Continuing Cardiology Education

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1 Continuing Cardiology Education REVIEW ARTICLE How to follow a patient with heart failure and a biventricular device E. K. Theofilogiannakos & V. P. Vassilikos Heart Failure Unit, 3rd Cardiology Department, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece Keywords Cardiac resynchronization therapy, follow up, heart failure Correspondence E. K. Theofilogiannakos, Heart Failure Unit, 3rd Cardiology Department, Hippokrateio Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece. Tel: ; Fax: ; etheofil@gmail.com Funding Information No external funding information provided. Continuing Cardiology Education, 2016; 2(4), doi: /cce2.39 Abstract Cardiac resynchronization therapy is the gold standard therapy for patients with moderate to severe heart failure symptoms on optimal medical treatment, with left ventricular ejection fraction <35% and broad QRS (>120 msec). However, one-third of them do not respond to CRT (defines as no any functional/symptomatic improvement and/or without left ventricular reverse remodeling). Some patients might potentially be responders if manages properly and for this reason, patient after CRT implantation should be followed up regularly. Given that a CRT patient is mainly a heart failure patient, follow up should not be focused only on device interrogation but it is essential to optimize the overall heart failure of the patient. This paper reviews the stages of an outpatient follow up of a CRT patient focusing primarily on the nonresponders management. Answer questions and earn CME: /Activity.aspx Introduction Cardiac resynchronization therapy (CRT) is a well-established therapy for patients with moderate to severe heart failure symptoms despite optimal medical therapy. CRT has been shown to improve symptoms, left ventricular function, hospitalization rates, and survival [1]. Moreover, CRT leads to cardiac reverse remodeling, a process characterized by a reduction in left ventricular volume leading to improved systolic and diastolic function [2]. Current selection criteria for CRT include moderate or severe heart failure (II, III, or IV NYHA class), depressed systolic function (left ventricular ejection fraction [LVEF] <35%), and wide QRS complex (>120 msec) [1]. Based on current criteria, only a small proportion of patients with heart failure (5 10%) are indicated for CRT, but this is still a large number of patients given that the prevalence of heart failure in developed countries has been steadily increasing [3].Average implantation rate of CRT devices in Europe is 140 units (including first implantations and replacements) per million habitants [1]. Despite the proper patient selection, according to the current guidelines, about 25 35% percent of them do not respond to CRT (nonresponders) that defined by a lack of clinically or hemodynamically improvement. Clinical improvement is considered the NYHA functional class improvement, the increase of exercise capacity, and/ or the heart failure related quality of life improvement. Aside from the patient selection criteria (e.g., it is known that patients with LBBB is more favorable than patients with RBBB and patients with this conduction abnormality yield the most benefit from CRT, [4]) and implantation techniques (how to customize leads positioning to enhance CRT effects [5]), postimplantation follow up is also crucial for patient s response on CRT. A variety of postimplant issues can contribute to suboptimal response. This paper focuses on the follow up of patients with CRT (Figure 1) and mainly how to improve the prognosis or the quality of life after the implantation as well as to improve the response of the patients on CRT. Continuing Cardiology Education, doi: /cce2.39 (192 of 197) ª 2016 Hellenic College of Cardiology

2 E. K. Theofilogiannakos & V. P. Vassilikos CRT Patient Follow up Figure 1. A schematic approach of a CRT patient follow up. Basic steps of systematic follow up of CRT patients. It is important to highlight that except of the device analysis all the other follow-up steps are the same in heart failure patients with or without CRT, given that a CRT patient is primarily a heart failure patient. NYHA (New York Heart Association), ECG (electrocardiogram), ECHO (echocardiogram). Clinical Evaluation: Reevaluate Medications, Check for Comorbidities, and Electrolyte Disturbances Optimal medical treatment is considered as the cornerstone of heart failure treatment. Current guidelines recommend CRT implantation on the top of the maximum tolerated dose of the heart failure medications (angiotensin-converting enzyme inhibitors or angiotensin receptors blockers, beta-blockers, mineralocorticoid receptor antagonist, ivabradine, digoxin, nitrates and hydralazine combination). Ideally, patients should be treated with evidence-based drug therapy for at least 3 months before CRT implantation. Beta-blockers therapy appears to be independently associated with good outcome in CRT recipients [6]. Up to 24% of patients were not received a guideline-directed medical therapy despite having no contraindications [7]. Moreover, the doses of heart failure medications are often limited due to their adverse effects (bradycardia, hypotension, renal dysfunction etc.). CRT improves hemodynamic function and blood pressure facilitating the optimization of medical treatment especially the introduction and up-titration of beta-blockers [8]. Therefore, it is important that medical treatment must be reevaluated after CRT implantation. Achieving maximal doses of medication after CRT prove that CRT and medical treatment are complementary strategies [8]. Heart failure patients have several comorbidities, like diabetes, coronary artery disease, chronic renal failure, and chronic obstructive pulmonary disease, all leading to higher all-cause mortality. Left ventricular reverse remodeling and functional improvement seems to be independent from comorbidity burden [9]. However, diabetes mellitus and chronic kidney disease were predictors of all-cause mortality, and the presence of chronic obstructive pulmonary disease was independently associated with heart failure admissions in CRT patients [9]. Therefore, comorbidities have an additive negative impact on survival and heart failure admissions in patients with CRT even in patients with reverse left ventricular remodeling, attenuating the beneficial effect of CRT. In cases of CRT nonresponders, routine laboratory tests were obtained (including standard electrolyte and renal panel, complete blood count, and BNP) to detect anemia, deterioration of renal function, electrical disturbances, and metabolic derangements. Check the ECG: Perform ECG with and Without BiV Pacing The baseline (preimplantation) electrocardiogram (ECG) should be direct compared with the follow-up ECG. If the baseline ECG is not available, the ECG performed after inactivated pacing can be compared with the active biventricular (BiV) pacing ECG, unless the patient is pacemaker dependent. If the baseline ECG QRS duration is less than 150 msec and/or it has not LBBB morphology, the patient was not the optimal candidate for CRT and there is lower likelihood to achieve an improved outcome even after reoptimization [10]. Patients with a broad QRS complex have a worse prognosis that may only be partially explained by having a lower left ventricular function [1]. It is known that LBBB patients benefit more from CRT than non-lbbb patients, showing substantial functional improvement and better reverse remodeling [11]. Patients with QRS duration >150 msec demonstrated the most significant effect of CRT comparing with those with QRS duration <150 msec [11]. For this reason, the current guidelines recommend CRT implantation in patients with heart failure (NYHA class II IV) with sinus rhythm (SR) and: (a) LBBB with QRS >150 msec as class I (level of evidence: A), (b) LBBB with QRS msec as class I (level of evidence: B), (c) Non-LBBB with QRS >150 msec as class IIa (level of evidence: B), (d) Non-LBBB with QRS msec as class IIb (level of evidence: B). Examining QRS morphology pattern is also a standard procedure in CRT patients follow up and is crucial to estimate the BiV capture. The QRS pattern in BiV pacing is usually composed of two merging activation wave fronts, which makes interpretation more difficult [12]. ª 2016 Hellenic College of Cardiology Continuing Cardiology Education, doi: /cce2.39 (193 of 197)

3 CRT Patient Follow up E. K. Theofilogiannakos & V. P. Vassilikos BiV QRS morphology is not standard and it depends on the ventricular leads position, the presence of scar at pacing sites, the fusion of intrinsic activation with the pacemaker activation, and the programming interventricular delay [12]. However, the QRS complex during BiV pacing most often has a dominant R wave in lead V1-2 and in lead avr [12].A negative QRS pattern should be examined, as LV lead displacement or lack of capture due to threshold rise is likely [13]. Fusion beats and QRS pattern noncompatible with BiV pacing require reprogramming by modifying atrioventricular and interventricular delay or pacing rate. Check for Basic Rhythm and Arrhythmias:Device Interrogation and Analysis Interrogation and analysis of device to assess device stored memory, atrial and ventricular arrhythmias, satisfactory sensing and pacing, rate response, and presence and frequency of continuous BiV capture is recommended [13]. Continuous BiV pacing (>97%, the mean percent CRT pacing in MADIT-CRT) is necessary for optimal CRT response and for the maximum clinical benefit [14]. However, heart failure patients have a high burden of supraventricular and ventricular arrhythmias that lead to lower percentage of BiV pacing and less reverse remodeling [14]. Poor outcomes were driven by the presence of premature ventricular contractions due to a lower percentage of CRT pacing and even a very small percentage of ectopic beats (0.1%) is associated with less CRT pacing and worse patient outcomes. [15]. Increased atrial pacing rate (from 70 to 85 beats/min) may decrease or eliminate frequent atrial and/or ventricular premature beats. Antiarrhythmic agents and catheter ablation have been used in order to reduce the ectopic beats burden and to increase the CRT delivery time, but the data are limited for the efficacy of these strategies. However, if the CRT recipient has unifocal PVCs, ablation of the ectopic focus can be an effective strategy to increase the BiV pacing delivery time [16]. Atrial fibrillation (AF) frequently coexists with heart failure. The prevalence of AF in heart failure series ranges from 13% to 27% [17]. Its prevalence is closely related to the New York Heart Association functional class, with up to 25% for class III and 50% for class IV HF [18]. CRT randomized trials have enrolled only a small percentage of patients with AF and the majority of studies was restricted to patients with SR [19]. It is known that the nonresponder rate of CRT is higher in AF than to SR patients. In AF, CRT can only correct VV and intraventricular dyssynchrony [20]. Moreover, CRT delivery is also hampered by high intrinsic ventricular rates and irregularity, leading to reduced capture, fusion, pseudofusion, and eventually to ineffective resynchronization [20]. There are two alternatives in order to increase BiV pacing in AF. The first one, that seems to have better outcome, is to perform AV junction ablation and the second one to prescribe rate-slowing drugs [21]. The efficacy of pulmonary vein isolation in CRT patients is still an enigma because of limited published data, but it could be an effective technique particularly in patients with paroxysmal AF [22]. If the CRT recipient is a nonresponder, reprogramming the device modifying the AV and VV delays or/and pacing rate can be considered in order to increase BiV delivery time, to deliver a more desirable QRS pattern, or/and to achieve mechanical synchronization improvement in echocardiography. Chest Radiography Upright anterior and lateral chest X-rays should be performed at the discharge after CRT implantation in order to rule out pneumothorax, to document leads position and to be a reference for the next follow up [13]. In any case of abrupt change in lead impedance, electrogram amplitude, or threshold, a chest X-ray should be performed to document any change in the lead tip position (lead dislodgement) [23]. Echocardiography-Guided Optimization According to the current guidelines, the need for routine, systematic echo-guided AV and VV delay optimization in all patients undergoing CRT is not recommended [13]. Empirically setting, the sensed AV interval to a standard AV delay of msec is the main strategy in many centers [13]. Echo-guided optimization of AV delay could improve LV filling (optimization of diastole) and optimization of IV delay adjusts contraction sequence of the two ventricles leading to further improvement in cardiac output (optimization of systole). However, echo-guided optimization seems to be beneficial only in a selected subgroup of nonresponders [24]. Generally, results on optimization of CRT device settings using echocardiographic indices have so far been rather disappointing, as results suffer from noise and there is a high interobserver and intraobserver variability in many echocardiographic parameters [25]. At that time, Echo Doppler assessment of left ventricular diastolic filling and LV ejection has been the most commonly utilized method for CRT optimization [26]. Applying first AV and then VV delay optimization seems to have the best result [27]. A consensus statement from the American Society of Echocardiography recommends an echo-guided AV optimization procedure only if the mitral inflow pattern by pulsed Doppler demonstrates Continuing Cardiology Education, doi: /cce2.39 (194 of 197) ª 2016 Hellenic College of Cardiology

4 E. K. Theofilogiannakos & V. P. Vassilikos CRT Patient Follow up stage II (pseudonormal) or stage III (restrictive) diastolic dysfunction. IF the transmitral inflow demonstrates stage I(E A reversal) diastolic dysfunction, no further changes to the AV delay are recommended [28]. Indeed in a recent study, most patients (53%) undergoing CRT exhibit satisfactory diastolic filling by Doppler suggesting optimized AV synchrony at empiric AV delay settings [29]. Of those exhibiting stage II or stage III diastolic pattern, only 12.7% improved diastolic function and lower atrial filling pressures with an Echo-guided AV optimization [29]. A wide variety of echo techniques have been proposed for AV optimization (aortic VTI, diastolic mitral flow pattern by Ritter s method, VTI of mitral inflow, diastolic filling time, tissue Doppler imaging, Doppler-derived dp/dt, and myocardial performance index) [26]. Diastolic mitral flow pattern and aortic VTI (a surrogate of stroke volume) are the most commonly utilized methods because of its better reproducibility. The role of VV optimization is even more controversial. Most patients appear to benefit from a standard LV preexcitation or simultaneous activation [30]. For nonresponders, VV only optimization has a role in patients in whom AV cannot be optimized such as in cases of atrial fibrillation [26]. But when AV optimization precedes, the VV optimization provide an incremental benefit [26]. The range of optimal VV is narrow and usually involves LV preexcitation within 20 ms [31]. Pulsed Doppler LV outflow (an index of stroke volume) is usually used for VV optimization. Optimization Based on Intracardiac Electrograms Echo-guided CRT optimization is time consuming and there is a high inter- and intravariability in echocardiographic variables [32]. For this reason alternative methods based mainly on intracardiac electrograms recordings have been developed. Three different intracardiac electrograms (IEGM)-based algorithms for CRT optimization have been used: QuickOpt â (St. Jude Medical), SmartDelay â (Boston Scientific), Adaptive-CRT â (Medtronic). Using direct measures on atrial, right-, and left ventricular intrinsic EGMs, these IEGM-based algorithms provide ambulatory adjustment of pacing configuration and AV and VV delays based on periodic automatic evaluation of electrical conduction in order to identify the best combination of AV and VV timings to fix conduction defects [32, 33]. Acute hemodynamic improvement can be obtained by IEGM-based optimization [34].These algorithms are safe and at least as effective as ECHO-guided optimization [35]. Conclusion CRT is a well-established therapy for patients with heart failure that meet the current guidelines. However, onethird of them fail to benefit from this treatment. A systemic follow up is recommended for all CRT patients. This follow up involves the clinical assessment, an ECG, an echocardiographic examination, and the device interrogation. For the subgroup of nonresponders, follow up is even more important in order to detect the possible causes of nonresponding and additionally to optimize the CRT function. This optimization is not only based on changing the device parameter but also on optimizing the general treatment of the patient given that a CRT patient is primarily a heart failure patient. Conflict of Interest Both authors have nothing to disclose. References 1. European Society of Cardiology (ESC)1; European Heart Rhythm Association (EHRA), Brignole, M, A Auricchio, and G Baron-Esquivias, et al ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 15: Verhaert, D, RA Grimm, C Puntawangkoon et al Long-term reverse remodeling with cardiac resynchronization therapy: results of extended echocardiographic follow-up. J. Am. Coll. Cardiol. 55: Zhang, Q, Y Zhou, and CM Yu Incidence, definition, diagnosis, and management of the cardiac therapy nonresponder. Curr. 30: Auricchio, A, J Lumens, and FW Prinzen Does cardiac resynchronization therapy benefit patients with right bundle branch block:cardiac resynchronization therapy has a role in patients with right bundle branch block. Circ. Arrhythm. Electrophysiol. 7: Vernooy, K, CJ van Deursen, M Strik et al Strategies to improve cardiac resynchronization therapy. Nat. Rev. Cardiol. 11: Voigt, A, A Shalaby, E Adelstein et al Beta-blocker utilization and outcomes in patients receiving cardiac resynchronization therapy. Clin. Cardiol. 33:E1 E6. 7. Mullens, W, RA Grimm, T Verga et al Insights from a cardiac resynchronization optimization clinic as part of a heart failure disease management program. J. Am. Coll. Cardiol. 53: ª 2016 Hellenic College of Cardiology Continuing Cardiology Education, doi: /cce2.39 (195 of 197)

5 CRT Patient Follow up E. K. Theofilogiannakos & V. P. Vassilikos 8. Kachboura, S, A Ben Halima, Z IbnElhadj et al Cardiac resynchronization therapy allows the optimization of medical treatment in heart failure patients. Ann. Cardiol. Angeiol. (Paris) 63: Verbrugge, FH, M Dupont, M Rivero-Ayerza et al Comorbidity significantly affects clinical outcome after cardiac resynchronization therapy regardless of ventricular remodeling. J. Card. Fail. 18: Kutyifa, V, and OA Breithardt How to assess the nonresponder to cardiac resynchronization therapy-a comprehensive stepwise approach. Rev. Esp. Cardiol. (Engl Ed) 65: Zareba, W, H Klein, I Cygankiewicz et al.; MADIT-CRT Investigators Effectiveness of cardiac resynchronization therapy by QRS morphology in the Multicenter Automatic Defibrillator Implantation Trial- Cardiac Resynchronization Therapy (MADIT- CRT).Circulation 123: Stipdonk, A, S Wijers, M Meine et al ECG patterns in cardiac resynchronization therapy. 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6 E. K. Theofilogiannakos & V. P. Vassilikos CRT Patient Follow up 32. Krum, H, B Lemke, D Birnie et al A novel algorithm for individualized cardiac resynchronization therapy: rationale and design of the adaptive cardiac resynchronization therapy trial. Am. Heart J. 163: Lunati, M, G Magenta, G Cattafi et al Clinical relevance of systematic CRT device optimization. JAFIB 7: Jensen, CJ, A Liadski, M Bell et al Echocardiography versus intracardiac electrocardiographybased optimization for cardiac resynchronization therapy: a comparative clinical long-term trial. Herz 36: Martin, DO, B Lemke, and D Birnie et al.; Adaptive CRT Study Investigators Investigation of a novel algorithm for synchronized left-ventricular pacing and ambulatory optimization of cardiac resynchronization therapy: results of the adaptive CRT trial. Heart Rhythm 9: ª 2016 Hellenic College of Cardiology Continuing Cardiology Education, doi: /cce2.39 (197 of 197)