Medication as a risk factor for hospitalization due to heart failure and shock: a series of case-crossover studies in Swiss claims data.

PURPOSE: Heart failure is among the leading causes for hospitalization in Europe. In this study, we evaluate potential precipitating factors for hospitalization for heart failure and shock. METHODS: Using Swiss claims data (2014-2015), we evaluated the association between hospitalization for heart failure and shock, and prescription of oral potassium supplements, non-steroidal anti-inflammatory drugs (NSAIDs), and amoxicillin/clavulanic acid. We conducted case-crossover analyses, where exposure was compared for the hazard period and the primary control period (e.g., 1-30 days before hospitalization vs. 31-60 days, respectively). Conditional logistic regression was applied and subsequently adjusted for addressing potential confounding by disease progression. Sensitivity analyses were conducted and stratification for co-medication was performed. RESULTS: We identified 2185 patients hospitalized with heart failure or shock. Prescription of potassium supplements, NSAIDs, and amoxicillin/clavulanic acid was significantly associated with an increased risk for hospitalization for heart failure and shock with crude odds ratios (OR) of 2.04 for potassium (95% CI 1.24-3.36, p = 0.005, 30 days), OR 1.8 for NSAIDs (95% CI 1.39-2.33, p < 0.0001, 30 days), and OR 3.25 for amoxicillin/clavulanic acid (95% CI 2.06-5.14, p < 0.0001, 15 days), respectively. Adjustment attenuated odds ratios, while the significant positive association remained (potassium OR 1.70 (95% CI 1.01-2.86, p = 0.046), NSAIDs OR 1.50 (95% CI 1.14-1.97, p = 0.003), and amoxicillin/clavulanic acid OR 2.26 (95% CI 1.41-3.62, p = 0.001). CONCLUSION: Prescription of potassium supplements, NSAIDs, and amoxicillin/clavulanic acid is associated with increased risk for hospitalization. Underlying conditions such as pain, electrolyte imbalances, and infections are likely contributing risk factors. Physicians may use this knowledge to better identify patients at risk and adapt patient management.

Prediction of health care expenditure increase: how does pharmacotherapy contribute?

BACKGROUND: Rising health care costs are a major public health issue. Thus, accurately predicting future costs and understanding which factors contribute to increases in health care expenditures are important. The objective of this project was to predict patients healthcare costs development in the subsequent year and to identify factors contributing to this prediction, with a particular focus on the role of pharmacotherapy. METHODS: We used 2014-2015 Swiss health insurance claims data on 373'264 adult patients to classify individuals' changes in health care costs. We performed extensive feature generation and developed predictive models using logistic regression, boosted decision trees and neural networks. Based on the decision tree model, we performed a detailed feature importance analysis and subgroup analysis, with an emphasis on drug classes. RESULTS: The boosted decision tree model achieved an overall accuracy of 67.6% and an area under the curve-score of 0.74; the neural network and logistic regression models performed 0.4 and 1.9% worse, respectively. Feature engineering played a key role in capturing temporal patterns in the data. The number of features was reduced from 747 to 36 with only a 0.5% loss in the accuracy. In addition to hospitalisation and outpatient physician visits, 6 drug classes and the mode of drug administration were among the most important features. Patient subgroups with a high probability of increase (up to 88%) and decrease (up to 92%) were identified. CONCLUSIONS: Pharmacotherapy provides important information for predicting cost increases in the total population. Moreover, its relative importance increases in combination with other features, including health care utilisation.

Analysis of Drug-Drug Interactions in Swiss Claims Data Using Tizanidine and Ciprofloxacin as a Prototypical Contraindicated Combination.

BACKGROUND: Potential drug-drug interactions (pDDIs) are described in various case reports, but few studies have evaluated the impact of specific combinations on a population level. OBJECTIVE: To analyze the type and frequency of multiple contraindicated (X-pDDIs) and major interactions (D-pDDIs) and to subsequently assess the impact of the particular combination of tizanidine and ciprofloxacin on outpatient physician visits and hospitalizations. METHODS: Anonymized Swiss claims data from 524 797 patients in 2014-2015 were analyzed. First, frequencies of X- and D-pDDIs were calculated. Next, a retrospective cohort study was conducted among patients prescribed tizanidine and ciprofloxacin (exposed, n = 199) or tizanidine and other antibiotics (unexposed, n = 960). Hospitalizations and outpatient physician visits within 7, 14, and 30 days after initiation of antibiotic therapy were evaluated using multiple binary logistic regression and multiple linear regression. RESULTS: The relative frequencies of X- and D-pDDIs were 0.4% and 6.65%, respectively. In the cohort study, significant associations between exposure to tizanidine and ciprofloxacin and outpatient physician visits were identified for 14 and 30 days (odds ratio [OR] = 1.61 [95% CI = 1.17-2.24], P = 0.004, and OR = 1.59 [95% CI = 1.1-2.34], P = 0.016). A trend for increased risk of hospitalization was found for all evaluated time periods (OR = 1.68 [95% CI = 0.84-3.17], OR = 1.52 [95% CI = 0.63-3.33], and OR = 2.19 [95% CI = 0.88-5.02]). Conclusion and Relevance: The interaction between tizanidine and ciprofloxacin is not only relevant for individual patients, but also at the population level. Further investigation of the impact of other clinically relevant DDIs is necessary to improve patient safety and reduce avoidable health care utilization.

Risks of inflammatory bowel disease treatment with glucocorticosteroids and aminosalicylates.

BACKGROUND: Glucocorticosteroids and aminosalicylates, mainly mesalazine (5-ASA), are both standard therapeutics in the treatment of inflammatory bowel disease (IBD) patients. The glucocorticosteroids are highly effective in inducing remission in both ulcerative colitis and Crohn's disease, but their use is limited by the high incidence and the potentially serious nature of adverse events. In an attempt to limit systemic side effects, rapidly metabolized corticosteroids such as budesonide have been introduced. The safety profile of aminosalicylates differs between the formulations. METHODS: We summarize the potential risks associated with glucocorticosteroid and aminosalicylate therapy in IBDs. RESULTS: The numerous adverse events of glucocorticosteroids, particularly at high doses and prolonged treatment, include opportunistic infections, diabetes mellitus, hypertension, ocular effects (glaucoma and cataracts), psychiatric complications, hypothalamic-pituitary-adrenal axis suppression and increased fracture risk. Partially, these systemic adverse events occur with budesonide, which only has a low systemic exposure. The safety profile of 5-ASA is comparable to placebo and superior to the old aminosalicylate prodrug sulfasalazine, which had a significantly higher incidence of intolerance reactions including allergic rashes. Only in rare cases has nephrotoxicity such as interstitial nephritis been associated with 5-ASA. CONCLUSION: Considering the toxicity profile of conventional glucocorticosteroids, one primary goal of treatment in IBD should be corticosteroid-free remission. Therapy with budesonide may result in a better safety profile. 5-ASA treatment is usually well tolerated, but with regard to the rare nephrotoxic events, it is advisable to assess renal function before and during treatment with 5-ASA.

[Thrombocyte aggregation inhibitors: what are the risks?]. / Thrombozytenaggregationshemmer: Was sind die Risiken?

The most common risks related to platelet inhibitor therapy are bleeding, drug-drug interactions and therapeutic failure. The new substances prasugrel and ticagrelor are more potent platelet inhibitiors than clopidogrel. This reduces the incidence of ischemic events, but also potentially increases the bleeding risk. Clopidogrel therapy has up to 20% non-response rates, which can partially be explained by genetic polymorphisms and drug-drug interactions. Currently no evidence exists that ticagrelor or prasugrel efficacy is affected by genetic polymorphisms. The therapy in patients at risk still has to be carefully adapted to minimize adverse events. Patients older than 75 years and/or weighing less than 60 kg should receive a reduced dose of prasugrel. The combination of ticagrelor with strong cytochrome-P450-3A4 inhibitors is contraindicated.

Les événements hémorragiques, les interactions médicamenteuses et l'échec de thérapie constituent les risques majeurs des traitements à base d'antiagrégants plaquettaires. Les substances nouvelles, prasugrel et ticagrelor, présentent un effet anitagrégant plus important et diminuent les épisodes ischémiques d'une manière plus efficacement que le clopidogrel. Cependent la possibilité existe d'une augmentation d'épisodes de saignement. Le risque de résistance à la thérapie atteint jusqu'à 20% pour les patients traités à base de clopidogrel, entre autre en raison de polymorphismes génétiques. Il n'existe pas d'evidence pour un mécanisme pareil pour le prasugrel et le ticagrelor. Dans certaines situations de risque par contre, une adaption du dosage est conseillée pour minimiser les effets secondaires négatifs: Chez les patients de plus de 75 ans, et/ou d'un poids corporel de moins de 60 kg, une réduction du dosage de prasugrel est conseillée en raison d'un risque élevé d'hémorragie. Il est contrindiqué d'utiliser ticagrelor en combinaison avec des inhibiteurs puissants du cytochrome-P450­3A4.

Low allopurinol doses are sufficient to optimize azathioprine therapy in inflammatory bowel disease patients with inadequate thiopurine metabolite concentrations.

PURPOSE: Recent studies in patients with inflammatory bowel diseases (IBD) on thiopurine therapy suggest that too low 6-thioguanine nucleotide concentrations (6-TGN) and too high methylmercaptopurine nucleotide concentrations (MMPN) can be reversed by a combination therapy of allopurinol and low-dose thiopurines. To date, however, optimal dosing has not been established. The aim of this study was to evaluate the minimal allopurinol doses necessary to achieve adequate 6-TGN concentrations in combination with low-dose azathioprine. METHODS: A stepwise dose-escalation of allopurinol was performed in 11 azathioprine-pretreated IBD patients with inadequately low 6-TGN concentrations (<235 pmol/8 × 10(8) erythrocytes) and/or elevated MMPN concentrations (>5,000 pmol/8 × 10(8) erythrocytes) and/or elevated liver enzymes (alanine aminotransferase and/or aspartate aminotransferase levels one- to threefold the upper limit of normal). Six patients were recruited into an open study, and five were treated in the context of an individualized therapeutic approach. Adverse effects, azathioprine metabolites, liver enzymes and whole blood counts were monitored two to three times per month. RESULTS: Adequate 6-TGN concentrations were achieved with a combination of 25 mg allopurinol and 50 mg azathioprine in one patient and with 50 mg allopurinol and 50 mg azathioprine in nine patients. Median 6-TGN concentrations (range) were 336 (290-488) pmol/8 × 10(8) erythrocytes after an 8-week-long intake of the final dose combination. One patient dropped out due to nausea after the first intake. MMPN concentrations and liver enzymes normalized immediately in all affected patients. All patients finishing the dose-escalation regimen tolerated the treatment without toxicity. CONCLUSIONS: Combination therapy with only 50 mg allopurinol and 50 mg azathioprine daily is sufficient, efficacious and safe in most IBD patients with inadequate thiopurine metabolite concentrations to optimize azathioprine-based IBD therapy.

Validation of a transparent decision model to rate drug interactions.

BACKGROUND: Multiple databases provide ratings of drug-drug interactions. The ratings are often based on different criteria and lack background information on the decision making process. User acceptance of rating systems could be improved by providing a transparent decision path for each category. METHODS: We rated 200 randomly selected potential drug-drug interactions by a transparent decision model developed by our team. The cases were generated from ward round observations and physicians' queries from an outpatient setting. We compared our ratings to those assigned by a senior clinical pharmacologist and by a standard interaction database, and thus validated the model. RESULTS: The decision model rated consistently with the standard database and the pharmacologist in 94 and 156 cases, respectively. In two cases the model decision required correction. Following removal of systematic model construction differences, the DM was fully consistent with other rating systems. CONCLUSION: The decision model reproducibly rates interactions and elucidates systematic differences. We propose to supply validated decision paths alongside the interaction rating to improve comprehensibility and to enable physicians to interpret the ratings in a clinical context.

Drug-related problems and factors influencing acceptance of clinical pharmacologists` alerts in a large cohort of neurology inpatients.

QUESTIONS UNDER STUDY/PRINCIPLES: Data regarding the prevalence and types of drug-related problems (DRPs) among neurology inpatients is sparse. The objective of this study was to characterise the types of DRPs seen among neurology inpatients and furthermore to study factors affecting the acceptance of clinical pharmacologists' and pharmacists' recommendations for improving drug safety. METHODS: 1,263 consecutive inpatient cases in a Swiss university hospital neurology unit were assessed for the presence of DRPs over 12 months. Treating neurologists' acceptance of the resulting recommendations was also recorded. Primary outcome measures were types of DRP, recommendations made by clinical pharmacologists and number of recommendations accepted. Factors potentially associated with acceptance were studied using univariate and multivariate generalised estimating equation modelling. RESULTS: Twenty-nine percent of cases demonstrated one or more DRPs. DRPs were the cause of admission in 10 cases (0.8%). In total 494 DRPs were identified and 467 recommendations given, of which 62% were accepted. Factors associated with an increased likelihood of acceptance were prescriptions involving regularly administered drugs (odds ratio [OR] 2.57 95% confidence interval [CI] 1.73-3.80), adverse drug events (OR 2.5; 95% CI 1.29-5.06), known drug side-effect (OR 1.85; 95% CI 1.06-3.22), high-risk drug-drug interactions (OR 3.22; 95% CI 1.07-9.69) and interventions involving changing a drug (OR 2.71; 95% CI 1.17-6.25). CONCLUSION: Clinical pharmacologists and pharmacists can play an important role in identifying DRPs among neurology inpatients. Their recommendations for optimising medication-safety are most likely to be accepted for regular prescriptions, prescriptions associated with an adverse drug event and high-risk drug combinations.

Comparative evaluation of three clinical decision support systems: prospective screening for medication errors in 100 medical inpatients.

PURPOSE: Clinical decision support systems (CDSS) are promoted as powerful screening tools to improve pharmacotherapy. The aim of our study was to evaluate the potential contribution of CDSS to patient management in clinical practice. METHODS: We prospectively analyzed the pharmacotherapy of 100 medical inpatients through the parallel use of three CDSS, namely, Pharmavista, DrugReax, and TheraOpt. After expert discussion that also considered all patient-specific clinical information, we selected apparently relevant alerts, issued suitable recommendations to physicians, and recorded subsequent prescription changes. RESULTS: For 100 patients with a median of eight concomitant drugs, Pharmavista, DrugReax, and TheraOpt generated a total of 53, 362, and 328 interaction alerts, respectively. Among those we identified and forwarded 33 clinically relevant alerts to the attending physician, resulting in 19 prescription changes. Four adverse drug events were associated with interactions. The proportion of clinically relevant alerts among all alerts (positive predictive value) was 5.7, 8.0, and 7.6%, and the sensitivity to detect all 33 relevant alerts was 9.1, 87.9, and 75.8% for Pharmavista, DrugReax and TheraOpt, respectively. TheraOpt recommended 31 dose adjustments, of which we considered 11 to be relevant; three of these were followed by dose reductions. CONCLUSIONS: CDSS are valuable screening tools for medication errors, but only a small fraction of their alerts appear relevant in individual patients. In order to avoid overalerting CDSS should use patient-specific information and management-oriented classifications. Comprehensive information should be displayed on-demand, whereas a limited number of computer-triggered alerts that have management implications in the majority of affected patients should be based on locally customized and supported algorithms.

Electronic prescribing increases uptake of clinical pharmacologists' recommendations in the hospital setting.

AIMS: To determine whether electronic prescribing facilitates the uptake of clinical pharmacologists' recommendations for improving drug safety in medical inpatients. METHODS: Electronic case records and prescription charts (either electronic or paper) of 502 patients hospitalized on medical wards in a large Swiss teaching hospital between January 2009 and January 2010 were studied by four junior and four senior clinical pharmacologists. Drug-related problems were identified and interventions proposed. The implementation and time delays of these proposed interventions were compared between the patients for whom paper drug charts were used and the patients for whom electronic drug charts were used. RESULTS: One hundred and fifty-eight drug-related problems in 109 hospital admissions were identified and 145 recommendations were made, of which 51% were implemented. Admissions with an electronic prescription chart (n= 90) were found to have 2.74 times higher odds for implementation of the change than those with a paper prescription chart (n= 53) (95% confidence interval 1.2, 6.3, P= 0.018, adjusted for any dependency introduced by patient, ward or clinical team; follow-up for two cases missing). The time delay between recommendations being made and their implementation (if any) was minimal (median 1 day) and did not differ between the two groups. CONCLUSIONS: Electronic prescribing in this hospital setting was associated with increased implementation of clinical pharmacologists' recommendations for improving drug safety when compared with handwritten prescribing on paper.

Trimethoprim/Sulfamethoxazole pharmacokinetics in two patients undergoing continuous venovenous hemodiafiltration.

OBJECTIVE: To determine the extent of elimination of trimethoprim (TMP) and sulfamethoxazole (SMX) via continuous venovenous hemodiafiltration (CVVHDF) in 2 critically ill patients with renal failure. CASE SUMMARY: A 62-year-old woman with Pneumocystis jirovecii pneumonia (PCP) was admitted to our intensive care unit for severe acute respiratory distress syndrome. A 77-year-old man was admitted for aortic root replacement and developed septic shock and nosocomial pneumonia due to Stenotrophomonas maltophilia. Both patients developed acute renal failure, necessitating CVVHDF. They were treated with intravenous TMP/SMX adapted to renal function. The first patient received TMP 6.4 mg/kg/day and SMX 32 mg/kg/day, corresponding to 50% of the recommended high-dose TMP/SMX regimen in PCP patients. The second patient received TMP 1.7 mg/kg/day and SMX 8.6 mg/kg/day, corresponding to 50% of the usual dose in bacterial infections. We determined peak and trough serum TMP and SMX concentrations and the extent of TMP/SMX CVVHDF clearance at steady-state while the patients were still anuric and oliguric. DISCUSSION: Data on TMP and SMX pharmacokinetics in CVVHDF are lacking and dosing recommendations are inconclusive. In both patients, CVVHDF clearance of TMP ranged from 21.5 to 28.9 mL/min, corresponding with normal renal clearance (20-80 mL/min). SMX clearance in CVVHDF showed high variability (18.7, 26.7, and 42.6 mL/min) and exceeded renal clearance values in normal renal function (1-5 mL/min). Accordingly, peak TMP serum concentrations were within the recommended range in the patient treated with a reduced TMP/SMX dose for PCP, whereas her SMX peak concentrations were only one third of recommended target concentrations. CONCLUSIONS: Our data indicate that both TMP and SMX are removed by CVVHDF to a significant degree, and dose reduction of TMP/SMX in CVVHDF bears the risk of underdosing. Given variability in drug exposure in critically ill patients, therapeutic drug monitoring is advisable in anuric or oliguric patients undergoing continuous renal replacement therapy to ensure optimal TMP/SMX dosing.

[Adverse reactions and risks associated with non compliance]. / Risiken und Nebenwirkungen durch Non Compliance.

Non compliance is a frequent and underestimated problem in clinical practice, that is associated with considerable risks, adverse reactions and costs. Next to omitting one or several doses with consequent lack of efficacy, other forms of non compliance can be described. These include administration of a wrong dose or at a wrong time, early termination of therapy or also its unwarranted continuation, and self-administered comedication without consideration of potential interactions. A number of risks and adverse effects can be derived from these different forms of non compliance, for which we present several examples from clinical practice and the literature. Anticipation, recognition and appropriate countermeasures are important elements for the prevention of non compliance, which may target the pharmacotherapy itself, the patient, or the health system providing the therapeutic framework. Furthermore, a climate of trust and good communication between the patient and the health care provider is the cornerstone for all strategies that aim to improve compliance. Computerized physician order entry and clinical decision support systems may have an additional important role for the prevention of non compliance in the future.