prediction of late arrhythmic events after acute myocardial infarction from combined use of...

clm:zcan’ MAY15,1993,VOL. 71,NO.13

1 Journal ~

Prediction of Late Arrhythmic Events After Acute Myocardial Infarction from Combined Use of Noninvasive Prognostic Variables and

Inducibility of Sustained Monomorphic Ventricular Tachycardia

Roberto Pedretti, MD, Mario D. Etro, MD, Antonio Laporta, MD, Simona Sarzi Braga, MD, and Bruno Car& MD

A comhinsd use of noninvasive teclmiies and elecbophysiologicstudyinthepredictionof~ rhythmic events was pmqectively evaluated in 303 surviving patients of acute myocanlii im tion (AIM). lhe most powerful comhinatii of nom invasive pro@mHk vatiables in identifying pa tients suitable for invasive strate@es was also a9 sessed.Patienbwhohada-amwgleft ventricular ejection &action *oA, ventricular late potentiils and mpetiive ventticular premature complexes (WCs) were considered eliihle for ~ventdcularstimulation.After15-t7 months of follouwp, 19 patients (6%) had an aIc rhythmic event. Left ventricular dyskinegia (p ~0.00001)andejectii fraction *0.4(p c0400001),latepotentials (p *O.OOl),filtered QRSduration2106ms(p <040001),VPCs/hour .6 (p d.Os), paired vpcs (p <O.Ol), 2 Nns of ull- sustained ventriwlartachycardii (VT) per mom itoring (p eO.OOl), heart rate variability index 529 (p *0.00001) aml mean RR interval 1750 ms (p cO.O1)wemfoundtobesi@tiicant univariateprcc dictors of events. At multivariate analysis, only low left ventricular ejection fraction, prolonged fib tered QRS duration, reduced heart rate variability indexanddetecWnof22runsofunsustainedVT permonibinghadanindependent relation to late arrhythmic even& Of 67 eliible patkntq 47 (7o%)consentedtou~~stimuls tii. A positive w study was foundtobethestmngestimkpembtpredictor of events among patients preselected by noninv*

sive techniques. WRh a good sensitMi (Sl%), a combined use of noninvasive tests and m phy*WNstudy-~w@wofWIpa tients at -eMly high risk (event rate 65%) to he con&Wed cmdidatesfor intewentiil thera py.llBec4nnbinationof~variaMea~leQt ventricular ejection fracth eO.4 filtered QR6 duration 2lO6 ms and 22 rims of unsustained W was superiortotheotheronesinidenWyi~~ subjects (positiie and negative predictive values for anl@hmic events of 44 and 99%, fwspec&e- ly).Onthebasisofthedata,thisscheme~ tohethemostappropriateforselectingpatients suitahle for elect- testing and inva sive strate@s after AMI.

(Am J Cadiol1993;71:1131-1141)

T he occurrence of malignant ventricular tachyarrhythmias after hospital discharge is the major cause of death in the first year after acute myo-

cardial infarction (AIM).’ Thus, great effort has been made to identify high-risk groups in which further investigation or intervention is needed. Electrophysiologic testing can be used to stratify surviving ATMI patients into a large group at very low risk and a smaller group at high risk of late arrhythmic events during follow-

2-s However, most centers have been reluctant to use z method to assess ventricular electrical instability after Ah4I. This is partly explained by conflicting results published on the use of programmed ventricular stimulation for this purpose. 2-s Furthermore, noninvasive markers such as depressed left ventricular ejection fraction, high-grade ventricular ectopic activity on Holter monitoring, and ventricular late potentials appear to be useful in identifying a group of surviving AMI patients with significantly higher incidence of late malignant ventricular tachyarrhythmias.9-13 The findings suggest that stratification on the basis of noninvasive risk factors could be used to diminish the proportion of surviving

From Fondazione Clinica de1 Lavoro, Istituto di Ricovero e Cura a Carattere Scientifico, Divisione di Cardiologia, Centro Medico di Tra- date, T&ate, Italy. Manuscript received September 2, 1992; revised manuscript received and accepted December 3, 1992.

Address for reprints: Roberto Pedretti, MD, Fondazione Clinica de1 Lavoro, Istituto di Ricovero e Cura a Carattere Scientifico, Divisione di Cardiologia, Centro Medico di Tradate, Via Roncaccio 16/l 8, 21049, Tradate (VA), Italy.

ARRHYTHMIC RISK EVALUATION AFTER AMI 1131

AMI patients needing electrophysiologic testing, and a “Zlevel strategy” could be used in the evaluation of arrhythmic risk after AMI. Some investigators9-’ l,r3 suggested this possibility, but no study verified it prospectively. Recently, reduced heart rate variability was found to be a predictor of arrhythmic events after AMIlb17 and was added to the other already available noninvasive risk markers. However, as suggested in a recent editorial, few data are available regarding the use of all these prognostic variables in combination to evalu- ate arrhythmic propensity after AMI.18 We performed a prospective study of patients surviving a recent AMI to assess: (1) the diagnostic accuracy of noninvasive risk markers such as low left ventricular ejection fraction, ventricular late potentials, high-grade ventricular ectopic activity and reduced heart rate variability in the prediction of at-rhythmic events after AMI; (2) the clinical implication of a 2-level strategy, performing programmed ventricular stimulation in a limited group of patients preselected by noninvasive techniques; and (3) the most powerful combination of noninvasive prognostic variables in identifying patients suitable for invasive strategies.

Mf3HODS patsent population: From September 1989 to De-

cember 1991,305 consecutive patients (262 men and 43 women; mean age 54 * 9 years) surviving an AMI and admitted to our institute within 30 days of AMf for cardiac rehabilitation were enrolled in this study. Twenty- four patients (8%) had a prior AMI. AMI was anterior in 144 patients (47%), inferior in 161 (53%) and non-Q- wave in 81 (26%). Ventricular fibrillation during the first 5 days after AMI occurred in 33 patients (11%). Of patients included in the study, 164 (54%) received intra- venous tbrombolytic therapy, and 122 (40%) were treat- ed conventionally. In 19 patients (6%), some information regarding therapy in the coronary care unit was not available. All patients aged >70 years, with bundle branch block, flutter or atrial fibrillation (or both), ventricular paced rhythm, heart failure, unstable angina, poor quality echocardiogram, balloon angioplasty or coronary artery grafting before being admitted to our institute were excluded from the study.

Study de&@ A standard risk stratification protocol was performed, including measurement of left ventricular ejection fraction by 2dimensional echocardiography, detection of ventricular late potentials by signal-averaged electrocardiography, and Holter monitor analysis for ventricular premature complexes (VPCs) and heart rate variability. Signal-averaged electrocardiography and Holter monitoring were performed with pharmacologic washout in all patients. The period of washout from dig- italis, B blockers, calcium antagonists and antiarrhytbmic drugs was 25 times the plasma half-life of the drug. Lown 4A-B class VPCs, late potentials and left ventricular ejection fraction ~0.4 were considered noninvasive markers of arrhytbmic risk. Patients who had 22 of these risk factors were considered eligible for programmed ventricular stimulation after consent of both patient and attending physician. Neither B blockers nor other antiarrhytbmic drugs were prescribed routinely to

patients with or without inducible ventricular tachycardia (VT) or high-grade ventricular ectopic activity. Fol- low-up data of all patients were available; 186 (61%) were recalled for assessment of clinical status, and 119 (39%) had follow-up contact by phone. A “late arrhythmic event” was defined as sudden death, or the occurrence of symptomatic or sustained ventricular arrhythmia 25 days after AMI. Sudden death was defined as a witnessed, unexpected death occurring within 1 hour of the onset of symptoms or during sleep. Sustained ventricular arrhythmia was defined as spontaneous ventricular fibrillation or VT lasting >30 seconds or necessitat- ing cardioversion because of hemodynamic collapse. This definition was also used to include patients who subsequently had syncope during follow-up and were found to have inducible sustained VT at electrophysiologic study in the absence of other identifiable causes for syncope.

signal-averaged em ography: Signal-averaged electrocardiography was performed in all patients 20 f 7 days after AMI (range 6 to 36) using a com- mercially available system (Fidelity Medical LP 3000). The principles and operation of this device were reported in a previous study of ours.19 The high-pass filter was set at 40 Hz, and signals from 205 f 58 beats were averaged to achieve a final noise level co.5 p,V The normal values of a signal-averaged electrocardiogram were defined as follows: filtered QRS duration 914 ms, root- mean-square voltage of the last 40 ms of the tiltered QRS complex 220 pV, and duration of terminal low- amplitude (~40 pV) signal 138 ms. Late potentials were considered present if 22 determinants of the signal-averaged electrocardiogram were abnormal. The aforemen- tioned normal values were originally described for a band-pass filter range of 40 to 250 Hz by Gomes et a120 and recently accepted by a task force c~mmittee.~~ Because these values apply to the ART equipment, whereas in our laboratory a different device is used (as shown in a previous investigation19), we contirmed similar normal values using the Fidelity Medical system.

Halter mw Holter monitoring (recorded 21 + 6 days after AMI) was available in all patients and analyzed with a Marquette Electronics Holter 8000 T, 246 patients (81%) underwent 48-hour Holter monitoring, whereas 59 (19%) had 24-hour monitoring. The following ventricular arrhythmia data were quantitied for each tape: VPCs/hour; number of ventricular couplets per monitoring, number of runs of unsustained VT (run of 23 consecutive VPCs lasting c30 seconds) per monitoring, rate of the fastest run of unsustained VT, and length of the longest run of unsustained VT

Heart rate vari8bility arraument: Heart rate variability was computed over the first 24-hour interval of Holter monitoring in 294 of 305 patients. In 11 patients the test was not performed, because of insulin-controlled diabetes mellitus (n = 6) or poor quality recording (n = 5). Heart rate variability was calculated by a previously described method.15 Each beat was targed as normal or aberrant according to its recognition by the algorithm for tape analysis and after human overreading, and the total number of normal-to-normal beat intervals was determined. The frequency distribution of durations

Id.32 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71 MAY 15,1993

TABLE I Characteristics of Patients With and Without Arrhythmic Events

Events No Events (n = 19) (n = 284) p Value

Clinical data Age (year) 58 + 9 54 + 9 NS Men/women (n) 18/l 242142 NS Past AMI (%) 4119 (21) 201284 (7) NS VF O-5 days after AMI (%) 2/19 (10) 301284 (10) NS Antenor AMI (%) 13/19 (t-38) 130/284 (46) NS Q-wave AMI (%) 16/19 (84) 2071284 (73) NS Thrombolysis (%) 7/19 (37) 156/265 (59) NS

2-dimensional echocardiographic data LVEF < 0.4 (%) 15119 (79) 421284 (15) <0.000001 Dyskinesia (%) 13119 (68) 53/284 (19) <0.00001

Signal-averaged ECG data Late potentials (%I 12/19 (63) 65/284 (23) <O.OOl QRSD (ms) 113 t 12 100 + 11 <0.00001 RMS40 (IL’.‘)* 17, 7,41 32, 17, 50 <O.Ol LAS40 (ms) 42 + 22 32 + 11 <O.OOl

Holter monitoring data VPCs/hour > 6 (%I 8/19 (42) 481284 (17) <0.05 Multiform VPCs (%) 12/19 (63) 164/284 (58) NS Paired VPCs (%) 13/19 (68) 941284 (33) -co.01 Unsustained VT (%) 9/19 (47) 721284 (25) NS

Heart rate variability data HR variability index 24 t 9 352 11 <0.0001 Mean RR (ms)* 772, 722,847 845,789,909 <O.Ol HR variability index 229 (%) 16/18 (89) 871274 (32) <0.00001 Mean RR 5 750 ms (%I 7118 (39) 42/274 (15) <O.Ol

Continuous variables are expressed as mean -t 1 SD or (*I median, lower and upper quartiles. AMI = acute myocardlal infarction; ECG = electrocardiographic; HR = heart rate; LAS40 = duration of low-amplitude

signals ~40 &V: LVEF = left ventricular ejection fraction; QRSD = duration of filtered QRS complex: RMS40 = root-mean-square voltage of last 40 ms of filtered (IRS complex; VF = ventricular fibrillation; VPCs = ventricular premature complexes: VT = ventricular tachycardia.

of normal-to-normal RR intervals was constructed by a Marquette Electronics software program, and the modal RR interval frequency was determined. Heart rate variability was expressed by means of the “triangular index” that is derived from the following calculation: total number of normal-to-normal RR intervals/modal RR interval frequency. The index was expressed without units. In each recording, the mean duration of normal RR intervals was also computed.

Ptu#anmd venbkular stimulation: In 47 of 67 eligible patients (70%), 25 + 8 days after AMI, programmed ventricular stimulation was performed after pharmacologic washout, with a pacing wire positioned in the right ventricular apex; 20 patients (30%) were not tested, because of patient or physician refusal. In each case, 6 surface electrocardiographic leads and 1 intra- cardiac electrogmm from the right ventricle were continuously monitored on a multichannel oscilloscope (Siemens-Elema Mingoskop SM), and printed on an ink- jet recorder (Siemens-Elema Mingograph 7). Ventricular stimulation was performed using a programmable stim- ulator (Medtronics 5328), delivering rectangular pulses of 2 ms duration at twice the diastolic threshold. Up to 3 extrastimuli were introduced after 8 ventricular paced beats at 3 drive cycle lengths (600, 500 and 400 ms). There was a 5-second delay between each pacing sequence. During introduction of the thud extrastimulus, coupling intervals 480 ms were not used. The protocol was discontinued on the induction of a sustained ventricular arrhythmia, but only the induction of sustained monomorphic VT at a rate ~270 beatslmin was regard- ed as a positive result. Polymorphic VT (i.e., VT with

a continuously varying QRS complex configuration in any recorded electrocardiographic lead), ventricular fibrillation and unsustained arrhythmias were each regard- ed as a nonspecific response.

Bi studies: A 2dimensional echocardiogram, using a Ving Med CFM 750 unit, was obtained 16 f 6 days after AMI. Evaluation of left ventricular ejection fraction by Simpson’s formula, and detection of left ventricular dyskinesia were performed. _ _ gtabsbcal analysis: Continuous variables were tested for normal distribution with the Kolmogorov-Smirnov goodness-of-fit test for normality. When a normal distribution was observed, continuous variables were expressed as mean f 1 SD and were compared using Stu- dent’s unpaired t test. When observed frequencies were significantly different from the expected normal distribution, continuous variables were expressed as median, lower and upper quartiles, and were compared using the nonparametric Mann-Whitney test. Discrete variables were compared by chi-square analysis with Yates’ correction for continuity or Fisher’s exact test. A p value ~0.05 was considered statistically significant. When 3 groups were compared, l-way analysis of variance, Kruskall-Wallis l-way analysis by ranks, and &i-square analysis were used, where appropriate. When a p value ~0.05 was found, differences between each group were analyzed, and Bonferroni’s adjustment was applied to correct the significance level (a p value CO.017 was considered statistically significant). To compare proportions of both false-positive and false-negative results of 3 different diagnostic protocols, McNemar’s test with Yates’ correction for continuity was used, and Bonferroni’s


529 131 533

0 10 20 30 40 50 60 70 80 90 100

100 - SPECIFICITY (%)

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FWURE 1. Receive characteri, ticcmvesfarheartratevWWityindex (tap), number of runs of unsu~ned VW

D-divisionsbeWeennommlamdabnor- mal valu6s.

13.34 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71 MAY 15,1993

adjustment was applied to correct the significance level (a p value co.017 was considered statistically significant). Using the BMDP LR program (BMDP Sta- tistical Software, Inc., 1988), stepwise logistic regression analysis was performed to determine which variables contributed independent prognostic information to the prediction of late arrhythmic events. Selections were based on the maximal likelihood ratio method. The p values used for entry and removal of variables were set at 0.05 and 0.10, respectively. The standard definitions for relative risk, sensitivity, specificity, and positive and negative predictive values were used.

RESULTS Followup data: Of 305 patients, 2 had noncardiac

deaths and were withdrawn from follow-up. Follow-up data of 303 patients were analyzed; 15 + 7 months after AMI, 19 patients (6%) developed a late arrhythmic event. Of 19 events, 15 (79%) occurred in the iirst 2 months after AMI (mean 28 f 17 days, range 8 to 55). Ten patients had sustained VT, 4 had sudden death, and 5 had aborted sudden death with evidence of ventricular fibrillation at the time of cardioversion. None of 15 patients with late sustained ventricular tachyarrhythmias developed new Q waves on the electrocardiogram.

Comparison of patients with and without late glr. hythmic events Of the variables listed in Table I, the following had a significant relation to late arrhythmic events: left ventricular dyskinesia (p <O.OOOOl) and ejection fraction CO.4 (p <O.OOOOOl), late potentials (p <O.OOl), filtered QRS duration (p <O.OOOOl), terminal root-mean-square voltage (p <O.Ol), duration of terminal low-amplitude signals (p <O.OOl), VPCs/hour >6 (p <0.05), paired VPCs (p <o.Ol), heart rate variability index (continuous p <O.OOOl and dichotomized p <O.OOOOl) and mean RR interval over 24 hours (continuous p co.01 and dichotomized p ~0.01). Dichotomy points for VPCs/hour and left ventricular ejection fraction were based on previous reports.9Jo~22 As in the study of Kleiger et a1,14 mean RR interval was dichotomized at a level of 750 ms. As in other studies,15 for heart rate variability index, we selected the point of optimal trade-off between sensitivity and specificity (Fig- ure 1). - . ~ofumwstainedverr tiZ?ZZs anl anhyttrnic m In patients with unsustained VT, both the number of runs (p ~0.01) and the rate of the fastest run (p ~0.05) of VT were significantly higher in the group with late arrhythmic events (Table II). No significant difference was observed regarding the length of the longest run of VT. For the number of runs of unsustained VT, the point of optimal trade-off between sensitivity and specificity was selected (Figure 1). Of patients with unsustained VT, the prevalence of 22 runs of VT per monitoring was significantly (p ~0.01) greater in the group with arrhythmic events. The clinical meaning of unsustained VT frequency was assessed. Of 19 patients with events, 8 (42%) had 22 runs of unsustained VT per monitoring compared with 24 of 284 patients (8%) without events (p <O.OOl). In 107 patients with paired VPCs, the clinical meaning of ventricular couplet frequency was ana-

TABLE II Relation Among Characteristics of Unsustained Ventricular Tachycardia and Arrhythmic Events

Events No Events p (n = 9) (n = 72) Value

No. of runs of unsustained VT per monitoring(n)*

2,2,3 1, 1,2 <O.Ol

Rate of fastest run of unsustained VT 161 f 64 129 + 38 < 0.05 (beats/min)

Length of longest run of unsustained 4!4,9 4,3,6 NS VT (beats)*

2 2 runs of unsustained VT per mom- 8 (89) 24 (33) <O.Ol toring (%)

24.hour Holter monitoring (%) l(11) 13 (18) NS

Continuous variables are expressed as mean f 1 SD or (9 median, lower and upper quartiles.

VT = ventricular tachycardla.

TABLE Ill Characteristics of Patients Preselected by Noninvasive Tests With and Without Available Electro- physiologic Study

No Electrophysiologic Electrophysiologic

Study (n = 47) Study (n = 20)

Clinical data Age (year) Men/women(n) Past AMI (%) VF O-5 days after AMI (%) Anterior AMI (%I Q-wave AMI (%I

Thrombolysls (%) 2-dimensional echocardiographic

data LVEF <0.4 (%) Dyskinesia (%)

Signal-averaged ECG data Late potentials (%) QRSD (ms) RMS40 (kV)* LAS40 (ms)

Holter monitoring data VPCs/hour >6 (%) Multiform VPCs (%I Paired VPCs (%) Unsustained VT (%)

Heart rate variability data HR variability index 529 (%) Mean RR I 750 ms (%)

58 k 7 4215

10/47 (21) 8147 (17)

31/47 (66) 45/47 (96)

-P 19/46 (41)

36147 (77) 19147 (40)

32/47 (68) 110 t 13 14, 8, 30 402 12

22147 (47) 5/20 (25) 36147 (77) 13/20 (65) 33147 (70) 14/20 (70) 24147 (51) 8/20 (40)

31/46 (67) 24146 (52)

8/20 (40) 13/20 (65)

55 rt 10 16/4

6/20 (30) 3/20 (15) 9/20 (45)

15/20 (75) <0.05 --

9/18 (50)

10/20 (53) 8/20 (40)

16/20 (80) 108 + 13 13, 8. 16 43 + 23

Continuous variables are expressed as mean t 1 SD or (*I median, lower and upper quartiles. Unless stated otherwe, statistical comparisons were not significant

Abbtevlatlons as in Table I.

lyzed. No significant difference was observed between the group of 13 patients with events and the group of 94 without (4, 3,20 vs 3, 1,6; p = NS [continuous variable expressed as median, lower and upper quartiles]).

Plq#Kacpoweracinlud#g~~ mofphic-lartadycaclia: Pmgrammed ventricular stimulation was performed in 47 of 67 patients (70%) at high risk of events who were preselected by noninvasive tests. Of these patients, 20 (42%) had a positive electrophysiologic study, because sustained monomorphic VT at a rate ~270 beatslmin was inducible. Late arrhythmic events occurred in 13 of 20 patients (65%) with a positive electrophysiologic study compared to 1 of 27 (4%) with a negative study (p <O.OOOl). In-

ARRHYlHMlC RISK EVALUATION AFTER AMI 1135

ducibility of sustained monomorphic VT at a rate ~270 beats/min had sensitivity, speciticity, and positive and negative predictive values for atrhythmic events of 93, 79, 65 and 96%, respectively. Relative risk was 17. Be- cause 30% of eligible patients were not tested, the characteristics of patients with and without electrophysiologic study were compared. Of the variables listed in Table III, only prevalence of Q-wave AMI was significantly (p ~0.05) different between the 2 groups of patients. Even arrhythmic event rate was not signiticantly different; 3 of 20 nontested patients (15%) had events compared with 14 of 47 tested patients (30%) (p = NS).

CUniealmwhgdatwohml ~basadona ciolwhdweof~ -wand- SDve tests: Analysis was performed in 283 patients, because programmed ventricular stimulation was not available in 20 eligible subjects. The results are shown in Figure 2. After evaluation by electrophysiologic testing, we obtained a relevant reduction in false-positive results, and an improvement in both speciticity and positive predictive value. At the lirst and second levels, sensitivity and negative predictive value were similar, because only 1 new false-negative result was observed after programmed stimulation.

Presuipth of antianhythmk drug therapy: Of 19 arrhythmic events, 14 (74%) occurred during the in- hospital period, during this period, patients both with and without events were in pharmacologic washout. At hospital discharge, empiric an&rhythmic therapy was administered by the attending physician to 9 of 289 asymptomatic patients (3%) (mexiletine in 4, and amio- darone in 5), because of inducible sustained ventricular arrhythmias or high-grade ventricular ectopic activity. Because of the small number of patients on postdis- charge antiarrhythmic treatment, this was not considered in the statistical analysis. At hospital discharge, B blockers were prescribed to 107 of 289 asymptomatic patients (37%) owing to residual ischemic symptoms or hyper- tension. None of 107 patients with B blockers developed arrhythmic events compared with 5 of 182 (3%) without (p = NS).

~powertivellmcNlarlatepatentlalsand cruantltative--~ a#es: At univariate analysis, the presence of ventricular late potentials, filtered QRS duration, terminal root- mean-square voltage and duration of terminal low-amplitude signals were all significantly related to the occurrence of late arrhythmic events (Table I). Stepwise

2 2 VARIABLES

236 PATIENTS

SENS: 87% SPEC: 88% PPV: 30% NPV 99%

NO SMVT < 270 BPM 27 PATIENTS

SENS: 81% SPEC: 97% PPV: 65% NPV 99%

FmuNE 2. Clinkal meanlng of combhsd -0fw-smzi-l nonlnvaslvetestslnpredkungpostl~ farctknanhythmkeventaAMI=aarte lnyocwdkl I- EPS=&cbe physlokgk~FN=fakewgatlve; FP=fakeposNhqlP=ktepotwualr; LVEF=kftvenbtcukreJectknfraetkn; NPV q negative pmdktive value; PPV q

posltlve predktlve value; SENS q SW*

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ty;lN=twenegaUve;lP=trueposMve;

VPCS q vwtrkular premature wxes

1136. THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71 MAY 15,1993

TABLE IV Characteristics of Patients With and Without t Two Runs of Unsustained Ventricular Tachycardia per Monitoring

1 Run of VT 22 Runs of VT No VT (n = 50) (n = 32) (n = 223)

Clinical data Age (year) 53 k 9 56 2 8 54 t 9 Men/women(n) 4515 30/2 187136 VF O-5 days after AMI (%) 10/50 (20) 5132 (16) 18/223 (8) Past AMI (%I 5/50 (10) 5132 (16) 14/223 (6) Anterior AMI (%I 25150 (50) 13/32 (41) 106/223 (47) Q-wave AMI (%) 40150 (80) 28132 (87) 156/223 (70) Thrombolysis (%) 30149 (61) 17129 (59) 1171208 (56)

2-dimensional echo cardrographic data LVEF <0.4 t%) 10/50 (20) 12/32 (37) 35/223 (16) Dyskinesra (%) 9/50 (18) 8132 (25) 50/223 (22)

Signal-averaged ECG data Late potentials (%I 1 l/50 (22) 7132 (22) 59/223 (26) QRSD tms) 100 + 10 102 + 13 100 IT 12 RMS40 ($I)* 37,22, 53 36, 19, 52 30, 16, 50 LAS40 (ms) 312 11 32 + 11 33 + 12

Holter monitoring data VPCs/hour (n)* 0.9,0.5,3 12,3, 79 0.4,0.1,2

I p < 0.000001 I I p < 0.0000011 I p <O.OOl’

Ventricular couplets per monitoring(n)* 1,0,2 9,2,34 0, 0, 1 I p <0.0001- I p < 0.000001 I I p <0.0001 I

Heart rate variability data HR variability index 37 * 12 29k 11 35+ 11

I p <0.011 I p co.01 I Mean RR (ms)* 857,822,937 809,750,869 843,769,908

Continuous variables are expressed as mean f 1 SD or (*) median, lower and upper quartiles. Unless stated otherwise. statistical comparisons were not slgnlficant. Abbreviations as in Table I.

logistic regression analysis was performed to determine which of these 4 variables contributed independent information; tiltered QRS duration was found to be the only independent predictor of late arrhythmic events (improvement &i-square 18; p <O.OOOl). For tiltered QRS duration, we selected the point of optimal trade- off between sensitivity and specificity (Figure 1). Of 19 patients with arrhythmic events, 15 (79%) had filtered QRS duration 2106 ms compared with 72 of 284 (25%) without events (p <0.00001). When late potentials were detected, the relative risk for arrhythmic events was 5; when filtered QRS duration 2106 ms was used as the diagnostic criterion, the relative risk was 9.

Multivdab analysrs: When stepwise logistic regression analysis was used to determine the independent prognostic power of 13 variables (see Appendix), left ventricular ejection fraction ~0.4 (improvement chi- square 32; p <0.0001), filtered QRS duration 2106 ms (improvement chi-square 12; p = 0.0005), 22 runs of unsustained VT per monitoring (improvement &i-square 10; p = 0.002), and heart rate variability index 529 (improvement &i-square 7; p = 0.009) had a significant relation to arrhythmic events. We performed a second analysis in the group of patients who underwent electrophysiologic study, including inducibility of sustained monomorphic VT at a rate ~270 beats/nun among independent variables. Inducibility of sustained monomorphic VT at a rate ~270 beats/min (improvement chi- square 21; p <O.OOOl), paired VPCs (improvement chi- square 8; p = 0.004), heart rate variability index 129 (improvement &i-square 6; p = 0.01) and left ventricu-

lar dyskinesia (improvement &i-square 5; p = 0.03) were found to be independent predictors of late arrhythmic events.

-of-*ti-geater thantwolUU!BOfUnou&alnedventrleulatadyeab

per monRo&@ of available Holter monitoring data, only detection of 22 runs of unsustained VT had independent prognostic value. Therefore, we compared the characteristics of patients with and without 22 runs of unsustained VT per monitoring. Of the variables listed in Table IV, VPCs/hour, number of ventricular couplets per monitoring, and heart rate variability index were significantly different between 32 patients with 22 runs of unsustained VT, 50 patients with only 1 episode of unsustained VT and 223 patients with no evidence of unsustained VT.

h#hnceacHolter monltorrlne-~- ucvdeaf --lartachycrrda:of 246 patients who underwent 48-hour Holter monitoring, 1 (~1%) had noncardiac death, 13 (5%) had an arrhythmic event, and 232 (94%) remained asymptomatic during follow-up. After 24 hours of monitoring, 3 of 13 patients (23%) with events had unsustained VT compared with 35 of 232 (15%) without events (p = NS). Conversely, after 48 hours of monitoring, the proportion of unsustained VT was significantly greater in the group with events (8 of 13 [61%] vs 59 of 232 [25%]; p <O.Ol). After 24 hours of monitoring, 2 of 13 patients (15%) with events had 22 runs of unsustained VT compared with 12 of 232 asymptomatic patients (5%) (p = NS). After 48 hours of monitoring, a significantly greater rate


TABLE V Value of Independent Noninvasive Prognostic Variables in Predicting Arrhythmic Events

t Relative Risk Sensitivity (%) Specificity (%) PPV (%I NPV (%)

LVEF <0.4 16 79 a5 26 98 HR variability index 529 15 89 68 15 99 QRSD ~106 ms 9 79 75 17 98 2 2 runs of unsustained VT 6 42 91 25 96

NPV = negative predictive value; PPV = positive predictive value; other abbreviations as in Table I.

TABLE VI Value of Combinations of Independent Noninvasive Prognostic Variables in Predicting Arrhythmic Events --

Prognostic Variables

HR Variability QRSD Event P LVEF < 0.4 Index 529 2 106 ms Rate Value

- 0 0 0 o/131 + 0 0 l/11 NS 0 + 0 l/49 NS 0 0 + l/41 NS + + 0 2118 0.01 + 0 + O/6 NS 0 + + 2116 0.01 + f + 1 l/20 <0.000001

22 Runsof QRSD LVEF ~0.4 Unsustained VT t 106 ms

0 0 0 l/164 + 0 0 O/23 NS 0 + 0 O/16 NS 0 0 + l/53 NS + + 0 316 < 0.000001 + 0 + 8120 < 0.000001 0 + + 214 < 0.000001 + + + 316 < 0.000001

~mparwns were performed dehveen each group with 2 1 variable and relative group with norm&y of all 3 variables.

+ = present; 0 = absent; other abbreviations as in Table I. - -_--

of patients with arrhythmic events had 22 runs of unsustained VT (8 of 13 [61%] vs 22 of 232 [9%]; p <o.OOOl).

predictive accuracy of pro@wstic varidles for late anhythmic events: Relative risk, sensitivity, specificity, positive and negative predictive values of left ventricular ejection fraction ~0.4, heart rate variability index 129, filtered QRS duration 2206 ms and unsustained VT frequency 22 are listed in Table \! Because of their independent nature, combinations of variables were evaluated. Analysis was performed in a group of 292 patients, because 11 subjects did not undergo heart rate variability assessment. A negligible rate of arrhythmic events occurred in patients with normal left ventricular ejection fraction and signal-averaged electrocardiogram who had either a normal heart rate variability index or <2 runs of unsustained VT (Table VI). Abnormality of only 1 of these variables was not associated with a signiiicantly greater rate of arrhythmic events. Conversely, combinations of 22 of these variables were associated with a significantly greater prevalence of malignant arrhythmias.

Conparisonoftlswl-ncni-~ cdsfcr~~at~riskof~~ II& m With the use of different combinations of noninvasive prognostic markers, we defined 3 different noninvasive protocols to select patients at high risk of

arrhythmic events (Table VII). The tit protocol was the one used in the present investigation to select patients for programmed ventricular stimulation. The other 2 protocols were based on the combination of the 2 most powerful independent variables (left ventricular ejection fraction co.4 and filtered QRS duration 2106 ms) with either 22 runs of unsustained VT or heart rate variability index 529. Analysis was performed in a group of 292 patients, because in 11 cases, heart rate variability assessment was not available. Proportions of false-negative results were not significantly different, and sensitivity and negative predictive value of all 3 protocols were similar, Conversely, using the second protocol (based on left ventricular ejection fraction 4.4, liltered QRS duration 2106 ms and 22 runs of unsustained VT), the number of false-positive results was significantly (p <O.OOOOl) less, and both specificity and positive predictive value were significantly greater.

DISCUSSION Mecfleft-lardysfunctialh~

risk~dteraaWmyocgdali~ Patients with left ventricular dysfunction, especially those with a well-defined left ventricular aneurysm, have been found to be more likely to develop arrhythmic events during the lirst year after AIvII?,~,~,~,~-~* Therefore, it is not surprising that the present study identilied low left ventricular ejection fraction as the most powerful predictor of arrhythmic outcome. However, the rate of arrhythmic events in patients with an abnormal left ventricular ejection fraction, in the absence of other prognostic variables, was not significantly different than that in those with a normal ejection fraction. Similar tidings were reported by other investigators.9*10+12 Hearts with large infarcts may be more likely to incorporate intra- ventricular reentrant circuits than may those with small infarcts, but impaired ventricular function, per se, did not identify an arrhythmogenic substrate. Additional fat- tors appear to be necessary for the spontaneous mani- festation of sustained ventricular arrhythmias.

Role of ventricular late potentials in mmic risk stratificatii after acute myocmlid infarctii: The signal-averaged electrocardiogram enables the noninvasive detection of ventricular late potentials.23 Late potentials represent low-amplitude, fractionated electrical activity, are markers for an arrhythmogenic substrate that may become the site for reentry24 and provide important prognostic information in identifying patients at risk of late arrhythmic events after AMI.2,~13J6J9 Even in the present study, late potentials were independent predictors of malignant ventricular

1138 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71 MAY 15,1993

TABLE VII Comparison of Three Noninvasive Protocols for Selecting Patients at High Risk of Arrhythmic Events

LVEF ~0.4, LP and Lown LVEF ~0.4, 22 Runs of LVEF ~0.4, HR Variability 4A-B Class VPCs: Unsustained VT, and QRSD 2 106 ms: Index 529 and QRSD 2 106 ms:

2 2 of These Variables 22 of These Variables 2 2 of These Variables

Sensitivity (%I 89 89 83 TP WFN (n) 16/2 1612 1513

Specificity 82 93 83 TN WFP(n) 224150 254120 229145

I p <0.00001 II p <0.000011 PPV (%I 24 44 25

TP WFP (n) 16/50 16120 15145 I p <0.00001 I: p <0.000011

NPV (%I 99 99 99 TN WFN (n) 22412 25412 22913

Unless stated otherwise, statistical comparisons were not significant. FN = false negative; FP = false positive; LP = late potentials; TN = true negatw; TP = true positive; other abbrevlatlons as m Tables I and V.

arrhythmias after AMI. The signal-averaged electrocardiogram is usually analyzed by measuring filtered QRS duration, and also by computing the root-mean-square voltage of the last 40 ms of the filtered QRS complex and the duration of the terminal low-amplitude signals. In accordance with Gomes et al” and Steinberg et al,i3 we found that the terminal voltage and duration did not independently predict the risk of arrhythmic events. In the present study, the signal-averaged electrocardiogram became a more powerful tool, if only filtered QRS duration was used to predict arrhythmic events. It is not clear why terminal QRS measurements did not have great clinical relevance. One can speculate that an abnormal duration of the signal-averaged QRS complex may reflect a greater mass of myocardium with inhomoge- neous propagation of conduction, thereby facilitating the occurrence of VT or ventricular fibrillation, or both. 1 1 In addition, both terminal root-mean-square voltage and terminal low-amplitude QRS signals may be highly sen- sitive to the signal-to-noise interface, and small changes in the QRS offset could markedly reduce their accuracy.13 Therefore, filtered QRS duration appears to be a less arbitrary measurement that includes the late poten- tial and conventional QRS.

Role of ventricular ectopic activity in adtythmic risk stmtification after acute myocardial infawtii: Previous prospective multicenter studies found that fre- quent or complex VPCs, or both, on predischarge Holter monitoring represent an independent prognostic factor for late arrhythmic events after AMI.25-28 In the present investigation, both the number of VPCs/hour and paired VPCs were univariate predictors of malignant arrhythmias, but only unsustained VT frequency (dichotomized at a level 22 runs per monitoring) had an independent relation to arrhythmic event occurrence. The VPC fea- ture of repetitiveness, in particular unsustained VT, on predischarge Holter recordings has been proposed as an important risk factor for arrhythmic events after AMI’; however, the prognostic signiticance of VT characteristics was not generally evaluated. Characteristics of VT were analyzed from the Multicenter Post-Infarction Research Group; no significant association with all- cause mortality was found (only a weak trend was evi- dent) but the relation between VT characteristics and arrhythmic events was not assessed.27 In the present study, patients with 22 runs of unsustained VT were sig-

nificantly different from those with only 1 episode of VT in some important characteristics. Unsustained VT frequency 22 identified patients with a more reduced heart rate variability and a greater number of triggers, such as VPCs and paired VPCs. A more reduced electrical heart stability could be present in these subjects, and a greater arrhythmic propensity may be possible. These findings were not previously reported in surviving patients of a recent AMI, and suggest that unsustained VT frequency may be an important prognostic factor not only in patients with mild to moderate heart failure,29 but in post-AMI patients too. In the present study, the prognostic value of both unsustained VT and unsustained VT frequency 22 was strongly related to the duration of monitoring. The results suggest that if detection of 22 runs of unsustained VT is used as a prognostic marker, 48-hour Holter recording will be necessary for an appropriate risk evaluation.

Roleofheatratevviria#lityinathyhmc .

-afteraarte myocdid infmdhi Klez et all4 found that heart rate variability was a significant and independent predictor of mortality in the first year after AMI. Furthermore, some frequency domain measures of heart period variability were significantly associated with both all-cause mortality and at-rhythmic death.” It appears that reduced heart rate variability after AMI reflects a disturbance of sympathovagal interaction toward a decrease in parasympathetic activity.3o This imbalance is thought to facilitate the emergence of VT and ventricular fibrillation. In the present investigation, heart rate variability index had a strong association with late arrhythmic events, and as previously described by Kleiger et al,14 we found that heart rate variability provided prognostic information above that obtainable from left ventricular ejection fraction and VPC Holter detection. Furthermore, we found that reduced heart rate variability index predicted at-rhythmic events independently of signal-averaged electrocardiogram. As recently noted by Bigger et al, I7 there have been no large-scale longitudinal studies to determine whether late potentials and 2 component of heart rate variability provide independent prediction of arrhythmic events. The relation of late potentials and heart rate variability to arrhythmic events has been evaluated only in the study of Farrell et ali6 and the present investigation. In both studies, signal-averaged electrocardiography and analysis of heart


rate variability provided independent prognostic information. These data may have clinical importance.

lsacodineduseof~sludyand -m Vd&kSUSdUltOS6ktSUlc

viving~ofmyocadlal i~suitdeforin tenfentiom trials? Programmed ventricular stimulation probably identifies a specific mechanism for malignant ventricular tachyarrhythmias, but it is an invasive pro- cedure and therefore not ideally suited as a screening test in a large number of patients. It would be prefera- ble to limit electrophysiologic study to a high risk group of patients. Such an approach was suggested by several investigators,3~5~9~10~13 but this hypothesis has not been prospectively evaluated. We identified a small subgroup of patients on the basis of combinations of low left ventricular ejection fraction, ventricular late potentials and repetitive VPCs on Holter monitoring. In these patients, inducible sustained monomorphic VT at a rate ~270 beats/mm had the strongest independent relation to late arrhythmic events. The data showed that in a group of patients, preselected by noninvasive tests, with a higher prevalence of events, programmed ventricular stimulation was useful in improving diagnostic accuracy (Fig- ure 2). The major tinding of this study is that a combined use of noninvasive tests and electrophysiologic study selected with a good sensitivity (81%) a group of post-AMI patients at sufficiently high risk (arrhythmic event rate 65%) to consider them candidates for implantable cardioverter-defibrillators or therapy guided by electrophysiologic testing. Programmed stimulation had a high negative predictive value, suggesting that no specific treatment appears needed if sustained monomorphic VT is not inducible, despite the presence of different noninvasive risk markers. These tindings may have clinical relevance.

whatisthebestltahdve~for~

fa~~a*lE~ -T-----l

In the present study, no patient had an arrhythmic event when 22 runs of unsustained VT alone were present, and even reduced heart rate variability index alone did not have a significantly greater risk of future arrhythmic events. Therefore, Holter monitoring does not appear necessary in patients who have a normal left ventricular function and signal-averaged electrocardiogram (61% of the study group), in whom a negligible rate of arrhythmic events (~1%) occurred. The prevalence of arrhythmic events was very high (44%) when both left ventricular ejection fraction ~0.4 and filtered QRS duration 2106 ms were present. Even in this group of patients (9% of the study group), Holter monitoring does not appear necessary, and an interventional approach may be appropriate. Conversely, in the group of surviving AMI patients with either left ventricular dysfunction or abnormal signal averaging (30% of the study group), Holter monitoring may be useful in selecting those in whom programmed ventricular stimulation could be tested. Reduced heart rate variability (on 24-hour monitoring) or a number of runs of unsustained VT 22 (on 48-hour monitoring) may be investigated. The protocol based on left ventricular ejection fraction ~0.4, filtered QRS duration 2106 ms and 22 runs of unsustained VT was more

specitic and minimized false-positive results; the data suggest that it may be the most appropriate method for selecting patients at high risk in whom expensive invasive strategies could be performed. This scheme is a simple and new method of risk stratification; 70% of patients would need only an echocardiographic measurement of left ventricular ejection fraction and a signal-averaged electrocardiogram to be defined at high or low risk of at-rhythmic events. In the other 30% of patients, the addition of 48-hour Holter monitoring would be necessary for an appropriate stratification of arrhythmic risk.

Study limitations: This was an uncontrolled study; thus, it is possible that the use of antiarrhythmic drugs and B blockers influenced the arrhythmic event rate. A greater proportion of patients without than with an arrhythmic event were receiving B-adrenergic blocking agents. However, this difference did not reach statistical signiiicance, and the prevalence of antiarrhythmic drug therapy was low. Of our patients, 19% underwent 24- hour Holter monitoring; this could have undervalued the clinical meaning of unsustained VT. In the study group, unsustained VT showed a borderline p value (0.06), whereas in the subgroup with 48-hour monitoring, unsustained VT reached the significance level (p 4.01). Of patients suitable for electrophysiologic study, only 70% underwent programmed ventricular stimulation. Therefore, there is doubt regarding the applicability of these results to our population of patients, preselected by noninvasive tests, as a whole. However, patients not studied with electrophysiologic testing appeared to be similar to the study group in their demographic characteristics, the frequency of positive results in the noninvasive tests, and in at-rhythmic event rate. Furthermore, the small number of arrhytbmic events, and the short follow-up duration represent a limitation of this study.

Aciu~owledgment: We thank Luigi Ballardini and Mario Comelli for statistical assistance, Emanuela Ra- dice for creation of the data collection software program, Enrico Gianfranceschi, Cinzia Guicciardi and Francesco Salamone for managing patient follow-up, and Deborah Bazzoni for secretarial assistance.

APPENDIX Clinical and noninvasive variables used in the step-

wise logistic regression analysis were age, prior AMI, site of AMI, Q-wave AMI, left ventricular dyskinesia and ejection fraction ~0.4, filtered QRS duration 2106 ms, VPCs/hour >6, paired VPCs, unsustained VT, 22 runs of unsustained VT per monitoring, heart rate variability index 129 and mean RR interval over 24 hours 1750 ms.

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1140 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71 MAY 15,1993

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