Periprocedural Management of Cardiac Resynchronization Therapy

Curr Treat Options Cardio Med (2014) 16:298DOI 10.1007/s11936-014-0298-1

Heart Failure (W Tang, Section Editor)

Periprocedural Managementof Cardiac ResynchronizationTherapyJohn Rickard, MD, MPH1

Niraj Varma, MD2,*

Address1Division of Cardiology, The Johns Hopkins Hospital, Baltimore, USA*,2Cardiac Pacing and Electrophysiology, Department of CardiovascularMedicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USAEmail: [email protected]

Published online: 19 February 2014* Springer Science+Business Media New York 2014

This article is part of the Topical Collection on Heart Failure

Keywords Heart failure I Cardiac Resynchronization Therapy I QRS morphology I Echocardiography I Leftventricular dyssynchrony

Opinion Statement

Cardiac resynchronization therapy (CRT) is an important therapy in heart failure but 30 %40 % of patients may not respond. Improving this rate is an important goal and requiresattention to candidate selection, intraoperative procedure, and postoperative follow-up.Factors to be considered are QRS morphology, duration, and left ventricular lead positionwith attention to paced effects on QRS. Postprocedure follow-up is critical to correct inter-fering conditions (eg, anodal capture, loss of 100 % biventricular pacing because of pre-mature ventricular complexes (PVCs) or atrial fibrillation (AF). Echocardiographicimprovement following CRT, which may take up to 18 months, is a potent predictor oflong-term outcomes. Correcting the status of nonresponders, when possible, is important.Remote monitoring, in conjunction with CRT optimization clinics, may facilitate multidis-ciplinary follow-up and enable early intervention to improve outcome.

IntroductionCardiac resynchronization therapy (CRT) representsone of the biggest advances in the treatment of systolicheart failure over the last 15 years. Its goal is to miti-gate left ventricular (LV) dyssynchrony via a LV leadplaced either endovascularly via the coronary sinusor surgically, to improve LV function. The first trialsof CRT were small and demonstrated the benefit of

CRT in terms of relatively soft functional endpointssuch as improvement in 6 min hall walk times andNew York Heart Failure Class [1, 2]. Over time, CRTwas shown effective in terms of increasingly objectiveendpoints such as the demonstration of reverse ven-tricular remodeling, decreased heart failure hospitali-zations, and improved all-cause survival [3, 4••]. At

first, trials of CRT included patients with advancedheart failure symptoms, with left ventricular dilata-tion, and a QRS duration 9120 ms [1–3, 4••]. Morerecently, CRT has been shown beneficial in patientswith less symptomatic heart failure regardless of LV

size [5–9]. Despite the significant advance that CRTrepresents, approximately 30 % 40 % of patients re-ceiving CRT fail to respond to the therapy [10]. The ex-act response rate varies based on which definition ofresponse is used [10].

Considerations Prior to CRT ImplantPatient Selection

According to the 2008 ACC/AHA/HRS guidelines for appropriate device im-plantation, CRT was recommended in New York Heart Association (NYHA)functional class III or IV patients with an Left ventricular ejection fraction(LVEF)≤ 35 % despite optimal medical therapy, and a QRS duration≥120 ms [11]. Since the publication of these guidelines, multiple retro-spective single center cohort studies as well as subgroup analyses from largerandomized control trials were published seeking to refine these implanta-tion criteria [12–14]. In particular, the importance of QRS morphology inaddition to duration was noted as patients with a left bundle branch blockmorphology were noted to benefit to a greater extent than patients with ei-ther a nonspecific intraventricular conduction delay or right bundle branchblock [12–14]. Still, the benefit of CRT has been suggested in patients with anon- Left bundle branch block (LBBB) when they are associated with greaterQRS durations (typically 9150 ms) [15]. Given the absence of a large scaleclinical trial comparing patients with non-LBBB morphologies with andwithout CRT, the true effect of CRT in this population remains somewhatcontroversial. In addition to a greater understanding of the value of bundlebranch morphology in terms of response, 3 large randomized control trialsdemonstrated the benefits of CRT in patients with minimally symptomaticheart failure and QRS ≥150 ms [6–8]. The REVERSE and MADIT-CRT wereconvincing in terms of the benefit of CRT in inducing reverse remodelingand improving heart failure in patients with systolic dysfunction. The RAFTtrial followed which established a mortality benefit for CRT in minimallysymptomatic patients [9]. In the 2012 HRS Focused Update, the criteria forCRT were modified to account for bundle branch lock morphology andexpanded to includeminimally \symptomatic patients [16]. In addition,it has been shown that CRT may be more effective in patients innormal sinus rhythm compared with atrial fibrillation. This is likelydue to less effective and frequent biventricular pacing in patients withatrial fibrillation (AF) [17]. Still, CRT is recommended in patientswith atrial fibrillation but at a lower level of evidence [16].

Issues during CRT implantationLead positioning strategies

The placement of the LV lead is typically accomplished via a transvenousapproach with the lead inserted into one of the tributaries of the coronary

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sinus. Vascular access is first obtained and the coronary sinus (CS) is cannulatedwith a guiding sheath. Cannulation of the CS with a splittable guiding sheath isaccomplished typically either via probing for the CS with a guidewire or with theuse of nondeflectable or deflectable electrophysiology catheters. Once the guidingsheath has been placed, a balloon catheter is inserted into the CS and coronaryvenography performed. Typically, coronary venography is performed in an leftanterior oblique (LAO) projection and a shallow right anterior oblique (RAO)view todelineate the coronary venous vasculature. Once a target vein is chosen, anLV lead of appropriate size is selected. LV leads come inmultiple shapes and sizesdiffering by manufacturer [18]. In addition, LV leads are available in unipolar,bipolar, and more recently multipolar configurations. Multipolar LV leads havethe option of providing multiple pacing vectors which can be useful when dia-phragmatic stimulation or high capture thresholds are noted. Often, the guidingsheath itself does not provide enough distal support or reach to navigate smallvenous targets [18]. Therefore, telescoping sheaths are often used to mitigate thisproblem [18]. Telescoping sheaths come with various shapes distally to facilitatethe cannulationof venous tributarieswithmanydifferent proximal takeoff shapes[18]. Once the desired tributary has been cannulated, the LV lead is typicallyinserted into the venous tributary via an over the wire technique utilizing a thinguidewire. Once a desired position has been reached, pacing thresholds and ev-idence for diaphragmatic stimulation are determined via all pacing vectors. Thesheaths are then split and the LV lead suture sleeve is tied down in the pocket.

The best location in which to place the LV lead is a source of come con-troversy. Traditionally, a posterolateral vein has been targeted with the beliefthat this site represents the latest activated LV region. Although this principlegenerally still holds, more nuanced considerations for LV lead placementhave been established [19]. The distance between the LV and right ventricular(RV) leads has been shown to be associated with better long-terms outcomes[20]. Targeting sites which produce the maximum electrical delay is anothertechnique that has shown promise in improving outcomes [21]. This tech-nique involves targeting an area where the LV lead electrogram occurs late inthe QRS complex. Alternatively, targeting areas of maximal mechanical delayhas also been studied [1]. Using echocardiography with strain or speckletracking technology, the latest activated segment is identified and subse-quently targeted [22]. The most compelling data suggest that apical leadpositions are unfavorable [23•]. The reason behind this is likely multifac-torial. During LV depolarization, the apex is activated relatively early on inthe LV activations sequence compared to the base [19]. Secondly, an apicalLV position will lead to minimal separation between the LV and RV lead[20]. Lastly, an apical position produces an activation sequence notcompletely dissimilar from RV pacing, which is known to be hemodynami-cally unfavorable [23•, 24]. The effects of anterior lead positioning have beeninconsistent with some reports indicating poorer outcomes [25] but others[eg, Multicenter Automatic Defibrillator Implantation Trial with CardiacResynchronization Therapy (MADIT-CRT)] no difference to other nonapicalpositions. Placing the LV lead in an area free of scar is also thought to lead toimproved outcomes [26]. Rademakers and colleagues found in a caninemodel that LV positions in areas free of scar were associated with the mostbenefit [26]. When an LV lead is located within scar, slow conductionthrough the scar can result in a greater amount of LV activation coming from

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the RV lead, which is likely to be hemodynamically unfavorable [26]. Pre-implant magnetic resonance imaging to guide avoidance of scar may beuseful [27–29]. In some instances, functional conduction barriers to LVpacing may develop at otherwise ideal lead positions (ie, delayed activationin nonscar areas) and preclude successful LV pre-excitation [30]. MultipolarLV leads offer a mechanism to overcome these with pacing vectors selectedon an individual basis [31].

ComplicationsPlacement of an endovascular CS lead may be in some circumstances verydifficult due to tortuous venous anatomy and enlarged chamber sizes. Evenwhen delivered to ideal anatomical locations, phrenic nerve stimulation maypreclude use of such positions. From the large clinical trials of CRT, suc-cessful endovascular CS lead implantation was achieved in 88 % 97 % ofpatients [32]. This may be improved with multipolar leads [33]. In terms ofin hospital mortality following CRT placement, Reynolds and colleaguesreported an incidence of 1.1 % from a population of 30,984 Medicare pa-tients, an incidence slightly higher than implantable cardioverter defibrillator(ICD) implants alone (0.9 %; P=0.07) [34]. Complications associated withCRT implant itself largely mirror those of right sided pacing and ICD systemswith a few additional considerations related to the LV lead itself. Pneumo-thorax during CRT implant was noted in 30/3300 patients collectively fromthe large CRT trials for an incidence of (0.9 %) [32]. Coronary vein dissectionwas noted in 1.3 % of patients as was coronary vein perforation (1.3 %) [32].Coronary venous dissection often prevents completion of the procedure butrarely results in adverse outcomes. Re-implant may be attempted severalweeks later. In rare cases, however, coronary venous dissection can result inthe development of a pericardial effusion and tamponade. The need forsurgical intervention to repair a coronary venous perforation is rare. Post-implantation, pocket hematomas occur in roughly 2.4 % of patients under-going CRT, a rate slightly higher than for ICD implants alone (2.2 %) [32].LV lead dislodgement in the large CRT trials occurred in 2.9 % to 10.6 % ofcases [32]. Upgrading previously implanted systems may be associated withhigher complication rates [35]. It is common practice to observe patientswho undergo CRT implant for one day in the hospital to screen for potentialcomplications.

Peri-implant management of anticoagulantsFor implantation of ICDs and simple pacemakers, coumadin is typicallycontinued without cessation. In the BRUISE CONTROL trial, 681 patientsundergoing cardiac electronic implantable device surgery who were takingwarfarin were randomized to continuation of warfarin throughout the sur-gery versus stopping warfarin 5 days prior to the procedure with initiation ofheparin which was stopped 4 h prior to the procedure and restarted 24 hafter the procedure [36]. The primary outcome of significant device pockethematoma occurred in 3.5 % of the warfarin continuation group and 16.0 %in the bridging group [36]. New CRT implants accounted for only approxi-mately 13 % of devices and results specific to this group were not reported[36]. Whether to hold coumadin for a few doses prior to CRT implant is


somewhat controversial. Given the small risk of coronary venous perforationduring CRT implant, some implanters choose to hold coumadin for a fewdosages prior to device implantation while others continue coumadinwithout holding any doses. Intravenous heparin is universally held prior toand for at least 2 3 days after device implantation as the incidence of pockethematoma formation with IV heparin is substantially elevated. In addition,the risks of hemopericardium attributable to coronary venous perforationleading to tamponade would likely be greater on heparin. The decision ofwhether to hold and when to restart newer anticoagulants such as dabigitranor ximelagtran is less clear. In a cohort of 25 patients receiving continuousdabigitran prior to and following cardiac implantable electronic device im-plant, only one minor bleeding event was reported at 30 days follow-up [37].

Issues after CRT implantationDocumentation post-CRT implant

Following successful CRT implant, lead threshold, sensing, and impedancedata should be documented as these data will provide a basis for futurecomparisons. A post- CRT paced ECG may be valuable to assess the change inQRS duration as the difference in QRS duration between the pre-CRT andfirst paced ECG may predict outcomes following CRT [38, 39•]. A PA andlateral chest X-ray is indicated in all patients to assess for complications (suchas lead dislodgement or pneumothoraces) and to characterize lead position.While far from perfect, a PA and lateral CXR can provide a rough estimate oflead position. In the PA view, the LV lead position is characterized as basal,mid, or apical and in the lateral view, anterior, lateral, and posterior [25].

Initial device programmingOnce implanted, initial CRT programming entails choosing a pacing mode,AV interval, the lower and upper rate limits, and antitachycardia therapysettings. As opposed to pacemakers and defibrillators without CRT capacity,the goal of CRT programming is to achieve as close to 100 % biventricularpacing. Even small diversions from this ideal (eg, 90 %) have been shown tohave a significant adverse impact on patient outcomes [40]. In terms of AVdelay programming, a paced delay of 100 ms and sensed delay of 130 ms arethe typical out of box settings with simultaneous RV and LV activation.

Role of AV/VV optimizationIn the SMART-AV trial, which compared device based algorithmic Atrio-ventricular (AV) optimization, echocardiographic based optimization, andstandard out of the box settings, AV optimization has not been shown to beof benefit over standard out of the box settings [41]. Therefore, routine AVoptimization in all comers is not recommended. The routine use of rightventricular-left ventricular (VV) optimization in all comers is similarly notindicated. Both the RHYTHM II ICD and DECREASE HF trials showed nobenefit for VV optimization in all comers [42, 43]. In nonresponders to CRT,however, AV and VV optimization may have a role [44••]. In the small RE-SPONSE HF trial, VV optimization was shown beneficial in patients initiallynot-responding to CRT [45].


In terms of AV optimization, a variety of methods have been employed. Thethreemost common are the Ritter’smethod, the iterativemethod, and the aorticvelocity time integral (VTI) methods. The Ritter’s method, originally used inpatients with dual chamber pacemakers with AV block [46]. Thismethod strivestomaximize LV filling by allowingmitral valve closure only after completion ofthe atrial contraction. In Ritter’s method, the AV delay is first programmed to anonphysiologic short interval and the time between the end of the a wave theventricular contraction spike measured using mitral inflow pulsed waveDoppler. This is then repeated using a nonphysiologic long AV delay. The in-tervalsmeasured in these two steps are then subtracted from the long AV intervalused in the second step to calculate the optimal AV delay.

Of the three methods, the iterative method is the most widely employedin clinical practice. In this method, a long AV delay is first programmedwhich produces fusion of the e and A wave forms in the mitral inflow view[17, 47]. The delay is subsequently shortened in 10–20 ms intervals untiltruncation of the a wave is observed. The AV delay is then lengthened by10 ms increments until a wave truncation is no longer observed.

Lastly, in the aortic VTI method, aortic VTIs are calculated at various AVdelays until the AV delay producing the greatest VTI is noted. This method,which is the least commonly used for AV delay optimization, is the mostcommon method used for VV optimization. The aortic VTI technique pro-duces an estimation of LV stroke volume [48]. The AV delay that producesthe greatest aortic VTI is determined to be the optimal setting. In VV opti-mization, the standard ‘out–of–box’ setting is no offset between RV and LVactivation. Programming RV pacing first is undesirable in the vast majority ofpatients and has been associated with worse outcomes [49]. Hence, for manydevices this is an unprogrammable option. VV optimization is commonlyperformed by programming by calculating the aortic VTI at baseline and thenat increasing increments of LV first pacing (typically 10 ms increments). Theoptimal VV delay is that which produces the greatest aortic VTI [17]. Theaortic VTI method for both AV and VV optimization is limited by technicallimitations (small changes in the transducer angle can introduce significanterrors) [17].

Assessment for anodal captureDuring cathodal capture, a single wave front is initiated which pacescardiac tissue representing the desired mechanism of cardiac pacing. Incertain circumstances, however, hyperpolarization of local tissue mayoccur resulting in capture at the anode [50]. When anodal capture ispresent, the left ventricle is effectively RV-paced which may not only leadto nonresponse to CRT but could lead to deterioration [51]. This phe-nomenon has been described primarily in CRT systems, which employ anarrow electrode as the right ventricular anode. This situation is mostcommonly in CRT pacemakers but has been observed in CRT defibril-lators as well [52]. Anodal capture is far more common in dedicatedrather than integrated bipolar RV lead and at high pacing outputs [51].Anodal capture can be recognized when the biventricular paced QRSmorphology is identical to the RV paced morphology or when the pacedwaveform is inconsistent with the LV lead position (most commonly


seen as positive QRS waveform in V1 or a negative in V1 [51, 52] Ofnote, when the LV and RV leads are close together, identical ECG find-ings to anodal capture may be present despite the absence of anodalcapture.

Optimization clinic for nonrespondersOnce a patient has been implanted with a CRT device, an oftenoverlooked aspect of management is rechecking an echocardiogram be-tween 6 and 12 months following implant to assess for response. Echo-cardiographic improvement following CRT, which may take up to18 months, is a potent predictor of long-term outcomes [53, 54••]. Basedon the results of this follow-up echocardiogram, patients can be catego-rized as super-responders, responders, and nonresponders each of whichhave different long-term outcomes. Defined echocardiographically, super-responders to CRT are those patients who either normalize their ejectionfraction or have a dramatic improvement from baseline (typically definedas 915 % 20 % improvement) [55, 56]. Responders are those patientswith a more modest degree of reverse ventricular remodeling and nonre-sponders are those with very little remodeling or worsening in LV func-tion. Recently, super-responders to CRT have been shown to normalizetheir survival compared to an age and gender matched population [57].On the other hand, nonresponders to CRT have an incredibly poorprognosis akin to patents with many well-known malignancies [58, 59].Therefore, attempting to change a nonresponder to a responder (or evento a super-responder) if possible, is an important goal. Recently CRTseveral optimization clinics have been developed with this goal in mind[44••, 60, 61]. Such clinics employ a multidisciplinary approach incor-porating heart failure, imaging, and electrophysiology specialists with thegoal of tracking down specific reasons for lack of response and developinga plan to increase the chances of subsequent response [44••, 60, 61].Many reasons have been cited for nonresponse, the most common ofwhich are suboptimal AV and VV delays, arrhythmias, anemia, suboptimalLV lead position, G90 % biventricular pacing (because of AF, PVCs orsimply inappropriate programming), a poor underlying electrical substrateand patient compliance issues [44••]. Addressing comorbidities (eg, ane-mia, renal dysfunction, sleep apnea) may be required. In nonrespondersin whom a specific reason for nonresponse can be positively identifiedand corrected, survival improves dramatically compared to those in whoma specific cause cannot be found [44••]. Conversely, if nonresponse can-not be corrected, then early consideration of advanced heart failure ther-apies (eg, LVAD) may be appropriate. Remote monitoring technologiesmay facilitate the follow-up of CRT function and enable early interventionwhen necessary [62••]. Prompt identification of system problems or dis-covery of conditions that diminish CRT effect (AF, PVCs) or are associatedwith general reduction in compensated status (heart rate variability (HRV),fluid balance, intracardiac hemodynamics) may permit preemptive treat-ment to reduce risk of HF decompensation and hospitalization [63, 64].These abilities may underlie the survival advantage imparted to patientsmanaged by this method and underlie the Class IIa recommendation


(Level of Evidence A) for adoption of remote monitoring in recent CRTguidelines [65•, 66, 67].

Conclusions

CRT remains one of the most important advances in the treatment of heartfailure over the last 15 years. Despite recent changes to the guidelines, theproblem of nonresponse is likely to persist given the heterogeneity of thepopulation to which CRT is applied. Proper lead position is vitally importantto long term CRT success and every effort should be made to place the LVlead in an optimal location. Complications associated with CRT largelymirror those of dual chamber pacemaker and ICD implants with only a slightincrease in risk attributable to the LV lead. Immediately post implant, CRTdevices should be programmed to maximize biventricular pacing. AV and VVoptimization in comers has not been shown to be beneficial however bothtechniques may have a role in nonresponders. Anodal capture is an un-common but likely under-recognized cause of nonresponse which physiciansshould be cognizant of. A post-CRT echocardiogram performed 6 12 monthsfollowing CRT is important to assess for response. Echocardiographicallydefined “nonresponders” have a poor prognosis following CRT, and CRToptimization clinics may have a role in improving outcomes in such patients.

Compliance with Ethics Guidelines

Conflict of InterestDr. John Rickard received honoraria from St. Jude Medical and travel/accommodations expenses covered or re-imbursed by Medtronic Inc.Dr. Niraj Varma received honoraria from Medtronic, St. Jude Medical, Boston Scientific, Sorin and Biotronik.Dr. Varma received payment for the development of educational presentations including service on speakers’bureaus from Medtronic, Boston Scientific, St. Jude Medical and Biotronik. Dr. Varma received travel/accommo-dations expenses covered or reimbursed by St. Jude Medical, Biotronik, Medtronic, Sorin, and Boston Scientific.

Human and Animal Rights and Informed ConsentThis article does not contain any studies with human or animal subjects performed by any of the authors.

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Periprocedural Management of Cardiac Resynchronization Therapy

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