REVIEW
Cardiac resynchronisation therapy in 2015: keeping up with the pace A. Voskoboinik,1,2 A. D. McGavigan3 and J. A. Mariani2,4 1
Department of Cardiology, Western Hospital, 2Department of Cardiology, Alfred Hospital, 4Cardiac Investigation Unit, St Vincent' Hospital, Melbourne, Victoria, and 3Department of Cardiovascular Medicine, Adelaide, South Australia, Australia
Key words cardiac resynchronisation therapy, biventricular pacing, heart failure, dyssynchrony. Correspondence Alex Voskoboinik, Department of Cardiology, Western Hospital, Melbourne, Vic. 3011, Australia. Email: [email protected]; [email protected] Received 17 February 2015; accepted 24 March 2015.
Abstract Despite improved understanding of the pathophysiology of heart failure (HF) and availability of better medical therapies, HF continues to grow as a cause of morbidity and mortality in Australia and worldwide. Over the past decade, cardiac resynchronisation therapy (CRT), or biventricular pacing, has been embraced as a powerful weapon against this growing epidemic. However, much has changed in our understanding of dyssynchrony in HF, and this has led to a change in guidelines to ensure more appropriate selection of CRT candidates to improve the ‘non‐response’ rate. More data have also emerged about the use of CRT in atrial fibrillation and in pacemaker‐dependent patients. There has also been a growing focus on multimodality imaging to guide patient selection and lead positioning. Exciting new lead technologies are also emerging, with the potential to improve CRT outcomes further.
doi:10.1111/imj.12774
Introduction Dyssynchrony in heart failure (HF) As HF progresses, pathological remodelling of the heart results in cellular and interstitial changes that also adversely affect the conduction system. Electrical dyssynchrony causes mechanical dyssynchrony, which refers to differences in the timing of contraction between different myocardial regions. This occurs at multiple levels in the failing heart, particularly atrioventricular (AV), interventricular and intraventricular. Intraventricular dyssynchrony is often manifested by QRS prolongation and occurs in approximately one third of cardiomyopathy patients. A left bundle branch block (LBBB) is the most common disturbance.1 The presence of an LBBB results in delayed activation of the lateral wall relative to the right ventricle and septum, leading to reduced mechano‐energetic efficiency of the heart. This is similar to the effects of chronic right ventricular (RV) pacing, with a slow depolarisation wavefront propagating through the myocardium, rather than the Purkinje system. There are numerous adverse Funding: None. Conflict of interest: None.
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haemodynamic sequelae of LBBB, including abnormal septal motion causing decreased regional ejection fraction, redistribution of myocardial fibre strain with altered regional blood flow, diastolic dysfunction due to shortened left ventricular (LV) filling time, depressed dP/dt and worsening mitral regurgitation.2–4 Further, LBBB, as either a contributor to, or simply a surrogate marker of, progressive cardiac dysfunction, is associated with increased morbidity and mortality.5
Cardiac resynchronisation therapy (CRT) CRT aims to reverse the deleterious effects of LBBB, as the right and left ventricular pacing leads generate two ventricular activation wavefronts that move towards each other. The benefit of CRT lies in the effective fusion of these two depolarisation wavefronts, synchronising the walls of the LV (Fig. 1). Since implantation of the first transvenous CRT system in 1998, numerous large randomised multicentre trials have demonstrated significant benefit of CRT in appropriately selected HF patients with respect to multiple end‐points. These have included functional class, exercise capacity, hospitalisation, quality of life, and reverse remodelling with improvement in ejection fraction, and reduction in LV size and mitral regurgitation.6,7 Since the
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Figure 1 Pacing the septal and lateral walls with cardiac resynchronisation therapy (CRT) (leads denoted by yellow stars) resynchronises the heart, negating the adverse effects of left bundle branch block (LBBB).
Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) and Cardiac Resynchronization – Heart Failure (CARE‐HF) trials, there has also been a reproducible demonstration of mortality benefit (Table 1).
Patient selection Current guidelines While CRT is ‘life‐changing’ for some, an estimated one third of patients derive little or no benefit.20 Given the heterogeneity of the various studies, it has taken time to develop a better understanding of which patients are most likely to benefit to improve patient selection. This has led to a change in the recommendations for CRT since 2006, when this topic was last reviewed in this journal.21 At that time, the widely accepted Class I indication was ‘severe systolic dysfunction’ (LV ejection fraction less than 35%) in sinus rhythm (SR) with QRS duration of at least 120 ms, and moderate‐severe HF symptoms (New York Heart Association (NYHA) Class III–IV) despite optimal medical therapy. Increasing data have emerged regarding the critical importance of a LBBB pattern in deriving clinical benefit from CRT. Patients with right bundle branch block (RBBB) do not have a dyssynchrony pattern suitable for CRT (activation of their lateral wall is already early), and often have concomitant RV dysfunction, pulmonary hypertension and more extensive conduction disease conferring a worse prognosis. Patients with RBBB undergoing CRT have significantly lower rates of symptomatic and echocardiographic response, and a lower survival free from heart transplantation or ventricular
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assist device placement.22 A recent meta‐analysis reinforced this lack of benefit of CRT in patients with either RBBB or non‐specific intraventricular conduction delay.23 In the recently published Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT‐CRT) long‐term follow up,24 there was even the suggestion that CRT without LBBB was associated with harm (adjusted hazard for all‐cause mortality 1.57; 95% confidence interval (CI): 1.03–2.39). While the lack of CRT benefit in narrow QRS width (150 ms.25 In a large meta‐analysis of 5813 patients, there was no statistically significant reduction in death and HF hospitalisation with CRT in this ‘intermediate QRS width’ group.26 Only those with QRS duration ≥150 ms now receive a Class IA indication in major society guideline statements6,7 (Fig. 2). Unfortunately, studies utilising various imaging modalities to assess dyssynchrony have been largely disappointing, and electrocardiogram (ECG) still remains the gold standard for this purpose. Also now receiving a Class I indication for CRT are mildly symptomatic patients (NYHA Class II). The Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT)27 was the first study to show a significant reduction in mortality in this group (hazard ratio (HR) 0.75; 95% CI: 0.62–0.91) in addition to reduced hospitalisation for HF. This was reinforced by MADIT‐ CRT,28,29 the largest CRT trial to date, of whom 85% of patients were NYHA II, with significant reductions seen
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≤35%
≤30%
≤30%
≤40%
≤35%
≤35%
≤35%
≤35%
≤35%
III/IV
II/III
I/II
I‡/II
III
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III/IV
II
II/III/IV
III/IV
III/IV
≤35% ≤35%
NYHA class
LVEF
200
≥130
≥120
150 ms who otherwise satisfy the criteria, CRT is still better than no CRT (just not as beneficial as for SR
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patients with QRS width >150 ms). Unfortunately, Medicare does not currently provide a rebate for CRT in AF patients, regardless of ejection fraction or QRS duration. The Australian prospective randomised Cardiac Resynchronisation Therapy and AV Nodal Ablation Trial in Atrial Fibrillation (CAAN‐AF)33 is currently recruiting patients to assess further the role of AVNA in AF patients with broad QRS and severe systolic dysfunction.
Pacemaker induced dyssynchrony and the role of CRT RV apical pacing for patients with symptomatic AV block creates dyssynchrony, with QRS prolongation similar to an LBBB morphology, and results in adverse ventricular remodelling.34–36 Importantly, LV systolic dysfunction is seen in up to 40% of these patients and is related to the percentage of RV pacing.24 The detrimental effects of RV pacing on LV systolic function is well documented, with increased AF,37 as well as HF hospitalisation and mortality. In the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial of 506 HF patients with implantable cardioverter defibrillator (ICD), patients randomised to a backup mode (VVI‐40) had significantly superior outcomes (mortality and hospitalisation) compared with those with a dual‐chamber pacing mode (DDDR‐70).38 Various strategies have been employed to minimise RV apical pacing. These have included bradycardia prevention, programming long AV delays to promote intrinsic conduction and alternate pacing sites, such as the high RV septum or His bundle. While undoubtedly the most physiological site, His‐ bundle pacing (HBP) is more technically challenging. Sharma et al. recently reported an 80% success rate in achieving permanent HBP (without a mapping catheter or backup RV lead) using the Medtronic Select Secure active fixation lead delivered through a fixed‐shaped catheter. The majority of patients in this study had >40% ventricular pacing, and HF hospitalisation was significantly reduced in the HBP group compared with the RV‐paced group (2% vs 15%; P = 0.02).39 Disappointingly, the randomised Protection of Left Ventricular Function During Right Ventricular Pacing
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Cardiac resynchronisation therapy Figure 3 Major society guidelines for CRT in patients with conventional indications for anti‐bradycardia pacing. CRT, cardiac resynchronisation therapy; EF, ejection fraction; ICD, implantable cardioverter defibrillator; PPM, permanent pacemaker; RV, right ventricular.
(PROTECT‐PACE) study of 240 patients did not demonstrate any difference in ejection fraction drop between RV apical and high RV septal positions at 2 years.40 However, in recent years, CRT has emerged as a promising option in these patients. The largest trial of its kind, Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK‐HF),41 randomised 918 patients with AV block (with a need for significant ventricular pacing), ejection fraction (EF) 15% increase in the left ventricular end‐systolic volume index) occurred in 55.6% of RV‐paced patients, compared with 45.8% of BiV‐paced patients (HR 0.74; 95% CI: 0.60–0.90). Certainly, there remains a paucity of data to support the practice of routinely implanting CRT for all patients with indications for a pacemaker. Most will not develop LV dysfunction or HF, and subjecting them to a longer procedure with increasing peri-procedural complications is inappropriate. However, in RV-paced patients who, during follow up, develop symptoms of HF and have a deteriorating EF should be upgraded to CRT to reduce hospitalisation, and improve symptoms and cardiac function.6 Current international guidelines (Fig. 3) advocate ‘up‐front’ implantation of a CRT device in patients with severe pre‐existing systolic dysfunction (EF 40% RV‐paced was found to be predictive of adverse outcomes in a substudy of the DAVID trial42). While there are no Australian guidelines for this, the results of BLOCK‐HF suggest this practice should even be considered in those with milder degrees of systolic dysfunction.
Role of multimodality imaging As stated, electrical dyssynchrony results in mechanical dyssynchrony, and multiple imaging modalities have been used to confirm its presence and determine the site of latest LV activation. Studies have shown that up
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to 50% of patients with a narrow QRS (130 ms). After following 809 patients for a mean 19.4 months, the study was stopped early due to increased mortality in the CRT arm (11.1% vs 6.4%). This reinforced the notion that current dyssynchrony indices (apart from the ECG) are ineffective at selecting narrow QRS patients for CRT, and may worsen outcomes in patients with narrow QRS. Accordingly, QRS width (with or without mechanical dyssynchrony) remains the key determinant of clinical response to CRT, and the only Class I indication. While availability is currently limited in many Australasian centres, cardiac MRI (CMR) enables the assessment of both dyssynchrony and scar burden in a single study. It has been well established that pacing in regions of scar, as detected by delayed enhancement MRI, predicts lack of response to CRT.49,50 Combined with numerous validated measures of dyssynchrony (cine MRI, myocardial tagging, strain imaging), CMR is gaining increasing attention due to its excellent tissue characterisation, high spatial resolution and reproducibility.51 Like multidetector cardiac computed tomography (CT), CMR also enables the assessment of cardiac venous anatomy.
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In patients with significant scar who may exhibit less extensive venous anatomy, this may mean a minimally invasive surgical approach rather than a transvenous approach. Notably, delineation of the precise number and location of tributaries of the coronary sinus by CT minimises peri‐procedural venography, and has been shown to shorten procedural times and limit contrast and radiation exposure.52 Looking towards the future, myocardial imaging has the potential to individualise CRT. It can confirm candidacy by demonstrating significant mechanical dyssynchrony in an otherwise borderline candidate on ECG criteria. It can also guide lead placement by targeting an appropriate vein adjacent to the latest activated region of myocardium and away from scar.
CRT leads: optimal position and new technologies Lead positioning Appropriate positioning of the LV lead is a key determinant of CRT success. In the absence of additional information regarding activation sequence, the lead should be positioned in the lateral or posterolateral walls, which are usually activated last and are furthest away from the RV lead. In a retrospective analysis of 457 CRT recipients, Dong et al. demonstrated greater improvement in NYHA class with lateral LV lead positions compared with anterior locations.53 Anterior LV lead positions also have a significantly higher risk of ventricular arrhythmias than posterior or lateral positions.54 Basal or mid‐ventricular LV lead positions are superior to apical locations. In an analysis of 799 patients in the MADIT‐CRT study, apical LV lead position was associated with a significantly increased risk of HF (HR 1.72; 95% CI: 1.09–2.71) and death (HR 2.91; 95% CI: 1.42–5.97).55 The location of the RV lead is less important, and there is certainly no clinical benefit of non‐apical RV lead locations (i.e. septum, RV outflow tract) compared with apical locations.56 There is also some evidence that a larger horizontal inter‐lead distance (as measured on a lateral chest X‐ray), which correlates with a longer LV lead electrical delay, can improve LV anatomic reverse remodelling post‐CRT.57 The amount of QRS shortening post‐CRT (DeltaQRS), which relates to both inter‐lead distance and LV lead electrical delay, is a strong predictor of improved outcomes post‐CRT. Molhoek et al. demonstrated that a DeltaQRS >10 ms has a high sensitivity (73%) while a DeltaQRS >50 ms has a high specificity (88%) for CRT response.58 Showing promise is the use of echocardiography to guide lead placement. Unlike tissue Doppler, speckle
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tracking radial strain can distinguish between active and passive motion (scar tethering) and is able to determine the site of latest contraction. The Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy (TARGET) study59 randomised 220 patients to either standard unguided CRT or LV lead positioning at the site of latest peak contraction with an amplitude of >10% to signify freedom from scar. The latter group had a greater response rate (70% vs 55%, P = 0.031) with respect to reverse remodelling, as well as lower all‐cause mortality and hospitalisation. However, significant variability in coronary venous anatomy exists between patients, and the ability to target directly LV lead position is a limitation of the transvenous route. In a large series investigating distribution of venous anatomy and its effects on LV lead targeting, Khan et al. demonstrated that limitations of coronary venous anatomy restrict LV lead placement to a single vein with little scope for site selection in almost half of all patients.60 In patients with multiple target veins, intraprocedural coronary venous electroanatomic mapping has been assessed as a means of guiding LV lead placement to the latest activated region free from phrenic nerve stimulation. In a recently published series, Rad et al. demonstrated that this latest activated region (region with an electrical delay >75% of total QRS duration) was more often located anterolaterally, rather than the empirically targeted inferolateral vein.28
Epicardial leads Direct surgical epicardial approach may overcome these limitations, and should be considered in non‐responders due to suboptimal lead placement, and in those with high thresholds or intractable phrenic nerve stimulation. Previously only performed by thoracotomy (or sternotomy), newer techniques have emerged to limit surgical morbidity, including left lateral mini‐thoracotomy, video‐ assisted thoracoscopy and the use of robotic technology. While long‐term outcomes with respect to mortality and functional improvement are similar to the transvenous route, these patients often have longer in‐hospital length of stay29 and higher perioperative complications, including renal failure and infection.27
Emerging lead technologies Compared with isolated RV pacing, patients undergoing CRT with standard bipolar leads have higher rates of LV lead complications, including lead dislodgement (5.7%) and coronary sinus complications (2.0%).61 In addition to loss of capture related to these problems, some patients also require reoperation due to phrenic nerve stimulation or increased LV pacing thresholds without obvious
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dislocation. New quadripolar leads have four independent electrodes, which enable programming of additional different vectors for LV pacing. This provides the operator greater flexibility, as they can programme different electrode configurations, rather than having to reposition an entire lead. Down the track, they are more likely to find a stable position with reasonable pacing thresholds while minimising phrenic nerve stimulation.46,62 Quadripolar leads also enable multipoint pacing, which provides greater flexibility for optimal pacing configurations. This technology (MultiPoint Pacing, St. Jude Medical) delivers two LV pulses per pacing cycle from a single quadripolar lead. Early studies show some promise in further optimising haemodynamics, improving contractility with echocardiographic guidance63 and reducing the rate of CRT non‐response.64 Newer leads are also now being designed to monitor haemodynamic parameters, which will hopefully enable device optimisation, guide LV lead positioning and aid in clinical management. Intracardiac impedance reflects LV volume changes well in animal models, and early studies involving Biotronik's intracardiac impedance sensing technology have demonstrated good correlation with LV stroke volume.65 Sorin's SonR system utilises a sensor embedded in the lead tip that detects cardiac muscle vibrations (peak endocardial acceleration signal system). In a recent randomised study, automatic optimisation of AV and ventriculo‐ventricular (VV) delays based on this system resulted in improved CRT response, with significant improvement in NYHA class.48
Device programming and follow up Improving %BiV pacing: arrhythmia suppression The greatest benefit is derived from CRT when it is used maximally. Hayes et al. demonstrated a 24% reduction in mortality in patients receiving above 98.5% BiV pacing, as compared with those receiving 10 000 PVC in a 24‐h period.68
Improving %BiV pacing: pacing algorithms While routine optimisation of AV delay is controversial, an inappropriately programmed long AV delay may result in loss of BiV pacing in many patients.69 Avoidance of right atrial pacing is preferred, because pacing the right atrial appendage delays left atrial activation, which may impair LV preload and worsen myocardial performance. This can be achieved by programming a VDD mode, rather than a DDD mode.70 A novel adaptive CRT algorithm (AdaptivCRT, Medtronic) in patients with SR and normal AV conduction is also showing great promise. This algorithm provides LV pacing synchronised to produce fusion with intrinsic RV activation (to minimise RV pacing), with dynamic optimisation of AV and VV delays. It has been shown to be safe and at least as effective as BiV pacing with echocardiographic optimisation,71 with the suggestion of better clinical outcomes in those with a higher percentage of LV pacing.72
Echocardiographic optimisation The use of echocardiography to assess mechanical dyssynchrony and select patients for CRT has been disappointing. However, modern CRT devices enable programming of AV and VV delays, which can be optimised based on echocardiographic evaluation of haemodynamics. With respect to optimising AV delay, numerous Doppler echocardiographic parameters have been studied. These include LV outflow tract velocity time integral (VTI), diastolic filling time and transmitral flow (EA VTI), with the latter correlating best with invasive measurements (LV dP/dtmax).73 However, the SmartDelay Determined AV Optimization (SMART‐AV) randomised trial of 980 patients demonstrated no clinical benefit of an echocardiography‐optimised AV delay over a fixed empirical AV delay of 120 ms.74 While many of the landmark CRT trials incorporated some form of echocardiography‐guided AV delay optimisation (based on small haemodynamic studies), long‐term randomised data supporting this practice are lacking. Several small studies of echocardiography‐guided VV optimisation have demonstrated acute haemodynamic improvements compared with simultaneous BiV pacing. Bordachar et al. demonstrated that improvements in intraventricular dyssynchrony (using tissue Doppler) correlated with an increase in cardiac output, with simultaneous BiV pacing being the optimal setting in only 15% of patients.75 In a randomised study of 238 patients with
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VV intervals adjusted to minimise septal to posterior wall delay, significantly more patients improved based on a clinical composite score; however, no significant differences were found with respect to exercise capacity, quality of life or HF event rate. Again, simultaneous BiV pacing was the optimal setting in only 18%.76 In addition to a paucity of consistent clinical data demonstrating clear benefit, echocardiographic optimisation of AV and VV delays is time‐consuming and resource‐intensive, and requires significant skill. However, it may be useful in CRT non‐responders.
Integrated teams and remote monitoring With the burden of hospital readmission rates for HF rapidly increasing, multidisciplinary clinics encompassing nurse practitioners, physiotherapists, social workers, dieticians, psychologists and specialists are being developed to deliver holistic, patient‐centred care. A multidisciplinary approach, coupled with individualised CRT optimisation (incorporating echocardiography‐ guided adjustment in device settings and optimisation of medical therapy), led to significant improvements in LV function and reduction in adverse events in 75 CRT non‐responders. A reason for CRT non‐response was identified in most patients, and multidisciplinary recommendations led to a change in treatment in 74%.77 Remote monitoring of CRT devices, with the regular transmission of important data such as atrial and ventricular arrhythmia burden, heart rate histograms, device safety issues and ‘%BiV‐paced’, enables regular ‘contact’ with cardiologists and earlier optimisation of therapy.
References 1 Kashani A, Barold SS. Significance of QRS complex duration in patients with heart failure. J Am Coll Cardiol 2005; 46: 2183–92. 2 Grines CL, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF. Functional abnormalities in isolated left bundle branch block. The effect of interventricular asynchrony. Circulation 1989; 79: 845–53. 3 Zhou Q, Henein M, Coats A, Gibson D. Different effects of abnormal activation and myocardial disease on left entricular ejection and filling times. Heart 2000; 84: 272–6. 4 Bramlet DA, Morris KG, Coleman RE, Albert D, Cobb FR. Effect of rate-dependent left bundle branch block on global and regional left
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In the Implant-based Multiparameter Telemonitoring of Patients with Heart Failure (IN‐TIME) randomised trial of 716 patients, most of whom had CRT‐D (CRT and defibrillator) devices, those receiving automatic, daily multi‐parameter tele‐monitoring had a significantly lower incidence of the primary end‐point (combined all‐cause mortality, hospitalisation, change in NYHA class and symptoms). This was largely driven by earlier recognition of suboptimal device function, detection of arrhythmias and patient interview prompted by remote monitoring findings.78 Early results from the Patient Related Determinants of ICD Remote Monitoring Utilization and Outcomes (PREDICt‐RM) study, which analysed registry data from 37 742 patients with new ICD or CRTD implants, demonstrated lower mortality (HR = 0.67; 95% CI: 0.64–0.7) and hospitalisation (HR = 0.81; 95% CI: 0.79–0.83) in those who used remote monitoring. Despite its many benefits, remote monitoring is currently underutilised in Australia.79
Conclusion CRT remains one of the key successes of the ‘device era’ of HF therapy. The past decade has given us a greater understanding about the importance of appropriate patient selection, correct lead positioning and device optimisation to ensure a high percentage of BiV pacing. With novel indications, new lead technologies, better remote monitoring tools and integrated multimodality imaging showing great promise, CRT remains an exciting and rapidly evolving field.
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11 Abraham WT, Young JB, León AR, Adler S, Bank AJ, Hall SA et al. Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter‐defibrillator, and mildly symptomatic chronic heart failure. Circulation 2004; 110: 2864–8. 12 Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T et al. Cardiac‐resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 350: 2140–50. 13 Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352: 1539–49. 14 Beshai JF1, Grimm RA, Nagueh SF, Baker JH 2nd, Beau SL, Greenberg SM et al. Cardiac‐resynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med 2007; 357: 2461–7. 15 Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol 2008; 52: 1834–43. 16 Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP et al. Cardiac‐resynchronization therapy for the prevention of heart‐failure events. N Engl J Med 2009; 361: 1329–38. 17 Goldenberg I, Kutyifa V, Klein HU, Cannom DS, Brown MW, Dan A et al. Survival with cardiac‐resynchronization therapy in mild heart failure. N Engl J Med 2014; 370: 1694–701. 18 Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S et al. Cardiac‐resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010; 363: 2385–95. 19 Ruschitzka F, Abraham WT, Singh JP, Bax JJ, Borer JS, Brugada J et al. Cardiac‐resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 2013; 369: 1395–405. 20 Yu CM, Hayes DL. Cardiac resynchronization therapy. Eur Heart J 2013; 34: 1396–403.
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21 Mariani JA, Gould PA, Broughton A, Kaye DM. Cardiac resynchronisation therapy for heart failure. Intern Med J 2006; 36: 114–23. 22 Adelstein EC, Saba S. Usefulness of baseline electrocardiographic QRS complex pattern to predict response to cardiac resynchronization. Am J Cardiol 2009; 103: 238–42. 23 Sipahi I, Chou JC, Hyden M, Rowland DY, Simon DI, Fang JC. Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: meta‐analysis of randomized controlled trial. Am Heart J 2012; 163: 260–7. 24 Begg GA, Gierula J, Waldron ZL, Witte KK. Patients receiving standard pacemaker generator replacements frequently have impaired left ventricular function and exercise intolerance, related to the percentage of right ventricular pacing. Heart 2011; 97: A86. 25 Haghjoo M, Bagherzadeh A, Fazelifar AF, Haghighi ZO, Esmaielzadeh M, Alizadeh A et al. Prevalence of mechanical dyssynchrony in heart failure patients with different QRS durations. Pacing Clin Electrophysiol 2007; 30: 616–22. 26 Sipahi I, Carrigan TP, Rowland DY, Stambler BS, Fang JC. Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy: meta‐analysis of randomized controlled trials. Arch Intern Med 2011; 171: 1454–62. 27 Ailawadi G, Lapar DJ, Swenson BR, Maxwell CD, Girotti ME, Bergin JD et al. Surgically placed left ventricular leads provide similar outcomes to percutaneous leads in patients with failed coronary sinus lead placement. Heart Rhythm 2010; 7: 619–25. 28 Rad MM, Blaauw Y, Dinh T, Pison L, Crijns HJ, Prinzen FW et al. Left ventricular lead placement in the latest activated region guided by coronary venous electroanatomic mapping. Europace 2015; 17: 84–93. 29 Koos R, Sinha AM, Markus K, Breithardt OA, Mischke K, Zarse M et al. Comparison of left ventricular lead placement via the coronary venous approach versus lateral thoracotomy in patients receiving cardiac resynchronization therapy. Am J Cardiol 2004; 94: 59–63.
30 Wilton SB, Leung AA, Ghali WA, Faris P, Exner DV. Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and meta‐analysis. Heart Rhythm 2011; 8: 1088–94. 31 Ganesan AN, Brooks AG, Roberts‐Thomson KC, Lau DH, Kalman JM, Sanders P. Role of AV nodal ablation in cardiac resynchronization in patients with coexistent atrial fibrillation and heart failure a systematic review. J Am Coll Cardiol 2012; 59: 719–26. 32 Gasparini M, Leclercq C, Lunati M, Landolina M, Auricchio A, Santini M et al. Cardiac resynchronization therapy in patients with atrial fibrillation. JACC Heart Fail 2013; 1: 500–7. 33 National Institute of Mental Health, University of Virginia. Cardiac resynchronisation therapy and AV nodal ablation trial in atrial fibrillation patients (CAAN‐AF). In: Sanders P, ed. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US); 2000 [cited 2015 Jan 20]. Available from URL: https://clinicaltrials.gov/ct2/ show/NCT01522898 34 Nielsen JC, Kristensen L, Andersen HR, Mortensen PT, Pedersen OL, Pedersen AK. A randomized comparison of atrial and dual‐chamber pacing in 177 consecutive patients with sick sinus syndrome: echocardiographic and clinical outcome. J Am Coll Cardiol 2003; 42: 614–23. 35 Karpawich PP, Rabah R, Haas JE. Altered cardiac histology following apical right ventricular pacing in patients with congenital atrioventricular block. Pacing Clin Electrophysiol 1999; 22: 1372–1377. 36 Vernooy K, Dijkman B, Cheriex EC, Prinzen FW, Crijns HJ. Ventricular remodeling during long‐term right ventricular pacing following His bundle ablation. Am J Cardiol 2006; 97: 1223–7. 37 Sweeney MO, Hellkamp AS, Ellenbogen KA, Greenspon AJ, Freedman RA, Lee KL et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction (MOST). Circulation 2003; 107: 2932–7. 38 Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H et al. Dual‐chamber pacing or ventricular
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backup pacing in patients with an implantable defibrillator (DAVID). JAMA 2002; 288: 3115–23. 39 Sharma PS, Dandamudi G, Naperkowski A, Oren JW, Storm RH, Ellenbogen KA et al. Permanent His‐bundle pacing is feasible, safe, and superior to right ventricular pacing in routine clinical practice. Heart Rhythm 2015; 12: 305–12. 40 Kaye GC, Linker NJ, Marwick TH, Pollock L, Graham L, Pouliot E et al. Effect of right ventricular pacing lead site on left ventricular function in patients with high‐grade atrioventricular block: results of the Protect‐Pace study. Eur Heart J 2015; 36: 856–62. 41 Curtis AB, Worley SJ, Adamson PB, Chung ES, Niazi I, Sherfesee L et al.; Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) Trial Investigators. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 2013; 368: 1585–93. 42 Sharma AD, Rizo‐Patron C, Hallstrom AP, O'Neill GP, Rothbart S, Martins JB et al. Percent right ventricular pacing predicts outcomes in the DAVID trial. Heart Rhythm 2005; 2: 830–4. 43 Yu CM, Lin H, Zhang Q, Sanderson JE. High prevalence of left ventricular systolic and diastolic asynchrony in patients with congestive heart failure and normal QRS duration. Heart 2003; 89: 54–60. 44 Pitzalis MV, Iacoviello M, Romito R, Massari F, Rizzon B, Luzzi G et al. Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony. J Am Coll Cardiol 2002; 40: 1615–22. 45 Pitzalis MV, Iacoviello M, Romito R, Guida P, De Tommasi E, Luzzi G et al. Ventricular asynchrony predicts a better outcome in patients with chronic heart failure receiving cardiac resynchronization therapy. J Am Coll Cardiol 2005; 45: 65–9. 46 Burger H, Schwarz T, Ehrlich W, Sperzel J, Kloevekorn WP, Ziegelhoeffer T. New generation of transvenous left ventricular leads – first experience with implantation of multipolar left ventricular leads. Exp Clin Cardiol 2011; 16: 23–6. 47 Donahue T, Niazi I, Leon A, Stucky M, Herrmann K. Acute and chronic response to CRT in narrow QRS patients
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(ESTEEM‐CRT study). J Cardiovasc Transl Res 2012; 5: 232–41. 48 Ritter P, Delnoy PP, Padeletti L, Lunati M, Naegele H, Borri‐Brunetto A et al. A randomized pilot study of optimization of cardiac resynchronization therapy in sinus rhythm patients using a peak endocardial acceleration sensor vs. standard methods. Europace 2012; 14: 1324–33. 49 White JA, Yee R, Yuan X. Delayed enhancement magnetic resonance imaging predicts response to cardiac resynchronization therapy in patients with intraventricular dyssynchrony. J Am Coll Cardiol 2006; 48: 1953–60. 50 Bleeker GB, Kaandorp TA, Lamb HJ. Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation 2006; 113: 969–76. 51 Delgado V, Bax JJ. Assessment of systolic dyssynchrony for cardiac resynchronization therapy is clinically useful. Circulation 2011; 123: 640–55. 52 Girsky MJ, Shinbane JS, Ahmadi N, Mao S, Flores F, Budoff MJ. Prospective randomized trial of venous cardiac computed tomographic angiography for facilitation of cardiac resynchronization therapy. Pacing Clin Electrophysiol 2010; 33: 1182–7. 53 Dong YX1, Powell BD, Asirvatham SJ, Friedman PA, Rea RF, Webster TL et al. Left ventricular lead position for cardiac resynchronization: a comprehensive cinegraphic, echocardiographic, clinical, and survival analysis. Europace 2012; 14: 1139–47. 54 Kutyifa V, Zareba W, McNitt S, Singh J, Hall WJ, Polonsky S et al. Left ventricular lead location and the risk of ventricular arrhythmias in the MADIT‐CRT trial. Eur Heart J 2013; 34: 184–90. 55 Singh JP, Klein HU, Huang DT, Reek S, Kuniss M, Quesada A et al. Left ventricular lead position and clinical outcome in the multicenter automatic defibrillator implantation trial–cardiac resynchronization therapy (MADIT‐CRT) Trial. Circulation 2011; 123: 1159–66. 56 Singh JP, Klein HU, Huang DT, Reek S, Kuniss M, Quesada A et al. Impact of the right ventricular lead position on clinical outcome and on the incidence of ventricular tachyarrhythmias in patients
with CRT‐D. Heart Rhythm 2013; 10: 1770–7. 57 Merchant FM, Heist EK, Nandigam KV, Mulligan LJ, Blendea D, Riedl L et al. Interlead distance and left ventricular lead electrical delay predict reverse remodeling during cardiac resynchronization therapy. Pacing Clin Electrophysiol 2010; 33: 575–82. 58 Molhoek SG, Van Erven L, Bootsma M, Steendijk P, Van Der Wall EE, Schalij MJ. QRS duration and shortening to predict clinical response to cardiac resynchronization therapy in patients with end‐stage heart failure. Pacing Clin Electrophysiol 2004; 27: 308–13. 59 Khan FZ, Virdee MS, Palmer CR, Pugh PJ, O'Halloran D, Elsik M et al. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial. J Am Coll Cardiol 2012; 59: 1509–18. 60 Khan FZ, Virdee MS, Gopalan D, Rudd J, Watson T, Fynn SP et al. Characterization of the suitability of coronary venous anatomy for targeting left ventricular lead placement in patients undergoing cardiac resynchronization therapy. Europace 2009; 11: 1491–5. 61 Van Rees JB, de Bie MK, Thijssen J, Borleffs CJ, Schalij MJ, van Erven L. Implantation‐related complications of implantable cardioverter‐defibrillators and cardiac resynchronization therapy devices: a systematic review of randomized clinical trials. J Am Coll Cardiol 2011; 58: 995–1000. 62 Forleo GB, Della Rocca DG, Papavasileiou LP, Molfetta AD, Santini L, Romeo F. Left ventricular pacing with a new quadripolar transvenous lead for CRT: early results of a prospective comparison with conventional implant outcomes. Heart Rhythm 2011; 8: 31–7. 63 Rinaldi CA, Leclercq C, Kranig W, Kacet S, Betts T, Bordachar P et al. Improvement in acute contractility and hemodynamics with multipoint pacing via a left ventricular quadripolar pacing lead. J Interv Card Electrophysiol 2014; 40: 75–80. 64 Pappone C, Ćalović Ž, Vicedomini G, Cuko A, McSpadden LC, Ryu K et al. Multipoint left ventricular pacing in a single coronary sinus branch improves mid‐term echocardiographic and clinical response to cardiac resynchronization
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therapy. J Cardiovasc Electrophysiol 2015; 26: 58–63. 65 Bocchiardo M, Meyer zu Vilsendorf D, Militello C, Lippert M, Czygan G, Gaita F et al. Intracardiac impedance monitors stroke volume in resynchronization therapy patients. Europace 2010; 12: 702–7. 66 Hayes DL, Boehmer J, Day J. Cardiac resynchronization therapy and relationship of percent biventricular pacing. Heart Rhythm 2011; 8: 1469–75. 67 Santini M, Gasparini M, Landolina M, Lunati M, Proclemer A, Padeletti L et al. Device‐detected atrial tachyarrhythmias predict adverse outcome in real‐world patients with implantable biventricular defibrillators. J Am Coll Cardiol 2011; 57: 167–72. 68 Lakkireddy D, Di Biase L, Ryschon K, Biria M, Swarup V, Reddy YM et al. Radiofrequency ablation of premature ventricular ectopy improves the efficacy of cardiac resynchronization therapy in nonresponders. J Am Coll Cardiol 2012; 60: 1531–9. 69 Cheng A, Landman SR, Stadler RW. Reasons for loss of cardiac resynchronization therapy pacing: insights from 32 844 patients. Circ Arrhythm Electrophysiol 2012; 5: 884–8. 70 Bernheim A, Ammann P, Sticherling C, Burger P, Schaer B, Brunner‐La Rocca
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HP et al. Right atrial pacing impairs cardiac function during resynchronization therapy: acute effects of DDD pacing compared to VDD pacing. J Am Coll Cardiol 2005; 45: 1482–7. 71 Martin DO, Lemke B, Birnie D, Krum H, Lee KL, Aonuma K et al. Investigation of a novel algorithm for synchronized left‐ ventricular pacing and ambulatory optimization of cardiac resynchronization therapy. Heart Rhythm 2012; 9: 1807–14. 72 Birnie D1, Lemke B, Aonuma K, Krum H, Lee KL, Gasparini M et al. Clinical outcomes with synchronized left ventricular pacing: analysis of the adaptive CRT trial. Heart Rhythm 2013; 10: 1368–74. 73 Jansen AH, Bracke FA, van Dantzig JM, Meijer A, van der Voort PH, Aarnoudse W et al. Correlation of echo‐Doppler optimization of atrioventricular delay in cardiac resynchronization therapy with invasive hemodynamics in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 2006; 97: 552–7. 74 Ellenbogen KA, Gold MR, Meyer TE, Fernndez Lozano I, Mittal S, Waggoner AD et al. Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART‐AV) trial: a randomized trial
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comparing empirical, echocardiography‐ guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy. Circulation 2010; 122: 2660–8. Bordachar P, Lafitte S, Reuter S, Sanders P, Jaïs P, Haïssaguerre M et al. Echocardiographic parameters of ventricular dyssynchrony validation in patients with heart failure using sequential biventricular pacing. J Am Coll Cardiol 2004; 44: 2157–65. Abraham WT, León AR, St John Sutton MG, Keteyian SJ, Fieberg AM, Chinchoy E et al. Randomized controlled trial comparing simultaneous versus optimized sequential interventricular stimulation during cardiac resynchronization therapy. Am Heart J 2012; 164: 735–41. Mullens W, Grimm RA, Verga T, Dresing T, Starling RC, Wilkoff BL et al. Insights from a cardiac resynchronization optimization clinic as part of a heart failure disease management program. J Am Coll Cardiol 2009; 53: 765–73. Hindricks G, Taborsky M, Glikson M, Heinrich U, Schumacher B, Katz A et al. Implant‐based multiparameter telemonitoring of patients with heart failure (IN‐TIME): a randomised controlled trial. Lancet 2014; 384: 583–90. Akar JG. Abstract LB03‐03. Presented at: Heart Rhythm Society Annual Scientific Sessions; May 7–10, 2014, San Francisco.
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Cardiac resynchronisation therapy in 2015: keeping up with the pace A. Voskoboinik,1,2 A. D. McGavigan3 and J. A. Mariani2,4 1
Department of Cardiology, Western Hospital, 2Department of Cardiology, Alfred Hospital, 4Cardiac Investigation Unit, St Vincent' Hospital, Melbourne, Victoria, and 3Department of Cardiovascular Medicine, Adelaide, South Australia, Australia
Key words cardiac resynchronisation therapy, biventricular pacing, heart failure, dyssynchrony. Correspondence Alex Voskoboinik, Department of Cardiology, Western Hospital, Melbourne, Vic. 3011, Australia. Email: [email protected]; [email protected] Received 17 February 2015; accepted 24 March 2015.
Abstract Despite improved understanding of the pathophysiology of heart failure (HF) and availability of better medical therapies, HF continues to grow as a cause of morbidity and mortality in Australia and worldwide. Over the past decade, cardiac resynchronisation therapy (CRT), or biventricular pacing, has been embraced as a powerful weapon against this growing epidemic. However, much has changed in our understanding of dyssynchrony in HF, and this has led to a change in guidelines to ensure more appropriate selection of CRT candidates to improve the ‘non‐response’ rate. More data have also emerged about the use of CRT in atrial fibrillation and in pacemaker‐dependent patients. There has also been a growing focus on multimodality imaging to guide patient selection and lead positioning. Exciting new lead technologies are also emerging, with the potential to improve CRT outcomes further.
doi:10.1111/imj.12774
Introduction Dyssynchrony in heart failure (HF) As HF progresses, pathological remodelling of the heart results in cellular and interstitial changes that also adversely affect the conduction system. Electrical dyssynchrony causes mechanical dyssynchrony, which refers to differences in the timing of contraction between different myocardial regions. This occurs at multiple levels in the failing heart, particularly atrioventricular (AV), interventricular and intraventricular. Intraventricular dyssynchrony is often manifested by QRS prolongation and occurs in approximately one third of cardiomyopathy patients. A left bundle branch block (LBBB) is the most common disturbance.1 The presence of an LBBB results in delayed activation of the lateral wall relative to the right ventricle and septum, leading to reduced mechano‐energetic efficiency of the heart. This is similar to the effects of chronic right ventricular (RV) pacing, with a slow depolarisation wavefront propagating through the myocardium, rather than the Purkinje system. There are numerous adverse Funding: None. Conflict of interest: None.
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haemodynamic sequelae of LBBB, including abnormal septal motion causing decreased regional ejection fraction, redistribution of myocardial fibre strain with altered regional blood flow, diastolic dysfunction due to shortened left ventricular (LV) filling time, depressed dP/dt and worsening mitral regurgitation.2–4 Further, LBBB, as either a contributor to, or simply a surrogate marker of, progressive cardiac dysfunction, is associated with increased morbidity and mortality.5
Cardiac resynchronisation therapy (CRT) CRT aims to reverse the deleterious effects of LBBB, as the right and left ventricular pacing leads generate two ventricular activation wavefronts that move towards each other. The benefit of CRT lies in the effective fusion of these two depolarisation wavefronts, synchronising the walls of the LV (Fig. 1). Since implantation of the first transvenous CRT system in 1998, numerous large randomised multicentre trials have demonstrated significant benefit of CRT in appropriately selected HF patients with respect to multiple end‐points. These have included functional class, exercise capacity, hospitalisation, quality of life, and reverse remodelling with improvement in ejection fraction, and reduction in LV size and mitral regurgitation.6,7 Since the
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Figure 1 Pacing the septal and lateral walls with cardiac resynchronisation therapy (CRT) (leads denoted by yellow stars) resynchronises the heart, negating the adverse effects of left bundle branch block (LBBB).
Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) and Cardiac Resynchronization – Heart Failure (CARE‐HF) trials, there has also been a reproducible demonstration of mortality benefit (Table 1).
Patient selection Current guidelines While CRT is ‘life‐changing’ for some, an estimated one third of patients derive little or no benefit.20 Given the heterogeneity of the various studies, it has taken time to develop a better understanding of which patients are most likely to benefit to improve patient selection. This has led to a change in the recommendations for CRT since 2006, when this topic was last reviewed in this journal.21 At that time, the widely accepted Class I indication was ‘severe systolic dysfunction’ (LV ejection fraction less than 35%) in sinus rhythm (SR) with QRS duration of at least 120 ms, and moderate‐severe HF symptoms (New York Heart Association (NYHA) Class III–IV) despite optimal medical therapy. Increasing data have emerged regarding the critical importance of a LBBB pattern in deriving clinical benefit from CRT. Patients with right bundle branch block (RBBB) do not have a dyssynchrony pattern suitable for CRT (activation of their lateral wall is already early), and often have concomitant RV dysfunction, pulmonary hypertension and more extensive conduction disease conferring a worse prognosis. Patients with RBBB undergoing CRT have significantly lower rates of symptomatic and echocardiographic response, and a lower survival free from heart transplantation or ventricular
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assist device placement.22 A recent meta‐analysis reinforced this lack of benefit of CRT in patients with either RBBB or non‐specific intraventricular conduction delay.23 In the recently published Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT‐CRT) long‐term follow up,24 there was even the suggestion that CRT without LBBB was associated with harm (adjusted hazard for all‐cause mortality 1.57; 95% confidence interval (CI): 1.03–2.39). While the lack of CRT benefit in narrow QRS width (150 ms.25 In a large meta‐analysis of 5813 patients, there was no statistically significant reduction in death and HF hospitalisation with CRT in this ‘intermediate QRS width’ group.26 Only those with QRS duration ≥150 ms now receive a Class IA indication in major society guideline statements6,7 (Fig. 2). Unfortunately, studies utilising various imaging modalities to assess dyssynchrony have been largely disappointing, and electrocardiogram (ECG) still remains the gold standard for this purpose. Also now receiving a Class I indication for CRT are mildly symptomatic patients (NYHA Class II). The Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT)27 was the first study to show a significant reduction in mortality in this group (hazard ratio (HR) 0.75; 95% CI: 0.62–0.91) in addition to reduced hospitalisation for HF. This was reinforced by MADIT‐ CRT,28,29 the largest CRT trial to date, of whom 85% of patients were NYHA II, with significant reductions seen
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≤35%
≤30%
≤30%
≤40%
≤35%
≤35%
≤35%
≤35%
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≤35% ≤35%
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LVEF
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≥130
≥120
150 ms who otherwise satisfy the criteria, CRT is still better than no CRT (just not as beneficial as for SR
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patients with QRS width >150 ms). Unfortunately, Medicare does not currently provide a rebate for CRT in AF patients, regardless of ejection fraction or QRS duration. The Australian prospective randomised Cardiac Resynchronisation Therapy and AV Nodal Ablation Trial in Atrial Fibrillation (CAAN‐AF)33 is currently recruiting patients to assess further the role of AVNA in AF patients with broad QRS and severe systolic dysfunction.
Pacemaker induced dyssynchrony and the role of CRT RV apical pacing for patients with symptomatic AV block creates dyssynchrony, with QRS prolongation similar to an LBBB morphology, and results in adverse ventricular remodelling.34–36 Importantly, LV systolic dysfunction is seen in up to 40% of these patients and is related to the percentage of RV pacing.24 The detrimental effects of RV pacing on LV systolic function is well documented, with increased AF,37 as well as HF hospitalisation and mortality. In the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial of 506 HF patients with implantable cardioverter defibrillator (ICD), patients randomised to a backup mode (VVI‐40) had significantly superior outcomes (mortality and hospitalisation) compared with those with a dual‐chamber pacing mode (DDDR‐70).38 Various strategies have been employed to minimise RV apical pacing. These have included bradycardia prevention, programming long AV delays to promote intrinsic conduction and alternate pacing sites, such as the high RV septum or His bundle. While undoubtedly the most physiological site, His‐ bundle pacing (HBP) is more technically challenging. Sharma et al. recently reported an 80% success rate in achieving permanent HBP (without a mapping catheter or backup RV lead) using the Medtronic Select Secure active fixation lead delivered through a fixed‐shaped catheter. The majority of patients in this study had >40% ventricular pacing, and HF hospitalisation was significantly reduced in the HBP group compared with the RV‐paced group (2% vs 15%; P = 0.02).39 Disappointingly, the randomised Protection of Left Ventricular Function During Right Ventricular Pacing
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Cardiac resynchronisation therapy Figure 3 Major society guidelines for CRT in patients with conventional indications for anti‐bradycardia pacing. CRT, cardiac resynchronisation therapy; EF, ejection fraction; ICD, implantable cardioverter defibrillator; PPM, permanent pacemaker; RV, right ventricular.
(PROTECT‐PACE) study of 240 patients did not demonstrate any difference in ejection fraction drop between RV apical and high RV septal positions at 2 years.40 However, in recent years, CRT has emerged as a promising option in these patients. The largest trial of its kind, Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK‐HF),41 randomised 918 patients with AV block (with a need for significant ventricular pacing), ejection fraction (EF) 15% increase in the left ventricular end‐systolic volume index) occurred in 55.6% of RV‐paced patients, compared with 45.8% of BiV‐paced patients (HR 0.74; 95% CI: 0.60–0.90). Certainly, there remains a paucity of data to support the practice of routinely implanting CRT for all patients with indications for a pacemaker. Most will not develop LV dysfunction or HF, and subjecting them to a longer procedure with increasing peri-procedural complications is inappropriate. However, in RV-paced patients who, during follow up, develop symptoms of HF and have a deteriorating EF should be upgraded to CRT to reduce hospitalisation, and improve symptoms and cardiac function.6 Current international guidelines (Fig. 3) advocate ‘up‐front’ implantation of a CRT device in patients with severe pre‐existing systolic dysfunction (EF 40% RV‐paced was found to be predictive of adverse outcomes in a substudy of the DAVID trial42). While there are no Australian guidelines for this, the results of BLOCK‐HF suggest this practice should even be considered in those with milder degrees of systolic dysfunction.
Role of multimodality imaging As stated, electrical dyssynchrony results in mechanical dyssynchrony, and multiple imaging modalities have been used to confirm its presence and determine the site of latest LV activation. Studies have shown that up
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to 50% of patients with a narrow QRS (130 ms). After following 809 patients for a mean 19.4 months, the study was stopped early due to increased mortality in the CRT arm (11.1% vs 6.4%). This reinforced the notion that current dyssynchrony indices (apart from the ECG) are ineffective at selecting narrow QRS patients for CRT, and may worsen outcomes in patients with narrow QRS. Accordingly, QRS width (with or without mechanical dyssynchrony) remains the key determinant of clinical response to CRT, and the only Class I indication. While availability is currently limited in many Australasian centres, cardiac MRI (CMR) enables the assessment of both dyssynchrony and scar burden in a single study. It has been well established that pacing in regions of scar, as detected by delayed enhancement MRI, predicts lack of response to CRT.49,50 Combined with numerous validated measures of dyssynchrony (cine MRI, myocardial tagging, strain imaging), CMR is gaining increasing attention due to its excellent tissue characterisation, high spatial resolution and reproducibility.51 Like multidetector cardiac computed tomography (CT), CMR also enables the assessment of cardiac venous anatomy.
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In patients with significant scar who may exhibit less extensive venous anatomy, this may mean a minimally invasive surgical approach rather than a transvenous approach. Notably, delineation of the precise number and location of tributaries of the coronary sinus by CT minimises peri‐procedural venography, and has been shown to shorten procedural times and limit contrast and radiation exposure.52 Looking towards the future, myocardial imaging has the potential to individualise CRT. It can confirm candidacy by demonstrating significant mechanical dyssynchrony in an otherwise borderline candidate on ECG criteria. It can also guide lead placement by targeting an appropriate vein adjacent to the latest activated region of myocardium and away from scar.
CRT leads: optimal position and new technologies Lead positioning Appropriate positioning of the LV lead is a key determinant of CRT success. In the absence of additional information regarding activation sequence, the lead should be positioned in the lateral or posterolateral walls, which are usually activated last and are furthest away from the RV lead. In a retrospective analysis of 457 CRT recipients, Dong et al. demonstrated greater improvement in NYHA class with lateral LV lead positions compared with anterior locations.53 Anterior LV lead positions also have a significantly higher risk of ventricular arrhythmias than posterior or lateral positions.54 Basal or mid‐ventricular LV lead positions are superior to apical locations. In an analysis of 799 patients in the MADIT‐CRT study, apical LV lead position was associated with a significantly increased risk of HF (HR 1.72; 95% CI: 1.09–2.71) and death (HR 2.91; 95% CI: 1.42–5.97).55 The location of the RV lead is less important, and there is certainly no clinical benefit of non‐apical RV lead locations (i.e. septum, RV outflow tract) compared with apical locations.56 There is also some evidence that a larger horizontal inter‐lead distance (as measured on a lateral chest X‐ray), which correlates with a longer LV lead electrical delay, can improve LV anatomic reverse remodelling post‐CRT.57 The amount of QRS shortening post‐CRT (DeltaQRS), which relates to both inter‐lead distance and LV lead electrical delay, is a strong predictor of improved outcomes post‐CRT. Molhoek et al. demonstrated that a DeltaQRS >10 ms has a high sensitivity (73%) while a DeltaQRS >50 ms has a high specificity (88%) for CRT response.58 Showing promise is the use of echocardiography to guide lead placement. Unlike tissue Doppler, speckle
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tracking radial strain can distinguish between active and passive motion (scar tethering) and is able to determine the site of latest contraction. The Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy (TARGET) study59 randomised 220 patients to either standard unguided CRT or LV lead positioning at the site of latest peak contraction with an amplitude of >10% to signify freedom from scar. The latter group had a greater response rate (70% vs 55%, P = 0.031) with respect to reverse remodelling, as well as lower all‐cause mortality and hospitalisation. However, significant variability in coronary venous anatomy exists between patients, and the ability to target directly LV lead position is a limitation of the transvenous route. In a large series investigating distribution of venous anatomy and its effects on LV lead targeting, Khan et al. demonstrated that limitations of coronary venous anatomy restrict LV lead placement to a single vein with little scope for site selection in almost half of all patients.60 In patients with multiple target veins, intraprocedural coronary venous electroanatomic mapping has been assessed as a means of guiding LV lead placement to the latest activated region free from phrenic nerve stimulation. In a recently published series, Rad et al. demonstrated that this latest activated region (region with an electrical delay >75% of total QRS duration) was more often located anterolaterally, rather than the empirically targeted inferolateral vein.28
Epicardial leads Direct surgical epicardial approach may overcome these limitations, and should be considered in non‐responders due to suboptimal lead placement, and in those with high thresholds or intractable phrenic nerve stimulation. Previously only performed by thoracotomy (or sternotomy), newer techniques have emerged to limit surgical morbidity, including left lateral mini‐thoracotomy, video‐ assisted thoracoscopy and the use of robotic technology. While long‐term outcomes with respect to mortality and functional improvement are similar to the transvenous route, these patients often have longer in‐hospital length of stay29 and higher perioperative complications, including renal failure and infection.27
Emerging lead technologies Compared with isolated RV pacing, patients undergoing CRT with standard bipolar leads have higher rates of LV lead complications, including lead dislodgement (5.7%) and coronary sinus complications (2.0%).61 In addition to loss of capture related to these problems, some patients also require reoperation due to phrenic nerve stimulation or increased LV pacing thresholds without obvious
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dislocation. New quadripolar leads have four independent electrodes, which enable programming of additional different vectors for LV pacing. This provides the operator greater flexibility, as they can programme different electrode configurations, rather than having to reposition an entire lead. Down the track, they are more likely to find a stable position with reasonable pacing thresholds while minimising phrenic nerve stimulation.46,62 Quadripolar leads also enable multipoint pacing, which provides greater flexibility for optimal pacing configurations. This technology (MultiPoint Pacing, St. Jude Medical) delivers two LV pulses per pacing cycle from a single quadripolar lead. Early studies show some promise in further optimising haemodynamics, improving contractility with echocardiographic guidance63 and reducing the rate of CRT non‐response.64 Newer leads are also now being designed to monitor haemodynamic parameters, which will hopefully enable device optimisation, guide LV lead positioning and aid in clinical management. Intracardiac impedance reflects LV volume changes well in animal models, and early studies involving Biotronik's intracardiac impedance sensing technology have demonstrated good correlation with LV stroke volume.65 Sorin's SonR system utilises a sensor embedded in the lead tip that detects cardiac muscle vibrations (peak endocardial acceleration signal system). In a recent randomised study, automatic optimisation of AV and ventriculo‐ventricular (VV) delays based on this system resulted in improved CRT response, with significant improvement in NYHA class.48
Device programming and follow up Improving %BiV pacing: arrhythmia suppression The greatest benefit is derived from CRT when it is used maximally. Hayes et al. demonstrated a 24% reduction in mortality in patients receiving above 98.5% BiV pacing, as compared with those receiving 10 000 PVC in a 24‐h period.68
Improving %BiV pacing: pacing algorithms While routine optimisation of AV delay is controversial, an inappropriately programmed long AV delay may result in loss of BiV pacing in many patients.69 Avoidance of right atrial pacing is preferred, because pacing the right atrial appendage delays left atrial activation, which may impair LV preload and worsen myocardial performance. This can be achieved by programming a VDD mode, rather than a DDD mode.70 A novel adaptive CRT algorithm (AdaptivCRT, Medtronic) in patients with SR and normal AV conduction is also showing great promise. This algorithm provides LV pacing synchronised to produce fusion with intrinsic RV activation (to minimise RV pacing), with dynamic optimisation of AV and VV delays. It has been shown to be safe and at least as effective as BiV pacing with echocardiographic optimisation,71 with the suggestion of better clinical outcomes in those with a higher percentage of LV pacing.72
Echocardiographic optimisation The use of echocardiography to assess mechanical dyssynchrony and select patients for CRT has been disappointing. However, modern CRT devices enable programming of AV and VV delays, which can be optimised based on echocardiographic evaluation of haemodynamics. With respect to optimising AV delay, numerous Doppler echocardiographic parameters have been studied. These include LV outflow tract velocity time integral (VTI), diastolic filling time and transmitral flow (EA VTI), with the latter correlating best with invasive measurements (LV dP/dtmax).73 However, the SmartDelay Determined AV Optimization (SMART‐AV) randomised trial of 980 patients demonstrated no clinical benefit of an echocardiography‐optimised AV delay over a fixed empirical AV delay of 120 ms.74 While many of the landmark CRT trials incorporated some form of echocardiography‐guided AV delay optimisation (based on small haemodynamic studies), long‐term randomised data supporting this practice are lacking. Several small studies of echocardiography‐guided VV optimisation have demonstrated acute haemodynamic improvements compared with simultaneous BiV pacing. Bordachar et al. demonstrated that improvements in intraventricular dyssynchrony (using tissue Doppler) correlated with an increase in cardiac output, with simultaneous BiV pacing being the optimal setting in only 15% of patients.75 In a randomised study of 238 patients with
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VV intervals adjusted to minimise septal to posterior wall delay, significantly more patients improved based on a clinical composite score; however, no significant differences were found with respect to exercise capacity, quality of life or HF event rate. Again, simultaneous BiV pacing was the optimal setting in only 18%.76 In addition to a paucity of consistent clinical data demonstrating clear benefit, echocardiographic optimisation of AV and VV delays is time‐consuming and resource‐intensive, and requires significant skill. However, it may be useful in CRT non‐responders.
Integrated teams and remote monitoring With the burden of hospital readmission rates for HF rapidly increasing, multidisciplinary clinics encompassing nurse practitioners, physiotherapists, social workers, dieticians, psychologists and specialists are being developed to deliver holistic, patient‐centred care. A multidisciplinary approach, coupled with individualised CRT optimisation (incorporating echocardiography‐ guided adjustment in device settings and optimisation of medical therapy), led to significant improvements in LV function and reduction in adverse events in 75 CRT non‐responders. A reason for CRT non‐response was identified in most patients, and multidisciplinary recommendations led to a change in treatment in 74%.77 Remote monitoring of CRT devices, with the regular transmission of important data such as atrial and ventricular arrhythmia burden, heart rate histograms, device safety issues and ‘%BiV‐paced’, enables regular ‘contact’ with cardiologists and earlier optimisation of therapy.
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In the Implant-based Multiparameter Telemonitoring of Patients with Heart Failure (IN‐TIME) randomised trial of 716 patients, most of whom had CRT‐D (CRT and defibrillator) devices, those receiving automatic, daily multi‐parameter tele‐monitoring had a significantly lower incidence of the primary end‐point (combined all‐cause mortality, hospitalisation, change in NYHA class and symptoms). This was largely driven by earlier recognition of suboptimal device function, detection of arrhythmias and patient interview prompted by remote monitoring findings.78 Early results from the Patient Related Determinants of ICD Remote Monitoring Utilization and Outcomes (PREDICt‐RM) study, which analysed registry data from 37 742 patients with new ICD or CRTD implants, demonstrated lower mortality (HR = 0.67; 95% CI: 0.64–0.7) and hospitalisation (HR = 0.81; 95% CI: 0.79–0.83) in those who used remote monitoring. Despite its many benefits, remote monitoring is currently underutilised in Australia.79
Conclusion CRT remains one of the key successes of the ‘device era’ of HF therapy. The past decade has given us a greater understanding about the importance of appropriate patient selection, correct lead positioning and device optimisation to ensure a high percentage of BiV pacing. With novel indications, new lead technologies, better remote monitoring tools and integrated multimodality imaging showing great promise, CRT remains an exciting and rapidly evolving field.
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