Physician adjudication of angioedema diagnosis codes in a population of patients with heart failure prescribed angiotensin-converting enzyme inhibitor therapy.

PURPOSE: Our objective was to calculate the positive predictive value (PPV) of the ICD-9 diagnosis code for angioedema when physicians adjudicate the events by electronic health record review. Our secondary objective was to evaluate the inter-rater reliability of physician adjudication. METHODS: Patients from the Cardiovascular Research Network previously diagnosed with heart failure who were started on angiotensin-converting enzyme inhibitors (ACEI) during the study period (July 1, 2006 through September 30, 2015) were included. A team of two physicians per participating site adjudicated possible events using electronic health records for all patients coded for angioedema for a total of five sites. The PPV was calculated as the number of physician-adjudicated cases divided by all cases with the diagnosis code of angioedema (ICD-9-CM code 995.1) meeting the inclusion criteria. The inter-rater reliability of physician teams, or kappa statistic, was also calculated. RESULTS: There were 38 061 adults with heart failure initiating ACEI in the study (21 489 patient-years). Of 114 coded events that were adjudicated by physicians, 98 angioedema events were confirmed for a PPV of 86% (95% CI: 80%, 92%). The kappa statistic based on physician inter-rater reliability was 0.65 (95% CI: 0.47, 0.82). CONCLUSIONS: ICD-9 diagnosis code of 995.1 (angioneurotic edema, not elsewhere classified) is highly predictive of angioedema in adults with heart failure exposed to ACEI.

A nonparametric method to detect increased frequencies of adverse drug reactions over time.

Signal detection is routinely applied to spontaneous report safety databases in the pharmaceutical industry and by regulators. As an example, methods that search for increases in the frequencies of known adverse drug reactions for a given drug are routinely applied, and the results are reported to the health authorities on a regular basis. Such methods need to be sensitive to detect true signals even when some of the adverse drug reactions are rare. The methods need to be specific and account for multiplicity to avoid false positive signals when the list of known adverse drug reactions is long. To apply them as part of a routine process, the methods also have to cope with very diverse drugs (increasing or decreasing number of cases over time, seasonal patterns, very safe drugs versus drugs for life-threatening diseases). In this paper, we develop new nonparametric signal detection methods, directed at detecting differences between a reporting and a reference period, or trends within a reporting period. These methods are based on bootstrap and permutation distributions, and they combine statistical significance with clinical relevance. We conducted a large simulation study to understand the operating characteristics of the methods. Our simulations show that the new methods have good power and control the family-wise error rate at the specified level. Overall, in all scenarios that we explored, the method performs much better than our current standard in terms of power, and it generates considerably less false positive signals as compared to the current standard.

Risk of subarachnoid hemorrhage and early case fatality associated with outpatient antithrombotic drug use.

BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) accounts for <7% of all strokes, but is an enormous individual and societal burden. We investigated the risk of SAH associated with prior use of antithrombotic drugs and their influence on 30-day case fatality. METHODS: We conducted a nested case-control study in a cohort of 13.4 million members of the German Pharmacoepidemiological Research Database. Ten controls were matched to each case hospitalized for SAH between July 2004 and November 2006 by health insurance, year of birth, and sex using risk set sampling. Exposure was assessed for the warfarin analog phenprocoumon, heparin, clopidogrel/ticlopidine, and acetylsalicylic acid. Multivariable-adjusted odds ratios (ORs) for SAH were estimated by conditional logistic regression. Risk factors for 30-day case fatality were assessed in patients with SAH by logistic regression. RESULTS: The nested case-control study included 2065 SAH cases and 20 649 matched controls. The risk of SAH was significantly increased for phenprocoumon (OR, 1.7; 95% confidence interval [CI], 1.3-2.3), clopidogrel/ticlopidine (OR, 1.7; 95% CI, 1.1-2.5), and for acetylsalicylic acid use (OR, 1.5; 95% CI, 1.2-2.0), but not for outpatient heparin use (OR, 1.2; 95% CI, 0.5-2.7). The early case fatality of 22.8% was associated with an age >70 years (OR, 2.3; 95% CI, 1.8-3.1) and arterial hypertension (OR, 1.3; 95% CI, 1.0-1.6), but not with any of the antithrombotic drugs. CONCLUSIONS: Outpatient antithrombotic drug use was associated with an increased risk of SAH, but no association was observed with early case fatality.

Does additional confounder information alter the estimated risk of bleeding associated with phenprocoumon use--results of a two-phase study.

PURPOSE: Claims databases are an important source for pharmacoepidemiological studies although they often lack information on some confounders. Two-phase methodology was used to estimate the bleeding risk in patients treated with phenprocoumon from claims data combined with additional information on body mass index (BMI) and smoking. METHODS: We conducted a nested case-control study using claims data from 2004 to 2007 (phase 1). Additional information was obtained from interviews in a subset of 505 insurants (phase 2). Adjusted bleeding OR were calculated using logistic regression using data from the complete case-control dataset. Furthermore, a two-phase analysis was conducted, taking into consideration phase 2 data on BMI and smoking. RESULTS: The phase 1 sample included 1248 cases and 24,960 controls. In phase 1, we observed an adjusted bleeding ORs of 3.93 (95%CI: 2.75-5.61) for male subjects aged 55 years taking phenprocoumon. The bleeding risk associated with phenprocoumon use decreased with increasing age. The two-phase analysis revealed smoking and a high BMI as risk factors for bleeding. The OR for phenprocoumon obtained from the two-phase analysis was of similar size as the phase 1 estimate. DISCUSSION: Phase 2 data added valuable information on smoking and BMI. However, phase 1 results did not change dramatically after accounting for phase 2 information, which is reassuring for the validity of database 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.

International Country-Level Trends, Factors, and Disparities in Compassionate Use Access to Unlicensed Products for Patients With Serious Medical Conditions.

Importance: Compassionate use (CU) is a treatment option for patients with serious or life-threatening medical conditions that provides access to locally unlicensed medications (generally free of charge) when all available treatment options have been exhausted and enrollment in a clinical trial is not possible. Objective: To examine the disparity in CU access observed across countries and explore the key driving factors. Design Settings and Participants: This study analyzed all Novartis CU requests (for individual/named patients and cohort programs) received between January 1, 2018, and December 31, 2020, and investigated selected country-specific factors for association with request activity. Data analysis was performed from February 2021 to February 2022. Main Outcomes and Measures: Country-specific request activity was quantified using request counts and rates per million population and examined in stratified and multivariable analyses (negative-binomial regression) for association with the following covariates: existence of local CU regulations and their public availability, clinical trial activity, population size, and gross domestic product. Results: During the 36-month observation period, 31 711 CU requests were received from 110 countries, 23 194 (73%) of which came from only 10 high-income countries. All high-income countries combined accounted for 27 612 (87%) of all requests, while lower-middle-income and low-income countries contributed only 1021 (3%). Of all requests, 29 870 (94%) were from countries with CU regulations made publicly available on the internet, and higher request activity was demonstrated in countries conducting more clinical trials. Presence and public availability of CU regulations, population size, gross domestic product, and clinical trial activity were independently associated with the CU request activity in multivariable analysis. Conclusions and Relevance: In this cohort study analyzing Novartis CU requests over a 3-year period, existence and public availability of CU regulations and local clinical trial activity were positively associated with higher CU request rates. The analysis also identified an association between macroeconomic factors and CU request activity, despite the generally free provision of unlicensed therapeutic products. Similar analyses of other comparable experiences are needed to supplement these initial observations. Ultimately, better understanding of factors associated with CU request activity would translate into improved early access to novel lifesaving products for patients with unmet medical needs around the world.

Drug interactions with phenprocoumon and the risk of serious haemorrhage: a nested case-control study in a large population-based German database.

PURPOSE: Phenprocoumon is the most frequently used vitamin K antagonist in Germany. The aim of this study was to estimate the risk of serious bleeding as a result of the use of drugs with potential interaction with phenprocoumon. METHODS: We conducted a nested case-control study in a cohort of 246,220 phenprocoumon users in the German Pharmacoepidemiological Research Database. Cases were patients hospitalised for haemorrhage of different kinds. Ten controls were matched to each case by health insurance, birth year and sex using incidence density sampling. Odds ratios (OR) with 95% confidence intervals (CI) of the risk of serious bleeding associated with combined use of phenprocoumon and potentially interacting drugs versus phenprocoumon alone were estimated using conditional logistic regression analysis. Our analyses considered multiple risk factors, such as bleeding history, other comorbidities or co-medication. RESULTS: Our study included 2,553 cases and 25,348 matched controls. An increased risk of bleeding was observed for the combined use of phenprocoumon and clopidogrel vs phenprocoumon use alone (OR: 1.83, 95% CI: 1.41-2.36). Antibiotic drugs associated with an increased risk of haemorrhage in the population of phenprocoumon users included the group of quinolones with ORs ranging from 2.74 (95% CI: 1.80-4.18) for ciprofloxacin to 4.40 (95% CI: 2.45-7.89) for levofloxacin, amoxicillin plus clavulanic acid (OR: 2.99, 95% CI: 1.39-6.42) and cotrimoxazole (OR 3.57, 95% CI: 2.36-5.40). Among non-steroidal anti-inflammatory drugs (NSAIDs), ketoprofen and naproxen were associated with the highest risks. CONCLUSION: Significantly elevated risks of major bleeding were mainly observed for drugs with known pharmacodynamic interaction with phenprocoumon, and less for drugs with possible pharmacokinetic interaction.

Risk of intracerebral hemorrhage associated with phenprocoumon exposure: a nested case-control study in a large population-based German database.

PURPOSE: Intracerebral hemorrhage (ICH) is the most serious complication of oral anticoagulation. This study investigated the risk of ICH for phenprocoumon which is the most widely used oral anticoagulant in Germany. METHODS: We conducted a nested case-control study in a cohort of 13.4 million insurants of 4 German statutory health insurances (SHIs) who were continuously enrolled for 6 months prior to cohort entry. Cases were patients hospitalized for ICH. Ten controls were matched to each case by SHI, birth year, and sex using incidence density sampling. Rate ratios (RR) of ICH for current phenprocoumon use as compared to non-use were estimated from odds ratios calculated by conditional logistic regression analyses considering multiple risk factors. RESULTS: Analysis of the full cohort revealed a strong increase in incidence of ICH with increasing age. In the nested case-control study including 8138 cases of ICH and 81,373 matched controls, we observed an increased risk of ICH for current phenprocoumon exposure that varied with age. The phenprocoumon-associated risk of ICH was lower in older age groups with RRs from 4.20 (95% confidence interval (CI) 2.44-7.21) for phenprocoumon users less than 55 years of age to 2.43 (95%CI, 1.81-3.27) for those older than 85 years. Our study confirmed known risk factors of ICH. DISCUSSION: Phenprocoumon exposure was associated with an increased risk of ICH. The interaction of risk for phenprocoumon with age was unexpected and needs further study.

A Database Cohort Study to Assess the Risk of Angioedema Among Patients with Heart Failure Initiating Angiotensin-Converting Enzyme Inhibitors in the USA.

INTRODUCTION: Real-world evidence on the risk of angioedema associated with angiotensin-converting enzyme inhibitors (ACEIs) in patients with heart failure (HF) is scarce. OBJECTIVE: This non-interventional study aimed to estimate the incidence of and risk factors for angioedema in patients with HF initiating an ACEI in real-world practice. METHODS: This was a retrospective cohort study using claims data from the PharMetrics Plus database, supplemented with consumer health data, from 1 January 2007 to 31 March 2015. Patients with HF initiating an ACEI were followed up for a maximum of 1 year, until the first occurrence of angioedema or until cohort exit. Angioedema incidence rates were estimated and stratified by potential risk factors such as race, age, sex, and time from initiation of ACEI therapy. For each risk factor, the unadjusted and adjusted hazard ratio (HR) was calculated; exploratory analyses were carried out to account for all potential confounders. RESULTS: We identified 21,639 patients with HF initiating an ACEI (mean age 58 years; 35.6% women; mean follow-up 205 days). The 1-year incidence of angioedema per 1000 patient-years was 3.3 [95% confidence interval (CI) 2.4-4.5]. The incidence was higher in Black [6.2 (95% CI 3.1-12.5)] than in non-black [2.9 (95% CI 2.1-4.1)] patients, higher in women [5.2 (95% CI 3.4-7.9)] than in men [2.3 (95% CI 1.5-3.6)], and greatest in the first 30 days of ACEI therapy. CONCLUSIONS: The risk of angioedema in patients with HF initiating an ACEI observed in this study is in line with published estimates for the general patient population treated with ACEIs.

Risk of Stroke after Herpes Zoster - Evidence from a German Self-Controlled Case-Series Study.

BACKGROUND: Herpes zoster (HZ) is caused by reactivation of the latent varicella-zoster virus (VZV). A severe complication of HZ is VZV vasculopathy which can result in ischemic or hemorrhagic stroke. The aims of our study were to assess the risk of stroke after the onset of HZ and to investigate the roles of stroke subtype, HZ location and the time interval between HZ onset and stroke. METHODS: A self-controlled case-series study was performed on a cohort of patients with incident stroke recorded in the German Pharmacoepidemiological Research Database (GePaRD), which covers about 20 million persons throughout Germany. We estimated adjusted incidence rate ratios (IRR) by comparing the rate of stroke in risk periods (i.e., periods following HZ) with the rate of stroke in control periods (i.e., periods without HZ) in the same individuals, controlling for both time-invariant and major potentially time-variant confounders. RESULTS: The cohort included 124,462 stroke patients, of whom 6,035 (5%) had at least one HZ diagnosis identified in GePaRD either as main hospital discharge diagnosis or as HZ treated with antivirals. The risk of stroke was about 1.3 times higher in the risk periods 3 months after HZ onset, than in the control periods (IRR: 1.29; 95% confidence interval: 1.16-1.44). An elevated risk of similar magnitude was observed for ischemic and unspecified stroke, but a 1.5-fold higher risk was observed for hemorrhagic stroke. A slightly stronger effect on the risk of stroke was also observed during the 3 months after HZ ophthalmicus (HZO) onset (1.59; 1.10-2.32). The risk was highest 3 and 4 weeks after HZ onset and decreased thereafter. CONCLUSIONS: Our study corroborates an increased risk of stroke after HZ, which is highest 3 to 4 weeks after HZ onset. The results suggest that the risk is more pronounced after HZO and is numerically higher for hemorrhagic than for ischemic stroke.