore, our population was larger. It is also the only study in which patients (n = 7) reached the elective replacement indicator. On the other hand, our population was one of the sickest (80% in NYHA FC III and 10% in FC IV; EF 25.66% ± 8.67%). As shown in other studies, there was no accelerated decline in survival during the later stages of FU.
      • Rickard J.
      • Cheng A.
      • Spragg D.
      • et al.
      Durability of the survival effect of cardiac resynchronization therapy by level of left ventricular functional improvement: fate of “non-responders”.

       Future directions

      Despite more than 20 years of experience and technological improvements, CRT continues to have a 30%–35% incidence of nonresponders, which might indicate an “intrinsic failure rate” inherent to this approach that cannot be improved. In contrast, most studies with eCRT demonstrate response rates of 90%–95%, with a very low incidence of severe complications and TE.

       Study limitations

      Our work is best understood in the context of its limitations. As an investigator-led study without external funding, we relied on assessments at each site, without a core laboratory or an outcomes adjudication committee. This precluded consistent collection of quantitative data regarding MR, so we relied on investigator assessment of clinically significant MR. Precise and heart failure hospitalization information before and after eCRT was not available. In addition, details regarding preprocedural anticoagulation management was not available.

      Conclusion

      eCRT using the Jurdham procedure is effective and safe in anticoagulated patients. The study findings show that this approach can be an attractive option for patients with failed CS implants and for CRT nonresponders. In addition, it seems to be a reasonable approach as a first option for treatment of patients requiring lifelong OAC.

      Acknowledgment

      Noemi Marotta de Aguilar for manuscript preparation.

      Appendix. Supplementary data

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