Rehospitalization in surviving patients of out-of-hospital ventricular fibrillation (the CASCADE study)

Rehospitalization in Surviving Patients of Out&Hospital Ventricular Fibrillation

(the CASCADE Study) Charles Maynard, PhD, for the CASCADE Investigators*

5urvlving patients of out441ospltal ventricular fl- brillation (VP) often need rehospita5zatlon after initial hospital discharge, but liile is known regarding the frequency of or reasonsforNhospRal= ization. RehospRalixation was examined in 224 patients enrolled in the CardSac Arrest in 5eattk Conventional Amiodarone Drug Evaluation (CAS- CADE) study, a randemized clinical trial comparing amicdarone with other antianhythmic drug therzk py in survivors of out&-hospital VP. The annual rate of rehospltallzation was 79/100 patients/ year; 108 of 224 patients (75%) were hospiilized atleastoncebeforecensoringorcardiacmor- talii. Baseline left ventricular ejection traction was sl@diicantly lower in patients who were CB hospiilixed. Rehospita5zaticn rates were lower in patii randomized to amiodarone therapy aid in those with the automatic implantable cardi* verterdefibri5ator, although neither difference was statistically signiticant. However, length of stay for the first rehospblization was shorter far patients wtth automatic implantable cardioverter- detlbrl5ators (p = 0.005). More than 50% of pa tients were rehospttalized in the first year after enrollment; 55% with ejection fractions 10.3 were relmspblized in the first year. Rehospbllzation was a frequent occurrence for surviving patients of out4hospii VP, particularly in those with low ejection fractions.

(Am J Cauliol lSS3;72:1295-1300)

From Providence Medical Center, Virginia Mason Medical Center, Harborview Medical Center, and University of Washington Medical Center, Seattle, Washington. The pilot study was supported in part by grants from the Medic I Foundation, Seattle, Washington, and Wyeth- Ayerst Laboratories, Philadelphia, Pennsylvania. The full study was supported in part by Grant ROl HL31472 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Manuscript received March 12, 1993; revised manuscript received June 22, 1993, and accepted June 23.

Address for reprints: H. Leon Greene, MD, Cardiology Division, University of Washington, Harborview Medical Center (ZA-35), 325 9th Avenue, Seattle, Washington 981042499.

‘See Appendix.

0 ut-of-hospital ventricular fibrillation (VF) in patients without a new Q-wave myocaidial infarction is a devastating event associated with a high

risk of recurrence of ventricular arrhythmia in survivors.1-5 These patients have the potential for rehospitalization for repeated ventricular arrhythmias. Because of the high rate of recurrence, and the need for aggres- sive therapy with a&t-rhythmic drugs or the automatic implantable cardioverter-defibrillator (AICD), or both, one may expect rehospitalization to be common in these patients, but the frequency is unknown. Furthermore, lit- tle is known regarding the reasons for hospitalization, and the events and procedures that occurred during the period of rehospitalization. This report describes the fre- quencies of and reasons for rehospitalization in surviving patients of out-of-hospital VF, and compares those with and without AICD devices, and with and without amiodarone therapy.

METHODS Patient population: Patients in this report were en-

rolled between 1984 and 1991 in the Cardiac Arrest in Seattle: Conventional Amiodarone Drug Evaluation (CASCADE) study, a randomized trial of empiric ad- ministration of amiodarone versus treatment with conventional antiarrhythmic drug therapy guided by electrophysiologic testing or Holter monitoring, or both. The trial included patients who had been resuscitated from an episode of out-of-hospital VF and did not have a new Q-wave myocardial infarction. Patients in whom the estimated l-year risk of recurrent VF was 220% were eligible for enrollment. The protocol6 and study results7 have been published.

This analysis includes 224 of the 228 patients (98%) enrolled in the randomized trial; 4 (1 - amiodarone; and 3 - conventional) were excluded because they died during the index hospitalization for study enrollment. Patients were randomized at a mean of 21 f 23 days from the index event. Therefore, this report includes all patients who survived the initial hospitalization for study enrollment and assignment to amiodarone or conventional drug therapy.

Study variables: Extensive baseline and follow-up information were collected in this study, and were described in previous reports. 6,7 The primary end points for this study were defined as sudden arrhythmic cardiac death, resuscitated out-of-hospital VF, including complete syncope followed by a shock from an AICD, and nonarrhythmic cardiac death. Death due to noncardiac causes was not considered a primary end point; patients who died of noncardiac events were censored at the time of death

REHOSPITALIZATION IN SURVIVORS OF VENTRICULAR FIBRILLATION 1295

TABLE I Annual Rates of Rehospitalization

Total Amlodarone Conventional (n = 224) (n = 112) (n = 112)

Average follow-up/patient 2.88 3.12 2.64 (years)

Number hospitalized 168 88 80 Number of hospitalizations 512 259 253 Annual rate of rehospitalization 79/100 741100 851100

. . RehospRahzation tiables: Study participants were followed intensively by nurses and physicians from the 3 participating hospitals. Each time that a patient was hospitalized after enrollment, research nurses completed appropriate data forms. Because patients who had resuscitated ventricular arrhythmias as a primary end point resulting in rehospitalization were not intensively followed after these events, information regarding hospitalizations after this piimary end point was not complete. Therefore, for patients who had resuscitated cardiac arrest (n = 32), only hospitalizations before or on the same day as this primary end point were considered. In the days after the primary end point, there were an additional 72 hospitalizations in 16 patients; 1 patient accounted for 20 hospital stays. Given the extensive con- tact between patients and nurses (follow-up in this study extended from 1984 to 1992 and was complete for all patients), there is good reason to believe that virtually all hospitalizations that occurred before the end point or censoring have been identified.

Data obtained included: (1) the primary reason for hospitalization, (2) cardiac events that occurred during hospitalization, (3) invasive cardiac procedures performed during the hospital stay, and (4) whether the hos-

pitalization was related to antiarrhythmic drug inefficacy or side effects. Other variables included the number of hospitalizations before the primary end point or censoring, the time to tit hospitalization after study enrollment, and the length of hospital stay.

The primary reasons for rehospitalization were clas- sified as: (1) noncardiac; (2) VF; (3) sustained ventricular tachycardia; (4) congestive heart failure; (5) angina/ myocardial infarction; (6) cardiac procedure or surgery; (7) beginning or changing an&rhythmic drug; and (8) other, including AICD shocks. Events that occurred during hospitalization were noted; they included: (1) resuscitated cardiac arrest or death, (2) ventricular tachycardia, (3) new or worsened congestive heart failure, and (4) angina/myocardial infarction. Cardiac procedures or surgery were categorized as follows: (1) coronary artery bypass surgery; (2) insertion of AICD electrodes only; (3) AICD implantation; (4) cardiac catheterization; (5) coronary angioplasty; and (6) other procedures including electrophysiologic study, pacemaker implantation and cardioversion.

Statistics Statistical comparisons between amiodarone and conventional groups were performed on the basis of “intention to treat.” The chi-square statistic was used to compare categoric variables, and the t test was used for continuous variables. Kaplan-Meier techniques were used to construct curves that described rehospitalization, and the log-rank statistic was used to compare time to rehospitalization between groups. Stepwise linear regression was used to identify predictors of rates of rehospitalization, and length of hospital stay. Finally, stepwise Cox regression analysis identified patient characteristics associated with time to lirst hospitalization after randomization.

[ABLE II Baseline Characteristics

Total (%) Hospitalized (%) Not Hospitalized (%) (n = 224) (n = 168) (n = 56)

Women 25 (11) 21 (12) 4 (7) Age (years) 632 11 64 f 12 62 + 10 Amiodarone 112 (50) 88 (52) 24 (43) Conventional 112 (50) 80 (48) 42 (57) Coronary artery disease 184 (82) 138 (82) 46 (82)

Prior myocardial infarction 149 (81) 111 (80) 38 (83) Noncoronaty artery disease 40 (18) 30 (18) 10 (18) Left ventricular ejection 98 (44) 84 (50) 14 (25)*

fraction 5 0.3 Drug failure before randomization 103 (46) 81 (48) 22 (39) Prior cardiac surgery 157 (70) 119 (71) 38 (68) Prior bypass coronary surgery 61 (27) 41 (24) 20 (36) Lefi ventricular ejection fraction 0.35 + 0.14 0.33 2 0.14 0.41 + 0.157 Baseline Holter recording

VPCs/hour 165 ? 239 169 + 253 153 k 200 Complex VPCs 171/191 (90) 129/142 (91) 42149 (86) VT 107/191 (54) 76/142 (71) 31/49 (63)

Sustained VT or VF inducible 109/181 (60) 85/138 (62) 24/43 (56) at baseline electrophysiologic study

Cycle length-induced VT (ms) 251 + 44 256 2 46 232 f 32 Inducible VF 35/181 (19) 26/138 (19) 9/43 (21) Automatic implantable 104 (46) 78 (46) 26 (46)

cardioverter-defibrillatort

l p = 0.001; tp = 0.002; all other comparisons p > 0.05. $Device beforeor ~30 daysafterrandomization, and before end point. VF = ventricular fibrillation; VPCs = ventricular premature complexes; VT = ventricular tachycardia.

I296 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72 DECEMBER 1,1993

RESULTS RehospRalization rates and patient characted*

tics: Of 224 patients in this analysis, 168 (75%) were hospitalized at least once before the end point or censoring (Table I). The annual rate of hospitalization was 79/100 patients/year for all patients; those randomized to conventional therapy had 11 more hospitalizations/100 patients/year than did those on amiodarone, although this difference was not statistically sign&ant (p = 0.33 by t test). The annual rates of hospitalization were 75 and 82/100 patients/year for patients with and without AlCDs, respectively (p = 0.53 by t test).

In regard to most baseline characteristics, hospitalized patients were similar to those who were not hospitalized (Table II). However, patients who were not hospitalized had higher baseline left ventricular ejection fractions than did those who were hospitalized (p = 0.002). There was no statistically significant difference with respect to baseline Holter or electrophysiologic characteristics in the subsets of patients who underwent these studies. There were 104 patients with AICDs; 53

were randomized to amiodarone and 51 to conventional therapy.

In the 56 patients never hospitalized, there were 15 primary end points (27%); 6 were due to VF, 6 to resuscitated VF and 3 to nonarrhythmic cardiac causes. End points occurred in 4 patients assigned to amiodarone and in 11 to conventional therapy. In the 168 patients hospitalized at least once, there were 68 (40%) who had primary end points; 23 were due to VF, 26 to resuscitated VF, and 19 to nonarrhythmic cardiac causes. Primary end points occurred in 29 patients assigned to amiodarone and in 39 randomized to conventional therapy. The occurrence of primary end points was similar in the groups who were and were not hospitalized (p = 0.36 by log-rank statistic).

Hospital admission on the same day as the primary end point occurred in 17 patients (7 - amiodarone; and 10 - conventional); an additional 25 deaths occurred in the hospital 21 day after the linal hospital admission (12 - amiodarone; and 13 - conventional). There were 10 amiodarone and 16 conventional patients who had

FIGURE 1. tinlay mason forfiretho!@ talizetii after randomization. CHF = cow gestive hewt fiiiure; MI = myoawdial h farction; Proced = procedure; Vl/VF = ventriwlar tachycardii/fiM2ation.

Fl9URE 2. Time to first mhespiMization. -i==tOfofw-* hospMbdatyeuuland88%byyetu6.

5o I I 0 Amiodarone m Conventional

4Ot -1 P e 30 ! r C e / n 20 t

10

Noncardiac VT/VF CHF Angina/Ml Proced Drug change (

Primary Reason for Rehospitalization Xher

P e r C 50 e n t

25

1

0 1 2 3 5 6 7 6

REHOSPlTALlZATlON IN SURVIVORS OF VENTRICULAR FIBRILLATION 1297

primary end points, but were not hospitalized as a result of the event or when the event occurred. Therefore, hospitalization rates remained similar in the 2 groups when admissions that occurred on the same day as the end point were censored.

First rehospitalization: The primary reason for the tirst hospitalization after randomization was different between the 88 amiodarone and 80 conventional patients (p = 0.03) (Figure 1). The major reason for this difference was that only 1 of 88 patients (1%) on amiodarone was hospitalized for drug changes, whereas 12 of 80 (15%) on conventional therapy had drugs changed during hospitalization. In 6 patients (2 amiodarone and 4 conventional), the Iirst hospitalization after randomization was the result of out-of-hospital VF, a primary end point. In addition, a slightly higher proportion of patients on amiodarone was hospitalized for congestive heart failure. The “other” category included various reasons; the most frequent were AICD shocks and syn- copal episodes presumed to be due to causes other than VF or sustained ventricular tachycardia.

The primary reason for the lirst rehospitalization was also different for patients with AICDs (p = 0.005). The proportion of noncardiac hospitalizations was higher in the AICD group (26 vs 13%). Almost 50% of patients with AICDs had coronary bypass surgery; only 1% of these were hospitalized for angina or myocardial infarction. Rehospitalization was procedure-related in 25% of patients with AICDs and in 16% of those without devices. In the group without AICDs at randomization, 9% had devices implanted during the lirst hospitalization after study enrollment.

Cardiac procedures during the tirst hospitalization after randomization were performed in 42 and 33% of amiodarone and conventional patients, respectively (p = 0.2). Late coronary artery bypass surgery was performed in only 2 patients (1 in each group). AICD im- plant-ations, including replacements, constituted 44% of the procedures performed during rehospitalization, whereas electrophysiologic studies constituted 30%. The use of these procedures was similar in the amiodarone and conventional groups. AICD replacement was the

100

Pm.44 by Lo9 Rank Statistic

Amiodarone. N-112 - Conventional, N.112

Years O. I I I I 1 I I

Amiodarone 4!% 68% 72% A% 905% 9!% 7 8

Conventional 69% 70% 78% 80%

Pg.001 by Log Rank Statistic

- EF ) 0.30, N.126 - EF ( 0.30, N-98

0 EF ) 0.30 49% 4% 76% 7$% 795% 2%

7 8

EF ( 0.30 66% 79% 90% 96%

1298 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 72 DECEMBER 1, 1993

FlGuRE3.TimeteRlstrehwpmiioa aculNiiite mMlomizatiea status.

FIGURE 4. Time to first mhospiWization accord@toejectlon-(EF)at baseline. Ejection fmction is a dii* mom variable: 5 or fi.3.

most frequent procedure performed in patients with AICDs.

The occurrence of significant events including VF, sustained ventricular tachycardia, congestive heart failure and angina during the course of hospitalization was relatively uncommon. Only 12% of patients had such events, which occurred equally in the amiodarone and conventional groups. Hospitalizations related to drug inefficacy were more frequent in conventionally treated patients (38 vs 6%; p = O.OOS), but were similar for patients with and without AICDs.

All rehospbkations: The tindings for all hospitalizations were similar to those for the lirst hospitalization. Of 512 hospitalizations, 81% were for cardiac reasons, and most were related to procedures or congestive heart failure. Since there were only 26 hospitalizations for beginning or changing drugs, the difference in reasons for admission between the amiodarone and conventional groups was not evident, as it was for the lirst hospital admission. Procedures were performed in 165 hospitalizations (32%); >75% of these included AICD implantation or replacement, electrophysiologic study or cardioversion. Approximately 15% of patients had a significant event during hospitalization; >50% of these events were VF or sustained ventricular tachycardia. The numbers of rehospitalizations owing to drug side effects or inefficacy were similar in the amiodarone and conventional groups, as was length of hospital stay.

Multivariate analysis: Using variables in Table II, stepwise linear regression was used to identify variables most highly associated with rates of rehospitalization, defined as the number of hospitalizations divided by average time to censoring or the primary end point for patients with and without AICDs. Only gender was associated with the dependent variable (i.e., women had higher rates of rehospitalization than did men; p = 0.02). In this analysis, 64% of women and 44% of men had AICDs (p = 0.06). After adjustment for gender, rehospitalization rates were lower for patients with AICDs, although the association was not statistically significant (p = 0.36).

In this group of surviving patients of out-of-hospital VF, 53% were hospitalized in the tirst year after the index event, and by the fourth year, 85% had been hospitalized (Figure 2). With the baseline characteristics in Table II, stepwise Cox regression was used to select fac- tors predictive of the time to the tirst rehospitalization. In 224 patients for whom complete information was available, only baseline left ventricular ejection fraction was significantly associated with rehospitalization (p <O.OOl). The odds of the first rehospitalization increased by 8% with a 1 point decrease in ejection fraction.

The Iirst rehospitalization was not associated with randomization assignment (p = 0.46; Figure 3) or presence of an AICD (p = 0.8). In patients with left ventricular ejection fractions 10.3, there was a much higher occurrence of tirst rehospitalization (Figure 4). At the end of year 1, 65% of patients with ejection fractions SO.3 had been rehospitalized compared with only 43% of those with ejection fractions >0.3. By the fourth year after out-of-hospital VF, almost all patients in the group with low ejection fractions had been rehospitalized.

Finally, using the variables in Table II, stepwise linear regression was used to select predictors of the length of stay for the ftrst rehospitalization after enrollment. The presence of an AICD was associated with a shorter length of stay. The mean length of stay for patients with AICDs was 3.8 f 3.2 days, whereas that for those without AICDs was 7.6 f 11.9 days (p = 0.005). When all hospitalizations were considered, the difference was not as apparent, because the length of stay was 4.9 + 7.2 days for patients with AICDs and 6.1 f 6.5 days for those without AICDs at baseline (p = 0.053).

DISCUSSION Out-of-hospital VF without a new Q-wave myocar-

dial infarction is often associated with a series of acute and chronic events, including old myocardial infarction, angina pectoris, acute non-Q-wave myocardial infarction and congestive heart failure. More than 80% of patients with coronary artery disease in this study had history of myocardial infarction, and >40% had ejection fractions 10.3 at baseline. Moreover, patients in the CASCADE study had received extensive treatments before randomization.

Therefore, it is not surprising that rehospitalization was a frequent occurrence for these surviving patients of out-of-hospital VF. More than 50% of patients were rehospitalized in the year after study enrollment. These hospital stays were not inconsequential; the average hospitalization was approximately 6 days, and was prompt- ed by both noncardiac and cardiac reasons. Rehospital- ization was particularly frequent for patients with ejection fractions 10.3; the annual rate of rehospitalization for this group was 98/100 patients/year.

Although the major finding of the CASCADE study was that patients assigned to amiodarone had better cardiac survival? the nature and extent of rehospitalization did not differ appreciably according to randomization assignment. However, patients assigned to amiodarone had fewer hospitalizations (ll/lOO patients/year) than did those assigned to conventional therapy.

Although the difference was not statistically significant, patients with AICDs were hospitalized less fre- quently than were those without AICDs (7/100 patients/ year). In addition, the length of stay associated with the tirst rehospitalization was shorter for patients with AICDs. This may be due to the fact that the primary reason for rehospitalization was different between patients with and without AICDs. This Iinding also reflects that patients with AICDs were generally healthier than were those without AICDs; a low ejection fraction at baseline was evident in 42% of those with AICDs and in 57% without. Furthermore, most patients received their AICDs in the last half of the study and may have had different clinical characteristics than those who received other treatments. However, in multivariate analysis, presence of an AICD was the only factor associated with length of stay.

There have been several reports concerning the long- term outcome and cost-effectiveness of the AICD8-13; 2 studies have considered rehospitalization as a factor in evaluating the cost-effectiveness of the AICD.“J3 Al- though the present study was prospective, findings con-

REHOSPITALIZATION IN SURVIVORS OF VENTRICULAR FIBRILLATION 1299

ceming AICDs, rehospitalization rates and length of stay are preliminary. Implantation of the AICD was not randomized. If these Iindings are true, the AICD may reduce the need for rehospitalization, as well as shorten the length of hospital stay. A randomized trial comparing use of the AICD with alternative therapies is need- ed to evaluate these findings.

A limitation of this study was that we could not identify all rehospitalizations that resulted after the occurrence of resuscitated VF, a primary study end point. Rehospitalizations that occurred 21 day after the primary end point were not considered in the analyses, because complete follow-up information was not available for all patients. It is unclear how the inclusion of these events would have affected the study results. It is also possible that hospitalizations occurring on the same day as primary end points may have been missed. However, these rehospitalizations were censored in the various analyses, and the key results of this study did not change. A major strength of this study was that patients were followed assiduously over a period of 8 years. The efforts of study nurses, and the cooperation of patients were critical in obtaining information regarding rehospitalization.

APPENDIX lhe CASCADE Investigators Harbowiav Medical

CenterlUniversity of Washington Medical Center, Uni- versity of Washington, Seattle, Washington: H. Leon Greene, MD (Principal Investigator), Jeanne E. Poole, MD, Peter J. Kudenchuk, MD, G. Lee Dolack, MD, Gust H. Bardy, MD, Leonard A. Cobb, MD, Ellen L. Graham-Renfroe, RN, Judy L. Powell, RN, Amy C. Gal- loway, RN, and Joanne Kellie, RN.

Virginia Mason Medical Center, Seattle, Washing- ton: Christopher L. Fellows, MD, Carolyn L. Main, RN, and Mary McMahon-Busch, RN.

Providence Medical Center, Seattle, Washington: David R. Broudy, MD, John Sanders, RN, Judy E. Gami, RN, and Donna Gerity, RN.

Coordinating Center, Seattle, Washington: Charles Maynard, PhD, Alfred P Hallstrom, PhD, and Ruth McBride.

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Rehospitalization in surviving patients of out-of-hospital ventricular fibrillation (the CASCADE study)