Journal of the American College of Cardiology © 2009 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
DAVID II Did Not Slay Goliath* Brian Olshansky, MD, FACC, Rakesh Gopinathannair, MD, MA, Renee M. Sullivan, MD Iowa City, Iowa
The DAVID II (Dual Chamber and VVI Implantable Defibrillator II) trial tested two bradycardia programming modalities for a population of patients who received dualchamber implantable cardioverter-defibrillators (ICDs) but had no clear indication for pacing. Two key questions arise when one considers the findings of this trial: Was there really a need to perform this study? Does it affect everyday clinical practice? The role of ICDs in improving the survival of patients with heart disease at risk of sudden death is well established (1), but modern devices do more than just defibrillate. Of the vast array of sophisticated programming possibilities (2), pacing options can mitigate bradycardia, chronotropic incompetence, episodic asystole and atrioventricular (AV) block should they develop (3), as they often do (4 – 6). However, dual chamber pacing for these and other soft indications may lead to adverse outcomes (7). See page 872
Some who implant ICDs attempt to tailor bradycardia programming based on clinical characteristics specific to each patient (8) or use strategic algorithms (9). Others simply ignore the issue completely and implant devices “out of the box” with default settings. Some advocate single chamber ICDs (10); others prefer dual chamber devices. In the U.S., dual chamber devices are implanted more commonly than single chamber devices (62% vs. 38%) (11) for several reasons (12,13). Nevertheless, the debate over optimal device type and mode of operation continues today (14). The DAVID trial investigators cast the first stone against dual chamber programming when they showed that patients who had programmed dual chamber rate responsive pacing
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the University of Iowa Hospitals and Clinics, Iowa City, Iowa. Dr. Olshansky has received honoraria and/or has engaged in consulting relationships with Boston Scientific, Medtronic, St. Jude, Novartis, Baxter, Reliant, and Biocontrol.
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at 70 beats/min (DDDR-70) had significantly greater risk of heart failure hospitalization and/or death compared with patients who had programmed single chamber pacing at 40 beats/min (VVI-40) (15). Right ventricular pacing in the DDDR arm (mean right ventricular [RV] pacing ⬎50%), not present in the VVI arm (mean RV pacing ⬍4%), explained these differences in outcomes (15,16). The DAVID trial taught us that excessive amounts of RV pacing can be harmful. Few dispute this finding, but some believe it is unproven (17). In any case, dual chamber programming has been maligned (18). Other trials are challenging (19) or have challenged the purported adverse impact of dual chamber programming (8,20). The INTRINSIC RV (Inhibition of Unnecessary RV Pacing With AVSH in ICDs) trial showed no harm, and even showed a trend toward benefit, with dual chamber programming (DDDR-60 to -130) compared with ventricular pacing alone (VVI-40) (20). In the INTRINSIC RV trial, dual chamber programming included the use of AV search hysteresis to reduce the percentage of RV pacing. The discrepancy between the INTRINSIC RV study and the DAVID trial results are explained readily by differences in RV pacing in the dual chamber arms (a mean of 10% in the INTRINSIC RV study compared with a mean ⬎50% in the DAVID trial). An INTRINSIC RV trial subanalysis showed that the lowest rates of events occurred with RV pacing between 10% and 20% (21). Some ventricular pacing was not harmful. A DAVID trial subanalysis showed that some ventricular pacing (⬍40%) did not appear to be detrimental (22). Hence, both trials indicated that some degree of RV pacing could be permissible and may even be beneficial for patients with ICDs. The purpose of the DAVID II trial was to identify whether atrial pacing contributed to the adverse outcomes observed in the DDDR arm of the DAVID trial and to determine if AAI pacing is a viable and safe bradycardia pacing mode in ICD recipients (17). The DAVID II trial showed that atrial-based, nonrate responsive, AAI-70 pacing is not harmful compared with VVI-40 pacing (17), but the clinical importance of this finding is questionable. Fixed-rate, atrial-based pacing is rarely used in the ICD population—for good reason. Recipients of an ICD have a ventricular lead that can defibrillate and pace as necessary. Unless it causes harm, it does not make practical sense to disable the pacing function of this lead. Proper dual chamber programming can limit excessive RV pacing but still provide backup pacing should it be needed. The AAI-70 pacing is not a pacing modality of choice and will not be used commonly in patients who have ICDs. This programming option does not ensure ventricular pacing if needed, does not ensure optimal AV synchrony, does not provide rate response, and paces too fast at night. The patient who has an indication for an ICD and no firm indication for pacing at implant still may benefit from
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some pacing, including ventricular pacing, at a future date. Progressive His-Purkinje, AV nodal, or sinus node disease may occur. Up-titration of drugs that slow rate, such as beta-blockers, the cornerstone of heart failure therapy, is within the realm of possibility. The ICD, implanted in the first place to prevent arrhythmic death, can treat bradyarrhythmias, including AV block, effectively as well. Why add risk by not providing adequate backup, knowing full well that an option to prevent such a catastrophe is possible? In the DAVID II trial, atrial pacing at 70 beats/min would not be expected to have much effect, since the average heart rate approached 70 beats/min at study initiation anyway. Ironically, atrial rate is not discussed in much detail in the DAVID II trial, but heart rate is important to understand a key message from this trial and that relates to the influence of heart rate on outcomes. Presumably, the higher heart rate observed in the AAI versus the VVI arm (73 ⫾ 6 beats/min vs. 65 ⫾ 12 beats/min) at 24 months was due to atrial pacing. The high percent of atrial pacing (nearly 50%) in the AAI arm may be due to unnecessary nighttime pacing, but the time course of pacing is unknown. Atrial pacing during sleep may affect quality of life and even ventricular function adversely over time, particularly at faster rates (23,24). Perhaps that is why the quality-of-life data in the DAVID II trial seem counter to expectations. The Short Form-36 Health Survey physical subscale, evaluating change from baseline to 6 months, showed greater improvement in the VVI-40 compared with the AAI-70 arm, whereas 57% of those reporting better health between 3 and 6 months were in the AAI arm. It is not clear what these measures actually mean, if anything. Increasing atrial rate to 70 beats/min with pacing did not influence outcomes. This is the most interesting aspect of the study. Intrinsic mean heart rate is a potent predictor of outcomes in many populations (25–31), including patients with ICDs (32). The reasons for this are uncertain, but several mechanisms have been postulated, including the direct effect of heart rate itself. Alternatively, intrinsic heart rate may indicate differences in autonomic tone (33,34). The DAVID II trial, in a sense, is consistent with the BEAUTIFUL (Morbidity–Mortality Evaluation of the If Inhibitor Ivabradine in Patients with Coronary Disease and Left-Ventricular Dysfunction) trial (35). In the BEAUTIFUL study, while the intrinsic rate was an important indicator of outcomes (28), modifying the rate, and nothing else, as in the DAVID II trial (but in the opposite direction), does not affect outcomes (35). The DAVID II trial showed no harm from atrial-based pacing in the normal range, but it did not indicate that rate-responsive atrial-based pacing, potentially useful in patients with chronotropic incompetence, is safe. Theoretically, atrial pacing could improve medication management, especially beta-blocker dose optimization. Doses in excess of what the sinus node can bear, but allowable with proper atrial pacing, may have survival advantages. Betablocker dosing may only be linked loosely to, and independent
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from, rate effects. This concept, while provocative, was not tested. The DAVID II trial design had some weaknesses. Data from other ICD trials seem to indicate that most clinically significant events occur early after randomization (8). Therefore, patients from the DAVID trial, re-randomized into the DAVID II trial, pose a unique problem. Although these patients may represent a high-risk group, they had not undergone recent ICD implantation. Their outcomes may not represent those expected for newly implanted ICD patients. These patients likely represent a population with less fulminant disease compared with patients who had already reached the primary end point of the DAVID trial. A disconcerting issue is that 42 of the 600 patients in the DAVID II trial were reprogrammed in a dual chamber pacing mode for unclear reasons. If AV block were the cause that would be of major concern. Atrial pacing may be a “safe alternative” only for those who did not undergo ICD reprogramming. Finally, the DAVID II trial patients could undergo remote monitoring after the 6-month follow-up visit. It is unclear if there is a difference in heart failure hospitalizations or death in these patients compared with those who continue with in-person monitoring. Ultimately, the DAVID II trial seemed unnecessary before it began. What is the value of pacing the atria or ventricles without reason? Specifically, what is the benefit of pacing in AAI mode? How do the data help to manage patients? While the investigators assert that the DAVID II trial may explain the outcomes of the DAVID trial, the reason for the outcome of the DAVID trial seems selfevident. The most important and interesting clinical information was not related to the investigators’ purpose in doing this study. The stated focus is self-serving: to better understand the DAVID trial outcomes, not to improve patient care. It is highly unlikely that an implanting physician in the real world, based on the demonstrated noninferiority in the DAVID II trial, will choose AAI-70 programming in a dual chamber ICD. Whereas the DAVID trial cast the first stone against dual chamber ICD programming, its brother, the DAVID II trial, appears to have missed the shot at conquering the substantial challenges, the proverbial Goliath, that remain in our understanding of the best method for programming ICDs to protect against bradycardia and to ultimately optimize outcomes for our patients. Reprint requests and correspondence: Dr. Brian Olshansky, University of Iowa Hospital, 200 Hawkins Drive, 4426a JCP, Iowa City, Iowa 52242. E-mail:
[email protected].
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