Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Rivaroxaban in Chronic Hemodialysis.

BACKGROUND: This study aimed to characterize the single-dose pharmacokinetic (PK) and pharmacodynamic (PD) profile of rivaroxaban 15 mg administered before and after dialysis in subjects with end-stage renal disease (ESRD), and to compare this profile in subjects with ESRD to that in healthy control subjects (creatinine clearance ≥80 ml/min). METHODS: This was an open-label, single-dose, single-center, parallel-group study of rivaroxaban in ESRD subjects who had been clinically stable on maintenance hemodialysis for ≥3 months. In 8 subjects with ESRD, a 15-mg dose of rivaroxaban was administered 2 ± 0.5 h before a hemodialysis session and repeated 7-14 days later at 3 h after a 4-h hemodialysis session. Eight healthy control subjects, matched for age, sex, and body mass index, received one 15-mg rivaroxaban dose. RESULTS: Compared to healthy subjects, area under the rivaroxaban plasma concentration versus time curve (AUC) increased by 56% following post-dialysis administration. Assuming similar bioavailability between groups, this reflects an approximate 35% decrease in overall drug clearance in ESRD subjects. Pre-dialysis dosing resulted in only 5% lowering of AUC versus post-dialysis dosing, confirming the minimal impact of dialysis on the PK of rivaroxaban. PD effects, as assessed by change in prothrombin time, percent factor Xa inhibition, and anti-Xa activity, were generally concordant with observed changes in plasma PK. CONCLUSIONS: Changes in PK and PD parameters in chronic dialysis patients were generally comparable to changes observed previously in patients with moderate-to-severe renal impairment who were not undergoing dialysis, and support use of a 15-mg dose in this patient population.

Associations between atrial fibrillation and early outcomes of patients with heart failure and reduced or preserved ejection fraction.

BACKGROUND: The relative impact of atrial fibrillation on early outcomes of patients with heart failure with reduced or preserved ejection fraction (EF) is unknown. METHODS: We conducted a retrospective cohort study of clinical registry data linked to Medicare claims for patients with heart failure with reduced or preserved EF stratified by presence of atrial fibrillation at admission. Outcomes of interest were all-cause mortality and readmission at 30days. We used Kaplan-Meier methods to estimate mortality and calculated cumulative incidence estimates of readmission. We used Cox proportional hazards models to examine associations between atrial fibrillation and 30-day outcomes. RESULTS: Among 66,357 patients admitted to 283 hospitals between January 2001 and March 2006, 46% had atrial fibrillation (44% of patients with reduced EF and 48% of patients with preserved EF). After adjustment for other patient characteristics, atrial fibrillation was associated with a modestly higher risk of 30-day mortality (HR, 1.08; 95% CI, 1.03-1.14) and readmission (HR, 1.06; 95% CI, 1.02-1.11). In subgroup analyses, atrial fibrillation was associated with a higher risk of 30-day mortality (HR, 1.16; 95% CI, 1.08-1.25) among patients with preserved EF but not among patients with reduced EF. The association of atrial fibrillation with readmission did not differ by heart failure type (P=.37 for the interaction). CONCLUSIONS: Atrial fibrillation was associated with higher 30-day mortality among patients with heart failure with preserved EF but not reduced EF. The association of atrial fibrillation with 30-day readmission was modest and did not differ by heart failure type.

Atrial fibrillation in myocardial infarction patients: Impact on health care utilization.

BACKGROUND: Atrial fibrillation (AF) often complicates myocardial infarction (MI). While AF adversely impacts survival in MI patients, the impact of AF on health care utilization has not been studied. METHODS: The risk of hospitalizations, emergency department (ED) visits, and outpatient visits associated with prior, new-onset (<30 days post-MI), and late-onset (≥30 days post-MI) AF was assessed among incident MI patients from the Olmsted County, Minnesota, community. RESULTS: Of 1,502 MI patients, 237 had prior AF, 163 developed new-onset AF, 113 developed late-onset AF, and 989 had no AF. Over a mean follow-up of 3.9 years, 3,661 hospitalizations, 5,559 ED visits, and 80,240 outpatient visits occurred. After adjustment, compared with patients without AF, those with prior and new-onset AF exhibited a 1.6-fold and 1.3-fold increased risk of hospitalization, respectively. In contrast, late-onset AF carried a 2.2-fold increased risk of hospitalization. The hazard ratios were 1.4, 1.2, and 1.8 for ED visits and 1.4, 1.2, and 1.7 for outpatient visits for prior, new-onset, and late-onset AF. Additional adjustment for time-dependent recurrent MI and heart failure attenuated the results slightly for hospitalizations and ED visits; however, patients with late-onset AF still exhibited a >50% increased risk for both utilization measures. CONCLUSIONS: In MI patients, the risk of hospitalizations, ED visits, and outpatient visits differed by the timing of AF onset, with the greatest risk conferred by late-onset AF. Atrial fibrillation imparts an adverse prognosis after MI, underscoring the importance of its management in MI patients.

Early intravenous heart failure therapy and outcomes among older patients hospitalized for acute decompensated heart failure: findings from the Acute Decompensated Heart Failure Registry Emergency Module (ADHERE-EM).

BACKGROUND: Timing of initial treatment for acute decompensated heart failure (ADHF) varies across hospitals and its impact on outcomes remains poorly defined. We examined the association between time to first intravenous (IV) heart failure (HF) therapy and patient outcomes. METHODS: Using the ADHERE-EM linked to Medicare claims data, we identified patients ≥65 years old who were hospitalized for ADHF and received IV HF therapy during index admission. Cox proportional hazard model was used to assess the association of time to treatment with a composite of 30-day all-cause mortality or re-admission. Generalized linear mixed models were used to examine the association of time to treatment with in-hospital all-cause mortality, index hospitalization length of stay, and total days alive and out-of-hospital at 30 days. RESULTS: Of 6,971 patients, the median time to first IV HF therapy was 2.3-hours (interquartile range 1.1, 4.4). The cumulative incidence of 30-day all-cause mortality or readmission was 27.4%. After adjusting for covariates, time to treatment was not associated with increased risk of composite 30-day all-cause mortality or re-admission (HR 1.00; 95% CI 1.00-1.00; P = .221). However, every hour delay in treatment was associated with a modest increased risk of in-hospital mortality (adjusted OR 1.01; 95% CI 1.00-1.02; P = .001) and an approximately 1.4-hour increase in index admission length of stay (P < .001). CONCLUSION: Among older patients presenting with ADHF, delay in initiating IV HF therapy was associated with modestly higher risk for in-hospital mortality and longer length of stay, but was not associated with 30-day outcomes.

Warfarin use among older atrial fibrillation patients with non-ST-segment elevation myocardial infarction managed with coronary stenting and dual antiplatelet therapy.

BACKGROUND: We sought to determine the risk of readmission for bleeding and major cardiac events in stented non-ST-segment elevation myocardial infarction (NSTEMI) atrial fibrillation (AF) patients. METHODS: For this patient population, selection of an antithrombotic strategy poses a unique challenge in clinical practice, and comparative outcome data are sparse. We linked NSTEMI patients aged ≥ 65 years in the CRUSADE Registry (2003-2006) to Medicare claims data. We examined patients with AF who received coronary stenting and either dual antiplatelet therapy (DAPT, aspirin + clopidogrel) or triple therapy (DAPT + warfarin) upon discharge. Multivariable Cox analysis was used to compare the 1-year risks of major cardiac events and readmission for bleeding. RESULTS: We identified 1,648 stented NSTEMI AF patients. Of these, 1,200 (73%) received DAPT, and 448 (27%) received triple therapy at hospital discharge. Predicted thromboembolic and bleeding risks did not appear to influence the decision to receive DAPT or triple therapy. At 1 year, 20.4% had a major cardiac event, and 13.5% were admitted for bleeding. Use of triple therapy relative to DAPT at discharge was associated with a similar adjusted risk of major cardiac events (adjusted hazard ratio 0.94, CI 0.73-1.21) but a trend toward increased risk of readmission for bleeding (hazard ratio 1.29, CI 0.96-1.74, P = .09). CONCLUSIONS: In routine practice and in contrast with practice recommendations, most elderly NSTEMI patients with AF who undergo percutaneous coronary intervention with stent placement receive DAPT rather than triple therapy at discharge. Those receiving triple therapy versus DAPT had a similar risk of an ischemic event but a trend toward increased bleeding.

Clinical effectiveness of anticoagulation therapy among older patients with heart failure and without atrial fibrillation: findings from the ADHERE registry linked to Medicare claims.

BACKGROUND: Patients with heart failure are at higher risk for thromboembolic events, even in the absence of atrial fibrillation, but the effect of anticoagulation therapy on outcomes is uncertain. METHODS AND RESULTS: With data from a clinical registry linked to Medicare claims, we estimated the adjusted associations between anticoagulation and 1-year outcomes with the use of inverse probability of treatment weighting. Eligible patients had an ejection fraction ≤35%, had no concurrent atrial fibrillation, were alive at discharge, and had not received anticoagulation therapy before admission. Of 13,217 patients in 276 hospitals, 1,140 (8.6%) received anticoagulation therapy at discharge. Unadjusted rates of thromboembolic events and major adverse cardiovascular events did not differ by receipt of anticoagulation therapy. Patients discharged on anticoagulation therapy had lower unadjusted rates of all-cause mortality (27.2% vs 32.3%; P < .001) and readmission for heart failure (29.4% vs 35.4%; P < .001) and higher rates of bleeding events (5.2% vs 2.8%; P < .001). After adjustment for probability of treatment and discharge medications, there were no differences in all-cause mortality (hazard ratio 0.92; 95% confidence interval 0.80-1.06) or readmission for heart failure (0.91, 0.81-1.02), but patients receiving anticoagulation therapy were at higher risk for bleeding events (2.09, 1.47-2.97). CONCLUSIONS: Anticoagulation therapy at discharge is infrequent among older patients with heart failure and without atrial fibrillation. There were no statistically significant propensity-weighted associations between anticoagulation therapy and 1-year outcomes, except for a higher risk of bleeding.

B-type natriuretic peptide level and postdischarge thrombotic events in older patients hospitalized with heart failure: insights from the Acute Decompensated Heart Failure National Registry.

BACKGROUND: Patients hospitalized with heart failure (HF) have elevated B-type natriuretic peptide (BNP) levels and increased risk for thromboembolic events. Associations between BNP level and thromboembolic events in patients with HF without atrial fibrillation (AF) are not well studied. METHODS: We linked data from the ADHERE registry for 2003 through 2006 with Medicare claims to identify patients ≥65 years who were hospitalized with HF, did not have AF, and did not receive warfarin at discharge. We estimated rates of all-cause mortality, thromboembolic events, myocardial infarction (MI), and stroke using Kaplan-Meier methods and the cumulative incidence function. We used Cox models to assess associations between log BNP level and each outcome after adjustment for potential confounders. RESULTS: The study population included 11,679 patients from 146 sites. Patients in the highest quartile of BNP level were older and more often male and African American. They had higher rates of coronary artery disease, renal insufficiency, and peripheral vascular disease and lower rates of diabetes mellitus and chronic obstructive pulmonary disease. After multivariable adjustment, each 30% increase in BNP level was associated with increased risks of death (hazard ratio 1.07, 95% CI 1.05-1.08) and MI (1.07, 1.04-1.10) but not thromboembolism or stroke. CONCLUSION: Higher BNP level upon admission with HF among older patients without AF was associated with increased risks of MI and mortality; however, higher BNP level was not associated with subsequent thromboembolism or stroke.

Safety and effectiveness of antithrombotic strategies in older adult patients with atrial fibrillation and non-ST elevation myocardial infarction.

BACKGROUND: We aimed to study the comparative safety and effectiveness of various antithrombotic treatment strategies among older adults with non-ST elevation myocardial infarction (NSTEMI) and atrial fibrillation (AF). METHODS: Using the CRUSADE registry linked to longitudinal Medicare claims data, we examined NSTEMI patients aged ≥ 65 years with a concomitant diagnosis of AF. Multivariable Cox analysis was used to compare risk of rehospitalization for bleeding and a major cardiac composite end point of death, readmission for myocardial infarction, or stroke, according to discharge antithrombotic strategy. RESULTS: Among 7619 NSTEMI patients with AF, 29% were discharged on aspirin alone; 37%, on aspirin + clopidogrel; 7%, on warfarin alone; 17%, on aspirin + warfarin; and 10%, on warfarin + aspirin + clopidogrel. There was no difference in predicted stroke risk between groups. By 1 year, 12.2% of patients were rehospitalized for bleeding, and 33.1% had a major cardiac event. Relative to aspirin alone, antithrombotic intensification was associated with increased bleeding risk (aspirin + clopidogrel adjusted HR 1.22, 95% CI 1.03-1.46 and warfarin + aspirin HR 1.46, 95% CI 1.21-1.80). Patients treated with aspirin + clopidogrel + warfarin had the highest observed bleeding risk (HR 1.65, 95% CI 1.30-2.10). One-year risk of the major cardiac end point was similar between groups, although, relative to aspirin only, there was a trend toward lower risk for the warfarin + aspirin group (HR 0.88, 95% CI 0.78-1.00). CONCLUSIONS: Older NSTEMI patients with AF are at high risk for subsequent bleeding and major cardiac events. Increased antithrombotic management was associated with increased bleeding risk. Further investigation is needed to clarify whether these risks are counterbalanced by reduced thromboembolic events in this population.

Outcomes registry for better informed treatment of atrial fibrillation: rationale and design of ORBIT-AF.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with an increased risk of stroke, heart failure, and death. Data on contemporary treatment patterns and outcomes associated with AF in clinical practice are limited. METHODS/DESIGN: The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation is a multicenter, prospective, ambulatory-based registry of incident and prevalent AF. The registry will be a nationwide collaboration of health care providers, including internists, primary care physicians, cardiologists, and electrophysiologists. Initial target enrollment is approximately 10,000 patients to be recruited from approximately 200 US outpatient practices. Enrolled patients will be observed for ≥2 years. A patient-reported outcomes substudy in ≥1,500 patients will provide serial quality-of-life assessments. The goal is to characterize treatment and outcomes of patients with AF, thereby promoting better quality of AF care and improved patient outcomes. CONCLUSION: The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation will provide insights into "real-world" treatment including rate and rhythm control, stroke prevention, transitions to new therapies, and clinical and patient-centered outcomes among patients with AF in community practice settings (ClinicalTrials.gov NCT01165710).

Generalizability and longitudinal outcomes of a national heart failure clinical registry: Comparison of Acute Decompensated Heart Failure National Registry (ADHERE) and non-ADHERE Medicare beneficiaries.

BACKGROUND: Clinical registries are used increasingly to analyze quality and outcomes, but the generalizability of findings from registries is unclear. METHODS: We linked data from the Acute Decompensated Heart Failure National Registry (ADHERE) to 100% fee-for-service Medicare claims data. We compared patient characteristics and inpatient mortality of linked and unlinked ADHERE hospitalizations; patient characteristics, readmission, and postdischarge mortality of linked ADHERE patients to a random 20% sample of Medicare beneficiaries hospitalized for heart failure; and characteristics of Medicare sites participating and not participating in ADHERE. RESULTS: Among 135,667 ADHERE records for eligible patients ≥ 65 years, we matched 104,808 (77.3%) records to fee-for-service Medicare claims, representing 82,074 patients. Linked hospitalizations were more likely than unlinked hospitalizations to involve women and white patients; there were no meaningful differences in other patient characteristics. In-hospital mortality was identical for linked and unlinked hospitalizations. In Medicare, ADHERE patients had slightly lower unadjusted mortality (4.4% vs 4.9% in-hospital, 11.2% vs 12.2% at 30 days, 36.0% vs 38.3% at 1 year [P < .001]) and all-cause readmission (22.1% vs 23.7% at 30 days, 65.8% vs 67.9% at 1 year [P < .001]). After risk adjustment, modest but statistically significant differences remained. ADHERE hospitals were more likely than non-ADHERE hospitals to be teaching hospitals, have higher volumes of heart failure discharges, and offer advanced cardiac services. CONCLUSION: Elderly patients in ADHERE are similar to Medicare beneficiaries hospitalized with heart failure. Differences related to selective enrollment in ADHERE hospitals and self-selection of participating hospitals are modest.

Chagas Disease: Epidemiology and Barriers to Treatment.

Chronic human infection by the protozoan parasite Trypanosoma cruzi, known as Chagas disease, results in heart failure and death in 20%-30% of affected individuals. Recognition and treatment of the infection are difficult. Disease control requires elimination of the vector, the reduviid bug, that infests housing of poor quality in endemic areas. In South America, control has largely succeeded in the Southern Cone countries-Argentina, Chile, Uruguay, southern Brazil and São Paulo, and Paraguay-but lags severely in the Northern Triangle (Central American) countries: El Salvador, Honduras, and Guatemala. Surges in poverty and violence in Central America have increased immigration of persons at risk for Chagas disease to the United States, and immigrants to the United States with Chagas disease face multiple barriers to obtaining effective care. These include issues with financing and payment for health care, limited effectiveness of screening and diagnosis, limited effectiveness of available treatment, and lack of provider awareness, public health education, and research. Each of these barriers presents a unique public health challenge.

Impact of intravenous loop diuretics on outcomes of patients hospitalized with acute decompensated heart failure: insights from the ADHERE registry.

The optimal use of diuretics in decompensated heart failure remains uncertain. We analyzed data from the ADHERE registry to look at the impact of diuretic dosing. 62,866 patients receiving <160 mg and 19,674 patients > or =160 mg of furosemide were analyzed. The patients receiving the lower doses had a lower risk for in-hospital mortality, ICU stay, prolonged hospitalization, or adverse renal effects. These findings suggest that future studies should evaluate strategies for minimizing exposure to high doses of diuretics.

Impact of acute serum creatinine elevation in patients treated with nesiritide.

BACKGROUND: We assessed the effect of increases in serum creatinine on mortality in nesiritide-treated versus control subjects with acute decompensated heart failure (ADHF). HYPOTHESIS: Mortality effect of nesiritide-related increases in serum creatinine differs from that of standard therapies. METHODS: Scios Inc., granted unrestricted access to data from all 5 randomized, controlled nesiritide infusion trials completed to date in patients hospitalized with ADHF. We used 2 different definitions of acute serum creatinine increase: >0.3 mg/dL and > 0.5mg/dL within 30 days of study enrollment and determined 30-day mortality risk for nesiritide-treated versus control subjects utilizing each definition. RESULTS: A total of 1,270 subjects participated in the 5 trials. A >0.3 mg/dL increase in serum creatinine was associated with a significant increase in mortality risk in control subjects, (hazard ratio [HR]: 3.47, 95% confidence interval [CI]: 1.49-8.09) but not in nesiritide-treated subjects (HR: 1.65, 95% CI: 0.90-3.05). Results were similar for a >0.5 mg/dL increase (control HR: 5.12, 95% CI: 2.09-12.57 and nesiritide HR: 1.77, 95% CI: 0.90-3.51). In subjects with >0.3 mg/dL and >0.5 mg/dL increases in serum creatinine, respectively, the 30-day mortality odds ratios for nesiritide relative to control were 0.73 (95% CI: 0.29-1.93) and 0.52 (95% CI: 0.17-1.63) using a stratified Mantel-Haenszel analysis. CONCLUSIONS: The impact of increased serum creatinine on mortality was attenuated in nesiritide-treated patients compared to control, suggesting that the mechanism and clinical significance of increases in serum creatinine associated with nesiritide treatment may differ from those associated with standard therapies. Further investigation is warranted.

Characteristics of "Stage D" heart failure: insights from the Acute Decompensated Heart Failure National Registry Longitudinal Module (ADHERE LM).

BACKGROUND: An improved understanding of the characteristics, treatment, and outcome of patients with "Stage D" heart failure (HF) may improve patient outcomes. We conducted an analysis of the ADHERE LM to enhance this understanding. METHODS: ADHERE LM is a multicenter registry designed specifically to prospectively collect observational data on chronic Stage D HF. The findings were analyzed and compared to data from ADHERE CM, a multicenter registry designed to prospectively collect data on the entire spectrum of acute decompensated HF. Descriptive statistics and Kaplan-Meier analysis were used to evaluate data from all 1433 patients in ADHERE LM. RESULTS: Compared to patients with acute decompensated HF, patients with chronic Stage D HF tended to be younger (69.6 vs 72.8 years), males (65% vs 49%), with hyperlipidemia/dyslipidemia (65% vs 41%), and with coronary artery disease (73% vs 57%). In Stage D patients, use of intravenous diuretics (73%) and vasoactive agents (84%) was common. Kaplan-Meier-estimated 1-year survival was 71.9% (95% CI 69.3%-74.5%) and estimated 1-year freedom from hospitalization or death was 32.9% (95% CI 30.2%-35.6%). CONCLUSIONS: Patients with Stage D HF are frequently males with dyslipidemia and coronary artery disease. Morbidity and mortality are high. Therapeutic decisions based on studies in HF patients with different characteristics may not be applicable; additional research is needed to determine optimal therapeutic regimens for these patients.

Comparison of clinical features and outcomes of patients hospitalized with heart failure and normal ejection fraction (> or =55%) versus those with mildly reduced (40% to 55%) and moderately to severely reduced (<40%) fractions.

Heart failure (HF) with normal ejection fraction (EF) is an increasingly common presentation of acute decompensated HF. Differences between patients with HF and truly normal EF and those with mildly impaired EF have not been described. The Acute Decompensated Heart Failure Registry (ADHERE) contains information on >100,000 HF hospitalizations and may provide insight into this distinction. The ADHERE database was used to investigate differences between patients hospitalized with HF and severely (<25%), moderately (25% to 40%), and mildly (40% to 55%) decreased EF and those with normal EF (> or =55%). The group with normal EF was 69% women with a mean age of 74 years (p <0.0001 vs all other groups). Coronary artery disease was less frequent in the normal EF group, and hypertension played a larger role. Patients with EF > or =55% had increased pulse pressure, suggesting a role for arterial stiffening. Treatment differed by EF. Creatinine increased > or =0.5 mg/dl more often in the group with HF and normal EF than in the group with HF and severely decreased EF. In-hospital mortality and length of stay in the intensive care unit varied inversely with EF; overall length of stay was similar. In conclusion, patients with HF and normal EF are more likely to be women, have a history of high pulse pressure hypertension, less coronary artery disease, and a lower risk of inpatient death but a higher likelihood of deterioration in renal function during hospitalization. These observations may be important considerations in the design of future clinical trials.

Endogenous B-type natriuretic peptide: a limb of the regulatory response to acutely decompensated heart failure.

Acutely decompensated heart failure (ADHF) represents an episodic failure of cardiorenal homeostasis that may resolve with upregulation of natriuretic peptides, bradykinin, and certain prostacyclins. B-type natriuretic peptide (BNP) has multiple favorable effects, including vasodilation, diuresis, natriuresis, and inhibition of vascular endothelial proliferation and cardiac fibrosis. By antagonizing the effects of activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system in volume overload, the endogenous BNP response may help rescue patients from episodic ADHF. Although knowledge of BNP physiology is expanding, we still have limited understanding of the heterogeneity of proBNP-derived molecules, including active 32 amino acid BNP and less active junk BNP forms. Emerging evidence suggests that in ADHF, the endogenous BNP response is overwhelmed by neurohormonal activation. This relative BNP deficiency may also be accompanied by physiologic resistance to BNP. Additionally, abnormalities of BNP production may result in a lower proportion of active BNP relative to less active forms that may also be detected by point-of-care tests. Improved detection of the various BNP species may clarify these concepts and facilitate improved clinical management of ADHF.