A comparison of coronary angioplasty and coronary artery bypass grafting outcomes in chronic dialysis patients

A Comparison of Coronary Angioplasty and Coronary Artery Bypass Grafting Outcomes in Chronic Dialysis Patients Ann L. Rinehart, MD, MPH, Charles A. Herzog, MD, Allan J. Collins, MD, John M. Flack, MD, MPH, Jennie Z. Ma, MS, and John A. Opsahl, MD 0 The objective of this study was to compare the outcomes of angina, myocardial infarction (Ml), cardiac death, and all-cause death following percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG). The study design was based on retrospective, nonrandomized analysis and was set in referral teaching hospitals and community hospitals. Eighty-four chronic dialysis patients with symptomatic coronary artery disease without prior revascularization were included in the study. Twenty-four patients underwent PTCA of one or more vessels, and 60 patients underwent CABG. Recurrence of angina, Ml, cardiac death, and all-cause death following revascularization as well as the number of inpatient days preprocedure and postprocedure were recorded. The two patient groups were comparable in terms of age, sex, history of Ml, left ventricular mass and function, and angina severity. Diabetes mellitus was more prevalent in the PTCA group. The CABG group had more severe coronary artery disease. The P-year survival rate of the CABG patients (66%; 95% confidence interval = !53,79) did not differ from that of the PTCA patients (51%; 95% confidence interval = 27,65). Thirteen PTCA patients were restudied 106 r+_ 108 days after recurrence of angina; nine (69%) of these patients were found to have angiographic restenosis. The postprocedure risk of angina and the combined endpoints of angina, Ml, and cardiovascular death were significantly greater following PTCA than CABG. Percutaneous transluminal coronary angioplasty was the only consistent predictor of outcomes; the adjusted relative risks (compared with CABG) of postprocedure angina and combined endpoints were 16.4 and 10.2, respectively, and were several-fold higher than the unadjusted risks. We conclude that in chronic dialysis patients with symptomatic coronary disease, patients undergoing PTCA have a higher risk of subsequent angina and combined angina, Ml, and cardiovascular death than those undergoing CABG. The optimal approach to coronary revascularization in this patient population remains to be determined. 0 1995 by the National Kidney Foundation, Inc. INDEX survival.

WORDS:

Coronary

arteriosclerosis;

aortocoronary

C

bypass;

transluminal

angioplasty;

dialysis;

hemodialysis;

ARDIAC DISEASE is the most common cause of death in chronic dialysis patients and is responsible for 40% to 60% of all-cause mortality.’ Approximately one third of these deaths are attributable to acute myocardial infarction (MI), a risk borne disproportionately by older patients. Over the past 5 years, the number of end-stage renal disease patients has grown at a rate of 10% per year, with most of this increase occurring in patients over the age of 65 years.’ Thus, the need for cardiac interventions in this patient population is certain to increase rapidly. Favorable results of coronary artery bypass grafting (CABG) in dialysis patients have been reported recently by several centers,2-6 but scant literature exists regarding outcome in dialysis patients after percutaneous transluminal coronary angioplasty (PTCA). The largest series of chronic dialysis patients undergoing CABG was reported from the Regional Kidney Disease Program (RKDP) at Hennepin County Medical Center in 1988.* Thirty-nine patients who underwent CABG from 1976 to 1988 were matched 1: 1 with patients having the same cardiovascular mortality risk factors. The perioperative mortality rate

was 3%; the 2-year survival rate was 92% compared with 5 1% in the nonsurgical group (P < 0.05). Other reports confirm the efficacy of CABG in relieving angina pectoris in dialysis patients,3-6 but the perioperative mortality rate varies widely and is as high as 20% in some series.‘,4 In addition to the RKDP, only two other centers have reported long-term outcome after CABG in dialysis patients, with 2-year survival rates of 77%3 and 85%.6 Kahn et al reported a series of 17 chronic dialysis patients who underwent PTCA, two of whom had previously undergone CABG.7 Fortyseven of 49 vessels were successfully dilated, but

American

1995:

Journal

of Kidney

Diseases,

Vol 25, No 2 (February),

From the Divisions of Nephrology and Cardiology, Hennepin County Medical Center, School of Medicine and Public Health, and Divisions of General Internal Medicine and Epidemiology, University of Minnesota, Minneapolis, MN. Received November 29, 1993; accepted in revised form September 20, 1994. Address reprint requests to John A. Opsahl, MD, Division of Nephrology, Hennepin County Medical Center, Medical Specialty Center, 914 S 8th St, Minneapolis, MN 55404. 0 1995 by the National Kidney Foundation, Inc. 0272.6386/95/2502-0010$3.00/O

pp 281-290

281

RINEHART

282

angina recurred within 6 months in 12 of 15 patients following initial angioplasty. In 26 of 32 (81%) dilated vessels, restenosis was angiographically demonstrated. Reusser et al recently reported a retrospective cohort of 13 hemodialysis patients matched with 13 nonhemodialysis patients, all of whom underwent PTCA.’ At 2 years, 50% of the dialysis group experienced a cardiac event, defined as angina recurrence, MI, cardiac death, or bypass surgery, compared with 15% of the controls. Only three patients underwent subsequent cardiac angiography, and two of those demonstrated restenosis. Most recently, Ahmed et al pooled data from 21 chronic hemodialysis patients who had undergone PTCA at three separate hospitals.g Most of the patients had multivessel disease, but 90% underwent singlevessel angioplasty. Angioplasty was successful in 57% of the patients, but carried a high complication rate. Only 15 (71%) of the original cohort had a patent vessel at the time of discharge from the hospital. After 27 2 15 months of followup, four (27%) of those patients had died, while angina recurred in nine (60%). Seven of the nine patients with recurrent angina were restudied and had angiographic restenosis a mean of 4.4 + 4.0 months after the initial procedure. Given the potentially low perioperative mortality rate and excellent long-term survival following CABG, and the apparently high restenosis rates following PTCA as reported by Kahn et a1,7 Reusser et al,’ and Ahmed et al,’ the optimal approach to coronary revascularization in the dialysis population remains unclear. The purpose of this study was to compare the incidence of recurrent angina, MI, cardiovascular death, all-cause death, procedural complications, and hospitalization following PTCA or CABG in a retrospective cohort of chronic dialysis patients. MATERIALS

AND

METHODS

Patient Population The computerized database of the RKDP at Hennepin County Medical Center was used to identify RKDP patients who had undergone PTCA or CABG at any regional hospital while receiving maintenance hemodialysis or peritoneal dialysis. Twenty-eight chronic dialysis patients underwent PTCA from July 1985 to July 1991. Four were excluded from the study because they had undergone prior surgical coronary revascularization. Sixty-eight chronic dialysis patients who had undergone CABG between November 1977 and July

ET AL

1991 were also identified. Eight were excluded from the study because of concomitant valve replacement or prior CABG. Ultimately, 24 PTCA and 60 CABG patients were available for study, with 23 bypass surgeries performed prior to July 1985 and 37 after that date.

Dejkitions Patient charts and available echocardiograms and angiograms were reviewed. Information on demographics and potential risk factors for death were collected for each patient, including age at time of procedure, gender, ethnicity, cause of end-stage renal disease, type of dialysis, and time from initiation of dialysis to procedure. Dialysis exposure time was corrected for prior renal transplantation by subtracting the time off dialysis from the total time elapsed from initiation of dialysis to the date of procedure. Type I or II diabetes mellitus status was determined using the National Diabetes Data Group classification system.“’ Actual M-mode echocar diograms or their reports were used to determine the presence or absence of left ventricular hypertrophy, and left ventricular mass was calculated by the method of Troy et al.” Left ventricular systolic function (ejection fraction) was measured by either left ventriculography or visual assessment from twodimensional echocardiography. Qualitative visual assessment of left ventricular function by two-dimensional echocardiography was performed using criteria similar to those used in the Stroke Prevention in Atria1 Fibrillation Study.” Ejection fraction was categorized. as being normal (~50%), mildly decreased (4 1% to 49%), or moderately to severely decreased (540%). Ventricular arrhythmia was considered to be present only if there was a history of sustained ventricular tachycardia. Predialysis and postdialysis systolic blood pressures were extracted from a computerized database of dialysis runs. Severity of coronary artery disease was ascertained through actual review of films or cardiac catheterization reports if films were not available. Patients were classified as having coronary artery disease of one to three vessels described by the following major vascular territories: left anterior descending or first diagonal, circumflex or marginal, and right coronary artery or posterior descending artery. Vessels with luminal narrowing ~70% were considered diseased, while luminal stenosis ~50% was considered to be left main disease. Restenosis was defined as a ~70% luminal narrowing of the previously site of angioplasty. Angina classification prompting the procedure was based on the Canadian Angina Classification System.13 Recurrence of angina following intervention was defined as the presence of substemal chest, arm, or jaw discomfort, or dyspnea without evidence of volume overload. A history of MI was based on the presence of Q-waves on old electrocardiograms or on physicians’ reports if no charts were available. A Q-wave MI after the procedure was defined as the development of new Q-waves in 22 electrocardiogram leads. A subendocardial MI was defined as symptoms consistent with myocardial ischemia with new ST segment depression and either (1) total creatine kinase levels greater than the 95% confidence interval (CI) for the laboratory reference range and a positive MB fraction with a timeappropriate decrease in total creatine kinase values, or (2) a peak creatine kinase level less than the 95% CI for the normal reference value, but a threefold increase in total creatine kinase from baseline, accompanied by an increase in MB frac-

CORONARY

ANGIOPLASTY

IN DIALYSIS

PATIENTS

tion of greater than 3% and followed by an undetectable MB fraction. Peripheral vascular disease was defined by the presence of bruits, absent peripheral pulses, claudication symptoms, or a history of limb amputations for ischemia. If a persistent neurologic deficit or head scan report of an infarct was present, the patient was considered to have cerebral vascular disease. Chronic obstructive pulmonary disease was considered present if FEVJFVC was ~0.80. Current smoking status was positive if the patient smoked more than one half-pack per day after hospital discharge. Prior smoking status was positive for a greater than five pack years smoking history before the procedure. Insurance status was extracted from the RKDP billing department and was classified as no insurance, Medicare only, or Medicare plus other insurance.

Ascertainment

of Complications

Charts were also reviewed for complications occurring within the first 30 days after the procedure. Femoral artery trauma was defined as a more than 4 g/dL decrease in hemoglobin or the need for surgical repair of the femoral artery Atria1 arrhythmias were considered present if they were new in onset and of sufficient duration to require intervention with medications or cardioversion. Pericarditis was defined as a pericardial rub that persisted for at least 24 hours. Pulmonary complications included atelectasis requiring bronchoscopy, or pneumonia characterized by chest film infiltrate, neutrophilia, and sputum production. Access clotting was recorded if a surgical declotting procedure was performed. Patients were followed for recurrence of angina, MI, and cardiovascular and all-cause death. The angina recurrence date was the first date on which a pattern of ischemic symptoms was noted during careful review of inpatient and outpatient records. If an MI occurred within 24 hours of the first recurrence of angina, then MI alone was recorded and was classified as Q-wave or non-Q-wave. Two different reviewers classified the MI endpoint; if the reviewers disagreed, a third person acted as arbiter. Death status was obtained through the RKDP database or the US Renal Network. Death was classified as cardiovascular if MI was the known cause of death or if sudden death occurred without suspicion of hyperkalemia or dialysis noncompliance. Patients were censored on the date of renal transplantation, cross-over to the other procedure, repeated PTCA, termination of study, or loss to follow-up. The latter affected only the angina and MI analyses, as death ascertainment was complete. Hospitalization days were also counted. Procedural stay was defined as the number of inpatient days from the date of the procedure until discharge. Days to next hospitalization were counted from the day of discharge to the first date of rehospitalization for any cause. Hospitalization rates before and after the procedure were determined for cardiac and all causes. Preprocedure inpatient days were counted from the date of initiation of chronic dialysis to the procedural date, while postprocedural days were counted from the date of the procedure to transplantation, loss to follow-up, cross-over, death, or end of the study. Hospitalization rates were expressed as (inpatient days/days at risk) x 1,000. Cardiac admissions included unstable angina, MI, pericarditis, and cardiac decompensation thought not to be secondary to volume overload. All-cause hosuitalization rates did not include

283 elective procedures, such as access declots colonoscopy, cystoscopy, and biopsies.

and

revisions,

Description of Percutaneous Transluminal Coronary Angioplasty Percutaneous transluminal coronary angioplasty was performed with over-the-wire or fixed-tip balloon dilatation catheters. Aspirin was routinely administered 24 hours before the procedure, with heparinization during PTCA. Percent luminal stenosis was ascertained by visual estimation of the reduction in coronary artery diameter. Initial PTCA success was defined as a reduction of stenosis severity by at least 30%. For example, a lesion with 90% stenosis severity must have had ~60% stenosis severity after PTCA.

Description Grafting

of Coronary Artery Bypass

Patients not on digitalis preoperatively received a loading dose prior to surgery and maintenance doses for several weeks postoperatively. Patients were dialyzed to dry weight and a serum potassium of 4.0 to 4.5 mEq/L and were transfused on dialysis to achieve hematocrits ~~36% the day before surgery. Saphenous vein grafts or left internal mammary arteries were used for revascularization. Patients generally required dialysis within 24 hours after surgery to correct fluid overload and/or hyperkalemia related to the bypass pump run, and then every 24 to 48 hours thereafter. Regional or minimal heparin or regional citrate anticoagulation was used for hemodialysis for 7 to 10 days postoperatively, with hematocrits maintained at ~36% with transfusions during this time.

Statistical Methods All descriptive variables were analyzed using SPSS-PC version 4.0 software (SPSS Inc, Chicago, IL) and are reported as two-tailed tests. Data are presented as mean ? SD or mean and 95% CIs. Differences between the procedural groups were analyzed with the chi-squared test or with Fisher’s exact test for categorical variables, while continuous variables were analyzed nonparametrically using the Mann-Whitney U test. Diseased vessel severity and ejection fraction were analyzed with the Mantel-Haenszel test for linear association. Ninetyfive percent confidence intervals for cumulative event curves were calculated using S(t) . exp[? 1.96 SE [S(t)]/S(t)]. BMDP/386 Dynamic software (BMDP Statistical Software, Inc, Los Angeles, CA) was used for the survival analysis. Survival curves were generated using the life-table analysis, and the log-rank test was used to test for the difference in cumulative survival between the two groups. Variables were tested individually in the Cox proportional hazards model and were later forced into the model already containing the procedure variable. They were retained in the model if the likelihood ratio chi-squared significance level was ~0.05. Confounding was considered present if the fl coefficient for a procedure changed by 20% with the introduction of another variable in the model.

RINEHART

284 Table

1. Baseline

Characteristics

Patients

CABG (n = 60)

PTCA (n = 24)

Probability Value

62.1 2 11.1 37-79

63.6 + 11.7 38-81

0.526

15.8 + 18.9 46 (77)

31.4 + 40.4 14 (58)

0.043 0.093

54 (90)

16 (67) 4 (17)

0.010

6 (10) 0 0 21 (35) 8 (13) 13 (22)

14 (58) 4 (17) 10 (42)

0.050

16(27)

13 (54)

0.027

Characteristic Age (yr) Mea” ? SD Flange Time from initiation of dialysis (mo) Males (%) Ethinic group (%) White Native America” Black Other Diabetes mellitus (%) TYPO l Type II Cause of renal failure

of Study

W) Diabetes mellitus Hypertension/

17 (28)

MlOYSSCUlS~

Glomerulonephritis Other Unknown Peritoneal dialysis w Current smoker (%) Chronic obstructive pulmonary disease (%) Peripheral vascular disease (%) Prior cerebrovascular accident (%) Non-skin malignancy W) Insurance (%) NO”e Medicare only Medicare and other

4 V) 17 (28)

6 (10)

2 (8) 2 (8)

2 4 4 1

(8) (17) (17) (4)

1 (4) 5 (21)

0.871 0.285

12 (20)

5 (21)

1 .ooo

47 (78)

16 (67)

0.265

7 (12)

4 (17)

0.721

4 (17)

0.268

1 (4) 3 (13) 20 (83)

0.899

3 (5)

6 (1’3)

4 (7) 8 (13) 48 (80)

RESULTS

Demographic

Several important differences existed between the two revascularization groups. In the PTCA group, time from dialysis initiation to procedure was twice as long, and a larger proportion of patients were minorities and diabetic (Table 1). In the CABG group, renovascular disease was much more common. The CABG group also had more severe coronary artery disease, based on a greater proportion of persons with multivessel and left main disease (Table 2). Cardiac and allcause hospitalization rates ([inpatient days/days at risk] X 1,000) prior to revascularization were both higher in the CABG group than in the PTCA group (270 rt 379 v 151 % 319 [P = 0.011 and 333 + 378 v 155 2 245 [P = 0.021, respectively). The two patient groups did not differ with respect to mean age at initiation of dialysis; percentage of males; current and prior smoking Table

2. Cardiac

Data

Sixty CABG and 24 PTCA patients were identified for study. Patient characteristics are summarized in Table 1 and the cardiac history findings are presented in Table 2. Clinical indications for consideration of intervention during the period of study included unstable angina, pulmonary edema not explained by volume overload, inability to perform hemodialysis because of hypotension, or cardiac arrest (Table 2). No intervention was performed as part of a routine pretransplant work-up. Patients were selected for PTCA if they were not surgical candidates (n = 2), if they had single-vessel disease (n = 13), or if they had multivessel disease and the vessel containing the culprit lesion was technically approachable (n = 9).

History CABG (n = 60)

Characteristic

5 (8)

ET AL

No. of diseased vessels 1 2 3 Left main disease Left anterior descending disease Prior myocardial infarction Myocardial infarction within 6 months Left ventricular mass index (gIm2)t Me” Women Left ventricular hypertrophy Me” Women Ejection fraction Normal Mildly decreased Moderately to severely decreased Ventricular arrhythmias Reasons for evaluation Angina class O-3 Angina class 4 Cardiac arrest Pulmonary edema Recent myocardial infarction Systolic blood pressure* Predialysis (mean) Postdialysis (mean)

w

6 (10)

of Study

Patients

PTCA (n = 24) w

Probability Value

13 (54) 4 (17) 7 (29) 0


16 (27) 38 (63) 13 (22) 54 (90) 48 (80)

18 (75) 15 (63)

0.08 0.094

23 (39)

8 (33)

0.724

191 2 26 172 2 24

191 + 60 186 2 45

0.02

0.99 0.48

22 (48) 11 (79)

6 (43) 7 (70)

0.745 0.633

31 (52) 11 (18)

11 (46) 5 (21)

0.693’

16 (27) 11 (18)

7 (29) 3 (13)

9 44 4 2

(15) (73) (7) (3)

1

(2)

146 t 19 138 k 18

3 14 1 5

(13) (58) (4) (21)

0.747 0.109

1 (4) 142 2 12 140 + 10

0.540 0.534

*From Mantel-Haenszel test for linear association. t Left ventricular mass (g)/body surface area (m’). M-mode data only available for 34 men and 18 women, both groups combined. $ Systolic blood pressure only available for 31 (predialysis) and 40 (postdialysis) patients, both groups combined.

CORONARY

ANGIOPLASTY

IN DIALYSIS

PATIENTS

history; prevalence of chronic obstructive pulmonary disease, peripheral vascular disease, prior cerebrovascular accident; non-skin malignancy; insurance status; prevalence of ventricular arrhythmias; and reason for cardiac evaluation (Tables 1 and 2). The incidence of prior MI was similar in both groups; 48 of 60 patients in the CABG group and 15 of 24 patients in the PTCA group (Table 2). M-mode echocardiograms were available for review in 15 PTCA and in 37 CABG patients, and both groups and sexes had markedly elevated mean left ventricular mass indices (normal female, <109 g/m”; normal male, ~135 g/m”) (Table 2). When two-dimensional echocardiography reports were also used, information on left ventricular hypertrophy was available for 81 of 84 cases and demonstrated a high prevalence of left ventricular hypertrophy in both groups. Ejection fraction was also similar in both groups, and normal in approximately half the patients (Table 2). Perioperative

Outcome

The procedural admission record was available for review for 23 of 24 PTCA patients and for 58 of 60 CABG patients. All attempted PTCAs were single vessel with one exception. The initial PTCA success rate was 92% (23 of 25 vessels attempted). Seven of the 60 CABG patients underwent revascularization that included the left internal mammary artery to left anterior descending, while the remaining patients had saphenous vein grafts only. A mean of 2.9 t 0.9 vessels were bypassed. The hospital stay from procedure to discharge was longer in the CABG group than in the PTCA group (23.6 2 20.7 days v 12.5 ? 15.4 days, respectively; P < 0.001). Fifteen PTCA patients were known to be maintained on aspirin after the procedure, and all but two were receiving either aspirin or dipyridamole. The mean number of complications per person in each group was similar, with 1.24 ? 0.29 complications in the CABG group and 1.00 +- 0.57 in the PTCA group (P = 0.15). However, more CABG patients were complication free (43 of 58 compared with 12 of 24 PTCA patients; P = 0.02). Two deaths occurred in the CABG group (both secondary to MI); one occurred in the PTCA group (from sepsis at day 29) (P = 1.00). Perioperative MI occurred in four of 58 CABG patients and in one of 24 PTCA patients

285

(P = 0.64). The most common complication in the CABG group was a new atria1 arrhythmia (11 of 54 compared with two of 21 in the PTCA group; P = 0.27). In the PTCA group, femoral artery trauma was the most common complication (five of 24 compared with five of 58 in the CABG group; P = 0.06). Survival

Analysis

Percutaneous transluminal coronary angioplasty and CABG patients were followed for 66 months (the longest period that PTCA patients were available for observation). The mean observation time was 19.6 + 3.5 months and 30.7 + 3.9 months, respectively, with the difference in follow-up time largely determined by a shorter time to death in the PTCA group. Death ascertainment was complete. In two of 60 CABG patients and one of 24 PTCA patients, angina and MI endpoints could not be ascertained because the patients were transferred to different dialysis centers. The pattern of censoring between groups was studied. A trend toward more frequent censoring for renal transplantation was noted in the CABG group compared with the PTCA group (10 of 60 v 1 of 24, respectively; P = 0.166). Prior to July 1985 (when the first PTCA procedure was performed), eight of 23 CABG patients were censored for renal transplantation, compared with two of 37 patients after this time. The mean age of the CABG patients who received transplants was 49.6 ? 10.1 years compared with 64.6 + 9.5 years for those not transplanted (P = 0.0002). Neither the number of diseased vessels (P = 0.220) nor left main disease prevalence (P = 0.327) was different between CABG transplant and nontransplant patients. For the angina endpoint, the cumulative event curves diverged dramatically within 6 months (Fig 1). Six percent (95% CI = 0,12) of the CABG group and 47% (95% CI = 26,68) of the PTCA group experienced angina within the first 6 months. The log-rank test for difference in cumulative angina recurrence was highly signincant (P < 0.0001). During the same period of follow-up, the PTCA group experienced a total of five MIS (two Q-wave and three non-Q-wave) and seven MIS were identified in the CABG group (three Qwave and four non-Q-wave). The cumulative

286

RINEHART

ET AL

1.0 5 i

0.8

5 ‘o

0.6

8 h 9 B i 5

0.4

p,,

,

,

,

,

,

,

,

,

,

24

30

36

42

48

54

60

66

~

0.2 0 tt

0

I

I

I

I

I

I

I

I

I

I

6 12 18 24 30 36 42 48 54 60 66 Months after Procedure

Fig 1. Cumulative proportion patients free of angina after curves are significantly different log-rank test.

of chronic dialysis CABG or PTCA. The (P < 0.0001) by the

1 o.z?f, , , , , , , , , , , 1 a 12

18

24 30 36 42 48 Months after Procedure

Fig 2. Cumulative proportion patients free of Ml after CABG log-rank test.

54

60

66

12

72

of chronic dialysis or PTCA. P = 0.11 by

18

72

Months after Procedure Fig 3. Cumulative proportion of chronic patients free of cardiovascular death after PTCA. P = 0.08 by log-rank test.

dialysis CABG or

CABG group and 88% of the PTCA group eventually had one of these events (Fig 4). By 6 months, 23% (95% CI = 12,34) of the CABG group and 60% (95% CI = 40,SO) of the PTCA group experienced one of these events. The influence of diabetes mellitus on these outcomes was also examined. The cumulative event curves segregated by procedure and not by diabetes mellitus status. The log-rank test was again highly significant for difference in cumulative events (P < 0.0001). After 66 months of follow-up, 32 CABG and

g- 1.0 & 2

0.8

z

0.6

i h 8 3 E

o4

a

f

6

6

72

event curves diverged at 18 months, with 11% (95% CI = 5,22) in the CABG group and 25% (95% CI = 10,62) in the PTCA group having an MI (Fig 2). Despite the trend suggesting a better outcome after CABG, the log-rank test for difference in cumulative MI events was not significant (P = 0.11). During follow-up, 19 CABG and 10 PTCA patients died of cardiac causes (Fig 3). Although there was a trend toward decreased cumulative cardiac deaths in the CABG group, this did not reach statistical significance (P = 0.08). To increase the ability to detect an outcome difference between procedures, the angina, MI, and cardiovascular death endpoints were combined. In 66 months of follow-up, 47% of the

0

0

I

0.2 Diabetic 0

0

6

12

\. PTCA: Nondiabetic ’ I I I 24 30 36 42 48

I

I

,

18 54 Months after Procedure

60

66

Fig 4. Cumulative proportion of chronic dialysis patients free of angina, Ml, or cardiovascular death after CABG or PTCA. The two upper curves represent CABG patients with (solid line) and without (dashed line) diabetes mellitus. The two lower curves represent PICA patients with (solid line) and without (dashed line) diabetes mellitus. The log-rank test for differences between CABG (with or without diabetes mellitus) and PTCA (with or without diabetes mellitus) curves is significant at P < 0.0001.

;2

CORONARY

ANGIOPLASTY

IN DIALYSIS

PATIENTS

t-1 0 6 12 18 24 30 36 42 48 54 60 66 72 Months after Procedure Fig 5. Cumulative proportion of chronic patients surviving (ail-cause death) after PTCA. P = 0.28 by log-rank test.

dialysis CABG or

12 PTCA patients had died. The 2-year cumulative survival rate for the CABG and PTCA patients was 66% (95% CI = 53,79) and 51% (95% CI = 27,65), respectively (Fig 5). The 5-year cumulative survival rate was 40% (95% CI = 25,95) for CABG patients and 14% (95% CI = 10,23) for PTCA patients. Although CABG patients tended to have longer overall survival, there was no statistical difference in cumulative survival (P = 0.275) between the two groups. Cox Proportional

Hazards Survival Analysis

An exploratory Cox regression analysis was first performed for the endpoints of angina, MI, the combined endpoints (angina, MI, or cardiovascular death), and all-cause death. The following variables were entered into each model individually: PTCA (reference = CABG), age, (age)2, presence of type I or II diabetes mellitus, white race (reference = non-white), male sex, ejection fraction (three levels: normal, mildly decreased, or moderately to severely decreased), left main disease, prior MI, current smoking, number of diseased vessels (one, two, or three), dialysis duration (months), and (dialysis duration)2. Variables were kept in the model only if the log-likelihood chi-squared test resulted in a probability value of 10.05. Because PTCA was the only consistently significant predictor of outcome, covariates were added to PTCA to determine whether confounding was present, defined as a change of 20% in the p coefficient for PTCA. The interaction of PTCA with diabetes, duration

287

of dialysis, age, and number of diseased vessels was also examined. For the angina outcome, PTCA was the only significant predictor in the model, and left main disease and number of diseased vessels acted as confounders (Table 3). The unadjusted relative risk (RR) of angina after PTCA was 6.3 (95% Cl = 2.814.2). Adjusting for left main disease and the number of diseased vessels, the RR increased to 16.4 (95% CI = 5.1,53.1). In the combined endpoint analysis, PTCA, number of diseased vessels, and left main disease were significant predictors in the model (Table 3). The unadjusted RR was 3.9 (95% CI = 2.1,7.1). Adjusting for left main disease and number of diseased vessels, the RR increased to 10.9 (95% CI = 4.5,22.4). For the MI and cardiovascular death endpoints, no variable alone was a significant predictor of outcome (Table 3). However, PTCA became statistically significant when the number of diseased vessels was entered into the Cox model for the MI endpoint. The unadjusted RR for MI after PTCA was 2.5 (95% CI = 0.8,8.2). With adjustment for the number of diseased vessels, the RR increased to 4.4 (95% CI = 1.1,17.0). The RR for cardiovascular death after PTCA was 2.0 (95% CI = 0.9,4.3), increasing to 2.6 (95% CI = 0.9,6.9) after inclusion of the number of diseased vessels in the model. The use of cardiac procedures between groups was analyzed. Thirteen PTCA patients underwent a subsequent cardiac catheterization, with a mean time from recurrence of angina to reevaluation of 106 + 108 days (range, 2 to 337 days). Restenosis was demonstrated in nine (69%) of those patients. Only six CABG patients underwent an additional cardiac catheterization. Percutaneous transluminal coronary angioplasty was later performed in one CABG patient and in four PTCA patients. Four PTCA patients eventually underwent coronary bypass surgery, while no CABG patients were rebypassed. The mean number of cardiac medications and hospital days before and after the revascularization procedure also were studied. The mean number of cardiac medications, including calcium channel blockers, nitrates, digoxin, and betablockers, was 1.7 2 1.1 in the CABG group compared with 1.5 + 1.1 in the PTCA group (P = 0.61) preprocedure and 1.4 2 0.9 compared

RINEHART

288 Table

3. Relative

Risks

for

Angina,

Myocardial

Infarction,

Cardiac

Death,

and

Combined

ET AL

Endpoints

Endpoint Angina

Variable

PTCA PTCA (adjusted) Left main disease One-vessel disease Two-vessel disease Three-vessel disease

6.3 16.4*

(2.8, (5.1,

MI

14.2)$ 53.1)s

NOTE. The data are expressed as RR (95% * Adjusted for left main disease and number T Adjusted for number of diseased vessels. *P < 0.001. §P = 0.11. 11P = 0.03. fi P = 0.08. #P = 0.07. **P = 0.02.

2.5 4.47

Cl). of diseased

1.3 -+ 1.0, respectively, postprocedure (P = 0.71). The number of days to next hospitalization (any cause) was not different between groups: 130 + 62 in the CABG group and 83 + 52 in the PTCA group (P = 0.23). Postprocedure, the cardiac inpatient rate decreased by 88 + 402 for the CABG group compared with 31 + 383 for the PTCA group (P = 0.14). The CABG group experienced a decrease of 119 2 396 in all-cause inpatient days following the procedure, compared with a slight increase of 19 -t 356 in the PTCA group (P = 0.12). DISCUSSION

In this retrospective study, chronic dialysis patients undergoing PTCA had a substantially greater risk of angina recurrence and combined cardiovascular events after the procedure than patients undergoing CABG. The results of statistical tests for differences in cumulative events for these two endpoints were highly significant. Myocardial infarction and cardiovascular death rates showed a trend favoring CABG, although all-cause mortality was not different between the two groups. In the Cox analysis, PTCA was consistently the strongest predictor for future cardiac events. Unadjusted for other covariates, the RRs of angina and combined cardiac events were 6.3 and 3.9, respectively. Given that RRs from significant predictors in the Cox model are multiplicative in nature, patients with multivessel disease

(0.8, 8.2)s (1 .I, 17.O)jj

Cardiac

2.0 2.6t

(0.9, (0.9,

Combined

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4.3)! 6.9)#

3.9 10.2* 3.5 1.0 2.4 3.1

(2.1, 7.1)$ (4.5, 22.4)$ (1.5, 7.9)** (1.0, (1.4,

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vessels.

who underwent PTCA had an even greater RR (approximately 30) for a subsequent cardiac event. In any retrospective study, patient numbers as well as group selection and comparability can markedly affect study validity, outcome, and conclusions. Among the 24 PTCA patients, only two were felt to be inoperable; in fact, half (54%) had single-vessel coronary artery disease. Since there were some significant differences (time on dialysis prior to procedure, proportion of minority and diabetic patients) between the PTCA and CABG groups that could have affected outcome, the Cox proportional hazards model was used in an attempt to account for between-group differences. Despite accounting for the effect of these differences and other known predictors of survival in dialysis patients,14-” PTCA consistently appeared to be a strong predictor for cardiac endpoints. Thus, the procedure itself, not selection bias or between-group differences, seems to best predict cardiac outcome in these patients. Given the small sample size in this study, the estimated power to detect a RR of 2.0 with CY= 0.05 in the combined endpoint analysis was 25%, limiting our ability to detect variables as true risk factors. Although this may explain our inability to establish diabetes mellitus as a risk factor for future cardiac events, it certainly does not detract from the strong predictive power of the choice of procedure on outcome in these patients. Simi-

CORONARY

ANGIOPLASTY

IN DIALYSIS

PATIENTS

larly, the lack of statistical difference in MI as well as cardiovascular and all-cause mortality between the PTCA and CABG groups, all critically important clinical endpoints, may reflect the small number of patients available for study and the even smaller numbers of postprocedure events. The use of recurrent angina as a surrogate endpoint for restenosis in this study limits the comparability of these results to studies of dialysis patients using angiography to define restenosis.7.9 In this study, angina recurrence was presumed to represent restenosis of the vessel dilated, but could have resulted from progression of disease in that or other vessels. Approximately half of the patients studied had more than one diseased coronary artery but had only one vessel, thought to be the culprit lesion, dilated. Therefore, angina recurrence and the other poor outcomes after PTCA in this study may simply reflect incomplete revascularization. However, in those patients restudied, we observed a 69% restenosis rate, suggesting that the cardiac endpoints observed were, in fact, secondary to restenosis. That observation and the surrogate endpoint data (60% of the PTCA patients experienced a cardiac event within the first 6 months) are both consistent with the data of Kahn et a1,7 who noted an 81% angiographically determined restenosis rate within the first 6 months in chronic dialysis patients, and Ahmed et a1,9 who reported angina recurrence in 60% of patients (mean time to recurrence, 3 months) and angiographic restenosis in 78% of those restudied 4.4 + 4.0 months after the initial procedure. Both of those patient populations had somewhat more severe disease than the patients ‘in the current study. Although most patients in the series of Ahmed et al underwent single-vessel angioplasty, in the series of Kahn et al 12 of 17 patients underwent multivessel PTCA. Thus, even a more aggressive approach with PTCA (in patients with multivessel disease) than was applied in the current study is unlikely to improve outcomes. The trend toward an increased rate of MI after PTCA (compared with CABG) observed in this study is disconcerting. This could be the result of patients with recurrent angina not being restudied or MI being the first manifestation of restenosis. Thirteen of the 14 patients who experienced angina after PTCA eventually underwent

289

cardiac catheterization. However, the time from angina recurrence to recatheterization was highly variable, with the mean time being 106 t 108 days (range, 2 to 337 days). Only four patients with recurrent angina underwent another PTCA. The delay prior to intervention for recurrent symptoms in this study may indicate that retrospective review identified angina recurrence earlier than primary care physicians did, since symptoms often were subtle and more easily identified retrospectively. However, in five of the 24 PTCA patients, MI or cardiac death occurred without angina1 warning. Similarly, in the series reported by Ahmed et al,” four of 15 (27%) of the patients leaving the hospital with a patent vessel died cardiac deaths (three of sudden death and one of MI), suggesting that restenosis after PTCA may present more frequently as an acute MI or sudden death in these patients than in the nondialysis population.‘s~‘9 This study suggests that for centers with low perioperative mortality for bypass grafting in dialysis patients, surgery is the preferable revascularization strategy, particularly for those patients with multivessel or left main disease. For less severe vascular disease, the role of PTCA is unclear, particularly since comparison with medical management was not made. If PTCA is to be performed on chronic dialysis patients, aggressive follow-up must certainly be part of the management plan. However, in our experience, it is difficult to accurately identify recurrent, symptomatic myocardial ischemia as a marker for restenosis or disease progression after PTCA in this patient population. These patients, with a high prevalence of left ventricular hypertrophy and attendant abnormalities of left ventricular diastolic function, can experience similar symptoms from either myocardial ischemia or volume overload, ie, angina and/or dyspnea. For this reason, if angiography is not performed routinely in follow-up, we feel it would be prudent to perform provocative stress testing at time intervals after PTCA when restenosis is likely to occur. However, since the first manifestation of recurrent myocardial ischemia may be MI or death in some patients, even this approach may not be adequate. Moreover, the risk of recurrent myocardial ischemia does not appear to decrease after 6 months, unlike in the nondialysis population,LX,‘9 suggesting that these patients will need close ongo-

RINEHART

ing coronary follow-up. With the high incidence of peripheral vascular disease in this population, pharmacologic stress echocardiography or methods using radionuclear imaging techniques appear to be reasonable alternatives to exercise stress testing. Ultimately, the optimal approach to revascularization must rest on the individual institution’s experience with bypass surgery in chronic dialysis patients and include the knowledge that angioplasty may not be a definitive procedure and that MI or death may be the first manifestation of treatment failure. ACKNOWLEDGMENT The authors are indebted to Rosanne Avelar for her assistance in the preparation of this manuscript, and to Hovald K. Helseth, MD, Division of Cardiothoracic Surgery at Hennepin County Medical Center, for his assistance in the review of this manuscript.

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ET AL

WL, Giorgi LV, Hartzler GO: Short- and long-term outcome of percutaneous transluminal coronary angioplasty in chronic dialysis patients. Am Heart J 119:484-489, 1990 8. Reusser LM, Osbom LA, White HJ, Sexson R, Crawford MH: Increased morbidity after coronary angioplasty in patients on chronic hemodialysis. Am J Cardiol 73:965-967, 1994 9. Ahmed WH, Shubrooks SJ, Gibson CM, Bairn DS, Bitt1 JA: Complications and long-term outcome after percutaneous coronary angioplasty in chronic hemodialysis patients. Am Heart 3 128:252-255, 1994 10. National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:1039-1057, 1979 11. Troy BL, Pombo J, Rackley CE: Measurement of left ventricular wall thickness and mass by echocardiography. Circulation 45:602-611, 1972 12. The Stroke Prevention in Atria1 Fibrillation Investigators: Predictors of thromboembolism in atria1 fibrillation: II. Echocardiographic features of patients at risk. Ann Intern Med 116:6-12, 1992 13. Campeau L: Grading of angina pectoris. Circulation 54:522-523, 1976 (letter) 14. Wolfe RA, Port FK, Hawthorne VM, Guire KE: A comparison of survival among dialytic therapies of choice: In-center hemodialysis versus continuous ambulatory peritoneal dialysis at home. Am J Kidney Dis 15:433-440, 1990 15. Held PJ, Pauly MV, Diamond L: Survival analysis of patients undergoing dialysis. JAMA 257645-650, 1986 16. Eggers PW: Mortality rates among dialysis patients in Medicare’s end-stage renal disease program. Am J Kidney Dis 15:414-421, 1990 17. Collins AJ, Hanson G, Umen A, Kjellstrand C, Keshaviah P: Changing risk factor demographics in end-stage renal disease patients entering hemodialysis and the impact on long-term mortality. Am J Kidney Dis 15:422-432, 1990 18. Ernst SM, van der Feltz TA, Bal ET, van Bogerijen L, van den Berg E, Ascoop CA, Plokker HW: Long-term angiographic follow-up, cardiac events, and survival in patients undergoing percutaneous transluminal coronary angioplasty. Br Heart J 57:220-225, 1987 19. Weintraub WS, Ghazzal ZM, Cohen CL, Douglas JS Jr, Liberman H, Morris DC, King SB: Clinical implications of late proven patency after successful coronary angioplasty. Circulation 84:572-582, 1991