Adverse drug events in hospitalized patients.
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Drug Therapy↗
Biomedical subjects
J Hasford
Publications and source records attributed to J Hasford.
Adverse drug reaction monitoring--cost and benefit considerations. Part I: frequency of adverse drug reactions causing hospital admissions.
In an era of health care cost containment it is of particular interest to identify measures that reduce costs and at the same time improve health care quality. One of these cost cutting measures might be the reduction of the frequency of Adverse Drug Reactions (ADR). The objective of this paper is to summarize all original work on ADR frequencies at hospital admission and to come up with a valid estimate for the actual frequency of ADR-related hospital admissions. Additionally, we compared established concepts of ADR monitoring with respect to their utility for drug safety monitoring and pharmacoepidemiologic research. We reviewed 25 studies from the past 25 years. Analysing the effect of methodological characteristics showed that variation of reported ADR frequency mainly depends on differing study bases and the concepts of ADR monitoring. Investigations that thoroughly screened all members of the study population for the presence of adverse drug reactions (comprehensive ADR monitoring) generally yielded highest ADR proportions. Studies that concentrated screening on selected high-risk patients (preselective ADR monitoring) and those applying spontaneous or intensified spontaneous reporting detected lower ADR proportions (2.9% and 2.5%). The ADR proportion among admissions to departments of internal medicine was higher than among mixed hospital populations including surgical patients. In conclusion 4.2-6.0% (lower and upper quartile) and in median 5.8% of all admissions to medical departments are caused by adverse drug reactions. A two-step preselective ADR monitoring appears to be appropriate and efficient for both signal generation and signal validation as compared to spontaneous reporting and comprehensive monitoring. In conclusion, adverse drug reactions are a common cause of hospital admissions. As hospital care is expensive, attempts to prevent ADR and thus hospital admission need active encouragement.
Journal Article↗
Adverse drug reaction monitoring--cost and benefit considerations. Part II: cost and preventability of adverse drug reactions leading to hospital admission.
Although adverse drug reactions (ADR) are common, there is little knowledge on their direct, indirect and intangible costs. Our study is focused on the direct costs caused by ADR leading to hospital admission. The objective is to quantify the achievable financial benefits if avoidable ADRs were actually prevented by appropriate measures. A literature search on two subjects was done, first on length of stay (LOS) of hospital admissions due to ADR as a proxy measure for direct costs and second on their preventability. Thirteen studies on the length of stay of hospital admissions due to ADR, published between 1975 and 1996, were identified. The median LOS is 8.7 days (lower quartile=8.0 days; upper quartile=12.3 days). Assuming 4.5 million admissions to departments of internal medicine in Germany with a cost of DM 465 per hospital day and a median proportion of 5.8% of medical hospital admission to be due to ADR this yields direct costs of 1050 million DM per year in Germany. A cost table for other regions is provided. Preventability of ADR was the subject of 14 publications that revealed about 30% of all ADRs to be preventable. With regard to Germany this means that 350 million DM per year could be saved by preventing adverse drug reactions. These conservative estimates-no indirect and intangible costs, no ADRs that occur during hospital stay, no ADRs in outpatient care are included-show a considerable economic burden of ADRs. As about 30% of these ADRs are considered avoidable policy-makers are asked to invest more into ADR monitoring and preventive measures. Their benefit would surmount costs and at the same time increase the quality of care.
Journal Article↗
Drug use assessment and risk evaluation in pregnancy--the PEGASUS-project.
Since the thalidomide tragedy it is well accepted that drugs can have adverse effects on the unborn child. Although numerous studies show that drug use during pregnancy is widespread, there still is a serious lack of comprehensive and valid data on the risks of drug use during pregnancy. One objective of the PEGASUS-project, which focuses on Munich, is to enlarge the knowledge on embryo- and fetotoxic properties of drugs by prospectively recording information on drug exposure during pregnancy and analysing these data with regard to untoward fetal outcome. First results of PEGASUS confirm that drug utilization during pregnancy is rather common-85% of women use at least one preparation. The most frequent groups are haematologicals, minerals, iodide, and vitamins. Randomized studies have shown that periconceptional folic acid supplementation considerably reduces the risk of neural tube defects. However, only very few women in the PEGASUS-project recorded folic acid intake during the critical period or in sufficient dosage.
Journal Article↗
Comparative analysis of the impact of risk profile and of drug therapy on survival in CML using Sokal's index and a new score. German chronic myeloid leukaemia (CML)-Study Group.
Survival times in chronic myeloid leukaemia (CML) may vary widely depending on the risk profiles of patients. This fact is frequently not, or not sufficiently, considered in evaluating survival in CML, and some studies do not report risk profiles. Therefore we analysed the relative impact of risk profile and therapy on survival using the median survival times of therapy groups and of risk groups of the three-arm randomized German CML Study I (interferon alpha v hydroxyurea v busulphan; median survival times 65 v 56 v 45 months, n = 490, median observation time 70.4 months). The impact of risk profile (Sokal) on survival as determined by the survival difference between high and low risk patients (40 months) was twice the maximum survival difference between treatment groups (20 months). A similar ratio was obtained after stratification for therapy and for risk profile. Since Sokal's index has been reported to prognostically discriminate IFN-treated patients less well than chemotherapy-treated patients, a new score with better discrimination of IFN-treated patients was also used. The results were similar for both scores. We conclude that the risk profile at diagnosis is still more important for survival of CML patients than therapy. Therefore patients should be stratified according to risk profile for comparisons of survival times between studies and treatment arms.
Adolescent↗
Randomized studies with interferon in chronic myelogenous leukemia (CML) and comparative molecular aspects. German CML Study Group.
Four randomized prospective studies on interferon alpha (IFN) in CML report varying degrees of prolongation of the chronic phase of CML and of survival as compared to conventional therapies. There is agreement that IFN prolongs survival as compared to standard busulfan. There is disagreement, however, as to which degree IFN is superior to hydroxyurea. Whereas the randomized studies of the Italian cooperative group and of the British MRC find a statistically significant survival advantage of IFN over hydroxyurea of about 20 months, this difference is only 10 months in the German randomized study and not significant. One reason for this difference might be the more intensive treatment schedule for the hydroxyurea control group in the German study. Other reasons might be differences in risk profiles between the patient groups studied and in strategies of IFN therapy. About 1% of the human genome consists of retroviral or retroviral-like sequences. By analogy to animal models, endogenous retroviruses might also have pathogenic potential in human disease. The transposon-like structure of retroviruses that enables them to integrate at almost any position in the host genome and the capability of retroviruses to serve as efficient vehicles of cellular genes are in support of a pathogenic potential. Furthermore, particles resembling retroviruses have been observed long ago in human embryonic and malignant tissues and cell lines. Sequence information and the transcriptional activity of the endogenous sequences argue against the possibility that these sequences are only fossil relics of early evolutionary periods. Most of the sequences appear to be inactivated by stop codons or frameshifts, making the genomic localization of open reading frames with biological activity difficult. Up to now, mutagenesis by insertion of retroviral-like sequences in sporadic cases of human disease appears to be the only example of pathogenic relevance of retroviruses in man.
Antineoplastic Agents↗
The PEGASUS project--a prospective cohort study for the investigation of drug use in pregnancy. PEGASUS Study Group.
Since the thalidomide disaster, it is well accepted that drugs can have adverse effects on the developing human being. Although numerous studies show that medication during pregnancy is wide-spread, there still is a serious lack of comprehensive and valid data concerning the risks of drug use during pregnancy. One objective of the PEGASUS project, a population-based cohort study focusing on Munich, is to prospectively record information on drug exposure during pregnancy, to evaluate these data with regard to teratogenic properties, and to contribute to the quality assurance of medical treatment in pregnancy. The results of PEGASUS confirm that drug utilization during pregnancy is rather common--84% of the women use at least one preparation. The most frequent groups are minerals (mainly magnesium), iodide, and iron preparations. Although randomized studies have shown that periconceptional folic acid supplementation considerably reduces the risk of neural tube defects, only very few women in the PEGASUS project recorded folic acid intake during the critical period and in sufficient dosage. Moreover, only 42% of the pregnant women apply iodide prophylaxis in the recommended dosage.
Adverse Drug Reaction Reporting Systems↗
Interferon-alpha and hydroxyurea in early chronic myeloid leukemia: a comparative analysis of the Italian and German chronic myeloid leukemia trials with interferon-alpha.
In 1994, the Italian and the German Chronic myeloid leukemia (CML) trials comparing interferon-alpha (IFN-alpha) with conventional chemotherapy were published. The survival advantage in favor of IFN-alpha compared with hydroxyurea (HU; 72 v 52 months) was significant in the Italian (P < .002), but not in the German trial (66 v 56 months, P < .44). We set up a collaborative study to identify the reasons for the different outcomes. There are major differences in the trial protocols concerning admission criteria, treatment strategy, and definitions. The German patients were older and more seriously sick. Fifty-two of the 327 patients in the German IFN and HU arms did not fulfil Italian admission criteria, and 41 of the 322 Italian patients did not fulfil German admission criteria. Using mutually uniform admission criteria, the median survival times of the IFN patients are 76 (Italian) and 72 (German) months (P = .56). The Italian group administered IFN combined with HU as needed, whereas the German group strictly used IFN as monotherapy with rerandomization to busulfan (BU) or HU after IFN resistance or intolerability. The differences seen between the Italian and the German trial results can be accounted for by objective differences in study design, especially the admission criteria, treatment strategy, and bias due to intention to treat analysis. The detailed analysis of the data suggests that the combination of IFN with HU as needed is more effective than either agent alone.
Adult↗
Injection of fibrin tissue adhesive versus laser photocoagulation in the treatment of high-risk bleeding peptic ulcers: a controlled randomized study.
BACKGROUND AND STUDY AIMS: A controlled and randomized multicenter study was carried out in order to compare the efficacy of fibrin sealant and Nd:YAG laser photocoagulation in patients with high-risk arterial bleeding from peptic ulcers of the stomach and the small intestine. PATIENTS AND METHODS: In four teaching hospitals, 53 patients presenting with either active arterial ulcer bleeding (Forrest class 1 a) or a large visible vessel in the ulcer base (diameter over 2 mm, Forrest class 2 a) were treated with infiltration of epinephrine 1: 10,000 followed by the injection of fibrin tissue adhesive (n = 28), or with epinephrine plus laser photocoagulation (n = 25). Permanent hemostasis for at least seven days served as the principal end point; rebleeding, emergency surgery, and hospital mortality served as further end points. RESULTS: There were no significant differences between the study groups in terms of age, risk factors, initial hemoglobin values, number of patients showing signs of hemodynamic impairment, ulcer size and localization, or bleeding activity. Primary hemostasis was achieved in all patients. Rebleeding rates were seven of 28 and four of 25 among the patients treated with fibrin sealant and laser coagulation, respectively (not significant). There were no significant differences regarding the rates of ultimate hemostasis (24 of 28 vs. 24 of 25), emergency surgery (four of 28 vs. one of 25), or hospital mortality (0 vs. two of 25). No complications occurred with either form of treatment. Patients who had a visible vessel in the ulcer floor at the first control endoscopy had a significantly higher incidence of rebleeding, regardless of the type of endoscopic therapy. CONCLUSIONS: We conclude that both the injection of fibrin tissue adhesive and laser photocoagulation are effective methods of treating high-risk arterial peptic ulcer bleeding. As the number of high-risk patients necessary to reach significance are difficult to recruit within a reasonable period even in a multicenter study, a new meta-analysis of all studies now available should be considered.
Epinephrine↗
The Lupus Plasmapheresis Study Group: rationale and updated interim report.
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Antibodies↗
Randomized study of the combination of hydroxyurea and interferon alpha versus hydroxyurea monotherapy during the chronic phase of chronic myelogenous leukemia (CML Study II). The German CML Study Group.
It is the long-term goal of the German CML Study Group and of the Süddeutsche Hämoblastosegruppe (SHG) to improve survival of patients with chronic myelogenous leukemia (CML). In a first randomized study (CML Study I) monotherapies with hydroxyurea or interferon alpha (IFN-alpha) were compared with a standard busulfan regimen with regard to duration of the chronic phase and survival. The main results of this study were published, 1-3 and a long-term follow up is planned. In a second randomized study the effect of the combination of IFN-alpha and hydroxyurea versus hydroxyurea monotherapy on survival is being investigated. This paper provides a first preliminary report on the study concept, patient recruitment, state of documentation and initial patients' characteristics 9 months after closure of the study.
Adult↗
Analysis and validation of prognostic factors for CML. German CML Study Group.
The analysis and validation of prognostic factors is a decisive prerequisite with regard to the development and application of risk-adjusted therapies. Among others, the Sokal index 1 and Kantarjian's new staging system 2 were scores set up to assess the survival of every patient individually. By means of 504 Ph- and/or bcr-abl-positive patients of the German CML study I, we tried to validate both scores mentioned above. Whereas Kantarjian's staging system provided rather unsatisfactory results, the discrimination of different risk groups was more promising with respect to the Sokal index. Still, concerning the differentiation between risk groups for the interferon-alpha (IFN-alpha) treated patients of the German study I, the Sokal index also failed. Hence, we applied Cox stepwise regression technique and identified three prognostic factors for the IFN-alpha treated patients, i.e. eosinophils, erythroblasts (both in peripheral blood), and extramedullary manifestations. We developed our own score and found an encouraging 5-y survival rate of 90% (95% confidence interval (CI) 76-100%) for a certain low-risk group of 41 out of 120 IFN-alpha treated patients. With the need to validate our score and, if possible, not only to confirm the above result but also to identify other particular patient groups, we launched the European Prognostic Factors Project (E.P.F.P.). Within this project, our special interest will be dedicated to patient groups who might also benefit from a bone marrow transplantation.
Adolescent↗
Beneficial clinical effect of very early enalapril treatment in patients with acute left ventricular failure complicating myocardial infarction.
Acute myocardial infarction (AMI) leads to left ventricular dysfunction, the extent of which predicts mortality. We studied the effect of very early enalapril treatment in patients with left ventricular failure (Killip classification II-III) resulting from AMI. In a double-blind randomized trial, patients on conventional treatment were started on placebo (PL, n = 15) or 2.5 mg enalapril (EN, n = 15) twice daily as early as 24 to 30 h after AMI and were followed up over a period of 21 days. One patient died in each treatment group. There were three dropouts in the placebo group (progressive heart failure requiring antiotensin-converting enzyme inhibition) and one dropout in the enalapril group (malignant ventricular arrhythmias). Plasma atrial natriuretic peptide (ANP) and norepinephrine decreased similarly in both groups from elevated baseline concentrations. The patients with the highest baseline ANP levels died in both groups: EN: 579 fmol/ml (mean 65.3 +/- 34.4 fmol/ml), PL: 403 fmol/ml (mean 63.5 +/- 37.6 fmol/ml). Killip classification improved in 9 of 13 patients on enalapril but only in 5 of 11 patients on placebo. On echocardiography an increase in fractional shortening (FS) (3.2 +/- 7.5%, p < 0.05) was found with enalapril only. Patients on placebo required more diuretics, and plasma aldosterone increased threefold. Thus, very early enalapril treatment may help prevent left ventricular failure after AMI. Extremely high initial plasma ANP concentrations may predict an unfavorable outcome.
Aged↗
Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group.
As curative bone marrow transplantation is available only to a minority of patients with chronic myelogenous leukemia (CML), drug therapy remains of central interest. Several nonrandomized studies have suggested that interferon-alpha (IFN) may prolong survival in CML. In a randomized multicenter study the influence of IFN versus busulfan or hydroxyurea (HU) on survival of Philadelphia-positive (Ph+) CML was examined. A total of 513 Ph+ patients were randomized for treatment as follows: 133 for IFN, 186 for busulfan, and 194 for HU. IFN-treated CML patients have a significant survival advantage over busulfan-treated (P = .008), but not over HU-treated patients (P = .44). The longer survival is due to slower progression to blast crisis. Median survival of IFN-treated patients is 5.5 years [5-year survival, 59%; 95% confidence interval (CI), 48%-70%], of busulfan-treated patients, 3.8 years (5-year survival, 32%; CI, 24%-40%), and of HU-treated patients, 4.7 years (5-year survival, 44%; CI, 36%-53%). Patients who continue on IFN survive longer than those in whom IFN is discontinued before blast crisis (P = .007). Complete hematologic IFN-responders have a survival advantage over partial responders or nonresponders (P = .02). Cytogenetic IFN-responders have no significant survival advantage over nonresponders (P = .2). Patients who attain white blood cell (WBC) counts of 10 x 10(9)/L or less have a survival advantage in the IFN (P = .007) and HU (P = .05) groups. Whereas toxicity in the IFN group was considerably higher than in the busulfan or HU groups, long-lasting cytopenias necessitating discontinuation of therapy as observed with busulfan have not been seen with IFN or HU. The problems of conventional prognostic scores (Sokal's score, Score 1) that we observed in IFN-treated patients support the idea that IFN changes the natural course of CML. We conclude that, with regard to survival of CML in the chronic phase, IFN is superior to busulfan and as effective as HU. Whether and to what extent IFN is superior to HU appears to depend, at least in part, on the degree of WBC suppression by HU-therapy and on the risk profile of the patients.
Adolescent↗
Roferon (rIFN-alpha 2a) is more immunogenic than intron A (rIFN-alpha 2b) in patients with chronic myelogenous leukemia.
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Antibody Formation↗
Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. The German CML Study Group.
In a randomized multicenter study the influence of hydroxyurea versus busulfan on the duration of the chronic phase and on survival of chronic myelogenous leukemia (CML) was determined. In addition cross resistance and adverse reactions of the drugs were analyzed. From July 1983 to January 1991, 441 CML patients were randomized to receive hydroxyurea or busulfan. Of these, 90.7% were Philadelphia positive; 25.7% were low, 38.2% intermediate, and 36.2% high risk patients according to Sokal's score. The median survival of the busulfan treated Philadelphia-positive patients is 45.4 months and of the hydroxyurea group 58.2 months (P = .008). The survival advantage for the hydroxyurea treated patients is recognized in all risk groups. Sixty four patients reached therapy resistance before blast crisis and were crossed over to the alternative drug. The 23 patients with primary hydroxyurea had a median survival of 5.6 years, the 41 patients with primary busulfan therapy a median survival of 2.7 years (P = .02). Adverse reactions were less frequent with hydroxyurea with no severe adverse effects (lung fibrosis, long lasting bone marrow aplasia). The analysis of white blood cell counts in the course of treatment showed lower counts in the hydroxyurea patients. We conclude that hydroxyurea is superior to busulfan in therapy of CML in chronic phase and should be used as first line therapy. Busulfan may have a role as secondary therapy after hydroxyurea resistance or intolerance.
Blast Crisis↗
Chronic myelogenous leukemia: progress in chemotherapy and evaluation of prognostic score 1. The German CML Study Group.
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Busulfan↗
24-hour blood pressure measurement in antihypertensive drug trials: data requirements and methods of analysis.
Non-invasive ambulatory blood pressure monitoring is an appropriate technique for the identification of the target population requiring antihypertensive treatment, since the systematic bias seen in casual clinic measurement is removed. The use of the technique in controlled clinical trials leads to a reduction in the sample size required to show a treatment difference in antihypertensive effect compared to sporadic single measurements, although in practice the number of recruited patients can considerably exceed the number of evaluable patients, due to poor compliance or incompleteness of data. In addition, the equality of observation essential in clinical trials cannot be controlled to the same degree as is possible with clinic measurements. Comparison of estimators of the overall characteristic blood pressure reveals that the 24-hour mean value produces an adequate estimator. A description of the individual blood pressure profile is obtained using smoothing procedures, the moving interval average providing a robust and simple approach. Clinically meaningful characteristics of the profile are difficult to define due to a dearth of information on prognostic importance of the features of the 24-hour blood pressure profile. Smoothed individual profiles can be combined to produce graphical descriptive treatment group summaries.
Antihypertensive Agents↗