Sirolimus Adverse Event Profile in a Non-Clinical Trial Cohort of Heart Transplantation Patients.

BACKGROUND Sirolimus has been used increasingly in heart transplantation for its ability to reduce acute rejection, prevent the progression of cardiac allograft vasculopathy (CAV), and preserve renal function. We sought to assess the adverse reactions associated with the use of sirolimus compared to mycophenolate mofetil (MMF). MATERIAL AND METHODS We retrospectively reviewed the charts of 221 adult heart transplant patients who received either sirolimus or MMF as part of their immunosuppression from June 1, 2001 to April 1, 2005. Patients were assigned to 2 groups based upon immunosuppression use. The prevalence and types of complications were recorded in each group. RESULTS Sirolimus was received by 109 patients and 112 patients received MMF during the study period. Seventy-seven patients (71%) in the sirolimus group experienced adverse reactions compared to 45 patients (40%) in the MMF group (P<0.01). Compared to MMF, the use of sirolimus was associated with a higher prevalence of elevated triglyceride levels, lower-extremity edema, and oral ulcerations. Sirolimus was discontinued due to adverse reactions in 22% of patients, whereas no patients in the MMF group experienced adverse effects requiring drug discontinuation. CONCLUSIONS Compared to MMF, sirolimus use is associated with a higher prevalence of adverse reactions requiring drug discontinuation, but most patients were able to stay on therapy despite adverse effects.

Gene expression profiling to study racial differences after heart transplantation.

BACKGROUND: The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a function of calcineurin inhibitor (CNI) levels and gene expression profile (GEP) scores. METHODS: We determined the event rate of the primary outcome, comparing racial groups, stratified by time after transplant. Logistic regression was used to compute the relative risk across racial groups, and linear modeling was used to measure the dependence of CNI levels and GEP score on race. RESULTS: In 580 patients monitored for a median of 19 months, the incidence of the primary end point was 18.3% in African Americans, 22.2% in other non-Caucasians, and 8.5% in Caucasians (p < 0.001). There were small but significant correlations of race and tacrolimus trough levels to the GEP score. Tacrolimus levels were similar among the races. Of patients receiving tacrolimus, other non-Caucasians had higher GEP scores than the other racial groups. African American recipients demonstrated a unique decrease in expression of the FLT3 gene in response to higher tacrolimus levels. CONCLUSIONS: African Americans and other non-Caucasian heart transplant recipients were 2.5-times to 3-times more likely than Caucasians to experience outcome events in the Invasive Monitoring Attenuation through Gene Expression study. The increased risk of adverse outcomes may be partly due to the biology of the alloimmune response, which is less effectively inhibited at similar tacrolimus levels in minority racial groups.

The liver in heart failure: a biopsy and explant series of the histopathologic and laboratory findings with a particular focus on pre-cardiac transplant evaluation.

The pathologic liver changes in chronic heart failure have been characterized mostly based on autopsy series and include sinusoidal dilation and congestion progressing to pericellular fibrosis, bridging fibrosis, and ultimately to cardiac cirrhosis or sclerosis. Liver biopsies are commonly obtained as part of the work up before heart transplantation in patients with longstanding right heart failure, particularly if ascites, abnormal liver function tests or abnormal abdominal imaging are noted as part of the pre-transplant evaluation. In these cases, the liver biopsy findings may be used to further risk stratify patients for isolated heart or combined heart and liver transplantation. Thus, it is important to be able to correlate the histologic changes with post-transplant outcomes. We report the pathologic and clinical findings in liver explants from six patients who underwent combined heart-liver transplantation. We also report preoperative liver biopsy findings from 21 patients who underwent heart transplantation without simultaneous liver transplantation. We staged the changes related to chronic passive congestion as follows: stage 0-no fibrosis; stage I-pericellular fibrosis; stage II-bridging fibrosis; and stage III-regenerative nodules. Nineteen biopsies showed fibrosis with bridging fibrosis in 13 and regenerative nodules in 6. Fifteen patients were alive at 1 year post transplant. Only three patients had a post-operative course that was characterized by signs and symptoms of chronic liver disease. Pre-transplant liver biopsies from these patients all showed at least stage II fibrosis. These patients survived for 3, 6, and 10 months after cardiac transplant. The presence of bridging fibrosis was not significantly associated with post-operative survival (P=0.336) or post-operative liver failure (P=0.257). We conclude that patients with bridging fibrosis may still be considered viable candidates for isolated heart transplantation. Because the pattern of fibrosis due to passive congestion is highly variable throughout the liver, a diagnosis of cirrhosis, which implies fibrosis and regenerative nodules throughout the liver, should be made with great caution on biopsy.

Utility of gene expression profiling score variability to predict clinical events in heart transplant recipients.

BACKGROUND: Gene expression profiling test scores have primarily been used to identify heart transplant recipients who have a low probability of rejection at the time of surveillance testing. We hypothesized that the variability of gene expression profiling test scores within a patient may predict risk of future events of allograft dysfunction or death. METHOD: Patients from the IMAGE study with rejection surveillance gene expression profiling tests performed at 1- to 6-month intervals were selected for this cohort study. Gene expression profiling score variability was defined as the standard deviation of an individual's cumulative test scores. Gene expression profiling ordinal score (range, 0-39), threshold score (binary value=1 if ordinal score ≥ 34), and score variability were studied in multivariate Cox regression models to predict future clinical events. RESULTS: Race, age at time of transplantation, and time posttransplantation were significantly associated with future events in the univariate analysis. In the multivariate analyses, gene expression profiling score variability, but not ordinal scores or scores over threshold, was independently associated with future clinical events. The regression coefficient P values were <0.001, 0.46, and 0.773, for gene expression profiling variability, ordinal, and threshold scores, respectively. The hazard ratio for a 1 unit increase in variability was 1.76 (95% CI, 1.4-2.3). DISCUSSION: The variability of a heart recipient's gene expression profiling test scores over time may provide prognostic utility. This information is independent of the probability of acute cellular rejection at the time of testing that is rendered from a single ordinal gene-expression profiling test score.

Divergent trends in survival and readmission following a hospitalization for heart failure in the Veterans Affairs health care system 2002 to 2006.

OBJECTIVES: This study sought to determine recent trends over time in heart failure hospitalization, patient characteristics, treatment, rehospitalization, and mortality within the Veterans Affairs health care system. BACKGROUND: Use of recommended therapies for heart failure has increased in the U.S. However, it is unclear to what extent hospitalization rates and the associated mortality have improved. METHODS: We compared rates of hospitalization for heart failure, 30-day rehospitalization for heart failure, and 30-day mortality following discharge from 2002 to 2006 in the Veterans Affairs Health Care System. Odds ratios for outcome were adjusted for patient diagnoses within the past year, laboratory data, and for clustering of patients within hospitals. RESULTS: We identified 50,125 patients with a first hospitalization for heart failure from 2002 to 2006. Mean age did not change (70 years), but increases were noted for most comorbidities (mean Charlson score increased from 1.72 to 1.89, p < 0.0001). Heart failure admission rates remained constant at about 5 per 1,000 veterans. Mortality at 30 days decreased (7.1% to 5.0%, p < 0.0001), whereas rehospitalization for heart failure at 30 days increased (5.6% to 6.1%, p = 0.11). After adjustment for patient characteristics, the odds ratio for rehospitalization in 2006 (vs. 2002) was 0.54 (95% confidence interval [CI]: 0.47 to 0.61) for mortality, but 1.21 (95% CI: 1.04 to 1.41) for heart failure rehospitalization at 30 days. CONCLUSIONS: Recent mortality and rehospitalization rates in the Veterans Affairs Health Care System have trended in opposite directions. These results have implications for using rehospitalization as a measure of quality of care.

Gene-expression profiling for rejection surveillance after cardiac transplantation.

BACKGROUND: Endomyocardial biopsy is the standard method of monitoring for rejection in recipients of a cardiac transplant. However, this procedure is uncomfortable, and there are risks associated with it. Gene-expression profiling of peripheral-blood specimens has been shown to correlate with the results of an endomyocardial biopsy. METHODS: We randomly assigned 602 patients who had undergone cardiac transplantation 6 months to 5 years previously to be monitored for rejection with the use of gene-expression profiling or with the use of routine endomyocardial biopsies, in addition to clinical and echocardiographic assessment of graft function. We performed a noninferiority comparison of the two approaches with respect to the composite primary outcome of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or retransplantation. RESULTS: During a median follow-up period of 19 months, patients who were monitored with gene-expression profiling and those who underwent routine biopsies had similar 2-year cumulative rates of the composite primary outcome (14.5% and 15.3%, respectively; hazard ratio with gene-expression profiling, 1.04; 95% confidence interval, 0.67 to 1.68). The 2-year rates of death from any cause were also similar in the two groups (6.3% and 5.5%, respectively; P=0.82). Patients who were monitored with the use of gene-expression profiling underwent fewer biopsies per person-year of follow-up than did patients who were monitored with the use of endomyocardial biopsies (0.5 vs. 3.0, P<0.001). CONCLUSIONS: Among selected patients who had received a cardiac transplant more than 6 months previously and who were at a low risk for rejection, a strategy of monitoring for rejection that involved gene-expression profiling, as compared with routine biopsies, was not associated with an increased risk of serious adverse outcomes and resulted in the performance of significantly fewer biopsies. (ClinicalTrials.gov number, NCT00351559.)

Effect of rapamycin therapy on coronary artery physiology early after cardiac transplantation.

BACKGROUND: Rapamycin has been shown to reduce anatomical evidence of cardiac allograft vasculopathy, but its effect on coronary artery physiology is unknown. METHODS: Twenty-seven patients without angiographic evidence of coronary artery disease underwent measurement of fractional flow reserve (FFR), coronary flow reserve (CFR), and the index of microcirculatory resistance (IMR) within 8 weeks and then 1 year after transplantation using a pressure sensor/thermistor-tipped guidewire. Measurements were compared between consecutive patients who were on rapamycin for at least 3 months during the first year after transplantation (rapamycin group, n = 9) and a comparable group on mycophenolate mofetil (MMF) instead (MMF group, n = 18). RESULTS: At baseline, there was no significant difference in FFR, CFR, or IMR between the 2 groups. At 1 year, FFR declined significantly in the MMF group (0.87 +/- 0.06 to 0.82 +/- 0.06, P = .009) but did not change in the rapamycin group (0.91 +/- 0.05 to 0.89 +/- 0.04, P = .33). Coronary flow reserve and IMR did not change significantly in the MMF group (3.1 +/- 1.7 to 3.2 +/- 1.0, P = .76; and 27.5 +/- 18.1 to 19.1 +/- 7.6, P = .10, respectively) but improved significantly in the rapamycin group (2.3 +/- 0.8 to 3.8 +/- 1.4, P < .03; and 27.0 +/- 11.5 to 17.6 +/- 7.5, P < .03, respectively). Multivariate regression analysis revealed that rapamycin therapy was an independent predictor of CFR and FFR at 1 year after transplantation. CONCLUSION: Early after cardiac transplantation, rapamycin therapy is associated with improved coronary artery physiology involving both the epicardial vessel and the microvasculature.

Molecular testing for long-term rejection surveillance in heart transplant recipients: design of the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) trial.

BACKGROUND: Acute rejection continues to occur beyond the first year after cardiac transplantation, but the optimal strategy for detecting rejection during this late period is still controversial. Gene expression profiling (GEP), with its high negative predictive value for acute cellular rejection (ACR), appears to be well suited to identify low-risk patients who can be safely managed without routine invasive endomyocardial biopsy (EMB). METHODS: The Invasive Monitoring Attenuation Through Gene Expression (IMAGE) study is a prospective, multicenter, non-blinded, randomized clinical trial designed to test the hypothesis that a primarily non-invasive rejection surveillance strategy utilizing GEP testing is not inferior to an invasive EMB-based strategy with respect to cardiac allograft dysfunction, rejection with hemodynamic compromise (HDC) and all-cause mortality. RESULTS: A total of 199 heart transplant recipients in their second through fifth post-transplant years have been enrolled in the IMAGE study since January 13, 2005. The study is expected to continue through 2008. CONCLUSIONS: The IMAGE study is the first randomized, controlled comparison of two rejection surveillance strategies measuring outcomes in heart transplant recipients who are beyond their first year post-transplant. The move away from routine histologic evaluation for allograft rejection represents an important paradigm shift in cardiac transplantation, and the results of this study have important implications for the future management of heart transplant patients.

Prognostic value of electrocardiographic criteria for left ventricular hypertrophy.

BACKGROUND: Many electrocardiographic (ECG) criteria for left ventricular hypertrophy (LVH) exist, but few studies have compared their relative prognostic value for predicting cardiovascular (CV) mortality. METHODS: We analyzed the first ECG on 46950 consecutive veterans. We targeted male outpatients with a body mass index > 20 to avoid confounding by complicating catabolic illnesses and further excluded those with conduction abnormalities. Using Cox regression models adjusted for age, heart rate, and body mass index, we compared the hazard ratios (HRs) for CV mortality obtained from seventeen commonly used ECG criteria for LVH. RESULTS: During a mean follow-up of 7 +/- 4 years, in a total population of 19434 patients (mean age 54 +/- 14 years), 1254 (6%) patients died of CV causes. The adjusted HR for CV mortality ranged from 1.4 (95% CI 1.2-1.6) to 3.7 (95% CI 2.7-5.0) among the various criteria. Left ventricular hypertrophy defined by composite criteria was generally associated with higher adjusted HRs compared with voltage-only criteria. Among patients with ECG-LVH, the presence of a left ventricular strain pattern or increased negative P-terminal force were most predictive of CV mortality (HR 3.9 and 3.5, 95% CI 3.3-4.6 and 2.8-4.2). CONCLUSIONS: Compared with voltage-only criteria for detecting LVH, composite ECG criteria are more strongly predictive of CV mortality. By applying these ECG criteria into routine clinical practice, individuals with LVH who are at higher risk for CV mortality can be identified and appropriately treated.

Prognostic value of low-level cardiac troponin-I elevations in patients without definite acute coronary syndromes.

BACKGROUND: Low-level cardiac troponin-I (cTn-I) elevations predict adverse cardiovascular outcomes in patients with definite acute coronary syndromes (ACS), as defined by the presence of chest pain accompanied by ischemic electrocardiographic changes. However, their prognostic value in other clinical situations remains unclear. METHODS: We studied 366 patients with suspected myocardial infarction (MI) but without definite ACS, including 57 patients with low-level cTn-I elevations (1.0 to 3.0 ng/mL) and 309 patients with cTn-I <1.0 ng/mL. All cTn-I measurements were made with the Dade Stratus II analyzer. We determined the adjusted 1-year risk of nonfatal MI or death from coronary heart disease (CHD death) in each group by using Cox proportional hazards models. RESULTS: Among patients with cTn-I elevations between 1.0 and 3.0 ng/mL, 6 (11%) had a nonfatal MI or CHD death at 1 year compared with 12 (4%) patients in the cTn-I <1.0 ng/mL group [hazard ratio (HR), 3.5; 95% CI, 1.4 to 8.8]. After adjusting for baseline clinical characteristics, cTn-I levels between 1.0 and 3.0 ng/mL remained strongly associated with nonfatal MI or CHD death (adjusted HR, 3.4; 95% CI, 1.3 to 9.4). This association persisted even in the 215 patients who presented without chest pain (adjusted HR, 4.3; 95% CI, 1.4 to 13). CONCLUSIONS: Low-level cTn-I elevations identify a subset of patients at increased risk for future cardiovascular events, even when obtained outside the context of definite ACS or presentation with chest pain.