Clinical Investigations

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1 Clinical Investigations Natural History and Implantable Cardioverter-Defibrillator Implantation After Revascularization for Stable Coronary Artery Disease With Depressed Ejection Fraction Address for correspondence: Daniel P. Morin, MD 1514 Jefferson Highway New Orleans, LA Geoffrey F. Lewis, MD; Adam C. Harless, MD; Lauren Vazquez, PhD; Freddy M. Abi-Samra, MD; Michael L. Bernard, MD, PhD; Sammy Khatib, MD; Glenn M. Polin, MD; Daniel P. Morin, MD, MPH John Ochsner Heart and Vascular Institute (Lewis, Harless, Abi-Samra, Bernard, Khatib, Polin, Morin), Ochsner Medical Center, New Orleans, Louisiana; Department of Psychiatry (Vazquez), Ochsner Medical Center, New Orleans, Louisiana; Ochsner Clinical School (Morin), Queensland University School of Medicine, Ochsner Clinic Foundation, New Orleans, Louisiana Background: Following revascularization, most payors require 3 months of medical therapy, followed by left ventricular ejection fraction (LVEF) reassessment, before implantable cardioverter-defibrillator (ICD) implantation possibly contributing to incomplete follow-up and suboptimal utilization of ICD therapy. The natural history of these patients, and their fate regarding ICD implantation, is unknown. Hypothesis: We hypothesized that a waiting period after revascularization for stable CAD results in missed opportunities to provide care with regard to ICD implantation. Methods: We followed patients with LVEF 35% and no ICD who underwent revascularization (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI]) for stable CAD. Follow-up used chart review and scripted telephone interviews. Results: Among 3164 revascularized patients (2198 [69%] PCI, 966 [31%] CABG), only 62 (2%; 33 [53%] male, age 67 ± 12 y, LVEF 28% ± 6%) had stable CAD, depressed LVEF, and no ICD. Over 35 ± 19 months, 35 (56%) of these 62 patients were no longer candidates for ICD based on improved LVEF, 14 (23%) received an ICD, 5 (8%) declined ICD despite physician recommendation, 3 (5%) were not offered ICD despite continued eligibility, 2 (3%) died, 1 (2%) was not a candidate due to substance abuse, and 1 (2%) had ICD implantation temporarily deferred. Only 1 (2%) was lost to follow-up. Conclusions: Following revascularization for stable CAD with depressed LVEF, 50% of patients ventricular function improved enough to make ICD implantation unnecessary. A waiting period after revascularization prior to ICD implantation appears appropriate and does not significantly negatively impact follow-up or the rate of appropriate ICD implantation. L. Vazquez reports serving on the speakers bureau for Boston Scientific, Medtronic, and St. Jude Medical. F.M. Abi-Samra reports serving on the speakers bureau for Sorin and receiving fellowship support from Biotronik. S. Khatib reports serving on the speakers bureau for Medtronic and St. Jude Medical. G.M. Polin reports serving on the speakers bureau for Medtronic. D.P. Morin reports receiving research grants from Boston Scientific and Medtronic and serving on the speakers bureau for Cardionet, Biotronik, Boehringer Ingelheim, Boston Scientific, Medtronic, St. Jude Medical, and Zoll. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Received: March 16, 2015 Accepted with revision: September 3, 2015 Introduction Patients with moderate to severe systolic congestive heart failure are at risk for sudden cardiac death due to ventricular tachyarrhythmia. Previous trials have demonstrated a mortality benefit from implantable cardioverter-defibrillator (ICD) implantation for primary prevention of sudden cardiac death among patients with coronary artery disease (CAD) and a depressed left ventricular ejection fraction (LVEF). 1,2 However, the benefit of ICD therapy can be significantly lower depending on patient medical history. In particular, recent coronary ischemia and/or revascularization has been shown to adversely affect ICDs ability to extend life. For example, the Coronary Artery Bypass Graft Patch (CABG-Patch) trial failed to demonstrate survival benefit from routine ICD implantation in patients with LVEF <35% following surgical revascularization. 3 Similarly, 715 DOI: /clc Wiley Periodicals, Inc.

2 the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT) and Immediate Risk Stratification Improves Survival (IRIS) trials showed no benefit to ICD implantation in the weeks following myocardial infarction (MI). 1,4 Based on these results, current American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society guidelines call for a waiting period of 40 days after MI if revascularization is not performed, followed by reassessment of LVEF for improvement. 5 If revascularization is performed, Centers for Medicare & Medicaid Services regulations extend this waiting period to 3 months. A 3-month wait also is required for patients who have not suffered a recent MI but who are revascularized for stable CAD with a depressed LVEF. These recommendations largely are derived from the results of the Multicenter Automatic Defibrillator Implantation Trial (MADIT) and MADIT II studies, which used revascularization within 3 months as an exclusion criterion. 1,6 Within the cardiac electrophysiology community, there is a prevailing sense that many patients may be lost to followup during the 3-month postrevascularization waiting period, creating a significant unrealized opportunity to provide needed care. To our knowledge, there are no published data regarding the magnitude of this opportunity: that is, the number of postrevascularization patients who would meet criteria for ICD implantation but do not ultimately receive one. Recovery of left ventricular (LV) function following acute MI, with or without revascularization, has been described and currently is being studied elsewhere. 7,8 We sought to determine the natural history of LVEF recovery following revascularization for stable CAD with an initially depressed LVEF, as well as the number of patients who later did not receive ICDs despite meeting criteria for implantation. Methods The Ochsner Medical Center Institutional Review Board approved the study procedure. The study consisted of a chart review with scripted patient interviews performed when additional information was necessary. First, a query of the electronic medical record at the Ochsner Clinic Foundation system of hospitals identified patients meeting inclusion criteria during the years 2008 to To be included in our study, patients must have had LVEF 35% (as measured by echocardiography, angiography, or nuclear scanning) and obstructive CAD on nonemergent angiography, receiving subsequent revascularization with percutaneous coronary intervention (PCI) or CABG. Additional inclusion criteria included age 18 years and lack of ICD in situ. We excluded patients with an acute coronary syndrome (ACS) indication for the index revascularization, life expectancy <1 year due to medical conditions besides CAD and/or cardiomyopathy, or any other sustained contraindication to ICD therapy. A history of prior MI was not a reason for exclusion. Chart review was performed to determine the natural history of LVEF recovery after revascularization. Additionally, the ICD status of patients was determined (ie, implanted, not implanted, or ineligible). For those patients who did not receive ICDs despite continued apparent eligibility, we attempted to identify the reason for lack of ICD implantation. In cases in which information available in the medical record was inadequate, scripted telephone interviews were performed with patients and/or their family members to determine ICD status, current clinical condition, what (if any) follow-up occurred after revascularization, and specific reasons for lack of ICD implantation. Information regarding demographics and other patient characteristics, including comorbidities, was also collected by chart review. Significant valvular disease was defined as severe aortic stenosis, severe mitral regurgitation, and/or a history of valve replacement or repair. Cerebrovascular disease was defined as a history of cerebrovascular accident or transient ischemic attack. Patients with cancer had a history of or active diagnosis of cancer. Other comorbidities were identified as present or absent based on past medical history recorded in our electronic medical record. Results We identified 3164 patients who underwent revascularization during the study period. Of these, 2198 (69%) had PCI and 966 (31%) had CABG. For one or more reasons, 3102 (98%) patients receiving revascularization did not meet inclusion criteria: 1068 (34%) had ACS as the indication for revascularization (ie, their CAD was not stable ), 2722 (86%) had LVEF >35%, and 64 (2%) already had an ICD in place. We performed detailed follow-up on the 62 patients (2% of all patients receiving revascularization) who had stable CAD, depressed LVEF 35%, and no ICD at baseline. All but 2 patients, both of whom died (see below), had 1 post-revascularization assessment of LVEF. These patients had the following baseline characteristics (mean ± SD): 33 (53%) were male, age 67 ± 12 years, LVEF 28% ± 6% (Table 1). Baseline LVEF was determined by echocardiography in 50 patients, left ventriculogram in 6, and nuclear imaging in 6. The majority of patients were well treated with guidelinedirected medical therapy for ischemic cardiomyopathy (Table 2). The median duration of clinical follow-up was 35 months (interquartile range [IQR], months), which included time to disqualifying LVEF assessment or last patient contact. As this was a retrospective chart review, there was no standardization of follow-up LVEF assessment at 3 months after revascularization, as would have been ideal. In all patients, echocardiography was used for repeat LVEF assessment. The median time to follow-up echocardiogram was 4 months (IQR, 3 6 months). Following revascularization, the population s average increase in LVEF was 11% ± 13%, resulting in average LVEF of 39% ± 13%. At follow-up, 42/62 (68%) showed improvement in LVEF, 11 (18%) demonstrated no change as defined by < ±5% absolute change in LVEF, and 9 (15%) had a decline in LVEF. Patients underwent a median of 2 (IQR, 2 4) postrevascularization assessments of LVEF. Only 14 (23%) of the 62 initially ICD-eligible patients received an ICD (Figure 1). Thirty-five of the 62 (56%) were no longer candidates for ICD based on improvement in LVEF to >35%. Among these 35 patients, the median time to echocardiographic detection of LVEF 35% was 5 months (IQR, 4 14 months). 716

3 Table 1. Clinical Characteristics of the Studied Population of Patients With Stable CAD and Depressed LVEF (N = 62) Baseline Clinical Characteristics (N = 62) Age, y 67 ± 12 Male sex 33 (53) LVEF, % 28 ± 6 CABG 45 (73) PCI 17 (27) Never smoker 26 (42) Black race 10 (16) BMI, kg/m 2 30 ± 6 SBP, mm Hg 128 ± 21 DBP, mm Hg 72 ± 13 Cr, mg/dl 1.4 ± 1.4 DM 30 (48) Valvular disease 14 (23) Cerebrovascular disease 13 (21) COPD 4 (6) Cancer 3 (5) ESRD 3 (5) Baseline NYHA class 2.1 ± 0.8 I 14(23) II 32 (52) III 14 (23) IV 2 (3) Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; CABG, coronary artery bypass grafting; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; Cr, creatinine; DBP, diastolic blood pressure; DM, diabetes mellitus; ESRD, end-stage renal disease; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; SBP, systolic blood pressure. Data are presented as n (%) or mean ± SD. The remaining 13 patients (21%) did not receive ICDs for the following reasons: 5 (8%) declined ICD despite physician recommendation, 3 (5%) were not offered ICD despite continued eligibility, 2 (3%) died, 1 (2%) was not a candidate due to ongoing substance abuse, and 1 (2%) ICD implantation was temporarily deferred due to need for other medical procedures first. Only 1 (2%) had no available follow-up information. Five patients, representing 8% of the total subject population, declined ICD implantation despite physician recommendation. Of these patients, various reasons were given for declining recommended therapy. In each of these cases, the patient reported that their physician had adequately explained the risks and benefits of ICD implantation prior to their refusal. Table 2. Heart Failure Symptom Severity and Medication Use at Follow-Up All Patients, N = 62 Patients with LVEF 35% at Follow-up, N = 28 Follow-up NYHA class 1.6 ± ± 0.8 I 35(56) 11(39) II 17 (27) 10 (36) III 9 (15) 7 (25) IV 1(2) 0(0) Medication use at follow-up β-blocker 61 (98) 28 (100) ACEI/ARB 57 (92) 23 (82) Statin 59 (95) 27 (96) Clopidogrel 34 (55) 11 (39) Aspirin 59 (95) 28 (100) Spironolactone 7 (11) 4 (14) Digoxin 5 (8) 3 (11) Hydralazine 1 (2) 1 (4) Nitrate 2 (3) 2 (7) Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association. Data are presented as n (%) unless otherwise noted. Neither of the 2 postrevascularization deaths could be directly attributed to lack of ICD therapy. One of these patients had been evaluated for a heart/kidney transplant, and after learning of transplant ineligibility, he elected to discontinue dialysis treatment, expiring thereafter. In such a situation, the patient would not have been a candidate for ICD therapy, based on a short life expectancy. The cause of the other death could not be determined; only an obituary was available. No further information regarding the patient s death could be determined from chart review, and no surviving family members could be located. A single patient deferred ICD implantation due to need for other invasive procedures. This patient was appropriately referred to and evaluated by an electrophysiologist, but due to need for gallbladder and prostate surgeries, the patient elected to delay ICD implantation. Follow-up was scheduled with an electrophysiologist but had not yet occurred by the end of our study period. There was no difference in LVEF response according to method of revascularization, with similar proportions of CABG patients and PCI patients demonstrating postrevascularization improvement to >35% (56% and 59%, respectively; P = 0.82). Similarly, recovery of LV function after revascularization was not predicted by age at revascularization, race, body mass index, surgical vs percutaneous revascularization, number of vessels revascularized, revascularization in the left anterior descending coronary artery territory, comorbidities (diabetes mellitus, chronic 717

4 Figure 1. ICD-related status on follow-up of patients who underwent revascularization for stable CAD and depressed LV systolic function. Abbreviations: CAD, coronary artery disease; EF, ejection fraction; ICD, implantable cardioverter-defibrillator; LV, left ventricular. obstructive pulmonary disease, cerebrovascular disease, or valvular disease), creatinine clearance, or method of prerevascularization LVEF assessment (all P = ). Societal guidelines regarding ICD therapy for primary prophylaxis take into account both LVEF and New York Heart Association (NYHA) class. 5 Although patients with ischemic cardiomyopathy in all NYHA classes may be suitable for ICD therapy, this is limited to those with LVEF 30% in NYHA class I, or those with LVEF 35% in NYHA class II or III. As seen in Table 2, most patients in our study were in NYHA class 2, and this included all patients whose LVEF measured 31% to 35% on follow-up. Discussion In this investigation, our interest was in examining patients presenting with stable CAD and depressed LV systolic function, because this specific population s natural history was previously unknown. We excluded patients presenting with ACS and/or acute MI because ICD use in the post- ACS/post-MI population both has been studied previously and is the subject of ongoing research. 4,7,8 Our investigation has several important findings. Among patients presenting with depressed LVEF ( 35%) and stable CAD requiring revascularization, the majority received guideline-supported care with regard to ICD implantation. More than half (56%) experienced improvement in LVEF sufficient to render ICD implantation nonindicated. An additional 23% did go on to have ICDs implanted as supported by guidelines. Among the 13 patients (21%) who did not receive an ICD despite persistently depressed LVEF, 10 of 13 (77%) had been offered or appropriately considered for ICD implantation. Only 3 of the original 62 patients (5%) potentially received suboptimal care in terms of guidelinedirected referral for ICD implantation. One objective of this study was to determine what impact, if any, the currently recommended waiting period after revascularization may have on follow-up regarding ICD eligibility, and thereby on ICD implantation rates. Our investigation revealed that only 3 (5%) patients were not offered an ICD or referred to an electrophysiologist despite continued eligibility. We are unaware of any study that provides a direct comparison to our patient population regarding this surprisingly low rate of missed potential implants. However, a recent review of the Oregon Sudden Cardiac Arrest Study data highlights one example of low ICD implantation rates in other patient populations. Their retrospective population-based evaluation found that only 13% of previously ICD-eligible individuals who suffered sudden cardiac arrest had received ICD therapy for primary prevention. 9 The experience in our study demonstrates that although the allocation of ICD therapy may be far from perfect for the population at large, ICD use is more efficient in the higher-risk population of known CAD and persistently depressed LVEF. The other major objective of our study was to observe the natural history of LVEF improvement following revascularization. Our study suggests that the majority of patients with obstructive but stable CAD and an initially depressed LVEF experience significant improvement in LVEF following revascularization, and thus that a waiting period of some duration is indeed appropriate to prevent unnecessary ICD implantation. Although no prior studies specifically examined the effects on LVEF after revascularization for stable CAD with a depressed LVEF, some related data have been published regarding LVEF improvement in ischemic cardiomyopathy in general. The most similar to our patient population was published in 2004 by Bax et al, demonstrating an improvement in LVEF of 5% in only 27 of 74 (36%) patients presenting with LVEF <35% who subsequently underwent CABG. 10 Of note, it was not specified how many of these patients initially presented with ACS or MI. Yang et al, however, 718

5 demonstrated an absolute LVEF improvement of 5% in 32 of 52 (62%) patients with depressed LVEF after CABG, though only 58% of these patients had initial LVEF <35%. 11 Conflicting information in a similar population of patients with a depressed LVEF showed clinically significant LVEF improvement (again defined as a 5% increase) in only 39% of patients, and an average absolute improvement of only 3% (baseline 29 ± 7%, 32 ± 9% post-revascularization). 12 Of note, all these previously published data regarding LVEF response to revascularization refer to patients undergoing surgical revascularization. Although our study includes patients revascularized by both PCI and CABG, we did not find a significant difference in improvement in LVEF between these 2 groups. Our results also are in contrast to the findings of the DINAMIT trial, in which the subgroup with repeat LVEF assessment 6 to 8 weeks after acute MI showed minimal average absolute improvement in LVEF (2% ± 11% above a baseline mean of 28%). 4 A potential explanation for the discrepancy in LVEF recovery between DINAMIT and our own study is that patients with stable CAD may have hibernating myocardium that recovers more robustly following revascularization, as compared with patients who suffer irreversible myocardial damage from acute MI. In support of this hypothesis, the Bax study referenced above showed that among 44 patients with substantial viability on nuclear metabolic imaging prior to revascularization, 55% had LVEF improvement 5% after revascularization, compared with only 11% among patients with nonviable myocardium. 10 Our study also failed to identify any patient factors that might predict improvement in LVEF. Examination of a larger patient population might be necessary to achieve statistical significance in this area. Finally, the low rate of eligible patients not being offered an ICD suggests that a waiting period does not significantly negatively impact appropriate cardiology follow-up nor ICD implantation rates in this population. A prospective trial utilizing strictly standardized timing of post-revascularization reassessment of LVEF, perhaps at intervals of 1, 3, and 6 months, would be of interest. Study Limitations This is a retrospective, single-center study and is subject to the limitations inherent to all such analyses. Because only a small proportion of all revascularized patients met our fairly strict inclusion criteria of stable CAD, LVEF 35%, and no ICD at baseline, the available population meeting those criteria was small. Although the small size of this population subset was itself one interesting finding of our study, outliers could have skewed the results. However, our overall population represents a large real-world cohort with characteristics typically seen in clinical practice. Conclusions Among patients presenting with depressed LVEF ( 35%) and stable CAD undergoing revascularization, the vast majority received appropriate subsequent care with regard to ICD implantation. More than half had improvement in LVEF to >35%, thus obviating the need for ICD, and 23% had ICDs implanted appropriately. Among patients who did not receive ICDs despite continued eligibility, only a small minority were not offered ICD or referred to an electrophysiologist. In these patients, a waiting period after revascularization prior to ICD implantation is appropriate to allow recovery of LV function and likely does not negatively impact follow-up or ICD implant rates. References 1. Moss AJ, Zareba W, Hall WF, et al; Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346: Bardy GH, Lee DL, Mark DB, et al; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure [published correction appears in NEnglJMed.2005;352:2146]. N Engl J Med. 2005;352: Bigger JT Jr, et al; Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. Prophylactic use of implanted cardioverterdefibrillators in patients at high risk for ventricular arrhythmias after coronary artery bypass graft surgery. N Engl J Med. 1997;337: Hohnloser SH, Kuck KH, Dorian P et al; DINAMIT Investigators. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med. 2004;351: Epstein AE, DiMarco JP, Ellenbogen KA, et al ACCF/AHA/ HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2013;61:e6 e Moss AJ, Hall WF, Cannom DS, et al; Multicenter Automatic Defibrillator Implantation Trial Investigators. Improved survival with an implantable cardioverter-defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. NEnglJ Med. 1996;335: Olgin JE, Lee BK, Pletcher MJ, et al. Vest Prevention of Early Sudden Death Trial and VEST Registry. clinicaltrials.gov/ct2/show/nct Accessed July 2, Sjöblom J, Muhrbeck J, Witt N, et al. Evolution of left ventricular ejection fraction after acute myocardial infarction: implications for implantable cardioverter-defibrillator eligibility. Circulation. 2014;130: Narayanan K, Reinier K, Uy-Evanado A, et al. Frequency and determinants of ICD deployment among primary prevention candidates with subsequent sudden cardiac arrest in the community. Circulation. 2013;128: Bax JJ, Schinkel AFL, Boersma E, et al. Extensive left ventricular remodeling does not allow viable myocardium to improve in left ventricular ejection fraction after revascularization and is associated with worse long-term prognosis. Circulation. 2004;110:II-18 II Yang T, Lu MJ, Sun HS, et al. Myocardial scar identified by magnetic resonance imaging can predict left ventricular functional improvement after coronary artery bypass grafting. PLoS One. 2013;8:e Schinkel AF, Poldermans D, Vanoverschelde JL, et al. Incidence of recovery of contractile function following revascularization in patients with ischemic left ventricular dysfunction. Am J Cardiol. 2004;93: