- Email: [email protected]
Long-term survival of renal transplant recipients in the United States after acute myocardial infarction
Long-Term Survival of Renal Transplant Recipients in the United States After Acute Myocardial Infarction Charles A. Herzog, MD, Jennie Z. Ma, PhD, and Allan J. Collins, MD ● Cardiac disease is a major cause of death in renal transplant recipients. One third of the cardiac deaths are attributed to acute myocardial infarction (AMI). Few data exist on predictors of long-term survival of renal transplant recipients after AMI. The purpose of this study is to determine predictors of survival (including treatment era) for renal transplant recipients in the United States after AMI. The US Renal Data System database of 783,171 patients was used to retrospectively examine outcomes of renal transplant recipients hospitalized during 1977 to 1996 for a first AMI after initiation of renal replacement therapy. Long-term survival was estimated by life-table method, and independent predictors of survival were examined in a comorbidity-adjusted Cox model. There were 4,250 renal transplant recipients with AMI. The in-hospital death rate was 12.8%. Overall 2-year cardiac and all-cause mortality rates were 11.8% 6 0.6% (SE) and 33.6% 6 0.8%, respectively. The poorest survival after AMI occurred in patients with diabetic end-stage renal disease (ESRD), with 2-year cardiac and all-cause mortality rates of 14.9% 6 1.1% and 40.5% 6 1.4%, respectively. In the Cox model, the risks for cardiac and all-cause death from AMI were 51% (P 5 0.0003) and 45% less (P F 0.0001) in 1990 to 1996 compared with 1977 to 1984, respectively. The long-term survival of renal transplant recipients in the United States after AMI has markedly improved in the modern treatment era. Patients with diabetic ESRD experience the worst outcome. r 2000 by the National Kidney Foundation, Inc. INDEX WORDS: End-stage renal disease (ESRD); kidney; kidney transplantation; mortality; myocardial infarction.
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ARDIOVASCULAR disease is a major cause of death in patients with end-stage renal disease (ESRD). In chronic hemodialysis patients, approximately 44% of overall mortality is caused by cardiac disease, with approximately 22% of these deaths attributed to acute myocardial infarction (AMI).1 In 1996, there were approximately 79,000 patients in the United States with functioning renal transplants.2 In adult renal transplant recipients, cardiac disease accounted for 33% to 37% of all-cause death, and one third of these cardiac deaths were attributed to AMI.3 The risk for death from AMI in all patients with ESRD is greater in those who are older and have diabetes. Despite the burden of ischemic heart disease in patients with ESRD, few data are available on the survival of renal transplant recipients after AMI, and no published data exist on predictors of survival. Gunnarsson et al4 reported a 1-year mortality rate of 100% for 11 patients sustaining AMI identified from a consecutive series of 212 renal transplant recipients. A more favorable 30-month mean survival was reported by Janda et al5 for 12 patients with AMI in a series of 355 renal transplant recipients. In a recent publication, we reported the longterm survival after AMI of 34,189 chronic dialysis patients and 3,079 renal transplant recipients
in the United States.6 The overall 2-year mortality rate was 73% in the dialysis group compared with 30% in renal transplant recipients. Predictors of survival after AMI were examined in dialysis patients but not transplant recipients. The purpose of the present study is to determine predictors of survival of renal transplant recipients in the United States after AMI. METHODS All data were derived from the US Renal Data System (USRDS). The accuracy of these data has been previously validated.7
From the Department of Internal Medicine, Divisions of Cardiology and Nephrology, Hennepin County Medical Center, University of Minnesota, Minneapolis, MN; and the Department of Preventive Medicine, University of Tennessee– Memphis, TN. Received August 2, 1999; accepted in revised form February 4, 2000. Supported in part by grant no. 1 RO1 DK 49540 from the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. The data reported here have been supplied by the US Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an offıcial policy or interpretation of the US Government. Address reprint requests to Charles A. Herzog, MD, Hennepin County Medical Center, 701 Park Ave, Minneapolis, MN 55415. E-mail: [email protected]
r 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3601-0019$3.00/0 doi:10.1053/ajkd.2000.8287
American Journal of Kidney Diseases, Vol 36, No 1 (July), 2000: pp 145-152
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The study was a retrospective analysis of renal transplant recipients hospitalized for a first (index) AMI from January 1977 to June 1996 after the initiation of renal replacement therapy. (A renal transplant recipient with an AMI and a history of AMI sustained while previously undergoing chronic dialysis would therefore be excluded because the transplant recipient’s myocardial infarction would not be the index event.) Patients were identified (by claims data) from the USRDS database of 783,171 patients by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 410, 410.X, 410.X0, or 410.X1. Eligible patients underwent renal replacement therapy for at least 90 days and had a renal transplant for at least 60 days before AMI. Patient demographic data included age, sex, ethnicity (Hispanic patients not identified in database), prior ESRD duration, year of AMI occurrence, and primary renal diagnosis. The impact of comorbid conditions was examined using a previously developed comorbidity profiling method based on the ICD-9-CM diagnosis and procedure codes in the Medicare Part A institutional inpatient claims.8 Comorbid conditions were identified by ICD-9-CM codes from previous hospitalizations occurring before the index AMI. Comorbid conditions were atherosclerotic heart disease including AMI, congestive heart failure, other cardiac conditions (including valvular heart disease, arrhythmia, and arrhythmia requiring pacemaker), nonskin malignancies, peripheral vascular disease, cerebrovascular ischemia (cerebrovascular accident and transient ischemic attack), chronic obstructive pulmonary disease, gastrointestinal disease, gallbladder disease, and liver disease. Previous coronary revascularization (coronary bypass surgery or coronary angioplasty) was analyzed separately in the Cox proportional hazards model. In-hospital mortality (the percentage of patients dying during hospitalization for the index event) was estimated. If a renal transplant recipient had more than one AMI, the first was analyzed as the index event. Study end points were all-cause death and cardiac death. In the USRDS database, the main primary data source for information regarding cause of death is the revised Health Care Financing Administration (HCFA) ESRD Death Notification Form (HCFA2746).9 Censoring occurred if a patient initiated dialysis for renal graft failure and was still alive at the end of the study or lost to follow-up. (Censoring occurs when a prespecified end point is not reached during the period of follow-up in a survival analysis. For example, in a survival analysis for a cardiac death end point, censoring would occur at the time a patient died of cancer.) Survival time was calculated from the date of hospital admission for AMI to censor or end point. Chi-square test was used to compare differences in cumulative AMI occurrence per year after transplantation by renal failure cause. Long-term survival was estimated by the life-table method.10 The log-rank test was used to compare cumulative survival in different groups. A Cox proportional hazards model was used to evaluate the impact of independent predictors (demographics, comorbidity, and ESRD duration before AMI) on patient survival.11 The reported P in the Cox model are based on the Wald test statistics. All reported P are two-sided. All statistical analyses were per-
HERZOG, MA, AND COLLINS
formed using the SAS system for Windows, version 6.12 (SAS Institute, Cary, NC). This study was reviewed and approved by the Human Subject Research Committee of the Hennepin County Medical Center Institutional Review Board (Minneapolis, MN).
RESULTS
There were 4,250 renal transplant recipients who had AMI. The median and mean follow-up after myocardial infarction were 1.51 and 2.44 years (interquartile range [25th to 75th percentile], 0.26 to 3.77), respectively. Among the 4,250 patients, 1,788 patients died, 2,431 patients lost functioning transplants and began dialysis, and 31 patients were lost to follow-up. Demographic Characteristics Table 1 lists the demographic characteristics of the study patients and the prevalence of prior comorbid conditions. By sex, the group was 70.8% men and 29.2% women. The age distribution was 44 years or younger, 32.5%; 45 to 64 years, 54.7%; 65 to 74 years, 11.9%; and 75 years or older, 0.9%. The group was 82.9% white, 13.9% black, 0.9% Native American, 1.8% Asian, and 0.5% other races or ethnic groups. The cause of renal failure was diabetes in 34.0%, hypertension in 15.0%, and other conditions in 51.0%. The time of AMI occurrence was 1977 to 1984 in 4.5%, 1985 to 1989 in 22.5%, and 1990 to 1996 in 73.0% of patients. Figure 1 shows the temporal pattern of AMI occurrence versus transplant duration by ESRD cause. Within 2 years after transplantation, 33.0% of infarcts occurred in patients with ESRD caused by hypertension, 29.7% in those with diabetic ESRD, and 24.3% in patients with other causes of ESRD. These differences were statistically significant compared by years after transplantation (P , 0.001). Mortality The estimated in-hospital mortality for the entire cohort of renal transplant recipients with AMI was 12.8%. Of patients aged younger than 65 years, 12.0% (445 of 3,708 patients) died in the hospital, and 17.9% (97 of 542 patients) of patients aged 65 years or older died in the hospital. The in-hospital mortality for all patients with diabetic ESRD was 14.5% (210 of 1,444 patients). For patients with diabetic ESRD aged
TRANSPLANT PATIENTS AND MYOCARDIAL INFARCTION Table 1. Demographic Characteristics and Comorbid Conditions of the 4,250 Patients
Risk Factor
Age (y) #44 45-64 65-74 $75 Sex Women Men Ethnicity White Native American Black Asian Other ESRD cause Diabetes Hypertension Other Comorbidity ASHD CHF Cardiac (other) CA COPD CVA/TIA PVD GI Gallbladder Liver Prior ESRD duration (y) 0-,1 1-,2 2-5 .5 Prior coronary revascularization Time of AMI 1977-1984 1985-1989 1990-1996
No. of Patients
%
1,381 2,327 506 36
32.5 54.8 11.9 0.8
1,240 3,010
29.2 70.8
3,522 39 592 75 22
82.9 0.9 13.9 1.8 0.5
1,444 639 2,167
34.0 15.0 51.0
1,127 814 992 194 325 363 1,684 537 269 125
26.5 19.2 23.3 4.6 7.7 8.5 39.6 12.6 6.3 2.9
558 609 1,679 1,404 265
13.1 14.3 39.5 33.0 6.2
191 957 3,102
4.5 22.5 73.0
Abbreviations: ASHD, atherosclerotic heart disease; CA, nonskin malignancy; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVA/TIA, cerebrovascular accident/transient ischemic attack; GI, gastrointestinal; PVD, peripheral vascular disease.
younger than 65 years, the in-hospital mortality was 13.7% (187 of 1,364 patients), and for patients aged 65 years or older with diabetic ESRD, it was 28.8% (23 of 80 patients). Figure 2 shows the estimated long-term mortality rates according to ESRD cause. For the entire group, the 1-, 2-, 3-, 5-, and 10-year all-cause mortality rates were 27.1% 6 0.7%
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(SE), 33.6% 6 0.8%, 39.3% 6 0.8%, 50.5% 6 1.0%, and 69.1% 6 1.5%, respectively. By renal failure cause, the 1-, 2-, 3-, 5-, and 10-year all-cause mortality rates after AMI in diabetic ESRD were 31.7% 61.3%, 40.5% 6 1.4%, 47.7% 6 1.6%, 59.0% 6 1.8%, and 73.9% 6 2.9%, respectively. In patients with ESRD caused by hypertension, the mortality rates at similar time points were 24.6% 6 1.8%, 30.6% 6 2.0%, 36.8% 6 2.2%, 51.1% 62.9%, and 72.2% 6 4.4%, respectively. In patients with ESRD from other causes, the mortality rates at 1, 2, 3, 5, and 10 years were 23.3% 6 0.9%, 28.8% 6 1.0%, 33.7% 6 1.1%, 44.7% 6 1.3%, and 65.1% 6 1.9%, respectively. The all-cause mortality curves were significantly different for the three causes of ESRD (P , 0.0001). Figure 3 shows the estimated cardiac mortality by ESRD cause. For the entire group, the 1-, 2-, 3-, 5-, and 10-year cardiac mortality rates were 9.9% 6 0.5%, 11.8% 6 0.6%, 14.2% 6 0.7%, 18.2% 6 0.8%, and 26.3% 6 1.7%, respectively. In patients with diabetic ESRD, the 1-, 2-, 3-, 5-, and 10-year cardiac mortality rates after AMI were 12.3% 6 0.9%, 15.0% 6 1.1%, 18.4% 6 1.3%, 22.9% 6 1.7%, and 30.9% 6 5.4%, respectively. The 1-, 2-, 3-, 5-, and 10-year cardiac mortality rates in patients with ESRD caused by hypertension were 7.9% 6 1.2%, 9.6% 6 1.4%, 12.8% 6 1.7%, 17.0% 6 2.4%, and 26.5% 6 4.1%, respectively. In patients with ESRD from other causes, the cardiac mortality rates at 1, 2, 3, 5, and 10 years were 7.9% 6 0.6%, 9.6% 6 0.7%, 11.3% 6 0.8%, 15.0% 6 1.0%, and 21.6% 6 1.9%, respectively. The cardiac mortality curves were significantly different for these three ESRD groups (P , 0.0001). Figure 4 shows the estimated all-cause mortality related to the time of AMI occurrence. There was no significant difference in all-cause mortality for patients with AMI in 1977 to 1984, 1985 to 1989, and 1990 to 1996. Figure 5 shows the significantly different cardiac mortality related to time of AMI occurrence, with the lowest cardiac mortality in the most recent treatment period. The effects of independent predictors of allcause and cardiac mortality were examined by the Cox proportional hazards model. Table 2 lists independent predictors of all-cause death. The most powerful predictors of death were older age and diabetic ESRD. Sex and ethnicity were not
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Fig 1. Cumulative occurrence of AMI by cause of ESRD related to time after renal transplantation. The reported P reflect year-to-year differences for the three curves.
independent predictors of all-cause death, although there was a trend toward increased risk for Native Americans. Comorbid conditions had a variable impact on survival, with liver disease the most powerful predictor (risk ratio [RR], 1.64; 95% confidence interval [CI], 1.28 to 2.10) of all-cause death. Patients with a prior history of coronary revascularization had a 23% reduction in all-cause death risk. Compared with the reference treatment period of 1977 to 1984, the risk
for all-cause death was 22% less for patients with AMI in 1985 to 1989 and 45% less for patients sustaining AMI in 1990 to 1996. Table 3 lists independent predictors of cardiac death. Older age and diabetic ESRD were the most powerful independent predictors of cardiac death. Sex was not a predictor of cardiac death. In Native Americans but not other ethnic groups, there was an increased risk for cardiac death (RR, 2.10; 95% CI, 1.08 to 4.08) compared with
Fig 2. Estimated all-cause mortality of renal transplant recipients after AMI by ESRD cause. Bars indicate survival 6 SE.
Fig 3. Estimated cardiac mortality of renal transplant recipients after AMI by ESRD cause. Bars indicate survival 6 SE.
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149 Table 2. Cox Proportional Hazards Model for All Causes of Death
Risk Factor
Fig 4. Estimated all-cause mortality of renal transplant recipients after AMI by time of AMI occurrence. Bars indicate survival 6 SE.
Age (y) 45-64 65-74 $75 Sex Women Ethnicity Native American Black Other ESRD cause Diabetes Hypertension Comorbidity ASHD CHF Cardiac (other) CA COPD CVA/TIA PVD GI Gallbladder Liver Prior ESRD duration (y) 1-,2 2-5 .5 Prior coronary revascularization Time of AMI 1985-1989 1990-1996
Relative Risk (95% CI)
P
1.34 (1.20-1.50) ,0.0001 2.01 (1.70-2.37) ,0.0001 2.77 (1.77-4.33) ,0.0001 1.09 (0.98-1.20)
0.12
1.47 (0.96-2.24) 0.94 (0.81-1.09) 1.05 (0.78-1.42)
0.08 0.42 0.74
1.73 (1.55-1.93) ,0.0001 1.10 (0.95-1.27) 0.21 1.10 (0.98-1.24) 1.38 (1.22-1.56) 1.29 (1.15-1.45) 1.30 (1.04-1.61) 1.12 (0.94-1.34) 1.32 (1.12-1.55) 1.22 (1.10-1.36) 1.23 (1.07-1.42) 0.95 (0.78-1.16) 1.64 (1.29-2.10)
0.11 ,0.0001 ,0.0001 0.02 0.20 0.0008 ,0.0001 0.004 0.60 ,0.0001
1.00 (0.68-1.48) 0.92 (0.64-1.31) 1.20 (0.84-1.71) 0.77 (0.62-0.96)
0.98 0.64 0.31 0.02
0.78 (0.64-0.96) 0.02 0.55 (0.45-0.68) ,0.0001
NOTE. The reference group characteristics were: age 44 years or younger; men; white; other ESRD cause; no comorbidity or prior coronary revascularization; prior ESRD duration less than 1 year; AMI, 1977 to 1984. Abbreviations: ASHD, atherosclerotic heart disease; CA, nonskin malignancy; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVA/TIA, cerebrovascular accident/transient ischemic attack; GI, gastrointestinal; PVD, peripheral vascular disease.
Fig 5. Estimated cardiac mortality of renal transplant recipients after AMI by time of AMI occurrence. Bars indicate survival 6 SE.
white renal transplant recipients. The impact of comorbid conditions on cardiac survival was relatively modest; only peripheral vascular disease was statistically significant. Prior coronary revascularization was associated with a 25% reduction in cardiac death risk, but this was not statistically significant. Compared with the reference treatment period of 1977 to 1984, the risk for cardiac death in 1985 to 1989 was 4% less (P 5 not significant), but there was a significant 51% reduction in cardiac death risk for patients
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HERZOG, MA, AND COLLINS Table 3. Cox Proportional Hazards Model for Cardiac Death Relative Risk (95% CI)
Risk Factor
Age (y) 45-64 65-74 $75 Sex Women Ethnicity Native American Black Other ESRD cause Diabetes Hypertension Comorbidity ASHD CHF Cardiac (other) CA COPD CVA/TIA PVD GI Gallbladder Liver Prior ESRD duration (y) 1-,2 2-5 .5 Prior coronary revascularization Time of AMI 1985-1989 1990-1996
P
1.19 (0.98-1.46) 1.77 (1.30-2.40) 3.03 (1.40-6.59)
0.08 0.0002 0.005
1.01 (0.83-1.22)
0.93
2.10 (1.08-4.08) 0.83 (0.62-1.11) 1.40 (0.86-2.27)
0.03 0.20 0.18
1.92 (1.57-2.35) ,0.0001 1.14 (0.86-1.51) 0.36 1.15 (0.93-1.44) 1.26 (0.99-1.59) 1.23 (0.99-1.53) 0.99 (0.62-1.59) 1.15 (0.83-1.61) 1.23 (0.90-1.67) 1.24 (1.03-1.50) 1.24 (0.95-1.60) 0.87 (0.59-1.29) 1.50 (0.93-2.41)
0.20 0.06 0.06 0.98 0.40 0.19 0.02 0.11 0.49 0.10
0.88 (0.47-1.63) 0.73 (0.41-1.28) 0.84 (0.48-1.49) 0.75 (0.50-1.14)
0.68 0.27 0.55 0.17
0.96 (0.66-1.40) 0.49 (0.33-0.72)
0.82 0.0003
NOTE. Reference group characteristics were: age 44 years or younger; men; white; other ESRD cause; no comorbidity or prior coronary revascularization; prior ESRD duration less than 1 year; AMI, 1977 to 1984. Abbreviations: ASHD, atherosclerotic heart disease; CA, nonskin malignancy; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVA/TIA, cerebrovascular accident/transient ischemic attack; GI, gastrointestinal; PVD, peripheral vascular disease.
sustaining AMI in 1990 to 1996 (P 5 0.0003). Thus, after adjustment is made for comorbidity, there was marked improvement in cardiac survival after AMI in the most recent treatment period of 1990 to 1996, with similar trends for all-cause survival. DISCUSSION
There are few data on long-term survival after AMI among renal transplant recipients. In a
previously published article, we reported the more benign outcome for renal transplant recipients compared with dialysis patients after AMI.6 The present study confirms our earlier report of the more favorable survival after AMI for renal transplant recipients compared with dialysis patients. As noted for dialysis patients, the poorest long-term all-cause and cardiac survival occurred in renal transplant recipients with diabetic ESRD. There appear to be important differences in predictors of survival and overall trends in survival after AMI in the United States for renal transplant recipients compared with dialysis patients. We previously reported that the unadjusted all-cause and cardiac mortality in dialysis patients was greatest in the most recent treatment interval (1990 to 1995) in contradistinction to reported survival data in patients without ESRD.6 In the present study, we found no difference in unadjusted all-cause survival among the three treatment periods. In contrast to our previous study of dialysis patients, the cardiac survival for patients sustaining AMI in 1990 to 1996 was more favorable than the earlier time periods. There is also a marked difference in the proportion of attributable cardiac mortality to all-cause mortality between these two groups of patients. At two years after AMI, approximately 71% of deaths for all dialysis patients were ascribed to cardiac causes.6 In contrast, for renal transplant recipients 2 years after AMI, approximately 35% of deaths were from cardiac causes in the present study. The impact of ethnicity on survival after AMI appears considerably different in renal transplant recipients compared with dialysis patients. We previously reported an 18% reduction in allcause death risk in black dialysis patients after AMI compared with white patients, a finding consistent with published data.12 Our finding of no survival advantage for black renal transplant recipients after AMI compared with white patients is consistent with published survival data for renal transplant recipients.3,13 We found that Native American dialysis patients had a 13% reduction in all-cause death risk and 16% reduction in cardiac death risk after AMI compared with white patients.6 In contrast, Native American renal transplant recipients had a twofold
TRANSPLANT PATIENTS AND MYOCARDIAL INFARCTION
increased risk for cardiac death in the present study. In a Cox proportional hazards model, we found a striking reduction in the risk for all-cause and cardiac death for renal transplant recipients sustaining AMI in the most recent treatment period. There was a 45% reduction (RR, 0.55; 95% CI, 0.45 to 0.68) in the risk for all-cause death and a 51% reduction (RR, 0.49; 95% CI, 0.33 to 0.72) in cardiac death risk for patients sustaining AMI in 1990 to 1996 versus 1977 to 1984. This contrasts with our previously reported 13% reduction in all-cause death risk and 17% reduction in cardiac death risk for dialysis patients sustaining AMI in 1990 to 1995 versus 1977 to 1984.6 There appear to be marked differences in the temporal patterns of survival of dialysis patients and renal transplant recipients in the United States after AMI. Unlike dialysis patients but similar to patients without ESRD,14 renal transplant recipients appear to have reaped the expected benefit of the modern treatment era of AMI. There are several limitations to our study. The primary source of USRDS data was Medicare claims data, which may be subject to inaccuracies in AMI diagnosis. Jollis et al15 compared claims data with medical chart (clinical) data in a study of 12,937 patients undergoing inpatient cardiac catheterization and found an 88% rate of agreement between claims and clinical data for AMI diagnosis (with a 95% specificity and 76% sensitivity for AMI diagnosis by claims data compared with clinical data). The USRDS database provides few clinical data. Potentially important clinical predictors of survival after AMI, such as left ventricular ejection fraction, hemodynamic data, or coronary artery disease severity, were not available for our study. Our study is also limited by the absence of important clinical data regarding risk factors for the development of cardiac disease both before and after renal transplantation. As detailed in the Special Report from the National Kidney Foundation Task Force on Cardiovascular Disease, there are multiple risk factors for the development of cardiovascular disease in patients with chronic renal failure, including hypertension, dyslipidemia, hyperglycemia, smoking, physical inactivity, enhanced thrombogenicity, and elevated homocysteine levels.16 Aortic stiffness (assessed
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by aortic pulse wave velocity) is an independent predictor of all-cause and cardiovascular mortality.17 Quantitative data regarding these risk factors are not available in our study. In the renal transplant population, it is plausible that the type and intensity of immunosuppression could impact on the progression of cardiovascular disease, particularly relating to dyslipidemia exacerbated by steroid therapy. Information regarding drug therapy, including immunosuppression and treatment with lipid-reducing agents, antiplatelet drugs, and beta-blockers, unfortunately is not available in our study. The reason for the differing temporal trends in survival for dialysis patients and renal transplant recipients is unknown. In preliminary data, we have reported an apparent striking underutilization of thrombolytic therapy in dialysis patients with AMI.18 Based on preliminary data, this underutilization of thrombolytic therapy may also be true for renal transplant recipients sustaining AMI.19 The relative use of direct coronary angioplasty for coronary reperfusion in dialysis and renal transplant patients remains unknown. There may also be clinically important differences in these two ESRD populations with respect to both overall debility and coronary artery disease severity. Intuitively, the sickest patients requiring renal replacement therapy may be selectively excluded as potential renal transplant candidates. The recent publication of Wolfe et al20 supports the contention that healthier patients are placed on the waiting list for transplantation. The study of Wolfe et al20 also found that the long-term survival of patients undergoing renal transplantation was better than that of similar patients on the transplant waiting list. It is plausible that there may be similar differential patterns of survival in patients with ESRD with myocardial infarction, but our present study does not address this issue. Studies comparing the post-AMI survival of dialysis patients on the transplant waiting list and renal transplant recipients would be an appropriate focus for future research. The approach to coronary artery disease screening in these two ESRD populations is also likely to be different because the American Society of Transplant Physicians has recommended pretransplantation screening for all patients except those at lowest cardiac risk.21 No such approach has been recommended for dialysis patients who are
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not being considered for renal transplantation, although logically, the same strategy could potentially be used after the initiation of dialysis because the cardiovascular mortality is considerably greater in these patients. We conclude that the long-term cardiac outcome of renal transplant recipients in the United States sustaining AMI has significantly improved in the modern treatment era. The marked improvement in survival mirrors the outcome of patients without ESRD with AMI and is in sharp contrast to the previously reported modest improvement in comorbidity-adjusted survival of dialysis patients after AMI. REFERENCES 1. US Renal Data System: USRDS 1997 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1997, pp 91-101 2. US Renal Data System: USRDS 1998 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1998, pp C1-C54 3. US Renal Data System: USRDS 1998 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1998, pp 79-90 4. Gunnarsson R, Lofmark R, Nondlander R, Nyquist O, Groth CG: Acute myocardial infarction in renal transplant recipients: Incidence and prognosis. Eur Heart J 5:218-221, 1984 5. Janda P, Stribrna J, Korandova V, Kocandrle V: Acute myocardial infarction after renal transplantation. Cor Vasa 29:463-467, 1987 6. Herzog CA, Ma JZ, Collins AJ: Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med 339:799-805, 1998 7. US Renal Data System: USRDS 1992 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1992, pp 61-82 8. Collins AJ, Ma JZ, Constantini E, Everson S: Dialysis unit and patient characteristics associated with reuse prac-
tices and mortality: 1989-1993. J Am Soc Nephrol 9:21082117, 1998 9. US Renal Data System: USRDS 1999 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1999, pp 89-100 10. Kaplan EL, Meier P: Nonparametic estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 11. Cox DR: Regression models and life tables. J R Stat Soc 34:187-202, 1972 12. US Renal Data System: USRDS 1997 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1997, pp 69-89 13. US Renal Data System: USRDS 1998 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1998, pp D27-D29 14. McGovern PG, Pankow JS, Shahar E, Doliszny KM, Folsom AR, Blackburn H, Luepker V: Recent trends in acute coronary heart disease. N Engl J Med 334:884-890, 1996 15. Jollis JG, Ancukiewicz M, DeLong ER, Pryor DB, Muhlbaier LH, Mark DB: Discordance of databases designed for claims payment versus clinical information systems. Ann Intern Med 119:844-850, 1993 16. Levey AS: Controlling the epidemic of cardiovascular disease in chronic renal disease: Where do we start? Am J Kidney Dis 32:S5-S13, 1998 (suppl 3) 17. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM: Impact of aortic stiffness on survival in end-stage renal disease. Circulation 99:2434-2439, 1999 18. Herzog CA, Ma JZ, Collins AJ: Long-term survival of dialysis patients receiving thrombolytic therapy for acute myocardial infarction in the United States. Circulation 100:I304, 1999 19. Herzog CA, Ma JZ, Collins AJ: Outcome of renal transplant patients receiving thrombolytic therapy for acute myocardial infarction in the United States. Circulation 100:I304, 1999 20. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LYC, Held PJ, Port FK: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341:1725-1730, 1999 21. Kasiske BL, Ramos EL, Gaston RS, Bia MJ, Danovitch GM, Bowen PA, Murphy KJ: The evaluation of renal transplant candidates: Clinical practice guidelines. J Am Soc Nephrol 6:1-34, 1995
Editorial, p. 211
C
ARDIOVASCULAR disease is a major cause of death in patients with end-stage renal disease (ESRD). In chronic hemodialysis patients, approximately 44% of overall mortality is caused by cardiac disease, with approximately 22% of these deaths attributed to acute myocardial infarction (AMI).1 In 1996, there were approximately 79,000 patients in the United States with functioning renal transplants.2 In adult renal transplant recipients, cardiac disease accounted for 33% to 37% of all-cause death, and one third of these cardiac deaths were attributed to AMI.3 The risk for death from AMI in all patients with ESRD is greater in those who are older and have diabetes. Despite the burden of ischemic heart disease in patients with ESRD, few data are available on the survival of renal transplant recipients after AMI, and no published data exist on predictors of survival. Gunnarsson et al4 reported a 1-year mortality rate of 100% for 11 patients sustaining AMI identified from a consecutive series of 212 renal transplant recipients. A more favorable 30-month mean survival was reported by Janda et al5 for 12 patients with AMI in a series of 355 renal transplant recipients. In a recent publication, we reported the longterm survival after AMI of 34,189 chronic dialysis patients and 3,079 renal transplant recipients
in the United States.6 The overall 2-year mortality rate was 73% in the dialysis group compared with 30% in renal transplant recipients. Predictors of survival after AMI were examined in dialysis patients but not transplant recipients. The purpose of the present study is to determine predictors of survival of renal transplant recipients in the United States after AMI. METHODS All data were derived from the US Renal Data System (USRDS). The accuracy of these data has been previously validated.7
From the Department of Internal Medicine, Divisions of Cardiology and Nephrology, Hennepin County Medical Center, University of Minnesota, Minneapolis, MN; and the Department of Preventive Medicine, University of Tennessee– Memphis, TN. Received August 2, 1999; accepted in revised form February 4, 2000. Supported in part by grant no. 1 RO1 DK 49540 from the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. The data reported here have been supplied by the US Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an offıcial policy or interpretation of the US Government. Address reprint requests to Charles A. Herzog, MD, Hennepin County Medical Center, 701 Park Ave, Minneapolis, MN 55415. E-mail: [email protected]
r 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3601-0019$3.00/0 doi:10.1053/ajkd.2000.8287
American Journal of Kidney Diseases, Vol 36, No 1 (July), 2000: pp 145-152
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The study was a retrospective analysis of renal transplant recipients hospitalized for a first (index) AMI from January 1977 to June 1996 after the initiation of renal replacement therapy. (A renal transplant recipient with an AMI and a history of AMI sustained while previously undergoing chronic dialysis would therefore be excluded because the transplant recipient’s myocardial infarction would not be the index event.) Patients were identified (by claims data) from the USRDS database of 783,171 patients by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 410, 410.X, 410.X0, or 410.X1. Eligible patients underwent renal replacement therapy for at least 90 days and had a renal transplant for at least 60 days before AMI. Patient demographic data included age, sex, ethnicity (Hispanic patients not identified in database), prior ESRD duration, year of AMI occurrence, and primary renal diagnosis. The impact of comorbid conditions was examined using a previously developed comorbidity profiling method based on the ICD-9-CM diagnosis and procedure codes in the Medicare Part A institutional inpatient claims.8 Comorbid conditions were identified by ICD-9-CM codes from previous hospitalizations occurring before the index AMI. Comorbid conditions were atherosclerotic heart disease including AMI, congestive heart failure, other cardiac conditions (including valvular heart disease, arrhythmia, and arrhythmia requiring pacemaker), nonskin malignancies, peripheral vascular disease, cerebrovascular ischemia (cerebrovascular accident and transient ischemic attack), chronic obstructive pulmonary disease, gastrointestinal disease, gallbladder disease, and liver disease. Previous coronary revascularization (coronary bypass surgery or coronary angioplasty) was analyzed separately in the Cox proportional hazards model. In-hospital mortality (the percentage of patients dying during hospitalization for the index event) was estimated. If a renal transplant recipient had more than one AMI, the first was analyzed as the index event. Study end points were all-cause death and cardiac death. In the USRDS database, the main primary data source for information regarding cause of death is the revised Health Care Financing Administration (HCFA) ESRD Death Notification Form (HCFA2746).9 Censoring occurred if a patient initiated dialysis for renal graft failure and was still alive at the end of the study or lost to follow-up. (Censoring occurs when a prespecified end point is not reached during the period of follow-up in a survival analysis. For example, in a survival analysis for a cardiac death end point, censoring would occur at the time a patient died of cancer.) Survival time was calculated from the date of hospital admission for AMI to censor or end point. Chi-square test was used to compare differences in cumulative AMI occurrence per year after transplantation by renal failure cause. Long-term survival was estimated by the life-table method.10 The log-rank test was used to compare cumulative survival in different groups. A Cox proportional hazards model was used to evaluate the impact of independent predictors (demographics, comorbidity, and ESRD duration before AMI) on patient survival.11 The reported P in the Cox model are based on the Wald test statistics. All reported P are two-sided. All statistical analyses were per-
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formed using the SAS system for Windows, version 6.12 (SAS Institute, Cary, NC). This study was reviewed and approved by the Human Subject Research Committee of the Hennepin County Medical Center Institutional Review Board (Minneapolis, MN).
RESULTS
There were 4,250 renal transplant recipients who had AMI. The median and mean follow-up after myocardial infarction were 1.51 and 2.44 years (interquartile range [25th to 75th percentile], 0.26 to 3.77), respectively. Among the 4,250 patients, 1,788 patients died, 2,431 patients lost functioning transplants and began dialysis, and 31 patients were lost to follow-up. Demographic Characteristics Table 1 lists the demographic characteristics of the study patients and the prevalence of prior comorbid conditions. By sex, the group was 70.8% men and 29.2% women. The age distribution was 44 years or younger, 32.5%; 45 to 64 years, 54.7%; 65 to 74 years, 11.9%; and 75 years or older, 0.9%. The group was 82.9% white, 13.9% black, 0.9% Native American, 1.8% Asian, and 0.5% other races or ethnic groups. The cause of renal failure was diabetes in 34.0%, hypertension in 15.0%, and other conditions in 51.0%. The time of AMI occurrence was 1977 to 1984 in 4.5%, 1985 to 1989 in 22.5%, and 1990 to 1996 in 73.0% of patients. Figure 1 shows the temporal pattern of AMI occurrence versus transplant duration by ESRD cause. Within 2 years after transplantation, 33.0% of infarcts occurred in patients with ESRD caused by hypertension, 29.7% in those with diabetic ESRD, and 24.3% in patients with other causes of ESRD. These differences were statistically significant compared by years after transplantation (P , 0.001). Mortality The estimated in-hospital mortality for the entire cohort of renal transplant recipients with AMI was 12.8%. Of patients aged younger than 65 years, 12.0% (445 of 3,708 patients) died in the hospital, and 17.9% (97 of 542 patients) of patients aged 65 years or older died in the hospital. The in-hospital mortality for all patients with diabetic ESRD was 14.5% (210 of 1,444 patients). For patients with diabetic ESRD aged
TRANSPLANT PATIENTS AND MYOCARDIAL INFARCTION Table 1. Demographic Characteristics and Comorbid Conditions of the 4,250 Patients
Risk Factor
Age (y) #44 45-64 65-74 $75 Sex Women Men Ethnicity White Native American Black Asian Other ESRD cause Diabetes Hypertension Other Comorbidity ASHD CHF Cardiac (other) CA COPD CVA/TIA PVD GI Gallbladder Liver Prior ESRD duration (y) 0-,1 1-,2 2-5 .5 Prior coronary revascularization Time of AMI 1977-1984 1985-1989 1990-1996
No. of Patients
%
1,381 2,327 506 36
32.5 54.8 11.9 0.8
1,240 3,010
29.2 70.8
3,522 39 592 75 22
82.9 0.9 13.9 1.8 0.5
1,444 639 2,167
34.0 15.0 51.0
1,127 814 992 194 325 363 1,684 537 269 125
26.5 19.2 23.3 4.6 7.7 8.5 39.6 12.6 6.3 2.9
558 609 1,679 1,404 265
13.1 14.3 39.5 33.0 6.2
191 957 3,102
4.5 22.5 73.0
Abbreviations: ASHD, atherosclerotic heart disease; CA, nonskin malignancy; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVA/TIA, cerebrovascular accident/transient ischemic attack; GI, gastrointestinal; PVD, peripheral vascular disease.
younger than 65 years, the in-hospital mortality was 13.7% (187 of 1,364 patients), and for patients aged 65 years or older with diabetic ESRD, it was 28.8% (23 of 80 patients). Figure 2 shows the estimated long-term mortality rates according to ESRD cause. For the entire group, the 1-, 2-, 3-, 5-, and 10-year all-cause mortality rates were 27.1% 6 0.7%
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(SE), 33.6% 6 0.8%, 39.3% 6 0.8%, 50.5% 6 1.0%, and 69.1% 6 1.5%, respectively. By renal failure cause, the 1-, 2-, 3-, 5-, and 10-year all-cause mortality rates after AMI in diabetic ESRD were 31.7% 61.3%, 40.5% 6 1.4%, 47.7% 6 1.6%, 59.0% 6 1.8%, and 73.9% 6 2.9%, respectively. In patients with ESRD caused by hypertension, the mortality rates at similar time points were 24.6% 6 1.8%, 30.6% 6 2.0%, 36.8% 6 2.2%, 51.1% 62.9%, and 72.2% 6 4.4%, respectively. In patients with ESRD from other causes, the mortality rates at 1, 2, 3, 5, and 10 years were 23.3% 6 0.9%, 28.8% 6 1.0%, 33.7% 6 1.1%, 44.7% 6 1.3%, and 65.1% 6 1.9%, respectively. The all-cause mortality curves were significantly different for the three causes of ESRD (P , 0.0001). Figure 3 shows the estimated cardiac mortality by ESRD cause. For the entire group, the 1-, 2-, 3-, 5-, and 10-year cardiac mortality rates were 9.9% 6 0.5%, 11.8% 6 0.6%, 14.2% 6 0.7%, 18.2% 6 0.8%, and 26.3% 6 1.7%, respectively. In patients with diabetic ESRD, the 1-, 2-, 3-, 5-, and 10-year cardiac mortality rates after AMI were 12.3% 6 0.9%, 15.0% 6 1.1%, 18.4% 6 1.3%, 22.9% 6 1.7%, and 30.9% 6 5.4%, respectively. The 1-, 2-, 3-, 5-, and 10-year cardiac mortality rates in patients with ESRD caused by hypertension were 7.9% 6 1.2%, 9.6% 6 1.4%, 12.8% 6 1.7%, 17.0% 6 2.4%, and 26.5% 6 4.1%, respectively. In patients with ESRD from other causes, the cardiac mortality rates at 1, 2, 3, 5, and 10 years were 7.9% 6 0.6%, 9.6% 6 0.7%, 11.3% 6 0.8%, 15.0% 6 1.0%, and 21.6% 6 1.9%, respectively. The cardiac mortality curves were significantly different for these three ESRD groups (P , 0.0001). Figure 4 shows the estimated all-cause mortality related to the time of AMI occurrence. There was no significant difference in all-cause mortality for patients with AMI in 1977 to 1984, 1985 to 1989, and 1990 to 1996. Figure 5 shows the significantly different cardiac mortality related to time of AMI occurrence, with the lowest cardiac mortality in the most recent treatment period. The effects of independent predictors of allcause and cardiac mortality were examined by the Cox proportional hazards model. Table 2 lists independent predictors of all-cause death. The most powerful predictors of death were older age and diabetic ESRD. Sex and ethnicity were not
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Fig 1. Cumulative occurrence of AMI by cause of ESRD related to time after renal transplantation. The reported P reflect year-to-year differences for the three curves.
independent predictors of all-cause death, although there was a trend toward increased risk for Native Americans. Comorbid conditions had a variable impact on survival, with liver disease the most powerful predictor (risk ratio [RR], 1.64; 95% confidence interval [CI], 1.28 to 2.10) of all-cause death. Patients with a prior history of coronary revascularization had a 23% reduction in all-cause death risk. Compared with the reference treatment period of 1977 to 1984, the risk
for all-cause death was 22% less for patients with AMI in 1985 to 1989 and 45% less for patients sustaining AMI in 1990 to 1996. Table 3 lists independent predictors of cardiac death. Older age and diabetic ESRD were the most powerful independent predictors of cardiac death. Sex was not a predictor of cardiac death. In Native Americans but not other ethnic groups, there was an increased risk for cardiac death (RR, 2.10; 95% CI, 1.08 to 4.08) compared with
Fig 2. Estimated all-cause mortality of renal transplant recipients after AMI by ESRD cause. Bars indicate survival 6 SE.
Fig 3. Estimated cardiac mortality of renal transplant recipients after AMI by ESRD cause. Bars indicate survival 6 SE.
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149 Table 2. Cox Proportional Hazards Model for All Causes of Death
Risk Factor
Fig 4. Estimated all-cause mortality of renal transplant recipients after AMI by time of AMI occurrence. Bars indicate survival 6 SE.
Age (y) 45-64 65-74 $75 Sex Women Ethnicity Native American Black Other ESRD cause Diabetes Hypertension Comorbidity ASHD CHF Cardiac (other) CA COPD CVA/TIA PVD GI Gallbladder Liver Prior ESRD duration (y) 1-,2 2-5 .5 Prior coronary revascularization Time of AMI 1985-1989 1990-1996
Relative Risk (95% CI)
P
1.34 (1.20-1.50) ,0.0001 2.01 (1.70-2.37) ,0.0001 2.77 (1.77-4.33) ,0.0001 1.09 (0.98-1.20)
0.12
1.47 (0.96-2.24) 0.94 (0.81-1.09) 1.05 (0.78-1.42)
0.08 0.42 0.74
1.73 (1.55-1.93) ,0.0001 1.10 (0.95-1.27) 0.21 1.10 (0.98-1.24) 1.38 (1.22-1.56) 1.29 (1.15-1.45) 1.30 (1.04-1.61) 1.12 (0.94-1.34) 1.32 (1.12-1.55) 1.22 (1.10-1.36) 1.23 (1.07-1.42) 0.95 (0.78-1.16) 1.64 (1.29-2.10)
0.11 ,0.0001 ,0.0001 0.02 0.20 0.0008 ,0.0001 0.004 0.60 ,0.0001
1.00 (0.68-1.48) 0.92 (0.64-1.31) 1.20 (0.84-1.71) 0.77 (0.62-0.96)
0.98 0.64 0.31 0.02
0.78 (0.64-0.96) 0.02 0.55 (0.45-0.68) ,0.0001
NOTE. The reference group characteristics were: age 44 years or younger; men; white; other ESRD cause; no comorbidity or prior coronary revascularization; prior ESRD duration less than 1 year; AMI, 1977 to 1984. Abbreviations: ASHD, atherosclerotic heart disease; CA, nonskin malignancy; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVA/TIA, cerebrovascular accident/transient ischemic attack; GI, gastrointestinal; PVD, peripheral vascular disease.
Fig 5. Estimated cardiac mortality of renal transplant recipients after AMI by time of AMI occurrence. Bars indicate survival 6 SE.
white renal transplant recipients. The impact of comorbid conditions on cardiac survival was relatively modest; only peripheral vascular disease was statistically significant. Prior coronary revascularization was associated with a 25% reduction in cardiac death risk, but this was not statistically significant. Compared with the reference treatment period of 1977 to 1984, the risk for cardiac death in 1985 to 1989 was 4% less (P 5 not significant), but there was a significant 51% reduction in cardiac death risk for patients
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HERZOG, MA, AND COLLINS Table 3. Cox Proportional Hazards Model for Cardiac Death Relative Risk (95% CI)
Risk Factor
Age (y) 45-64 65-74 $75 Sex Women Ethnicity Native American Black Other ESRD cause Diabetes Hypertension Comorbidity ASHD CHF Cardiac (other) CA COPD CVA/TIA PVD GI Gallbladder Liver Prior ESRD duration (y) 1-,2 2-5 .5 Prior coronary revascularization Time of AMI 1985-1989 1990-1996
P
1.19 (0.98-1.46) 1.77 (1.30-2.40) 3.03 (1.40-6.59)
0.08 0.0002 0.005
1.01 (0.83-1.22)
0.93
2.10 (1.08-4.08) 0.83 (0.62-1.11) 1.40 (0.86-2.27)
0.03 0.20 0.18
1.92 (1.57-2.35) ,0.0001 1.14 (0.86-1.51) 0.36 1.15 (0.93-1.44) 1.26 (0.99-1.59) 1.23 (0.99-1.53) 0.99 (0.62-1.59) 1.15 (0.83-1.61) 1.23 (0.90-1.67) 1.24 (1.03-1.50) 1.24 (0.95-1.60) 0.87 (0.59-1.29) 1.50 (0.93-2.41)
0.20 0.06 0.06 0.98 0.40 0.19 0.02 0.11 0.49 0.10
0.88 (0.47-1.63) 0.73 (0.41-1.28) 0.84 (0.48-1.49) 0.75 (0.50-1.14)
0.68 0.27 0.55 0.17
0.96 (0.66-1.40) 0.49 (0.33-0.72)
0.82 0.0003
NOTE. Reference group characteristics were: age 44 years or younger; men; white; other ESRD cause; no comorbidity or prior coronary revascularization; prior ESRD duration less than 1 year; AMI, 1977 to 1984. Abbreviations: ASHD, atherosclerotic heart disease; CA, nonskin malignancy; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVA/TIA, cerebrovascular accident/transient ischemic attack; GI, gastrointestinal; PVD, peripheral vascular disease.
sustaining AMI in 1990 to 1996 (P 5 0.0003). Thus, after adjustment is made for comorbidity, there was marked improvement in cardiac survival after AMI in the most recent treatment period of 1990 to 1996, with similar trends for all-cause survival. DISCUSSION
There are few data on long-term survival after AMI among renal transplant recipients. In a
previously published article, we reported the more benign outcome for renal transplant recipients compared with dialysis patients after AMI.6 The present study confirms our earlier report of the more favorable survival after AMI for renal transplant recipients compared with dialysis patients. As noted for dialysis patients, the poorest long-term all-cause and cardiac survival occurred in renal transplant recipients with diabetic ESRD. There appear to be important differences in predictors of survival and overall trends in survival after AMI in the United States for renal transplant recipients compared with dialysis patients. We previously reported that the unadjusted all-cause and cardiac mortality in dialysis patients was greatest in the most recent treatment interval (1990 to 1995) in contradistinction to reported survival data in patients without ESRD.6 In the present study, we found no difference in unadjusted all-cause survival among the three treatment periods. In contrast to our previous study of dialysis patients, the cardiac survival for patients sustaining AMI in 1990 to 1996 was more favorable than the earlier time periods. There is also a marked difference in the proportion of attributable cardiac mortality to all-cause mortality between these two groups of patients. At two years after AMI, approximately 71% of deaths for all dialysis patients were ascribed to cardiac causes.6 In contrast, for renal transplant recipients 2 years after AMI, approximately 35% of deaths were from cardiac causes in the present study. The impact of ethnicity on survival after AMI appears considerably different in renal transplant recipients compared with dialysis patients. We previously reported an 18% reduction in allcause death risk in black dialysis patients after AMI compared with white patients, a finding consistent with published data.12 Our finding of no survival advantage for black renal transplant recipients after AMI compared with white patients is consistent with published survival data for renal transplant recipients.3,13 We found that Native American dialysis patients had a 13% reduction in all-cause death risk and 16% reduction in cardiac death risk after AMI compared with white patients.6 In contrast, Native American renal transplant recipients had a twofold
TRANSPLANT PATIENTS AND MYOCARDIAL INFARCTION
increased risk for cardiac death in the present study. In a Cox proportional hazards model, we found a striking reduction in the risk for all-cause and cardiac death for renal transplant recipients sustaining AMI in the most recent treatment period. There was a 45% reduction (RR, 0.55; 95% CI, 0.45 to 0.68) in the risk for all-cause death and a 51% reduction (RR, 0.49; 95% CI, 0.33 to 0.72) in cardiac death risk for patients sustaining AMI in 1990 to 1996 versus 1977 to 1984. This contrasts with our previously reported 13% reduction in all-cause death risk and 17% reduction in cardiac death risk for dialysis patients sustaining AMI in 1990 to 1995 versus 1977 to 1984.6 There appear to be marked differences in the temporal patterns of survival of dialysis patients and renal transplant recipients in the United States after AMI. Unlike dialysis patients but similar to patients without ESRD,14 renal transplant recipients appear to have reaped the expected benefit of the modern treatment era of AMI. There are several limitations to our study. The primary source of USRDS data was Medicare claims data, which may be subject to inaccuracies in AMI diagnosis. Jollis et al15 compared claims data with medical chart (clinical) data in a study of 12,937 patients undergoing inpatient cardiac catheterization and found an 88% rate of agreement between claims and clinical data for AMI diagnosis (with a 95% specificity and 76% sensitivity for AMI diagnosis by claims data compared with clinical data). The USRDS database provides few clinical data. Potentially important clinical predictors of survival after AMI, such as left ventricular ejection fraction, hemodynamic data, or coronary artery disease severity, were not available for our study. Our study is also limited by the absence of important clinical data regarding risk factors for the development of cardiac disease both before and after renal transplantation. As detailed in the Special Report from the National Kidney Foundation Task Force on Cardiovascular Disease, there are multiple risk factors for the development of cardiovascular disease in patients with chronic renal failure, including hypertension, dyslipidemia, hyperglycemia, smoking, physical inactivity, enhanced thrombogenicity, and elevated homocysteine levels.16 Aortic stiffness (assessed
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by aortic pulse wave velocity) is an independent predictor of all-cause and cardiovascular mortality.17 Quantitative data regarding these risk factors are not available in our study. In the renal transplant population, it is plausible that the type and intensity of immunosuppression could impact on the progression of cardiovascular disease, particularly relating to dyslipidemia exacerbated by steroid therapy. Information regarding drug therapy, including immunosuppression and treatment with lipid-reducing agents, antiplatelet drugs, and beta-blockers, unfortunately is not available in our study. The reason for the differing temporal trends in survival for dialysis patients and renal transplant recipients is unknown. In preliminary data, we have reported an apparent striking underutilization of thrombolytic therapy in dialysis patients with AMI.18 Based on preliminary data, this underutilization of thrombolytic therapy may also be true for renal transplant recipients sustaining AMI.19 The relative use of direct coronary angioplasty for coronary reperfusion in dialysis and renal transplant patients remains unknown. There may also be clinically important differences in these two ESRD populations with respect to both overall debility and coronary artery disease severity. Intuitively, the sickest patients requiring renal replacement therapy may be selectively excluded as potential renal transplant candidates. The recent publication of Wolfe et al20 supports the contention that healthier patients are placed on the waiting list for transplantation. The study of Wolfe et al20 also found that the long-term survival of patients undergoing renal transplantation was better than that of similar patients on the transplant waiting list. It is plausible that there may be similar differential patterns of survival in patients with ESRD with myocardial infarction, but our present study does not address this issue. Studies comparing the post-AMI survival of dialysis patients on the transplant waiting list and renal transplant recipients would be an appropriate focus for future research. The approach to coronary artery disease screening in these two ESRD populations is also likely to be different because the American Society of Transplant Physicians has recommended pretransplantation screening for all patients except those at lowest cardiac risk.21 No such approach has been recommended for dialysis patients who are
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not being considered for renal transplantation, although logically, the same strategy could potentially be used after the initiation of dialysis because the cardiovascular mortality is considerably greater in these patients. We conclude that the long-term cardiac outcome of renal transplant recipients in the United States sustaining AMI has significantly improved in the modern treatment era. The marked improvement in survival mirrors the outcome of patients without ESRD with AMI and is in sharp contrast to the previously reported modest improvement in comorbidity-adjusted survival of dialysis patients after AMI. REFERENCES 1. US Renal Data System: USRDS 1997 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1997, pp 91-101 2. US Renal Data System: USRDS 1998 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1998, pp C1-C54 3. US Renal Data System: USRDS 1998 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1998, pp 79-90 4. Gunnarsson R, Lofmark R, Nondlander R, Nyquist O, Groth CG: Acute myocardial infarction in renal transplant recipients: Incidence and prognosis. Eur Heart J 5:218-221, 1984 5. Janda P, Stribrna J, Korandova V, Kocandrle V: Acute myocardial infarction after renal transplantation. Cor Vasa 29:463-467, 1987 6. Herzog CA, Ma JZ, Collins AJ: Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med 339:799-805, 1998 7. US Renal Data System: USRDS 1992 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1992, pp 61-82 8. Collins AJ, Ma JZ, Constantini E, Everson S: Dialysis unit and patient characteristics associated with reuse prac-
tices and mortality: 1989-1993. J Am Soc Nephrol 9:21082117, 1998 9. US Renal Data System: USRDS 1999 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1999, pp 89-100 10. Kaplan EL, Meier P: Nonparametic estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 11. Cox DR: Regression models and life tables. J R Stat Soc 34:187-202, 1972 12. US Renal Data System: USRDS 1997 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1997, pp 69-89 13. US Renal Data System: USRDS 1998 Annual Data Report: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 1998, pp D27-D29 14. McGovern PG, Pankow JS, Shahar E, Doliszny KM, Folsom AR, Blackburn H, Luepker V: Recent trends in acute coronary heart disease. N Engl J Med 334:884-890, 1996 15. Jollis JG, Ancukiewicz M, DeLong ER, Pryor DB, Muhlbaier LH, Mark DB: Discordance of databases designed for claims payment versus clinical information systems. Ann Intern Med 119:844-850, 1993 16. Levey AS: Controlling the epidemic of cardiovascular disease in chronic renal disease: Where do we start? Am J Kidney Dis 32:S5-S13, 1998 (suppl 3) 17. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM: Impact of aortic stiffness on survival in end-stage renal disease. Circulation 99:2434-2439, 1999 18. Herzog CA, Ma JZ, Collins AJ: Long-term survival of dialysis patients receiving thrombolytic therapy for acute myocardial infarction in the United States. Circulation 100:I304, 1999 19. Herzog CA, Ma JZ, Collins AJ: Outcome of renal transplant patients receiving thrombolytic therapy for acute myocardial infarction in the United States. Circulation 100:I304, 1999 20. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LYC, Held PJ, Port FK: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341:1725-1730, 1999 21. Kasiske BL, Ramos EL, Gaston RS, Bia MJ, Danovitch GM, Bowen PA, Murphy KJ: The evaluation of renal transplant candidates: Clinical practice guidelines. J Am Soc Nephrol 6:1-34, 1995