The coronary artery bypass graft (CABG) patch trial

The Coronary Artery Bypass Graft (CABG) Patch Trial The CABG Patch Trial Investigators

HE CORONARY Artery Bypass Graft (CABG) Patch Trial is the only clinical trial currently underway or being planned that compares implantable cardioverters/defibrillators (ICD) therapy with no alternate therapy. In many ways the CABG Patch Trial is a surgical trial conducted as a tight collaboration between cardiothoracic surgeons and clinical cardiac electrophysiologists. This paper discusses the background and design of the CABG Patch Trial and also reports some data gathered in the CABG surgery survey done by the planning group and data gathered during the pilot phase of the trial.

T

RATIONALE

FOR THE CABG PATCH TRIAL

Sudden cardiac death is a common problem in the United States and Europe. Each year, more than 400,000 people die suddenly in the United States, almost one person per minute.‘,’ A comparable number die each year in western Europe. Unfortunately, fewer than 5% of cardiac arrest victims are resuscitated and leave the hospital alive. A few well-organized communities, eg, Seattle, have higher salvage rates, but even in these communities more than 75% of the cardiac arrest victims die. The poor salvage rate for patients experiencing cardiac arrest is an argument for prophylaxis. A substantial percentage of deaths due to cardiac arrest, perhaps 25%, cannot be addressed by prophylaxis, because sudden cardiac death is the first and last manifestation of coronary heart disease. Most of these deaths probably have an ischemic mechanism. About 75% of sudden cardiac deaths occur in patients with previously recognized heart disease, quite often severe heart disease. Arrhythmias related to myocardial scarring, not ischemia, seem to account for a significant fraction of deaths in patients with advanced coronary heart disease. Patients with previously recognized heart disease are available for screening, risk stratification, and prophylaxis? Patients who are at high risk for sudden cardiac death could be treated prophylactically with drugs, surgery, or implanted ICDs. So far, drug prophylaxis has not proven very effective. Progressm

CardiovascularDiseases,

Vol XXXVI,

No 2 (September/October),

and Coordinators

The only class of antiarrhythmic drugs shown to be effective against sudden cardiac death are B-adrenergic blocking drugs (class II antiarrhythmic action) when given after myocardial infarction, and the magnitude of their benefit is modest.5-s Many patients who are at very high risk for sudden cardiac death have severe left ventricular (LV) dysfunction (left ventricular ejection fraction [LVEF] < 0.36) or a clinical heart failure syndrome (New York Heart Association functional class II to IV), groups that physicians are reluctant to treat with B-adrenergic blocking drugs.” A substantial body of evidence suggests that class I antiarrhythmic drugs actually increase mortality when used to treat coronary heart disease patients with LV dysfunction and asymptomatic or minimally symptomatic ventricular arrhythmias.‘O-l6 Although data on drugs with class III action, amiodarone, or dl-sotalol are encouraging, they are not definitive.” Additional controlled data are needed before prophylactic use of drugs with class III action can be recommended to prevent sudden cardiac death. Coronary artery bypass graft surgery can increase survival in patients with critical coronary disease (especially patients with left main stenosis or triple vessel disease and LV dysfunction).i8-” However, the surgical mortality and the later mortality in this group are substantial.

From the Division of CardioloRv Department of Medicine, Columbia lJniversi@, New York. NY,, and the Ar&vthmia Control Unit, Columbia-Presbyterian Medico1 Center, New York, NY. Supported in part by National Institutes of Health Grants No. HL-48159 and HL-48120 from the Nationul Heart, Lung, and Blood Institute, Bethesda, MD and RR-00645 from the Uesearch Resources Administration, National Institutes of Health: and by funds from Cardiac Pacemakersv tnc, The Bu@er Foundation. The Dover Foundation, and Adelaide Segermun, New York, NY Note: Approved by the Data and Safety Monitoring Board on September 30, 1992. Approved by the Publicatrons Committee of The CABG Patch Trial on October IO, 1992. Address reprint requests to J. Thomas BigRer.lr, MD, College of Physicians and Surgeons, 9-445, Columbia lJniver@, 630 W 168th St, New York, NY 10032. Copyright 8 1993 by WB. Sa1mder.s Company 0033.062019313602-0003$5.OOlO 19%:

pp 97-l

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Also, almost half of the later mortality is from sudden cardiac death (see below). Uncontrolled data suggest that ICD treatment substantially reduces the rate of sudden cardiac death in patients who present with cardiac arrest or sustained ventricular tachycardia (VT).2Z However, no randomized clinical trials have been done to conclusively establish the efficacy of ICD therapy to prevent sudden death or to establish its superiority over drug therapy for this purpose. The question has been raised whether ICD therapy substantially reduces mortality of all causes even if it does significantly reduce sudden cardiac death.‘j Therapy with ICD is only capable of reversing malignant tachyarrhythmias. It is not capable of preventing deaths due to myocardial ischemia or deaths due to heart failure. Since malignant arrhythmias in coronary heart disease occur predominantly in patients who have severe multivessel coronary atherosclerosis and significant LV dysfunction, it is possible, even likely, that deaths from ischemia or heart failure may take a high toll when sudden death is prevented in high-risk coronary patients. Therefore, several randomized clinical trials are underway to compare ICD therapy with drug therapy in patients who present with cardiac arrest or sustained VT. There are only two clinical trials underway to evaluate ICD prophylaxis to prevent sudden cardiac death in high-risk patients who have not yet had malignant ventricular arrhythmias, the Multicenter Automatic Defibrillator Implantation Trial (MADIT) and the CABG Patch Trial.24.26

PHASES OF THE CABG PATCH AND THEIR OBJECTIVES

TRIAL

The CABG Patch Trial has had three phases: (1) a planning phase, (2) a pilot study, and (3) the full-scale trial. The Planning Phase

The planning phase of the CABG Patch Trial lasted 2.5 years, from February 1988 to September 1990. During this period, a group of investigators from seven institutions met regularly to discuss patient groups who might benefit from ICD prophylaxis to decrease the risk of sudden death, and how to design a clinical trial to

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evaluate prophylaxis. The planning committee first considered high-risk groups who could be identified early after acute myocardial infarction. However, the planning group finally realized that there were insurmountable scientific and logistic problems with this group of patients when considering a randomized controlled trial of ICD prophylaxis that would use leads implanted via thoracotomy in one group and no treatment in the other. The principal scientific problem is a likely substantial increase in the use of diagnostic and therapeutic procedures in the group randomized to ICD therapy. The planning group anticipated an excess of coronary angiograms in the ICD group because this group would have a thoracotomy that the control group would not have. The planning group also anticipated an excess in CABG surgery and angioplasty in the ICD group as a result of information revealed by the coronary angiogram. If the anticipated imbalance in revascularization occurred, the trial would be confounded. ie, better survival in the ICD group could either be due to the ICD or revascularization or both. In addition to this fatal scientific flaw, there was a logistic problem in the postinfarction group. The striking contrast between the treatments in the two groups, thoracotomy and implantation of an ICD system in one and no treatment in the other, had the potential to have a substantial negative impact on recruitment of patients and to engender an inequality in the USCof antiarrhythmic drug therapy between the two groups. After discussing various groups that could be used to evaluate ICD prophylaxis while avoiding these problems, the planning group identified high-risk CABG surgery patients as an attractive study group. A high-risk group can bc identified using LVEF alone and. using an additional arrhythmia marker, the fraction of deaths that are sudden should increase. All CABG surgery patients would have coronary angiography and complete revascularization. removing the scientific problem of confounding due to differences in revascularization rates between the control and ICD groups. All CABG surgery patients would have a thoracotomy, removing the contrast between intensity of intervention in the two groups which was anticipated to be a major barrier to recruitment.

THE CABG

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BACKGROUND

TRIAL

FOR THE CABG PATCH

99

TRIAL

There are no definitive controlled data on the benefit of surgery in patients with severely reduced LVEF (< 0.36) because the major randomized comparisons of medical and surgical treatment of coronary artery disease excluded patients with markedly reduced LVEF. The European Coronary Surgery Study excluded patients with LVEF below 0.50 (determined by angiographic left ventriculograms).27 The Coronary Artery Surgery Study (CASS) randomized trial excluded patients with LVEF below 0.35 (determined by dye left ventriculograms in the 30” right anterior oblique view).28,‘9 The literature does not clarify the overall survival experience or causes of death after CABG surgery in patients with significantly reduced LVEF. The reports of uncontrolled experience with CABG surgery in patients with LV dysfunction show a wide range of mortality rates. Some investigators report a high longterm mortality rate associated with severely compromised LV function and/or LVEF,““-“” while others report a much more optimistic experience.jh-j8 A number of studies have evaluated patient data stratifying them by LVEF or LV functional assessment measures, eg, LV segmental wall motion scores. These results, described below, are helpful, but because of their sampling methods and varied results they do not provide definitive conclusions. Hochberg et a13()reported the surgical mortality and long-term survival of 466 patients with LVEF below 0.40 undergoing CABG surgery at the Newark Beth Israel Hospital (Newark, NJ) between 1976 and 1982. The mean age in this group of patients was 58 years and 84% were male. All of the patients had previous myocardial infarction, all had either angina pectoris or a positive thallium 201 study, and 36% had symptoms or signs of congestive heart failure. Between 1976 and 1982, 425 patients with LVEF between 0.20 and 0.39 and 41 patients with LVEF between 0.10 and 0.19 had CABG surgery. For the group with a LVEF of 0.20 to 0.39, 89% survived to hospital discharge and 60% survived for at least 3 years. For the group with a LVEF of 0.10 to 0.19, only 63% survived to hospital discharge and 15% survived for at least 3 years. The patients were divided into six groups based on LVEF, each with a 5-point

range: 0.10 to 0.14, 0.15 to 0.19, 0.20 to 0.24, 0.25 to 0.29, 0.30 to 0.34, and 0.35 to 0.39. The groups with LVEF 0.10 to 0.14, and 0.15 to 0.19 had an identical survival experience and the groups with LVEF 0.20 to 0.24,0.25 to 0.29, and 0.30 to 0.34 had an identical survival experience that was substantially better than the groups with LVEF 0.10 of 0.19 and substantially worse than the group with LVEF 0.35 to 0.39. The relationships between preoperative LVEF and the 3-year survival experience provide the rationale for stratification of LVEF at 0.20 for randomization in the CABG Patch Trial. Alderman et al reported the surgical mortality and long-term survival of 231 patients in the CASS registry with LVEF below 0.36 undergoing CABG surgery between 1975 and 1979.31 This surgically treated group was compared with 420 medically treated patients with LVEF below 0.36 who also were in the CASS registry. All of these patients had an LV wall motion score at or above 12, a 70% or higher stenosis of one or more coronary artery, at least 1 year of follow-up, and lacked a history of previous CABG surgery. The average LVEF was 0.30 in medical and surgical groups; the average LV wall motion score was 16.0 in the medical group and 15.5 in the surgical group. The surgical mortality rate was 6.9%. The 3-year survival rate for surgically treated patients was 77% and the 3-year survival rate for medically treated patients was 66%. Rehospitalization occurred for the following reasons (surgical group versus the medical group): myocardial infarction 7.8% versus 10.7%; congestive heart failure 19.5% versus 25.2%; and arrhythmias 2.1.20/o versus 17.9%. This study suggests that arrhythmic problems represent a major cause of morbidity in patients with severe coronary disease and that CABG surgery does not reduce arrhythmic risk. Recently, Christakis et al presented a large mortality experience with CABG surgery.j7 Between January 1982 and December 1990, 12,471 patients had CABG surgery at the University of Toronto (Toronto, Ontario, Canada). For 9,445 patients with LVEF above 0.40, the operative mortality rate was 2.3%; for 2539 patients with LVEF between 0.20 and 0.40, the operative mortality rate was 4.8%; and for 487 patients with LVEF below 0.20, the operative mortality

100

rate was 9.8%. No cause-specific information was available for the deaths. It is especially difficult to obtain causespecific information on arrhythmic death after CABG surgery. Holmes reports the mortality experience during 5 years of follow-up in 11,843 medically treated patients and 8103 surgically treated patients in the CASS registry.“‘x4” In the surgically treated patients, death was sudden in 204 patients (2.5%) not sudden but cardiac in 390 patients (47%) and not cardiac in 230 patients (28%). In the medically treated patients, death was sudden in 557 patients (34%) not sudden but cardiac in 813 patients (50%) and not cardiac in 251 patients ( 16%).“9 In both medically and surgically treated groups, there were no baseline variables in the CASS database that predicted sudden death better than nonsudden cardiac death. This study supported a previous report by the same investigators that CABG surgery reduced sudden cardiac death in the highest-risk patients, but that substantial numbers of sudden deaths continue to occur after surgical treatment.40 It is likely that the observed reduction in sudden cardiac death was due to a reduction in ischemic events. Bolooki reported a 35% sudden death mortality after CABG surgery during a follow-up period of 50 months? Arrhythmic mortality has been analyzed after CABG surgery in patients who have malignant arrhythmias and LV dysfunction.‘8,4”,4’ Tresch et al reported the long-term follow-up of 49 patients who had CABG surgery after cardiac arrest.38 These 49 patients were a subset of the 459 patients who were resuscitated after out-ofhospital cardiac arrest in Milwaukee between 1973 and 1982. About one third had myocardial infarction in association with the cardiac arrest. Cardiac catheterization revealed significant three-vesseI disease in 70% of the 49 patients. The mean LVEF for the group was 45% and the LV end diastolic pressure was 15.3 mm Hg. Four of the patients (8%) died soon after surgery; one died 10 days after surgery of refractory VT. Seven of the 45 patients (16%) discharged alive died during an average follow-up of 55 months; these deaths occurred between 15 and 81 months after surgery. Five of the seven deaths (71%) were due to recurrent ventricular fibrillation (VF) and two (29%)

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ET AL

were due to congestive heart failure. In a second study, Ji 23 patients with malignant arrhythmias and LV dysfunction were treated with CABG surgery and ICD implantation. Eight patients (35% of the study’s total sample) were classified as tachyarrhythmic deaths, but actually were successfully rescued by ICDs. In a third study, the sudden death rate was reported for patients with LV dysfunction but no clinical arrhythmias who had CABG surgery. A 29% sudden arrhythmic mortality was reported, ie, two of seven deaths. One of these deaths was a documented in-hospital cardiac arrest and the other was an out-of-hospital sudden death.“’ More recently Kron et al, reported on two separate studies analyzing data from their CABG surgery experience. In the first of these studiesd3 eight patients who had presented with cardiac arrest due to VF, not preceded by sustained VT were treated with CABG surgery. The mean LVEF of these patients was 0.39 and seven of the eight patients had major LV wall motion abnormalities. Postoperatively, three of eight patients (38%) experienced a recurrence of VF not associated with recurrent ischemia; one of these patients could not be resuscitated. The investigators concluded: “The data presented in this study indicate that CABG surgery should not be presumed to provide effective therapy for patients with cardiac arrest and VF.” In the second of Kron and coworker’s studiesJ4 39 patients seen between 1983 and 1988 with chronic ischemic cardiomyopathy and LVEF below 0.20 were treated with CABG surgery rather than cardiac transplantation and followed long term to determine their survival status. None of these patients had previous episodes of sustained VT or VF prior to CABG surgery. Eight late deaths (21%) occurred during an average follow-up period of 21 months and seven of these (88%) were due to arrhythmias. If analyzed as the number of arrhythmic deaths occurring in the total study series. 18% (seven of 39 patients) experienced arrhythmic mortality despite revascularization by CABG surgery. In discussing these data, Spotnitzqs commented that this high arrhythmic mortality after CABG surgery suggested that such pa-

THE CABG

PATCH

TRIAL

tients “may well be candidates for ICD implantation.” Thus, a review of the available medical literature reporting on survival of patients with poor LV function (ie, LVEF < 0.36) who had CABG surgery yields a number of important findings: (1) the operative mortality rate for CABG surgery ranges from 3.9% to 24%; (2) the total postoperative “all cause” mortality at 3 years of follow-up ranges from 24% to 50%; and (3) the cumulative mortality rate from sudden cardiac death ranges from 25% to 35% at 5 years. These reports suggest that arrhythmias are a common cause of death after CABG surgery. Further, based upon data presented in several studies, the arrhythmic deaths usually are tachyarrhythmic in nature, leading some investigators to conclude that ICD therapy should be strongly considered in CABG surgery patients with LVEF below 0.36.4.‘-4’ SURVEY OF MORTALITY AFTER CABG SURGERY IN PATIENTS WITH LEFT VENTRICULAR DYSFUNCTION

The planning group was dismayed to find that the coronary surgery literature was not clear on the prevalence of patients with low LVEF or on the prognosis of these patients after CABG surgery. To obtain additional information needed to proceed with planning a clinical trial to evaluate the efficacy of ICD prophylaxis, seven of the planning group conducted a retrospective survey of CABG surgery in their institutions to determine the percentage of CABG surgery patients aged under 80 years who had a LVEF below 0.36 and their surgical and longterm mortality. All of the participating institutions were experienced in CABG surgery and in the management of arrhythmia patients. The investigators and their institutions are listed in Table 1. 0bjective.s

The objectives of the CABG surgery survey were to determine: (1) the total number of patients in participating institutions who had CABG surgery in 1986; (2) the fraction who had LVEF below 0.36; and (3) the hospital and long-term survival experience for patients with LVEF below 0.36. The survey was conducted between August and December of 1988. Sur-

Table

1. The CABG Surgery Investigators and

Survey: Institutions

Investigators

Gregory

Institutions

L. Kay, MD

David S. Cannom, Vincent Gaudiani, Roger A. Winkle, A. David Slater, lgor Singer, MD Joel Kupersmith,

Good MD MD

MD MD MD

Irving L. Kron, MD John P. DiMarco, MD, PhD Harold R. Kay, MD Leonard N. Horowitz, MD Henry M. Spotnitz, MD J. Thomas

Bigger

Participating

Jr, MD

Paul Werner, MD Masood Akhtar, MD

Samaritan

(Los Angeles, Sequoia Hospital

Hospital CA) (Redwood

City, CA) Humana Hospital, Hospital, Jewish (Louisville, University

Norton Hospital

KY) of Virginia

(Charlottesville,

Hospital VA)

Presbyterian Medical Center (Philadelphia, PA) The Presbyterian Hospital in the City of New York York, NY) Sinai Samaritan ter (Milwaukee,

Medical WI)

(New Cen-

gery done during the year 1986 was chosen for the survey as the providing long enough follow-up to provide significant long-term survival experience, but recent enough so that modern techniques of anesthesia and surgery, eg, myocardial preservation, were used. Results were coded so that the individual centers could not be identified. Data Set

Since the study was retrospective, a minimum of data was collected on the rationale that more extensive data would not only be hard to obtain, but also inaccurate. The following data were obtained: age at time of CABG surgery, date of birth, sex, date of CABG surgery, LVEF (measured just before surgery), status (alive or dead), and date of death or of last contact. Methods of Recruiting Subjects

Patients who had coronary artery bypass graft surgery in 1986 were identified by the cardiothoracic surgeons on the staff of the participating hospitals. Patients who were known to be dead or who, in the opinion of the attending cardiac surgeon, would be adversely affected by the follow-up questionnaire were removed from the mailing list. Instructions for data items to be collected, definitions of items, and specification of the format for each data item were prepared by the data coordinating center at Columbia University (New York, NY) and distributed to each investigator. A letter was sent by each

102

BIGGER

cardiac surgeon to his patients requesting that they participate by filling out the questionnaire enclosed with the letter. After 2 weeks, a telephone call was made to nonresponders to determine if (1) the patient received the letter and (2) whether they intended to participate. If the patient did not receive the questionnaire, another was mailed. If the patient did not want to participate, this was noted on the records so that this patient would not be contacted again. Data sets were submitted to Columbia University on floppy disks or on hard copy. Patients were identified only by code number. Data were checked and analyzed using the BMDP (BMDP Statistical Software, Inc., Los Angeles, CA) and SAS (SAS Institute, Inc., Cat-y, NC) statistical packages. Results of the CABG Surgery Survey The number of CABG operations done in the seven participating hospitals during 1986 totaled 3217. Ninety-five percent of the CABG surgery patients were under 80 years of age, and 17% of them had LVEF below 0.36. The surgical mortality rate for patients with LVEF below 0.36 averaged 11.6%. The 2-year mortality rate, accounting for patients who were lost to follow-up and for time of death by the KaplanMeier method, was 27.5% (Fig 1). Because the survey was multicenter and not affected by “publication bias” (more likely to publish low than high mortality rates), the mortality rates from the survey probably reflect the overall

1

0.64 1.0

0.0

YEARS

SINCE

20

CABG

SURGERY

Fig 1. Survival of patients with LVEF below 0.36 after CABG surgery. These data were gathered in the survey of CABG surgery in the seven institutions that participated in planning the CABG Patch Trial.

ET AL

operative experience more accurately than the medical literature previously reviewed. THE PILOT PHASE OF THE CABG PATCH TRIAL

The survey results were encouraging (set section BACKGROUND FOR THE CABG PATCH TRIAL), so a trial was designed for high-risk patients having CABG surgery. During the planning meetings, several questions were identified that were critical for the design of a full-scale trial and were not answered by the CABG surgery survey. First, the planning group wanted to use an arrhythmia marker to qualify patients for the trial in addition to low LVEF. Three possible qualifiers were considered: (1) frequent and/or repetitive ventricular arrhythmias detected in 24-hour continuous ECG recording, (2) programmed ventricular stimulation, and (3) the signal-averaged clectrocardiogram (ECG). The signal-averaged ECG was judged the most suitable of these three. considering the scientific and logistic features of the trial design. However, it was an unanswered question how much a positive signal-averaged ECG would increase the risk of arrhythmic death in the sample being proposed for the CABG Patch Trial. Second, it was not clear how the eligibility and exclusion criteria proposed for the study would affect recruitment and how willing cardiologists and cardiothoracic surgeons would be to enroll their patients into a randomized clinical trial to evaluate the effect of ICD therapy on survival after CABG surgery. The planning group thought that these important questions should be answered before planning the final trial. Accordingly, the pilot phase of the CABG Patch Trial was undertaken to determine whether the signal-averaged ECG was worthwhile as a qualifier of risk and to obtain cstimates of several other probabilities that arc required to design the final study, calculate sample size, and determine how many clinical centers would be required to conduct the study. Figure 2 shows the flow diagram for the CABG Patch Trial. It was thought that, for the study to be feasible, 33% of the eligible patients would have to be enrolled and that the risk of an endpoint event (death or nonfatal cardiac arrest) should be 2.0 or more times as high in the

THE CAEG

PATCH

TRIAL

103

Coronary Disease, CABG Surgery, Age <80, LVEF <0.38, SAECG +

Too Sick

urgeon’s Assessmen after CABG surgery

(3

O.K.

0 R

Fig 2. Flow diagram for the CABG Patch Trial. The Fi in the circle indicates the point of randomization. Randomization takes place in the surgery after the coronary artery bypass grafts have been completed and with the patient on partial cardiopulmonary bypass. The shaded boxes indicate the main comparison for the trial; ICD therapy is compared with no antiarrhythmic therapy. Abbreviations: CABG, coronary artery bypass graft surgery; LVEF. left ventricular ejection fraction; SAECG, signal-averaged electrocardiogram. (Reprinted by permission of Blackwell Scientific Publications, lncz6)

group with a positive signal-averaged ECG as in the group with a negative signal-averaged ECG. A l-year pilot study with a goal of recruiting 50 patients was initiated on September 1, 1990 and ended on August 31, 1991. Patients with coronary artery disease who were scheduled for elective CABG surgery were screened at the five CABG Patch Trial clinical centers: Good Samaritan Hospital in Los Angeles, CA: Sequoia Hospital in Redwood City, CA; three hospitals affiliated with the University of Louisville in Louisville, KY; University of Virginia Hospital, Charlottesville, VA; and the Presbyterian Medical Center, Philadelphia, PA. All patients had coronary angiography and measurement of LVEF within 1 year, most within a month of the CABG surgery. The coronary angiograms were reviewed and coded by study personnel and, if not previously done, the left ventriculograms were quantified for LVEF. A 12-lead ECG, signal-averaged ECG, and Holter recording were obtained at baseline. The criteria for a positive signal-averaged ECG were any one of the following: (1) a filtered QRS duration of at or above 114 milliseconds; (2) a root mean square voltage below 20 ~J,V in the terminal 40 milliseconds of the filtered QRS duration; or (3) duration of the terminal filtered

QRS complex of longer than 38 milliseconds after the QRS voltage fell below 40 r.r.V.Many of the Holter ECG recordings were substantially shorter than 24 hours because of the short time period between admission and surgery. The Holter was used for baseline information; there were no Holter requirements to qualify for the study. The main findings of the pilot study are shown in Table 2. During the l-year pilot study, 2508 patients were screened and 18% of them were under 80 years of age and had a LVEF below 0.36. About 65% of the otherwise eligible patients had a positive signal-averaged ECG. Overall, 3.3% of the screened patients were fully eligible and 68% of the eligible patients signed a consent form, about twice the percentage anticipated. Of those who signed a consent form, 80% were randomized in the operating room after CABG surgery was completed while 20% were deemed by their surgeon to be too unstable for an LCD implant. As a result of screening in the pilot study, 56 patients were enrolled and 44 were randomized (Fig 3). The relative risk for death of any cause or cardiac arrest of patients with a positive versus a negative signal-averaged ECG was greater than 3.0 (Fig 4) substantially greater than the criterion for adequate performance. However, with the small number of deaths and cardiac arrests that occurred in the pilot study, the association between signal-averaged ECG and death/cardiac arrest was not statistically significant. Due to the small number of endpoints, the 95% confidence interval for the relative risk was 0.9 to 15.8. Nevertheless, the preliminary signal-averaged ECG findings prompted the decision to use the signalaveraged ECG as the arrhythmia qualifier for the full-scale CABG Patch Trial. The baseline characteristics of the patients enrolled in the Table

2. Enrollment

in the CABG Patient

Patch

Trial

Pilot

Group

%

1. Age below 2. Age below 3. 4. 5. 6.

80 years 80 years, LVEF below 0.36 Otherwise eligible, positive signal-averaged Fully eligible for the trial Eligible patients who enrolled Enrolled patients who were randomized

7. Screened, *Total

number

enrolled, screened

and

randomized

2,508

Study*

95 18 ECG

65 3.3 68 80 1.8

104

BIGGER

Goal

50 4030-

0

I

I

I 3

I

I

I I 6 Months

9

I

12

Fig 3. Enrollment in the CABG Patch Trial pilot study. One of the main objectives of the pilot study was to evaluate whether it would be possible to enroll patients in a full-scale trial. The diagonal line indicates the goal for enrollment as a function of time after the beginning of the study and the horizontal line indicates the goal for the entire pilot study (n = 50). For nearly all of the pilot study, actual enrollment exceeded the goal. Fifty-six patients were enrolled to the main study and 44 of them were randomized in the l-year period, September 1, 1990 to August 31, 1991. An additional 99 patients were enrolled for follow-up only to evaluate the predictive accuracy of the signal-averaged ECG.

of the primary endpoint proposed by the CABG Patch Trial investigators on three grounds: (1) there was too much opportunity for bias in assigning the nonfatal endpoint, especially in an open trial, (2) the joint endpoint might be dominated by the nonfatal component so that ICD therapy would be judged successful even though it had a small effect on mortality, and (3) public health policy and planning on ICD therapy might never have the benefit of knowledge about the effect of ICD therapy on mortality. The IRG believed that these points were so important that the trial should not be supported by NHLBI unless the endpoint was changed. Also, there was an increasing awareness on the part of the investigators that lack of information about the effect of ICD therapy on all-cause mortality was fostering skepticism about its medical benefit and cost effectiveness. Accordingly, a revised proposal was submitted to 1.02

a

pilot study indicated that this was a sick group, likely to experience a substantial rate of endpoint events (Table 3). Since the pilot study showed that enrollment was feasible and that the signal-averaged ECG performed much better than the minimum requirement, a National Institutes of Health (NIH) grant application was submitted requesting funds for a full-scale trial. Cardiac Pacemakers, Inc (CPI) agreed to provide funds to keep the trial going until NIH funding could be obtained. THE CABG PATCH TRIAL

I

The CABG Patch Trial I was initiated with a primary objective to determine whether use of an ICD will prevent death or nonfatal cardiac arrest in CABG surgery patients who have an LVEF below 0.36 and a positive signal-averaged ECG. Using the assumptions shown in Table 4, it was calculated that 320 patients would have to be randomized, 160 to ICD therapy and 160 to no treatment, to have a 90% chance of finding a 33% reduction in endpoint events. The Initial Review Group (IRG) at the National Heart, Lung, and Blood Institute (NHLBI) was critical

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=.E fB

0.8

Negative SAECG

N=44

Positive SAECG

N=82

0.7

o.5J 0

.

, 3

,

,

PRy3.8.

6

9

1 12

Months Fig 4. The predictive accuracy of the signal-averaged ECG for death after CABG surgery. One of the main objectives of the pilot study was to evaluate the signal-averaged ECG as an arrhythmia qualifier in high-risk patients having CABG surgery. To make this determination, we enrolled and followed patients who were age below 80 years, had LVEF below 0.36, and lacked exclusions other than a negative signal-averaged ECG. Patients were categorized by their signal-averaged ECG, positive or negative. All patients enrolled in the pilot study have been followed for more than 1 year; the median follow-up is 14 months. The graph shows survival without experiencing an endpoint (death of any cause or sustained ventricular arrhythmia that required cardioversion for termination). The group with a positive signal-averaged ECG (n = 82) was compared with the group with a negative signal-averaged ECG (n = 44) using the method of Kaplan and Meier. At 1 year, the event rate in the group with a positive signal-averaged ECG is 17.0% compared with 4.5% in the group with a negative signal-averaged ECG, a relative risk of 3.6 (95% confidence limits 0.9,15.8).

THE CABG

Table

PATCH

TRIAL

3. Baseline

105

Characteristics

Randomized

in the CABG

(Before Patch

Trial

Surgery) Pilot

of Patients

Study

Characteristic

Age above

65 years

Male Education

10th grade

Previous Previous History History

CABG

7.0 7.0 79.1 39.5 54.2

200 mg/dL

Previous congestive heart LVEF at or below 0.20 QRS duration above Ventricular premature

failure

53.5 18.2

100 msec complexes

lo/hour Unsustained VT in 24.hour Oral antiarrhythmic drug

71.4 at or above 69.7

ECG recording

30.3 19.5

Antiplatelet drug Oral anticoagulant

Calcium Nitrates

The primary objective of the full-scale trial is to determine whether use of ICD therapy will improve the survival of CABG surgery patients who have an LVEF below 0.36 and a positive signal-averaged ECG. Eleven of the secondary objectives are listed in Table 5. The trial aims to determine the efficacy, risk/benefit, and cost effectiveness of ICD therapy when used as prophylaxis in a high-risk group of patients with coronary heart disease. Also, the effect of prophylactic ICD treatment on quality of life will be evaluated.

84.1 76.7

or higher

surgery

Antihypertensive B-Blocking drug

Objectives

47.7

above

56.1 14.6 drug

Organization of the CABG Patch Trial

34.1 22.0

channel-blocking

drug

The participating units include 30 clinical centers, a data coordinating center at Columbia University, and a project administrative office at Columbia University. Scientific, logistic, and ethical issues are addressed by the committees and subcommittees of the CABG Patch Trial. An independent data and safety monitoring board reviews scientific issues and monitors the accumulating data to detect any problems that threaten the safety of the patients who enroll in the CABG Patch Trial. An external endpoints committee reviews and classifies primary and secondary endpoint events and meets to reconcile differences of opinion.

46.3 78.0

Digitalis Diuretic

48.8 58.5

Converting Lipid-lowering

enzyme drug

inhibitor

36.4 7.3

-

NHLBI for the CABG Patch Trial II with all-cause mortality as the primary endpoint. The proposal was enthusiastically reviewed and recommended for funding. The CABG Patch Trial II began in 30 clinical centers on March 1, 1993 as a cooperative venture of the investigators, NHLBI, and CPI. Table

4. Design

Features

of ICD Prophylaxis

Trials

CABG Patch I

Stratification Eligibility

Primary

variable(s) criteria

Center CABG

LVEF surgery;

cardiac Minimum Average

follow-up follow-up

(mo) (mo)

Abbreviations:

~80;

rate (%) rate (%) size (each

(%)

group)

Ml, myocardial

LVEF surgery;

(36 mo) (36 mo)

Death

Heart

Disease MADIT

< 80;

Center time after Ml O-wave Ml; Age c 75; LVEF

SAECG

of any cause

36.5% 27.0%

unsustained procainamide Death

VT; inducible

of any cause

26.0 5.0 85.0

3.0 6.0

10.0 6.0 400 signal-averaged

6 26

(40 mo) (40 mo)

33.0 5.0 90.0

SAECG,

Coronary

24 40

160 infarction;

With

Age

LVEF < 0.36; positive

arrest 24

53.0% 35.4%

Significance level (%) Power (l-beta; %) Drop-in Dropout Sample

Age

Center CABG

36

Event rate Control group ICD group Percent reduction

in Patients CABG Patch II

LVEF < 0.36; SAECG positive Death of any cause,

endpoint

II

%

angioplasty of smoking of hypertension

Cholesterol

THE CABG PATCH TRIAL

(n = 44)

ECG; VT, ventricular

30.0% 16.3%

(26 mo) (26 mo) 46.0 5.0 85.0 < 5.0 < 5.0 140

tachycardia.

-~

< 0.36; VT; fail

106

BIGGER

Table

5. Secondary

Objectives

of the CABG

Patch

Trial

1

To determine

the effect

of ICD implantation

on opera-

2

tive mortality. To determine

the effect

of ICD implantation

on opera-

3

tive morbidity (infection, bleeding, length of stay). To determine whether the effect of ICD implantation greater on arrhythmic events than on other endpoints by studying ity, cardiac

the following death, sudden

death classified joint endpoint

or ventricular by cardioversion.

and the sustained

fibrillation that The period 30

days to 2 or more years (ie, excluding tive period) will be analyzed. 4

is

endpoints: all-cause mortalcardiac death, arrhythmic

by the Hinkle-Thaler criteria, of sudden cardiac death plus

ventricular tachycardia has to be terminated

II

the postopera-

To identify and quantify any long-term (30 days up to 4 years) adverse effects attributable to the ICD implant, eg, infection, body image.

5. To compare

spurious

shocks,

cost information

and concerns

for the ICD and control

groups over the follow-up period. 6. To evaluate the effects of ICD implantation ity of life. 7. To determine mic or other

any difference cardiovascular

and to document the time 9. To determine the predictors LVEF, severity of congestive arrhythmias,

on the qual-

in the use of antiarrhythdrugs between the group

with ICD implants and the control group. 8. To determine the proportion of implanted

ventricular

about

of RR variability

in a 24.

hour ECG recording, or severity of signal-averaged ECG findings. 10. To compare the mortality experience and the occurrence of sustained with a LVEF below

ventricular 0.36 and

arrhythmias in the group a positive signal-averaged

ECG (control group of the randomized who were eligible but did not enroll,

onds < 20 FV, duration of low amplitude [ < 40 kV] signal > 38 milliseconds), and have no other exclusion criteria are eligible for the trial. The CABG Patch Trial is relying on the negative predictive accuracy of the signal-averaged ECG to eliminate patients with low risk of arrhythmic events. Accordingly, patients with bundle branch block or intraventricular conduction defects are eligible if their signal-averaged ECG is positive. Women and members of minority groups are enrolled in the same proportion as they occur among patients having CABG surgery and their risk/benefit ratio is expected to be the same as for men and nonminority group patients. Patients who have had spontaneous sustained ventricular arrhythmias and those whose morbidity may be increased by implantation of a cardioverter-defibrillator are excluded (Table 6). Eligible patients are invited to enroll after permission has been obtained from their primary physician and their cardiothoracic surgeon.

ICDs that fire

and circumstances of firing. of ICD firing, eg. level of heart failure, frequency of level

study, patients and patients who

Design Features, Sample Size The CABG Patch Trial is a randomized, controlled intervention trial, but it is not blinded. The trial is a parallel study with random assignment of half of the eligible patients to the control group and half to treatment with an ICD. Randomization is stratified on the clinical center and on LVEF ( I 0.20 versus 0.21 to 0.35). The minimum follow-up period is 2 years

enrolled but were not randomized) and that in the group with LVEF below 0.36 and a negative signal-averaged ECG. 11. To determine tion between of the extent intraoperative rence death

the strength

and significance

ET AL

of associa-

the surgeons’ intraoperative assessment of revascularization, “scar index,” and myocardial infarction and the occur-

of ICD firing or the occurrence of sudden cardiac or spontaneous, sustained ventricular arrhyth-

mias.

Putient Eligibility All patients who are scheduled for CABG surgery in participating clinical centers are screened for the CABG Patch Trial. Those who are younger than 80 years of age, have an LVEF below 0.36, have a positive signal-averaged ECG (filtered QRS duration > 114 milliseconds, RMS voltage of the terminal 40 millisec-

Table

6. Exclusion

Criteria

for the CABG

1. History of sustained ventricular tachycardia, fibrillation, or cardiac arrest with inducible tachycardia 2. Renal dysfunction 3. Insulin-dependent

(creatinine diabetes

vascular recurrent 4. Unipolar

complications infections pacemakers

5. Previous

or concomitant

>3 mg/dL) mellitus with

or history

aoltic

of poor

or mitral

Patch

Trial

ventricular ventricular

significant control

valve

and

surgery

6. 7. 8. 9. 10.

Concomitant Emergency Thrombolysis Concomitant Comorbidity

cerebrovascular surgery CABG surgery in the 7 days prior to CABG surgery arrhythmia surgery or aneurysmectomy associated with expected survival less

11. 12. 13. 14.

than 2 years Lives too far away to return for follow-up visits inadequate time to obtain informed consent Enrolled in another randomized controlled cllnical Physician, surgeon, or patient refusal

trial

THE CABG

PATCH

TRIAL

and the average follow-up period is expected to be over 3 years. Using the assumptions given in Table 4, about 800 patients must be randomized to have an 85% chance of detecting a 26% difference between the two groups. The primary analysis will be by intention to treat, ie, the patients will be grouped by their assignment at randomization regardless of whether they actually received the treatment to which they were assigned. In our analysis of the study’s primary hypothesis, we will use Cox’s regression-based test to compare the ICD group with the control group, according to the intention-to-treat principle, using as the endpoint all-cause mortality. If the assumptions used to calculate sample size are correct, there will be 146 deaths in the control group at the end of the study and 108 deaths in the group assigned to ICD therapy. The test will stratify on the variables controlled for by stratification in the design: centers and ejection fraction dichotomized as at or below 0.20 versus 0.21 to 0.35. This test will be performed at the two-tailed .05 significance level. Secondary analyses will classify patients “astreated,” ie, according to whether they actually received a functioning ICD, and will use two joint endpoints-all-cause mortality and cardiac arrest and sudden cardiac death and cardiac arrest. Randomization in the Operating Room The randomization assignment is supplied by the data coordinating center in opaque envelopes sealed with a validating label. Randomization is stratified by clinical center and by LVEF. Randomization takes place in surgery after the bypass grafts are done. If the surgeon decides that he or she is willing to implant an ICD, the investigator or coordinator signs the envelope label, opens the envelope, and tells the surgeon whether to proceed with implantation. Patients are allocated to their treatment group the instant the envelope is opened. Patients must be analyzed as a member of the group to which they are assigned at the time of randomization regardless of whether they receive the treatment. For example, a patient assigned to the ICD group who does not actually receive an ICD implant must be analyzed as a member of the ICD group.

107

Randomization is done as late as possible in surgery to avoid early drop-outs (patients assigned to the ICD group who do not get implants). The higher the drop-out rate, the harder it is to find a difference between the ICD group and the control group (Fig 5). A 20% drop-out rate would occur if patients were randomized before CABG surgery. The effect of early dropout is large: a 20% drop-out rate in surgery would increase by 75% the sample size required to keep the chance of finding a 26% difference around 85%. Thus, a policy of randomization before CABG surgery would require an increase in the number of enrolling centers from 30 to 53 and also would increase the cost by 75%. Such a large increase in the size of the project is not feasible logistically or financially. If patients were randomized before CABG surgery and the target sample size were left at its current value of 800 patients, the difference in the mortality rates between the ICD-assigned group and the control (no treatment) group would decrease from 26% to 20% in the intention to treat analysis. An analysis comparing patients as treated, ie, those who were randomized to ICD therapy and received an implant with those randomized to the control group, would not be valid because the control group would be much sicker than the patients who received an TCD (Fig 5). Enroll

(n = 1,000) I

( Randomize

(n = 1 ,OOO)]

Fig 5. The rationale for randomizing after bypass grafts are completed. This figure diagrams the problem with randomizing patients before surgery. There would be a 20% drop-out rate in the group randomized to the ICD group, ie. of the 500 patients allocated to ICD therapy, 100 would leave surgery without it. The intention to treat analysis, the only valid comparison, would compare groups (1) and (2). However, with randomization before surgery, the magnitude of the effect of ICD therapy on mortality will be reduced by group (4). those who are allocated to ICD therapy but do not get implants. As-treated analyses, ie, comparison of group (3) with group (2) or comparison of group (3) with groups (2) and (4). are not valid because the level of risk is different among these groups.

108

BIGGER

GUIDELINES FOR IMPLANTATION OF LEADS AND GENERATORS IN THE CABG PATCH TRIAL

Testing the ICD System in Surgery Leads and ICD pulse generators are implanted only by surgeons fully trained in ICD procedures and registered at the data coordinating center. In cases where the primary surgeon is not experienced at ICD implantation, the ICD leads and pulse generator are implanted by a second surgeon who is qualified. In such instances, the implanting surgeon must be available to scrub immediately after randomization indicates that an ICD will be implanted. After the coronary bypass grafts are completed, the surgeon checks to be sure that the patient withdraws from cardiopulmonary bypass without a problem. Then partial cardiopulmonary bypass is reinstituted while the rate-sensing leads and patches are attached to the heart. Defibrillation thresholds and testing of the ICD also are done on partial cardiopulmonary bypass (Table 7). The rate-sensing leads are usually implanted epicardially. The R-wave voltage should be 5 mV or more 10 minutes or more after screwing in the leads, and the R-wave width should be less than 120 milliseconds. Two large patches, placed extrapericardially, are recommended for the defibrillating leads. The lead system is tested immediately after implantation. The electrophysiologist and the electrophysiologic equipment must be available in the surgical area when randomization occurs to avoid delays in Table

7. Guidelines

for ICD Implants Patch

Implant

leads

after

CABG

in the CABG

Trial

surgery

with

patient

on partial

cardiopulmonary bypass Evaluate electrograms from rate sensing leads R voltage z 5 mV, 2 10 minutes later R width < 120 msec Defibrillating patch electrodes Ventricular fibrillation induced

placed twice,

extrapericardially attempt conversion

with 20-J shocks delivered through the patch electrodes Connect ICD, test once against ventricular fibrillation Abdominal pouch made during warming Set rate cutoff to 200/min for post-open heart intensive care unit Program first-shock delay to 5 seconds Before discharge, reprogram rate cutoff to 175imin (higher rate cutoffs can be used for rapid atrial fibrillation)

ET AL

completing the test of the sensing leads, patches, and ICD pulse generator. The recommended testing of the defibrillating leads is to induce two episodes of VF and attempt defibrillation with 20-J shocks. If the two tests are successful, the ICD is connected to the lead systems and tested once against VF. If the ICD system is successful at terminating induced VF, testing is considered satisfactory and the pouch housing the pulse generator is sutured closed. ICD Settings for the Recovery Room For the open heart recovery room, the ICD is programmed to have probability density function (PDF), off; rate cutoff, 200 per minute; first shock delay, 5 seconds; and energy of the first shock, 30 J. The high rate cutoff is used to avoid shocking postoperative supraventricular arrhythmias, but to permit termination of rapid VT or VF. The ICD may be turned off if cardiac pacing is used in the open heart recovery room. The ICD is turned on when temporary cardiac pacing is discontinued. When the patient leaves the open heart recovery room, the device is reprogrammed (usually, PDF off, rate cutoff 175 per minute; first shock delay 5 seconds; and first shock energy 30 J). In patients with rapid atria1 fibrillation which is difficult to control, the rate cutoff can be left at a higher value until the ventricular rate is controlled. The first shock delay of 5 seconds was selected to avoid spurious shocks due to unsustained VT which is common for 3 to 4 months after CABG surgery. Experience With Implantation of Complete ICD Systems During CABG Surgery Implantation procedures dictated by the CABG Patch Trial protocol will provide interesting and potentially useful information to guide clinical practice in the future. Using current guidelines for ICD therapy, about 20% of ICD implants are done together with CABG surgery. Coronary artery anatomy and myocardial ischemia are evaluated in virtually all patients who present with sustained VT or cardiac arrest. Some cardiologists perform electrophysiologic studies in patients who are going to CABG surgery when they have low values for LVEF (eg, <0.40) and/or a positive signal-averaged ECG. Implantation of an ICD system in conjunction with CABG surgery usually is a one-stage

THE CABG

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109

TRIAL

procedure, but some centers prefer a two-stage procedure. Patients who present with malignant ventricular arrhythmias and have significant myocardial ischemia usually have CABG surgery together with implantation of the myocardial sensing and defibrillating leads for an ICD system. The pulse generator is implanted at the time of CABG surgery in some centers, or about a week after surgery in other centers. For patients who present with cardiac arrest, implantation of the pulse generator may be determined by the results of a postoperative electrophysiologic study. A postoperative electrophysiologic study also may play a key role in the decision to implant a full ICD system in patients with a low LVEF or a positive signalaveraged ECG. Some of these conventional practices are likely to be modified substantially if the long-term efficacy of transvenous or transvenous-subcutaneous ICD lead systems is established. For example, the electrophysiologic evaluation could be deferred until after surgery. Even if nonthoracotomy lead systems prove reasonably effective, it is likely that myocardial leads implanted via a thoracotomy will be preferred for many patients who will have a thoracotomy anyway for CABG surgery. This is especially likely to be so if the CABG Patch Trial shows that implantation of a full ICD system adds little or no risk to CABG surgery. In the CABG Patch Trial, the entire ICD system is implanted and tested together with CABG surgery as a one-stage affair. The rationale behind this approach had scientific and logistic elements. Scientifically, the early and total implant has the advantage of decreasing the drop-out rate, ie, patients who are randomized to an ICD system, but do not get one. Using a two-stage approach, the cardiac surgeon or cardiologist could decide, because of events in the postoperative period, that he or she does not want to proceed with ICD pulse generator implantation and testing. Similarly, a patient might decide that he or she does not want to be anesthetized a second time for the potential benetit of an ICD system reasoning that, if he or she experiences an arrhythmic event in the future, an ICD generator can be connected to the lead system implanted at the time of CABG surgery. Logistic considerations also played an important role in the decision to use a one-stage

ICD implant for the CABG Patch Trial. The planning group thought that the fewer the additional procedures required by the protocol and the less the hospital stay was extended in the ICD group, the better enrollment would be. Safety of ICD Implantation

Although the scientific and logistic benefits of one-stage implantation used in the CABG Patch Trial are substantial, the one-stage approach requires a change in the practice for implanting surgeons who customarily use a two-stage procedure. In conventional practice about half the systems implanted together with CABG surgery are done in one stage and half are done in two stages. Some surgeons who are accustomed to the two-stage procedure have concerns about the safety of the one-stage procedure, ie, are concerned about possible negative effects on the mortality and morbidity of CABG surgery. As of May 31, 1993, 264 patients had been randomized in the CABG Patch Trial (pilot and CABG Patch I) and had been followed for at least 1 month. This substantial implant experience provides at least partial answers to questions about the safety of one-stage implantation of ICD systems in the CABG Patch Trial. The first question was: How often does the cardiothoracic surgeon exercise his or her option to not randomize patients who have enrolled and signed a consent form. 7 In the CABG Patch Trial, randomization is done when the patient has come off of cardiopulmonary bypass, ie, after coronary bypass grafts have been completed. So far, randomization has been accomplished in 83% of the enrolled patients. Of the patients randomized to the ICD group, 95% had a system implanted and tested during the primary CABG surgery, ie, as a one-stage procedure. Because of events occurring after randomization, four patients assigned to ICD therapy did not receive an implant and nine patients had the pulse generator implanted or tested, not during surgery, but later in the hospitalization. Implanting and testing the ICD system increased the median duration of cardiopulmonary bypass by about 20 minutes. The surgical mortality rate (mortality within 30 days or before hospital discharge, whichever comes last) for the patients randomized in the CABG Patch Trial by May 31, 1993 was 4.5%

BIGGER

110

and there was no difference in the mortality rate between the ICD and control groups. The median length of hospitalization for CABG surgery, a global measure of morbidity, is not significantly different for the control and ICD there is no significant groups. Furthermore, difference between the ICD and control groups for surgical morbidity. So far, the CABG Patch Trial experience suggests that implanting and testing an ICD system as a one-stage procedure during CABG surgery in a high-risk group does not significantly increase mortality, morbidity, or hospital stay. Although the implant experience in the CABG Patch Trial is still relatively small, the preliminary results are quite encouraging in terms of safety of ICD implantation according to protocol guidelines. Follow-up Visits All patients have office/clinic follow-up every 3 months in the CABG Patch Trial. Since the primary result is the difference in occurrence of endpoints between the control group and the experimental group, face-to-face follow-up is equally important in the two groups. At each visit, information is obtained on the patient’s course during the previous 3 months and a set of forms is filled out. Details of each ICD firing are recorded as well as tachyarrhythmic symptoms. Additional information is obtained if the patient was hospitalized since the previous follow-up visit or had any of the following tests: 24-hour ECG (Holter) recording, coronary angiogram, electrophysiologic study, exercise test. measurement of LVEF, thallium exercise test, or a signal-averaged ECG. Health-related quality of life assessment is done at the 6-, 12-, and 1%month visits to obtain reliable average values for quality of life measurements in the two groups. Patients in both the treatment and control groups will be followed for an average of 40 months to a common termination date. As of June 30, 1993, 29 patients had been randomized; 800 patients will be randomized during the course of the study. Less than 155% of the follow-up information had accrued by June 30, 1993, and, of course, no information on outcome by treatment group will be available until the end of the study early in 1997.

Evaluation of Health-Related

ET AL

Quulity of Lije

For the purpose of the CABG Patch Trial, health-related quality of life is defined as the ability to perform the social roles and activities that people want and need to perform, as well as the degree of satisfaction that is derived from performing them. This definition covers occupational, social, recreational, familial, and other household activities. The primary hypothesis relating to health-related quality of life is that there will be no difference between the ICDtreated and control groups. Assessment will be accomplished using self-administered questionnaires that have all been found to be valid and reliable. The questionnaires will be administered in conjunction with the regularly scheduled 6-, 12-, and 18-month follow-up visits. Because there will be no assessment of changes in quality of life over time in individual patients. no baseline measure will be done. Treatment With Antiarrhythrnic Drugs and Aspitin In the CABG Patch Trial, no prophylactic antiarrhythmic drug treatment is given for ventricular arrhythmias. An investigator discusses this policy with the primary physician for each participating patient. Treatment or prophylaxis for atria1 fibrillation with antiarrhythmic drugs with class I action is permitted. An effort is made to stop prophylaxis or treatment for atria1 fibrillation by 6 to 12 weeks after surgery. The reasons for treatment with antiarrhythmic drugs beyond 3 months are documented. In the pilot study, about 20% of the randomized patients were taking a drug with class I action at the 3-month follow-up visit. Antiarrhythmic drug use was primarily for atria1 arrhythmias and was not significantly different between the control and ICD-treated groups. Aspirin treatment, 325 mg every day or every other day, is recommended for patients participating in the CABG Patch Trial. For patients who are not taking aspirin at the time of hospital discharge or during follow-up, the reason is recorded. The CABG Patch Trial will carefully record the USC of other cardiovascular drugs as well, especially looking for any confounding that may come from this source.

THE CABG

PATCH

111

TRIAL

Medic Alert Telephone Calls

All patients participating in the CABG Patch Trial are given Medic Alert bracelets. The CABG Patch Trial investigator or coordinator is available to talk to patients or doctors who are dealing with ICD firing or tachyarrhythmic symptoms. The Medic Alert calls provide an opportunity to acquire important information on events relevant for the CABG Patch Trial, and also to help the patient and his/her primary physician, especially with the management of ICD shocks or tachyarrhythmic symptoms. Study coordinators follow up on all Medic Alert telephone calls to determine how the problem was resolved and whether the primary physician was satisfied with the communications that resulted from the Medic Alert call. What Will We Learn From the CABS Patch Trial?

The CABG Patch Trial will determine whether ICD prophylaxis will improve survival of high-risk patients (LVEF < 0.36 and positive signal-averaged ECG) having CABG surgery. It will quantify the magnitude of benefit of ICD therapy on mortality from all causes. Since the control group is not being treated, the CABG Patch Trial will be able to estimate precisely the magnitude of the effect of ICD therapy on survival: it is the only ICD trial underway or contemplated that can do this. The CABG Patch Trial will be able to determine accurately how much, if any, ICD implantation adds to the mortality and morbidity of CABG surgery. The CABG Patch Trial is not confounded by antiarrhythmic drug therapy. It will not be confounded by the effects of thoracotomy or by ischemic events since both the ICDtreated group and the control group received thoracotomy and complete surgical revascularization. The control group will permit us to factor out the effect of thoracotomy so that we can estimate the efficacy of nonthoracotomy ICD systems. The CABG Patch Trial will provide much-needed information on the causes of death after CABG surgery. Since the treatment used in the CABG Patch Trial only addresses tachyarrhythmic deaths and the control group gets no treatment, the trial should clarify the extent to which some currently held concepts about sudden cardiac death are correct and

permit an evaluation of the validity of currently used mechanistic classifications of death. HOW DOES THE CABG PATCH TRIAL DIFFER FROM OTHER RANDOMIZED CONTROLLED TRIALS STUDYING ICD THERAPY?

The CABG Patch Trial addresses a question substantially different from the questions posed by other randomized controlled trials that involve ICD therapy. The Cardiac Arrest Study of Hamburg (CASH), the Canadian Implantable Defibrillator Study (CIDS), and the NIH study that will begin its pilot phase late in 1993 all enroll or propose to enroll patients who have experienced spontaneous, hemodynamically significant, sustained ventricular arrhythmias. All of these trials compare ICD therapy with drug therapy. The MADIT is comparing ICD prophylaxis with “conventional therapy,” much of which is amiodarone.2s~2h The Multicenter Unsustained Tachycardia Trial (MUS’IT) is studying the value of prophylactic electrophysiologically guided drug therapy in patients with LVEF below 0.40 and unsustained VT. In MUSTT, only a few drug-resistant patients are treated with ICDs. All of these important controlled studies involve drug comparisons and, therefore, cannot determine whether the ICD decreases mortality or, if so, estimate how much. PROPHYLACTIC

USE OF ICD THERAPY

The results of the two ongoing studies of ICD prophylaxis and others that follow them will importantly mold the use of ICD treatment in the future. There is no significant evidence that ICD therapy reduces all-cause mortality. Therefore, there is no scientific justification for ICD prophylaxis at the present time. Recent experience in cardiovascular clinical trials has taught us that hopes for therapeutic benefit often are not realized in practice. The cost and quality of life issues surrounding ICD therapy dictate that substantial scientific evidence for benefit must accumulate from randomized clinical trials before ICD prophylaxis is recommended for routine clinical practice. APPENDIX Participants in the CABG Patch Trial are as follows: Hospital of the Good Samaritan, Los Angeles. CA: David S. Cannom, MD (coprincipal investigator). Gregory L. Kay,

112

MD (coprincipal investigator), Anil K. Bhandari, MD, Mary Jane Jones, RN, and Beverly Firth, RN. Sequoia Hospital, Redwood City, CA: Roger A. Winkle. MD (coprincipal investigator), Vincent Gaudiani. MD (coprincipal investigator), Wally Buch, MD, and Juanita Fujii. RN University of Louisville, Louisville, KY: Igor Singer. MD (coprincipal investigator), A. David Slater, MD (coprincipal investigator), Joel Kupersmith. MD, Erle H. Austin. III. MD, Samuel Pollock. MD, Christodulos S. Stavens, MD. Michael J. Springer, MD. Tibor S. Szabo, MD. and Lesa Adams, RN University of Virginia, Charlottesville. VA: John P. DiMarco, MD, PhD (coprincipal investigator), Irving L. Kron. MD (coprincipal investigator), David E. Haines. MD, Michael J. Barber, MD. PhD, Curt Tribble. MD, William Spotnitz, MD, and Lorene Shaw. RN Presbyterian-University of Pennsylvania Medical Center. Philadelphia. PA: Leonard N. Horowitz, MD (coprincipal investigator, deceased). Charles Gottlieb. MD (coprincipal investigator), Francis E. Marchlinski. MD (coprincipal investigator), Harold R. Kay, MD (coprincipal investigator), Gretchen Foerster, RN, and Christine Vrabel. RN The Presbyterian Hospital in the City of New York, New York, NY: Henry Spotnitz, MD (coprincipal investigator). Frank D. Livelli Jr, MD (coprincipal investigator). and Laura Pawlicky Sentara Norfolk General Hospital, Norfolk. VA: John M. Herre, MD (coprincipal investigator), Lenox Baker, MD (coprincipal investigator). Kathy Barackman. RN, and Linette Klevan. RN University of Florida, Gainesville. FL: Anne B. Curtis. MD (coprincipal investigator). Edward Staples. MD (coprincipal investigator), Jamie Conti. MD. Kim Miller, RN, and Audra Wilson Hospital of the University of Pennsylvania, Philadelphia, PA: Francis E. Marchlinski, MD (coprincipal investigator). Mark Radcliffe, MD (coprincipal investigator), Nancy Adrlizzi, RN, and Belinda Flores, RN Washington Hospital Center, Washington, DC: Edward V. Platia. MD (coprincipal investigator), Luis A. Mispireta. MD (coprincipal investigator), Steven Boyce. MD (coprincipal investigator), Susan O’Donoghue, MD. and Jan Harrison. RN Cleveland Clinic. Cleveland, OH: James D. Maloney. MD (coprincipal investigator). Patrick M. McCarthy. MD (coprincipal investigator), Lori Alexander, PhD, MPH. and Susan Stein. RN, CCRN Westfalische Wilhelms-Universitat Munster. Munster, Germany: Gunther Breithardt. MD (coprincipal investigator), Hans H. Scheld, MD (coprincipal investigator). Michael Block, MD, Dieter Hammel. MD, Wolfgang Konertz, MD. and Dietmar Wietholt. MD Ruprecht-Karl%Universitat Heidelberg, Heidelberg, Grrmany: Johannes Brachmann. MD (coprincipal inveatigator), Werner Saggau, MD (coprincipal investigator). Kirsten Freygang, MD, and Annerose Pfeifer. RN Florida Hospital Medical Center, Orlando. FL: Kerry M. Schwartz, MD (coprincipal investigator). Cary L. Stowc.

BIGGER

ET AL

MD (coprincipal investigator). Deanna R. Dukes. RN. BSN, and Diane L. McCabe, CCPT Kaiser Permanente Medical Center, Los Angeles. <‘A: Peter R. Mahrer, MD (coprincipal investigator). Colleen F. Sintek, MD (coprincipal investigator), Carol Zaher. MD. Sirvosh Khonsari. MD, and Judy Fletcher. RN New England Medical Center Hospitals. Boston. MA: N. A. Mark Estes III. MD (coprincipal investigator). Hassan Rastegar. MD (coprincipal investigator), Paul Wang. MD. and Debbie Cliff. RN Jewish Hospital at Washington University Medical Center. St Louis, MO: Jeffrey N. Rottman, MD (coprincipal investigator), and Thomas H. Wareing. MD (coprincipal invealigator) Hermann Hospital, University of Texas Medical School. Houston. TX: Gerald V. Naccarelli. MD (coprincipal investigator), Michael S. Sweeney, MD (coprincipal investigntor), and Deborah Wilson, RN Medical College of Virginia, Richmond, VA: Mark A. Wood. MD (coprincipal investigator), Ralph J. Damiano. Jr, MD (coprincipal investigator). and Liz Arnold. RN Loyola Medical Center, Maywood. IL: David J. Wilher. MD (coprincipal investigator). Bradford P. Blakeman. MD (coprincipal investigator). and Nancy Perovic. RN East Carolina University School of Medicine, Greenville. NC: Rehan Mahmud, MD (coprincipal investigator). J. Mark Williams, MD (coprincipal investigator). and Cathy Grill. RN St Joseph’s Hospital. Atlanta. GA: Harry A. tiopclman. MD (coprincipal investigator). and Kenneth E. Thorna\. MD (coprincipal investigator) Bowman Gray School of Medicine. Winston-Salem. NC : David M. Fitzgerald, MD (coprincipal investigator), John W. Hammon. Jr. MD (coprincipal investigator), and Lisa A. Kiger. RN University of Nebraska Medical Center, Omaha. NE: John R. Windle. MD (coprincipal investigator). Timothy A. Galbraith, MD (coprincipal investigator). and Karen Tesina, RN Brigham and Women‘s Hospital. Boston. MA: I’ctrr I.. Friedman. MD (coprincipal investigator). Gregoy S. Couprr. MD (coprincipal investigator), and Julie B. Shea. MS. RN LDS Hospital. Salt Lake City, UT: Jetfrey L. Anderson, MD (coprincipal investigator). Roger C. Millar. MD (coprincipal investigator). and Marian Roskelley, BS Northwest Cardiovascular Research Institute. Spokane. WA: Ilartrld R. Goldberg, MD (coprincipal investigator). William S. Coleman, MD (coprincipal investigator). Donald A. Chilson. MD. David F. Oakes, MD. Dennis B. Cooke. MD, Marian Fisher. RN. and Sandra J. Vanvig, RN Nebraska Heart Institute, Lincoln, NE: Steven K. Krurgcl-. MD (coprincipal investigator). Edward I’ Raines. MD (coprincipal investigator). and Becci Olandcr. RN. MSN Massachusetts General Hospital, Boston, MA: Jeremy N. Ruskin, MD (coprincipal investigator), Gus J. VIahake\. MD (coprincipal investigator), and Elizabeth Simpson Emory University System of Health Care, Atlanta. GA: Paui F. Walter. MD (coprincipal investigator). Ellis Jones. MD (coprincipal investigator), and Carol Long. RN Minneapolis Heart Institute, Minneapolis. MN: Rebel t Ci.

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Hauser, MD (coprincipal investigator), Kent Arom, MD (coprincipal investigator), and Marc R. Pritzker. MD Data Coordinating Center-Columbia University, New York. NY: J. Thomas Bigger Jr, MD (coprincipal investigator). Joseph L. Fleiss, PhD (coprincipal investigator), Paul

Meier, PhD (senior statistical consultant), Linda M. Rolnitzky, MS, Eileen Koski, MA, Jeanne Campion, MA, RN. CNA, Richard C. Steinman, Reidar Bornholdt, Maryellen Gallagher, Shelley Gass. Morris Lee, Gloria McNeil. and Lucy Morales

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