Nosocomial pneumonia: a cost-of-illness analysis.

BACKGROUND: We investigated incremental cost of nosocomial pneumonia (NP) from the perspective of a hospital and health insurance funds. PATIENTS AND METHODS: The incremental cost was determined by calculating total costs for pneumonia patients and controls using prospective and retrospective matched-pairs analysis with 29 and 37 matched pairs, respectively. RESULTS: Compared to controls, patients who developed pneumonia had to be on artificial ventilation 5 days longer, needed markedly more intensive care with 6.55 additional days in intensive care. Excess cost per pneumonia patient amounted to DM 14,606 (95% CI: DM 5,285-23,927) from the hospital's perspective and to DM 7,988 (95% CI: DM 5,281-10,894) according to statutory insurance charges. According to the retrospective anaLysis carried out on the neurosurgical and neurological intensive care wards, pneumonia patients were ventiLated 5 days longer than patients without pneumonia, needed more intensive care over 30 days and had an additional 14.03 days of intensive care and 10.14 more days in hospital. Excess cost per patient was DM 29,610 (95% CI: DM 23,054-36,174) from the hospitals perspective and DM 18,000 (95% CI: 14,885-21,020) according to the statutory insurance criteria. CONCLUSION: The study gives insight into the structure of incremental cost caused by NP and shows that based on a conservative cost calculation the incremental cost per NP patient is higher for the hospital than for health insurance funds which indicates a significant financial deficit for the hospital. Antibiotics and microbiology together only contribute 6.8% to incremental cost. Therefore in a cost saving initiative their close relationship to length of hospitalization must be considered.

Identifying outliers of antibiotic usage in prevalence studies on nosocomial infections.

OBJECTIVE: To investigate whether the correlation between patients' antibiotic treatment (yes/no) and patients' infections (yes/no) in each hospital department, described by Pearson's correlation coefficient (p) for binary data as a measure for adequate use of antibiotics, is an appropriate quality indicator. DESIGN: Comparison of the results of repeated prevalence studies in different hospitals with the data of a national prevalence study, comparing the hospital (p) and reference (pNIDEP[Nosokomiale Infektionen in Deutschland: Erfassung und Pravention]) correlation coefficients for "use of antibiotics/ presence of infections." SETTING: The data of 5,377 surgical patients were separated from the total data of a national prevalence study in 72 representative hospitals to create a reference correlation coefficient (rhoNIDEP) with a reference range. Nine additional prevalence studies, involving a total of 4,984 patients, were repeatedly performed in the surgical departments of 8 other hospitals during a 12-month period, whereby the correlation coefficients rho(n) for every prevalence investigation were determined. RESULTS: In the national prevalence study, 15.3% of the surgical patients received antibiotics on the study day. Surgical patients had a 3.8% prevalence of nosocomial infections and a 7.0% prevalence of community-acquired infections. Pearson's correlation coefficient rhoNIDEP for correlation between patients' binary data use of antibiotics and presence of infection was 0.62. To compare the correlation coefficient of each department with the appropriate reference range, the coefficients of the single departments were plotted against the number of patients; in these plots, three lines indicated the value rhoNIDEP and the upper and lower reference ranges, depending on the number of patients. Seven of eight surgical departments investigated during the repeated prevalence studies were found to be within the reference range, near the reference value, in the majority of prevalence studies; only one of the departments was identified as an outlier as regards antibiotic use. CONCLUSION: The correlation between patients' antibiotic treatment (yes/no) and patients' infections (yes/no) in hospitals or departments, as described by Pearson's correlation coefficient p for binary data with a definitive reference range depending on the number of patients, is useful for quality management in identifying the overall necessity for evaluating the indications for antibiotic use in one's own hospital.

Estimation of extra hospital stay attributable to nosocomial infections: heterogeneity and timing of events.

Infections acquired in hospital are likely to affect the duration of hospitalization. Suitable statistical methods for estimating the extra days spent in hospital due to nosocomial infections should allow modeling of the heterogeneity of the patient population and the timing of events, as failure to account for important covariates and failure to model adequately the timing of events may lead to biased results. Three approaches have been used in the past to estimate the extra stay: a comparison of duration of stay of infected and uninfected patients, matching of infected and uninfected patients with respect to potentially important determinants of the length of hospital stay, and matching for time-to-infection in addition to the other factors. While these approaches can allow for the heterogeneity of the patient population, none takes sufficient account of the real timing of events and may overestimate the effect of nosocomial infections. We explored the statistical methods available for analyzing time-to-event data and derived alternative methods to estimate the extra stay that appropriately account for heterogeneity and timing. Data from two prospective cohort studies on postoperative wound infection and on nosocomial pneumonia showed that the two-group comparison yields the highest estimates of extra stay (21 and 14 extra days), while matching for confounders and time reduced the estimates to 11 and 8 extra days; our methods yield even lower results (10-12 and 3-4 extra days).

Low alpha-linolenic acid content of adipose breast tissue is associated with an increased risk of breast cancer.

Data derived from experimental studies suggest that alpha-linolenic acid may have a protective effect in breast cancer. Observations obtained from epidemiological studies have not allowed conclusions to be drawn about a potential protective effect of dietary alpha-linolenic acid on breast cancer, possibly because of methodological issues. This case-control study conducted in an homogeneous population from a central area in France was designed to explore the hypothesis that alpha-linolenic acid inhibits breast cancer, using fatty acid levels in adipose breast tissue as a biomarker of past qualitative dietary intake of fatty acids. Biopsies of adipose breast tissue at the time of diagnosis were obtained from 123 women with invasive non-metastatic breast carcinoma. 59 women with benign breast disease served as controls. Individual fatty acids were analysed by capillary gas chromatography. An unconditional logistic regression model was used to obtain odds ratio estimates whilst adjusting for age, menopausal status and body mass index (BMI). No association was found between fatty acids (saturates, monounsaturates, long-chain polyunsaturates n-6 or n-3) and the disease, except for alpha-linolenic acid which showed an inverse association with the risk of breast cancer. The relative risk of breast cancer for women in the highest quartile of adipose breast tissue alpha-linolenic acid level was 0.36 (95% confidence interval=0.12-1.02) compared with those in the lowest quartile (P trend=0.026), suggesting a protective effect of alpha-linolenic acid in the risk of breast cancer. The effects of dietary alpha-linolenic on the risk of breast cancer warrant further study.

Comparison of effectiveness and required time of two surveillance methods in intensive care patients.

The intensive care unit (ICU) standardized protocol of the NNIS (National Nosocomial Infections Surveillance) system is a surveillance method of hospital acquired infections (HAI), which provides device-associated infection rates. The aim of this study was to assess the effectiveness and the required time for data collection and analysis of a selective surveillance method (SSM) derived from the NNIS ICU surveillance protocol, and to compare its data with that of a reference surveillance method (RSM). The sensitivity, specificity and the positive predictive value (PPV) of the RSM were 87.5, 100 and 100%, respectively. The sensitivity, specificity and the PPV of the SSM were 59.4 97.6 and 79.2%, respectively. Considering device-related infections only (ventilator-related pneumonia, catheter-related urinary tract infections, central line-related sepsis), the sensitivities of the RSM and the SSM were 80.9 and 90.5%, respectively. The SSM required only one third of the time of the RSM (1.1 h and 3.4 h per 10 beds per week with the SSM and the RSM, respectively). We conclude that the SSM has a very high sensitivity for detecting device associated infections, but is not sensitive enough for surveying all types of HAI.

A note on estimating local recurrence rates in clinical trials on the treatment of breast cancer.

Local recurrence rates play an important role in the evaluation and judgement of local treatment modalities in breast cancer. In the medical literature different methods for the calculation of these rates have been used. In this note we discuss the methods, the observed differences, and the interpretation of the resulting estimates.

Prevalence and risk factors for nosocomial lower respiratory tract infections in German hospitals.

The prevalence and risk factors for nosocomial lower respiratory tract infections (LRTI) in Germany were determined as part of a national survey on nosocomial infections. The study included 14,966 patients in 72 representatively selected hospitals with departments of general medicine, surgery, obstetrics, gynecology, and intensive care units (ICU). Surveillance was carried out by four previously validated medical doctors who strictly applied the CDC-criteria for diagnosis of nosocomial infections. The overall prevalence of hospital-acquired LRTI was 0.72% with the highest rate in hospitals with more than 600 beds (1.08%) and among the patients on intensive care units (9.00%). Ventilator-associated pneumonia rates were highest in patients on ICUs (13.27). Polytrauma, impaired consciousness, chronic airway disease, prior surgery, and cardiovascular disease were significantly related to the occurrence of nosocomial LRTI. P. aeruginosa was the predominant organism causing nosocomial LRTI. Nosocomial LRTI remain a problem mainly on ICUs. Patients at risk should be monitored with extra care.

Prevalence of nosocomial infections in representative German hospitals.

The nosocomial infection (NI) rate in German hospitals was studied in order to create reference data for comparison in hospitals where ongoing surveillance is impossible. The study was designed as a one-day prevalence study. Patients in 72 selected hospitals (inclusion criteria: acute care hospitals with departments for general medicine, surgery, obstetrics/gynaecology) were examined by four external investigators (physicians trained and validated in the diagnosis of NI). A total of 14,996 patients were studied. The overall prevalence rate was 3.5% (CI 3.1-3.9) with a variation of 0-8.9% between hospitals. The commonest NI were: urinary tract infection (42.1%), lower respiratory tract infection (20.6%), surgical site infections (15.8%) and primary sepsis (8.3%). The highest prevalence rate (15.3%) was found in intensive care ward patients, followed by surgery (3.8%), general medicine (3.0%) and gynaecology/obstetrics (1.4%). The infection rate varied significantly with hospital size. A microbiology laboratory report was only available for 56.5% of patients thought to have an NI, and there were remarkable differences between hospitals with and without an on-site microbiology laboratory. Because of this and other methodological reasons the NI prevalence rates reported here may represent the absolute minimum of nosocomially infected patients in Germany.

Incidence and epidemiology of nosocomial infections in patients infected with human immunodeficiency virus.

In a prospective study, we investigated the incidence, characteristics, and risk factors of nosocomial infections (NIs) in patients with human immunodeficiency virus disease. There was a total of 528 admissions of 405 eligible patients; 46 NIs (8.7% per discharge) were identified in 39 patients. The proportional frequencies of NIs were as follows: 16 skin and/or soft-tissue infections (including localized catheter-associated infections), 3.0%; 14 respiratory tract infections, 2.7%; 11 bloodstream infections, 2.1%; and 5 urinary tract infections, 0.9%. The most common etiologic agents were Staphylococcus aureus (27.6%), Pseudomonas aeruginosa (13.8%), and Enterobacter cloacae (13.8%). The duration of hospitalization was not significantly prolonged by NI in the cohort.

Modeling psychotherapy outcome as event in time: an application of multistate analysis.

Standard survival analysis (SA) and multistate analysis (MSA) are methods for modeling categorical psychotherapy outcome events over time. The underlying principles, mathematical details, and indications for using each technique are discussed, and data from an anorexia nervosa psychotherapy outcome study comparing psychodynamic psychotherapy with psychodynamic psychotherapy plus cognitive-behavioral techniques are used to illustrate the use of SA and MSA techniques. MSA includes multiple competing outcome states in a single model. A single MSA model includes reaching target weight and treatment dropout before reaching target weight as competing events. It is concluded that MSA is an informative analytic technique in the domain of psychotherapy research.

[Nosocomial infections intensive care units. A nation-wide prevalence study]. / Nosokomiale Infektionen auf Intensivstationen. Eine bundesweite Prävalenzstudie (NIDEP).

UNLABELLED: In a large, multicenter survey in 1994, the prevalence of nosocomial infections in German hospitals was examined, predominant pathogens were identified, and possible risk factors evaluated. In this paper the results from the intensive care units (ICUs) are presented. METHODS: Seventy-two representative hospitals in Germany were selected by randomisation and divided into four different groups according to their size (< 200 beds; 200-400 beds; 400-600 beds; > 600 beds). During 10 months four especially trained doctors documented the patients clinical and laboratory data and possible endogenous and exogenous risk factors for nosocomial infections. For better evaluation, they discussed the cases with the responsible senior officers and health care workers and visited the patients. Diagnosis of nosocomial infection was based on CDC criteria. RESULTS: In 515 patients in 89 ICUs, 78 hospital-acquired infections were documented (15.3%). The most common were pneumonia (5.9%), bronchitis (2.7%), urinary tract infections (2.4%), and septicaemia (2.2%). Possible exogenous risk factors included: peripheral venous catheters (65.6%); catheterisation of the urinary tract (64.5%); central venous catheters (60.4%); gastric tubes (38.0%); wound drainage (28.6%) and artificial ventilation (27.6%). The most frequent concomitant diseases were cardiovascular (61.9%), diabetes (20.2%), malignancies (18.8%), pre-existing infections (15.3%), and chronic respiratory disease (14.0%). The prevalence of nosocomial infections was higher in hospitals with more than 600 beds than in smaller ones (28.3% versus 12.9%, P < 0.001). Predominant pathogens were Pseudomonas aeruginosa, enterococci, Staphylococcus aureus, Candida spp., Escherichia coli, and Klebsiella spp.. Fifty per cent of the ICUs changed ventilation tubes and 66.3% changed infusion sets daily; 34.8% of patients received drugs for the prevention of stress ulcers that neutralise or decrease production of gastric acid; only 7.6% received sucralfate. Routine microbiological surveillance of tracheal aspirates and urine was done by 25.9% and 24.6% of the ICUs, respectively. DISCUSSION: Nosocomial infections are seen far more often in ICUs than on normal wards due to the immuno-suppressed state of many ICU patients and the continuous use of invasive diagnostic and therapeutic procedures. Most of these infections are of endogenous origin. Other prevalence surveys have shown results comparable to ours. Daily changing of ventilation tubes is no longer necessary, but is still routine in many hospitals. Infusion sets were also changed more often than required. The use of selective decontamination of the digestive tract for the prevention of pneumonia is still controversial; in our study it was practised in only 1.5% of the cases. The most commonly used drugs for the prevention of stress ulcers were H2-receptor blocking agents, although it has been shown that sucralfate is the better choice, as it can help prevent nosocomial pneumonia. Routine microbiological surveillance of tracheal aspirates and urine was done in 25.9% and 24.6% of the ICUs. No study so far has shown that routine cultures of tracheal secretions and urine have a preventive effect regarding infection.

[Nosocomial infections in Germany. Microbiological diagnosis, preventive antibiotics and antibiotic therapy]. / Nosokomiale Infektionen in Deutschland (NIDEP). Mikrobiologische Diagnostik, Antibiotikaprophylaxe und Antibiotikatherapie.

BACKGROUND: The NIDEP-study (Nosocomial Infections in Germany-Prevalence and Prevention) is the first large multicenter survey to examine the prevalence of nosocomial infections (NI) in Germany. This part of the NIDEP-study describes the frequency and quality of the microbiological diagnosis, antimicrobial chemoprophylaxis and therapy in representative German hospitals. PATIENTS AND METHOD: Prevalence of nosocomial infections in 14 966 patients of 72 randomly selected representative German hospitals was determined. Frequency, nature and results of the microbiological diagnosis, antimicrobial chemoprophylaxis and therapy were recorded simultaneously. RESULTS: The total prevalence rate of nosocomial infections was 3.5%. The most common infections were urinary tract infections (42.1%), lower respiratory tract infections (20.6%), postoperative wound infections (15.8%), and septicemia (8.3%). Microbiological evaluation was done in 56.5% of the patients with infections. Only five of the 49 hospitals with less than 400 beds and only nine of the 23 hospitals with more than 400 beds had their own microbiological department. Antimicrobial chemotherapy was administered in 17.7% of the patients. In 35.1% of the patients who were treated with antibiotics, no clinical diagnosis of infection was made, criteria for nosocomial infections were not fulfilled or microbiological evaluation was not established. Antimicrobial chemoprophylaxis was done in one third of the patients. Prophylaxis was missed in 20.6% of patients with colorectal operations, 60.1% of appendectomies, 48% of vaginal hysterectomies, and 35.5% of total hip replacements. On the other hand antimicrobial chemoprophylaxis was frequently administered in clean procedures without increased risk of postoperative wound infections. CONCLUSION: Insufficient microbiological evaluation, inadequate perioperative antimicrobial chemoprophylaxis and administration of chemotherapy without documented infection were detected in representative German hospitals.

Scoring system for nosocomial pneumonia in ICUs.

OBJECTIVE: To develop a scoring system for stratifying patients in intensive care units (ICUs) by risk of developing nosocomial pneumonia (NP), based on variables generally available in an ICU, and to determine the probability of a patient developing NO in the ICU. DESIGN AND SETTING: a 2-year prospective cohort study conducted in a medical and surgical ICU. PATIENTS: 756 patients admitted to the ICU for 48 h or more were followed up until the development of NP or death or discharge from the ICU. MEASUREMENTS AND RESULTS: 129 (17.1%) patients developed NP, 106 (14%) in the first 2 weeks. The following independent risk factors were identified by multivariate analysis: no infection on admission [relative risk (RR) = 3.1, 95% confidence intervals (CI) = 2.0 to 4.81; thorax drainage (RR = 2.1, 95% CI = 1.2 to 3.5); administration of antacids (RR = 2.1, 95% CI = 1.4 to 3.1); partial pressure of oxygen (PO2) > 110 mmHg (RR = 1.6, 95% CI = 1.0 to 2.6); administration of coagulation factors (RR = 1.8 95% CI = 1.0 to 3.2); male gender (RR = 2.7, 95% CI = 1.2 to 6.3); urgent surgery (RR = 2.4, 95% CI = 0.9 to 6.4); and neurological diseases (RR = 4.2, 95% CI = 1.9 to 9.4). To obtain a predictive risk index for NP, a scoring system was developed using a multivariate model. The probability of developing NP varied between 11.0% in the lowest risk group and 42.3% in the highest risk group. The patients' risk of acquiring NP was seven times higher in the highest score category (i.v.) than in the lowest one (I). CONCLUSIONS: ICU patients can be stratified into high- and low-risk groups for NP. No infection on admission, thorax drainage, administration of antacids, and PO2 > 110 mmHg were associated with a higher risk of NP during the entire 2-week period.

Estimation of prolongation of hospital stay attributable to nosocomial infections: new approaches based on multistate models.

Evaluation of the impact of nosocomial infection on duration of hospital stay usually relies on estimates obtained in prospective cohort studies. However, the statistical methods used to estimate the extra length of stay are usually not adequate. A naive comparison of duration of stay in infected and non-infected patients is not adequate to estimate the extra hospitalisation time due to nosocomial infections. Matching for duration of stay prior to infection can compensate in part for the bias of ad hoc methods. New model-based approaches have been developed to estimate the excess length of stay. It will be demonstrated that statistical models based on multivariate counting processes provide an appropriate framework to analyse the occurrence and impact of nosocomial infections. We will propose and investigate new approaches to estimate the extra time spent in hospitals attributable to nosocomial infections based on functionals of the transition probabilities in multistate models. Additionally, within the class of structural nested failure time models an alternative approach to estimate the extra stay due to nosocomial infections is derived. The methods are illustrated using data from a cohort study on 756 patients admitted to intensive care units at the University Hospital in Freiburg.

Magnetic fields and childhood cancer--a pooled analysis of two Scandinavian studies.

To test the hypothesis that exposure to magnetic fields, of the type generated by high voltage installations, increases cancer incidence in children, the original data from two case-control studies were pooled. The Swedish study was based on children living within 300 m from transmission lines, and the Danish study on the total population of Denmark. In both these studies, national cancer registries were used to identify cases of leukaemia, lymphoma or central nervous system tumour. Controls were selected randomly from the study populations. Magnetic field exposure was assessed through theoretical calculations of the magnetic fields before the time of diagnosis. An elevated relative risk of childhood leukaemia was found for calculated magnetic field levels of > or = 0.2 microT, estimated at 2.0 (95% CI 1.0-4.1), and for magnetic field levels of > or = 0.5 microT, estimated at 5.1 (95% CI 2.1-12.6). The results support the hypothesis of an association between magnetic fields and childhood leukaemia.

Antiepileptic treatment and risk for hepatobiliary cancer and malignant lymphoma.

The possible influence of phenobarbital and phenytoin treatment on cancer risk was investigated in a case-control study nested in a cohort of 8004 epileptic patients in Denmark. Information on anticonvulsive treatments was abstracted for 95% of 60 patients with cancers of the liver and biliary tract or malignant lymphoma and for 94% of 171 cancer-free control patients. Use of anticonvulsive drugs was correlated with angiographic procedures that used Thorotrast, a well-known human liver carcinogen. After exclusion of study subjects exposed to Thorotrast, no association was seen between treatment with phenobarbital and cancer of the liver (odds ratio, 1.0; 95% confidence interval, 0.1-8.0) or biliary tract (odds ratio, 0.8; 95% confidence interval, 0.1-4.2). Furthermore, a histopathological evaluation of slides from 7 of 9 liver cancer patients not treated with Thorotrast revealed that 3 of the 4 cases of hepatocellular carcinoma involved cirrhosis of the liver, which suggested an etiological role for alcohol or viral hepatitis. A possible link was observed between use of phenytoin and risk for non-Hodgkin's lymphoma (1.8; 0.5-6.6), with a rising trend in risk with increasing dose. Our results suggest that the increased risk for cancers of the liver and biliary tract among Danish epileptic patients is likely to be due to Thorotrast administration and factors associated with cirrhosis of the liver rather than to anticonvulsive treatment.

Outcome-oriented cutpoints in analysis of quantitative exposures.

In the analysis of epidemiologic data in which exposure has been measured on a continuous scale, cutpoints can be defined to delineate categories or exposure can be modeled as a continuous covariate by assuming a special functional shape of the effect on disease status. Rules for classifying exposure into two or more categories range from a priori selection of cutpoints to data-oriented rules. The risk estimates may vary, however, with the choice of cutpoint. If the cutpoint selected is that for which the most impressive effect of exposure on outcome is observed, the final result must be qualified by adjustment. In this paper, the authors propose a method for adjusting results which are derived by varying the cutpoint on a specified selection interval. Adjustment is derived from the null distribution of the maximally selected test statistic. The method should be applied to correct p values if the cutpoint used to define different levels of exposure is selected in such a way that the measure of difference between two risk groups, such as the odds ratio or relative risk, is maximized. No method is yet available for adjusting the resulting risk estimate and the corresponding confidence limits. The authors illustrate the statistical method by applying it to data from a case-control study of the association between exposure to magnetic fields and risk of cancer in children which was conducted recently in Denmark.

[Electromagnetic fields from high-voltage installations and cancer in childhood]. / Elektromagnetiske felter fra højspaendingsanlaeg og børnecancer.

The objective of this population-based case-control study has been to investigate whether residence before and after birth near 50 Hz high voltage installations increases a child's risk of cancer and whether risk correlates with the strength of the magnetic field. One thousand seven hundred and seven children under the age of 15 with either leukaemia, a tumour of the central nervous system, or malignant lymphoma diagnosed in 1968-86 were identified in the Danish Cancer Registry and matched with 4788 population controls. Measures of exposure were proximity before and after birth to existing or former 50-400 kV electrical transmission connections and substations and associated historical electromagnetic fields calculated on the basis of current load on line, phase ordering of line, and distance from the dwelling. A significant association was seen between all major types of childhood cancer combined and exposure to magnetic fields from high voltage installations of > or = 0.4 microT (odds ratio 5.6). At > or = 0.25 microT no significant association was seen (odds ratio 1.5). A possible association was also seen with cases of Hodgkin's disease separately at > or = 0.1 microT. On the basis of these results and additional descriptive data on electricity consumption and incidence of childhood cancer in Denmark since the 1940s it was concluded that the proportion of childhood cancer possibly caused by 50 Hz electromagnetic fields must be small.

Captopril versus digoxin in patients with coronary artery disease and mild heart failure. A prospective, double-blind, placebo-controlled multicenter study. The CADS Study Group.

We conducted a prospective, double-blind, placebo-controlled multicenter trial in order to evaluate the long-term effects of captopril (50 mg/day), digoxin (0.25 mg/day) and placebo on quality of life, cardiovascular events, clinical symptoms and exercise tolerance in patients with documented myocardial infarction, resulting in regional wall motion abnormalities, and with mild heart failure (NYHA class II to III without treatment) and exercise not limited by angina. 222 patients were studied, 63 were randomized to captopril, 66 to digoxin, 67 to placebo. Follow-up was conducted for two years. Base line characteristics in the three treatment groups were similar. After one year of therapy, digoxin had significantly improved general well-being (p < 0.01 vs captopril), symptom score (p < 0.05 vs captopril and placebo), and vitality (p < 0.05 vs captopril). Digoxin improved NYHA class in 45% as compared to placebo (28%, p < 0.05). Worsening of angina was more frequent with captopril as compared to digoxin (p < 0.05). However, cardiovascular events during follow-up were lower in the captopril group as compared to placebo and digoxin (p < 0.01 captopril vs placebo). No differences between groups were observed in baseline and follow-up exercise tolerance between the three groups. Dizziness during upright tilt and cough were more frequent with captopril as compared to digoxin or placebo. After two years of follow-up (captopril n = 32, digoxin n = 29, placebo n = 27) general well-being was improved with both digoxin and captopril (p < 0.004 and p < 0.03 vs placebo).(ABSTRACT TRUNCATED AT 250 WORDS)