Hematoma Expansion and Clinical Outcomes in Patients With Factor-Xa Inhibitor-Related Atraumatic Intracerebral Hemorrhage Treated Within the ANNEXA-4 Trial Versus Real-World Usual Care.

BACKGROUND AND PURPOSE: It is unestablished whether andexanet alfa, compared with guideline-based usual care including prothrombin complex concentrates, is associated with reduced hematoma expansion (HE) and mortality in patients with factor-Xa inhibitor-related intracerebral hemorrhage (ICH). We compared the occurrence of HE and clinical outcomes in patients treated either with andexanet alfa or with usual care during the acute phase of factor-Xa inhibitor-related ICH. METHODS: Data were extracted from the multicenter, prospective, single-arm ANNEXA-4 trial (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) and a multicenter observational cohort study, RETRACE-II (German-Wide Multicenter Analysis of Oral Anticoagulant-Associated Intracerebral Hemorrhage - Part Two). HE was based on computed tomography scans performed within 36 hours from baseline imaging. Inverse probability of treatment weighting was performed to adjust for baseline comorbidities and ICH severity. Patients presenting with atraumatic ICH while receiving apixaban or rivaroxaban within 18 hours of admission were included. Patients with secondary ICH or not fulfilling the inclusion criteria for the ANNEXA-4 trial were excluded. We compared ANNEXA-4 patients, who received andexanet alfa for hemostatic treatment, with RETRACE-II patients who were treated with usual care, primarily administration of prothrombin complex concentrates. Primary outcome was rate of HE defined as relative increase of ≥35%. Secondary outcomes comprised mean absolute change in hematoma volume, as well as in-hospital mortality and functional outcome. RESULTS: Overall, 182 patients with factor-Xa inhibitor-related ICH (85 receiving andexanet alfa versus 97 receiving usual care) were selected for analysis. There were no relevant differences regarding demographic or clinical characteristics between both groups. HE occurred in 11 of 80 (14%) andexanet alfa patients compared with 21 of 67 (36%) usual care patients (adjusted relative risk, 0.40 [95% CI, 0.20-0.78]; P=0.005), with a reduction in mean overall hematoma volume change of 7 mL. There were no statistically significant differences among in-hospital mortality or functional outcomes. Sensitivity analysis including only usual care patients receiving prothrombin complex concentrates demonstrated consistent results. CONCLUSIONS: As compared with usual care, andexanet alfa was associated with a lower rate of HE in atraumatic factor-Xa inhibitor-related ICH, however, without translating into significantly improved clinical outcomes. A comparative trial is needed to confirm the benefit on limiting HE and to explore clinical outcomes across patient subgroups and by time to treatment. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT02329327 and NCT03093233.

Use of Nalmefene in Routine Practice: Results from a French Prospective Cohort Study and a National Database Analysis.

AIMS: Two complementary studies were used to assess the real-life use of nalmefene in alcohol-dependent patients and its impact on alcohol use health status. METHODS: USE-PACT was a prospective cohort study designed to evaluate the real-life effectiveness of nalmefene in the management of alcohol dependence, as assessed by total alcohol consumption (TAC) and number of heavy drinking days (HDD) at 1 year. USE-AM was a cohort study using data from the French nationwide claims database and was used to evaluate the external validity of the population in the prospective study. RESULTS: Overall, 256 of 700 new nalmefene users enrolled in the USE-PACT study had valid data at 1 year. After 1 year, patients treated with nalmefene showed a mean ± SD reduction from baseline in TAC (-41.5 ± 57.4 g/day) and number of HDD (-10.7 ± 11.7 days/4 weeks). Patients took a mean ± SD of 20.0 ± 12.0 tablets/4 weeks (median of 1 tablet/day) for the first 3 months and then reduced the dose. The proportion of patients who no longer took nalmefene gradually increased from 5% at 1 month to 52% at 1 year. The USE-AM study identified 486 patients with a first reimbursement for nalmefene in 2016; baseline characteristics confirmed external validity of the USE-PACT study. Overall, 46.3% of initial USE-AM prescriptions were made by GPs; most (91.8%) patients stopped treatment during follow-up. However, 15.2% of patients resumed treatment after stopping. CONCLUSIONS: In this analysis of French routine practice, patients with alcohol dependence treated with nalmefene showed reduced alcohol consumption, and nalmefene was generally well tolerated.

Safety and Persistence of Nalmefene Treatment for Alcohol Dependence. Results from Two Post-authorisation Safety Studies.

AIMS: Two post-authorisation studies assessed the safety and persistence of patients' use of nalmefene. METHODS: The START study (EUPAS5678) was a non-interventional, multi-country, prospective, 18-month (8 follow-up visits) cohort study including outpatients initiating nalmefene for the first time. The multi-database retrospective cohort study (MDRC, EUPAS14083) included baseline and follow-up data from German, Swedish and UK healthcare databases. Both studies permitted 'all comers' without explicit exclusion criteria; predefined subgroups of interest included the elderly (≥65 years) as well as patients with significant psychiatric and/or somatic comorbidities. RESULTS: START study: Overall, the mean duration of nalmefene treatment was 10.3 ± 7.3 months (N = 1348), with 49.0% of patients treated for ≥1 year; frequent reasons for treatment discontinuation were 'goal reached' and 'drug cost'. The most frequently reported adverse drug reactions (ADRs) were nausea (4.7%), dizziness (3.2%) and insomnia (2.0%). ADR rates appeared higher in the elderly subpopulation (18.6% reported ≥1 ADR vs. 12.0% in the total population) but were not higher in the other predefined subgroups.MDRC study: The database follow-up analysis followed 2892 patients over 18 months for whom the duration of nalmefene treatment was between 2 and 3 months and <5% of patients used nalmefene for ≥1 year. CONCLUSIONS: Despite the inclusion of a wider patient population (e.g. elderly patients and those with relevant co-morbidities), the safety and tolerability profile of nalmefene given in routine practice was consistent with previous clinical studies. The differing rates of persistence beyond 1 year likely reflect the different methodologies and highlight the relevance of psychosocial support at follow-up visits.

Sodium-glucose co-transporter-2 inhibitors and the risk of fractures of the upper or lower limbs in patients with type 2 diabetes: A nested case-control study.

AIMS: To investigate whether the use of SGLT-2 inhibitors is associated with an increased risk of fractures. MATERIAL AND METHODS: We conducted a cohort study with nested case-control analysis based on the InGef database between November 2011 and December 2016 among patients with type 2 diabetes who were initiating treatment with, switching to, or adding a new class of non-insulin antidiabetic drug. Patients with a hospital or ambulatory diagnosis of fractures of the upper or lower limbs were included and were matched to up to 40 randomly sampled control subjects. Conditional logistic regression was used to estimate confounder adjusted odds ratios (ORs) of fractures, comparing current use of metformin plus SGLT-2 inhibitor or metformin plus another antidiabetic drug class to metformin plus DPP-4 inhibitor as reference. RESULTS: The cohort comprised 210 042 new users of non-insulin antidiabetic drugs. For the nested case-control analysis, 7522 patients with fractures were matched to 296 845 control subjects. In the crude and confounder adjusted analyses, current use of metformin plus SGLT-2 inhibitor compared to current use of metformin plus DPP-4 inhibitor was not associated with fractures (OR: 1.00; 95% CI: 0.72-1.39 and OR: 0.99; 95% CI: 0.71-1.37, respectively). Similarly, no statistically significant association was found for current use of metformin plus another antidiabetic drug class. No treatment effect modification was observed after stratification by number of documented risk factors for falls and fractures (< 4 vs ≥ 4) and age (< 75 vs ≥ 75 years). CONCLUSION: Our study suggests that use of SGLT-2 inhibitors and other antidiabetic drug classes are not associated with an increased risk of fractures of the upper or lower limbs compared to use of DPP-4 inhibitors in patients with type 2 diabetes.

Immobilization and high platelet count are associated with thromboembolic complications in heparin-induced thrombocytopenia.

PURPOSE: Immune-mediated heparin-induced thrombocytopenia (HIT type II, HIT) is a potentially serious adverse drug reaction characterized by an increased risk of venous and arterial thrombosis. This study aimed to identify risk factors associated with the development of these complications. METHODS: Our study cohort included patients with HIT assembled in our pharmacovigilance center by reports from 51 collaborating hospitals in Berlin, Germany. To identify risk factors for thromboembolic complications, patients with thromboembolic events (cases) were compared to those without thromboembolic events (controls) in a case-control design. We applied univariable and multivariable logistic regression analysis to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) for potential risk factors of thromboembolic complications. RESULTS: Our cohort comprised 209 HIT patients. Of those, 53 developed thromboembolic complications. Most HIT patients received heparin for medical indications (42.1%) or in the context of cardiovascular surgery (40.2%). Of the 78 thromboembolic complications, 49 (63%) and 29 (37%) were observed in the venous and arterial vascular bed, respectively. The main locations were deep vein thrombosis (39.7%), pulmonary embolism (16.7%), and limb artery thrombosis (16.7%). In multivariable analysis, immobilization prior to HIT (OR 4.6, 95% CI 1.2-18.0; P = .026) and higher platelet counts before initiation of heparin therapy (OR 1.004, 95% CI 1.000-1.008; P = .046) were independently associated with the occurrence of thromboembolic events. CONCLUSIONS: Immobilization and a high platelet count (with a low effect size) are additional risk factors of thromboembolic complications in the course of HIT.

Simeprevir with pegylated interferon alfa 2a plus ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a meta-analysis and historical comparison.

BACKGROUND: About one third of patients infected with human immunodeficiency virus (HIV) also have chronic hepatitis due to hepatitis C virus (HCV). HCV therapy with simeprevir, pegylated interferon alfa (PegIFNα) and ribavirin (RBV) have been shown to be superior to PegIFNα + RBV alone in non-HIV patients, but no randomized trials in patients with HCV genotype 1 (HCV-1)/HIV coinfection are available. METHODS: This was a historical comparison of study C212 (simeprevir + PegIFNα-2a + RBV in patients with HCV-1/HIV coinfection) with studies in which HCV-1/HIV coinfected patients were treated with PegIFNα-2a + RBV alone. A systematic literature search was performed to identify eligible studies. Efficacy and safety results of PegIFNα-2a + RBV studies were combined in random- and fixed-effects inverse-variance weighted meta-analyses of proportions using the Freeman-Tukey double arcsin transformation method, and compared with the results of study C212. RESULTS: The literature search revealed a total of 2392 records, with 206 articles selected for full-text review. Finally, 11 relevant articles reporting on 12 relevant study groups were included. Results on sustained virologic response 24 weeks after end of treatment (SVR24) were available from all 12 study groups. Pooled SVR24 for PegIFNα-2a + RBV from the random-effects meta-analysis was 28.2% (95% CI 23.8% to 32.9%). The comparison between study C212 (SVR24 = 72.6%; 95% CI 63.1% to 80.9%) revealed substantial superiority of simeprevir + PegIFNα-2a + RBV compared to PegIFNα-2a + RBV alone, with an absolute risk difference of 45% (95% CI 34 to 55). This finding was robust in a sensitivity analysis that only included historical studies with a planned treatment duration of at least 48 weeks and the same RBV dose as in study C212. No increases in the frequency of important adverse event categories including anemia were identified, but these analyses were limited by the low number of studies. CONCLUSION: This historical comparison provides first systematic evidence for the superiority of simeprevir + PegIFNα-2a + RBV compared to PegIFNα-2a + RBV in patients with HCV-1/HIV coinfection. Given the limitations of the historical comparison for safety endpoints, additional data on the comparative safety of simeprevir in patients with HCV-1/HIV coinfection would be desirable. TRIAL REGISTRATION: Identifier for study TMC435-TiDP16-C212 (ClinicalTrials.gov): NCT01479868.

Characteristics and external validity of the German Health Risk Institute (HRI) Database.

PURPOSE: The aim of this study was to describe characteristics and external validity of the German Health Risk Institute (HRI) Database. METHODS: The HRI Database is an anonymized healthcare database with longitudinal data from approximately six Mio Germans. In addition to demographic information (gender, age, region of residence), data on persistence of insurants over time, hospitalization rates, mortality rates and drug prescription rates were extracted from the HRI database for 2013. Corresponding national reference data were obtained from official sources. RESULTS: The proportion of men and women was similar in the HRI Database and Germany, but the database population was slightly younger (mean 40.4 vs 43.7 years). The proportion of insurants living in the eastern part of Germany was lower in the HRI Database (10.1% vs 19.7%). There was good accordance to German reference data with respect to hospitalization rates, overall mortality rate and prescription rates for the 20 most often reimbursed drug classes, with the overall burden of morbidity being slightly lower in the HRI database. From insurants insured on 1 January 2009 (N = 6.2 Mio), a total of 70.6% survived and remained continuously insured with the same statutory health insurance until 31 December 2013. This proportion increased to 77.5% if only insurants ≥40 years were considered. CONCLUSIONS: There was good overall accordance of the HRI database and the German population in terms of measures of morbidity, mortality and drug usage. Persistence of insurants with the database over time was high, indicating suitability of the data source for longitudinal epidemiological analyses.

Frequency and clinical relevance of potential cytochrome P450 drug interactions in a psychiatric patient population - an analysis based on German insurance claims data.

BACKGROUND: Numerous drugs used in the treatment of psychiatric disorders are substrates of cytochrome P450 enzymes and are potential candidates for drug-drug interactions (DDIs). METHODS: Claims data of a German statutory health insurance company from severely mentally ill patients who registered in an integrated care contract from August 2004 to December 2009 were analysed. We measured time periods of concomitant prescription of drugs that have been reported to interact via cytochrome P450, with a focus on drugs acting as strong inhibitors. Such drug-drug exposure (DDE) is an incontrovertible precursor of DDIs. We assessed whether potential DDIs were considered clinically relevant based on the prescribing information of the respective drugs. RESULTS: Among all 1221 patients, 186 patients (15.2 %; Clopper-Pearson 95 % confidence interval (CI): 13.3-17.4 %) had at least one DDE prescription, and 58 patients (4.8 %; 95 % CI 3.6-6.1) had at least one DDE prescription involving a strong cytochrome P450 inhibitor. In 59 patients, (4.8 %; 95 % CI: 3.7-6.2 %) five or more DDEs were identified, and five or more DDEs with a strong inhibitor were identified in 18 patients (1.5 %; 95 % CI: 0.9-2.3). The rates of DDEs were 0.27 (Garwood 95%CI: 0.25-0.28) per person-year and 0.07 (95 % CI: 0.07-0.08) for strong-inhibitor DDEs. Four of the ten most frequent DDEs were identified as clinically relevant, and seven of the eight most frequent DDEs involving a strong inhibitor were clinically relevant. CONCLUSIONS: The number of patients with DDEs was not alarmingly high in our sample. Nevertheless, prescription information showed that some prescribed drug combinations could result in serious adverse consequences that are known to weaken or strengthen the effect of the drugs and should therefore be avoided.

Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study.

Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed.

Drug-induced liver injury: results from the hospital-based Berlin Case-Control Surveillance Study.

AIM: Drug-induced liver injury (DILI) is often responsible for acute liver failure, drug withdrawal, boxed warnings or drug non-approval. Therefore, we conducted a case-control study to determine the hepatotoxic risk of a wide range of drugs. METHODS: The Berlin Case-Control Surveillance Study FAKOS included all 51 Berlin hospitals in a hospital network. Between 2002 and 2011, 198 patients with acute idiopathic hepatitis, 377 inpatient controls and 708 outpatient controls were ascertained. Case patients were thoroughly validated using anamnestic, clinical, laboratory and histological data. Drug exposure was obtained in a face-to-face interview. A possible drug aetiology was assessed in individual patients by applying the updated Council for International Organizations of Medical Sciences (CIOMS) scale. Drug risks were further quantified [odds ratios (OR) with 95% confidence intervals (CI)] in a case-control design with unconditional logistic regression analysis. Drug intake in the last 28 days before index date was considered for the analysis. RESULTS: The study corroborated hepatotoxic risks for a number of drugs, including phenprocoumon (OR 3.3, 95% CI 1.5, 6.7), amiodarone (OR 5.5, 95% CI 1.3, 21.2), clozapine (OR 34.6, 95% CI 2.8, 824.9) and flupirtine (OR 40.2, 95% CI 5.5, 856.9). Increased risks were also suggested for less commonly reported substances such as angiotensin II receptor blockers, atypical antipsychotics and for biperiden, a drug never before reported to be hepatotoxic. CONCLUSIONS: Our study identified a large number of drugs as possible causes of hepatotoxicity. The observed risk for seldom reported substances highlights the need for further post-authorization safety studies not exclusively focusing on drugs already labelled as potentially hepatotoxic.

Metamizole-induced agranulocytosis revisited: results from the prospective Berlin Case-Control Surveillance Study.

PURPOSE: Treatment with metamizole (dipyrone) has steadily increased in Germany over the last decade. The consequences of this increase for metamizole-induced agranulocytosis (MIA) are unclear. The present study addressed this topic using data from the Berlin Case-Control Surveillance Study. METHODS: Adult patients (≥18 years of age) with acute nonchemotherapy-induced agranulocytosis were identified by active surveillance in all 51 Berlin hospitals between 2000 and 2010. Cases related to metamizole were ascertained applying the drug causality criteria of the World Health Organization. The incidence rate of MIA was calculated and standardised by age and sex based on the German standard population in 2010. RESULTS: Twenty-six MIA cases out of 88 (30 %) patients with validated agranulocytosis were ascertained. The incidence of MIA was 0.96 (95 % confidence interval (CI) 0.95-0.97) cases per million per year. The median age of MIA cases was 50 years (quartile (Q)1 31 years; Q3 68 years) and 19 (73 %) of them were women. In 17 (65 %) cases, neutrophil granulocytes dropped below the value of 0.1 × 10(9) cells/L with three patients suffering from sepsis. Headache and postoperative pain were the most frequent indications for metamizole in outpatients (n = 16) and inpatients (n = 10), respectively. The median treatment duration was 6 days (Q1 4 days; Q3 19 days). CONCLUSIONS: MIA persists as a severe condition in current pharmacotherapy. The continuous increase of metamizole applications should be critically assessed, especially in regard to indications in the outpatient setting and with respect to metamizole treatment duration.

Flupirtine-induced liver injury--seven cases from the Berlin Case-control Surveillance Study and review of the German spontaneous adverse drug reaction reporting database.

PURPOSE: The hepatotoxic potential of the analgesic flupirtine has attracted increased attention over the past years. Recently, risk minimisation measures such as maximum treatment duration of 2 weeks have been requested by the European Medicines Agency (EMA). This study was conducted to further elucidate the clinical pattern of flupirtine-induced liver injury (FILI). METHODS: Seven FILI patients were ascertained in all Berlin hospitals in the Berlin Case-control Surveillance Study (FAKOS) between 2002 and 2011. Furthermore, we reviewed the severe cases of flupirtine-associated hepatotoxicity included in the adverse drug reaction database of the Federal Institute for Drugs and Medical Devices (BfArM) in Germany from between 1991 and 2012. RESULTS: All seven FILI patients of FAKOS were hospitalised. Six of them were female, mean age was 58 [corrected] years, and the most common symptoms were fatigue and jaundice. Three patients developed acute liver failure (ALF). Discontinuation of flupirtine invariably led to clinical and laboratory improvement. Review of the BfArM cases (n = 248) showed female sex predominance and high prevalence of jaundice and ALF. Time to onset of symptoms was less than 2 weeks in 9 % of the patients with respective data. CONCLUSIONS: Our results corroborate previous findings on FILI's clinical pattern and on its potentially severe course. Although the hepatotoxic risk might be higher after the first 2 weeks of treatment, earlier onset of severe FILI cannot be ruled out. Postauthorisation safety studies are needed to evaluate EMA's risk minimisation measures and to quantify flupirtine's risk according to its duration of use.

Drug-induced agranulocytosis in the Berlin case-control surveillance study.

PURPOSE: Drug-induced agranulocytosis (DIAG) is a rare but serious adverse drug reaction. The Berlin Case-Control Surveillance Study (FAKOS) aimed to identify pharmaceuticals with an increased risk for this condition. METHODS: Adult patients with acute non-chemotherapy-induced agranulocytosis, developed in hospital or in the outpatient setting, were ascertained by active surveillance in all 51 Berlin hospitals between the years 2000 and 2010. Applying the criteria of the World Health Organization, a standardized drug causality assessment was conducted for each agranulocytosis patient to determine possible drug aetiology. Drug risks were quantified in a case-control design with unconditional logistic regression analysis. RESULTS: Sixty-three out of 88 validated cases of agranulocytosis were identified as being at least probably drug-related. Drug causality assessment resulted in 36 pharmaceuticals with a certain or probable relationship to agranulocytosis. Drugs involved in ≥ 3 cases with a probable or certain causality were metamizole (dipyrone) (N = 10), clozapine (N = 6), sulfasalazine (N = 5), thiamazole (N = 5), and carbamazepine (N = 3). In case-control analysis, six drugs were identified with significant odds ratios for DIAG. The highest odds ratios were observed for clozapine, sulfasalazine, and thiamazole. CONCLUSIONS: Our findings are generally in agreement with those of earlier case-control studies. The spectrum of drugs causing acute agranulocytosis has not changed considerably over recent years, despite many newly marketed drugs. Evidence for induction of agranulocytosis by some new pharmaceuticals is supported.

Drug-induced immune thrombocytopaenia: results from the Berlin Case-Control Surveillance Study.

PURPOSE: Drug-induced immune thrombocytopaenia is a rare, serious condition that can be triggered by numerous medications. To characterize the spectrum of drugs associated with immune thrombocytopaenia (ITP) in the Berlin Case-Control Surveillance Study (FAKOS). METHODS: Adult hospitalized patients with new onset idiopathic, secondary or drug-induced acute ITP and hospital control patients were ascertained by active surveillance in 50 Berlin hospitals (>180 clinical departments) between 2000 and 2009. Drug exposures were obtained in a personal interview. Chronic cases were excluded in a follow-up after 6 or more months. A standardized causality assessment was conducted for each ITP patient to assess possible drug aetiology. Drug risks were quantified in a case-control design with unconditional logistic regression analysis. RESULTS: Ninety out of 169 validated cases of acute ITP were assessed as being at least possibly drug-related (n= 85 different drugs overall, n = 30 drugs with certain or probable causality). Drugs involved in ≥ 2 cases with a probable or certain relationship were tirofiban (n = 10 cases), abciximab (n = 4), trimethoprim/sulphamethoxazole (n = 4), influenza vaccine (n = 3), and citalopram (n = 2). Pneumococcal and poliomyelitis vaccine were assessed as probably causing ITP in one case each. In the case-control analyses, significantly increased risks were observed for tirofiban, abciximab, trimethoprim/sulphamethoxazole, gentamicin, triamterene/hydrochlorothiazide, drospirenone/ethinylestradiol, and influenza vaccination. CONCLUSIONS: Our study confirms known ITP risks for glycoprotein IIb/IIIa receptor antagonists and sulphonamides and generates signals for several other drugs and vaccines. New onset of ITP should not only direct attention to drugs as possible aetiological agents, but also to vaccines that are known to cause autoimmune phenomena.

Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS).

PURPOSE: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system that has been reported as rare adverse drug reaction (ADR) of immunosuppressive drugs. We aimed to study signals of PML for immunosuppressants using a disproportionality analysis of spontaneous adverse event reports. METHODS: Within the US Adverse Event Reporting System, we analyzed all reports of ADRs submitted to the US Food and Drug Administration between January 1, 2004 and September 30, 2010. We used univariate and multivariate logistic regression analysis to calculate reporting odds ratios with 95% confidence intervals of PML for immunosuppressants according to the Anatomical Therapeutic Chemical classification system (L04), rituximab and cyclophosphamide compared to all other drugs. RESULTS: We identified 635 PML cases in a total of 1,978,706 patients eligible for analysis. Altogether, 21 out of 36 analyzed immunosuppressants were reported at least once with PML. In the univariate analyses, we found a signal for 11 of these drugs (azathioprine, cyclosporine, cyclophosphamide, efalizumab, leflunomide, methotrexate, mycophenolate mofetil, natalizumab, rituximab, tacrolimus and sirolimus). In the multivariate analysis, the signal was no longer present for sirolimus, leflunomide and methotrexate. DISCUSSION: Our study revealed signals of PML for a substantial number of immunosuppressants, including some drugs less considered so far as a risk factor of PML, especially when used for the treatment of autoimmune disorders. These drugs and possible interactions between different immunosuppressants should be studied more closely in future studies.

3-year prevalence of alcohol-related disorders in German patients treated with high-potency opioids.

PURPOSE: In November 2010, the European Medicines Agency's Committee for Medicinal Products for Human Use completed a review of the safety and effectiveness of modified-release oral high-potency opioids (HPO). The reason for this referral procedure was the concern that some of these controlled-release systems may be unstable when co-ingested with alcohol and that the active substance would be released too quickly. The aim of this study was to estimate the prevalence of alcohol-related disorders (ARD) in German patients treated with HPO approved for pain therapy. METHODS: The source of data was the German Pharmacoepidemiological Research Database including more than 14 million members of four statutory health insurances. The age and sex standardized 3-year prevalence of ARD in patients treated with any type of HPO and in patients receiving modified-release oral HPO was compared with the prevalence of ARD in the general population excluding HPO-treated patients. RESULTS: The age and sex standardized prevalence of ARD was significantly higher in patients treated with any type of HPO (5.5%, 95%confidence interval [CI]: 5.2%-5.9%) or with modified-release HPO (5.4%, 95%CI: 4.8%-5.9%) than in persons belonging to the general population (2.2%, 95%CI: 2.2-2.2%). CONCLUSIONS: Interactions with alcohol in patients receiving modified-release HPO may be of relevance in a substantial number of patients. Physicians should be aware of this potentially dangerous interaction.

Drug induced immune haemolytic anaemia in the Berlin Case-Control Surveillance Study.

Drug-induced immune haemolytic anaemia is a rare but serious condition. This study investigated the possibility of drug aetiology of immune haemolytic anaemia (IHA) in 134 patients with new onset of IHA who were identified in the Berlin Case-Control Surveillance Study between 2000 and 2009. Single drugs related to IHA in three or more patients and assessed more than once as a certain or probable cause of IHA in a standardized causality assessment included diclofenac, fludarabine, oxaliplatin, ceftriaxone and piperacillin. In a case-control study including all 124 IHA cases developed in outpatient care and 731 controls, significantly increased odds ratios (OR) were observed for beta-lactam antibiotics (OR=8·8; 95% confidence interval [CI] 3·2-25·2), cotrimoxazole (OR=6·5; CI 1·1-37·9), ciprofloxacin (OR=6·9, CI 1·3-38·5), fludarabine (OR=22·2; CI: 2·8-454·5) and lorazepam (OR=5·3; CI: 1·2-21·2). Excluding new onset cases with a chronic IHA disease course, an increased risk became also apparent for diclofenac with an OR of 3·1 (CI 1·3-7·0). This is the first case-control study investigating drugs as risk factors for IHA. It corroborates an increased risk for several drugs that have been implicated as a cause of IHA in the standardized causality assessment of individual cases.

Clinical outcomes and characteristics of patients hospitalized for Influenza or COVID-19 in Germany.

OBJECTIVES: Since the beginning of the severe acute respiratory syndrome coronavirus 2 pandemic, there is a discussion about the severity of coronavirus disease-2019 (COVID-19) in comparison to infections with seasonal Influenza. The objective of this study was to compare clinical and demographic characteristics of German patients hospitalized for infection with either SARS-CoV-2 or Influenza. METHODS: This study used anonymized German healthcare claims data. Patients with a confirmed COVID-19 or Influenza diagnosis, for whom a complete hospital course was available (i.e., the patient was discharged or died in hospital) were included. The data set included detailed information on patient characteristics and hospital treatment. Patients were grouped according to whether they were transferred to the intensive care unit (ICU), received mechanical ventilation (MV), or had a severe course of the disease (SD). Charlson Comorbidity Index in the eight quarters prior to hospitalization and secondary diagnoses during hospitalization were analyzed. RESULTS: A total of 2343 hospitalized patients with COVID-19 and 6762 hospitalized patients with Influenza were included. Fifty-four percent of the patients were male patients, with men being twice as frequent in the COVID-19 severe groups. For both diseases, patients >49 years accounted for almost three-quarters of hospital cases and hypertension, diabetes mellitus, chronic kidney disease, and chronic obstructive pulmonary disease were the most common comorbidities. The proportion of cases with ICU, MV, and SD was substantially higher for patients with COVID-19 (ICU+: 21 vs. 13 %; MV+: 15 vs. 9%; and SD+: 28 vs. 16%). Overall inhospital mortality was more than two-fold higher in COVID-19 vs. Influenza (14 vs. 6%).). The length of ventilation and hospitalization, and the proportion of patients diagnosed with acute respiratory distress syndrome, systemic inflammatory response syndrome, or acute kidney injury were considerably higher in patients with COVID-19. CONCLUSIONS: COVID-19 resulted in higher inhospital mortality and worse clinical outcomes than Influenza. This was not attributable to demographic characteristics, preexisting comorbidities, or patient triage, because the German healthcare system had not reached its limits in the pandemic. Discussions suggesting that COVID-19 and seasonal Influenza have similar severity cannot be based on clinical evidence.

Dopamine agonists and the risk of cardiac-valve regurgitation.

BACKGROUND: Case reports and echocardiographic studies suggest that the ergot-derived dopamine agonists pergolide and cabergoline, used in the treatment of Parkinson's disease and the restless legs syndrome, may increase the risk of cardiac-valve regurgitation. METHODS: We used data from the United Kingdom General Practice Research Database to identify a population-based cohort comprising 11,417 subjects 40 to 80 years of age who were prescribed antiparkinsonian drugs between 1988 and 2005. We conducted a nested case-control analysis within this cohort in which each patient with newly diagnosed cardiac-valve regurgitation was matched with up to 25 control subjects from the cohort, according to age, sex, and year of entry into the cohort. Incidence-rate ratios for cardiac-valve regurgitation with the use of different dopamine agonists were estimated by conditional logistic-regression analysis. RESULTS: Of 31 case patients with newly diagnosed cardiac-valve regurgitation, 6 were currently exposed to pergolide, 6 were currently exposed to cabergoline, and 19 had not been exposed to any dopamine agonist within the previous year. The rate of cardiac-valve regurgitation was increased with current use of pergolide (incidence-rate ratio, 7.1; 95% confidence interval [CI], 2.3 to 22.3) and cabergoline (incidence-rate ratio, 4.9; 95% CI, 1.5 to 15.6), but not with current use of other dopamine agonists. CONCLUSIONS: In this study, use of the dopamine agonists pergolide and cabergoline was associated with an increased risk of newly diagnosed cardiac-valve regurgitation.