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Clinical predictors of cardiac events in patients with isolated syncope and negative electrophysiologic study
International Journal of Cardiology 109 (2006) 28 – 33 www.elsevier.com/locate/ijcard
Clinical predictors of cardiac events in patients with isolated syncope and negative electrophysiologic study Antoine Da Costa*, Jean-Luc Gulian, Ce´cile Romeyer-Bouchard, Marc Messier, Naı¨ma Zarqane, Bernard Samuel, Abdel Khiel, Karl Isaaz Division of Cardiology, University Jean Monnet of Saint-Etienne, 42000 Saint-Etienne, France Received 16 March 2005; received in revised form 1 May 2005; accepted 14 May 2005 Available online 21 June 2005
Abstract Background: Patients with syncope or near syncope of unknown etiology represent a great challenge to cardiologists. An initial symptomatic episode triggers a series of diagnostic analysis which remain unsatisfactory when negative. More invasive tools such as electrophysiologic testing yield only partial answers to risk stratification while the complementary implantable holter diagnostics are not usually considered until a recurrent episode is documented. Objective: This study targets predictors of significant cardiac rhythmic events in patients with a reported episode of syncope or near syncope presenting with negative diagnostics and electrophysiologic study results (EPS). A significant cardiac rhythmic event was defined as a combined end-point of (1) symptomatic AV block; (2) symptomatic conduction abnormalities requiring pacemaker therapy; (3) symptomatic sustained ventricular arrhythmia; and (4) sudden death. Methods: All patients undergoing EPS after a first episode of syncope or presyncope between January 1997 and December 2001 were included for analysis. The study population consisted of 329 pts (42.6% women), 21 to 96 years old (mean 70 T 15 years) referred for an EP study for syncope or near syncope. Results: Of the 329 patients who underwent EPS, 305 (92.7%) had follow-up data. The population, mean age 70 (T 15 years) and composed of 42% women, presented with hypertension (51.5%), diabetes mellitus (14.4%), hypercholesterolemia (30%), tobacco use (35%), a familial history of coronary heart disease (22%), history of stroke (4%), history of MI (12%), history of atrial fibrillation (10%), structural heart disease (17.4%), left ventricular ejection fraction 61 (T 11%) and ECG abnormalities (37%). These anomalies included right (RBBB) or left (LBBB) bundle branch blocks, left anterior fascicular block (LAFB), left posterior fascicular block (LPFB), bifascicular block (RBBB + LAFB) and traces of myocardial infarction. The mean follow-up was 31 T 20 months with 5% of patients recording significant cardiac rhythmic events (15 / 305): AV block requiring pacemaker therapy in 7 patients, sinus dysfunction in 4, sudden death in 3 and ventricular tachycardia in 1. Univariate analysis reveals structural heart disease, ECG abnormalities and LVEF associated with the risk of significant cardiac rhythmic events defined by the combined end-point. Multivariate analysis using a Cox model found that the only independent predictor of events was an ECG abnormality. The long-term risk of significant event in the subset with ECG abnormalities is of 10.6% (12 / 113). If unexplained syncope recurrence was included in the combined endpoint, ECG abnormality and LVEF were both determinants with a 13.3% (15 / 113) risk of a arrhythmic events analysis in the subset of patients presenting with ECG abnormalities and Cox model found ECG abnormality as the only independent predictor of event. Conclusions: This study demonstrated that an ECG abnormality is the only predictive variable associated with a significant arrhythmic event in patients with a lone episode of syncope or near syncope and a negative EPS. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Syncope; Risk stratification; Electrophysiology testing; Arrhythmia; Heart block; Electrocardiography; Risk factors
Abbreviations: EPS, negative electrophysiologic study; RBBB, right bundle branch block; LBBB, left bundle branch block; LAFB, left anterior fascicular block; LPFB, left posterior fascicular block; ECG, electrocardiogram; LVEF, left ventricular ejection fraction; VT, ventricular tachycardia. * Corresponding author. Service de Cardiologie, Hoˆpital Nord, Centre Hospitalier Universitaire de Saint-Etienne, 42 055 Saint-Etienne Cedex 2, France. Tel.: +33 4 77 82 83 40; fax: +33 4 77 82 84 51. E-mail address: [email protected] (A. Da Costa). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.05.025
A. Da Costa et al. / International Journal of Cardiology 109 (2006) 28 – 33
1. Introduction Syncope is a situation that can be caused by many conditions ranging from benign, self-limiting to malignant – recurrent and potentially fatal events [1 – 3]. A recent epidemiological study on prognosis concluded that patients with cardiac syncope are at increased risk of death from any cause and at an increased risk of cardiovascular events [4]. Clinical history and physical examination completed by a 12-lead EKG are sufficient to establish a diagnosis [1,2] in about 60% of patients reporting a syncope. The remaining 40% remain of unknown aetiology even after extensive clinical workup. The yield of laboratory investigation is disappointing as is the value of neurological evaluation in patients without evidence of epilepsy [5]. Similarly, the results from ambulatory ECG monitoring with transient high-degree AV block are disappointing when these can not be evidenced by an electrophysiological study (EPS) [6– 8]. More recently Brignole et al. reported most syncope recurrences were mainly attributable to sudden-onset paroxysmal AV blocks in patients with repetitive syncope, bundle branch block (BBB) and negative EPS [9]. Little is known, however, concerning patients after a first episode of syncope or near syncope with a negative workup including EPS. Neither is it clear how to stratify patients at high-risk. Several questions thus remain: how does one manage patients with negative results? Which anomaly should be addressed when numerous causes are suspected? The aim of this study was to assess clinical parameters as predictors of significant cardiac rhythmic events in patients with a first episode of syncope or near syncope yielding a negative workup and not indicated for an implantable Holter monitor according to current guidelines.
2. Methods 2.1. Study population All patients referred in our center between 01/97 and 12/01 after a first episode of syncope or presyncope and with a negative EPS were included. They were all already selected before being addressed for an EPS by an extensive negative workup including risk factors analysis, history, physical examination, elimination of postural hypotension or hypoglycemia, baseline ECG, carotid sinus massage, 24-h ambulatory monitoring and echocardiogram. The EPS was performed regarding both absence of evident aetiology and clinical suspected cardiac cause. An echocardiogram and a complete EPS were performed. The study population consisted of 329 pts (42.6% women), 21 to 96 years old (mean 70 T 15 years) with syncope or presyncope referred for EPS. Syncope was defined as a transient loss of consciousness with spontaneous recovery that did not require either chemical or electrical cardioversion. Presyncope was defined as a sensation of near
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fainting (dizziness, light-headedness, wooziness, spells) without actual loss of consciousness, with or without associated symptoms such as blurred vision, palpitations or sweating. All patients data were analyzed after an echocardiogram and a complete EPS. 2.2. EPS protocol The EPS study included measurement of the sinus node recovery time; HV interval at baseline and under stress by incremental pacing; inducibility of ventricular arrhythmia by means of programmed ventricular pacing (with 3 cycles and 3 extrastimuli) and inducibility of supraventricular arrhythmia by an atrial pacing protocol. EPS results were considered positive and the patients excluded from the study in the following cases: (1) sinus bradycardia and abnormal sinus recovery time; (2) baseline HV 70 ms, 2nd or 3rd degree His – Purkinje block demonstrated during incremental atrial pacing or highdegree His– Purkinje block elicited by IV administration of ajmaline; (3) induction of sustained monomorphic ventricular tachycardia or (4) induction of rapid supraventricular arrhythmia with a similarity to patient-reported symptoms. When the baseline study was inconclusive with an HV interval between 60 and 70 ms, then a slow infusion of ajmaline (1 mg/kg IV over 2 min) was performed in the absence of left ventricular dysfunction. 2.3. End-points The primary objective of the study was to identify predictive factors of significant cardiac rhythmic events defined by a combined end-point associating: (1) symptomatic AV block; (2) symptomatic conduction abnormalities requiring pacemaker therapy; (3) symptomatic sustained ventricular arrhythmia and (4) sudden death. The secondary objective was to identify predictive factors of events defined by the following modified combined endpoint associating: (1) unexplained syncope recurrence; (2) symptomatic AV block; (3) symptomatic recording rhythm abnormality requiring pacemaker therapy; (4) symptomatic ventricular arrhythmia; and (5) sudden death. A subanalysis was also carried out to identify the predictive factors of total mortality in this subset of patients. 2.4. Follow-up Clinical evaluation was made for each combined endpoint defined by at least one clinical event. One observer (JLG) blinded to patient initial status and carried out by interviewing the patients and their medical practitioner or cardiologist obtained follow-up. These were completed in 305 / 329 patients (92.7%) with twenty-four patients lost to follow-up (7.3%). Cumulative risk of events was determined by outpatient follow-up and on recurring symptoms. The outpatient follow-up was performed by the referring
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A. Da Costa et al. / International Journal of Cardiology 109 (2006) 28 – 33
Table 1 Population characteristics Study population (n = 305) Age (years) Gender (% female) Hypertension Diabetes mellitus Tobacco Hypercholesterolemia Familial history of coronary heart disease History of stroke History of MI History of atrial fibrillation Structural heart disease Left ventricular ejection fraction ECG abnormality Baseline HV interval length, ms
70 T 15 128 / 305 157 / 305 44 / 305 106 / 305 91 / 305 67 / 305 12 / 305 37 / 305 30 / 305 17.4% 61 T11% 37% 53 T 7
(42%) (51.5%) (14.4%) (35%) (30%) (22%) (4%) (12%) (10%)
initial model were as follows: age, gender, hypertension, diabetes mellitus, hypercholesterolemia ( 6.5 mmol/l or prior cholesterol treatment), tobacco, coronary heart disease family history, history of stroke, history of MI, history of atrial fibrillation, structural heart disease, left ventricular ejection fraction, ECG abnormalities. ECG abnormalities included right (RBBB) or left (LBBB) bundle branch block, left anterior fascicular block (LAFB), left posterior fascicular block (LPFB), bifascicular block (RBBB and LAB) and signs of ancient myocardial infarction. Multivariate analysis was performed using a Cox model and incorporated all variables found statistically significant by univariate analysis ( p value < 0.05).
3. Results cardiologist and by the medical practitioner. Electrocardiograms were programmed at each consultation, at the end of follow-up and on recurring symptoms. 2.5. Statistical analysis Data are expressed as mean T S.D. The differences among groups were analyzed by ANOVA. A probability value of p < 0.05 was accepted as statistically significant. Univariate analysis assessed whether clinical, ECG variables or LVEF predicted a clinical event. Univariate analysis was considered significant with a p-value below < 0.05. Log rank survival tests determined statistically significant ( p < 0.05) differences of categorical variables. Variables tested in the
3.1. Clinical characteristics of patients Population data for the 305 patients were as follows: (Table 1) age (mean 70 T 15 years), gender (42% women), hypertension (51.5%), diabetes mellitus (14.4%), hypercholesterolemia (30%), tobacco (35%), coronary heart disease family history (22%), history of stroke (4%), history of MI (12%), history of atrial fibrillation (10%), left ventricular ejection fraction (61 T11%), ECG abnormalities (37%). ECG abnormalities included right (RBBB) or left (LBBB) bundle branch block, left anterior fascicular block (LAFB), left posterior fascicular block (LPFB), bifascicular block (RBBB and LAB) and old myocardial
Table 2 Primary end-point Structural heart disease gender; age Ischaemic cardiomyopathy Male; 71 years Female; 88 years Male; 80 years Female; 75 years Male ; 75 years Ischaemic cardiomyopathy Male; 75 years Female; 71 years Male; 69 years Dilated cardiomyopathy Male; 72 years Ischaemic cardiomyopathy Female; 58 years Male; 92 Male; 65 years Dilated cardiomyopathy Male; 76 years Dilated cardiomyopathy Male; 71 years Female; 67 years
Time since EPS (months)
Basal ECG
Event description
Therapy
14 7 1 12 39
RBB + LAFB LBB RBB + LAFB LBB RBB + LAFB
3- AV block 2- AV block 3- AV block Sinus dysfunction 3- AV block
Pacemaker Pacemaker Pacemaker Pacemaker Pacemaker
15 56 9
LBB Normal LBB
2- AV block Sinus dysfunction 2- AV block + resynchronization
Pacemaker Pacemaker Pacemaker
19
RBB + LAFB
Sinus arrest
Pacemaker
4 48 1
LBB RBB LBB
Sinus arrest 2- AV block TV
Pacemaker Pacemaker ICD
42
Normal
Sudden death
–
70 9
LBB LBB
Sudden death Sudden death
– –
Right (RBBB) or left (LBBB) bundle branch block; left anterior fascicular block (LAFB), left posterior fascicular block (LPFB); bifascicular block (RBBB and LAB); implanted cardiac defibrillator (ICD).
A. Da Costa et al. / International Journal of Cardiology 109 (2006) 28 – 33
infarction. Fifty-three patients (17%) had structural heart disease: 30 coronary artery diseases, 15 dilated cardiomyopathy, hypertrophic cardiomyopathy in 6 cases and 2 valvular heart diseases (mitral regurgitation in 1 and aortic regurgitation in 1). 3.2. Primary end-point The mean follow-up was 31 T 20 months and 5% significant events (15 / 305) occurred; AV block requiring pacemaker therapy in 7, sinus dysfunction requiring pacemaker therapy in 4, sudden death in 3 (mean LVEF = 58%), and ventricular tachycardia in 1 (VT) (Table 2). By univariate analysis, structural heart disease ( p = 0.01), ECG abnormalities (0.003) and LVEF ( p = 0.02) were associated with the risk of significant event occurrence defined by the combined end-point (Table 3). Multivariate analysis using a Cox model found that the only independent predictor was an ECG abnormality ( p = 0.01). The long-term risk of significant event in the subset of patients with ECG abnormalities is of 10.6% (12 / 113), whereas the risk is of 1.6% (3 / 192) in patients without ECG abnormalities.
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3.4. Third end-point The overall long-term mortality in this study was å3% at 2.5 years with only 8% due to sudden death. By univariate analysis there were 3 variables associated with overall mortality: age ( p < 0001 ), LVEF ( p = 0.0054 ) and a history of myocardial infarction ( p = 0.049). By multivariate analysis only age ( p < 0001) and LVEF ( p = 0.02) were independent predictors of mortality.
4. Discussion 4.1. Major findings The main finding of this study is that patients with a first episode of syncope or presyncope and a negative EPS present a low (5%) long-term risk of significant arrhythmia, while the risk is å8% at 2.5 years when unexplained syncope recurrences were included in the analysis. In the subset with documented events the analysis emphasizes the role of homogeneous mechanism that is characterized by mainly paroxysmal or permanent AV block in 7 / 15 patients (å50%).
3.3. Secondary end-point 4.2. Overall prognosis of patients with unexplained syncope When unexplained syncope recurrence was included in the combined end-point, only ECG abnormalities ( p = 0.003) and LVEF ( p = 0.03) were predictors by univariate analysis. A Cox model found that ECG abnormality was the only independent predictor of cardiac rhythmic events ( p = 0.01). The long-term risk of significant events including unexplained syncope recurrence in the subset of patients with ECG abnormalities is of 13.3% (15 / 113).
Table 3 Univariate predictors of combined point (AV block, sinus dysfunction, sudden death, ventricular tachycardia) in the overall population
Age (years) Gender (% female) Hypertension Diabetes mellitus Tobacco Hypercholesterolemia Coronary heart disease family history History of stroke History of MI History of atrial fibrillation (10%) Structural heart disease Left ventricular ejection fraction ECG abnormalities
Arrhythmia event (n = 15)
No arrhythmia event (n = 290)
p value
74 T 9 6 / 15 10 / 15 3 / 15 6 / 15 3 / 15 2 / 15
70 T 15 123 / 290 149 / 290 87 / 290 100 / 290 87 / 290 64 / 290
0.3 ns 0.23 0.3 0.75 0.7 0.8
(40% ) (66%) (20%) (40%) (20%) (13.3%)
(42.4%) (51.4%) (30%) (34.4%) (30%) (22%)
0 / 15 (0%) 3 / 15 (20%) 0 / 15 (0%)
12 / 290 (4.1%) 38 / 290 (13.1%) 30 / 290 (10.3%)
ns 0.7 0.4
6 / 15 (40%) 54 T 11
47 / 290 (16.2%) 61 T11
0.01 0.02
11 / 15 (73%)
102 / 290 (35%)
0.003
Patients with syncope due to cardiac cause are at increased risk for death from any cause and cardiovascular events but despite extensive evaluation unexplained syncope was found in 14% to 36.6% of patients [4,10 – 12]. More recently Storiades et al. demonstrated that syncope of unknown cause is associated to a + 30% increased death rate [4]. Although the cardiac causes of syncope were shown in the 1980s to be associated with increased mortality, recent evidence showed that underlying heart disease, irrespective of the cause of syncope, is the factor associated with an increased mortality [13,14]. Several other studies have evaluated syncope of unknown causes and demonstrated a similarly higher mortality [15,16]. Generally, electrophysiological studies and electrocardiographic monitoring in highly selected subgroups of patients have suggested that 45% to 80% of syncope classified as being of unknown etiology could be assigned a cardiac origin [13]. A risk stratification study compiling cardiac arrhythmia or death (within 1 year) [17] highlighted 4 factors that were predictors: age, a history of heart failure, a history of ventricular arrhythmia and an abnormal ECG [17]. Our study found that three variables are predictive of longterm mortality: age, history of MI and LVEF though multivariate analysis selected the independent predictive factors of age and LVEF. These findings suggest that persons with cardiac syncope constitute a high-risk group predisposed to mortality that should be monitored closely and treated.
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A. Da Costa et al. / International Journal of Cardiology 109 (2006) 28 – 33
4.3. Cardiac prognosis of patients with unexplained syncope
4.4. Clinical implications
Little data exist concerning patients with a first syncopal or presyncopal episode and negative workup (comprising EPS). If symptoms suggest arrhythmic syncope, the negative results of the EPS could be due to the low sensitivity of EPS [17 –19]. Kushner et al. evaluated the natural history of patients with unexplained syncope and a negative yield for electrophysiologic study but could not evidence predictive variables despite a high recurrence rate [15]. Our analysis concerns only patients with an initial syncope or near syncope with a negative EPS: the results show that the risk of arrhythmic events is low (å5%) and similar to the 6.3% reported by others [15]. Three variables were predictive of a significant arrhythmic event: presence of structural heart disease, LVEF and an ECG abnormality; a Cox model analysis highlights the independent predictive value of ECG abnormality. These results agree with other reports [20 – 22]. The ECG abnormalities subgroup poses a risk of arrhythmia close to 11% at 30 months. Our study evidenced that the main mechanism of cardiac events is due to paroxysmal or permanent AV block (å50%). These results are consistent with others with Link et al. and Gaggioli et al. observing the development of AV block in 18% (after 30 months) and in 19% (after 62 months) of patients with repetitive syncopes and negative electrophysiological studies [7,8] respectively. While a syncope and abnormal EPS were shown to associate an increased risk of AV block, by 17% and 12% [23,24] respectively, there remains a significant problem in evaluating patients with only one syncopal event presenting with ECG abnormalities and negative EPS; this is may be due to the transient nature of a high-degree AV block, requiring long monitoring periods [25]. More recently, Brignole et al. signed the ISSUE landmark study which relied on an implantable loop recorder. They found that most syncopal recurrences were due to paroxysmal AV blocks in patients with repetitive syncopes (mean number of 3 / patients), bundle branch blocks and a negative EPS [9]. We find an additional 25% sinus node dysfunction causing recurrent events despite a normal sinus node recovery time, illustrating that the sensitivity of the sinus node recovery times ranges from 60% to 70% [26 –28]. Comparing the ventricular arrhythmic risk event, (sudden death and ventricular tachycardia) we find approximately 25% (4 / 15) event rates in the presence of patients with heart disease and without a severely LVEF [13], a rate much higher than that reported previously. Our results suggest that further diagnostic testing may be warranted in patients with one syncopal episode and identify ECG abnormalities as the only independent predictive factor of cardiac rhythmic events. In this subset of patients, current guidelines specifying implant only after a recurrence should be re-evaluated with a strategy relying on close monitoring with an implantable loop recorder immediately after initial events.
The risk of cardiac rhythmic events after an initial syncopal or near syncopal episode and a negative evaluation including EPS seems to be low, 5% at 2.5 years. In this subset, the majority of events were AV block in å50% (7 / 15) and sinus dysfunction in å25% (4 / 15) of patients, thus requiring pacemaker therapy. There are an additional å25% of patients, however, presenting with sudden death or VT. Three markers were evidenced as predictive factors (LVEF, structural heart disease and ECG abnormalities), with only one as an independent marker of cardiac arrhythmic event, initial ECG abnormalities. These results emphasize the role of AV block in recurrent syncope in a group with isolated syncope or presyncope despite negative EPS. The long-term risk of significant event in this subset in the presence of ECG abnormalities is of 10.6% (12 / 113), whereas the risk is of 1.6% (3 / 192) in patients without ECG abnormalities. Thus, a negative EPS investigation cannot rule out a paroxysmal AV block, a sinus dysfunction or a ventricular arrhythmia as the cause of syncope and new diagnostic approaches should be evaluated for patients with lone isolated syncope or presyncope and ECG abnormalities. This study should assist in optimizing the workup of lone syncope, avoiding some tests and focusing in a subset of patients at higher risk of arrhythmic events. 4.5. Study limitations Twenty-four patients were lost to follow-up (7.3%) and their outcome may have affected the conclusions of the study despite their weak number. The fact that ajmaline was only used when HV interval was slightly prolonged could have decreased the predictive power of EPS. Our study provides a retrospective analysis of patients and has the inherent limitations of this design. A large, prospective study would have better met the objectives. Diagnostic evaluation with extended monitoring was not performed and these devices may be helpful in patients whose initial test yielded false negative results after a first syncopal episode [29]. The fact that ajmaline was only used when HV interval was slightly prolonged could have decreased the predictive power of EPS. 4.6. Conclusions This study demonstrates that patients with an initial episode of syncope or near syncope and a negative workup including EPS should nevertheless be stratified according to ECG abnormality as this is found to be the only independent predictive variable associated with a significant cardiac rhythmic occurrence. In patients with ECG abnormalities the risk is estimated at 10.6% and while predominant events (å50%) are due to paroxysmal or permanent symptomatic AV block there seem to be at least 25% related to sudden death or ventricular tachycardia.
A. Da Costa et al. / International Journal of Cardiology 109 (2006) 28 – 33
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[16] Sra JS, Anderson AJ, Sheikh SH, et al. Unexplained syncope evaluated by electrophysiologic studies and head-up tilt testing. Ann Intern Med 1991;114:1013 – 9. [17] Linzer M, Yang EH, Estes NA, et al. Diagnosing syncope: Part II. Unexplained syncope: clinical efficacy assessment project of the American college of physicians. Ann Intern Med 1997;127:76 – 86. [18] Fujimura O, Yee R, Klein GJ, et al. The diagnostic sensitivity of electrophysiologic testing in patients with syncope caused by transient bradycardia. N Engl J Med 1989;321:1703 – 7. [19] Klein GJ, Gersh BJ, Yee R, Electrophysiological testing. The final court of appeal for diagnosis of syncope? Circulation; 92: 1332 – 1335. [20] Alboni P, Brignole M, Menozzi C, et al. The diagnostic value of history in patients with syncope with or without heart disease. J Am Coll Cardiol 2001;37:1921 – 8. [21] Middlekauff H, Stevenson W, Stevenson L, et al. Syncope in advanced heart failure: high risk of sudden death regardless of origin of syncope. J Am Coll Cardiol 1993;21:110 – 6. [22] Martin TP, Hanussa BH, Kapoor WN. Risk stratification of patients with syncope. Ann Emerg Med 1997;29:459 – 66. [23] McAnulty JH, Rahimtoola SH, Murphy E, et al. Natural history of ‘‘high risk’’ bundle branch block. Final report of a prospective study. N Engl J Med 1982;307:137 – 43. [24] Scheinman MM, Peters RW, Sauve´ MJ, et al. Value of the H – Q interval in patients with bundle branch block and the role of prophylactic permanent pacing. Am J Cardiol 1982;50:1316 – 22. [25] Bergfeldt L, Edvardsson N, Rosenqvist M, et al. Atrioventricular block progression in patients with bifascicular block assessed by repeated electrocardiography and a bradycardia-detecting pacemaker. Am J Cardiol 1994;74:1129 – 32. [26] Strauss HC, Bigger JT, Saroff AL, et al. Electrophysiologic evaluation of sinus node function in patients with sinus node dysfunction. Circulation 1976;53:763 – 6. [27] Scheinman MM, Strauss HC, Abott JA, et al. Electrophysiologic testing in patients with sinus pauses and/or sino-atrial exit block. Eur J Cardiol 1978;8:51 – 60. [28] Reiffel JA, Bigger JT, Cramer M, et al. Ability of holter electrocardiographic recording and atrial stimulation to detect sinus nodal dysfunction in symptomatic and asymptomatic patients with sinus bradycardia. Am J Cardiol 1977;40:189 – 94. [29] Roche F, Gaspoz JM, Pichot V, et al. Accuracy of an automatic and patient-triggered long term solid memory ambulatory cardiac event recorder. Am J Cardiol 1997;80:1095 – 8.
Clinical predictors of cardiac events in patients with isolated syncope and negative electrophysiologic study Antoine Da Costa*, Jean-Luc Gulian, Ce´cile Romeyer-Bouchard, Marc Messier, Naı¨ma Zarqane, Bernard Samuel, Abdel Khiel, Karl Isaaz Division of Cardiology, University Jean Monnet of Saint-Etienne, 42000 Saint-Etienne, France Received 16 March 2005; received in revised form 1 May 2005; accepted 14 May 2005 Available online 21 June 2005
Abstract Background: Patients with syncope or near syncope of unknown etiology represent a great challenge to cardiologists. An initial symptomatic episode triggers a series of diagnostic analysis which remain unsatisfactory when negative. More invasive tools such as electrophysiologic testing yield only partial answers to risk stratification while the complementary implantable holter diagnostics are not usually considered until a recurrent episode is documented. Objective: This study targets predictors of significant cardiac rhythmic events in patients with a reported episode of syncope or near syncope presenting with negative diagnostics and electrophysiologic study results (EPS). A significant cardiac rhythmic event was defined as a combined end-point of (1) symptomatic AV block; (2) symptomatic conduction abnormalities requiring pacemaker therapy; (3) symptomatic sustained ventricular arrhythmia; and (4) sudden death. Methods: All patients undergoing EPS after a first episode of syncope or presyncope between January 1997 and December 2001 were included for analysis. The study population consisted of 329 pts (42.6% women), 21 to 96 years old (mean 70 T 15 years) referred for an EP study for syncope or near syncope. Results: Of the 329 patients who underwent EPS, 305 (92.7%) had follow-up data. The population, mean age 70 (T 15 years) and composed of 42% women, presented with hypertension (51.5%), diabetes mellitus (14.4%), hypercholesterolemia (30%), tobacco use (35%), a familial history of coronary heart disease (22%), history of stroke (4%), history of MI (12%), history of atrial fibrillation (10%), structural heart disease (17.4%), left ventricular ejection fraction 61 (T 11%) and ECG abnormalities (37%). These anomalies included right (RBBB) or left (LBBB) bundle branch blocks, left anterior fascicular block (LAFB), left posterior fascicular block (LPFB), bifascicular block (RBBB + LAFB) and traces of myocardial infarction. The mean follow-up was 31 T 20 months with 5% of patients recording significant cardiac rhythmic events (15 / 305): AV block requiring pacemaker therapy in 7 patients, sinus dysfunction in 4, sudden death in 3 and ventricular tachycardia in 1. Univariate analysis reveals structural heart disease, ECG abnormalities and LVEF associated with the risk of significant cardiac rhythmic events defined by the combined end-point. Multivariate analysis using a Cox model found that the only independent predictor of events was an ECG abnormality. The long-term risk of significant event in the subset with ECG abnormalities is of 10.6% (12 / 113). If unexplained syncope recurrence was included in the combined endpoint, ECG abnormality and LVEF were both determinants with a 13.3% (15 / 113) risk of a arrhythmic events analysis in the subset of patients presenting with ECG abnormalities and Cox model found ECG abnormality as the only independent predictor of event. Conclusions: This study demonstrated that an ECG abnormality is the only predictive variable associated with a significant arrhythmic event in patients with a lone episode of syncope or near syncope and a negative EPS. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Syncope; Risk stratification; Electrophysiology testing; Arrhythmia; Heart block; Electrocardiography; Risk factors
Abbreviations: EPS, negative electrophysiologic study; RBBB, right bundle branch block; LBBB, left bundle branch block; LAFB, left anterior fascicular block; LPFB, left posterior fascicular block; ECG, electrocardiogram; LVEF, left ventricular ejection fraction; VT, ventricular tachycardia. * Corresponding author. Service de Cardiologie, Hoˆpital Nord, Centre Hospitalier Universitaire de Saint-Etienne, 42 055 Saint-Etienne Cedex 2, France. Tel.: +33 4 77 82 83 40; fax: +33 4 77 82 84 51. E-mail address: [email protected] (A. Da Costa). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.05.025
A. Da Costa et al. / International Journal of Cardiology 109 (2006) 28 – 33
1. Introduction Syncope is a situation that can be caused by many conditions ranging from benign, self-limiting to malignant – recurrent and potentially fatal events [1 – 3]. A recent epidemiological study on prognosis concluded that patients with cardiac syncope are at increased risk of death from any cause and at an increased risk of cardiovascular events [4]. Clinical history and physical examination completed by a 12-lead EKG are sufficient to establish a diagnosis [1,2] in about 60% of patients reporting a syncope. The remaining 40% remain of unknown aetiology even after extensive clinical workup. The yield of laboratory investigation is disappointing as is the value of neurological evaluation in patients without evidence of epilepsy [5]. Similarly, the results from ambulatory ECG monitoring with transient high-degree AV block are disappointing when these can not be evidenced by an electrophysiological study (EPS) [6– 8]. More recently Brignole et al. reported most syncope recurrences were mainly attributable to sudden-onset paroxysmal AV blocks in patients with repetitive syncope, bundle branch block (BBB) and negative EPS [9]. Little is known, however, concerning patients after a first episode of syncope or near syncope with a negative workup including EPS. Neither is it clear how to stratify patients at high-risk. Several questions thus remain: how does one manage patients with negative results? Which anomaly should be addressed when numerous causes are suspected? The aim of this study was to assess clinical parameters as predictors of significant cardiac rhythmic events in patients with a first episode of syncope or near syncope yielding a negative workup and not indicated for an implantable Holter monitor according to current guidelines.
2. Methods 2.1. Study population All patients referred in our center between 01/97 and 12/01 after a first episode of syncope or presyncope and with a negative EPS were included. They were all already selected before being addressed for an EPS by an extensive negative workup including risk factors analysis, history, physical examination, elimination of postural hypotension or hypoglycemia, baseline ECG, carotid sinus massage, 24-h ambulatory monitoring and echocardiogram. The EPS was performed regarding both absence of evident aetiology and clinical suspected cardiac cause. An echocardiogram and a complete EPS were performed. The study population consisted of 329 pts (42.6% women), 21 to 96 years old (mean 70 T 15 years) with syncope or presyncope referred for EPS. Syncope was defined as a transient loss of consciousness with spontaneous recovery that did not require either chemical or electrical cardioversion. Presyncope was defined as a sensation of near
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fainting (dizziness, light-headedness, wooziness, spells) without actual loss of consciousness, with or without associated symptoms such as blurred vision, palpitations or sweating. All patients data were analyzed after an echocardiogram and a complete EPS. 2.2. EPS protocol The EPS study included measurement of the sinus node recovery time; HV interval at baseline and under stress by incremental pacing; inducibility of ventricular arrhythmia by means of programmed ventricular pacing (with 3 cycles and 3 extrastimuli) and inducibility of supraventricular arrhythmia by an atrial pacing protocol. EPS results were considered positive and the patients excluded from the study in the following cases: (1) sinus bradycardia and abnormal sinus recovery time; (2) baseline HV 70 ms, 2nd or 3rd degree His – Purkinje block demonstrated during incremental atrial pacing or highdegree His– Purkinje block elicited by IV administration of ajmaline; (3) induction of sustained monomorphic ventricular tachycardia or (4) induction of rapid supraventricular arrhythmia with a similarity to patient-reported symptoms. When the baseline study was inconclusive with an HV interval between 60 and 70 ms, then a slow infusion of ajmaline (1 mg/kg IV over 2 min) was performed in the absence of left ventricular dysfunction. 2.3. End-points The primary objective of the study was to identify predictive factors of significant cardiac rhythmic events defined by a combined end-point associating: (1) symptomatic AV block; (2) symptomatic conduction abnormalities requiring pacemaker therapy; (3) symptomatic sustained ventricular arrhythmia and (4) sudden death. The secondary objective was to identify predictive factors of events defined by the following modified combined endpoint associating: (1) unexplained syncope recurrence; (2) symptomatic AV block; (3) symptomatic recording rhythm abnormality requiring pacemaker therapy; (4) symptomatic ventricular arrhythmia; and (5) sudden death. A subanalysis was also carried out to identify the predictive factors of total mortality in this subset of patients. 2.4. Follow-up Clinical evaluation was made for each combined endpoint defined by at least one clinical event. One observer (JLG) blinded to patient initial status and carried out by interviewing the patients and their medical practitioner or cardiologist obtained follow-up. These were completed in 305 / 329 patients (92.7%) with twenty-four patients lost to follow-up (7.3%). Cumulative risk of events was determined by outpatient follow-up and on recurring symptoms. The outpatient follow-up was performed by the referring
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A. Da Costa et al. / International Journal of Cardiology 109 (2006) 28 – 33
Table 1 Population characteristics Study population (n = 305) Age (years) Gender (% female) Hypertension Diabetes mellitus Tobacco Hypercholesterolemia Familial history of coronary heart disease History of stroke History of MI History of atrial fibrillation Structural heart disease Left ventricular ejection fraction ECG abnormality Baseline HV interval length, ms
70 T 15 128 / 305 157 / 305 44 / 305 106 / 305 91 / 305 67 / 305 12 / 305 37 / 305 30 / 305 17.4% 61 T11% 37% 53 T 7
(42%) (51.5%) (14.4%) (35%) (30%) (22%) (4%) (12%) (10%)
initial model were as follows: age, gender, hypertension, diabetes mellitus, hypercholesterolemia ( 6.5 mmol/l or prior cholesterol treatment), tobacco, coronary heart disease family history, history of stroke, history of MI, history of atrial fibrillation, structural heart disease, left ventricular ejection fraction, ECG abnormalities. ECG abnormalities included right (RBBB) or left (LBBB) bundle branch block, left anterior fascicular block (LAFB), left posterior fascicular block (LPFB), bifascicular block (RBBB and LAB) and signs of ancient myocardial infarction. Multivariate analysis was performed using a Cox model and incorporated all variables found statistically significant by univariate analysis ( p value < 0.05).
3. Results cardiologist and by the medical practitioner. Electrocardiograms were programmed at each consultation, at the end of follow-up and on recurring symptoms. 2.5. Statistical analysis Data are expressed as mean T S.D. The differences among groups were analyzed by ANOVA. A probability value of p < 0.05 was accepted as statistically significant. Univariate analysis assessed whether clinical, ECG variables or LVEF predicted a clinical event. Univariate analysis was considered significant with a p-value below < 0.05. Log rank survival tests determined statistically significant ( p < 0.05) differences of categorical variables. Variables tested in the
3.1. Clinical characteristics of patients Population data for the 305 patients were as follows: (Table 1) age (mean 70 T 15 years), gender (42% women), hypertension (51.5%), diabetes mellitus (14.4%), hypercholesterolemia (30%), tobacco (35%), coronary heart disease family history (22%), history of stroke (4%), history of MI (12%), history of atrial fibrillation (10%), left ventricular ejection fraction (61 T11%), ECG abnormalities (37%). ECG abnormalities included right (RBBB) or left (LBBB) bundle branch block, left anterior fascicular block (LAFB), left posterior fascicular block (LPFB), bifascicular block (RBBB and LAB) and old myocardial
Table 2 Primary end-point Structural heart disease gender; age Ischaemic cardiomyopathy Male; 71 years Female; 88 years Male; 80 years Female; 75 years Male ; 75 years Ischaemic cardiomyopathy Male; 75 years Female; 71 years Male; 69 years Dilated cardiomyopathy Male; 72 years Ischaemic cardiomyopathy Female; 58 years Male; 92 Male; 65 years Dilated cardiomyopathy Male; 76 years Dilated cardiomyopathy Male; 71 years Female; 67 years
Time since EPS (months)
Basal ECG
Event description
Therapy
14 7 1 12 39
RBB + LAFB LBB RBB + LAFB LBB RBB + LAFB
3- AV block 2- AV block 3- AV block Sinus dysfunction 3- AV block
Pacemaker Pacemaker Pacemaker Pacemaker Pacemaker
15 56 9
LBB Normal LBB
2- AV block Sinus dysfunction 2- AV block + resynchronization
Pacemaker Pacemaker Pacemaker
19
RBB + LAFB
Sinus arrest
Pacemaker
4 48 1
LBB RBB LBB
Sinus arrest 2- AV block TV
Pacemaker Pacemaker ICD
42
Normal
Sudden death
–
70 9
LBB LBB
Sudden death Sudden death
– –
Right (RBBB) or left (LBBB) bundle branch block; left anterior fascicular block (LAFB), left posterior fascicular block (LPFB); bifascicular block (RBBB and LAB); implanted cardiac defibrillator (ICD).
A. Da Costa et al. / International Journal of Cardiology 109 (2006) 28 – 33
infarction. Fifty-three patients (17%) had structural heart disease: 30 coronary artery diseases, 15 dilated cardiomyopathy, hypertrophic cardiomyopathy in 6 cases and 2 valvular heart diseases (mitral regurgitation in 1 and aortic regurgitation in 1). 3.2. Primary end-point The mean follow-up was 31 T 20 months and 5% significant events (15 / 305) occurred; AV block requiring pacemaker therapy in 7, sinus dysfunction requiring pacemaker therapy in 4, sudden death in 3 (mean LVEF = 58%), and ventricular tachycardia in 1 (VT) (Table 2). By univariate analysis, structural heart disease ( p = 0.01), ECG abnormalities (0.003) and LVEF ( p = 0.02) were associated with the risk of significant event occurrence defined by the combined end-point (Table 3). Multivariate analysis using a Cox model found that the only independent predictor was an ECG abnormality ( p = 0.01). The long-term risk of significant event in the subset of patients with ECG abnormalities is of 10.6% (12 / 113), whereas the risk is of 1.6% (3 / 192) in patients without ECG abnormalities.
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3.4. Third end-point The overall long-term mortality in this study was å3% at 2.5 years with only 8% due to sudden death. By univariate analysis there were 3 variables associated with overall mortality: age ( p < 0001 ), LVEF ( p = 0.0054 ) and a history of myocardial infarction ( p = 0.049). By multivariate analysis only age ( p < 0001) and LVEF ( p = 0.02) were independent predictors of mortality.
4. Discussion 4.1. Major findings The main finding of this study is that patients with a first episode of syncope or presyncope and a negative EPS present a low (5%) long-term risk of significant arrhythmia, while the risk is å8% at 2.5 years when unexplained syncope recurrences were included in the analysis. In the subset with documented events the analysis emphasizes the role of homogeneous mechanism that is characterized by mainly paroxysmal or permanent AV block in 7 / 15 patients (å50%).
3.3. Secondary end-point 4.2. Overall prognosis of patients with unexplained syncope When unexplained syncope recurrence was included in the combined end-point, only ECG abnormalities ( p = 0.003) and LVEF ( p = 0.03) were predictors by univariate analysis. A Cox model found that ECG abnormality was the only independent predictor of cardiac rhythmic events ( p = 0.01). The long-term risk of significant events including unexplained syncope recurrence in the subset of patients with ECG abnormalities is of 13.3% (15 / 113).
Table 3 Univariate predictors of combined point (AV block, sinus dysfunction, sudden death, ventricular tachycardia) in the overall population
Age (years) Gender (% female) Hypertension Diabetes mellitus Tobacco Hypercholesterolemia Coronary heart disease family history History of stroke History of MI History of atrial fibrillation (10%) Structural heart disease Left ventricular ejection fraction ECG abnormalities
Arrhythmia event (n = 15)
No arrhythmia event (n = 290)
p value
74 T 9 6 / 15 10 / 15 3 / 15 6 / 15 3 / 15 2 / 15
70 T 15 123 / 290 149 / 290 87 / 290 100 / 290 87 / 290 64 / 290
0.3 ns 0.23 0.3 0.75 0.7 0.8
(40% ) (66%) (20%) (40%) (20%) (13.3%)
(42.4%) (51.4%) (30%) (34.4%) (30%) (22%)
0 / 15 (0%) 3 / 15 (20%) 0 / 15 (0%)
12 / 290 (4.1%) 38 / 290 (13.1%) 30 / 290 (10.3%)
ns 0.7 0.4
6 / 15 (40%) 54 T 11
47 / 290 (16.2%) 61 T11
0.01 0.02
11 / 15 (73%)
102 / 290 (35%)
0.003
Patients with syncope due to cardiac cause are at increased risk for death from any cause and cardiovascular events but despite extensive evaluation unexplained syncope was found in 14% to 36.6% of patients [4,10 – 12]. More recently Storiades et al. demonstrated that syncope of unknown cause is associated to a + 30% increased death rate [4]. Although the cardiac causes of syncope were shown in the 1980s to be associated with increased mortality, recent evidence showed that underlying heart disease, irrespective of the cause of syncope, is the factor associated with an increased mortality [13,14]. Several other studies have evaluated syncope of unknown causes and demonstrated a similarly higher mortality [15,16]. Generally, electrophysiological studies and electrocardiographic monitoring in highly selected subgroups of patients have suggested that 45% to 80% of syncope classified as being of unknown etiology could be assigned a cardiac origin [13]. A risk stratification study compiling cardiac arrhythmia or death (within 1 year) [17] highlighted 4 factors that were predictors: age, a history of heart failure, a history of ventricular arrhythmia and an abnormal ECG [17]. Our study found that three variables are predictive of longterm mortality: age, history of MI and LVEF though multivariate analysis selected the independent predictive factors of age and LVEF. These findings suggest that persons with cardiac syncope constitute a high-risk group predisposed to mortality that should be monitored closely and treated.
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A. Da Costa et al. / International Journal of Cardiology 109 (2006) 28 – 33
4.3. Cardiac prognosis of patients with unexplained syncope
4.4. Clinical implications
Little data exist concerning patients with a first syncopal or presyncopal episode and negative workup (comprising EPS). If symptoms suggest arrhythmic syncope, the negative results of the EPS could be due to the low sensitivity of EPS [17 –19]. Kushner et al. evaluated the natural history of patients with unexplained syncope and a negative yield for electrophysiologic study but could not evidence predictive variables despite a high recurrence rate [15]. Our analysis concerns only patients with an initial syncope or near syncope with a negative EPS: the results show that the risk of arrhythmic events is low (å5%) and similar to the 6.3% reported by others [15]. Three variables were predictive of a significant arrhythmic event: presence of structural heart disease, LVEF and an ECG abnormality; a Cox model analysis highlights the independent predictive value of ECG abnormality. These results agree with other reports [20 – 22]. The ECG abnormalities subgroup poses a risk of arrhythmia close to 11% at 30 months. Our study evidenced that the main mechanism of cardiac events is due to paroxysmal or permanent AV block (å50%). These results are consistent with others with Link et al. and Gaggioli et al. observing the development of AV block in 18% (after 30 months) and in 19% (after 62 months) of patients with repetitive syncopes and negative electrophysiological studies [7,8] respectively. While a syncope and abnormal EPS were shown to associate an increased risk of AV block, by 17% and 12% [23,24] respectively, there remains a significant problem in evaluating patients with only one syncopal event presenting with ECG abnormalities and negative EPS; this is may be due to the transient nature of a high-degree AV block, requiring long monitoring periods [25]. More recently, Brignole et al. signed the ISSUE landmark study which relied on an implantable loop recorder. They found that most syncopal recurrences were due to paroxysmal AV blocks in patients with repetitive syncopes (mean number of 3 / patients), bundle branch blocks and a negative EPS [9]. We find an additional 25% sinus node dysfunction causing recurrent events despite a normal sinus node recovery time, illustrating that the sensitivity of the sinus node recovery times ranges from 60% to 70% [26 –28]. Comparing the ventricular arrhythmic risk event, (sudden death and ventricular tachycardia) we find approximately 25% (4 / 15) event rates in the presence of patients with heart disease and without a severely LVEF [13], a rate much higher than that reported previously. Our results suggest that further diagnostic testing may be warranted in patients with one syncopal episode and identify ECG abnormalities as the only independent predictive factor of cardiac rhythmic events. In this subset of patients, current guidelines specifying implant only after a recurrence should be re-evaluated with a strategy relying on close monitoring with an implantable loop recorder immediately after initial events.
The risk of cardiac rhythmic events after an initial syncopal or near syncopal episode and a negative evaluation including EPS seems to be low, 5% at 2.5 years. In this subset, the majority of events were AV block in å50% (7 / 15) and sinus dysfunction in å25% (4 / 15) of patients, thus requiring pacemaker therapy. There are an additional å25% of patients, however, presenting with sudden death or VT. Three markers were evidenced as predictive factors (LVEF, structural heart disease and ECG abnormalities), with only one as an independent marker of cardiac arrhythmic event, initial ECG abnormalities. These results emphasize the role of AV block in recurrent syncope in a group with isolated syncope or presyncope despite negative EPS. The long-term risk of significant event in this subset in the presence of ECG abnormalities is of 10.6% (12 / 113), whereas the risk is of 1.6% (3 / 192) in patients without ECG abnormalities. Thus, a negative EPS investigation cannot rule out a paroxysmal AV block, a sinus dysfunction or a ventricular arrhythmia as the cause of syncope and new diagnostic approaches should be evaluated for patients with lone isolated syncope or presyncope and ECG abnormalities. This study should assist in optimizing the workup of lone syncope, avoiding some tests and focusing in a subset of patients at higher risk of arrhythmic events. 4.5. Study limitations Twenty-four patients were lost to follow-up (7.3%) and their outcome may have affected the conclusions of the study despite their weak number. The fact that ajmaline was only used when HV interval was slightly prolonged could have decreased the predictive power of EPS. Our study provides a retrospective analysis of patients and has the inherent limitations of this design. A large, prospective study would have better met the objectives. Diagnostic evaluation with extended monitoring was not performed and these devices may be helpful in patients whose initial test yielded false negative results after a first syncopal episode [29]. The fact that ajmaline was only used when HV interval was slightly prolonged could have decreased the predictive power of EPS. 4.6. Conclusions This study demonstrates that patients with an initial episode of syncope or near syncope and a negative workup including EPS should nevertheless be stratified according to ECG abnormality as this is found to be the only independent predictive variable associated with a significant cardiac rhythmic occurrence. In patients with ECG abnormalities the risk is estimated at 10.6% and while predominant events (å50%) are due to paroxysmal or permanent symptomatic AV block there seem to be at least 25% related to sudden death or ventricular tachycardia.
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