Arnold G. Vulto

Overriding of Drug Safety Alerts in Computerized Physician Order Entry

Many computerized physician order entry (CPOE) systems have integrated drug safety alerts. The authors reviewed the literature on physician response to drug safety alerts and interpreted the results using Reasons framework of accident causation. In total, 17 papers met the inclusion criteria. Drug safety alerts are overridden by clinicians in 49% to 96% of cases. Alert overriding may often be justified and adverse drug events due to overridden alerts are not always preventable. A distinction between appropriate and useful alerts should be made. The alerting system may contain error-producing conditions like low specificity, low sensitivity, unclear information content, unnecessary workflow disruptions, and unsafe and inefficient handling. These may result in active failures of the physician, like ignoring alerts, misinterpretation, and incorrect handling. Efforts to improve patient safety by increasing correct handling of drug safety alerts should focus on the error-producing conditions in software and organization. Studies on cognitive processes playing a role in overriding drug safety alerts are lacking.

Recombinant human α-glucosidase from rabbit milk in Pompe patients

Summary Pompes disease is a fatal muscular disorder caused by lysosomal α-glucosidase deficiency. In an open-label study, four babies with characteristic cardiomyopathy were treated with recombinant human α-glucosidase (rhGAA) from rabbit milk at starting doses of 15 mg/kg or 20 mg/kg, and later 40 mg/kg. The enzyme was generally well tolerated. Activity of α-glucosidase normalised in muscle. Tissue morphology and motor and cardiac function improved. The left-ventricular-mass index decreased significantly. We recommend early treatment. Long-term effects are being studied.

Aerosolized Liposomal Amphotericin B for the Prevention of Invasive Pulmonary Aspergillosis during Prolonged Neutropenia: A Randomized, Placebo-Controlled Trial

BACKGROUND Invasive pulmonary aspergillosis (IPA) is a significant problem in patients with chemotherapy-induced prolonged neutropenia. Because pulmonary deposition of conidia is the first step in developing IPA, we hypothesized that inhalation of liposomal amphotericin B would prevent IPA. METHODS We performed a randomized, placebo-controlled trial of patients with hematologic disease with expected neutropenia for >or=10 days. Patients were randomized to receive liposomal amphotericin B or placebo inhalation twice a week, using an adaptive aerosol delivery system, until neutrophil counts increased to >300 cells/mm3. In subsequent neutropenic episodes, the assigned treatment was restarted. The primary end point was the occurrence of IPA according to European Organization for Research and the Treatment of Cancer-Mycoses Study Group definitions. Kaplan-Meier curves were compared with log-rank tests for intent-to-treat and on-treatment populations. RESULTS A total of 271 patients were studied during 407 neutropenic episodes. According to the intent-to-treat analysis, 18 of 132 patients in the placebo group developed IPA versus 6 of 139 patients in the liposomal amphotericin B group (odds ratio, 0.26; 95% confidence interval, 0.09-0.72; P=.005). According to the on-treatment analysis, 13 of 97 patients receiving placebo versus 2 of 91 receiving liposomal amphotericin B developed IPA (odds ratio, 0.14; 95% confidence interval, 0.02-0.66; P=.007). Some adverse effects, but none serious, in the liposomal amphotericin B group were reported, most frequently coughing (16 patients vs. 1 patient; P=.002). CONCLUSION In high-risk patients, prophylactic inhalation of liposomal amphotericin B significantly reduced the incidence of IPA.

Enzyme replacement therapy in late-onset Pompe's disease : A three-year follow-up

Pompes disease is an autosomal recessive myopathy. The characteristic lysosomal storage of glycogen is caused by acid α‐glucosidase deficiency. Patients with late‐onset Pompes disease present with progressive muscle weakness also affecting pulmonary function. In search of a treatment, we investigated the feasibility of enzyme replacement therapy with recombinant human α‐glucosidase from rabbit milk. Three patients (aged 11, 16, and 32 years) were enrolled in the study. They were all wheelchair‐bound and two of them were ventilator dependent with a history of deteriorating pulmonary function. After 3 years of treatment with weekly infusions of α‐glucosidase, the patients had stabilized pulmonary function and reported less fatigue. The youngest and least affected patient showed an impressive improvement of skeletal muscle strength and function. After 72 weeks of treatment, he could walk without support and finally abandoned his wheelchair. Our findings demonstrate that recombinant human α‐glucosidase from rabbit milk has a therapeutic effect in late‐onset Pompes disease. There is good reason to continue the development of enzyme replacement therapy for Pompes disease and to explore further the production of human therapeutic proteins in the milk of mammals. Ann Neurol 2004;55:000–000

Intravenous glycyrrhizin for the treatment of chronic hepatitis C: A double-blind, randomized, placebo-controlled phase I/II trial

Background : In Japan, glycyrrhizin therapy is widely used for chronic hepatitis C and reportedly reduces the progression of liver disease to hepatocellular carcinoma. The aims of this study were to evaluate the effect of glycyrrhizin on serum alanine aminotransferase (ALT), hepatitis C virus (HCV)‐RNA and its safety in European patients.

Spironolactone in type 2 diabetic nephropathy: Effects on proteinuria, blood pressure and renal function.

Objective To study the effects of addition of spironolactone to angiotensin-converting enzyme (ACE) inhibition or angiotensin II (AngII) receptor antagonism on proteinuria, blood pressure (BP) and renal function in overt type 2 diabetic nephropathy. Design A placebo-controlled, double-blind, parallel-group trial in patients from two outpatient clinics with a follow-up of 1 year. Methods Type 2 diabetic patients with macroalbuminuria, despite long-term use of an ACE inhibitor or AngII receptor blocker were allocated to spironolactone, 25–50 mg once daily (n = 29) or placebo (n = 30). Urinary albumin to creatinine ratio, BP and biochemical parameters were measured at regular intervals. Results Five patients of the spironolactone and one of the placebo group developed hyperkalemia and had to be excluded. Compared to other patients their baseline serum creatinine [161 (123–248) versus 88 (72–170) μmol/l] and potassium concentrations (4.7 ± 0.3 versus 4.2 ± 0.2 mmol/l) were elevated (P < 0.001). Albuminuria decreased by 40.6% [95% confidence interval (CI) 23.4–57.8%] and BP by 7 mmHg (2–12 mmHg)/3 mmHg (1–6 mmHg) with spironolactone, but did not change with placebo. Estimated glomerular filtration rate (eGFR) during the 1-year follow-up declined on average by 12.9 ml/min per 1.73 m2 (9.5–16.5 ml/min per 1.73 m2) in the spironolactone and by 4.9 ml/min per 1.73 m2 (0.8–8.9 ml/min per 1.73 m2) in the placebo group (P = 0.004). This decline was progressive in the placebo but leveled off in the spironolactone group. In the spironolactone group changes in albuminuria and GFR were correlated (r = 0.48, P = 0.007). Conclusion Addition of spironolactone to an ACE inhibitor or AngII receptor blocker is associated with a marked and sustained antiproteinuric effect, which in part relates to the more pronounced reduction in GFR.

The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon

The principal enzyme involved in coumarin metabolism is CYP2C9. Allelic variants of CYP2C9, CYP2C9*2 and CYP2C9*3, code for enzymes with reduced activity. Despite increasing evidence that patients with these genetic variants require lower maintenance doses of anticoagulant therapy, there is lack of agreement among studies on the risk of bleeding and CYP2C9 polymorphisms. It was, therefore, our objective to study the effect of the CYP2C9 polymorphisms on bleeding complications during initiation and maintenance phases of coumarin anticoagulant therapy. The design of the study was a population-based cohort in a sample of the Rotterdam Study, a study in 7,983 subjects. All patients who started treatment with acenocoumarol or phenprocoumon in the study period from January 1, 1991 through December 31, 1998 and for whom INR data were available were included. Patients were followed until a bleeding complication, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of a bleeding complication in relation to CYP2C9 genotype after adjustment for several potentially confounding factors such as age, gender, target INR level, INR, time between INR measurements, and aspirin use. The effect of variant genotype on bleeding risk was separately examined during the initiation phase of 90 days after starting therapy with coumarins. The 996 patients with analysable data had a mean follow-up time of 481 days (1.3 years); 311 (31.2%) had at least 1 variant CYP2C9 allele and 685 (68.8%) had the wild type genotype. For patients with the wild type genotype, the rate of minor bleeding, major bleeding and fatal bleeding was 15.9, 3.4 and 0.2 per 100 treatment-years, respectively. For patients with a variant genotype, the rate of minor, major and fatal bleeding was 14.6, 5.4 and 0.5 per 100 treatment-years. Patients with a variant genotype on acenocoumarol had a significantly increased risk for a major bleeding event (HR 1.83, 95% CI: 1.01-3.32). During the initiation phase of therapy we found no effect of variant genotype on bleeding risk. In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, having a variant allele of CYP2C9 was associated with an increased risk of major bleeding events in patients on acenocoumarol, but not in patients on phenprocoumon. Although one might consider the assessment of the CYP2C9 genotype of a patient for dose adjustment before starting treatment with acenocoumarol, a prospective randomised trial should demonstrate whether this reduces the increased risk of major bleeding events.

Glycyrrhizin-induced reduction of ALT in European patients with chronic hepatitis C.

OBJECTIVE:In Japan, ALT normalization induced by long-term i.v. glycyrrhizin treatment reportedly reduces the progression of liver disease to hepatocellular carcinoma in chronic hepatitis C patients. The aim of this study was to evaluate the short-term (4-wk) feasibility and efficacy on serum ALT of three or six times per week i.v. glycyrrhizin therapy in European patients.METHODS:Patients with chronic hepatitis C, nonresponders, or unlikely to respond (genotype 1/cirrhosis) to interferon therapy were included in this study. Medication was administered i.v. three or six times per week for 4 wk; follow-up also lasted 4 wk.RESULTS:Sixty-nine out of 72 treatment courses were completed according to protocol. There were no significant changes in ALT levels within the placebo group (n = 13). The mean percentage ALT decrease from baseline at the end of treatment was 26% and 47% for the three times per week and six times per week treatment group, respectively (both p < 0.001 vs placebo). At the end of active treatment, 10% (four of 41) and 20% (three of 15) of the patients reached normal ALT levels for the three times per week and six times per week treatment group, respectively. The ALT lowering effect disappeared after cessation of treatment. No major side effects were observed.CONCLUSION:It appeared feasible to treat European outpatients with chronic hepatitis C three or six times per week with i.v. glycyrrhizin. Glycyrrhizin treatment induces a significant ALT decrease in patients with chronic hepatitis C. Six times per week treatment appears more effective than three times per week.

Genetic Variation in the CYP2D6 Gene Is Associated With a Lower Heart Rate and Blood Pressure in β‐Blocker Users

Several β‐blockers are metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). CYP2D6*4 is the main polymorphism leading to decreased enzyme activity. The clinical significance of impaired elimination of β‐blockers is controversial, and most studies suffer from inclusion of small numbers of poor metabolizers (PMs) of CYP2D6. In this study, the association between CYP2D6*4 and blood pressure or heart rate was examined in 1,533 users of β‐blockers in the Rotterdam Study, a population‐based cohort study. In CYP2D6 *4/*4 PMs, the adjusted heart rate in metoprolol users was 8.5 beats/min lower compared with *1/*1 extensive metabolizers (EMs) (P < 0.001), leading to an increased risk of bradycardia in PMs (odds ratio = 3.86; 95% confidence interval 1.68–8.86; P = 0.0014). The diastolic blood pressure in PMs was 5.4 mm Hg lower in users of β‐blockers metabolized by CYP2D6 (P = 0.017) and 4.8 mm Hg lower in metoprolol users (P = 0.045) compared with EMs. PMs are at increased risk of bradycardia.

Drug safety alert generation and overriding in a large Dutch university medical centre

To evaluate numbers and types of drug safety alerts generated and overridden in a large Dutch university medical centre.