- Email: [email protected]
Multispecialty approach: The need for heart failure disease management for refining cardiac resynchronization therapy
Multispecialty approach: The need for heart failure disease management for refining cardiac resynchronization therapy W.H. Wilson Tang, MD,* John Boehmer, MD,† Daniel Gras, MD‡ From the *Cleveland Clinic, Cleveland Ohio, †Pennsylvania State College of Medicine, Hershey, Pennsylvania, and ‡ Nouvelles Cliniques Nantaises, Nantes, France. Cardiac resynchronization therapy (CRT) has been proven in clinical trials to be a very effective therapy in appropriate patients. However, although the literature has primarily focused on appropriate implanting techniques and inclusion criteria for CRT devices by electrophysiologists, most patients who receive CRT are managed by their primary care providers with the help of general cardiologists and/or heart failure (HF) specialists. As CRT has been more broadly applied over the past decade, the fragmentation and specialization of care in the current health care system have created challenges in optimizing this otherwise invasive but potentially beneficial intervention in the complex HF patient. Furthermore, cost considerations as well as appropriate follow-up care continue to challenge the optimal application of these devices, particularly when evidence to support multidisciplinary approaches is lacking. The challenge begins with identification of appropriate candidates for CRT, which is an evolving concept due to data emerging from new studies with a wide range of inclusion and exclusion criteria coupled with increasing oversight from
Introduction Within a decade of its development as a clinical therapy, cardiac resynchronization therapy (CRT) has seen tremendous progress in the development of supporting clinical evidence and broad clinical adoption for patients with heart failure (HF). On the one hand, randomized controlled trials have provided justification for broad adoption of CRT in a wide range of patient populations.1–5 On the other hand, CRT application strategies have been refined by better characterization of the specific subgroups that may or may not benefit from CRT. Electrophysiology (EP) specialists have refined their techniques and their knowledge base regarding strategies to maximize the application of CRT, identify appropriate disease substrates, and improve implantation techniques and pacing algorithms. Nevertheless, there remains a paucity of research efforts focusing Dr. Tang has served as an advisor or consultant for Medtronic and St. Jude Medical. Dr. Boehmer has served as an advisor or consultant for Boston Scientific; as a speaker or a member of a speakers’ bureau for Medtronic; and has received grants for clinical research from Boston Scientific. Dr. Gras has no financial relationship with industry that is applicable to this study. Address reprint requests and correspondence: Dr. W.H. Wilson Tang, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH 44195. E-mail address: [email protected].
providers or even logistical hurdles from patients. Postimplant management practices and procedures are still evolving. The important and so-far unresolved concept of the “nonresponder” to CRT remains largely subjective and is variably defined in the literature, and the lack of understanding of the underlying mechanisms of “nonresponse” continues to challenge long-term management of CRT, even given the recent developments in advanced sensor technologies. Therefore, further investigations into HF disease management with a multispecialty approach, pre-CRT and post-CRT, are warranted. KEYWORDS Cardiac resynchronization therapy; Multidisciplinary; Multispecialty approach; Nonresponder; Postimplant ABBREVIATIONS CRT ⫽ cardiac resynchronization therapy; EF ⫽ ejection fraction; EP ⫽ electrophysiology; HF ⫽ heart failure; LV ⫽ left ventricle; NYHA ⫽ New York Heart Association (Heart Rhythm 2012;9:S45–S50) © 2012 Heart Rhythm Society. All rights reserved.
on how to best apply CRT for arrhythmic HF patients as part of their overall care plans. As a result, the latest clinical guidelines have included few specific recommendations regarding how to manage patients who have received, or who are eligible to receive, CRT device implantations. The result of these uncoordinated developments is that fragmentation of care across different specialties and subspecialties is one of the major challenges to providing appropriate management of HF patients regarding CRT- and non–CRT-related issues. Beyond the physicians who are responsible for the implantation of CRT devices, many other health care providers are now intricately involved in periprocedural care, in troubleshooting device problems and/or arrhythmic complications, and in optimizing medical management. These other providers include non–EP cardiologists and other non– cardiologist physicians, as well as HF- and device-clinic nurses in clinical practices where patients are treated with CRT. Hence, although maintenance of device functionality has traditionally been the focus of postimplant care, a shift has now occurred toward understanding how different treatment teams can interact with the patient and with each other in order to optimize benefit and minimize harm.
1547-5271/$ -see front matter © 2012 Heart Rhythm Society. All rights reserved.
http://dx.doi.org/10.1016/j.hrthm.2012.04.028
S46 This article explores the necessity for, the challenges to, and the hurdles facing a multispecialty approach to the use of CRT for HF patients, particularly with regard to ● ● ●
appropriateness of patient selection consistency of adjunctive treatment protocols, and current challenges in CRT optimization. In addition, some potential best practice approaches as well as the future role of sensor technologies will be considered.
Appropriateness of patient selection Potential underutilization of CRT As a first step, identification of appropriate candidates for referral for possible CRT implantation is of utmost importance. It may seem to be a relatively straightforward concept for any health care provider to identify the inclusion and exclusion criteria as outlined in major clinical trials and summarized in clinical guideline recommendations, but in practice recognition of appropriate candidates and achievement of a recommended utilization rate for CRT are far from satisfactory. The true rate of underutilization of CRT is difficult to determine, in part due to the insufficient documentation of clinical criteria in medical records. Nevertheless, findings from several large registries have suggested that underutilization of CRT in potentially appropriate candidates definitely exists.6 – 8 Utilization varies widely among contemporary outpatient HF practices, ranging from 38.8% of eligible patients receiving a CRT pacing device to 84.1% of eligible patients receiving a CRT plus defibrillator device.6 Among patients hospitalized with HF, 4.8% of patients with left ventricular ejection fraction (LVEF) ⱕ35% were discharged with a new CRT implant (although this varied greatly by hospital), while 10% of patients discharged with a new CRT implant had LVEF ⬎35%.8 One of the primary reasons for this wide variation may be heterogeneity of expertise among practice settings and health care providers, particularly those who may (1) not be familiar with the indications for CRT; (2) not appreciate the disease severity of their patients; (3) overlook or fail to appreciate the potential benefits of an upgrade to CRT from an existing ICD, particularly if unaware of the evolving data from recent clinical trials; and (4) have misconceptions about the procedural risks and device complications, which may discourage referrals for implantation. Logistic and economic issues, as well as personal preferences, also may play a role in the record of missed opportunities. Finally, some patients may have been referred for a CRT device but may have missed the implantation opportunity for a wide variety of reasons, including delayed scheduling, financial constraints, or other logistic hurdles. All of these factors represent important practical issues that current research efforts have failed to address well. In contrast to the overall record of missed opportunities and failure to deliver appropriate CRT implantations, a substantial proportion of patients may have received CRT implantation beyond guideline-based indications. Nearly 1 in 4 patients receiving CRT devices did not meet guideline-
Heart Rhythm, Vol 9, No 8S, August Supplement 2012 based indications in a recent study,9 and it should be borne in mind that this “overreach” beyond the guideline recommended use for CRT may be contributing to the “nonresponder” rate that is an important source for current criticism of CRT.
Indication creep There are several possible explanations for this “overreach” of CRT implantations. First, there is a clear “indication creep” whenever new technologies become available for clinical use. In the case of CRT, this means that the therapy may be applied in patients who do not meet the eligibility criteria defined in the relevant clinical trial protocols. This often occurs when patients have remained symptomatic even when health care providers have already optimized medical therapy. In this case, there may be desperation from the perspectives of both patients and health care providers to offer any potential treatment that may confer the slightest chance of benefit, and patients who may not fully fit the enrollment criteria for clinical trials (eg, due to comorbidities) are nevertheless considered for CRT. This is exacerbated when a lack of communication and collaborative assessment between EP and non–EP providers is present, as this may result in patients who do not have a clear-cut indication for CRT but have a low threshold for implantation because of their symptom severity.
Implanter creep Second, there is “implanter creep,” which occurs when less experienced physicians nevertheless implant CRT devices. This inevitably results in greater complication rates and lower CRT success rates. In this scenario, implanters may have a narrow perspective that regards CRT as a procedure rather than as a comprehensive therapeutic approach that needs careful selection and adjunctive management. The evidence supporting device implantation is evolving rapidly and in many cases is very broadly defined. As a result, patients may appear to fulfill implantation criteria, yet clinically their disease may have progressed beyond the point of recovery, often with significant comorbid conditions such as end-organ dysfunction. In this situation, CRT implantation may be too late to succeed, even when it results in restoration of mechanical synchrony. Although no direct evidence supports this assertion, it is conceivable that the lack of knowledge regarding how best to manage these very sick patients following their CRT implantation may contribute to some of the “nonresponse” results.
Subjectivity of selection criteria Another issue hindering broad adoption of CRT stems from the fact that the appropriate selection criteria are far from objective, reliable, and reproducible. Two of the principal criteria, New York Heart Association (NYHA) HF functional class and LVEF, are plagued with variability. NYHA functional classification is largely self-reported and subjective, and echocardiographically derived LVEF measurements have at least a 5- to 7-point interinvestigator standard
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HF Disease Management Using a Multispecialty Approach
deviation, even with expert acquisition and interpretation. As a result, the qualities of these assessments may vary widely, depending on the expertise and specialty of health care providers and sometimes depending on specific clinical situations.
Consistency of adjunctive treatment protocols Inconsistency in postimplant care Optimal adjunctive therapy is a very important component of any surgical or interventional procedure. Nevertheless, the large majority of randomized controlled trials of CRT do not have a rigorous postimplantation schedule as part of the study protocol. Moreover, few implantation centers currently have formalized follow-up protocols specifically for patients who have received CRT devices, even if most have regular follow-up and “optimization” protocols for CRT patients who fail to exhibit robust responses. The majority of CRT centers follow the traditional approach of overnight observation following an uncomplicated device implantation, with predischarge incision site and device checks. This is usually followed by outpatient visits at 1 and 3 months, with subsequent 3-month in-person or remote follow-up visits, based mainly on self-reported symptoms, clinical evaluation, and surveillance of device functionality. However, in clinical practice, the large majority of patients do not receive the benefit of a structured postimplant optimization protocol, particularly with respect to postimplant adjustments of medications or specific follow-up procedures. On the other hand, the benefits of structured postimplant protocols have yet to be demonstrated, as the results of recent studies did not demonstrate benefit with routine optimization protocols.10 Originally, when CRT implantation was largely restricted to patients with advanced HF, often after referral by HF specialists, EP providers could rely on the HF specialists to focus on delivering postimplant care. However, with the recent trend to broader referral from non–HF health care providers, the safety net of proper prescription and dosing of evidence-based medications or nutritional or exercise counseling may be lacking. As a result, there are no doubt subsets of patients with advanced HF whose only regularly scheduled follow-up is with their EP providers, and these specialists may fail to appreciate that the underlying cardiac condition of these HF patients can benefit from medical optimization as well as lifestyle modification. Finally, some patients (even those who have been enrolled in HF disease management clinics) may be “lost” to the system when both their device checks and their HF treatment lapse due to logistic hurdles, scheduling difficulties, suboptimal medical coverage, or financial constraints.
Gaps in transition of care Several gaps in the transition of care between EP and non–EP health care providers exist and may hinder appropriate postimplant care.
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1. A large proportion of patients with HF may not have the opportunity to see a cardiologist, much less an HF or EP specialist. 2. There is an evolving knowledge gap with the rapidly evolving device technologies and the complex array of device models, all with different functionalities, due to lack of updated education and basic training on device interrogation or adequate knowledge for basic troubleshooting for non–EP providers (particularly for the noncardiologists). 3. The large majority of non–EP practice locations do not have access to any interrogation tools (even though some vendors have created point-of-care interrogation devices for such purposes). 4. There is a general lack of skills and knowledge among non–EP health care providers regarding review of device-derived diagnostic data (even when such device data may be available at the practice settings), as it has yet to be incorporated into the everyday clinical work flow.
Current challenges in optimization Defining nonresponders As with any interventions, there will be patients who respond to CRT in rigorous clinical trial protocols and others who fail to respond to CRT in “real-world” clinical experience. One of the consistently observed realities of CRT is that across all patients who receive a CRT device, only about 70% of the patients will have a therapeutic response to the device. It is an empiric reality that this “response rate” is actually quite favorable, and in fact it probably is better than that of the majority of HF therapies. However, because CRT is an expensive and invasive therapy, there is close scrutiny with regard to its cost-to-benefit or cost-effectiveness ratios. One of the complications with “success rates” for CRT concerns the wide discrepancies among clinicians regarding the definition of “nonresponder.” Broadly speaking, this stems from a division between those who identify “nonresponse” as a lack of subjective clinical improvement (eg, functional capacity or self-reported symptom levels or health status) vs others who define “nonresponse” as a lack of objective improvement in cardiac structure or function (often identified by serial imaging techniques).11 This variability in criteria and findings has impeded consensus as to how best to define the subsets of patients who may or may not respond to CRT. Early attempts to identify objective criteria for “nonresponse” focused on detecting underlying mechanical (either intraventricular or interventricular) dyssynchrony. This appears to be a logical definition of the intended benefits of CRT because inadequate resynchronization (or an absence of underlying dyssynchrony) may lead directly to a lack of intended benefits following CRT.12 In a prospective series of HF patients who failed to show evidence of either clinical and/or echocardiographic responses after at least 3 months of follow-up post-CRT implantation, it was found that not
S48 Table 1
Heart Rhythm, Vol 9, No 8S, August Supplement 2012 Determinants of potential nonresponders to CRT
1. Device-related nonresponders: Examples include device malfunction or poor lead positioning or integrity, inappropriate pacing settings, suboptimal atrial–ventricular timing or inadequate pacing, or complications associated with the implanted device (eg, persistent infections). 2. Substrate-related nonresponders: Examples include arrhythmia, anemia, persistent mechanical dyssynchrony, underlying narrow or non–left bundle branch block morphology QRS, primary right ventricular dysfunction, or large scar burden from ischemic cardiomyopathy. In fact, some may even benefit from switching off the coronary sinus lead because of worsening dyssynchrony. 3. Logistics-related nonresponders: Suboptimal medical therapy due to inadequate titration or dietary or medication nonadherence. 4. Medically related nonresponders: Clinical deterioration or coexisting comorbidities (eg, obesity, sleep apnea, anemia, other end-organ dysfunction, depression).
only device-related factors but also substrate-related and logistic-related factors could be identified as contributing to CRT nonresponse (Table 1).13
Cardiac imaging in optimization protocols There is an ongoing debate on whether device “optimization” for interventricular pacing intervals in patients with implanted CRT should be necessary.14 As with any intervention, the concept of optimization is good, even though it may not be necessary for all patients. However, the term “optimization” can have different meanings on several levels, and sometimes incorrect assumptions are made regarding the presence or absence of ectopic beats or lead positioning, which can lead to intrinsic errors in the delay intervals calculated by the devices. In addition, subtle changes in medications may be necessary because of overall improvement in hemodynamic reserve following CRT initiation. For example, diuretic doses may need to be reduced, and this may allow for up-titration of neurohormonal antagonists in the setting of more preserved cardiac output. The improvements seen with CRT may also mean that patients are able to tolerate higher drug doses, and this may result in further augmentation of the probability of a favorable responses to CRT.15
Potential current best practices following CRT implantation Although there have been no formal guideline recommendations regarding the integration of care regimens for CRT patients, best practice mandates should work to integrate the optimal care pathways of the EP and HF specialists. One of the most important existing gaps continues to be the lack of even the most basic data about the patient’s current device therapy at the point of care. Physicians may have to spend a great deal of time simply trying to figure out which make of device has been implanted in the patient, because most patients do not necessarily bring this information with them
to the clinic and/or they may have been referred from a clinic different from the facility where their implantation was performed. Many non-cardiologists may even fail to pay attention to whether an individual has an implanted device, let alone what it does or whether it is working properly. For patients with advanced HF who have already been enrolled in a comprehensive HF disease management program and then receive a CRT device, predischarge review and longitudinal follow-up of the appropriateness of the medical regimen are key requisites. Achieving these goals requires cross-training and integration of care plans among the specialties, plus collaborative design of treatment protocols, in order to optimize preimplant and postimplant therapy and treatment response assessment. Even without access to device interrogation data or remote monitoring portals, non–EP health care providers can perform several basic checks at the point of care, such as obtaining a careful history and examination, standard 12-lead ECG, and chest X-ray film (Table 2).16 It is important to emphasize that the indications (and potential benefits) for routine surveillance echocardiograms or echocardiographic-guided optimization following CRT implantation are still not well defined, and several protocols have been described.14 Many institutions evaluate changes in cardiac structure and function at 3 to 6 months following CRT implantation only when a patient fails to show a clinical response in order to determine whether optimization then is necessary. However, few clinics perform assessment and optimization during exercise, although careful evaluation by EP experts may identify subtle effects (eg, ectopic beats, malpositioning of the leads) that can be interfering with accurate calculation of the atrioventricular delay settings and thus explain the lack of clinical improvement.
Table 2 care
Basic checks for patients with CRT at the point of
1. Checking on lead positioning: Inspection of lead position by posteroanterior and lateral chest X-ray films is a simple way to identify potential issues related to inappropriate implantations. 2. Ruling out loss of capture or arrhythmia: Inspection of the 12-lead ECG with comparison of preimplant and postimplant ECGs allows easy identification of changes in pacing frequency as well as changes in QRS morphology and/or axis that may indicate subclinical loss of capture. Holter monitor and/or ECG also can be helpful in identifying these changes in morphology consistent with loss of capture, new-onset arrhythmic events, or adequacy of treatment. 3. Preventing phrenic nerve stimulation: Complaints of “pounding sensation” or “hiccups” may warrant further examination of the pacing threshold in relation to the phrenic and capture thresholds of the lead. 4. Health care utilization: Identification of who follows the device and who manages the medication titrations.
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HF Disease Management Using a Multispecialty Approach
Sensor technologies and CRT treatment algorithms Development of sensor technologies to ensure device integrity has evolved to the point where they can register physiological and diagnostic information that can be delivered at the point of care in a noninvasive manner and thereby assist in optimization of device function. Basic information such as heart rate, activity level, atrial or ventricular tachyarrhythmic burden, defibrillator shocks, and adequacy of biventricular pacing are readily available from almost all implanted devices. More specialized information such as heart rate variability or intrathoracic impedance is available with some devices, and other specialized implantable devices can directly measure intracardiac hemodynamic variables.17 The portals where the information from the implanted devices is delivered can also be the collection points for clinical information and measurements from external devices (eg, blood pressure and body weight).18 Access to these data remains a problem, however, in part because device interrogation is a procedure that is historically performed by EP-related health care providers, and many non–EP physicians and nurses simply do not have the appropriate access to the data (particularly with devices made in different eras and by different vendors). As a result, there is an institutional barrier to accessing the experience or knowledge on how to incorporate such information into day-to-day clinical practice. Many device-implanting physicians are EP specialists whose primary focus is the integrity of device function and optimal performance. With the more recent adoption of remote monitoring and wireless-linked devices, there is a growing trend toward reliance on remote device interrogation, which translates into fewer opportunities for direct face-to-face interactions with the patient. This promotes a shift away from attention to other potentially important aspects of care, such as optimization of medications and identifying and treating comorbid conditions. This means that many HF patients fail to achieve the maximally tolerated doses of lifesaving neurohormonal therapies or that overzealous diuretic regimens may not be adjusted following improvement in cardiac performance. Opportunities for lifestyle and dietary counseling as well as efforts to improve adherence to medical advice and medications also may be lost.
Conclusions and future directions One of the critical issues regarding implementation of any new technology is the sustainability of the long-term impact of the therapy, from the discovery of the therapy to ongoing clinical trial results, clinical experience, and continuing education. When CRT was introduced across a multicenter domain about a decade ago, there was a major emphasis on research and education for those directly involved in CRT implantation and management. Once the evidence of success of the new therapy becomes established and the tech-
S49
nology begins to be clinically adopted, there will be a cadre of physicians who can perform highly accurate or highly technically feasible implantations. At this stage in the development of CRT, however, newer concepts such as imaging of dyssynchrony or new sensor technologies for optimization of resynchronization have yet to advance beyond the experienced implantation centers or even CRT manufacturers’ research laboratories. These new concepts will require ongoing research and refinement before they can be incorporated into clinical practice, especially as part of the multidisciplinary algorithm. The term “multispecialty approach” summarizes an important departure from the traditional concept of CRT as a simple intervention to a true process of care that requires not only device implantation but also optimal comprehensive and integrated medical management before, during, and after device implantation. Simply putting different health care providers side by side will not solve the problem. To achieve a truly collaborative approach, it will be important to resolve how to use all the competencies in the field of HF therapy. This will require ownership of patient care responsibilities; understanding of the clinical, logistic, and implanted device hurdles; cooperation among health care providers; and, above all, a seamless integration of information, knowledge, and coordination of care. Although reimbursement restrictions for multiple physicians to optimize care for CRT patients may pose major hurdles for establishing such multidisciplinary clinics, it is important for health care providers to have cross-training in EP and HF disciplines and to recognize that CRT recipients do have underlying advanced HF that may warrant more periprocedural and postprocedural care. How to best achieve that has not been best evaluated. In the future, optimization of CRT may be achieved by new LV lead designs that can incorporate more automaticity, more sophisticated pacing configurations, and more integrated follow-up by enhanced telemonitoring capabilities. An understanding of the best lead positions (or even location of lead placement) coupled with optimal postprocedural management work flow should further augment what is already seen as remarkable benefit for many patients with dyssynchronous HF.
Acknowledgement Editorial assistance (referencing, production of graphics, copyediting, and proofreading) for the articles in this publication was provided by David Good, Independent Publishing Solutions, LLC, and support for this editorial assistance and for publication of this open-access article was provided by St. Jude Medical.
References 1. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853. 2. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140 –2150.
S50 3. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352: 1539 –1549. 4. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329 –1338. 5. Tang AS, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010;363:2385–2395. 6. Curtis AB, Yancy CW, Albert NM, et al. Cardiac resynchronization therapy utilization for heart failure: findings from IMPROVE HF. Am Heart J 2009; 158:956 –964. 7. Fonarow GC, Yancy CW, Hernandez AF, Peterson ED, Spertus JA, Heidenreich PA. Potential impact of optimal implementation of evidence-based heart failure therapies on mortality. Am Heart J 2011;161:1024 –1030.e1023. 8. Piccini JP, Hernandez AF, Dai D, et al. Use of cardiac resynchronization therapy in patients hospitalized with heart failure. Circulation 2008;118:926 –933. 9. Fein AS, Wang Y, Curtis JP, Masoudi FA, Varosy PD, Reynolds MR. Prevalence and predictors of off-label use of cardiac resynchronization therapy in patients enrolled in the National Cardiovascular Data Registry Implantable Cardiac-Defibrillator Registry. J Am Coll Cardiol 2010;56:766 –773. 10. Ellenbogen KA, Gold MR, Meyer TE, 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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14. 15.
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comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy. Circulation 2010; 122:2660 –2668. Auricchio A, Prinzen FW. Non-responders to cardiac resynchronization therapy: the magnitude of the problem and the issues. Circ J 2011;75:521–527. Abraham TP, Lardo AC, Kass DA. Myocardial dyssynchrony and resynchronization. Heart Fail Clin 2006;2:179 –192. Mullens W, Grimm RA, Verga T, et al. Insights from a cardiac resynchronization optimization clinic as part of a heart failure disease management program. J Am Coll Cardiol 2009;53:765–773. Mullens W, Tang WH, Grimm RA. Using echocardiography in cardiac resynchronization therapy. Am Heart J 2007;154:1011–1020. Mullens W, Kepa J, De Vusser P, et al. Importance of adjunctive heart failure optimization immediately after implantation to improve long-term outcomes with cardiac resynchronization therapy. Am J Cardiol 2011;108:409 – 415. Mullens W, Tang WH. Optimizing cardiac resynchronization therapy in advanced heart failure. Congest Heart Fail 2011;17:147–151. Samara MA, Tang WH. Device monitoring strategies in acute heart failure syndromes. Heart Fail Rev 2011;16:491–502. Saxon LA, Hayes DL, Gilliam FR, et al. Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation 2010;122:2359 –2367.
Introduction Within a decade of its development as a clinical therapy, cardiac resynchronization therapy (CRT) has seen tremendous progress in the development of supporting clinical evidence and broad clinical adoption for patients with heart failure (HF). On the one hand, randomized controlled trials have provided justification for broad adoption of CRT in a wide range of patient populations.1–5 On the other hand, CRT application strategies have been refined by better characterization of the specific subgroups that may or may not benefit from CRT. Electrophysiology (EP) specialists have refined their techniques and their knowledge base regarding strategies to maximize the application of CRT, identify appropriate disease substrates, and improve implantation techniques and pacing algorithms. Nevertheless, there remains a paucity of research efforts focusing Dr. Tang has served as an advisor or consultant for Medtronic and St. Jude Medical. Dr. Boehmer has served as an advisor or consultant for Boston Scientific; as a speaker or a member of a speakers’ bureau for Medtronic; and has received grants for clinical research from Boston Scientific. Dr. Gras has no financial relationship with industry that is applicable to this study. Address reprint requests and correspondence: Dr. W.H. Wilson Tang, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH 44195. E-mail address: [email protected].
providers or even logistical hurdles from patients. Postimplant management practices and procedures are still evolving. The important and so-far unresolved concept of the “nonresponder” to CRT remains largely subjective and is variably defined in the literature, and the lack of understanding of the underlying mechanisms of “nonresponse” continues to challenge long-term management of CRT, even given the recent developments in advanced sensor technologies. Therefore, further investigations into HF disease management with a multispecialty approach, pre-CRT and post-CRT, are warranted. KEYWORDS Cardiac resynchronization therapy; Multidisciplinary; Multispecialty approach; Nonresponder; Postimplant ABBREVIATIONS CRT ⫽ cardiac resynchronization therapy; EF ⫽ ejection fraction; EP ⫽ electrophysiology; HF ⫽ heart failure; LV ⫽ left ventricle; NYHA ⫽ New York Heart Association (Heart Rhythm 2012;9:S45–S50) © 2012 Heart Rhythm Society. All rights reserved.
on how to best apply CRT for arrhythmic HF patients as part of their overall care plans. As a result, the latest clinical guidelines have included few specific recommendations regarding how to manage patients who have received, or who are eligible to receive, CRT device implantations. The result of these uncoordinated developments is that fragmentation of care across different specialties and subspecialties is one of the major challenges to providing appropriate management of HF patients regarding CRT- and non–CRT-related issues. Beyond the physicians who are responsible for the implantation of CRT devices, many other health care providers are now intricately involved in periprocedural care, in troubleshooting device problems and/or arrhythmic complications, and in optimizing medical management. These other providers include non–EP cardiologists and other non– cardiologist physicians, as well as HF- and device-clinic nurses in clinical practices where patients are treated with CRT. Hence, although maintenance of device functionality has traditionally been the focus of postimplant care, a shift has now occurred toward understanding how different treatment teams can interact with the patient and with each other in order to optimize benefit and minimize harm.
1547-5271/$ -see front matter © 2012 Heart Rhythm Society. All rights reserved.
http://dx.doi.org/10.1016/j.hrthm.2012.04.028
S46 This article explores the necessity for, the challenges to, and the hurdles facing a multispecialty approach to the use of CRT for HF patients, particularly with regard to ● ● ●
appropriateness of patient selection consistency of adjunctive treatment protocols, and current challenges in CRT optimization. In addition, some potential best practice approaches as well as the future role of sensor technologies will be considered.
Appropriateness of patient selection Potential underutilization of CRT As a first step, identification of appropriate candidates for referral for possible CRT implantation is of utmost importance. It may seem to be a relatively straightforward concept for any health care provider to identify the inclusion and exclusion criteria as outlined in major clinical trials and summarized in clinical guideline recommendations, but in practice recognition of appropriate candidates and achievement of a recommended utilization rate for CRT are far from satisfactory. The true rate of underutilization of CRT is difficult to determine, in part due to the insufficient documentation of clinical criteria in medical records. Nevertheless, findings from several large registries have suggested that underutilization of CRT in potentially appropriate candidates definitely exists.6 – 8 Utilization varies widely among contemporary outpatient HF practices, ranging from 38.8% of eligible patients receiving a CRT pacing device to 84.1% of eligible patients receiving a CRT plus defibrillator device.6 Among patients hospitalized with HF, 4.8% of patients with left ventricular ejection fraction (LVEF) ⱕ35% were discharged with a new CRT implant (although this varied greatly by hospital), while 10% of patients discharged with a new CRT implant had LVEF ⬎35%.8 One of the primary reasons for this wide variation may be heterogeneity of expertise among practice settings and health care providers, particularly those who may (1) not be familiar with the indications for CRT; (2) not appreciate the disease severity of their patients; (3) overlook or fail to appreciate the potential benefits of an upgrade to CRT from an existing ICD, particularly if unaware of the evolving data from recent clinical trials; and (4) have misconceptions about the procedural risks and device complications, which may discourage referrals for implantation. Logistic and economic issues, as well as personal preferences, also may play a role in the record of missed opportunities. Finally, some patients may have been referred for a CRT device but may have missed the implantation opportunity for a wide variety of reasons, including delayed scheduling, financial constraints, or other logistic hurdles. All of these factors represent important practical issues that current research efforts have failed to address well. In contrast to the overall record of missed opportunities and failure to deliver appropriate CRT implantations, a substantial proportion of patients may have received CRT implantation beyond guideline-based indications. Nearly 1 in 4 patients receiving CRT devices did not meet guideline-
Heart Rhythm, Vol 9, No 8S, August Supplement 2012 based indications in a recent study,9 and it should be borne in mind that this “overreach” beyond the guideline recommended use for CRT may be contributing to the “nonresponder” rate that is an important source for current criticism of CRT.
Indication creep There are several possible explanations for this “overreach” of CRT implantations. First, there is a clear “indication creep” whenever new technologies become available for clinical use. In the case of CRT, this means that the therapy may be applied in patients who do not meet the eligibility criteria defined in the relevant clinical trial protocols. This often occurs when patients have remained symptomatic even when health care providers have already optimized medical therapy. In this case, there may be desperation from the perspectives of both patients and health care providers to offer any potential treatment that may confer the slightest chance of benefit, and patients who may not fully fit the enrollment criteria for clinical trials (eg, due to comorbidities) are nevertheless considered for CRT. This is exacerbated when a lack of communication and collaborative assessment between EP and non–EP providers is present, as this may result in patients who do not have a clear-cut indication for CRT but have a low threshold for implantation because of their symptom severity.
Implanter creep Second, there is “implanter creep,” which occurs when less experienced physicians nevertheless implant CRT devices. This inevitably results in greater complication rates and lower CRT success rates. In this scenario, implanters may have a narrow perspective that regards CRT as a procedure rather than as a comprehensive therapeutic approach that needs careful selection and adjunctive management. The evidence supporting device implantation is evolving rapidly and in many cases is very broadly defined. As a result, patients may appear to fulfill implantation criteria, yet clinically their disease may have progressed beyond the point of recovery, often with significant comorbid conditions such as end-organ dysfunction. In this situation, CRT implantation may be too late to succeed, even when it results in restoration of mechanical synchrony. Although no direct evidence supports this assertion, it is conceivable that the lack of knowledge regarding how best to manage these very sick patients following their CRT implantation may contribute to some of the “nonresponse” results.
Subjectivity of selection criteria Another issue hindering broad adoption of CRT stems from the fact that the appropriate selection criteria are far from objective, reliable, and reproducible. Two of the principal criteria, New York Heart Association (NYHA) HF functional class and LVEF, are plagued with variability. NYHA functional classification is largely self-reported and subjective, and echocardiographically derived LVEF measurements have at least a 5- to 7-point interinvestigator standard
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deviation, even with expert acquisition and interpretation. As a result, the qualities of these assessments may vary widely, depending on the expertise and specialty of health care providers and sometimes depending on specific clinical situations.
Consistency of adjunctive treatment protocols Inconsistency in postimplant care Optimal adjunctive therapy is a very important component of any surgical or interventional procedure. Nevertheless, the large majority of randomized controlled trials of CRT do not have a rigorous postimplantation schedule as part of the study protocol. Moreover, few implantation centers currently have formalized follow-up protocols specifically for patients who have received CRT devices, even if most have regular follow-up and “optimization” protocols for CRT patients who fail to exhibit robust responses. The majority of CRT centers follow the traditional approach of overnight observation following an uncomplicated device implantation, with predischarge incision site and device checks. This is usually followed by outpatient visits at 1 and 3 months, with subsequent 3-month in-person or remote follow-up visits, based mainly on self-reported symptoms, clinical evaluation, and surveillance of device functionality. However, in clinical practice, the large majority of patients do not receive the benefit of a structured postimplant optimization protocol, particularly with respect to postimplant adjustments of medications or specific follow-up procedures. On the other hand, the benefits of structured postimplant protocols have yet to be demonstrated, as the results of recent studies did not demonstrate benefit with routine optimization protocols.10 Originally, when CRT implantation was largely restricted to patients with advanced HF, often after referral by HF specialists, EP providers could rely on the HF specialists to focus on delivering postimplant care. However, with the recent trend to broader referral from non–HF health care providers, the safety net of proper prescription and dosing of evidence-based medications or nutritional or exercise counseling may be lacking. As a result, there are no doubt subsets of patients with advanced HF whose only regularly scheduled follow-up is with their EP providers, and these specialists may fail to appreciate that the underlying cardiac condition of these HF patients can benefit from medical optimization as well as lifestyle modification. Finally, some patients (even those who have been enrolled in HF disease management clinics) may be “lost” to the system when both their device checks and their HF treatment lapse due to logistic hurdles, scheduling difficulties, suboptimal medical coverage, or financial constraints.
Gaps in transition of care Several gaps in the transition of care between EP and non–EP health care providers exist and may hinder appropriate postimplant care.
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1. A large proportion of patients with HF may not have the opportunity to see a cardiologist, much less an HF or EP specialist. 2. There is an evolving knowledge gap with the rapidly evolving device technologies and the complex array of device models, all with different functionalities, due to lack of updated education and basic training on device interrogation or adequate knowledge for basic troubleshooting for non–EP providers (particularly for the noncardiologists). 3. The large majority of non–EP practice locations do not have access to any interrogation tools (even though some vendors have created point-of-care interrogation devices for such purposes). 4. There is a general lack of skills and knowledge among non–EP health care providers regarding review of device-derived diagnostic data (even when such device data may be available at the practice settings), as it has yet to be incorporated into the everyday clinical work flow.
Current challenges in optimization Defining nonresponders As with any interventions, there will be patients who respond to CRT in rigorous clinical trial protocols and others who fail to respond to CRT in “real-world” clinical experience. One of the consistently observed realities of CRT is that across all patients who receive a CRT device, only about 70% of the patients will have a therapeutic response to the device. It is an empiric reality that this “response rate” is actually quite favorable, and in fact it probably is better than that of the majority of HF therapies. However, because CRT is an expensive and invasive therapy, there is close scrutiny with regard to its cost-to-benefit or cost-effectiveness ratios. One of the complications with “success rates” for CRT concerns the wide discrepancies among clinicians regarding the definition of “nonresponder.” Broadly speaking, this stems from a division between those who identify “nonresponse” as a lack of subjective clinical improvement (eg, functional capacity or self-reported symptom levels or health status) vs others who define “nonresponse” as a lack of objective improvement in cardiac structure or function (often identified by serial imaging techniques).11 This variability in criteria and findings has impeded consensus as to how best to define the subsets of patients who may or may not respond to CRT. Early attempts to identify objective criteria for “nonresponse” focused on detecting underlying mechanical (either intraventricular or interventricular) dyssynchrony. This appears to be a logical definition of the intended benefits of CRT because inadequate resynchronization (or an absence of underlying dyssynchrony) may lead directly to a lack of intended benefits following CRT.12 In a prospective series of HF patients who failed to show evidence of either clinical and/or echocardiographic responses after at least 3 months of follow-up post-CRT implantation, it was found that not
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Heart Rhythm, Vol 9, No 8S, August Supplement 2012 Determinants of potential nonresponders to CRT
1. Device-related nonresponders: Examples include device malfunction or poor lead positioning or integrity, inappropriate pacing settings, suboptimal atrial–ventricular timing or inadequate pacing, or complications associated with the implanted device (eg, persistent infections). 2. Substrate-related nonresponders: Examples include arrhythmia, anemia, persistent mechanical dyssynchrony, underlying narrow or non–left bundle branch block morphology QRS, primary right ventricular dysfunction, or large scar burden from ischemic cardiomyopathy. In fact, some may even benefit from switching off the coronary sinus lead because of worsening dyssynchrony. 3. Logistics-related nonresponders: Suboptimal medical therapy due to inadequate titration or dietary or medication nonadherence. 4. Medically related nonresponders: Clinical deterioration or coexisting comorbidities (eg, obesity, sleep apnea, anemia, other end-organ dysfunction, depression).
only device-related factors but also substrate-related and logistic-related factors could be identified as contributing to CRT nonresponse (Table 1).13
Cardiac imaging in optimization protocols There is an ongoing debate on whether device “optimization” for interventricular pacing intervals in patients with implanted CRT should be necessary.14 As with any intervention, the concept of optimization is good, even though it may not be necessary for all patients. However, the term “optimization” can have different meanings on several levels, and sometimes incorrect assumptions are made regarding the presence or absence of ectopic beats or lead positioning, which can lead to intrinsic errors in the delay intervals calculated by the devices. In addition, subtle changes in medications may be necessary because of overall improvement in hemodynamic reserve following CRT initiation. For example, diuretic doses may need to be reduced, and this may allow for up-titration of neurohormonal antagonists in the setting of more preserved cardiac output. The improvements seen with CRT may also mean that patients are able to tolerate higher drug doses, and this may result in further augmentation of the probability of a favorable responses to CRT.15
Potential current best practices following CRT implantation Although there have been no formal guideline recommendations regarding the integration of care regimens for CRT patients, best practice mandates should work to integrate the optimal care pathways of the EP and HF specialists. One of the most important existing gaps continues to be the lack of even the most basic data about the patient’s current device therapy at the point of care. Physicians may have to spend a great deal of time simply trying to figure out which make of device has been implanted in the patient, because most patients do not necessarily bring this information with them
to the clinic and/or they may have been referred from a clinic different from the facility where their implantation was performed. Many non-cardiologists may even fail to pay attention to whether an individual has an implanted device, let alone what it does or whether it is working properly. For patients with advanced HF who have already been enrolled in a comprehensive HF disease management program and then receive a CRT device, predischarge review and longitudinal follow-up of the appropriateness of the medical regimen are key requisites. Achieving these goals requires cross-training and integration of care plans among the specialties, plus collaborative design of treatment protocols, in order to optimize preimplant and postimplant therapy and treatment response assessment. Even without access to device interrogation data or remote monitoring portals, non–EP health care providers can perform several basic checks at the point of care, such as obtaining a careful history and examination, standard 12-lead ECG, and chest X-ray film (Table 2).16 It is important to emphasize that the indications (and potential benefits) for routine surveillance echocardiograms or echocardiographic-guided optimization following CRT implantation are still not well defined, and several protocols have been described.14 Many institutions evaluate changes in cardiac structure and function at 3 to 6 months following CRT implantation only when a patient fails to show a clinical response in order to determine whether optimization then is necessary. However, few clinics perform assessment and optimization during exercise, although careful evaluation by EP experts may identify subtle effects (eg, ectopic beats, malpositioning of the leads) that can be interfering with accurate calculation of the atrioventricular delay settings and thus explain the lack of clinical improvement.
Table 2 care
Basic checks for patients with CRT at the point of
1. Checking on lead positioning: Inspection of lead position by posteroanterior and lateral chest X-ray films is a simple way to identify potential issues related to inappropriate implantations. 2. Ruling out loss of capture or arrhythmia: Inspection of the 12-lead ECG with comparison of preimplant and postimplant ECGs allows easy identification of changes in pacing frequency as well as changes in QRS morphology and/or axis that may indicate subclinical loss of capture. Holter monitor and/or ECG also can be helpful in identifying these changes in morphology consistent with loss of capture, new-onset arrhythmic events, or adequacy of treatment. 3. Preventing phrenic nerve stimulation: Complaints of “pounding sensation” or “hiccups” may warrant further examination of the pacing threshold in relation to the phrenic and capture thresholds of the lead. 4. Health care utilization: Identification of who follows the device and who manages the medication titrations.
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Sensor technologies and CRT treatment algorithms Development of sensor technologies to ensure device integrity has evolved to the point where they can register physiological and diagnostic information that can be delivered at the point of care in a noninvasive manner and thereby assist in optimization of device function. Basic information such as heart rate, activity level, atrial or ventricular tachyarrhythmic burden, defibrillator shocks, and adequacy of biventricular pacing are readily available from almost all implanted devices. More specialized information such as heart rate variability or intrathoracic impedance is available with some devices, and other specialized implantable devices can directly measure intracardiac hemodynamic variables.17 The portals where the information from the implanted devices is delivered can also be the collection points for clinical information and measurements from external devices (eg, blood pressure and body weight).18 Access to these data remains a problem, however, in part because device interrogation is a procedure that is historically performed by EP-related health care providers, and many non–EP physicians and nurses simply do not have the appropriate access to the data (particularly with devices made in different eras and by different vendors). As a result, there is an institutional barrier to accessing the experience or knowledge on how to incorporate such information into day-to-day clinical practice. Many device-implanting physicians are EP specialists whose primary focus is the integrity of device function and optimal performance. With the more recent adoption of remote monitoring and wireless-linked devices, there is a growing trend toward reliance on remote device interrogation, which translates into fewer opportunities for direct face-to-face interactions with the patient. This promotes a shift away from attention to other potentially important aspects of care, such as optimization of medications and identifying and treating comorbid conditions. This means that many HF patients fail to achieve the maximally tolerated doses of lifesaving neurohormonal therapies or that overzealous diuretic regimens may not be adjusted following improvement in cardiac performance. Opportunities for lifestyle and dietary counseling as well as efforts to improve adherence to medical advice and medications also may be lost.
Conclusions and future directions One of the critical issues regarding implementation of any new technology is the sustainability of the long-term impact of the therapy, from the discovery of the therapy to ongoing clinical trial results, clinical experience, and continuing education. When CRT was introduced across a multicenter domain about a decade ago, there was a major emphasis on research and education for those directly involved in CRT implantation and management. Once the evidence of success of the new therapy becomes established and the tech-
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nology begins to be clinically adopted, there will be a cadre of physicians who can perform highly accurate or highly technically feasible implantations. At this stage in the development of CRT, however, newer concepts such as imaging of dyssynchrony or new sensor technologies for optimization of resynchronization have yet to advance beyond the experienced implantation centers or even CRT manufacturers’ research laboratories. These new concepts will require ongoing research and refinement before they can be incorporated into clinical practice, especially as part of the multidisciplinary algorithm. The term “multispecialty approach” summarizes an important departure from the traditional concept of CRT as a simple intervention to a true process of care that requires not only device implantation but also optimal comprehensive and integrated medical management before, during, and after device implantation. Simply putting different health care providers side by side will not solve the problem. To achieve a truly collaborative approach, it will be important to resolve how to use all the competencies in the field of HF therapy. This will require ownership of patient care responsibilities; understanding of the clinical, logistic, and implanted device hurdles; cooperation among health care providers; and, above all, a seamless integration of information, knowledge, and coordination of care. Although reimbursement restrictions for multiple physicians to optimize care for CRT patients may pose major hurdles for establishing such multidisciplinary clinics, it is important for health care providers to have cross-training in EP and HF disciplines and to recognize that CRT recipients do have underlying advanced HF that may warrant more periprocedural and postprocedural care. How to best achieve that has not been best evaluated. In the future, optimization of CRT may be achieved by new LV lead designs that can incorporate more automaticity, more sophisticated pacing configurations, and more integrated follow-up by enhanced telemonitoring capabilities. An understanding of the best lead positions (or even location of lead placement) coupled with optimal postprocedural management work flow should further augment what is already seen as remarkable benefit for many patients with dyssynchronous HF.
Acknowledgement Editorial assistance (referencing, production of graphics, copyediting, and proofreading) for the articles in this publication was provided by David Good, Independent Publishing Solutions, LLC, and support for this editorial assistance and for publication of this open-access article was provided by St. Jude Medical.
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