key: cord-0693749-7okoyupi authors: Enners, Salka; Gradl, Gabriele; Kieble, Marita; Böhm, Michael; Laufs, Ulrich; Schulz, Martin title: Utilization of drugs with reports on potential efficacy or harm on COVID‐19 before, during, and after the first pandemic wave date: 2021-07-21 journal: Pharmacoepidemiol Drug Saf DOI: 10.1002/pds.5324 sha: a5e37c691d84f5a887f3eef8fe740e5ee90a3328 doc_id: 693749 cord_uid: 7okoyupi PURPOSE: Conflicting information on potential benefits of drugs as well as reports on hypothetical harm of commonly used drugs in COVID‐19 treatment have challenged clinicians and healthcare systems. We analyzed the change in ambulatory drug utilization before, during, and after the first wave of the pandemic in 2020. METHODS: We explored dispensing data of nearly 19 000 pharmacies at the expense of the statutory health insurance funds covering 88% of Germany's population. We analyzed utilization of publicly discussed drugs with conflicting information. Drug utilization as number of packages dispensed per week from January to June 2020, reflecting 314 million claims, was compared with 2019. RESULTS: Utilization of hydroxychloroquine increased +110% during March 2020 and then slightly decreased until week April 13–19. Renin–angiotensin–aldosterone system inhibitors and simvastatin/atorvastatin increased, +78% and +74%, respectively, and subsequently decreased below 2019 levels. Utilization of azithromycin and all systemic antibiotics decreased continuously from March 2–8 until June to levels considerably lower compared to 2019 (June 22–28: azithromycin: −55%, all systemic antibiotics: −27%). Pneumococcal vaccines utilization initially increased +373%, followed by supply shortages. Paracetamol utilization showed an initial increase of +111%, mainly caused by an increase of over‐the‐counter dispensings. CONCLUSIONS: Apart from the pandemic itself, the data suggest that dissemination of misinformation and unsound speculations as well as supply shortages influenced drug prescribing, utilization, and purchasing behavior. The findings can inform post‐pandemic policy to prevent unfounded over‐ and underprescribing and off‐label use as well as drug shortages during a public health crisis. Healthcare systems and clinicians around the world faced major challenges in drug supply during the coronavirus disease (COVID-19) pandemic in 2020. The spreading of the severe acute respiratory coronavirus 2 (SARS-CoV-2) was accompanied by dissemination of misinformation and unsound speculations concerning potential treatment efficacy or harm of some drugs, primarily via public media and social networks. 1 A media analysis identified 2311 reports of rumors, stigma, and conspiracy theories in 25 languages from 87 countries. 19% of the claims were related to treatment and cure. 2 Several drugs were being tested for treatment or prevention of COVID- 19 and might have been used off-label. 1, [3] [4] [5] Consequently, patients may have been exposed to adverse effects of these drugs without proven benefits. Hydroxychloroquine, approved for malaria prophylaxis and treatment as well as treatment of rheumatoid arthritis and systemic lupus erythematosus (SLE), is a potent in vitro replication inhibitor of most coronaviruses. It was therefore discussed for treating The human immunodeficiency virus therapeutics lopinavirs' and ritonavirs' protease inhibiting abilities were discussed to be effective against SARS-CoV-2. 6, 7 For other drugs, an increasing risk for infection and critical outcomes of COVID-19 was hypothesized. This has been mainly discussed for drugs inhibiting the renin-angiotensin-aldosterone system (RAAS), among them widely used angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). 8 The mechanism for SARS-CoV-2 infection is the requisite binding of the virus to the membrane-bound form of the angiotensin-converting enzyme 2 (ACE2) and internalization of the complex by the host cell. 8, 9 ACE2, however, is a key enzymatic component of the RAAS. Experimental evidence suggests that RAAS blockade enhance ACE2, which, in part, contributes to the benefit of these regimens. 8 Statins were proposed as an adjunct therapy for COVID -19 because of their anti-inflammatory and other potential beneficial effects. 10 However, statins have been shown to upregulate the expression of ACE2, 11 with the potential for increasing viral entry into cells. 12 It was even suggested to cease cholesterol-lowering therapy in patients with COVID-19. 13 Fang et al. 14 suggested that ACE2 can also be increased by the non-steroidal inflammatory drug ibuprofen. This theoretical concern led to a recommendation by the World Health Organization (WHO) 15 on March 17, 2020 that ibuprofen should not be used by patients who show symptoms of COVID-19, but be replaced by paracetamol. 16 Pneumococci infections can lead to severe pneumonia and sepsis and can potentially require artificial ventilation of intensive care patients. It has been hypothesized that pneumococcal vaccinations could stimulate an immune response in older adults potentially lowering the severity of other infections. 17 However, clinical data supporting this hypothesis with regard to COVID-19 are scarce. [18] [19] [20] [21] Data on drug utilization during the pandemic is limited 4 but potentially helpful for future public health crises. We aimed, therefore, to investigate the change in ambulatory drug utilization before, during, and after the first wave of the COVID-19 pandemic in 2020. We hypothesized an increase in utilization for drugs reported to be beneficial, such as hydroxychloroquine, and a decline in utilization of drugs, such as RAASi and ibuprofen, for which an increase of risk was speculated. We performed a descriptive drug utilization study. Drug prescriptions were analyzed using the database of the German Institute for Drug Use Evaluation (DAPI), which contains anonymous dispensing data of community pharmacies claimed to the statutory health insurance (SHI) funds and thus covers 88% of Germany's population, that is, approximately 73.3 million people. 22 All claims data from a representative sample of more than 80% (until June 2019) and more than 95% (from July 2019 onwards) of community pharmacies were available. The data were extrapolated by regional factors to 100% of the SHI-insured population. Dispensing data were linked to a database containing information on the name, composition, active ingredients, package size, dosage form, and route of administration using the specific product code (Pharmazentralnummer, an identification number for pharmaceutical products in Germany). Allocation of active ingredients was based on the official version of the Anatomical Therapeutic Chemical classification system published by the German Institute of Medical Documentation and Information. 23 We analyzed the time course of utilization for hydroxychloroquine, RAASi (ACEi and ARB), azithromycin, the two most frequent used statins (simvastatin and atorvastatin), pneumococcal vaccines, ibuprofen and lopinavir-ritonavir. We also analyzed the time course of paracetamol utilization. For an overview on the general course of utilizations in 2020, we analyzed dispensings of all prescribed drugs, all systemic antibiotics, the most frequently used substance in the classes of penicillins (amoxicillin), cephalosporins (cefuroxime), and quinolones (ciprofloxacin). We determined three periods: A, from January 2020 until week For ibuprofen und paracetamol, we included dispensing data from private health insurance (PHI)-insured patients and self-medication utilization from the INSIGHT Health database to portray full utilization since those drugs are not primarily prescription drugs but over-thecounter (OTC) products. This database includes extrapolated data from a representative sample of over 4500 community pharmacies. 24 We determined the distribution of the package sizes per analyzed drug in 2020 compared to 2019 to rule out possible bias due to different amounts of drugs per package in both evaluation periods. Further, we supplemented the data on dispensed packs of the study drugs with defined daily doses 23 per 1000 SHI-insured persons per day (DID). The number of persons insured by the SHI system was obtained from the Federal Ministry of Health. 25 There were no relevant differences in the distribution of package sizes in the analyzed drugs in 2020 compared to 2019 (Table S1 in Data S1). There were no differences in the weekly time courses between DID and packages ( Table S2 in Data S1). Figure 1A ). Compared to 2019, utilization of hydroxychloroquine increased +110% to 10 700 packages per week at the end of period A, and then decreased to 4700 packages per week at the end of period B with still +22% packages compared to 2019 (Table 1, Figure 1A ). Simvastatin and atorvastatin, similar to RAASi and all prescription drugs, peaked at 623 000 packages per week (+74%) at the end of period A and then dropped to 405 500 packages (À15%) at the beginning of period C. Utilization approximated to 2019 values until the end of the observation period (Table 1 , Figure 1A ). The amount of ambulatory dispensed packages of lopinavirritonavir was low (approximately 102 packages per week) and did not show differences between 2020 and 2019 (Table 1) . During period A, azithromycin use slightly increased to 77 400 packages (+9%) in week March 2-8 and 72 000 packages (+16%) in week Figure 2 ). Figure 3 ). The main finding of our analyses is that drug prescribing, utilization, and purchasing behavior was significantly altered, particularly during the first weeks of the COVID-19 pandemic in early 2020, possibly influenced by misinformation and speculations on potential treatment A study in diabetic rats found upregulation of ACE2 by ibuprofen, however, lower ACE2-levels were documented in the diabetic compared to healthy rats. 53 Other in vitro studies suggested ibuprofen may even facilitate cleavage of ACE2 from the membrane, preventing membranedependent viral entry into the cell. 54, 55 In a nationwide register-based cohort study, there was no significant association between ibuprofen prescription claims and severe COVID-19. 56 Recently, ibuprofen use in COVID-19 patients was shown not to be associated with worsening clinical outcomes, compared with paracetamol or no antipyretic. 57 59 This highlights the weakness of the distribution system and its vulnerability to sudden (justified) peaks in demands during pandemics. Prescription fills for all systemic antibiotics, amoxicillin, cefuroxime as well as for azithromycin declined substantially (between À37% and À58%). These data were unexpected and in contrast to hydroxychloroquine. The use of ciprofloxacin did not decrease considerably after the start of the pandemic, as in previous years. We assume that this fluoroquinolone antibiotic was only used for severe infections of the lower respiratory tract and for complicated urinary tract infections, but not for non-serious respiratory tract infections, according to guidelines and recommendations. 61,62 The data show that the use of pneumococcal vaccines peaked after a recommendation by the German Federal Minister of Health on March 9, followed by drug shortages and increased again after imports of vaccines from England and Japan. [63] [64] [65] Our findings demonstrate that an unexpected rise in use of vaccines, for example, pneumococcal can result in drug shortages. These are difficult to counteract as vaccines have a long manufacturing time. Since pseudonymized data were unavailable we do not have patient level information including prescription indications and potential impact on patients' outcome. Whether intake of potentially beneficial drugs against COVID-19 is associated with an increase in long-term adverse events remains to be seen. We can only speculate that increase in utilization was connected to off-label use for COVID-19. Apart from the pandemic itself, the data suggest that dissemination of misinformation and unsound speculations as well as supply shortages influenced drug prescribing, utilization, and purchasing behavior. The findings can inform post-pandemic policy to prevent unfounded overand underprescribing and off-label use as well as drug shortages during a public health crisis. 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Accessed COVID-19 und Impfen: FAQ Safety Conflict of Interest disclosure form and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could have influenced the submitted work. This study used anonymized claims data, so no ethical approval was needed.