Use of fixed-dose combinations for cardiovascular indications from 2018 to 2023: a nationwide population-based study.

AIMS: Clinical guidelines support the use of fixed-dose combinations (FDC) for prevention of cardiovascular disease. Implementation of FDC into clinical care remains challenging, and current population-based data are scarce. METHODS AND RESULTS: Claims data on dispensed drugs in an outpatient care setting of approximately 87% of the German population were analysed regarding the use of FDC according to time, age of the insured persons, and active ingredients. The overarching trend for all FDC revealed a decrease from 77.3 defined daily doses per 1000 statutory health-insured (SHI) persons per day (DID) in the second half-year of 2018 (2018HY02) to 60.8 DID in the first half-year of 2023 (2023HY01) (Spearman ρ = -0.988; P < 0.001). The total DID for all antihypertensives (AHT) increased from 590.6 in 2018HY02 to 624.8 in 2023HY01 (ρ = 0.855; P = 0.002), but the DID for fixed-dose AHT (AHT-FDC) declined from 74.1 in 2018HY02 to 55.0 in 2023HY01 (ρ = -0.988; P < 0.001). Conversely, the use of all lipid-lowering agents (LLA) and LLA-FDC continuously increased: The total DID of all LLA rose from 92.5 in 2018HY02 to 134.4 in 2023HY01 (ρ = 1.000; P = 0.000), and for LLA-FDC from 3.1 in 2018HY02 to 5.5 DID in 2023HY01 (ρ = 0.915; P < 0.001). AHT-FDC and LLA-FDC were less frequently dispensed to patients at least 80 years than to patients less than 80 years. Dispensing of multiple purpose FDC increased from 2018HY02 to 2023HY01 from 0.11 DID to 0.26 DID (ρ = 1.000; P = 0.000) but remained negligible. CONCLUSION: Use of AHT-FDC in Germany is declining. In contrast, FDC containing LLA are increasingly prescribed. Dispensing of multiple purpose FDC is very low. Strategies are needed to facilitate the use of FDC as recommended by current guidelines.

Use of fixed-dose combination antihypertensives in Germany between 2016 and 2020: an example of guideline inertia.

BACKGROUND: The 2018 European Society of Cardiology (ESC)/European Society of Hypertension (ESH) guidelines for the management of hypertension highlight the importance of fixed-dose combinations (FDC) for the treatment of hypertension and recommend initial single-pill combination therapy in almost all patients. However, data on the implementation of these recommendations in clinical practice are scarce. METHODS: Data from the German Institute for Drug Use Evaluation (DAPI) were analyzed and extrapolated accounting for approximately 88% of Germany's population (approximately 73.3 million subjects). All antihypertensive (AHT) FDC products available on the German market were included in the analyses. We examined the time course of dispensed packages between January 2016 and December 2020. RESULTS: FDCs accounted for 15.4% of all AHT in 2016 and for 10.9% in 2020. While dispensing of all AHT increased slightly from year to year (2016: 143.8 million, 2020: 153.2 million packs), dispensing of FDCs decreased from 22.2 million (2016) to 16.6 million (2020) packs. Dispensing of FDCs containing hydrochlorothiazide (HCT) declined considerably from 2016 to 2020 (Q1 2016: 4.65 million, Q4 2020: 3.13 million packs). Accordingly, the proportion of HCT-containing combinations in all FDCs decreased from 85.3 to 74.2% from Q1 2016 to Q4 2020. Patients younger than 80 years were prescribed FDCs more frequently (14.6% of all AHT, based on the entire evaluation period) than patients 80 years and older (10.0%). In both age groups, this proportion decreased continuously over time. CONCLUSIONS: Almost 2 years following the release of the 2018 ESC/ESH guidelines, only 10.9% of the prescribed packs of antihypertensive drugs in 2020 were FDC products, documenting underutilization of current guideline recommendations on pharmacotherapy in hypertension. Structured programs to evidence-based decision support are required to improve guideline inertia and patient outcomes, eventually.

Assessment of the Prescriptions of Systemic Antibiotics in Primary Dental Care in Germany from 2017 to 2021: A Longitudinal Drug Utilization Study.

(1) Background: Due to increasing antibiotic resistance, the frequency of antibiotic use should be questioned in dentistry and attention paid to the choice of the best suited substance according to guidelines. In Germany, overprescribing of clindamycin was noteworthy in the past. Therefore, the aim of our study was to determine the trend of antibiotic prescriptions in primary dental care. (2) Methods: Prescriptions of antibiotics in German primary dental care from 2017 to 2021 were analysed using dispensing data from community pharmacies, claimed to the statutory health insurance (SHI) funds, and compared with all antibiotic prescriptions in primary care. Prescriptions were analysed based on defined daily doses per 1000 SHI-insured persons per day (DID). (3) Results: Amoxicillin was the most frequently prescribed antibiotic (0.505 DID in 2017, 0.627 in 2021, +24.2%) in primary dental care, followed by clindamycin (0.374 DID in 2017, 0.294 in 2021, -21.4%). Dental prescriptions still made up 56% of all clindamycin prescriptions in primary care in 2021. (4) Conclusions: Our study suggests that the problem of overuse of clindamycin in German dentistry has improved, but still persists.

Trends in Ezetimibe Prescriptions as Monotherapy or Fixed-Dose Combination in Germany 2012-2021.

Aims: Addition of ezetimibe to statin therapy is recommended by current guidelines when low-density lipoprotein cholesterol (LDL-C) targets are not achieved with statin monotherapy. Fixed-dose combinations (FDC) improve medication adherence and facilitate risk factor control. We assessed prescription trends of ezetimibe as monotherapy or FDC with statins. Methods: Data from the German Institute for Drug Use Evaluation (DAPI) containing dispensing data of >80% of community pharmacies were analyzed. Prescriptions over time of lipid-lowering agents at the expense of the statutory health insurance (SHI) were extrapolated to all SHI-insured persons, representing approximately 88% of the total German population. Drug utilization was expressed as defined daily doses per 1,000 SHI-insured persons per day (DID). Results: Of all lipid-lowering drug prescriptions in 2021, 91.2% were statin monotherapy. Ezetimibe was prescribed as monotherapy or FDC with statin in 4.4 and 2.9%, respectively. DID steadily increased for statin (69%) and ezetimibe (424%) monotherapies between 2012 and 2021. In contrast, statin-ezetimibe FDC prescriptions exhibited only a minor increase (29%). The proportion of statin-ezetimibe FDC among all statin prescriptions was stable over time at approximately 3%. FDC prescription rates by specialists were higher compared to general practitioners and varied considerably between geographic areas. Conclusion: Combination lipid-lowering therapy is prescribed to a minority of patients. Prescriptions of ezetimibe as monotherapy increased to a much greater extent than statin-ezetimibe FDC. Considering the low proportion of patients achieving their LDL-C target and improved adherence to FDC compared to separate pills, statin-ezetimibe FDC may be utilized to improve the management of dyslipidemia.

Quality Appraisal of Ambulatory Oral Cephalosporin and Fluoroquinolone Use in the 16 German Federal States from 2014-2019.

BACKGROUND: Despite concerns about causing bacterial resistance and serious side effects, oral cephalosporins and fluoroquinolones are still frequently prescribed in Germany. We aimed to test a method for the detection of regional quality differences in the use of oral cephalosporins and fluoroquinolones and to apply this to the German federal states. METHODS: Use of antibiotics from 2014-2019 was analyzed using dispensing data from community pharmacies claimed to the statutory health insurance (SHI) funds. Quality of regional antibiotic use in 2019 was assessed by calculating indicators based on defined daily doses per 1000 SHI-insured persons per day (DID). Oral cephalosporin and fluoroquinolone use was followed by linear regression analyses. RESULTS: The method used was suitable to find meaningful quality differences in ambulatory oral cephalosporin and fluoroquinolone use between the German federal states. In 2019, DID varied from 1.62 in Brandenburg to 3.17 in Rhineland-Palatinate for cephalosporins and from 0.47 in Brandenburg to 0.89 in Saarland for fluoroquinolones. The city-states Hamburg, Bremen, and Berlin showed highest quality with the applied indicator set. From 2014-2019, a significant decrease in utilization of oral cephalosporins was found in all federal states. During 2017-2019, all states showed a significant decline of fluoroquinolone use.

Utilization of drugs with reports on potential efficacy or harm on COVID-19 before, during, and after the first pandemic wave.

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.

Impact of angiotensin receptor blocker product recalls on antihypertensive prescribing in Germany.

In Germany, ~8 million patients take angiotensin receptor blockers (ARBs) and 2.25 million of them valsartan. In 2018, contamination of generic ARBs with probable carcinogenic nitrosamines resulted in more than 30 recalls. The impact of such a huge recall has never been explored in Europe. We analyzed the utilization of valsartan, all ARBs, and other alternative antihypertensive drugs in Germany. We used our database of anonymized dispensing data from >80% of community pharmacies at the expense of the statutory health insurance (SHI) funds from January 2017 to December 2019. We analyzed 290.8 million prescriptions, including all oral mono- and fixed-dose combinations of ARBs and plausible alternatives, i.e. ACE inhibitors (ACEi), beta-blockers (BB), and calcium channel blockers (CCB). Utilization was calculated by defined daily doses per 1000 SHI-insured persons per day (DID). Valsartan use decreased substantially after the recalls in July 2018 from 39.0 to 14.2 DID (-64%) in the second quarter of 2019 and to 16.9 DID (-57%) in the fourth quarter of 2019. Simultaneously, the use of alternative ARBs increased from 77.7 DID in the second quarter of 2018 to 121.9 DID (+57%) in the fourth quarter of 2019, mainly due to an increase of candesartan dispensing to 99.8 DID (+73%). There were no changes in the utilization of ACEi, BB, or CCB. The majority of recalled generic valsartan products were replaced by other ARBs, predominantly candesartan, despite documented drug shortages. In contrast to previous safety warnings/recalls, our data do not suggest an under-prescription of antihypertensives during this period.

Comparing outpatient oral antibiotic use in Germany and the Netherlands from 2012 to 2016.

PURPOSE: Overuse of antibiotics is of concern, but may differ between European countries. This study compares outpatient use of oral antibiotics between Germany (DE) and the Netherlands (NL). METHODS: For DE, we used the DAPI database with information on dispensings at the expense of the Statutory Health Insurance Funds from > 80% of community pharmacies. For NL, data were obtained from the Dutch Foundation for Pharmaceutical Statistics. Use of oral antibiotics was estimated as defined daily doses per 1000 inhabitants per day (DID), except for age comparisons as packages per 1000 inhabitants annually. National time trends were assessed with linear regression, stratified for the major antibiotic classes, and individual substances. RESULTS: From 2012 to 2016, outpatient antibiotic use was lower in NL than in DE (9.64 vs 14.14 DID in 2016) and non-significantly decreased slightly over time in both countries. In DE, dispensings of oral antibiotics to children were higher compared with NL for the age groups 2 to 5 (2.0-fold in 2016) and 6 to 14 years (2.7-fold in 2016). Use of cephalosporins was very low in NL (0.02 DID in 2016), but the second most frequently dispensed class in DE (2.95 DID in 2016). CONCLUSION: From 2012 to 2016, outpatient use of oral antibiotics was lower in NL than in DE. Differences were primarily observed in the age groups 2 to 5 and 6 to 14 years, although the recommendations of evidence-based guidelines in both countries were in agreement.

In search of a standard when analyzing medication adherence in patients with heart failure using claims data: a systematic review.

To determine and address medication non-adherence is important and may improve patient outcomes. Our aim was to perform a systematic review on the operationalization of adherence measures in patients with heart failure using claims data. We searched the MEDLINE, EMBASE, and Cochrane databases. A quality check of the full-text articles was performed using the Quality in Prognosis Studies tool. We included 28 studies. Eleven studies used the medication possession ratio, 15 the proportion of days covered, and six studies used own methods to calculate medication adherence. Almost all studies used an observation period of 1 year. Twenty-one studies considered angiotensin converting enzyme inhibitors or angiotensin receptor antagonists, 17 beta-blockers, 11 diuretics, eight mineralocorticoid receptor antagonists, six digitalis-glycosides, and six statins. Eight studies looked at single substance classes; 18 studies analyzed more than one drug class. Different assumptions for the dosage were used. In seven studies, switching within therapeutic classes was allowed. Three studies allowed stockpiling, nine studies censored hospital stays, and four studies censored death. Seventeen studies dichotomized the results, applying the cutoff ≥ 0.8 to define a patient as adherent. Eight studies analyzed adherence as a continuous value. The reporting quality of the methodology applied varied widely between studies. A gold standard is currently not available for the quantification of medication adherence in patients with chronic heart failure via claims data. To assess the methodology, the following parameters should be described: method of measurements, observation period, substances, dosing, switches, stockpiling, truncations, statistical analysis, and cutoff for adherence.

Adherence to Disease Modifying Drugs among Patients with Multiple Sclerosis in Germany: A Retrospective Cohort Study.

BACKGROUND: Long-term therapies such as disease modifying therapy for Multiple Sclerosis (MS) demand high levels of medication adherence in order to reach acceptable outcomes. The objective of this study was to describe adherence to four disease modifying drugs (DMDs) among statutorily insured patients within two years following treatment initiation. These drugs were interferon beta-1a i.m. (Avonex), interferon beta-1a s.c. (Rebif), interferon beta-1b s.c. (Betaferon) and glatiramer acetate s.c. (Copaxone). METHODS: This retrospective cohort study used pharmacy claims data from the data warehouse of the German Institute for Drug Use Evaluation (DAPI) from 2001 through 2009. New or renewed DMD prescriptions in the years 2002 to 2006 were identified and adherence was estimated during 730 days of follow-up by analyzing the medication possession ratio (MPR) as proxy for compliance and persistence defined as number of days from initiation of DMD therapy until discontinuation or interruption. FINDINGS: A total of 52,516 medication profiles or therapy cycles (11,891 Avonex, 14,060 Betaferon, 12,353 Copaxone and 14,212 Rebif) from 50,057 patients were included into the analysis. Among the 4 cohorts, no clinically relevant differences were found in available covariates. The Medication Possession Ratio (MPR) measured overall compliance, which was 39.9% with a threshold MPR≥0.8. There were small differences in the proportion of therapy cycles during which a patient was compliant for the following medications: Avonex (42.8%), Betaferon (40.6%), Rebif (39.2%), and Copaxone (37%). Overall persistence was 32.3% at the end of the 24 months observation period, i.e. during only one third of all included therapy cycles patients did not discontinue or interrupt DMD therapy. There were also small differences in the proportion of therapy cycles during which a patient was persistent as follows: Avonex (34.2%), Betaferon (33.4%), Rebif (31.7%) and Copaxone (29.8%). CONCLUSIONS: Two years after initiating MS-modifying therapy, only 30-40% of patients were adherent to DMDs.