Charles A. Herzog

Poor long-term survival after acute myocardial infarction among patients on long-term dialysis.

BACKGROUND Cardiovascular disease is common in patients on long-term dialysis, and it accounts for 44 percent of overall mortality in this group. We undertook a study to assess long-term survival after acute myocardial infarction among patients in the United States who were receiving long-term dialysis. METHODS Patients on dialysis who were hospitalized during the period from 1977 to 1995 for a first myocardial infarction after the initiation of renal-replacement therapy were retrospectively identified from the U.S. Renal Data System data base. Overall mortality and mortality from cardiac causes (including all in-hospital deaths) were estimated by the life-table method. The effect of independent predictors on survival was examined in a Cox regression model with adjustment for existing illnesses. RESULTS The overall mortality (+/-SE) after acute myocardial infarction among 34,189 patients on long-term dialysis was 59.3+/-0.3 percent at one year, 73.0+/-0.3 percent at two years, and 89.9+/-0.2 percent at five years. The mortality from cardiac causes was 40.8+/-0.3 percent at one year, 51.8+/-0.3 percent at two years, and 70.2+/-0.4 percent at five years. Patients who were older or had diabetes had higher mortality than patients without these characteristics. Adverse outcomes occurred even in patients who had acute myocardial infarction in 1990 through 1995. Also, the mortality rate after myocardial infarction was considerably higher for patients on long-term dialysis than for renal-transplant recipients. CONCLUSIONS Patients on dialysis who have acute myocardial infarction have high mortality from cardiac causes and poor long-term survival.

Chronic Kidney Disease and the Risk for Cardiovascular Disease, Renal Replacement, and Death in the United States Medicare Population, 1998 to 1999

Knowledge of the excess risk posed by specific cardiovascular syndromes could help in the development of strategies to reduce premature mortality among patients with chronic kidney disease (CKD). The rates of atherosclerotic vascular disease, congestive heart failure, renal replacement therapy, and death were compared in a 5% sample of the United States Medicare population in 1998 and 1999 (n = 1,091,201). Patients were divided into the following groups: 1, no diabetes, no CKD (79.7%); 2, diabetes, no CKD (16.5%); 3, CKD, no diabetes (2.2%); and 4, both CKD and diabetes (1.6%). During the 2 yr of follow-up, the rates (per 100 patient-years) in the four groups were as follows: atherosclerotic vascular disease, 14.1, 25.3, 35.7, and 49.1; congestive heart failure, 8.6, 18.5, 30.7, and 52.3; renal replacement therapy, 0.04, 0.2, 1.6, and 3.4; and death, 5.5, 8.1, 17.7, and 19.9, respectively (P < 0.0001). With use of Cox regression, the corresponding adjusted hazards ratios were as follows: atherosclerotic vascular disease, 1, 1.30, 1.16, and 1.41 (P < 0.0001); congestive heart failure, 1, 1.44, 1.28, and 1.79 (P < 0.0001); renal replacement therapy, 1, 2.52, 23.1, and 38.9 (P < 0.0001); and death, 1, 1.21, 1.38, and 1.56 (P < 0.0001). On a relative basis, patients with CKD were at a much greater risk for the least frequent study outcome, renal replacement therapy. On an absolute basis, however, the high death rates of patients with CKD may reflect accelerated rates of atherosclerotic vascular disease and congestive heart failure.

Acute Myocardial Infarction and Renal Dysfunction: A High-Risk Combination

Context Advanced renal failure worsens survival after myocardial infarction (MI). The effect of milder renal insufficiency on prognosis is unknown. Contribution Among 3106 patients with MI, those who also had renal insufficiency received less aggressive therapy than those with normal renal function and were twice as likely to die in the hospital. Even after adjustment for cardiovascular treatment differences, post-MI mortality rates increased as creatinine clearance decreased. Reperfusion therapy, aspirin, and -blockers were associated with better survival at all levels of renal function. Implications Even mild degrees of renal insufficiency confer poor MI outcomes. Clinicians should use reperfusion, aspirin, and -blockers aggressively in patients with renal dysfunction. The Editors Patients with end-stage renal disease have increased cardiovascular death and morbidity (1-13). In the United States, approximately 44% of all deaths can be attributed to cardiovascular disease (3) and more than one in five cardiac deaths can be attributed to acute myocardial infarction (MI) (1). Population-based data demonstrate an increased prevalence of coronary artery disease, congestive heart failure, and left ventricular hypertrophy in patients with end-stage renal disease (14-17). Patients with severe renal dysfunction exhibit a vasculopathic state (14) that is secondary in part to increased prevalence of smoking (18), hyperlipidemia (16, 19), hyperhomocystinemia (16, 19), and secondary hypertension (17, 20). These risk factors contribute to accelerated atherosclerosis and may influence outcome after acute MI. Although recent reports have highlighted the dismal prognosis of patients with end-stage renal disease and acute MI (1, 2, 13), little is known about how such patients are managed (1, 2, 13, 21). It is unclear what percentage are treated with reperfusion or other more modern adjunctive therapies (1, 2, 13, 21). General surveys of patients with end-stage renal disease suggest that -blockers, aspirin, and angiotensin-converting enzyme (ACE) inhibitors are underutilized despite increased prevalence of hypertension, congestive heart failure, and coronary artery disease (22). There are fewer data examining use of these therapies in patients with acute MI (13) and a paucity of information about patients with less severe renal dysfunction who have acute MI. One report suggested that the latter group is at increased cardiovascular risk (13). Little is known about the treatment and outcomes of such patients, with the exception of one report suggesting that current treatment practices are less aggressive and contribute to increased mortality rates (13). We compared outcomes in patients with acute MI and any degree of renal failure, including end-stage renal disease, to determine whether treatment of these patients differs from that of patients with normal renal function. We examined treatment patterns and compared rates of heart failure, in-hospital complications, and short- and long-term survival to determine the extent to which treatment factors explain differences in prognosis. Methods From our coronary care unit database, we identified 3106 consecutive patients who had acute MI between 1988 and 2000. A trained nurse collected the data from the medical record. The study was approved by the Mayo Foundation Institutional Review Board. All patients gave informed consent as required by Minnesota law. Definitions Acute MI was defined by World Health Organization criteria (23) and was classified as related or not related to ST-segment elevation on the basis of the presence or absence of at least 1 mm of ST-segment elevation in two or more contiguous leads on initial electrocardiography. Location of acute MI was classified as anterior, inferior, or other. Since patients often develop multiple symptoms before seeking care, we defined acute MI onset as the time at which care was sought. Time of initial presentation was defined as the time of arrival at the hospital. Primary reperfusion therapy was defined as use of intravenous fibrinolytic therapy, percutaneous coronary revascularization, or immediate coronary artery bypass graft surgery as initial therapy to restore coronary blood flow. The use of adjunctive therapy during hospitalization was recorded. Killip classification was defined at admission (24). Left ventricular ejection fraction was recorded if demonstrated by echocardiography, radionuclide angiography, or left ventriculography. Smoking status (current or ever use of tobacco) was also determined. Renal function was estimated according to a calculated creatinine clearance derived from creatinine concentration at admission by using the CockcroftGault formula (140 age [in years] body weight [in kg]/serum creatinine concentration [in mg/dL] 72 [in men] or 0.85 [in women]) (25). We included only patients for whom body weight and creatinine values at admission were available. We analyzed renal function as a continuous variable and also as a stratified variable using five groups (26) to provide clinically relevant cut-points: normal renal function, defined as a creatinine clearance greater than 1.25 mL/s (>75 mL/min); mild renal insufficiency, defined as a creatinine clearance greater than 0.84 mL/s (>50 mL/min) but less than or equal to 1.25 mL/s ( 75 mL/min); moderate renal insufficiency, defined as a creatinine clearance greater than or equal to 0.59 mL/s ( 35 mL/min) but less than or equal to 0.84 mL/s ( 50 mL/min); severe renal insufficiency, defined as a creatinine clearance less than 0.59 mL/s (<35 mL/min); and end-stage renal disease, defined as treatment with renal replacement therapy (hemodialysis or peritoneal dialysis) for at least 1 month before admission. Major complications of acute MI were identified by documentation of death, mechanical complications, ischemic complications, or electrical complications. Death was classified as in-hospital (death before discharge during a patients admission to a critical care unit) or postdischarge (the number of days from hospital discharge to death or censoring at last follow-up). The exact dates of death were used. For living patients, the last follow-up date was the last date on which a service was performed at any Mayo facility. Mechanical complications included cardiac tamponade, acute ventricular septal defect, papillary muscle rupture, or free-wall rupture. Ischemic complications included recurrent MI, cardiogenic shock, or congestive heart failure, and electrical complications included cardiac arrest, electromechanical dissociation, or ventricular arrhythmia. A Killip class greater than I was defined as the presence of heart failure at time of hospitalization, and congestive heart failure was defined as the development of heart failure during hospitalization. Statistical Analysis Associations between binary characteristics and continuous creatinine clearance were determined by using the Wilcoxon rank-sum test. Differences in creatinine clearance were examined for the presence or absence of each characteristic. The KruskalWallis test was used for categorical characteristics with more than two groups. Associations between continuous characteristics and creatinine clearance were assessed by using a test based on the Spearman rank correlation coefficient. Categorical variables are reported as counts and percentages, and continuous variables are reported as medians and interquartile ranges. All P values, unless designated otherwise, refer to comparisons across all groups. We graphically assessed the gradient of risk associated with changing renal dysfunction. The variable of creatinine clearance was split into deciles based on relative ranks; the in-hospital mortality rate was plotted against the median value for creatinine clearance within each decile. Linear interpolation was used to connect the 10 points. Similar plots were created for 1-, 3-, and 5-year mortality rates across decile of creatinine clearance. To assess significance, we used the score test from a Cox proportional-hazards model with continuous creatinine clearance as the only variable. Univariate assessment of continuous creatinine clearance suggested that the distribution was skewed right. The mean creatinine clearance (SD) was 1.2 0.65 mL/s (72 39 mL/min), and the median creatinine clearance was 1.14 mL/s (68 mL/min) (interquartile range, 0.77 to 1.54 mL/s [46 to 92 mL/s]). Therefore, we used a log transformation for modeling outcomes. Logistic regression was used to examine associations between renal dysfunction and in-hospital mortality rate. We examined creatinine clearance using the creatinine clearance groups and tested overall significance of creatinine clearance using a test with four degrees of freedom. To ensure accurate adjustment of all potential confounders, we used forced-entry multivariable modeling to estimate odds ratios and 95% CIs adjusted for all available variables. We tested for goodness of fit with the HosmerLemeshow test. Multivariable modeling for postdischarge survival was similar. The log-rank test was used to assess the differences in survival across groups. A Cox regression model was developed to estimate the hazard rate ratio of postdischarge death for each group of patients with renal failure compared with the nonrenal failure group. Patients who underwent renal transplantation were not censored. The Cox regression model included four interaction terms with time to account for the nonproportional hazards for age, diabetes, Killip class, and ST-segment elevation; we report the adjusted hazards ratios. We took appropriate measures to examine the noninformative censoring assumption. All analyses were done by using SAS (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Sources The funding sources had no role in the collection, analysis, and interpretation of the data or in the decision to submit the manuscript for publication. Results Baseline Characteristics Patients

Predictive Value of Cardiac Troponin I and T for Subsequent Death in End-Stage Renal Disease

Background—This study determined the prevalence of increased cardiac troponin I (cTnI) and T (cTnT) in end-stage renal disease (ESRD) patients and whether an increased troponin was predictive of death. Methods and Results—Serum was obtained from 733 ESRD patients and measured for cTnI and cTnT. Relative risks were estimated using Cox proportional hazards regressions univariately and adjusted for age, time on dialysis, and coronary artery disease. Kaplan-Meier curves compared time to event data between groups. Greater percentages of patients had an increased cTnT versus cTnI at each cutoff, as follows: 99th percentile, 82% versus 6%; 10% coefficient of variation, 53% versus 1.0%; and receiver operator characteristic, 20% versus 0.4%. Increased versus normal cTnT was predictive of increased mortality using all cutoffs and only above the 99th percentile for cTnI. Two-year cumulative mortality rates increased (P <0.001) with changes in cTnT from normal (<0.01 &mgr;g/L, 8.4%) to small (≥0.01 to <0.04 &mgr;g/L, 26%), moderate (≥0.04 to <0.1 &mgr;g/L, 39%), and large (≥0.1 &mgr;g/L, 47%) increases. Two-year mortalities were 30% for cTnI <0.1 &mgr;g/L and 52% if ≥0.1 &mgr;g/L. Univariate and adjusted relative risks of death associated with elevated (>99th percentile) cTnT were 5.0 (CI, 2.5 to 10;P <0.001) and 3.9 (CI, 1.9 to7.9;P <0.001) and cTnI were 2.0 (CI, 1.3 to 3.3;P =0.008) and 2.1 (CI, 1.3 to 3.3;P =0.007). Age, coronary artery disease, and time on dialysis were also independent predictors of mortality. Conclusions—Increases in cTnT and cTnI in ESRD patients show a 2- to 5-fold increase in mortality, with a greater number of patients having an increased cTnT.

Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis

BACKGROUND Disorders of mineral metabolism, including secondary hyperparathyroidism, are thought to contribute to extraskeletal (including vascular) calcification among patients with chronic kidney disease. It has been hypothesized that treatment with the calcimimetic agent cinacalcet might reduce the risk of death or nonfatal cardiovascular events in such patients. METHODS In this clinical trial, we randomly assigned 3883 patients with moderate-to-severe secondary hyperparathyroidism (median level of intact parathyroid hormone, 693 pg per milliliter [10th to 90th percentile, 363 to 1694]) who were undergoing hemodialysis to receive either cinacalcet or placebo. All patients were eligible to receive conventional therapy, including phosphate binders, vitamin D sterols, or both. The patients were followed for up to 64 months. The primary composite end point was the time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event. The primary analysis was performed on the basis of the intention-to-treat principle. RESULTS The median duration of study-drug exposure was 21.2 months in the cinacalcet group, versus 17.5 months in the placebo group. The primary composite end point was reached in 938 of 1948 patients (48.2%) in the cinacalcet group and 952 of 1935 patients (49.2%) in the placebo group (relative hazard in the cinacalcet group vs. the placebo group, 0.93; 95% confidence interval, 0.85 to 1.02; P=0.11). Hypocalcemia and gastrointestinal adverse events were significantly more frequent in patients receiving cinacalcet. CONCLUSIONS In an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis. (Funded by Amgen; EVOLVE ClinicalTrials.gov number, NCT00345839.).

Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO)

Cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD) is high, and the presence of CKD worsens outcomes of cardiovascular disease (CVD). CKD is associated with specific risk factors. Emerging evidence indicates that the pathology and manifestation of CVD differ in the presence of CKD. During a clinical update conference convened by the Kidney Disease: Improving Global Outcomes (KDIGO), an international group of experts defined the current state of knowledge and the implications for patient care in important topic areas, including coronary artery disease and myocardial infarction, congestive heart failure, cerebrovascular disease, atrial fibrillation, peripheral arterial disease, and sudden cardiac death. Although optimal strategies for prevention, diagnosis, and management of these complications likely should be modified in the presence of CKD, the evidence base for decision making is limited. Trials targeting CVD in patients with CKD have a large potential to improve outcomes.

Comparative Survival of Dialysis Patients in the United States After Coronary Angioplasty, Coronary Artery Stenting, and Coronary Artery Bypass Surgery and Impact of Diabetes

Background—The optimal method of coronary revascularization in dialysis patients is controversial. The purpose of this study was to compare the long-term survival of dialysis patients in the United States after PTCA, coronary stenting, or CABG. Methods and Results—Dialysis patients hospitalized from 1995 to 1998 for first coronary revascularization procedures after renal replacement therapy initiation were identified from the US Renal Data System database. All-cause and cardiac survival was estimated by the life-table method and compared by the log-rank test. The impact of independent predictors on survival was examined in a Cox regression model. The in-hospital mortality was 8.6% for 6668 CABG patients, 6.4% for 4836 PTCA patients, and 4.1% for 4280 stent patients. The 2-year all-cause survival (mean±SEM) was 56.4±1.4% for CABG patients, 48.2±1.5% for PTCA patients, and 48.4±2.0% for stent patients (P <0.0001). After comorbidity adjustment, the relative risk (RR) for CABG (versus PTCA) patients was 0.80 (95% CI 0.76 to 0.84, P <0.0001) for all-cause death and 0.72 (95% CI 0.67 to 0.77, P <0.0001) for cardiac death. For stent (versus PTCA) patients, the RR was 0.94 (95% CI 0.88 to 0.99, P =0.03) for all-cause death and 0.92 (95% CI 0.85 to 0.99, P =0.04) for cardiac death. In diabetic (versus PTCA) patients, the RR for CABG surgery was 0.81 (95% CI 0.75 to 0.88, P <0.0001) for all-cause death and 0.71 (95% CI 0.64 to 0.78, P <0.0001) for cardiac death, and the RR for the stent procedure was 0.99 (95% CI 0.91 to 1.08, P =NS) for all-cause death and 0.99 (95% CI 0.89 to 1.11, P =NS) for cardiac death. Conclusions—In this retrospective study, dialysis patients in the United States had better long-term survival after CABG surgery than after percutaneous coronary intervention. Stent outcomes were relatively worse in diabetic patients. Our data support the need for large clinical registries and prospective trials of surgical and percutaneous coronary revascularization procedures in dialysis patients.

Serum Phosphorus Levels Associate with Coronary Atherosclerosis in Young Adults

Phosphorus levels correlate with atherosclerosis in both animal models and humans with advanced chronic kidney disease, but whether this relationship exists among individuals with normal kidney function is unknown. This study aimed to determine whether an association exists between phosphorus levels and coronary artery calcium levels in a community-based cohort of 3015 healthy young adults in the prospective Coronary Artery Risk Development in Young Adults (CARDIA) study. Phosphorus levels were measured at baseline, and presence of coronary artery calcium was assessed by computed tomography 15 yr later. Mean age at study inception was 25.2 yr, and the mean levels of phosphorus and calcium were 3.6 and 9.5 mg/dl, respectively. Only 0.2% of participants had estimated GFR <60 ml/min per 1.73 m(2). Phosphorus levels were associated with coronary artery calcium in unadjusted models. In multivariate models, however, phosphorus levels were significantly associated with the category of coronary artery calcium level. In conclusion, higher serum phosphorus levels, even within the normal range, may be a risk factor for coronary artery atherosclerosis in healthy young adults.

The Prevalence of Cardiac Valvular Insufficiency Assessed by Transthoracic Echocardiography in Obese Patients Treated with Appetite-Suppressant Drugs

BACKGROUND After case reports of cardiac-valve abnormalities related to the use of appetite suppressants were published, we undertook a study to determine the prevalence of the problem using transthoracic echocardiography. METHODS We examined patients who had taken dexfenfluramine alone, dexfenfluramine and phentermine, or fenfluramine and phentermine for various periods. We enrolled obese patients who had taken or were taking these agents during open-label trials from January 1994 through August 1997. We also recruited subjects who had not taken appetite suppressants and who were matched to the patients for sex, height, and pretreatment age and body-mass index. The presence of cardiac-valve abnormalities, defined by the Food and Drug Administration and Centers for Disease Control and Prevention as at least mild aortic-valve or moderate mitral-valve insufficiency, was determined independently by at least two cardiologists. Multivariate logistic-regression analysis was used to identify factors associated with cardiac-valve abnormalities. RESULTS Echocardiograms were available for 257 patients and 239 control subjects. The association between the use of any appetite suppressant and cardiac-valve abnormalities was analyzed in a final matched group of 233 pairs of patients and controls. A total of 1.3 percent of the controls (3 of 233) and 22.7 percent of the patients (53 of 233) met the case definition for cardiac-valve abnormalities (odds ratio, 22.6; 95 percent confidence interval, 7.1 to 114.2; P<0.001). The odds ratio for such cardiac-valve abnormalities was 12.7 (95 percent confidence interval, 2.9 to 56.4) with the use of dexfenfluramine alone, 24.5 (5.9 to 102.2) with the use of dexfenfluramine and phentermine, and 26.3 (7.9 to 87.1) with the use of fenfluramine and phentermine. CONCLUSIONS Obese patients who took fenfluramine and phentermine, dexfenfluramine alone, or dexfenfluramine and phentermine had a significantly higher prevalence of cardiac valvular insufficiency than a matched group of control subjects.

Excerpts From the US Renal Data System 2009 Annual Data Report

This 21st US Renal Data System Annual Data Report covers data through 2007, and again includes a section on chronic kidney disease (CKD) in the United States. Using NHANES and employer group health plan data, we estimate the relationship between kidney disease markers and mortality risk and the likelihood of blood pressure and lipid control by CKD stage; illustrate use of the new ICD-9-CM CKD diagnosis codes; and report on morbidity, mortality, care and costs during the transition to ESRD. New chapters address CKD patient care, the transition to ESRD, and acute kidney injury. In 2007, 111,000 patients started end-stage renal disease (ESRD) therapy, and the prevalent population reached 527,283 (including 368,544 dialysis patients); 17,513 transplants were performed, and 158,739 patients had a functioning graft at year’s end. Program expenditures reached