Prognostic implications of ventricular arrhythmias during 24 hour ambulatory monitoring in patients undergoing cardiac catheterization for coronary artery disease

Prognostic Implications of Ventricular Arrhythmias During 24 hour Ambulatory Monitoring in Patients Undergoing Cardiac Catheterization for Coronary Artery Disease

ROBERT RAY

M. CALIFF,

MD

A. McKINNIS,

PhD

JOHN BURKS, MD KERRY L. LEE, PhD FRANK E. HARRELL, VICTOR DAVID

S. BEHAR, B. PRYOR,

Jr.,

PhD

MD MD

GALEN S. WAGNER, ROBERT A. kOSATI,

MD MD

Durham, North Carolina

From the Division of Cardiology, Department of Medicine, The Division of Biometry, Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina. This work was supported by Contract HRA 23076-0300 and @ant HS 03834 from the National Center for Health Services Research, and the National Center for Health Care Technology, Hyattsville, Maryland, Research Grant HL-17670 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland; Training Grant LM 07003 and Grants LM 03373 and LM 00042 from the National Library of Medicine, Bethesda, Maryland; and grants from the Prudential Insurance Company of America, Newark, New Jersey, the Kaiser Family Foundation, Palo Alto, California, and the Andrew W. Mellon Foundation, New York City, New York. Manuscript received August 10, 1981; revised manuscript received January 5, 1982, accepted January 8, 1982. Address for reprints: Robert A. Rosati, MD, P.O. Box 3337, Duke University Medical Center, Durham, North Carolina 27710.

The prognostic importance of ventricular arrhythmias detected during 24 hour ambulatory monitoring was evaluated in 395 patients with and 260 patients without significant coronary artery disease. Ventricular arrhythmias were found to be strongly related to abnormal left ventricular function. A modification of the Lown grading system (ventricular arrhythmia score) was the most useful scheme for classifying ventricular arrhythmias according to prognostic importance. When only noninvasive characteristics were considered, the score contributed independent prognostic information, and the complexity of ventricular arrhythmias as measured by this score was inversely related to survival. However, when invasive measurements were included, the ventricular arrhythmia score did not contribute independent prognostic information. Furthermore, ejection fraction was more useful than the ventricular arrhythmia score in identlfying patients at high risk of sudden death.

In the setting of coronary artery disease, ventricular arrhythmias have been associated with decreased survival.‘-” However, ventricular arrhythmias are also associated with abnormal left ventricular function.4,5 It has been proposed that many patients die suddenly because of primary ventricular arrhythmias independent of the degree of myocardial dysfunction, and that these patients can be identified on the basis of ventricular arrhythmias detected during ambulatory electrocardiographic monitoring.6,7 An alternative hypothesis, that ventricular arrhythmias predict cardiac death because the ectopic activity reflects the extent of damaged myocardium, has also been proposed.“,” The simplicity of ambulatory electrocardiography makes it an attractive technique, and its use in detecting ventricular arrhythmias has increasingly made it a part of the routine clinical profile in patients with coronary artery disease. Therefore, an understanding of the clinical implications of these rhythm disturbances is important. No large study of patients with chronic coronary artery disease has assessed the prognostic importance of ventricular arrhythmias relative to other clinical characteristics when detailed anatomic and hemodynamic measurements are known. This study was designed to determine whether the detection of ventricular arrhythmias during a 24 hour monitoring period adds significant information concerning the risk of cardiac death when other important prognostic variables are known. This information may be useful in identifying patients at high risk of cardiac death for whom a trial of antiarrhythmic agents might be warranted. Methods Study patients: The study group was obtained from all patients undergoing cardiac catheterization for suspected coronary artery disease at Duke University Medical Center between

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August 1975 and November

1979. Patients

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with valvular

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TABLE I or congenital heart disease were excluded except those with mitral regurgitation as a complication of coronary artery disease. Of the 3,129 patients meeting these entry criteria, a total of 1,009 underwent 24 hour ambulatory monitoring as a part of a prospective protocol before discharge from the hospital. The 655 patients from this group who were treated without coronary bypass grafting form the basis of this report. Of this number, 395 had and 260 did not have significant coronary artery disease. Patients underwent ambulatory monitoring solely on the basis of availability of monitoring equipment without knowledge of cardiac catheterization findings or possible clinical indications. A comparison of baseline characteristics revealed no differences with regard to age, sex, number of diseased vessels and ejection fraction between the 1,009 patients who underwent monitoring and 2,120 patients who did not. The patients who were not monitored had a lesser prevalence of both left main coronary artery disease (4.6 versus 7.2 percent) and a history of congestive heart failure (7.2 versus 11.6 percent). Information system: The computerized information system used in this study has previously been described.8 In summary, a complete medical history, physical examination, chest X-ray film and standard 12 lead electrocardiogram were obtained prospectively on all patients at the time of cardiac catheterization. These data were itemized into 48 characteristics that formed the noninvasive data set analyzed in this study. In addition, 20 invasive hemodynamic, angiographic and ventriculographic descriptors were obtained by cardiac catheterization.g Left ventricular ejection fraction was calculated routinely when technically feasible (94 percent of patients). Follow-up survival status was obtained at 6 months and 1 year after cardiac catheterization, and at yearly intervals thereafter as reported previously.g Sudden death was defined as death within 2 hours of the onset of acute systems in patients without refractory congestive heart failure. Death occurring while the patient was asleep or otherwise not observed was counted as a sudden death if the patient was asymptomatic when last seen. Ambulatory electrocardiographic data: A two channel model 425 Avionics Holter recorder was used for continuous 24 hour recordings as previously described.2The same system was also used in routine clinical practice at our institution. Patients were ambulatory in the hospital as permitted by symptoms. Counts were made of the number of premature ventricular complexes during each hour. The average number per hour and the maximal number in any 1 hour were calculated. Note was made of the occurrence of multiform complexes (premature ventricular complexes with different QRS configurations), bigeminy (alternating premature ventricular complexes and sinus beats), pairs (two consecutive premature ventricular complexes) and ventricular tachycardia (three or more consecutive premature ventricular complexes). Patients were assigned the highest applicable ventricular arrhythmia score based on a modification of Lown’s grading system (Table I). The R on T phenomenon was not evaluated in this report. Cardiac catheterization: Biplane left ventriculography and single plane coronary arteriography were performed in all patients. Results were reviewed by at least two senior angiographers on the day of cardiac catheterization. Significant coronary artery disease was defined as 75 percent or greater narrowing of the luminal diameter of a major coronary artery.

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Modified Lown Grading System for Ventricular Arrhythmias Ventricular

Lown Grade

Definition No PVCs Maximal hourly PVC rate <30 Unifocal, maximal hourly PVC rate 230 Multiform PVCs Two consecutive PVCs Ventricular tachycardia R on T PVC = premature ventricular

Arrhythmia Score

0

0

:

:

3

3 4 5

2 5

-

complex.

Major coronary arteries were considered the left main, the left anterior descending or large diagonal branch, the left circumflex or large marginal branch, and the right coronary artery. Left ventricular ejection fraction was calculated using the modified area-length method.‘O In patients whose ejection fraction was not obtained because of technical difficulties, an estimate based on the subjective description of the quality of left ventricular contraction was used (Harris PJ et al., unpublished data). Statistica! procedures: Associations between the ventricular arrhythmia score and other baseline characteristics were assessed using the Spearman rank-order correlation. Univariable comparisons of two (or more) groups were made on the basis of the Wilcoxon rank sum (or Goodman-Kruskal-Wallis) test statistics. Multivariable analysis to assess the relation between ventricular arrhythmia score and other baseline characteristics was performed using the multiple linear regression model. For analyses to assess the relation between survival time and various patient characteristics, Breslow’s formation of the Cox proportional hazard survival model was used.“-is Rao’s efficient score statistic was used with the model to determine univariable associations.‘” In the multivariable survival analyses, to test whether a particular factor added information independent of a given set of other variables, the model was fit first using only the given set and secondly using the given set along with the factor of interest. Twice the difference in the log likelihood function was used as a test statistic having a chi-square distribution with 1 degree of freedom to determine the independent significance of that added factor. Complete survival curves were plotted from Kaplan-Meier product-limit estimates of the survival probabilities from time of catheterization.14 The displays of 2 year survival probabilities were drawn from predicted values calculated from fitting the Cox model to the ventricular arrhythmia score alone (unadjusted) and to this score with the 68 other clinical characteristics (adjusted). To quantify the usefulness of clinical data for individual patients, an index, denoted by c, was computed that estimates the probability that, of two randomly chosen patients, the one with the lower ventricular arrhythmia score will have lived longer. The index was calculated using a procedure similar to the computation of the Kendall-Goodman-Kruskal rank correlation coefficient.‘” Concordance for ventricular arrhythmia score and survival time was determined for every pairing of patients in whom the order of survival times could be determined. Thus, pairs were excluded in which both patients were alive at follow-up study or in which the length of

PROGNOSTIC IMPLICATIONS OF VENTRICULAR ARRHYTHMIAS-CALIFF ET AL

time until the death of’ one exceeded the length of time the other had been followed up. A concordant pair was defined as a pair in which the patient with the lower ventricular arrhythmia score also had the longest survival time. The c index is the proportion of total pairs that are concordant.

TABLE II Baseline Characteristics of 395 Medically Treated Patients With Significant Coronary Artery Disease Undergoing 24 Hour Ambulatory Monitoring Frequency

Characteristic

Results Characteristics of patients with significant coronary artery disease: The baseline characteristics of the 395 patients with significant coronary artery disease are displayed in Table II. Eighty-five percent (336) were male, and the median age was 49 years. Most patients had chronic symptoms of coronary artery disease with a median duration of symptoms of more than 20 months. Only 29 percent (115) had progressive angina. Thirty-two percent (127) had single vessel coronary disease, 24 percent (95) had two vessel disease and 44 percent (173) had three vessel disease. Only 12 patients (3 percent) had left main coronary artery disease. After 1975 most patients at this institution with left main coronary stenosis were treated surgically. Although only 11 percent (44) of the patients had symptoms of congestive heart failure, 24 percent (95) had an ejection fraction of less than 40 percent. Sixty-three percent (249) had completely normal left ventricular contraction. Spectrum of arrhythmias: The grades of ventricular arrhythmias found in the patients with significant coronary artery disease are depicted in Table III. No ventricular arrhythmia was detected in 118 of the 395 patients. The mean number of premature ventricular complexes/hour was 30 (range 0 to 1,697), however, the median number/hour was 1, and 259 of the 395 patients averaged less than 2lhour. When patients were grouped by ventricular arrhythmia score, the majority had a score of less than 2. In most of the patients with frequent premature ventricular complexes, the complexes were multiform, so that only 10 patients had a ventricular arrhythmia score of 2. Thirty-three patients had pairs and 21 patients had ventricular tachycardia. Association of arrhythmias with presence and severity of coronary artery disease: The relation of ventricular arrhythmia score to selected baseline characteristics is displayed in Table IV. The presence and grade of ventricular arrhythmias were associated closely with the extent of coronary artery disease and left ventricular dysfunction. Thirty-seven percent of patients with no premature ventricular complexes (ventricular arrhythmia score = 0) had single vessel disease, whereas only 28 percent of patients with a score of 3 and 19 percent of patients with a score of 5 had single vessel disease. Patients with three vessel disease constituted an increasing proportion of the groups as ventricular arrhythmia score increased. Similarly, 13 percent of patients with no premature ventricular complexes had an ejection fraction of less than 40 percent compared with 26 percent of patients with a ventricular arrhythmia score of 3 and 71 percent of patients with a score of 5 (ventricular tachycardia). A more detailed analysis of the relation between

(a.%) 336, 65% 213, 54%

Male Age 550 years Historical features Peripheral vascular disease Previous myocardial infarction Congestive heart failure Progressive pain History of diabetes History of smoking Laboratory findings Q waves in electrocardiogram Cardiomegaly in chest X-ray film Catheterization features LVEDP > 18 avOzD >5.5 Ejection fraction <40% Normal LV contraction Left main coronary artery disease Number of vessels with Z 75 % stenosis

29, 7.3% 210, 53% 44, 11% 115, 29% 44,11% 299, 76% 176, 45% 69. 17%

56, 14% 47, 12% 95, 24% 249, 63% 12, 3% 127,32% 95, 24% 173. 44%

2 n

J

avOsD = arteriovenous oxygen difference (vol %); LV = left ventricular; LVEDP = left ventricular end-diastolic pressure.

ventricular arrhythmias and ejection fraction is displayed in Table V. With increasing ventricular arrhythmia score, the median ejection fraction declined from a high of 58 percent for patients with grade 0 arrhythmias to a low of 32 percent for patients with grade 5 arrhythmias. As a group, patients with high grade arrhythmias had a much lower ejection fraction than did patients with low grade arrhythmias (probability [p] = 0.001); however, the correlation coefficient was only 0.30. The results of a stepwise linear regression analysis relating ventricular arrhythmia score to the other patient characteristics are displayed in Table Vi. The score was related most closely to localized left ventricular asynergy and ejection fraction. No measurements of coronary anatomy or age were significantly related to the score after adjusting for the effects of other factors.

TABLE Ill Ventricular Arrhythmia Scores in 395 Medically Treated Patients With Significant Coronary Artery Disease Ventricular Arrhythmia Score

No premature ventricular <30/hour maximum ?dOlhour, uniform Multiform Two consecutive Ventricular tachycardia

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Patients (n, %)

Definition complexes

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118.30% 84, 21% 10, 3% 129.33% 33, a% 21, 5%

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TABLE IV Relation Between Ventricular Arrhythmia Score and Selected Baseline Characteristics in 395 Patients With Significant Coronary Artery Disease Ventricular

(n =‘119) Ck;zl

Arrhythmia

Score

(n 1 83)

(n 110)

(n =3129)

(n ,433)

(n ,521)

67 (81% 39 (48% 3( 4%

g yy; 2 (202)

111(86%) 45 (35%) 14(11%)

27 (81%) 15 (45%) 3( 9%)

41(49%)

6 (60%)

77 (60%)

24 (73%)

17 (81%)

l(lO%)

23 (18%)

6 (18%)

6 (29%)

characteristics

Age (50 years History of peripheral vascular disease History of myocardial infarction History of congestive heart failure Progressive chest pain History of diabetes History of smoking Laboratory characteristics Q waves in ECG Cardiomegaly on chest X-ray film Catheterization characteristics E$c$o; fraction 00 1 vessel CAD 2 vessel CAD 3 vessel CAD

45 (38%) 2(

2%)

6(

7%)

26 (22%)

29 (35%)

2 (20%)

43 (33%)

6 (18%)

9 (43%)

11( 9%) 86 (72%)

8 (10%) 61 (73%)

2 (20% 8 (80%

18 (14%) 104 (80%)

l( 3%) 24 (73%)

4 (19%) 16 (76%)

32 (27%) 8( 7%)

34(41%) 11 (13%)

5 (50%) l(lO%)

66 (61%) 26 (20%)

22 (67%) 10 (30%)

17 (81%) 13 (62%)

15 (13%)

14 (17%)

2 (20%)

34 (26%)

17 (52%)

15 (71%)

44 (37%)

33 (40%) 17 (20%) 33 (40%)

4 (40%) 4 (40%) 2 (20%)

36 (28%)

;; {;;;; 0

4 (19%) 4 (19%) 13 (62%)

CAD = coronary artery disease; ECG = electrocardiogram

Possible influence of drugs: Because some patients were taking cardiac medications at the time of ambulatory monitoring, we studied the effects of these drugs on arrhythmia occurrence. The ventricular arrhythmia score in the 391 patients taking beta receptor blocking agents did not differ from that of the 264 patients not taking these agents (including patients with no significant coronary artery disease) (p = 0.779). However, the 43 patients taking other antiarrhythmic agents (p = 0.01) and the 72 patients taking digoxin (p = 0.0001) had a higher ventricular arrhythmia score than that of the remaining patients in the study group. The ejection fraction in patients taking antiarrhythmic medications (median ejection fraction 44 percent) or digoxin (median 35 percent) was considerably lower than that of the

remaining patients (median 5.5 percent) (p
TABLE VI TABLE V

Invasive and Noninvasive Characteristics Related to Ventricular Arrhythmia Score in 395 Medically Treated Patients With Significant Coronary Artery Disease

Relation Between Ejection Fraction and Ventricular Arrhythmia Score in 396 Medically Treated Patients Median Ejection Fraction (%)

25th Percentile

75th Percentile

0 :

58 53 51

50 42

r!:

3

49

zl

zt 53 44

Ventricular Arrhythmia Score

5”

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3”:

z

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Characteristic

F Value

Localized left ventricular asynergy Ejection fraction PVCs in resting electrocardiogram History of peripheral vascular disease Cardiomegaly in chest X-ray film History of Prfnzmetal’s angina

31 20

Model R* = 0.23 PVCs = premature ventricular

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complexes.

:: :;

Probability (o) Value 0.0001 0.001 0.01 0.01 0.01 0.01

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.80 lq

5 .70 tx 3 * .60 _

.50 t FIGURE 1. Survival of 395 patients with significant coronary artery disease according to ventricular arrhythmia (VA) score.

.40

analysis. Thus, the average number of premature ventricular complexes/hour, the maximal number of such complexes in any 1 hour, and the occurrence of isolated complexes, multiform complexes, pairs and ventricular tachycardia were evaluated as predictors of survival. Each arrhythmia characteristic, when considered alone, was associated with decreased survival. When combinations were considered, each of the variables indicating complexity (multiformity, pairs, ventricular tachycardia) added prognostic information. When the relation between maximal number of premature ventricular complexes/hour and survival was examined, the figure of 30/hour was an empirically useful breakpoint in predicting survival. The average number of such complexes/hour was found not to add prognostic information. When all of these arrhythmia variables were placed in a model with the ventricular arrhythmia score, only the ventricular arrhythmia score was independently related to survival.

-

VA SCORE

------

VA SCORE = 1

**.-*--VA

-.-.-. ___-

I -b-~ass-.~-.-.~

I -_

=0

VA SCORE

=3

-*--.----

VA SCORE VA SCORE

=4 =5

1

I_..

i_______

SCORE=2

----

ET AL.

... . ... . . . .. . . . . . . . . . . . . . . . . . . . . .

. I I-.*-...

G

ARRHYTHMIAS-CALIFF

I

I

I

0

1

2 YEARS

I 3

FOLLOWUP

The independent prognostic value of the ventricular arrhythmia score was first tested by determining its importance in relation to descriptors of the history, physical examination, chest X-ray film and resting electrocardiogram. The ventricular arrhythmia score added statistically significant prognostic information to the amount of information provided by these commonly used noninvasive characteristics (chi-square = 4.6, p = 0.03). However, when the descriptors from cardiac catheterization were added (coronary anatomy, ejection fraction, wall motion and hemodynamic data) the score no longer added significant prognostic information (chi-square = 0.8, p = 0.4). Figure 2 demonstrates graphically the results of multivariable analysis. Before adjustment for all other variables (noninvasive and invasive), 2 year survival rates ranged from 90 percent in patients with no ventricular arrhythmias to 70 percent in patients with ventricular tachycardia. When other variables were held

TABLE

VII

Ventricular Arrhythmia Scores in Patients With an Ejection Fraction (EF) Above and Below 40 Percent Frequency of Score -3

20

0 Unodiurted 0

I Oo

2 Year

Ventricular Arrhythmia Score

Survival

Ad,u.tcd 2 Year Surrwal

Patients With EF 140% (n, %)

Patients With EF <40% (n, %)

I

1

1234

106.35% 70: 23% a, 3% 9532% 15, 5% 6. 2%

5

VA SCORE

FIGURE 2. Relation between ventricular arrhythmia (VA) score and survival before and after adjusting for other clinical characteristics in 395 patients with significant coronary artery disease.

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TABLE

VIII

Ventricular Significant

Arrhythmla Scores in 260 Patients Coronary Artery Disease Ventricular Arrhythmia Score

Patients (n, %)

0 1 :

103,38% 66, 34% 6, 2% 49,19% 16, 7% 0. 0%

4 5

401 0

1

1 2 VA

3 SCORE

4

k 5

FIGURE 3. Relation between 2 year survival rate and ventricular arrhythmia (VA) score in patients with an ejection fraction of less than 40 percent and those with an ejection fraction of 40 percent or greater.

constant, the estimated 2 year survival rate for each ventricular arrhythmia score was almost identical. The results for patients with a score of 2 may be unreliable because this group included only 10 patients. The c index was used to evaluate the relative clinical usefulness of the ventricular arrhythmia score. Results of the noninvasive evaluation, including only the history, physical examination, chest X-ray film and electrocardiogram, were combined into a single score reflecting the information content with respect to survival. With this simple noninvasive evaluation, a c index of 0.73 was obtained. Thus the probability that, of two randomly chosen patients, the patient with the worse noninvasive evaluation had the worse prognosis was 0.73. When the ventricular arrhythmia score was added to the noninvasive evaluation, the probability of correctly classifying pairs of patients according to prognosis increased only to 0.76. When the noninvasive and invasive evaluations were combined without the ventricular arrhythmia score, the c index increased to 0.83. The addition of the score to these descriptors increased the c index to only 0.84. Sudden death and ventricular arrhythmia score: Sixty of the 395 patients with significant coronary artery disease died during the follow-up period. In 36 patients death occurred within 2 hours of the onset of acute symptoms. Of the remaining 24 patients, 2 died of noncardiovascular causes, 19 died more than 2 hours after the onset of symptoms due to cardiac disease and 3 died of stroke. The preceding analyses were repeated using only sudden death as an end point. The ventricular arrhythmia score by itself was a significant prognostic factor (chi-square = 9.6, p = 0.002). However, the score did not add to the amount of prognostic information provided by the invasive and noninvasive variables (chi-square = 0.5, p = 0.5).

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Ejection fraction and ventricular arrhythmia score in relation to survival: To illustrate the distribution of ventricular arrhythmia score in relation to ejection fraction, the scores of patients with an ejection fraction of 40 percent or greater were compared with those of patients with an ejection fraction of less than 40 percent (Table VII). The distribution of the scores clearly is skewed so that patients with an ejection fraction of less than 40 percent have a higher ventricular arrhythmia score. The 2 year survival rate in relation to ventricular arrhythmia score is given for patients with an ejection fraction above and below 40 percent in Figure 3. The relation between the score and survival was much less strong in the patients with an ejection fraction of 40 percent or greater. In patients with an ejection fraction of less than 40 percent the 2 year survival rate ranged from 89 percent in patients with a score of 0 to 60 percent in patients with a score of 4. Patients with no significant coronary artery disease: The ventricular arrhythmia scores of the 260 patients without significant coronary artery disease are depicted in Table VIII. Although 71 of these patients had “high grade” ventricular arrhythmias (ventricular arrhythmia score of 2 or higher), none of the 71 died during the follow-up period. The only death in this group of patients was a sudden death 15 months after cardiac catheterization in a patient with a maximum of 1 premature ventricular complex/hour. Discussion Ventricular arrhythmia and left ventricular dysfunction: The relation between ventricular arrhythmia and extent and severity of coronary artery disease has previously been reported.4 A preliminary report from this medical center5 found that left ventricular dysfunction was the predominant factor relating to ventricular arrhythmia. When the degree of left ventricular dysfunction was held constant, the number of diseased vessels was not independently associated with the presence or complexity of ventricular arrhythmia. Our previous result is confirmed with the addition of 367 patients in this report. The correlation of only 0.30 between arrhythmia grade and ejection

PROGNOSTIC IMPLICATIONS

fraction indicates that ventricular ectopic rhythm cannot predict the degree of left ventricular dysfunction accurately. Nonetheless, ventricular dysfunction is the clinical variable most closely associated with ventricular arrhythmia. Effect of drugs: Because some patients were taking antiarrhythmic drugs at the time of ambulat,ory monitoring, the analysis for possible effects of drugs on arrhythmia occurrence during monitoring was necessary. Beta receptor blocking agents had no discernible effect. The increased occurrence of arrhythmias in patients receiving antiarrhythmic agents and digoxin appeared to be related to poor ventricular function. No difference in survival was detected between patients taking beta receptor blocking drugs or ant&rhythmic agents during the follow-up period and the remainder of the study group. Any differences may have been obscured by the small sample size and the variety of reasons for which the drugs were given. Furthermore, because the follow-up information was based on patient reports, compliance may have been variable during the follow-up period. Ventricular arrhythmia and survival: The relation between the presence and complexity of ventricular arrhythmias and decreased survival has been documented in many previous studies.6v7J6J7 Most investigators studied survival in patients immediately after infarction or in ambulatory persons without documentation of coronary anatomy or ventricular function. Moss3 and Ruberman et a1.2 found that ventricular arrhythmia observed during the postinfarction period was associated with decreased survival. Bigger et al.ls were unable to confirm these findings, but they analyzed the data from only 100 patients. Ruberman et al.lg and Hinkle et al.“” extended the finding that ventricular arrhythmia is related to survival to include patients with symptoms of coronary artery disease outside of the setting of the immediate postinfarction period. Ventricular arrhythmia score versus ejection fraction: The direct relations among ventricular arrhythmia score, ejection fraction and survival have not previously been reported. The small number of patients in postinfarction studies and the infrequency of coronary events in ambulatory studies have not allowed such an analysis to this point. In a preliminary report of a large number of postinfarction patients (without direct knowledge of ventricular function), Moss7 found that only early cycle premature ventricular complexes and multiform premature ventricular complexes had independent prognostic value. Other studies7 have used different methods of classifying ventricular arrhythmias. Individual studies probably will find different permutations among these variables but, in general, increasing arrhythmia complexity as initially defined by Lown and WoP1 is associated with poor ventricular function and decreased survival. Noninvasive prognostic variables: The noninvasively obtained measurements used to test the independent prognostic significance of ventricular arrhythmias were those that have been collected in our

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entire population of patients with significant coronary artery disease documented by arteriography.g The finding that ventricular arrhythmias were important prognostically even when other noninvasively obtained variables were controlled is consistent with previous data. Moss et a1.22 evaluated 954 postinfarction patients and found that when a limited number (six) of clinical measurements were considered in multivariable analysis, the presence of at least one premature ventricular complex in a 6 hour Holter recording remained a significant prognostic indicator. Luria et a1.“3 used discriminant analysis of 22 noninvasive variables and found that ventricular arrhythmias remained prognostically important when other factors were considered. In a study of 1,379 men after myocardial infarction, Ruberman et al.’ found that complex premature ventricular complexes were related to cardiac death independently of 16 clinical variables including the presence of congestive heart failure. In a follow-up study of men with angina, a similar result was obtained.‘9 The c index: This index indicates that the probability that a patient’s prognosis could be better classified with the addition of ambulatory monitoring is not as great as one might expect. With a simple noninvasive evaluation available to every physician, 73 percent of randomly chosen pairs of patients could be correctly ranked with respect to prognosis. The addition of the ventricular arrhythmia score increased this value to only 76 percent. Thus, although the vent,ricular arrhythmia score adds information that is statistically significant, its clinical value (if the clinician makes appropriate use of ‘
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Multivariable analysis of prognostic predictors: The significance of the multivariable analysis is underscored by reviewing the special subgroups. In patients with no intrinsic heart disease (in this instance without coronary artery disease) no relation was found between arrhythmias and mortality.. This finding is consistent with the reports of Kennedy et a1.25 using ambulatory monitoring in patients with frequent and complex arrhythmia. Similarly, exercise-induced arrhythmias in the general asymptomatic population have been found to be poor predictors of cardiac events.2”J7 Because one objective of our study was to identify a high risk group of patients without poor ventricular function, the patients with an ejection fraction of 40 percent or higher were evaluated separately. Although 31 percent of these patients had a ventricular arrhythmia score of 2 or more, survival was not as closely related to this score as in the patients with increased risk associated with poor ventricular function. Implications: Our findings have several therapeutic implications. We found no relation between ventricular arrhythmias and decreased survival in patients without significant. organic heart disease. Because other investigators have reported similar results, it seems prudent to avoid using antiarrhythmic agents in these patients so long as they have no symptoms. However, this strategy must be individualized, because rare patients without other discernible heart disease have sustained ventricular tachyarrhythmias leading to hypotension or sudden death. In patients with an ejection fraction of 40 percent or greater, we found a weak relation between ventricular arrhythmia score and cardiac death. Of 124 patients with a ventricular arrhythmia score of 2 or more, 13 died suddenly. Thus an attempt to prevent sudden death in patients with an ejection fraction of 40 percent or greater using ambulatory monitoring to select candidates for therapy would be expensive with low yield. Even if one had a drug that was 100 percent effective, 10 patients would be treated needlessly for each death prevented if patients with a ventricular arrhythmia

score of 2 or more were selected for therapy. At the same time, 4 percent of patients with a ventricular arrhythmia score of less than 2 would die suddenly without therapy. Because sustained ventricular tachycardia was rare in this group, no conclusions can be drawn from our study regarding therapy for patients with sustained ventricular tachycardia and an ejection fraction greater than 40 percent. The group with an ejection fraction of less than 40 percent poses a more difficult problem. In one 24 hour recording, 90 percent had some ventricular arrhythmia and 75 percent had complex arrhythmia. Almost certainly, with more sophisticated computerized recording systems and more prolonged monitoring, the frequency of complex ectopic activity will approach 100 percent in this population. The risk of both sudden and nonsudden death is high in this group. However, the outlook for these patients is not as dismal as once thought and many of them are leading productive lives without severe symptoms. After 2 years 70 percent of these patients remain alive. Only 16 percent of the survivors have significant symptoms of congestive heart failure and 36 percent are employed. With recent advances in electrophysiology many investigators now believe that the major factor leading to sudden death in these patients is the ability to sustain reentrant circuits in areas of ischemic and infarcted muscle. 28,2gBecause the capacity for such arrhythmias may exist in almost all patients with a low ejection fraction, 24 hour ambulatory monitoring may be less helpful than once thought in choosing candidates for therapy. Instead, a trial of antiarrhythmic drugs might be based on the presence of low ejection fraction alone. Such a trial would not necessarily require cardiac catheterization, because left ventricular ejection fraction can be measured accurately noninvasively with radionuclide angiography. Only a clinical trial will delineate the individual and combined effects of antiarrhythmic drugs, afterload reduction and myocardial revascularization in this high risk group of patients with a low ejection fraction.

References 1. Coronary Drug Project Research Group: Prognostic importance of premature beats following myocardial infarction. JAMA 1973;223:1116-23. 2. Ruberman W, Weinblatt E, Goldberg JD, Frank CW, Shapiro S. Ventricular premature beats and mortality after myocardial infarction. N Engl J Med 1977;297:750-7. 3. Moss AJ. Factors influencing prognosis after myocardial infarction. Curr Probl Cardiol 1979;4:1-52. 4. Calvert A, Lown B, Gorlin R. Ventricular premature beats and anatomically defined heart disease. Am J Cardiol 1977;39: 627-34. 5. Califf R, Burks J, Behar V, Margolis J, Wagner G. Relationships among ventricular arrhythmias, coronary artery disease, and angiographic and electrocardiographic indicators of myocardial fibrosis. Circulation 1977;57:725-32. 6. Lown B, Podrid PJ, Graboys TB. Sudden cardiac death-man-

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agement of the patient at risk. Curr Probl Cardiol 1980;5: l-62. 7. Moss AJ. Clinical significance of ventricular arrhythmias in patients with and without coronary artery disease. Prog Cardiovasc Dis 1980;23:33-52. 8. RosatlRA, McNeer JF, Starmer CF, Mtttler SS, Morris JJ, Wallace AG. A new information system for medical practice. Arch Intern Med 1975;135:1017-24. 9. Harris PJ, Harrell FE, Lee KL, Behar VS, Rosati RA. Survival in medically treated coronary artery disease. Circulation 1979;60: 1259-69. 10. Rackley CE, Behar VS, Whalen RE, McIntosh HP. Biplane cineangiographic determinants of left ventricular function: pressure-volume relationships. Am Heart J 1979;74:766-79. 11. Cox DR. Regression models and life tables (with discussion). J R Stat Sot B 1972;34:187-220. 12. Breslow NE. Covariance analysis of censored survival data. Bio-

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metrics 1979;30:89-99. 13. Harrell FE. PHGLM in SAS Supplemental Library User’s Guide. Cary, NC: SAS Institute, 1980; 119-31. 14. Kaplan EL, Meier P. Nonparametric estimates from incomplete observations. J Am Stat Assoc 1958;53:457-8 1. 15. Brown BW. Hollander M, Korwar RM. Nonparametric tests of independence for censored data with application to heart transplant studies. In: Proschan F, Serfling RJ, eels. Reliability and Biometry. Philadelphia: Social and Industrial Applied Mathematics 1974: 327-54. 16. Schulz RA, Strauss HW, Pitt B. Sudden death in the year following myocardial infarction. Am J Med 1977;62:192-9. 17. Winkle RA. Ambulatory e(ectrocardiography and the prognosis, evaluation and treatment of chronic ventricular arrhythmias. Prog Cardiovasc Dis 1980;23:99- 128. 18. Bigger JT, Heller CA, Wenger TL, et al. Risk stratification after acute myocardial infarction. Am J Cardiol 1978;42:202-10. 19. Ruberman W, Weinblatt E, Goldberg JD, Frank CW, Shapiro S, Chaudharg BS. Ventricular premature complexes in prognosis of angina. Circulation 1980;61:1172-8. 20. Hinkle LE, Carver ST, Argyros DC. The prognostic significance of ventricular premature contractions in healthy people and in people with coronary heart disease. Acta Cardiol (Suppl) 1974; 1815-32. 21. Lown 9, Wolf M. Approaches to sudden death from coronary artery disease. Circulation 1971;48:130-42.

22. Moss AJ, Davis HT, DeCamilla J, Bayer LW. Ventricular ectopic beats and their relation to sudden and nonsudden cardiac death after myocardial infarction. Circulation 1980;60:998-1003. 23. Luria MH, Knocke JD, Margolis RM, Hendricks FH, Kuplic JB. Acute myocardial infarction: prognosis after recovery. Ann Intern Med 1976;85:561-5. 24. Taylor GJ, Humphries JO, Mellits ED, et al. Predictors of clinical course, coronary anatomy and left ventricular function after recovery from acute myocardial infarction. Circulation 1981;62: 960-70. 25. Kennedy HL, Pescarmona JE, Bouchard RJ, Goldberg RJ. Coronary artery status of apparently healthy subjects with frequent and complex ventricular ectopy. Ann Intern Med 1979;92:17985. 26. Blackburn H, Taylor H, Keys A. The exercise ECG in prediction of five-year coronary heart disease incidence among men aged 40-59. Circulation 1970;41:154-61. 27. Froelicher V, Thomas M, Pillow C. Epidemiologic study of asymptomatic men screened by maximal exercise testing for latent coronary artery disease. Am J Cardiol 1974;34:770-6. 28. Josephson ME, Spielman SR, Greenspan AM, Horowitz LN. Mechanism of ventricular fibrillation in man. Am J Cardiol 1979; 44:623-3 1. 29. Zipes DP, Heger JJ, Pryslowsky EN. Sudden cardiac death. Am J Med 1981:70:1151-4.

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