- Email: [email protected]
Impact of revascularization in patients with sustained ventricular arrhythmias, prior myocardial infarction, and preserved left ventricular ejection fraction
Author's Accepted Manuscript
Impact of Revascularization in Patients with Sustained Ventricular Arrhythmias, Prior Myocardial Infarction and Preserved Left Ventricular Ejection Fraction Blandine Mondésert MD, Paul Khairy MD, PhD, Gernot Schram MD, PhD, Azadeh Shohoudi PhD, Mario Talajic MD, Jason G. Andrade MD, Marc Dubuc MD, Peter G. Guerra MD, Laurent Macle MD, Denis Roy MD, Katia Dyrda MD, Bernard Thibault MD, Miguel Barrero MD, Ariel Diaz MD, Simon Kouz MD, Serge McNicoll MD, Dominika Nowakowska MD, Léna Rivard MD, MSc
PII: DOI: Reference:
S1547-5271(16)00065-5 http://dx.doi.org/10.1016/j.hrthm.2016.01.019 HRTHM6599
To appear in:
Heart Rhythm
www.elsevier.com/locate/buildenv
Cite this article as: Blandine Mondésert MD, Paul Khairy MD, PhD, Gernot Schram MD, PhD, Azadeh Shohoudi PhD, Mario Talajic MD, Jason G. Andrade MD, Marc Dubuc MD, Peter G. Guerra MD, Laurent Macle MD, Denis Roy MD, Katia Dyrda MD, Bernard Thibault MD, Miguel Barrero MD, Ariel Diaz MD, Simon Kouz MD, Serge McNicoll MD, Dominika Nowakowska MD, Léna Rivard MD, MSc, Impact of Revascularization in Patients with Sustained Ventricular Arrhythmias, Prior Myocardial Infarction and Preserved Left Ventricular Ejection Fraction, Heart Rhythm, http://dx.doi. org/10.1016/j.hrthm.2016.01.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Impact of Revascularization in Patients with Sustained Ventricular Arrhythmias, Prior Myocardial Infarction, and Preserved Left Ventricular Ejection Fraction Blandine Mondésert, MD; Paul Khairy, MD, PhD; Gernot Schram, MD, PhD; Azadeh Shohoudi, PhD; Mario Talajic, MD; Jason G. Andrade, MD; Marc Dubuc, MD; Peter G. Guerra, MD; Laurent Macle, MD; Denis Roy, MD; Katia Dyrda, MD; Bernard Thibault, MD; Miguel Barrero, MD; Ariel Diaz, MD; Simon Kouz, MD; Serge McNicoll, MD; Dominika Nowakowska, MD; Léna Rivard, MD, MSc From the Department of Electrophysiology, Montreal Heart Institute, Université de Montréal, Montreal, Canada (B.M., P.K., M.T., J.G.A., M.D., P.G.G., L.M., D.R., K.D., B.T., L.R.); Montreal Health Innovations Coordinating Center (MHICC) (P.K., A.S.); Lakeshore General Hospital (G.S.); Centre Hospitalier Régional de Trois-Rivières (M.B., A.D.); Centre Hospitalier Régional de Lanaudière (S.K.); Hôpital Régional de Saint-Jérome (S.M.); and Hôpital PierreBoucher (D.N.), Longueuil, Canada
Short Title: Revascularization and ventricular arrhythmias
Conflict of Interest Disclosure: Dr. Rivard is supported by a C-SPIN Award and has received research grants from Medtronic Inc., St. Jude Medical, and Bayer Inc. Dr. Thibault has received research grants from Medtronic Inc. and St. Jude Medical. Dr. Dubuc has received research grants from St. Jude Medical and Medtronic Inc. Dr. Dyrda has received consulting fees from Hydro Quebec. Dr. Andrade is supported by a Michael Smith Foundation Scholar Award and has received research support from Medtronic Inc. Dr. Khairy has received research grants from St. Jude Medical, Medtronic Inc., and Boehringer Ingelheim. All other authors report no potential conflicts of interest. Sources of Funding: None Correspondence: Dr. Lena Rivard, Electrophysiology Service, Montreal Heart Institute, 5000 Belanger Street, Montreal, QC H1T 1C8, Canada. Tel.: (514) 376-3330#6279; Fax: (514) 593-2496. E-mail: [email protected]
Abstract Background: The impact of revascularization on recurrent ventricular arrhythmias in patients with coronary artery disease and a relatively preserved left ventricular ejection fraction (LVEF) remains unknown. Objectives: To determine the impact of revascularization on recurrent ventricular arrhythmias or death. Methods: A cohort study was conducted on consecutive patients with prior myocardial infarction and an LVEF ≥40% presenting with a first clinical sustained ventricular arrhythmia in the absence of an acute coronary syndrome. The impact of revascularization on recurrent ventricular arrhythmias and all-cause mortality was assessed. Results: A total of 274 patients, mean age 66.1±9.7 years, 84.3% male, mean LVEF 48.3±7.2%, were included. Eight-eight (32.1%) patients underwent coronary revascularization. During a mean followup of 6.2±5.1 years, 140 (51.1%) died or had recurrent sustained ventricular arrhythmias or appropriate implantable-cardioverter defibrillator (ICD) therapy. Revascularization was not associated with a significantly lower rate of recurrent ventricular arrhythmias or death [multivariable hazard ratio (HR) 0.86, 95% confidence interval (CI; 0.60–1.24), P=0.43], regardless of whether it was complete or incomplete [HR 0.65, 95% CI (0.25–1.69), P=0.37], or performed by percutaneous or surgical means [HR 1.02, 95% CI (0.53–1.94), P=0.96]. An ICD was associated with a significant reduction in mortality [HR 0.23, 95% CI (0.09–0.55), P=0.001]. Conclusion: Patients with prior myocardial infarction and an LVEF ≥40% who present with sustained ventricular arrhythmias in the absence of an acute coronary syndrome remain at high risk for recurrent ventricular arrhythmias and all-cause death. Coronary revascularization does not systemically mitigate this risk.
Key Words: coronary artery disease, ventricular tachycardia, implantable cardioverter- defibrillator
2
Abbreviations list ATP
anti-tachycardia pacing
CABG
coronary artery bypass graft
CAD
coronary artery disease
CI
confidence interval
CL
cycle length
EGM
electrograms
HR
hazard ratio
ICD
implantable cardioverter-defibrillator
IQR
interquartile range
LVEF
left ventricular ejection fraction
MHI
Montreal Heart Institute
PCI
percutaneous coronary interventions
SCD
sudden cardiac death
VAs
ventricular arrhythmias
VF
ventricular fibrillation
VT
ventricular tachycardia
Introduction Coronary artery disease (CAD) remains a leading cause of ventricular arrhythmias (VAs). In patients with impaired left ventricular function in the chronic phase of myocardial infarction, several studies have shown improved survival and a reduction in sudden cardiac death (SCD) following revascularization.1-4 Improvements in survival and left ventricular ejection fraction
3
(LVEF) were demonstrated in patients with preserved myocardial viability, with recovery of contractile function after restoration of flow to hibernating myocardium.5-9 Based on these studies, current guidelines recommend aggressive attempts to treat myocardial ischemia in this context.10 However, to our knowledge, no study has specifically addressed the impact of revascularization on recurrent VAs in patients with preserved LVEF. We, therefore, sought to determine the impact of revascularization on recurrent VAs or death in patients with an LVEF ≥40% presenting with a first clinical episode of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF).
Methods Study Design and Patient Population A retrospective cohort study was conducted on all consecutive patients hospitalized at the Montreal Heart Institute (MHI) between 1995 and 2011 who met the following criteria: 1) first sustained episode of VT or VF; 2) prior myocardial infarction; and 3) LVEF ≥40% at the time of VA. Patients in whom clinical, electrocardiographic, or enzymatic data suggested an acute ischemic event within 48 hours as a possible trigger for the VT/VF were excluded.11 The MedEcho hospital discharge summary database was used to identify all patients hospitalized between 1995 and 2011 with a primary or secondary diagnosis of VT or VF. A total of 2534 potentially eligible patients were identified. This primary search strategy was supplemented by screening two additional hospital databases, i.e., the implantable cardiac device database and the electrophysiology laboratory database. No additional patient was identified. Over a 6-month period, medical records of all potentially eligible patients were retrieved and analyzed. All candidates meeting qualifying criteria were retained for analysis.
4
Data Collection Baseline demographics, medical and surgical history, ECG characteristics, details regarding the qualifying VT/VF episode, imaging parameters, results of coronary angiography, and implantable cardioverter-defibrillator (ICD) interrogations were extracted from medical records. In addition, after receiving institutional review board approval, all regional community hospitals were contacted regarding jointly followed patients and secondary source data were obtained in order to maximize completeness of follow-up. Details regarding coronary angiography and myocardial ischemia imaging studies performed during the index hospitalization were collected. Indications for revascularization reflected institutional practices. The decision to implant an ICD was at the discretion of the treating team and based on applicable guideline-directed recommendations (years 1995 to 2011) individualized according to the patient's clinical status. Echocardiographic data were scored as recommended by the American Society of Echocardiography, including wall motion analysis: normal or hyperkinetic, hypokinetic (reduced thickening), akinetic (absent or negligible thickening, e.g. scar), and dyskinetic (systolic thinning or stretching, e.g. aneurysm).12
Endpoints The primary combined endpoint consisted of recurrent VT or VF or all-cause mortality. Individual components of the combined outcome were considered secondary endpoints. In patients with an ICD, occurrence of an ICD shock or anti-tachycardia pacing (ATP) was confirmed by device interrogation with analysis of stored electrograms (EGM), and classified as appropriate or inappropriate.
5
Statistical Analysis Continuous variables are expressed as mean±SD or median and interquartile range (IQR: 25th, 75th percentile), depending on whether or not they were normally distributed. Continuous variables were compared using independent Student-t or non-parametric Kruskal-Wallis tests, where appropriate. Categorical variables are presented by frequencies and percentages and compared by chi-square or Fisher’s exact tests. Event-free survival curves were plotted using the Kaplan-Meier technique, and were compared by log-rank tests. Factors associated with recurrent VT/VF or all-cause mortality were assessed in univariate and multivariable Cox regression models. Variables associated with P-values <0.2 in univariate analyses were considered in multivariable analyses, with forced retention of revascularization status as the main exposure variable. The only instance in which the proportionality assumption was violated was with the inclusion of ICD as a covariate in the multivariable model. This was overcome by dividing timeto-event into intervals. With this approach, the proportionality assumption was respected. Moreover, a sensitivity analysis was conducted by modeling ICD implantation as a timedependent variable. The impact of revascularization on components of the primary outcome (i.e., VT/VF and all-cause mortality) was assessed by means of a competing risk approach, using a proportional subdistribution hazard model.13 Two-tailed P-values <0.05 were considered statistically significant. All analyses were performed using the SAS software version 9.4 (SAS Institute, Cary, North Carolina, USA).
6
Results Baseline Characteristics A total of 274 patients, mean age 66.1±9.7 years, 231 (84.3%) male, met inclusion criteria. Baseline characteristics are presented in Table 1. Characteristics of the presenting clinical ventricular arrhythmias are summarized in Table 2. The mean LVEF was 48.3±7.2%, with 78 (28.5%) patients having an LVEF>50%. Most patients (N=251; 91.6%) had regional wall motion abnormalities. All but 7 underwent coronary angiography during their index hospitalization, with myocardial ischemia imaging studies performed in the remainder. A total of 88 (32.1%) patients underwent coronary revascularization: 30 (34.1%) by coronary artery bypass graft (CABG) surgery, and 58 (65.9%) by percutaneous coronary interventions (PCI). Complete revascularization was obtained in 76 (86.4%) patients, 27 (90.0%) after CABG, and 49 (84.5%) after PCI (P=0.7442). ICDs were implanted in 232 (84.7%) patients (173 single and 59 dual chamber devices). Mean age at implantation was 66.8±9.0 years and the mean time between first VT episode and ICD implantation was 7.7±3.3 months. Overall, 12 patients were lost to follow-up (5 with revascularization; 7 without revascularization), 2 of whom had no ICD.
Ventricular Arrhythmias and Death During a mean follow-up of 6.2±5.1 years (median 4.8 years; IQR: 2.2-8.9), 140 (51.1%) patients experienced the primary endpoint (Figure 1). VAs recurred in 107 patients (39.1%), with a mean cycle length of 318±59 ms. Recurrent VAs had a cycle length >30 ms shorter than the presenting arrhythmia in 4 patients, >30 ms longer in 6 patients, and within 30 ms of the presenting arrhythmia in the remainder. A total of 58 (21.2%) patients died, with 25 experiencing recurrent VA prior to death. The primary endpoint occurred in 40 of 88 (45.5%) in patients who underwent
7
revascularization versus 100 of 186 (53.8%) patients without revascularization (P=0.20). In the revascularization group, 31 patients experienced VAs (35.2%) and 11 (12.5%) died during a mean follow-up of 5.5±4.3 years. In the non-revascularization group, 76 (40.9%) experienced VAs and 47 (25.3%) died during a mean follow-up of 6.5±5.4 years. Prevalence of detected VAs was 102 of 232 (44.0%) in ICD recipients versus 5 of 44 (11.4%) in patients without ICDs. In ICD recipients, 63 (27.2%) received one or more appropriate shock (median of 2.0 shocks, IQR: 1.0-6.8) and 69 (29.7%) were treated with ATP (median of 3.0 ATPs, IQR: 1.0-7.0). Anti-arrhythmic drugs were prescribed to 100 patients and 15 had VT ablation.
Device-Related Complications Overall, 23 (9.9%) ICD recipients received 32 inappropriate shocks due to supraventricular arrhythmias (N=29), lead fracture (N=2), or an inappropriate chiropractor intervention (N=1). Additional complications included lead fracture (N=11; 4.7%), lead dysfunction (N=14; 6.0%), lead dislodgement (N=6; 2.6%), lead recall (N=6; 2.6%), and device infection (N=11; 4.7%), with two cases of endocarditis.
Factors Associated with Recurrent Ventricular Arrhythmias and Death Univariate and multivariable predictors of the combined primary endpoint and its components are summarized in Tables 3 and 4, respectively. In multivariable analysis, age was the only factor independently associated with recurrent VAs or death [hazard ratio (HR) 1.03 per year, 95% confidence interval (CI; 1.01–1.05), P=0.003]. Importantly, revascularization was not associated with a significantly lower rate of recurrent VAs or death [HR 0.86, 95% CI (0.60–1.24), P=0.43], regardless of whether it was complete or incomplete [HR 0.65, 95% CI (0.25–1.69), P=0.37], or
8
performed by percutaneous or surgical means [HR 1.02, 95% CI (0.53–1.94), P=0.96]. Similarly, revascularization was not associated with a lower rate of recurrent VAs or death regardless of whether the presenting arrhythmia was monomorphic VT or polymorphic VT/VF [HR 1.19, 95% CI (0.81–1.75), P=0.36]. Freedom from the primary outcome is plotted in Figure 2 according to whether or not revascularization was performed. In multivariable analyses, ICDs were associated with a 77% mortality reduction [HR 0.23, 95% CI (0.09–0.55), P=0.001].
Discussion To our knowledge, this study is the first to specifically address the impact of coronary revascularization on patients with prior myocardial infarction and a relatively preserved LVEF presenting with clinical sustained VAs. Our main findings are as follows: 1) Despite having an LVEF >40%, patients with chronic CAD and sustained VAs are at very high risk of recurrent sustained VA or death, with this combined endpoint occurring in >50% over an average follow-up of 6.2 years; 2) Risk of recurrent VA or death is not mitigated by coronary revascularization; and 3) ICDs are associated with a significant (>70%) mortality reduction.
Effect of Coronary Revascularization in Chronic CAD The influence of ischemia in the genesis of sustained VAs in patients with chronic stable CAD remains controversial, with some authors suggesting that such VAs are predominantly due to regional or intramural reentry circuits that incorporate regions of diseased myocardium and electrically unexcitable scars, which are not affected by revascularization.14 Theoretically, if ischemia is a trigger for VAs, correction of CAD lesions amenable to revascularization in patients with reversible ischemia should prevent arrhythmia occurrence. Indeed, several studies suggest that patients with moderate or severe left ventricular dysfunction and ischemic or viable
9
myocardium experience superior arrhythmia-free survival and lower mortality following revascularization.4, 5, 7, 15-17 However, results remain inconsistent. In a study of 64 patients with prior myocardial infarction, a mean LVEF of 38±9%, and spontaneous VT, VT remained inducible in 52 of 59 patients despite complete revascularization and >50% experienced arrhythmia recurrence during a follow-up of 32±26 months.9 Similarly, no reduction in appropriate ICD therapies was noted in 130 CAD patients with an LVEF of 36±12% following complete revascularization.18 Moreover, a study of 93 patients with an LVEF of 36±15% reported a comparable incidence of recurrent arrhythmias in patients with VAs before (N=53) versus after (N=40) surgical revascularization.19 The current study expands this discussion to the understudied population with a relatively preserved LVEF and suggests that the preponderance for recurrent VAs is not systematically altered by coronary revascularization.
Mortality The all-cause mortality rate in our study (i.e., 21.2% at a median of 4.8 years) is consistent with prior reports20 and lower than mortality rates observed in patients with VAs and impaired left ventricular systolic function.21-23 The magnitude of the mortality reduction conferred by ICDs observed in our study (i.e., HR 0.23) is likewise consistent with secondary prevention ICD trials and previous reports suggesting that patients with VAs and relatively preserved left ventricular function (LVEF >35%) derive greater benefit from ICDs than those with advanced heart failure.23 This may be due, in part, to a lesser influence of competing risks for mortality, such as heart failure-related deaths.
10
Study Limitations The study is retrospective in nature and, hence, subject to the limitations inherent in observational research. While every effort was made to control for baseline imbalances and potential confounders, multivariable analyses cannot adjust for unmeasured or unknown potential confounders. Importantly, the higher rate of recurrent VAs observed in ICD recipients may be subject to a detection bias due to the recording capabilities of ICDs.24 In order to address this potential bias, all multivariable analyses adjusted for the presence of an ICD. In addition, a sensitivity analysis was conducted by excluding the 44 (16%) patients without ICDs. All results and conclusions regarding the potential impact of revascularization remained unaltered. Moreover, sensitivity analyses that modeled ICD implantation as a time-dependent variable further confirmed the lack of association between revascularization and recurrent VAs [HR 0.87, 95% CI (0.56–1.33), P=0.51] or death [HR 0.97, 95% CI (0.46–2.05), P=0.94]. Additional limitations include the long period of observation (1995-2011), which was incorporated to maximize study power but during which changes to clinical practice occurred, including indications for ICDs and pharmacological therapy. Finally, the presence of reversible ischemia was not systematically assessed prior to angiography, thereby precluding an analysis of the impact of revascularization on a subgroup of patients with a hibernating myocardium.
Conclusion In conclusion, patients with prior myocardial infarction and relatively preserved left ventricular systolic function (LVEF>40%) who present with VAs in the absence of an acute coronary syndrome remain at high risk for recurrent VAs and all-cause death during an intermediate follow-up period. Importantly, coronary revascularization does not appear to mitigate this risk.
11
References 1.
Hillis LD, Cigarroa JE, Lange RA. Late revascularization reduces mortality in survivors of myocardial infarction. Cardiol Rev. 1999;7:144-148.
2.
Carnendran L, Steinberg JS. Does an open infarct-related artery after myocardial infarction improve electrical stability? Prog Cardiovasc Dis. 2000;42:439-454.
3.
Hsia J, Jablonski KA, Rice MM, et al. PEACE Investigators. Sudden cardiac death in patients with stable coronary artery disease and preserved left ventricular systolic function. Am J Cardiol. 2008;101:457-461.
4.
Van der Burg AE, Bax JJ, Boersma E, Pauwels EK, van der Wall EE, Schalij MJ. Impact of viability, ischemia, scar tissue, and revascularization on outcome after aborted sudden death. Circulation. 2003;108:1954-1959.
5.
Chareonthaitawee P, Gersh BJ, Araoz PA, Gibbons RJ. Revascularization in severe left ventricular dysfunction: The role of viability testing. J Am Coll Cardiol. 2005;46:567-574.
6.
Carluccio E, Biagioli P, Alunni G, Murrone A, Giombolini C, Ragni T, Marino PN, Reboldi G, Ambrosio G. Patients with hibernating myocardium show altered left ventricular volumes and shape, which revert after revascularization: evidence that dyssynergy might directly induce cardiac remodeling. J Am Coll Cardiol. 2006;47:969977.
7.
Tarakji KG, Brunken R, McCarthy PM, Al-Chekakie MO, Abdel-Latif A, Pothier CE, Blackstone EH, Lauer MS. Myocardial viability testing and the effect of early intervention in patients with advanced left ventricular systolic dysfunction. Circulation. 2006;113:230-237.
8.
Brugada J, Aguinaga L, Mont L, Betriu A, Mulet J, Sanz G. Coronary artery
12
revascularization in patients with sustained ventricular arrhythmias in the chronic phase of a myocardial infarction: Effects on the electrophysiologic substrate and outcome. J Am Coll Cardiol. 2001;37:529-533. 9.
Brockes C, Rahn-Schonbeck M, Duru F, Candinas R, Seifert B, Turina M. ICD implantation with and without combined myocardial revascularisation--incidence of ICD therapy and late survival. Thorac Cardiovasc Surg. 2002;50:333-336.
10.
Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation. 2006;114:e385-484.
11.
Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes. J Am Coll Cardiol. 2014;64:e139-228.
12.
Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging, J Am Soc Echocardiogr 2015;28:1-39.
13.
Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999;94:496-509.
14.
Stevenson WG, Khan H, Sager P, Saxon LA, Middlekauff HR, Natterson PD, Wiener I. Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of ventricular tachycardia late after myocardial infarction. Circulation. 1993;88:1647-1670.
15.
Elhendy A, Chapman S, Porter TR, Windle J. Association of myocardial ischemia with mortality and implantable cardioverter-defibrillator therapy in patients with coronary artery disease at risk of arrhythmic death. J Am Coll Cardiol. 2005;46:1721-1726.
13
16.
Alderman EL, Bourassa MG, Cohen LS, Davis KB, Kaiser GG, Killip T, Mock MB, Pettinger M, Robertson TL. Ten-year follow-up of survival and myocardial infarction in the randomized coronary artery surgery study. Circulation. 1990;82:1629-1646.
17.
Bell MR, Gersh BJ, Schaff HV, Holmes DR, Jr., Fisher LD, Alderman EL, Myers WO, Parsons LS, Reeder GS. Effect of completeness of revascularization on long-term outcome of patients with three-vessel disease undergoing coronary artery bypass surgery. A report from the Coronary Artery Surgery Study (CASS) registry. Circulation. 1992;86:446-457.
18.
Bourke JP, Richards DA, Ross DL, Wallace EM, McGuire MA, Uther JB. Routine programmed electrical stimulation in survivors of acute myocardial infarction for prediction of spontaneous ventricular tachyarrhythmias during follow-up: Results, optimal stimulation protocol and cost-effective screening. J Am Coll Cardiol. 1991;18:780-788.
19.
Nageh MF, Kim JJ, Chen LH, Yao JF. Implantable defibrillators for secondary prevention of sudden cardiac death in cardiac surgery patients with perioperative ventricular arrhythmias. J Am Heart Association. 2014;3. doi: 10.1161/JAHA.113.000686.
20.
Olshansky B, Hartz V, Hahn E, Mason J, Weaver MD; ESVEM Investigators. Location of death (in-hospital or out-of-hospital) and type of death (arrhythmic, nonarrhythmic, noncardiac) after inducible sustained ventricular tachyarrhythmias after syncope, sustained ventricular tachycardia, or nonfatal cardiac arrest (the ES V EM trial). Am J Cardiol. 2000;86:846-851.
21.
Cook JR, Rizo-Patron C, Curtis AB, Gillis AM, Bigger JT, Jr., Kutalek SP, Coromilas J, Hofer BI, Powell J, Hallstrom AP; AVD Investigators. Effect of surgical revascularization in patients with coronary artery disease and ventricular tachycardia or fibrillation in the Antiarrhythmics Versus Implantable Defibrillators (AVID) registry. Am Heart J. 2002;143:821-826.
14
22.
Oseroff O, Retyk E, Bochoeyer A. Subanalyses of secondary prevention implantable cardioverter-defibrillator trials: Antiarrhythmics Versus Implantable Defibrillators (AVID), Canadian Implantable Defibrillator Study (CIDS), and Cardiac Arrest Study Hamburg (CASH). Current Opinion Cardiol. 2004;19:26-30.
23.
Ronn F, Kesek M, Hoglund N, Jensen SM. Long-term follow-up of patients treated with ICD: Benefit in patients with preserved left ventricular function. Scandinavian Cardiovasc J. 2008;42:125-129.
24.
Ellenbogen KA, Levine JH, Berger RD, Daubert JP, Winters SL, Greenstein E, Shalaby A, Schaechter A, Subacius H, Kadish A. Defibrillators in Non-ischemic Cardiomyopathy Treatment Evaluation I. Are implantable cardioverter defibrillator shocks a surrogate for sudden cardiac death in patients with nonischemic cardiomyopathy? Circulation. 2006;113:776-782.
Clinical Perspectives Several studies have demonstrated that coronary revascularization improves survival in patients with chronic ischemic heart disease and left ventricular dysfunction. However, the impact of revascularization on cardiovascular outcomes remains controversial for patients with relatively preserved ventricular function post myocardial infarction. The current study tackles this knowledge gap by specifically addressing the question of whether coronary revascularization reduces the rate of recurrent ventricular arrhythmias and all-cause mortality in patients with coronary disease, a left ventricular ejection fraction ≥40%, and clinical sustained ventricular arrhythmias in the absence of an acute coronary syndrome. Coronary revascularization, whether complete or incomplete, or achieved by percutaneous or surgical means, was not associated with a reduction in the combined outcome consisting of recurrent ventricular arrhythmias or death in
15
this patient population. Moreover, revascularization was not associated with a reduction in recurrent ventricular arrhythmias considered separately, or of all-cause death. Results remained consistent whether patients presented with sustained monomorphic ventricular tachycardia or polymorphic ventricular tachycardia/ventricular fibrillation. In contrast, as may be expected, implantable cardioverter-defibrillators (ICD) were associated with a large morality reduction (>70%). These results suggest that coronary revascularization should not be considered primary therapy for ventricular arrhythmias in patients with coronary artery disease and relatively preserved ventricular function, nor as a substitute for an ICD.
Figure Legends Figure 1. Flowchart of Clinical Outcomes CAD denotes coronary artery disease; LVEF, left ventricular ejection fraction; ICD, implantable cardioverter-defibrillator; VAE, ventricular arrhythmia event; FU, follow-up
Figure 2. Freedom from Recurrent Ventricular Arrhythmias or Death according to Whether Revascularization Was Performed CI denotes confidence interval
16
Tables Table 1. Baseline Characteristics Baseline Characteristics
Gender, male Age, years Hypertension Diabetes mellitus Dyslipidemia Tobacco Renal failure* NYHA 1-2 3-4 Time from last MI, years Coronary artery disease Location of MI Anterior Inferior Lateral Number of diseased vessels† One Two Three ECG data QRS width (ms) Echocardiographic data Hypokinesia/akinesia Aneurysm LVEF, % LVEF>50% Pharmacological therapy Anti-arrhythmic agent Amiodarone Sotalol ß-Blocker ACE inhibitor Aldosterone antagonist
Total Population N=274 231 (84.3) 66.1 ± 9.7 168 (61.3) 68 (24.8) 208 (75.9) 121 (44.2) 50 (18.3)
Population with Revascularization N=88 76 (86.4) 65.7 ± 9.5 55 (62.5) 26 (29.5) 66 (75.0) 32 (36.4) 17 (19.3)
Population without Revascularization N=186 158 (84.9) 66.4 ± 9.8 113 (60.8) 42 (22.6) 142 (76.3) 89 (47.8) 33 (17.7)
P-Value
268 (97.8) 6 (2.2) 11.1 ± 9.8
84 (95.4) 4 (4.6) 8.6 ± 10.1
184 (98.9) 2 (1.1) 12.3 ± 9.6
0.006
52 (20.2) 200 (77.8) 5 (2.0)
16 (18.2) 63 (71.6) 3 (3.4)
36 (19.4) 137 (73.4) 2 (1.1)
0.84 0.79 0.17
97 (36.3) 66 (24.7) 104 (39.0)
27 (30.7) 26 (29.5) 34 (38.6)
70 (37.6) 40 (21.5) 70 (37.6)
0.21 0.17 0.98
110 ± 23.2
105.4 ± 22.5
113.0 ± 23.0
0.01
251 (91.6) 26 (9.5) 48.3 ± 7.2 78 (28.5)
79 (89.8) 8 (9.1) 48.3 ± 6.6 25 (28.4)
172 (92.5) 18 (9.7) 48.4 ± 7.4 53 (28.5)
0.45 0.88 0.89 0.99
100 (36.5) 59 (21.5) 22 (8.0) 178 (65.0) 141 (51.5) 6 (2.2)
27 (30.7) 23 (26.1) 3 (3.4) 62 (70.5) 42 (47.7) 2 (2.3)
73 (39.2%) 36 (19.4) 19 (10.2) 116 (62.4) 99 (53.2) 4 (2.2)
0.17 0.20 0.053 0.19 0.39 0.95
0.76 0.60 0.70 0.21 0.81 0.07 0.75 0.07
Continuous variables are expressed as mean ± standard deviation and categorical variables as frequency (percentage). NYHA denotes New York Heart Association; MI, myocardial infarction; LVEF, left ventricular ejection fraction; ACE, angiotensin-converting enzyme *
Defined as a creatinine clearance <50 mL/min
†
Coronary angiography was not performed in 7 patients
17
Table 2. Characteristics of the Presenting Arrhythmia
Monomorphic ventricular tachycardia, N (%)
201 (73.4)
Mean cycle length, ms
303 ± 64
Median cycle length, ms (25th, 75th percentile)
300 (260, 340)
Polymorphic ventricular tachycardia/Torsade de Pointes, N (%)
25 (9.1)
Ventricular fibrillation, N (%)
48 (17.5)
Hemodynamically well-tolerated, N (%)
137 (50.0)
Time since myocardial infarction, years Mean ± standard deviation
11.1 ± 9.8
Median (25th, 75th percentile)
9.8 (1.3, 17.9)
18
Table 3. Univariable Predictors of Recurrent Ventricular Arrhythmias or Death
Gender, male Age, years Hypertension Diabetes mellitus Dyslipidemia Tobacco Renal failure* NYHA I-II vs III-IV Coronary artery disease Location of MI Anterior Inferior Lateral Number of diseased vessels† One Two Three ECG data QRS width (ms) Echocardiographic data Hypokinesia/akinesia Aneurysm LVEF, 40-50% vs >50% Pharmacological therapy Amiodarone
Recurrent VA or death HR [95% PCI] value 1.50 0.88 – 0.14 2.56 1.03 [1.02 – 0.0006 1.06] 0.87 [0.62 – 0.42 1.22] 1.60 [1.09 – 0.02 2.35] 0.76 [0.53 – 0.15 1.11] 1.08 [0.78 – 0.63 1.51] 1.89 [1.24 – 0.003 2.88] 0.73 [0.23 – 0.59 2.29]
0.83 [0.19 – 3.54] 1.32 [0.32 – 5.34] Reference
0.80
0.96 [0.65 – 1.111.42] [0.72 –
0.10
0.70
0.07
1.71] Reference
Recurrent VA HR [95% CI] Pvalue 1.37 0.79 – 0.26 2.36 1.02 [1.00 – 0.040 1.05] 1.01 [0.68 – 0.96 1.50] 1.60 [1.03 – 0.035 2.48] 0.79 [0.51 – 0.29 1.22] 1.00 [0.68 – 0.98 1.48] 1.27 [0.74 – 0.39 2.18] 0.57 [0.18 – 0.35 1.82]
1.24 [0.16 – 9.76] 2.34 [0.32 – 17.05] Reference
0.83
1.12 [0.70 – 1.241.78] [0.74 –
0.63
0.40
0.40
2.07] Reference
Death HR [95% CI] 1.58 0.47 – 5.29 1.03 [1.01 – 1.08] 0.55 [0.28 – 1.07] 0.97 [0.42 – 2.23] 0.73 [0.35 – 1.52] 1.23 [0.62 – 2.45] 3.43 [1.69 – 6.99] 0.82 [0.05 – 14.51]
Pvalue 0.46
0.036 0.07 0.94 0.40 0.55
0.0007 0.89
0.33 [0.04 – 2.68] 0.55 [0.08 – 3.67] Reference
0.30
0.73 [0.34 – 0.711.57] [0.30 –
0.41
0.54
0.44
1.69] Reference
1.01 [0.99 – 1.01]
0.18
1.00 [0.99 – 1.01]
0.74
1.01 [1.00 – 1.02]
0.07
1.14 [0.56 – 2.33] 1.22 [0.72 – 2.05] 1.47 [0.45 – 1.39]
0.72
1.03 [0.48 – 2.22] 1.18 [0.63 – 2.25] 1.27 [0.79 – 2.04]
0.94
0.44 [0.07 – 2.88] 0.91 [0.30 – 2.83] 0.54 [0.21 – 1.36]
0.39
0.82 [0.56 –
0.31
1.41 [0.94 –
0.10
0.66 [0.28 –
0.35
0.46 0.07
19
0.60 0.31
0.87 0.19
Sotalol ß-Blocker ACE inhibitor Aldosterone antagonist Well-tolerated VA Monomorphic VT vs PVT/VF Revascularization Complete vs incomplete Angioplasty vs CABG ICD implantation
1.20] 0.73 [0.39 – 1.37] 0.86 [0.61 – 1.20] 0.88 [0.63 – 1.23] 1.66 [0.53 – 5.23] 0.83 [0.60 – 1.17] 1.19 [0.81 – 1.75] 0.90 [0.62 – 1.29] 0.65 [0.25 – 1.69] 1.02 [0.53 – 1.94] 1.73 [0.98 – 3.07]
0.96 0.37 0.46 0.39 0.29 0.36 0.55 0.37 0.96 0.06
2.11] 0.98 [0.45 – 2.11] 0.94 [0.63 – 1.40] 0.97 [0.66 – 1.42] 1.16 [0.34 – 5.62] 0.88 [0.60 – 1.30] 1.53 [0.96 – 2.45] 0.88 [0.57 – 1.35] 0.83 [0.29 – 2.38] 0.90 [0.42 – 1.92] 4.96 [1.85 – 13.31]
0.95 0.74 0.86 0.86 0.53 0.07 0.55 0.73 0.79 0.002
1.56] 0.59 [0.14 – 2.60] 0.77 [0.39 – 1.51] 0.63 [0.32 – 1.27] 1.99 [0.25– 15.81] 1.04 [0.53 – 2.03] 0.55 [0.28 – 1.09] 1.00 [0.48 – 2.07] 0.55 [0.11 – 2.78] 1.06 [0.33 – 3.48] 0.32 [0.15 – 0.73]
0.48 0.45 0.20 0.51 0.92 0.09 1.00 0.47 0.94 0.006
VA denotes ventricular arrhythmia; HR, hazard ratio; CI, confidence interval; NYHA, New York Heart Association; MI, myocardial infarction; ECG, electrocardiogram; LVEF, left ventricular ejection fraction; ACE, angiotensin-converting enzymbe; VT, ventricular tachycardia; PVT, polymorphic VT; VF, ventricular fibrillation; CABG, coronary artery bypass graft; ICD, implantable cardioverterdefibrillator *
Defined as a creatinine clearance <50 mL/min
†
Coronary angiography was not performed in 7 patients
20
Table 4. Multivariable Predictors of Recurrent Ventricular Arrhythmias or Death Recurrent VA or death HR [95%
P-value
Recurrent VA HR [95% CI]
Death
P-value
HR [95% CI]
P-value
1.04 [0.99 –
0.06
CI] Age, years
1.03 [1.01 –
0.003
1.05]
1.09] 1.45 [0.93 – 2.29]
Diabetes mellitus Renal failure*
1.48 [0.93 –
0.11 4.94 [2.16 –
0.09
2.36]
11.30] 1.61 [1.01 –
Monomorphic VT vs PVT/VF ICD implantation
0.12
2.83] Revascularization
0.048
2.57] 1.59 [0.89 –
0.86 [0.60 – 1.24]
0.0002
4.85 [1.82 –
0.84 [0.55 – 1.29]
0.008
0.76] 0.002
12.98] 0.43
0.35 [0.16 –
0.23 [0.09 –
0.001
0.55] 0.43
0.98 [0.47 –
0.97
2.04]
VA denotes ventricular arrhythmia; HR, hazard ratio; CI, confidence interval; MI, myocardial infarction; VT, ventricular tachycardia; PVT, polymorphic VT; VF, ventricular fibrillation; ICD, implantable cardioverter-defibrillator *
Defined as a creatinine clearance <50 mL/min
21
22
23
Impact of Revascularization in Patients with Sustained Ventricular Arrhythmias, Prior Myocardial Infarction and Preserved Left Ventricular Ejection Fraction Blandine Mondésert MD, Paul Khairy MD, PhD, Gernot Schram MD, PhD, Azadeh Shohoudi PhD, Mario Talajic MD, Jason G. Andrade MD, Marc Dubuc MD, Peter G. Guerra MD, Laurent Macle MD, Denis Roy MD, Katia Dyrda MD, Bernard Thibault MD, Miguel Barrero MD, Ariel Diaz MD, Simon Kouz MD, Serge McNicoll MD, Dominika Nowakowska MD, Léna Rivard MD, MSc
PII: DOI: Reference:
S1547-5271(16)00065-5 http://dx.doi.org/10.1016/j.hrthm.2016.01.019 HRTHM6599
To appear in:
Heart Rhythm
www.elsevier.com/locate/buildenv
Cite this article as: Blandine Mondésert MD, Paul Khairy MD, PhD, Gernot Schram MD, PhD, Azadeh Shohoudi PhD, Mario Talajic MD, Jason G. Andrade MD, Marc Dubuc MD, Peter G. Guerra MD, Laurent Macle MD, Denis Roy MD, Katia Dyrda MD, Bernard Thibault MD, Miguel Barrero MD, Ariel Diaz MD, Simon Kouz MD, Serge McNicoll MD, Dominika Nowakowska MD, Léna Rivard MD, MSc, Impact of Revascularization in Patients with Sustained Ventricular Arrhythmias, Prior Myocardial Infarction and Preserved Left Ventricular Ejection Fraction, Heart Rhythm, http://dx.doi. org/10.1016/j.hrthm.2016.01.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Impact of Revascularization in Patients with Sustained Ventricular Arrhythmias, Prior Myocardial Infarction, and Preserved Left Ventricular Ejection Fraction Blandine Mondésert, MD; Paul Khairy, MD, PhD; Gernot Schram, MD, PhD; Azadeh Shohoudi, PhD; Mario Talajic, MD; Jason G. Andrade, MD; Marc Dubuc, MD; Peter G. Guerra, MD; Laurent Macle, MD; Denis Roy, MD; Katia Dyrda, MD; Bernard Thibault, MD; Miguel Barrero, MD; Ariel Diaz, MD; Simon Kouz, MD; Serge McNicoll, MD; Dominika Nowakowska, MD; Léna Rivard, MD, MSc From the Department of Electrophysiology, Montreal Heart Institute, Université de Montréal, Montreal, Canada (B.M., P.K., M.T., J.G.A., M.D., P.G.G., L.M., D.R., K.D., B.T., L.R.); Montreal Health Innovations Coordinating Center (MHICC) (P.K., A.S.); Lakeshore General Hospital (G.S.); Centre Hospitalier Régional de Trois-Rivières (M.B., A.D.); Centre Hospitalier Régional de Lanaudière (S.K.); Hôpital Régional de Saint-Jérome (S.M.); and Hôpital PierreBoucher (D.N.), Longueuil, Canada
Short Title: Revascularization and ventricular arrhythmias
Conflict of Interest Disclosure: Dr. Rivard is supported by a C-SPIN Award and has received research grants from Medtronic Inc., St. Jude Medical, and Bayer Inc. Dr. Thibault has received research grants from Medtronic Inc. and St. Jude Medical. Dr. Dubuc has received research grants from St. Jude Medical and Medtronic Inc. Dr. Dyrda has received consulting fees from Hydro Quebec. Dr. Andrade is supported by a Michael Smith Foundation Scholar Award and has received research support from Medtronic Inc. Dr. Khairy has received research grants from St. Jude Medical, Medtronic Inc., and Boehringer Ingelheim. All other authors report no potential conflicts of interest. Sources of Funding: None Correspondence: Dr. Lena Rivard, Electrophysiology Service, Montreal Heart Institute, 5000 Belanger Street, Montreal, QC H1T 1C8, Canada. Tel.: (514) 376-3330#6279; Fax: (514) 593-2496. E-mail: [email protected]
Abstract Background: The impact of revascularization on recurrent ventricular arrhythmias in patients with coronary artery disease and a relatively preserved left ventricular ejection fraction (LVEF) remains unknown. Objectives: To determine the impact of revascularization on recurrent ventricular arrhythmias or death. Methods: A cohort study was conducted on consecutive patients with prior myocardial infarction and an LVEF ≥40% presenting with a first clinical sustained ventricular arrhythmia in the absence of an acute coronary syndrome. The impact of revascularization on recurrent ventricular arrhythmias and all-cause mortality was assessed. Results: A total of 274 patients, mean age 66.1±9.7 years, 84.3% male, mean LVEF 48.3±7.2%, were included. Eight-eight (32.1%) patients underwent coronary revascularization. During a mean followup of 6.2±5.1 years, 140 (51.1%) died or had recurrent sustained ventricular arrhythmias or appropriate implantable-cardioverter defibrillator (ICD) therapy. Revascularization was not associated with a significantly lower rate of recurrent ventricular arrhythmias or death [multivariable hazard ratio (HR) 0.86, 95% confidence interval (CI; 0.60–1.24), P=0.43], regardless of whether it was complete or incomplete [HR 0.65, 95% CI (0.25–1.69), P=0.37], or performed by percutaneous or surgical means [HR 1.02, 95% CI (0.53–1.94), P=0.96]. An ICD was associated with a significant reduction in mortality [HR 0.23, 95% CI (0.09–0.55), P=0.001]. Conclusion: Patients with prior myocardial infarction and an LVEF ≥40% who present with sustained ventricular arrhythmias in the absence of an acute coronary syndrome remain at high risk for recurrent ventricular arrhythmias and all-cause death. Coronary revascularization does not systemically mitigate this risk.
Key Words: coronary artery disease, ventricular tachycardia, implantable cardioverter- defibrillator
2
Abbreviations list ATP
anti-tachycardia pacing
CABG
coronary artery bypass graft
CAD
coronary artery disease
CI
confidence interval
CL
cycle length
EGM
electrograms
HR
hazard ratio
ICD
implantable cardioverter-defibrillator
IQR
interquartile range
LVEF
left ventricular ejection fraction
MHI
Montreal Heart Institute
PCI
percutaneous coronary interventions
SCD
sudden cardiac death
VAs
ventricular arrhythmias
VF
ventricular fibrillation
VT
ventricular tachycardia
Introduction Coronary artery disease (CAD) remains a leading cause of ventricular arrhythmias (VAs). In patients with impaired left ventricular function in the chronic phase of myocardial infarction, several studies have shown improved survival and a reduction in sudden cardiac death (SCD) following revascularization.1-4 Improvements in survival and left ventricular ejection fraction
3
(LVEF) were demonstrated in patients with preserved myocardial viability, with recovery of contractile function after restoration of flow to hibernating myocardium.5-9 Based on these studies, current guidelines recommend aggressive attempts to treat myocardial ischemia in this context.10 However, to our knowledge, no study has specifically addressed the impact of revascularization on recurrent VAs in patients with preserved LVEF. We, therefore, sought to determine the impact of revascularization on recurrent VAs or death in patients with an LVEF ≥40% presenting with a first clinical episode of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF).
Methods Study Design and Patient Population A retrospective cohort study was conducted on all consecutive patients hospitalized at the Montreal Heart Institute (MHI) between 1995 and 2011 who met the following criteria: 1) first sustained episode of VT or VF; 2) prior myocardial infarction; and 3) LVEF ≥40% at the time of VA. Patients in whom clinical, electrocardiographic, or enzymatic data suggested an acute ischemic event within 48 hours as a possible trigger for the VT/VF were excluded.11 The MedEcho hospital discharge summary database was used to identify all patients hospitalized between 1995 and 2011 with a primary or secondary diagnosis of VT or VF. A total of 2534 potentially eligible patients were identified. This primary search strategy was supplemented by screening two additional hospital databases, i.e., the implantable cardiac device database and the electrophysiology laboratory database. No additional patient was identified. Over a 6-month period, medical records of all potentially eligible patients were retrieved and analyzed. All candidates meeting qualifying criteria were retained for analysis.
4
Data Collection Baseline demographics, medical and surgical history, ECG characteristics, details regarding the qualifying VT/VF episode, imaging parameters, results of coronary angiography, and implantable cardioverter-defibrillator (ICD) interrogations were extracted from medical records. In addition, after receiving institutional review board approval, all regional community hospitals were contacted regarding jointly followed patients and secondary source data were obtained in order to maximize completeness of follow-up. Details regarding coronary angiography and myocardial ischemia imaging studies performed during the index hospitalization were collected. Indications for revascularization reflected institutional practices. The decision to implant an ICD was at the discretion of the treating team and based on applicable guideline-directed recommendations (years 1995 to 2011) individualized according to the patient's clinical status. Echocardiographic data were scored as recommended by the American Society of Echocardiography, including wall motion analysis: normal or hyperkinetic, hypokinetic (reduced thickening), akinetic (absent or negligible thickening, e.g. scar), and dyskinetic (systolic thinning or stretching, e.g. aneurysm).12
Endpoints The primary combined endpoint consisted of recurrent VT or VF or all-cause mortality. Individual components of the combined outcome were considered secondary endpoints. In patients with an ICD, occurrence of an ICD shock or anti-tachycardia pacing (ATP) was confirmed by device interrogation with analysis of stored electrograms (EGM), and classified as appropriate or inappropriate.
5
Statistical Analysis Continuous variables are expressed as mean±SD or median and interquartile range (IQR: 25th, 75th percentile), depending on whether or not they were normally distributed. Continuous variables were compared using independent Student-t or non-parametric Kruskal-Wallis tests, where appropriate. Categorical variables are presented by frequencies and percentages and compared by chi-square or Fisher’s exact tests. Event-free survival curves were plotted using the Kaplan-Meier technique, and were compared by log-rank tests. Factors associated with recurrent VT/VF or all-cause mortality were assessed in univariate and multivariable Cox regression models. Variables associated with P-values <0.2 in univariate analyses were considered in multivariable analyses, with forced retention of revascularization status as the main exposure variable. The only instance in which the proportionality assumption was violated was with the inclusion of ICD as a covariate in the multivariable model. This was overcome by dividing timeto-event into intervals. With this approach, the proportionality assumption was respected. Moreover, a sensitivity analysis was conducted by modeling ICD implantation as a timedependent variable. The impact of revascularization on components of the primary outcome (i.e., VT/VF and all-cause mortality) was assessed by means of a competing risk approach, using a proportional subdistribution hazard model.13 Two-tailed P-values <0.05 were considered statistically significant. All analyses were performed using the SAS software version 9.4 (SAS Institute, Cary, North Carolina, USA).
6
Results Baseline Characteristics A total of 274 patients, mean age 66.1±9.7 years, 231 (84.3%) male, met inclusion criteria. Baseline characteristics are presented in Table 1. Characteristics of the presenting clinical ventricular arrhythmias are summarized in Table 2. The mean LVEF was 48.3±7.2%, with 78 (28.5%) patients having an LVEF>50%. Most patients (N=251; 91.6%) had regional wall motion abnormalities. All but 7 underwent coronary angiography during their index hospitalization, with myocardial ischemia imaging studies performed in the remainder. A total of 88 (32.1%) patients underwent coronary revascularization: 30 (34.1%) by coronary artery bypass graft (CABG) surgery, and 58 (65.9%) by percutaneous coronary interventions (PCI). Complete revascularization was obtained in 76 (86.4%) patients, 27 (90.0%) after CABG, and 49 (84.5%) after PCI (P=0.7442). ICDs were implanted in 232 (84.7%) patients (173 single and 59 dual chamber devices). Mean age at implantation was 66.8±9.0 years and the mean time between first VT episode and ICD implantation was 7.7±3.3 months. Overall, 12 patients were lost to follow-up (5 with revascularization; 7 without revascularization), 2 of whom had no ICD.
Ventricular Arrhythmias and Death During a mean follow-up of 6.2±5.1 years (median 4.8 years; IQR: 2.2-8.9), 140 (51.1%) patients experienced the primary endpoint (Figure 1). VAs recurred in 107 patients (39.1%), with a mean cycle length of 318±59 ms. Recurrent VAs had a cycle length >30 ms shorter than the presenting arrhythmia in 4 patients, >30 ms longer in 6 patients, and within 30 ms of the presenting arrhythmia in the remainder. A total of 58 (21.2%) patients died, with 25 experiencing recurrent VA prior to death. The primary endpoint occurred in 40 of 88 (45.5%) in patients who underwent
7
revascularization versus 100 of 186 (53.8%) patients without revascularization (P=0.20). In the revascularization group, 31 patients experienced VAs (35.2%) and 11 (12.5%) died during a mean follow-up of 5.5±4.3 years. In the non-revascularization group, 76 (40.9%) experienced VAs and 47 (25.3%) died during a mean follow-up of 6.5±5.4 years. Prevalence of detected VAs was 102 of 232 (44.0%) in ICD recipients versus 5 of 44 (11.4%) in patients without ICDs. In ICD recipients, 63 (27.2%) received one or more appropriate shock (median of 2.0 shocks, IQR: 1.0-6.8) and 69 (29.7%) were treated with ATP (median of 3.0 ATPs, IQR: 1.0-7.0). Anti-arrhythmic drugs were prescribed to 100 patients and 15 had VT ablation.
Device-Related Complications Overall, 23 (9.9%) ICD recipients received 32 inappropriate shocks due to supraventricular arrhythmias (N=29), lead fracture (N=2), or an inappropriate chiropractor intervention (N=1). Additional complications included lead fracture (N=11; 4.7%), lead dysfunction (N=14; 6.0%), lead dislodgement (N=6; 2.6%), lead recall (N=6; 2.6%), and device infection (N=11; 4.7%), with two cases of endocarditis.
Factors Associated with Recurrent Ventricular Arrhythmias and Death Univariate and multivariable predictors of the combined primary endpoint and its components are summarized in Tables 3 and 4, respectively. In multivariable analysis, age was the only factor independently associated with recurrent VAs or death [hazard ratio (HR) 1.03 per year, 95% confidence interval (CI; 1.01–1.05), P=0.003]. Importantly, revascularization was not associated with a significantly lower rate of recurrent VAs or death [HR 0.86, 95% CI (0.60–1.24), P=0.43], regardless of whether it was complete or incomplete [HR 0.65, 95% CI (0.25–1.69), P=0.37], or
8
performed by percutaneous or surgical means [HR 1.02, 95% CI (0.53–1.94), P=0.96]. Similarly, revascularization was not associated with a lower rate of recurrent VAs or death regardless of whether the presenting arrhythmia was monomorphic VT or polymorphic VT/VF [HR 1.19, 95% CI (0.81–1.75), P=0.36]. Freedom from the primary outcome is plotted in Figure 2 according to whether or not revascularization was performed. In multivariable analyses, ICDs were associated with a 77% mortality reduction [HR 0.23, 95% CI (0.09–0.55), P=0.001].
Discussion To our knowledge, this study is the first to specifically address the impact of coronary revascularization on patients with prior myocardial infarction and a relatively preserved LVEF presenting with clinical sustained VAs. Our main findings are as follows: 1) Despite having an LVEF >40%, patients with chronic CAD and sustained VAs are at very high risk of recurrent sustained VA or death, with this combined endpoint occurring in >50% over an average follow-up of 6.2 years; 2) Risk of recurrent VA or death is not mitigated by coronary revascularization; and 3) ICDs are associated with a significant (>70%) mortality reduction.
Effect of Coronary Revascularization in Chronic CAD The influence of ischemia in the genesis of sustained VAs in patients with chronic stable CAD remains controversial, with some authors suggesting that such VAs are predominantly due to regional or intramural reentry circuits that incorporate regions of diseased myocardium and electrically unexcitable scars, which are not affected by revascularization.14 Theoretically, if ischemia is a trigger for VAs, correction of CAD lesions amenable to revascularization in patients with reversible ischemia should prevent arrhythmia occurrence. Indeed, several studies suggest that patients with moderate or severe left ventricular dysfunction and ischemic or viable
9
myocardium experience superior arrhythmia-free survival and lower mortality following revascularization.4, 5, 7, 15-17 However, results remain inconsistent. In a study of 64 patients with prior myocardial infarction, a mean LVEF of 38±9%, and spontaneous VT, VT remained inducible in 52 of 59 patients despite complete revascularization and >50% experienced arrhythmia recurrence during a follow-up of 32±26 months.9 Similarly, no reduction in appropriate ICD therapies was noted in 130 CAD patients with an LVEF of 36±12% following complete revascularization.18 Moreover, a study of 93 patients with an LVEF of 36±15% reported a comparable incidence of recurrent arrhythmias in patients with VAs before (N=53) versus after (N=40) surgical revascularization.19 The current study expands this discussion to the understudied population with a relatively preserved LVEF and suggests that the preponderance for recurrent VAs is not systematically altered by coronary revascularization.
Mortality The all-cause mortality rate in our study (i.e., 21.2% at a median of 4.8 years) is consistent with prior reports20 and lower than mortality rates observed in patients with VAs and impaired left ventricular systolic function.21-23 The magnitude of the mortality reduction conferred by ICDs observed in our study (i.e., HR 0.23) is likewise consistent with secondary prevention ICD trials and previous reports suggesting that patients with VAs and relatively preserved left ventricular function (LVEF >35%) derive greater benefit from ICDs than those with advanced heart failure.23 This may be due, in part, to a lesser influence of competing risks for mortality, such as heart failure-related deaths.
10
Study Limitations The study is retrospective in nature and, hence, subject to the limitations inherent in observational research. While every effort was made to control for baseline imbalances and potential confounders, multivariable analyses cannot adjust for unmeasured or unknown potential confounders. Importantly, the higher rate of recurrent VAs observed in ICD recipients may be subject to a detection bias due to the recording capabilities of ICDs.24 In order to address this potential bias, all multivariable analyses adjusted for the presence of an ICD. In addition, a sensitivity analysis was conducted by excluding the 44 (16%) patients without ICDs. All results and conclusions regarding the potential impact of revascularization remained unaltered. Moreover, sensitivity analyses that modeled ICD implantation as a time-dependent variable further confirmed the lack of association between revascularization and recurrent VAs [HR 0.87, 95% CI (0.56–1.33), P=0.51] or death [HR 0.97, 95% CI (0.46–2.05), P=0.94]. Additional limitations include the long period of observation (1995-2011), which was incorporated to maximize study power but during which changes to clinical practice occurred, including indications for ICDs and pharmacological therapy. Finally, the presence of reversible ischemia was not systematically assessed prior to angiography, thereby precluding an analysis of the impact of revascularization on a subgroup of patients with a hibernating myocardium.
Conclusion In conclusion, patients with prior myocardial infarction and relatively preserved left ventricular systolic function (LVEF>40%) who present with VAs in the absence of an acute coronary syndrome remain at high risk for recurrent VAs and all-cause death during an intermediate follow-up period. Importantly, coronary revascularization does not appear to mitigate this risk.
11
References 1.
Hillis LD, Cigarroa JE, Lange RA. Late revascularization reduces mortality in survivors of myocardial infarction. Cardiol Rev. 1999;7:144-148.
2.
Carnendran L, Steinberg JS. Does an open infarct-related artery after myocardial infarction improve electrical stability? Prog Cardiovasc Dis. 2000;42:439-454.
3.
Hsia J, Jablonski KA, Rice MM, et al. PEACE Investigators. Sudden cardiac death in patients with stable coronary artery disease and preserved left ventricular systolic function. Am J Cardiol. 2008;101:457-461.
4.
Van der Burg AE, Bax JJ, Boersma E, Pauwels EK, van der Wall EE, Schalij MJ. Impact of viability, ischemia, scar tissue, and revascularization on outcome after aborted sudden death. Circulation. 2003;108:1954-1959.
5.
Chareonthaitawee P, Gersh BJ, Araoz PA, Gibbons RJ. Revascularization in severe left ventricular dysfunction: The role of viability testing. J Am Coll Cardiol. 2005;46:567-574.
6.
Carluccio E, Biagioli P, Alunni G, Murrone A, Giombolini C, Ragni T, Marino PN, Reboldi G, Ambrosio G. Patients with hibernating myocardium show altered left ventricular volumes and shape, which revert after revascularization: evidence that dyssynergy might directly induce cardiac remodeling. J Am Coll Cardiol. 2006;47:969977.
7.
Tarakji KG, Brunken R, McCarthy PM, Al-Chekakie MO, Abdel-Latif A, Pothier CE, Blackstone EH, Lauer MS. Myocardial viability testing and the effect of early intervention in patients with advanced left ventricular systolic dysfunction. Circulation. 2006;113:230-237.
8.
Brugada J, Aguinaga L, Mont L, Betriu A, Mulet J, Sanz G. Coronary artery
12
revascularization in patients with sustained ventricular arrhythmias in the chronic phase of a myocardial infarction: Effects on the electrophysiologic substrate and outcome. J Am Coll Cardiol. 2001;37:529-533. 9.
Brockes C, Rahn-Schonbeck M, Duru F, Candinas R, Seifert B, Turina M. ICD implantation with and without combined myocardial revascularisation--incidence of ICD therapy and late survival. Thorac Cardiovasc Surg. 2002;50:333-336.
10.
Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation. 2006;114:e385-484.
11.
Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes. J Am Coll Cardiol. 2014;64:e139-228.
12.
Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging, J Am Soc Echocardiogr 2015;28:1-39.
13.
Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999;94:496-509.
14.
Stevenson WG, Khan H, Sager P, Saxon LA, Middlekauff HR, Natterson PD, Wiener I. Identification of reentry circuit sites during catheter mapping and radiofrequency ablation of ventricular tachycardia late after myocardial infarction. Circulation. 1993;88:1647-1670.
15.
Elhendy A, Chapman S, Porter TR, Windle J. Association of myocardial ischemia with mortality and implantable cardioverter-defibrillator therapy in patients with coronary artery disease at risk of arrhythmic death. J Am Coll Cardiol. 2005;46:1721-1726.
13
16.
Alderman EL, Bourassa MG, Cohen LS, Davis KB, Kaiser GG, Killip T, Mock MB, Pettinger M, Robertson TL. Ten-year follow-up of survival and myocardial infarction in the randomized coronary artery surgery study. Circulation. 1990;82:1629-1646.
17.
Bell MR, Gersh BJ, Schaff HV, Holmes DR, Jr., Fisher LD, Alderman EL, Myers WO, Parsons LS, Reeder GS. Effect of completeness of revascularization on long-term outcome of patients with three-vessel disease undergoing coronary artery bypass surgery. A report from the Coronary Artery Surgery Study (CASS) registry. Circulation. 1992;86:446-457.
18.
Bourke JP, Richards DA, Ross DL, Wallace EM, McGuire MA, Uther JB. Routine programmed electrical stimulation in survivors of acute myocardial infarction for prediction of spontaneous ventricular tachyarrhythmias during follow-up: Results, optimal stimulation protocol and cost-effective screening. J Am Coll Cardiol. 1991;18:780-788.
19.
Nageh MF, Kim JJ, Chen LH, Yao JF. Implantable defibrillators for secondary prevention of sudden cardiac death in cardiac surgery patients with perioperative ventricular arrhythmias. J Am Heart Association. 2014;3. doi: 10.1161/JAHA.113.000686.
20.
Olshansky B, Hartz V, Hahn E, Mason J, Weaver MD; ESVEM Investigators. Location of death (in-hospital or out-of-hospital) and type of death (arrhythmic, nonarrhythmic, noncardiac) after inducible sustained ventricular tachyarrhythmias after syncope, sustained ventricular tachycardia, or nonfatal cardiac arrest (the ES V EM trial). Am J Cardiol. 2000;86:846-851.
21.
Cook JR, Rizo-Patron C, Curtis AB, Gillis AM, Bigger JT, Jr., Kutalek SP, Coromilas J, Hofer BI, Powell J, Hallstrom AP; AVD Investigators. Effect of surgical revascularization in patients with coronary artery disease and ventricular tachycardia or fibrillation in the Antiarrhythmics Versus Implantable Defibrillators (AVID) registry. Am Heart J. 2002;143:821-826.
14
22.
Oseroff O, Retyk E, Bochoeyer A. Subanalyses of secondary prevention implantable cardioverter-defibrillator trials: Antiarrhythmics Versus Implantable Defibrillators (AVID), Canadian Implantable Defibrillator Study (CIDS), and Cardiac Arrest Study Hamburg (CASH). Current Opinion Cardiol. 2004;19:26-30.
23.
Ronn F, Kesek M, Hoglund N, Jensen SM. Long-term follow-up of patients treated with ICD: Benefit in patients with preserved left ventricular function. Scandinavian Cardiovasc J. 2008;42:125-129.
24.
Ellenbogen KA, Levine JH, Berger RD, Daubert JP, Winters SL, Greenstein E, Shalaby A, Schaechter A, Subacius H, Kadish A. Defibrillators in Non-ischemic Cardiomyopathy Treatment Evaluation I. Are implantable cardioverter defibrillator shocks a surrogate for sudden cardiac death in patients with nonischemic cardiomyopathy? Circulation. 2006;113:776-782.
Clinical Perspectives Several studies have demonstrated that coronary revascularization improves survival in patients with chronic ischemic heart disease and left ventricular dysfunction. However, the impact of revascularization on cardiovascular outcomes remains controversial for patients with relatively preserved ventricular function post myocardial infarction. The current study tackles this knowledge gap by specifically addressing the question of whether coronary revascularization reduces the rate of recurrent ventricular arrhythmias and all-cause mortality in patients with coronary disease, a left ventricular ejection fraction ≥40%, and clinical sustained ventricular arrhythmias in the absence of an acute coronary syndrome. Coronary revascularization, whether complete or incomplete, or achieved by percutaneous or surgical means, was not associated with a reduction in the combined outcome consisting of recurrent ventricular arrhythmias or death in
15
this patient population. Moreover, revascularization was not associated with a reduction in recurrent ventricular arrhythmias considered separately, or of all-cause death. Results remained consistent whether patients presented with sustained monomorphic ventricular tachycardia or polymorphic ventricular tachycardia/ventricular fibrillation. In contrast, as may be expected, implantable cardioverter-defibrillators (ICD) were associated with a large morality reduction (>70%). These results suggest that coronary revascularization should not be considered primary therapy for ventricular arrhythmias in patients with coronary artery disease and relatively preserved ventricular function, nor as a substitute for an ICD.
Figure Legends Figure 1. Flowchart of Clinical Outcomes CAD denotes coronary artery disease; LVEF, left ventricular ejection fraction; ICD, implantable cardioverter-defibrillator; VAE, ventricular arrhythmia event; FU, follow-up
Figure 2. Freedom from Recurrent Ventricular Arrhythmias or Death according to Whether Revascularization Was Performed CI denotes confidence interval
16
Tables Table 1. Baseline Characteristics Baseline Characteristics
Gender, male Age, years Hypertension Diabetes mellitus Dyslipidemia Tobacco Renal failure* NYHA 1-2 3-4 Time from last MI, years Coronary artery disease Location of MI Anterior Inferior Lateral Number of diseased vessels† One Two Three ECG data QRS width (ms) Echocardiographic data Hypokinesia/akinesia Aneurysm LVEF, % LVEF>50% Pharmacological therapy Anti-arrhythmic agent Amiodarone Sotalol ß-Blocker ACE inhibitor Aldosterone antagonist
Total Population N=274 231 (84.3) 66.1 ± 9.7 168 (61.3) 68 (24.8) 208 (75.9) 121 (44.2) 50 (18.3)
Population with Revascularization N=88 76 (86.4) 65.7 ± 9.5 55 (62.5) 26 (29.5) 66 (75.0) 32 (36.4) 17 (19.3)
Population without Revascularization N=186 158 (84.9) 66.4 ± 9.8 113 (60.8) 42 (22.6) 142 (76.3) 89 (47.8) 33 (17.7)
P-Value
268 (97.8) 6 (2.2) 11.1 ± 9.8
84 (95.4) 4 (4.6) 8.6 ± 10.1
184 (98.9) 2 (1.1) 12.3 ± 9.6
0.006
52 (20.2) 200 (77.8) 5 (2.0)
16 (18.2) 63 (71.6) 3 (3.4)
36 (19.4) 137 (73.4) 2 (1.1)
0.84 0.79 0.17
97 (36.3) 66 (24.7) 104 (39.0)
27 (30.7) 26 (29.5) 34 (38.6)
70 (37.6) 40 (21.5) 70 (37.6)
0.21 0.17 0.98
110 ± 23.2
105.4 ± 22.5
113.0 ± 23.0
0.01
251 (91.6) 26 (9.5) 48.3 ± 7.2 78 (28.5)
79 (89.8) 8 (9.1) 48.3 ± 6.6 25 (28.4)
172 (92.5) 18 (9.7) 48.4 ± 7.4 53 (28.5)
0.45 0.88 0.89 0.99
100 (36.5) 59 (21.5) 22 (8.0) 178 (65.0) 141 (51.5) 6 (2.2)
27 (30.7) 23 (26.1) 3 (3.4) 62 (70.5) 42 (47.7) 2 (2.3)
73 (39.2%) 36 (19.4) 19 (10.2) 116 (62.4) 99 (53.2) 4 (2.2)
0.17 0.20 0.053 0.19 0.39 0.95
0.76 0.60 0.70 0.21 0.81 0.07 0.75 0.07
Continuous variables are expressed as mean ± standard deviation and categorical variables as frequency (percentage). NYHA denotes New York Heart Association; MI, myocardial infarction; LVEF, left ventricular ejection fraction; ACE, angiotensin-converting enzyme *
Defined as a creatinine clearance <50 mL/min
†
Coronary angiography was not performed in 7 patients
17
Table 2. Characteristics of the Presenting Arrhythmia
Monomorphic ventricular tachycardia, N (%)
201 (73.4)
Mean cycle length, ms
303 ± 64
Median cycle length, ms (25th, 75th percentile)
300 (260, 340)
Polymorphic ventricular tachycardia/Torsade de Pointes, N (%)
25 (9.1)
Ventricular fibrillation, N (%)
48 (17.5)
Hemodynamically well-tolerated, N (%)
137 (50.0)
Time since myocardial infarction, years Mean ± standard deviation
11.1 ± 9.8
Median (25th, 75th percentile)
9.8 (1.3, 17.9)
18
Table 3. Univariable Predictors of Recurrent Ventricular Arrhythmias or Death
Gender, male Age, years Hypertension Diabetes mellitus Dyslipidemia Tobacco Renal failure* NYHA I-II vs III-IV Coronary artery disease Location of MI Anterior Inferior Lateral Number of diseased vessels† One Two Three ECG data QRS width (ms) Echocardiographic data Hypokinesia/akinesia Aneurysm LVEF, 40-50% vs >50% Pharmacological therapy Amiodarone
Recurrent VA or death HR [95% PCI] value 1.50 0.88 – 0.14 2.56 1.03 [1.02 – 0.0006 1.06] 0.87 [0.62 – 0.42 1.22] 1.60 [1.09 – 0.02 2.35] 0.76 [0.53 – 0.15 1.11] 1.08 [0.78 – 0.63 1.51] 1.89 [1.24 – 0.003 2.88] 0.73 [0.23 – 0.59 2.29]
0.83 [0.19 – 3.54] 1.32 [0.32 – 5.34] Reference
0.80
0.96 [0.65 – 1.111.42] [0.72 –
0.10
0.70
0.07
1.71] Reference
Recurrent VA HR [95% CI] Pvalue 1.37 0.79 – 0.26 2.36 1.02 [1.00 – 0.040 1.05] 1.01 [0.68 – 0.96 1.50] 1.60 [1.03 – 0.035 2.48] 0.79 [0.51 – 0.29 1.22] 1.00 [0.68 – 0.98 1.48] 1.27 [0.74 – 0.39 2.18] 0.57 [0.18 – 0.35 1.82]
1.24 [0.16 – 9.76] 2.34 [0.32 – 17.05] Reference
0.83
1.12 [0.70 – 1.241.78] [0.74 –
0.63
0.40
0.40
2.07] Reference
Death HR [95% CI] 1.58 0.47 – 5.29 1.03 [1.01 – 1.08] 0.55 [0.28 – 1.07] 0.97 [0.42 – 2.23] 0.73 [0.35 – 1.52] 1.23 [0.62 – 2.45] 3.43 [1.69 – 6.99] 0.82 [0.05 – 14.51]
Pvalue 0.46
0.036 0.07 0.94 0.40 0.55
0.0007 0.89
0.33 [0.04 – 2.68] 0.55 [0.08 – 3.67] Reference
0.30
0.73 [0.34 – 0.711.57] [0.30 –
0.41
0.54
0.44
1.69] Reference
1.01 [0.99 – 1.01]
0.18
1.00 [0.99 – 1.01]
0.74
1.01 [1.00 – 1.02]
0.07
1.14 [0.56 – 2.33] 1.22 [0.72 – 2.05] 1.47 [0.45 – 1.39]
0.72
1.03 [0.48 – 2.22] 1.18 [0.63 – 2.25] 1.27 [0.79 – 2.04]
0.94
0.44 [0.07 – 2.88] 0.91 [0.30 – 2.83] 0.54 [0.21 – 1.36]
0.39
0.82 [0.56 –
0.31
1.41 [0.94 –
0.10
0.66 [0.28 –
0.35
0.46 0.07
19
0.60 0.31
0.87 0.19
Sotalol ß-Blocker ACE inhibitor Aldosterone antagonist Well-tolerated VA Monomorphic VT vs PVT/VF Revascularization Complete vs incomplete Angioplasty vs CABG ICD implantation
1.20] 0.73 [0.39 – 1.37] 0.86 [0.61 – 1.20] 0.88 [0.63 – 1.23] 1.66 [0.53 – 5.23] 0.83 [0.60 – 1.17] 1.19 [0.81 – 1.75] 0.90 [0.62 – 1.29] 0.65 [0.25 – 1.69] 1.02 [0.53 – 1.94] 1.73 [0.98 – 3.07]
0.96 0.37 0.46 0.39 0.29 0.36 0.55 0.37 0.96 0.06
2.11] 0.98 [0.45 – 2.11] 0.94 [0.63 – 1.40] 0.97 [0.66 – 1.42] 1.16 [0.34 – 5.62] 0.88 [0.60 – 1.30] 1.53 [0.96 – 2.45] 0.88 [0.57 – 1.35] 0.83 [0.29 – 2.38] 0.90 [0.42 – 1.92] 4.96 [1.85 – 13.31]
0.95 0.74 0.86 0.86 0.53 0.07 0.55 0.73 0.79 0.002
1.56] 0.59 [0.14 – 2.60] 0.77 [0.39 – 1.51] 0.63 [0.32 – 1.27] 1.99 [0.25– 15.81] 1.04 [0.53 – 2.03] 0.55 [0.28 – 1.09] 1.00 [0.48 – 2.07] 0.55 [0.11 – 2.78] 1.06 [0.33 – 3.48] 0.32 [0.15 – 0.73]
0.48 0.45 0.20 0.51 0.92 0.09 1.00 0.47 0.94 0.006
VA denotes ventricular arrhythmia; HR, hazard ratio; CI, confidence interval; NYHA, New York Heart Association; MI, myocardial infarction; ECG, electrocardiogram; LVEF, left ventricular ejection fraction; ACE, angiotensin-converting enzymbe; VT, ventricular tachycardia; PVT, polymorphic VT; VF, ventricular fibrillation; CABG, coronary artery bypass graft; ICD, implantable cardioverterdefibrillator *
Defined as a creatinine clearance <50 mL/min
†
Coronary angiography was not performed in 7 patients
20
Table 4. Multivariable Predictors of Recurrent Ventricular Arrhythmias or Death Recurrent VA or death HR [95%
P-value
Recurrent VA HR [95% CI]
Death
P-value
HR [95% CI]
P-value
1.04 [0.99 –
0.06
CI] Age, years
1.03 [1.01 –
0.003
1.05]
1.09] 1.45 [0.93 – 2.29]
Diabetes mellitus Renal failure*
1.48 [0.93 –
0.11 4.94 [2.16 –
0.09
2.36]
11.30] 1.61 [1.01 –
Monomorphic VT vs PVT/VF ICD implantation
0.12
2.83] Revascularization
0.048
2.57] 1.59 [0.89 –
0.86 [0.60 – 1.24]
0.0002
4.85 [1.82 –
0.84 [0.55 – 1.29]
0.008
0.76] 0.002
12.98] 0.43
0.35 [0.16 –
0.23 [0.09 –
0.001
0.55] 0.43
0.98 [0.47 –
0.97
2.04]
VA denotes ventricular arrhythmia; HR, hazard ratio; CI, confidence interval; MI, myocardial infarction; VT, ventricular tachycardia; PVT, polymorphic VT; VF, ventricular fibrillation; ICD, implantable cardioverter-defibrillator *
Defined as a creatinine clearance <50 mL/min
21
22
23