The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial.

Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.

Temporal trends in the incidence, treatment and outcomes of hip fracture after first kidney transplantation in the United States.

It is currently unknown whether any secular trends exist in the incidence and outcomes of hip fracture in kidney transplant recipients (KTR). We identified first-time KTR (1997-2010) who had >1 year of Medicare coverage and no recorded history of hip fracture. New hip fractures were identified from corresponding diagnosis and surgical procedure codes. Outcomes studied included time to hip fracture, type of surgery received and 30-day mortality. Of 69,740 KTR transplanted in 1997-2010, 597 experienced a hip fracture event during 155,341 person-years of follow-up for an incidence rate of 3.8 per 1000 person-years. While unadjusted hip fracture incidence did not change, strong confounding by case mix was present. Using year of transplantation as a continuous variable, the hazard ratio (HR) for hip fracture in 2010 compared with 1997, adjusted for demographic, dialysis, comorbid and most transplant-related factors, was 0.56 (95% confidence interval [CI]: 0.41-0.77). Adjusting for baseline immunosuppression modestly attenuated the HR (0.68; 95% CI: 0.47-0.99). The 30-day mortality was 2.2 (95% CI: 1.3-3.7) per 100 events. In summary, hip fractures remain an important complication after kidney transplantation. Since 1997, case-mix adjusted posttransplant hip fracture rates have declined substantially. Changes in immunosuppressive therapy appear to be partly responsible for these favorable findings.

Visit-to-visit systolic blood pressure variability and outcomes in hemodialysis.

Visit-to-visit blood pressure variability (VTV-BPV) is an independent risk factor for cardiovascular events and death in the general population. We sought to determine the association of VTV-BPV with outcomes in patients on hemodialysis, using data from a National Institutes of Health-sponsored randomized trial (the HEMO study). We used the coefficient of variation (CV) and the average real variability in systolic blood pressure (SBP) as metrics of VTV-BPV. In all, 1844 out of 1846 randomized subjects had at least three visits with SBP measurements and were included in the analysis. Median follow-up was 2.5 years (interquartile range 1.3-4.3 years), during which time there were 869 deaths from any cause and 408 (adjudicated) cardiovascular deaths. The mean pre-dialysis SBP CV was 9.9 ± 4.6%. In unadjusted models, we found a 31% higher risk of death from any cause per 10% increase in VTV-BPV. This association was attenuated after multivariable adjustment but remained statistically significant. Similarly, we found a 28% higher risk of cardiovascular death per 10% increase in VTV-BPV, which was attenuated and no longer statistically significant in fully adjusted models. The associations among VTV-BPV, death and cardiovascular death were modified by baseline SBP. In a diverse, well-dialyzed cohort of patients on maintenance hemodialysis, VTV-BPV, assessed using metrics of variability in pre-dialysis SBP, was associated with a higher risk of all-cause mortality and a trend toward higher risk of cardiovascular mortality, particularly in patients with a lower baseline SBP.

Systolic blood pressure and mortality in prevalent haemodialysis patients in the HEMO study.

Previous studies of blood pressure and mortality in haemodialysis have yielded mixed results, perhaps due to confounding by comorbid conditions. We hypothesized that after improved accounting for confounding factors, higher systolic blood pressure (SBP) would be associated with higher all-cause mortality. We conducted a secondary analysis of data from the haemodialysis study, a randomized trial in prevalent haemodialysis patients. We used three proportional hazard models to determine the relative hazard at different levels of SBP: (1) Model-BL used baseline SBP; (2) Model-TV used SBP as a time-varying variable; and (3) Model-TV-Lag added a 3-month lag to Model-TV to de-emphasize changes in SBP associated with acute illness. In all the models, pre-dialysis SBP <120 mm Hg was associated with a higher risk of mortality compared with the referent group (140-159 mm Hg); higher pre-dialysis SBP was not associated with higher risk of mortality. In conclusion, we observed a robust association between lower pre-dialysis SBP and higher risk for all-cause and cardiovascular mortality in a well-characterized cohort of prevalent haemodialysis patients. Randomized clinical trials are needed to define optimal blood pressure targets in the haemodialysis population.

Vitamin D deficiency and frailty in older Americans.

OBJECTIVE: To explore the relation between 25-hydroxyvitamin D deficiency and frailty. Frailty is a multidimensional phenotype that describes declining physical function and a vulnerability to adverse outcomes in the setting of physical stress such as illness or hospitalization. Low serum concentrations of 25-hydroxyvitamin D are known to be associated with multiple chronic diseases such as cardiovascular disease and diabetes, in addition to all cause mortality. DESIGN: Using data from the Third National Health and Nutrition Survey (NHANES III), we evaluated the association between low serum 25-hydroxyvitamin D concentration and frailty, defined according to a set of criteria derived from a definition previously described and validated. SUBJECTS: Nationally representative survey of noninstitutionalized US residents collected between 1988 and 1994. RESULTS: 25-Hydroxyvitamin D deficiency, defined as a serum concentration <15 ng mL(-1), was associated with a 3.7-fold increase in the odds of frailty amongst whites and a fourfold increase in the odds of frailty amongst non-whites. This association persisted after sensitivity analyses adjusting for season of the year and latitude of residence, intended to reduce misclassification of persons as 25-hydroxyvitamin D deficient or insufficient. CONCLUSION: Low serum 25-hydroxyvitamin D concentrations are associated with frailty amongst older adults.

The elderly patients on hemodialysis.

Nephrologists care for an increasing number of elderly patients on hemodialysis. As such, an understanding of the overlap among complications of hemodialysis and geriatric syndromes is crucial. This article reviews hemodialysis management issues including vascular access, hypertension, anemia and bone and mineral disorders with an attention towards the distinct medical needs of the elderly. Key concepts of geriatrics frailty, dementia and palliative care are also discussed, as nephrologists frequently participate in decision-making directed toward balancing longevity, functional status and the burden of therapy.

Neighborhood poverty and kidney transplantation among US Asians and Pacific Islanders with end-stage renal disease.

The degree to which low transplant rates among Asians and Pacific Islanders in the United States are confounded by poverty and reduced access to care is unknown. We examined the relationship between neighborhood poverty and kidney transplant rates among 22 152 patients initiating dialysis during 1995-2003 within 1800 ZIP codes in California, Hawaii and the US-Pacific Islands. Asians and whites on dialysis were distributed across the spectrum of poverty, while Pacific Islanders were clustered in the poorest areas. Overall, worsening neighborhood poverty was associated with lower relative rates of transplant (adjusted HR [95% CI] for areas with > or =20% vs. <5% residents living in poverty, 0.41 [0.32-0.53], p < 0.001). At every level of poverty, Asians and Pacific Islanders experienced lower transplant rates compared with whites. The degree of disparity increased with worsening neighborhood poverty (adjusted HR [95% CI] for Asians-Pacific Islanders vs. whites, 0.64 [0.51-0.80], p < 0.001 for areas with <5% and 0.30 [0.21-0.44], p < 0.001 for areas with > or =20% residents living in poverty; race-poverty level interaction, p = 0.039). High levels of neighborhood poverty are associated with lower transplant rates among Asians and Pacific Islanders compared with whites. Our findings call for studies to identify cultural and local barriers to transplant among Asians and Pacific Islanders, particularly those residing in resource-poor neighborhoods.

The risk of acute renal failure in patients with chronic kidney disease.

Few studies have defined how the risk of hospital-acquired acute renal failure varies with the level of estimated glomerular filtration rate (GFR). It is also not clear whether common factors such as diabetes mellitus, hypertension and proteinuria increase the risk of nosocomial acute renal failure independent of GFR. To determine this we compared 1,746 hospitalized adult members of Kaiser Permanente Northern California who developed dialysis-requiring acute renal failure with 600,820 hospitalized members who did not. Patient GFR was estimated from the most recent outpatient serum creatinine measurement prior to admission. The adjusted odds ratios were significantly and progressively elevated from 1.95 to 40.07 for stage 3 through stage 5 patients (not yet on maintenance dialysis) compared to patients with estimated GFR in the stage 1 and 2 range. Similar associations were seen after controlling for inpatient risk factors. Pre-admission baseline diabetes mellitus, diagnosed hypertension and known proteinuria were also independent risk factors for acute kidney failure. Our study shows that the propensity to develop in-hospital acute kidney failure is another complication of chronic kidney disease whose risk markedly increases even in the upper half of stage 3 estimated GFR. Several common risk factors for chronic kidney disease also increase the peril of nosocomial acute kidney failure.

Community-based incidence of acute renal failure.

There is limited information about the true incidence of acute renal failure (ARF). Most studies could not quantify disease frequency in the general population as they are hospital-based and confounded by variations in threshold and the rate of hospitalization. Earlier studies relied on diagnostic codes to identify non-dialysis requiring ARF. These underestimated disease incidence since the codes have low sensitivity. Here we quantified the incidence of non-dialysis and dialysis-requiring ARF among members of a large integrated health care delivery system - Kaiser Permanente of Northern California. Non-dialysis requiring ARF was identified using changes in inpatient serum creatinine values. Between 1996 and 2003, the incidence of non-dialysis requiring ARF increased from 322.7 to 522.4 whereas that of dialysis-requiring ARF increased from 19.5 to 29.5 per 100,000 person-years. ARF was more common in men and among the elderly, although those aged 80 years or more were less likely to receive acute dialysis treatment. We conclude that the use of serum creatinine measurements to identify cases of non-dialysis requiring ARF resulted in much higher estimates of disease incidence compared with previous studies. Both dialysis-requiring and non-dialysis requiring ARFs are becoming more common. Our data underscore the public health importance of ARF.

Frequent Hemodialysis Network (FHN) randomized trials: study design.

Observational studies suggest improvements with frequent hemodialysis (HD), but its true efficacy and safety remain uncertain. The Frequent Hemodialysis Network Trials Group is conducting two multicenter randomized trials of 250 subjects each, comparing conventional three times weekly HD with (1) in-center daily HD and (2) home nocturnal HD. Daily HD will be delivered for 1.5-2.75 h, 6 days/week, with target eK(t)/V(n) > or = 0.9/session, whereas nocturnal HD will be delivered for > or = 6 h, 6 nights/week, with target stdK(t)/V of > or = 4.0/week. Subjects will be followed for 1 year. The composite of mortality with the 12-month change in (i) left ventricular mass index (LVMI) by magnetic resonance imaging, and (ii) SF-36 RAND Physical Health Composite (PHC) are specified as co-primary outcomes. The seven main secondary outcomes are between group comparisons of: change in LVMI, change in PHC, change in Beck Depression Inventory score, change in Trail Making Test B score, change in pre-HD serum albumin, change in pre-HD serum phosphorus, and rates of non-access hospitalization or death. Changes in blood pressure and erythropoiesis will also be assessed. Safety outcomes will focus on vascular access complications and burden of treatment. Data will be obtained on the cost of delivering frequent HD compared to conventional HD. Efforts will be made to reduce bias, including blinding assessment of subjective outcomes. Because no large-scale randomized trials of frequent HD have been previously conducted, the first year has been designated a Vanguard Phase, during which feasibility of randomization, ability to deliver the interventions, and adherence will be evaluated.

Phosphorus balance and mineral metabolism with 3 h daily hemodialysis.

Poor control of mineral metabolism is independently associated with mortality in patients receiving hemodialysis. We analyzed data from a 12-month, prospective, non-randomized, controlled study of daily hemodialysis (DHD) (six sessions/week 3 h each) (n=26) vs conventional hemodialysis (CHD) (three sessions/week 4 h each) (n=51) for achievement of mineral metabolism goals and we performed a substudy of weekly dialytic phosphorus removal in DHD vs CHD. Phosphorus control was superior in the DHD group (% change from baseline to end-of-study -27+/-30% vs +7%+/-35% in the CHD group, P=0.0001). Percentage of patients using phosphate binders decreased from 77 to 40% among subjects on DHD, whereas these parameters did not change (76 vs 77%) in the CHD group (P=0.03 by Breslow-Day test for homogeneity of the odds ratios). Weekly mean phosphorus removal was higher in the DHD group (2452+/-720 mg/week vs 1572+/-366 mg/week, P=0.04). Mean normalized protein catabolic rate increased (0.90+/-0.43-1.22+/-0.26 g/kg/day, P=0.0013). DHD was also associated with an increase in the percent of subjects achieving three or more mineral metabolism goals (for phosphorus, calcium x phosphorus and parathyroid hormone) (15 vs 46%, P=0.046). In conclusion, DHD improves phosphorus control by increasing dialytic phosphorus removal while maintaining nutritional status and reducing the use of phosphate binders. The net effect allows for improved achievement of mineral metabolism goals.

Mortality after acute renal failure: models for prognostic stratification and risk adjustment.

To adjust adequately for comorbidity and severity of illness in quality improvement efforts and prospective clinical trials, predictors of death after acute renal failure (ARF) must be accurately identified. Most epidemiological studies of ARF in the critically ill have been based at single centers, or have examined exposures at single time points using discrete outcomes (e.g., in-hospital mortality). We analyzed data from the Program to Improve Care in Acute Renal Disease (PICARD), a multi-center observational study of ARF. We determined correlates of mortality in 618 patients with ARF in intensive care units using three distinct analytic approaches. The predictive power of models using information obtained on the day of ARF diagnosis was extremely low. At the time of consultation, advanced age, oliguria, hepatic failure, respiratory failure, sepsis, and thrombocytopenia were associated with mortality. Upon initiation of dialysis for ARF, advanced age, hepatic failure, respiratory failure, sepsis, and thrombocytopenia were associated with mortality; higher blood urea nitrogen and lower serum creatinine were also associated with mortality in logistic regression models. Models incorporating time-varying covariates enhanced predictive power by reducing misclassification and incorporating day-to-day changes in extra-renal organ system failure and the provision of dialysis during the course of ARF. Using data from the PICARD multi-center cohort study of ARF in critically ill patients, we developed several predictive models for prognostic stratification and risk-adjustment. By incorporating exposures over time, the discriminatory power of predictive models in ARF can be significantly improved.

The tortoise and hare on hemodialysis: does slow and steady win the race?

The importance of hemodialysis session length relative to small solute (e.g., urea) clearance has been debated for many years. Longer session length augments clearance of larger molecules and may facilitate ultrafiltration; however, the independent effects of session length on survival and other outcomes are unknown. In this report, we review two recently published observational studies examining the association between hemodialysis session length and survival. Prospective clinical trials will be required to resolve the debate.

Guided medication dosing for inpatients with renal insufficiency.

CONTEXT: Usual drug-prescribing practices may not consider the effects of renal insufficiency on the disposition of certain drugs. Decision aids may help optimize prescribing behavior and reduce medical error. OBJECTIVE: To determine if a system application for adjusting drug dose and frequency in patients with renal insufficiency, when merged with a computerized order entry system, improves drug prescribing and patient outcomes. DESIGN, SETTING, AND PATIENTS: Four consecutive 2-month intervals consisting of control (usual computerized order entry) alternating with intervention (computerized order entry plus decision support system), conducted in September 1997-April 1998 with outcomes assessed among a consecutive sample of 17 828 adults admitted to an urban tertiary care teaching hospital. INTERVENTION: Real-time computerized decision support system for prescribing drugs in patients with renal insufficiency. During intervention periods, the adjusted dose list, default dose amount, and default frequency were displayed to the order-entry user and a notation was provided that adjustments had been made based on renal insufficiency. During control periods, these recommended adjustments were not revealed to the order-entry user, and the unadjusted parameters were displayed. MAIN OUTCOME MEASURES: Rates of appropriate prescription by dose and frequency, length of stay, hospital and pharmacy costs, and changes in renal function, compared among patients with renal insufficiency who were hospitalized during the intervention vs control periods. RESULTS: A total of 7490 patients were found to have some degree of renal insufficiency. In this group, 97 151 orders were written on renally cleared or nephrotoxic medications, of which 14 440 (15%) had at least 1 dosing parameter modified by the computer based on renal function. The fraction of prescriptions deemed appropriate during the intervention vs control periods by dose was 67% vs 54% (P<.001) and by frequency was 59% vs 35% (P<.001). Mean (SD) length of stay was 4.3 (4.5) days vs 4.5 (4.8) days in the intervention vs control periods, respectively (P =.009). There were no significant differences in estimated hospital and pharmacy costs or in the proportion of patients who experienced a decline in renal function during hospitalization. CONCLUSIONS: Guided medication dosing for inpatients with renal insufficiency appears to result in improved dose and frequency choices. This intervention demonstrates a way in which computer-based decision support systems can improve care.

Correlates of acute renal failure in patients receiving parenteral amphotericin B.

BACKGROUND: While parenteral amphotericin B is an effective therapy for serious fungal infections, it frequently causes acute renal failure (ARF). This study identified correlates of ARF in amphotericin B therapy and used them to develop clinical prediction rules. METHODS: All 643 inpatients receiving parenteral amphotericin B therapy at one tertiary care hospital were included. Data regarding correlates were obtained both electronically and from manual chart review in a subsample of 231 patients. ARF was defined as a 50% increase in the baseline creatinine with a peak > or =2.0 mg/dL. RESULTS: Among 643 episodes, ARF developed in 175 (27%). In the larger group, the only independent correlate of ARF was male gender (OR = 2.2, 95% CI, 1.5 to 3.3). In the subsample (N = 231), independent correlates of ARF were maximum daily amphotericin dosage, location at the time of initiation of amphotericin therapy, and concomitant use of cyclosporine. These data were used to develop two clinical prediction rules. A rule using only data available at initiation of therapy stratified patients into groups with probability of ARF ranging from 15 to 54%, while a rule including data available during therapy (maximum daily dose) stratified patients into groups with probability of ARF ranging from 4 to 80%. CONCLUSIONS: Acute renal failure occurred in a quarter of the patients. Correlates of ARF at the beginning and during the course of amphotericin therapy were identified and then combined to allow stratification according to ARF risk. These data also provide evidence for guidelines for the selection of patients for alternative therapies.

Determinants of physical performance in ambulatory patients on hemodialysis.

BACKGROUND: Physical performance measures, particularly gait speed, have been useful as predictors of loss of independence, institutionalization, and mortality in older nonuremic individuals. Gait speed has not been evaluated as a predictor of these important outcomes in patients on hemodialysis, nor have the determinants of gait speed in the dialysis population been studied. METHODS: We performed a cross-sectional analysis to determine whether demographic, clinical, or nutritional status variables were related to physical performance in a group of 46 hemodialysis patients treated at three University of California San Francisco-affiliated dialysis units. Three physical performance measures were examined, including gait speed, time to climb stairs, and time to rise from a chair five times in succession. Forward stepwise linear-regression analysis was performed with each physical performance measure as the dependent variable and the following candidate predictor variables: age, gender, body mass index, dialysis vintage, Kt/V, albumin, blood urea nitrogen, creatinine, hematocrit, lean body mass, phase angle, ferritin, and the following comorbidities: hypertension, diabetes mellitus, coronary artery disease, peripheral vascular disease, and cerebrovascular disease. RESULTS: Subjects included 31 men and 15 women aged 22 to 87 years (mean +/- SD, 52 +/- 17). The mean gait speed for the group was 113.1 +/- 34.5 cm/s (low compared with norms established for persons of similar age). Results of multivariable regression showed that age, albumin, and Kt/V were important determinants of gait speed in this population. Overall, the model explained 52% of the variability in gait speed (r = 0.72, P < 0.0001). Qualitatively similar results were obtained using stair-climbing time or chair-rising time as the dependent variables, except that comorbidity was more important than age for stair climbing. The addition of physical activity level to the models did not eliminate the associations of albumin or Kt/V with physical performance. CONCLUSIONS: Physical performance is significantly impaired in ambulatory hemodialysis patients and is related to age, serum albumin, and dialysis dose. Prospective studies are needed to determine whether modification of dialysis dose or nutritional interventions can improve physical performance in patients on hemodialysis.

Inflammation and dietary protein intake exert competing effects on serum albumin and creatinine in hemodialysis patients.

BACKGROUND: Cross-sectional studies have shown an inverse correlation between serum C-reactive protein (CRP) and serum albumin concentration in hemodialysis patients. The net effects of inflammation and dietary protein intake on nutritional markers over time are unknown. METHODS: To explore the effects of CRP and normalized protein catabolic rate (nPCR) on serum albumin and creatinine, we analyzed six consecutive months of laboratory data from 364 hemodialysis patients, using a multivariable Mixed model with conservative biases. RESULTS: The overall trend over time in serum albumin was slightly positive (0.039 g/dL/month) and in serum creatinine slightly negative (-0.052 mg/dL/month). With increasing CRP, serum albumin declined significantly (-0.124 g/dL/month per unit increase in log CRP, adjusted for age, gender, race, diabetes, and nPCR, P < 0.0001). Serum albumin increased with increasing nPCR (0.021 g/dL/month per 0.1 g/kg/day, P < 0.0001). The effect of CRP on albumin was attenuated in African Americans and at a higher nPCR. Corresponding values for creatinine mirrored those for albumin. With increasing CRP, creatinine declined significantly [-0.142 mg/dL/month per unit increase in log CRP, adjusted for age, gender, race, diabetes (time since initiation of dialysis; vintage), Kt/V, and nPCR, P = 0.002]. Serum creatinine increased with increasing nPCR (0.183 mg/dL/month per g/kg/day, P < 0.0001). CONCLUSIONS: Proxies of inflammation and dietary protein intake exert competing effects on serum albumin and creatinine in hemodialysis patients. These data provide a rationale for prospective testing of dietary protein supplementation in hemodialysis patients with biochemical evidence of ongoing inflammation and "malnutrition."

Cardiac arrest and sudden death in dialysis units.

BACKGROUND: For patients with end-stage renal disease and their providers, dialysis unit-based cardiac arrest is the most feared complication of hemodialysis. However, relatively little is known regarding its frequency or epidemiology, or whether a fraction of these events could be prevented. METHODS: To explore clinical correlates of dialysis unit-based cardiac arrest, 400 reported arrests over a nine-month period from October 1998 through June 1999 were reviewed in detail. Clinical characteristics of patients who suffered cardiac arrest were compared with a nationally representative cohort of> 77,000 hemodialysis patients dialyzed at Fresenius Medical Care North America-affiliated facilities. RESULTS: The cardiac arrest rate was 400 out of 5,744,708, corresponding to a rate of 7 per 100,000 hemodialysis sessions. Cardiac arrest was more frequent during Monday dialysis sessions than on other days of the week. Case patients were nearly twice as likely to have been dialyzed against a 0 or 1.0 mEq/L potassium dialysate on the day of cardiac arrest (17.1 vs. 8.8%). Patients who suffered a cardiac arrest were on average older (66.3 +/- 12.9 vs. 60.2 +/- 15.4 years), more likely to have diabetes (61.8 vs. 46.8%), and more likely to use a catheter for vascular access (34.1 vs. 27.8%) than the general hemodialysis population. Sixteen percent of patients experienced a drop in systolic pressure of 30 mm Hg or more prior to the arrest. Thirty-seven percent of patients who suffered cardiac arrest had been hospitalized within the past 30 days. Sixty percent of patients died within 48 hours of the arrest, including 13% while in the dialysis unit. CONCLUSIONS: Cardiac arrest is a relatively infrequent but devastating complication of hemodialysis. To reduce the risk of adverse cardiac events on hemodialysis, the dialysate prescription should be evaluated and modified on an ongoing basis, especially following hospitalization in high-risk patients.