Stroke and Ischemic Heart Disease With Enzyme-inducing Antiseizure Medications: Time to Change Prescribing Habits

Importance: Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease. Objective: To quantify and model the putative hazard of cardiovascular disease secondary to eiASM use. Design, Setting, and Participants: This cohort study covered January 1990 to March 2019 (median [IQR] follow-up, 9 [4–15], years). The study linked primary care and hospital electronic health records at National Health Service hospitals in England. People aged 18 years or older diagnosed as having epilepsy after January 1, 1990, were included. All eligible patients were included with a waiver of consent. No patients were approached who withdrew consent. Analysis began January 2021 and ended August 2021. Exposures: Receipt of 4 consecutive EI ASMs (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate) following an adult-onset (age >/=18 years) epilepsy diagnosis or repeated exposure in a weighted cumulative exposure model. Main Outcomes and Measures: Three cohorts were isolated, 1 of which comprised all adults meeting a case definition for epilepsy diagnosed after 1990, 1 comprised incident cases diagnosed after 1998 (hospital linkage date), and 1 was limited to adults diagnosed with epilepsy at 65 years or older. Outcome was incident cardiovascular disease (ischemic heart disease or ischemic or hemorrhagic stroke). Hazard of incident cardiovascular disease was evaluated using adjusted propensity-matched survival analyses and weighted cumulative exposure models. Results: Of 10,916,166 adults, 50,888 (.6%) were identified as having period-prevalent cases (median [IQR] age, 32 [19–50] years; 16 584 [53%] female), of whom 31,479 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline. In a propensity-matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status, and cardiovascular risk factors, the hazard ratio for incident cardiovascular disease was 1.21 (95% CI, 1.06–1.39) for those receiving eiASMs. The absolute difference in cumulative hazard diverges by more than 1% and greater after 10 years. For those with persistent exposure beyond 4 prescriptions, the median hazard ratio increased from a median (IQR) of 1.54 (1.28–1.79) when taking a relative defined daily dose of an eiASM of 1 to 2.38 (1.52–3.56) with a relative defined daily dose of 2 throughout a maximum of 25 years' follow-up compared with those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed when older than 65 years. Conclusions and Relevance: The hazard of incident cardiovascular disease is higher in those receiving eiASMs. The association is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.

Association Between Nonselective Beta-Blocker Use and Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Without Cirrhosis and Decompensation

Background: Nonselective beta-blockers (NSBBs) can reduce the incidence or mortality of certain types of cancers, and NSBBs exert a protective effect on hepatocellular carcinoma (HCC) in patients with cirrhosis. However, the potential preventive effect of NSBBs has not yet been investigated in patients with chronic hepatitis B (CHB) who have a high HCC risk regardless of the presence of underlying cirrhosis.Aim: This study evaluated the association between NSBB use and HCC incidence in patients with CHB without cirrhosis and decompensation.Methods: From the 2000 Longitudinal Generation Tracking Database, we enrolled patients who were newly diagnosed as having CHB from January 2001 to December 2011 and then followed them up for at least 5 years. To estimate the causal effect of NSBBs on the time-to-event outcomes of HCC, a marginal Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).Results: After adjustment, no significant benefit of HCC risk reduction was observed between the NSBB users and nonusers (adjusted HR, 0.82; 95% CI, 0.52–1.31). The cumulative defined daily dose (cDDD) analysis revealed no significant dose correlation among the three groups [adjusted HR (95% CI): 1.08, (0.56–2.05), 0.54 (0.17–1.77), and 0.76 (0.40–1.42) in the <90 cDDD, 90 to <180 cDDD, and ≥180 cDDD groups, respectively]. Duration-dependent associations were not observed. Multivariable stratified analysis results demonstrated that HCC risk markedly decreased in the patients aged >55 years (adjusted HR, 0.49; 95% CI, 0.25–0.96; p = 0.04).Conclusion: NSBB did not significantly prevent HCC in the patients with CHB infection without cirrhosis and decompensation. This study provided one of valuable results that it is not clinically required to use NSBBs as recommended chemoprevention for HCC in high-risk patients who have CHB.

Antimicrobial usage in cattle and poultry production in Dar es Salaam, Tanzania: pattern and quantity

Background Antimicrobials are extensively used in cattle and poultry production in Tanzania. However, there is dearth of information on its quantitative use. A questionnaire-based cross-sectional study was conducted from August to September 2019 in randomly selected poultry and small-scale dairy farms, in three districts of Dar es Salaam City eastern, Tanzania, to assess the practice and quantify antimicrobial use. Descriptive and statistical analyses were performed at a confidence interval of 95%. The ratio of Used Daily Dose (UDD) and Defined Daily Dose (DDD) were used to determine whether the antimicrobial was overdosed or under dosed. Results A total of 51 poultry and 65 small-scale dairy farms were involved in the study. The route of antimicrobial administration was 98% orally via drinking water and 2% in feeds for poultry and for small-scale dairy farms, all through parenteral route. Seventeen types of antimicrobials comprising seven classes were recorded in poultry farms while nine belonging to six classes in the small dairy farms. Majority of the farms (poultry, 87.7% and small scale dairy, 84.3%) used antimicrobials for therapeutic purposes. About 41% of the poultry and one third (34%) of the dairy farmers’ were not compliant to the drug withdrawal periods. Beta-lactams, fluoroquinolones, sulphonamides, tetracyclines and macrolides were the commonly used antimicrobials on these farms. In the poultry farms both those with records and those which relied on recall, antimicrobials were overdosed whereas in the small dairy farms, sulfadimidine, oxytetracycline and neomycin were within the appropriate dosing range (0.8–1.2). The majority (58.6%) of farmers had adequate level of practices (favorable) regarding antimicrobial use in cattle and poultry production. This was associated with the age and level of education of the cattle and poultry farmers. Conclusion The study revealed a widespread misuse of antimicrobials of different types and classes in both poultry and small-scale dairy farming in Dar es Salaam, Tanzania. This result gives insight into the antimicrobial use practices and its quantification. The information obtained can guide and promote prudent use of antimicrobials among the farmers by developing mitigate strategies that reduce antimicrobial resistance risk potentials.

Costs and consumption of analgesics, with special reference to opiates in Serbia and Montenegro from 2015 to 2019

Background/Aim: Patients in developing countries do not always receive adequate painrelieving treatment. Monitoring of analgesic consumption is of great importance, since this can help assessing the quality of painful condition management. The aim of this paper is to present a five-year consumption and costs of drugs with analgesic effects in developing countries, exemplified by Serbia and Montenegro, and indicate the main reasons for their (in)adequate prescribing. Methods: The observational, retrospective, cross-sectional study was conducted in order to analyse consumption of all analgesics, both opioid and non-opioid, in Serbia and Montenegro, as developing countries. The data concerning analgesic consumption and drug prices were obtained from annual editions of the publications of the Medicines and Medical Devices Agency of Serbia and Montenegro. The WHO methodology with defined daily dose (DDD) as a unit of measure (it is defined by the number of DDD per 1000 inhabitants per day) was used in these publications. Results: In the course of the fiveyear period (from 2015 to 2019) in Serbia, the total allocations for analgesic therapy had a rising trend; from about 43.6 million to 63.3 million of Euros, while in Montenegro expenditures showed annual variations with highest value in 2018. Most of the money in both countries was invested in M01A group of drugs, for which the highest consumption was also recorded. Significantly higher consumption of opioid analgesics in Montenegro comparing with Serbia was observed in the same period, and it predominatly reflected the difference in fentanyl (N02AB03, transdermal patch) prescribing. In Montenegro, consumption of M01group of drugs was prominently higher in comparison to M01AE group during the whole five-year period, similarly like in Serbia in which this was not the case only in 2018. Conclusions: Taking into account the importance of analgesics for everyday medical practice, more rational prescribing of these drugs is necessary both in Serbia and Montenegro in the future.

The use of anti-hyperlipidemia in a private hospital in Yogyakarta during 2013-2019

Background: Lipid modifying agents have an important role in the primary and secondary prevention of cardiovascular diseases such as coronary heart disease and stroke. The use of lipid-modifying agents tends to increase along with the increasing prevalence of these diseases. Objectives: To determine the utilization of lipid modifying agents for hospitalized patients in a private hospital in Yogyakarta during the period of 2013 - 2019 in regard to the agents used and their quantity. Methods: The main data for this study were aggregate data on the use of lipid modifying agents for hospitalized patients during 2013-2019 obtained from the hospital pharmacy department. After identification of the names of lipid modifying agents, the quantities of these drugs were then calculated in units of defined daily dose (DDD) and the final quantity was expressed in DDD/100 bed days (BD). The R2 value from linear regression was used to determine the trend of use of individual agents over the period. Results: There were two pharmacological subgroups of lipid modifying agents used during the period of 2013 – 2019 with an average of total quantity of 14.81 DDD/100 BD. Utilization of statins was approximately 90% of the total use, and utilization of fibrates tended to decrease over the period. Individually, simvastatin use decreased significantly over the period (R2 = 0.885), but atorvastatin use continued to increase (R2 = 0.908) with 10-fold increase from 2013 to 2019. Conclusion: The lipid modifying agents used during the period 2013 - 2019 were predominantly statins, and the utilization of atorvastatin increased significantly during this period. Keywords: lipid modifying agents, ATC/DDD, fibrates, statins

Improved renal cancer prognosis among users of drugs targeting renin-angiotensin system

Purpose We explored renal cell cancer (RCC) survival among users of antihypertensive medication as hypertension is proposed to be a risk factor for RCC and ACE-inhibitors and angiotensin receptor blockers (ARBs) have been associated with improved prognosis of RCC. Methods Finnish cohort of 13,873 participants with RCC diagnosed between 1995–2012 was formed from three national databases. RCC cases were identified from Finnish Cancer Registry, medication usage from national prescription database and co-morbidities from Care Registry of Healthcare. Logistic regression was used to calculate odds ratios for metastatic tumor extent at the time of diagnosis. Risk of RCC specific death after diagnosis was analyzed using Cox regression adjusted for tumor clinical characteristics. Results A total of 5,179 participants died of RCC during the follow-up. No risk association was found for metastatic tumor extent for any drug group. ACE-inhibitors, but no other drug group were associated with decreased risk of RCC specific death overall (HR 0.88, 95% CI 0.82–0.95) compared to non-users. In time-dependent analysis high-dose use of ACE-inhibitors (392 Defined Daily Dose (DDD)/year), HR 0.54, 95% CI 0.45–0.66) and ARBs (786.1 DDD/year, HR 0.66, 95% CI 0.50–0.87) associated with improved RCC survival. No information of TNM-classification or tobacco smoking was available. Conclusion ACE-inhibitors and ARBs in high dose associated with improved RCC specific survival. This may reflect overall benefit of treating hypertension with medication targeting renin-angiotensin system (RAS) system among RCC patients. Further studies are needed to explore the role of RAS in RCC.

Consumption of single products versus fixed-dose combination medicines for hypertension and hyperlipidemia during 2015–2019 in South Korea

Background Fixed-dose combinations can simplify prescribing, and numerous combination products exist for hypertension and dyslipidemia in South Korea. This study’s aim was to compare trends in the consumption of single products versus fixed-dose combinations for hypertension and hyperlipidemia. Methods and findings We analyzed the Korean national health insurance claims database from January 2015 through December 2019. Consumption of medicines was calculated using the defined daily dose per 1,000 inhabitants per day (DIDs) and expenditures over time. During 2015–2019, the use of antihypertensive drugs increased with an annual growth rate (AGR) of 0.9% for single products and with an AGR of 35.6% for fixed-dose combinations. A notable increase was observed for antihyperlipidemic combination drugs with an AGR of 268.1% compared to single products with 35.7%. For older adults (65+ years), the consumption of drugs for hypertension and hyperlipidemia was 3–4.5 and about 3 times higher, respectively, than in adults aged 20–64 years, and a sharp increase was found in antihyperlipidemic fixed-dose combinations among older adults. A large increase was seen for C09 (agents acting on the renin-angiotensin system) with an AGR of 36.5%, especially C09DB (angiotensin II receptor blockers + calcium channel blockers) was widely used and steeply increased with 114.2%. For antihyperlipidemic drugs, C10AA (HMG CoA reductase inhibitors) accounted for a large share and sharply increased, with 52.1 DIDs in 2019 and with an AGR of 78.4%, whereas C10BA (combinations of various lipid modifying agents) increased 9.6 times from 2.9 DIDs (96 million USD) in 2015 to 27.7 DIDs (912 million USD) in 2019. Conclusion The findings of increased consumption and drug spending among older adults underscores the need for real-world evidence about health outcomes of fixed-dose combinations in this population.

Gambaran Kuantitatif Antibiotik Menggunakan Metode Defined Daily Dose (DDD) Di Ruang Rawat Inap RSPI Prof. Dr. Sulianti Saroso Pada Januari-Juni 2019

Latar Belakang. Penggunaan antibiotik yang tepat dapat meminimalkan terjadinya resistensi antibiotika. selain penghematan secara ekonomi. Oleh karena itu perlu adanya pemantauan dan evaluasi penggunaan antibiotik di fasilitas kesehatan dan feedback terhadap peresepan antibiotik. Tujuan penelitian ini adalah untuk mengevaluasi secara kuantitatif penggunaan antibiotik baik jenis dan jumlah antibiotik berdasarkan klasifikasi Anatomical Therapeutic Chemical (ATC) dengan pengukuran Defined Daily Dose (DDD) sebagai metode terstandar pengukuran kuantitas penggunaan antibiotik. Metode. Penelitian ini adalah observasional deskriptif, menggunakan rancangan potong lintang pada periode Januari-Juni 2019 pada RSPI Prof. Dr. Sulianti Saroso. Kriteria inklusi berupa kasus pasien dewasa bukan kasus TB yang dirawat di ruang rawat inap non ICU dan penggunaan antibiotiknya masuk ke dalam klasifikasi Anatomical Therapueutic Chemical (ATC). Berdasarkan data rekam medik terkumpul dalam lembar pengumpul data. Hasil. Sebanyak 96 status rekam medik dengan 51 kasus penyakit infeksi non bedah dan 45 kasus infeksi bedah yang menggunakan antibiotik. Difteri merupakan kasus infeksi non bedah terbanyak yaitu 10.5%. Distribusi penggunaan antibiotik golongan beta laktam kombinasi inhibitor betalaktamase sebanyak 37.28%, golongan sefalosporin 33.90%, golongan penisilin sebanyak 10,17%. Berdasarkan nilai DDD/patient day antibiotik Penicillin Prokain memiliki nilai tertiggi yaitu sebesar 97.22 dan nilai DDD/patient day terendah yaitu pada antibiotik meropenem yaitu sebesar 0.22. Kesimpulan. Pada penelitian ini, kuantitas antibiotik berdasarkan nilai DDD/100 patient day tertinggi adalah Penisilin Prokain, seiring dengan difteri sebagai kasus penyakit infeksi non bedah terbanyak pada periode Januari-Juni 2019. Mengingat penelitian dilakukan pada saat kejadian luar biasa difteri, perlu dilakukan penelitian lebih lanjut pada periode berikutnya sebagai data pembanding kuantitas antibiotik di masa depan.

Surveilans Retrospektif Penggunaan Antibiotik Pada Pasien Anak Dengan Luka Bakar

Luka bakar merupakan salah satu bentuk trauma dengan tingkat risiko infeksi yang tinggi. Modalitas utama pada infeksi akibat luka bakar ialah pemberian antibiotik. Tujuan penelitian ini ialah untuk mengevaluasi penggunaan antibiotik pada pasien luka bakar anak secara kualitatif menggunakan metode Gyssens dan secara kuantitatif menggunakan metode ATC/defined daily dose (DDD). Pengambilan data dilakukan secara retrospektif melalui data rekam medik pasien luka bakar anak yang memenuhi kriteria inklusi yang dirawat di RSUD Dr. Soetomo pada tahun 2017-2019. Data diambil pada bulan November 2019 hingga Maret 2020. Didapatkan 18 pasien luka bakar anak yang memenuhi kategori inklusi. Antibiotik terbanyak yang digunakan pada penelitian ini yaitu ceftazidime sebesar 64,28%. Berdasarkan metode Gyssens didapatkan 27,77% antibiotik berada dalam kategori sudah sesuai dan sisanya termasuk dalam kategori kurang tepat dengan 84,6% termasuk kategori IIa (tidak tepat dosis) dan 15,4% termasuk kategori IVa (antibiotik lain yang lebih efektif). Berdasarkan metode ATC DDD, didapatkan nilai total DDD /100 patients-days sebesar 88,92 DDD/100patient-days dengan ceftazidime merupakan antibiotik dengan nilai terbesar yaitu 23,03 DDD/100 patient-days. Jenis antibiotik yang termasuk dalam DU 90% adalah ceftazidime (23,03), ampicillin-sulbactam (15,45), ceftriaxon (13,65), amikacin (11,91), gentamicin (9,67) dan meropenem (8,51). Kesimpulannya ialah secara kualitatif penggunaan antibiotik pada pasien luka bakar anak masih kurang sesuai dan secara kuantitatif penggunaan antibiotik melebihi standar WHO. Diperlukan perbaikan dalam rangka meningkatkan rasionalitas penggunaan antibiotik pada pasien luka bakar anak. Kata Kunci: Antibiotik, Luka Bakar, Anak, Gyssens, Defined Daily Dose

Evaluating antimicrobial prescribing in a Tertiary Healthcare Institution in Nigeria

Background Regular evaluation of antimicrobials prescriptions is important for optimal use. Objective This study determined the prescription patterns, class and costs of antimicrobials in the adult out-patient pharmacy of a Teaching Hospital in Nigeria. Methods A 1-year retrospective study from 1st January to 31st December 2018. The data, which included identification code, age, sex, antibiotics prescribed, number of antibiotics per prescription, number of medicines per prescription, dosage form, generic prescribing, drug on the essential drug list, and cost, were used in the analysis. The Chi-square test and Analysis of Variance were used to compare our data with the WHO–developed antimicrobial prescription Guidelines for Anatomical Therapeutic Chemical and Defined Daily Dose assignment of 2019. Results From 450 patient records, significantly more females (70%) were prescribed with antimicrobials (P = 0.0038). The prescription pattern showed that antimicrobials selection by class was significantly different (P < 0.0001) (top three being Amino-penicillin > Nitroimidazoles > Fluoroquinolone). In addition, age differed significantly (P < 0.0001) with 46–50 as the highest class. Dosage forms profile showed that the percentage of encounter with injections prescribed (1.8%) was less than WHO recommendation (13.4–24.1%). Most of the prescriptions (84.22%) were from the Essential Drug List. The average cost of prescriptions with two antimicrobials was the highest ($14.0807), then three ($10.7949), and one ($6.39858). The average number of drugs per prescription that had one (4.28), two (4.46), and three (5.55) antimicrobials, respectively, were more than double the average (2) recommended by WHO. Conclusion The study showed that most of the patterns are within limit, however, highlights the need for frequent evaluation.